User login
Continuous glucose monitors aren’t just for abdomens anymore
Close to two-thirds of people with diabetes who wear a continuous glucose monitor position it on an area of the body other than the abdomen, the only site sanctioned by the device’s manufacturer and federal authorities. And that lack of compliance has resulted in no apparent ill effects, according to a new study of related social media.
Michelle L. Litchman, PhD, of the University of Utah in Salt Lake City, and her colleagues, examined nearly 3,000 online postings of photos of continuous glucose monitors (CGM) manufactured by Dexcom, currently the most popular brand of CGMs in the United States. The results of their study, presented at this year’s annual meeting of the American Association of Diabetes Educators, showed that about 74% of device-wearing patients place it on the upper arm, thigh, buttocks, or back, rather than the abdomen, as indicated by the Food and Drug Administration. The device is indicated for use on the abdomen in adults because that was the only location used for the clinical studies of the device, Dr. Litchman explained in an interview.
Overall, out of 2,923 Instagram posts concerning the Dexcom CGM device, Dr. Litchman and her fellow investigators culled 353 photos of the device being worn on the body. Of these, 26.1% indicated the device was placed according to FDA guidance, while 63.7% of the remaining photos depicted the device placed on the inner arm, the forearm, thigh, calf, buttock, or back. In just over 10% of the photos, the device’s location on the body was unclear. Dr. Litchman and her colleagues concluded that when the device was worn according to directions, the failure rate was 6.2%. When placed on the outer arm it had a 2.2% failure rate, and there was a 3.3% failure rate when the device was worn on the thigh.
Since the combined nonabdomen and abdomen failure rates were similar, Dr. Litchman suggested any noncompliance was simply pragmatism. Although the CGM is meant to be relocated weekly around the abdomen, that is also the area of the body typically used for insulin injections several times a day, often resulting in scar tissue build-up that lessens insulin absorption. “It boils down to how much real estate someone has for effective insulin administration,” Dr. Litchman noted. “Individuals with diabetes need to protect the sites where they will inject insulin for the rest of their lives.”
For tips on how to do this effectively, Dr. Litchman said people with diabetes increasingly turn to online communities.
“There are differences in the FDA-approved, by the book, information patients are given and what they do in real life. While some may view this as a threat, I like to see this as opportunity to learn from patients. Patients are finding successes outside of [official instructions], therefore, we should be seeking out this experiential evidence. This research is a start to better understanding the safety related to CGM use in sites other than the abdomen,” she said in the interview.
Dr. Litchman reported that she had no conflict of interest to disclose.
Close to two-thirds of people with diabetes who wear a continuous glucose monitor position it on an area of the body other than the abdomen, the only site sanctioned by the device’s manufacturer and federal authorities. And that lack of compliance has resulted in no apparent ill effects, according to a new study of related social media.
Michelle L. Litchman, PhD, of the University of Utah in Salt Lake City, and her colleagues, examined nearly 3,000 online postings of photos of continuous glucose monitors (CGM) manufactured by Dexcom, currently the most popular brand of CGMs in the United States. The results of their study, presented at this year’s annual meeting of the American Association of Diabetes Educators, showed that about 74% of device-wearing patients place it on the upper arm, thigh, buttocks, or back, rather than the abdomen, as indicated by the Food and Drug Administration. The device is indicated for use on the abdomen in adults because that was the only location used for the clinical studies of the device, Dr. Litchman explained in an interview.
Overall, out of 2,923 Instagram posts concerning the Dexcom CGM device, Dr. Litchman and her fellow investigators culled 353 photos of the device being worn on the body. Of these, 26.1% indicated the device was placed according to FDA guidance, while 63.7% of the remaining photos depicted the device placed on the inner arm, the forearm, thigh, calf, buttock, or back. In just over 10% of the photos, the device’s location on the body was unclear. Dr. Litchman and her colleagues concluded that when the device was worn according to directions, the failure rate was 6.2%. When placed on the outer arm it had a 2.2% failure rate, and there was a 3.3% failure rate when the device was worn on the thigh.
Since the combined nonabdomen and abdomen failure rates were similar, Dr. Litchman suggested any noncompliance was simply pragmatism. Although the CGM is meant to be relocated weekly around the abdomen, that is also the area of the body typically used for insulin injections several times a day, often resulting in scar tissue build-up that lessens insulin absorption. “It boils down to how much real estate someone has for effective insulin administration,” Dr. Litchman noted. “Individuals with diabetes need to protect the sites where they will inject insulin for the rest of their lives.”
For tips on how to do this effectively, Dr. Litchman said people with diabetes increasingly turn to online communities.
“There are differences in the FDA-approved, by the book, information patients are given and what they do in real life. While some may view this as a threat, I like to see this as opportunity to learn from patients. Patients are finding successes outside of [official instructions], therefore, we should be seeking out this experiential evidence. This research is a start to better understanding the safety related to CGM use in sites other than the abdomen,” she said in the interview.
Dr. Litchman reported that she had no conflict of interest to disclose.
Close to two-thirds of people with diabetes who wear a continuous glucose monitor position it on an area of the body other than the abdomen, the only site sanctioned by the device’s manufacturer and federal authorities. And that lack of compliance has resulted in no apparent ill effects, according to a new study of related social media.
Michelle L. Litchman, PhD, of the University of Utah in Salt Lake City, and her colleagues, examined nearly 3,000 online postings of photos of continuous glucose monitors (CGM) manufactured by Dexcom, currently the most popular brand of CGMs in the United States. The results of their study, presented at this year’s annual meeting of the American Association of Diabetes Educators, showed that about 74% of device-wearing patients place it on the upper arm, thigh, buttocks, or back, rather than the abdomen, as indicated by the Food and Drug Administration. The device is indicated for use on the abdomen in adults because that was the only location used for the clinical studies of the device, Dr. Litchman explained in an interview.
Overall, out of 2,923 Instagram posts concerning the Dexcom CGM device, Dr. Litchman and her fellow investigators culled 353 photos of the device being worn on the body. Of these, 26.1% indicated the device was placed according to FDA guidance, while 63.7% of the remaining photos depicted the device placed on the inner arm, the forearm, thigh, calf, buttock, or back. In just over 10% of the photos, the device’s location on the body was unclear. Dr. Litchman and her colleagues concluded that when the device was worn according to directions, the failure rate was 6.2%. When placed on the outer arm it had a 2.2% failure rate, and there was a 3.3% failure rate when the device was worn on the thigh.
Since the combined nonabdomen and abdomen failure rates were similar, Dr. Litchman suggested any noncompliance was simply pragmatism. Although the CGM is meant to be relocated weekly around the abdomen, that is also the area of the body typically used for insulin injections several times a day, often resulting in scar tissue build-up that lessens insulin absorption. “It boils down to how much real estate someone has for effective insulin administration,” Dr. Litchman noted. “Individuals with diabetes need to protect the sites where they will inject insulin for the rest of their lives.”
For tips on how to do this effectively, Dr. Litchman said people with diabetes increasingly turn to online communities.
“There are differences in the FDA-approved, by the book, information patients are given and what they do in real life. While some may view this as a threat, I like to see this as opportunity to learn from patients. Patients are finding successes outside of [official instructions], therefore, we should be seeking out this experiential evidence. This research is a start to better understanding the safety related to CGM use in sites other than the abdomen,” she said in the interview.
Dr. Litchman reported that she had no conflict of interest to disclose.
FROM AADE 2017
Key clinical point:
Major finding: Over one quarter of continuous glucose monitors are worn successfully in a non-FDA-approved location on the body.
Data source: Review of 353 photos posted online by persons with diabetes depicting them with the device worn elsewhere than the abdomen.
Disclosures: Dr. Litchman reported she had no relevant disclosures.
VIDEO: Lenvatinib’s real-world thyroid cancer performance matches trial
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT WCTC 2017
Key clinical point:
Major finding: The median time of progression-free survival was 10 months in the registry and 18 months in the pivotal trial.
Data source: A retrospective review of the first 75 French patients with advanced differentiated thyroid cancer who received lenvatinib following its marketing approval.
Disclosures: Dr. Schlumberger has received research funding from Eisai, the company that markets lenvatinib (Lenvima). He has also received research support and honoraria from AstraZeneca, Bayer, and Excelixis.
AGA Clinical Practice Update: Opioids in gastroenterology
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Sequential pazopanib and everolimus nets good survival in metastatic RCC
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
op@frontlinemedcom.com
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
op@frontlinemedcom.com
Sequential treatment with pazopanib and everolimus yields a median overall survival exceeding 2 years in predominantly older and sicker patients with metastatic renal cell carcinoma (RCC) treated in real-world settings, according to results of an Italian multicenter cohort study.
“These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance,” wrote Sabrina Rossetti, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale, Naples, and associates (Front Pharmacol. 2017 Jul 20;8:484).
“Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile and may be feasible even for elderly patients or with multiple comorbidities,” they said.
The investigators prospectively enrolled 31 consecutive patients with newly diagnosed metastatic RCC. They had a median age of 68 years. Fully 73.3% underwent nephrectomy before treatment; 87.1% had at least one comorbidity, and 25.8% had at least three of them.
All patients were treated with the antiangiogenic tyrosine kinase inhibitor pazopanib (Votrient) as first-line therapy and, after disease progression on that agent or discontinuation for toxicity, with the mTOR inhibitor everolimus (Afinitor) as second-line therapy.
The median overall survival with the two-drug sequence was 26.5 months. Median progression-free survival was 10.6 months with pazopanib and 5.3 months with everolimus.
Patients were able to continue on pazopanib for a median time of 8.1 months, with 31% requiring dose reduction. They were able to continue on everolimus for a median time of 4.4 months, with 16% requiring dose reduction.
Main adverse events of any grade on pazopanib were hypertension (48.4%), fatigue (32.2%), and thyroid disorders (19.3%). Those on everolimus were anemia (32.2%), hypercholesterolemia (22.6%), and hyperglycemia (22.6%).
“The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib,” noted Dr. Rossetti and colleagues. “The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.”
op@frontlinemedcom.com
FRONTIERS IN PHARMACOLOGY
Key clinical point:
Major finding: Median overall survival with first-line pazopanib followed by second-line everolimus was 26.5 months.
Data source: A real-world prospective multicenter cohort study of 31 patients with untreated metastatic RCC.
Disclosures: Dr. Rossetti and colleagues disclosed no relevant conflicts of interest. The study was supported by Novartis Farma SpA.
Umbilical hernia repair during pregnancy safe, but often serious
Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.
A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.
“Additional studies are needed to determine the long-term recurrence rate of umbilical hernia repairs performed in pregnant patients and the effects of surgical intervention and approach on the fetus,” the investigators concluded.
Find the study in Hernia (doi: 10.1007/s10029-017-1633-8).
Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.
A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.
“Additional studies are needed to determine the long-term recurrence rate of umbilical hernia repairs performed in pregnant patients and the effects of surgical intervention and approach on the fetus,” the investigators concluded.
Find the study in Hernia (doi: 10.1007/s10029-017-1633-8).
Umbilical hernia repair during pregnancy is rare and safe, but more than half of surgeries required incarceration or strangulation repair, according to Dr. I.N. Haskins and associates.
A total of 126 pregnant women underwent umbilical hernia repair from 2005 to 2014, according to data collected from the American College of Surgeons National Surgical Quality Improvement Program. All but six women underwent open surgery, and of these 120 patients, 71 had umbilical hernia incarceration or strangulation at the time of surgery.
“Additional studies are needed to determine the long-term recurrence rate of umbilical hernia repairs performed in pregnant patients and the effects of surgical intervention and approach on the fetus,” the investigators concluded.
Find the study in Hernia (doi: 10.1007/s10029-017-1633-8).
FROM HERNIA
ACA: Five tactics could lead to implosion
With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:
1. Lax enforcement of the individual mandate
Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.
As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.
“What the Trump administration has done has weakened it even further by effectively saying that they will not enforce the mandate if anyone challenges it,” said Dr. Forman, a practicing radiologist and operational chief for radiology at Yale New Haven Hospital. “So if an individual claims that they shouldn’t have to face the mandate for religious reasons or other objections, that they would be allowed out. By encouraging that, you’re basically weakening the mandate even more, [which] hurts the exchanges and ultimately drives up prices.”
2. Little advertising, outreach
The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.
In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added. 
“One way you discourage healthy people from enrolling is by pulling back on advertising at the very moment they may be paying attention,” she said in an interview. “It sends a bad signal. Now as the next enrollment period is about to come up in November, it raises a concern about – what are the plans for outreach?”
Without sufficient promotion, the number of patients who learn about the ACA and enroll could drop off, and the percentage of sicker enrollees in the marketplace could rise, according to analysts. The Trump administration has not said whether it plans to advertise or promote enrollment during the upcoming November enrollment period. The Centers for Medicare & Medicaid Services recently shortened open enrollment from the previous 3 months to 45 days.
In a final rule issued in April, the CMS stated the change will “improve individual market risk pools by reducing opportunities for adverse selection ... and will encourage healthier individuals who might have previously enrolled in partial year coverage after December 15th to instead enroll in coverage for the full year.”
3. Highlight what’s “wrong” with the ACA
In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.
Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.
“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”
Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.
“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”
Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.
Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%. 
“We’re talking pretty small numbers, that’s about 15,000 people out of 10 million or so who get their coverage through an exchange,” Ms. Grow said in an interview. “It’s important for those people to have options, so the health plans have been working very hard to try to get into those counties.”
4. Work for Medicaid recipients
Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.
On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”
Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.
Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.
5. Withhold cost sharing reduction payments
For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”
Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.
Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.
President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.
“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”
While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.
Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.
“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”
agallegos@frontlinemedcom.com
On Twitter @legal_med
With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:
1. Lax enforcement of the individual mandate
Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.
As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.
“What the Trump administration has done has weakened it even further by effectively saying that they will not enforce the mandate if anyone challenges it,” said Dr. Forman, a practicing radiologist and operational chief for radiology at Yale New Haven Hospital. “So if an individual claims that they shouldn’t have to face the mandate for religious reasons or other objections, that they would be allowed out. By encouraging that, you’re basically weakening the mandate even more, [which] hurts the exchanges and ultimately drives up prices.”
2. Little advertising, outreach
The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.
In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added.
“One way you discourage healthy people from enrolling is by pulling back on advertising at the very moment they may be paying attention,” she said in an interview. “It sends a bad signal. Now as the next enrollment period is about to come up in November, it raises a concern about – what are the plans for outreach?”
Without sufficient promotion, the number of patients who learn about the ACA and enroll could drop off, and the percentage of sicker enrollees in the marketplace could rise, according to analysts. The Trump administration has not said whether it plans to advertise or promote enrollment during the upcoming November enrollment period. The Centers for Medicare & Medicaid Services recently shortened open enrollment from the previous 3 months to 45 days.
In a final rule issued in April, the CMS stated the change will “improve individual market risk pools by reducing opportunities for adverse selection ... and will encourage healthier individuals who might have previously enrolled in partial year coverage after December 15th to instead enroll in coverage for the full year.”
3. Highlight what’s “wrong” with the ACA
In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.
Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.
“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”
Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.
“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”
Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.
Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%.
“We’re talking pretty small numbers, that’s about 15,000 people out of 10 million or so who get their coverage through an exchange,” Ms. Grow said in an interview. “It’s important for those people to have options, so the health plans have been working very hard to try to get into those counties.”
4. Work for Medicaid recipients
Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.
On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”
Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.
Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.
5. Withhold cost sharing reduction payments
For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”
Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.
Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.
President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.
“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”
While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.
Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.
“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”
agallegos@frontlinemedcom.com
On Twitter @legal_med
With legislative efforts to repeal and/or replace the Affordable Care Act shelved for now, President Trump has tweeted that he wants to “let ObamaCare implode, then deal.” But just what can – and is – his administration doing to foster an implosion? Policy experts help us count the ways:
1. Lax enforcement of the individual mandate
Shortly after he took office, President Trump issued an executive order aimed at “minimizing the economic burden” of the ACA. The order directed all federal agencies to take legal steps to waive, defer, grant exemptions from, or delay the implementation of any ACA provision or requirement that would impose a fiscal burden on states, patients, providers, or health insurers.
As a result, the Internal Revenue Service announced that it would not reject tax returns that do not indicate whether the taxpayer has health insurance. That question is included to determine whether taxpayers will incur a financial penalty under the individual mandate.
“What the Trump administration has done has weakened it even further by effectively saying that they will not enforce the mandate if anyone challenges it,” said Dr. Forman, a practicing radiologist and operational chief for radiology at Yale New Haven Hospital. “So if an individual claims that they shouldn’t have to face the mandate for religious reasons or other objections, that they would be allowed out. By encouraging that, you’re basically weakening the mandate even more, [which] hurts the exchanges and ultimately drives up prices.”
2. Little advertising, outreach
The Trump administration canceled advertising and outreach efforts in the final week of the 2017 open enrollment period. As many as half a million people missed out on enrolling in a health insurance plan as a result, Joshua Peck, former chief marketing officer for healthcare.gov, estimated in a recent blog post.
In the past, the federal government has played a significant role in informing the public about marketplace coverage, their rights and responsibilities under the ACA, and the process of enrollment, said Sarah Lueck, a senior policy analyst for the Center on Budget and Policy Priorities, a nonpartisan research and policy institute. The last week of enrollment is known as a critical time to enroll patients, she said. In 2016 for example, about 700,000 people enrolled during the final week. It’s often the healthiest patients who wait until the last minute, Ms. Lueck added.
“One way you discourage healthy people from enrolling is by pulling back on advertising at the very moment they may be paying attention,” she said in an interview. “It sends a bad signal. Now as the next enrollment period is about to come up in November, it raises a concern about – what are the plans for outreach?”
Without sufficient promotion, the number of patients who learn about the ACA and enroll could drop off, and the percentage of sicker enrollees in the marketplace could rise, according to analysts. The Trump administration has not said whether it plans to advertise or promote enrollment during the upcoming November enrollment period. The Centers for Medicare & Medicaid Services recently shortened open enrollment from the previous 3 months to 45 days.
In a final rule issued in April, the CMS stated the change will “improve individual market risk pools by reducing opportunities for adverse selection ... and will encourage healthier individuals who might have previously enrolled in partial year coverage after December 15th to instead enroll in coverage for the full year.”
3. Highlight what’s “wrong” with the ACA
In addition to pulling positive advertisements about ACA, the Trump administration has also launched a campaign that criticizes the law.
Since January, the Department of Health & Human Services has published more than 20 videos featuring stories about how the ACA has harmed patients. The HHS has also used its Twitter account to advocate repeal and replacement of the ACA. Sen. Ron Wyden (D-Ore.), ranking member of the Finance Committee, and other legislators have raised concerns that the HHS is misusing federal resources to advance partisan legislation by funding the messages.
“It’s not just pulling advertisements and going dark and not telling people [information], but it’s also putting things out there that talk about people who don’t like the law,” Ms. Lueck said. “It’s counterproductive propaganda if you’re coming from the perspective of wanting people to sign up for coverage. The agencies that have been very engaged in trying to get people through the process and covered, are now working in cross purposes with that.”
Ms. Lueck said that the federal government is also putting a negative spin on the current participation of marketplace insurers and the future of the exchanges. On Aug. 2, the CMS released a map on projected insurer participation in the ACA’s 2018 health insurance exchanges. The map shows that 19 counties are projected to have no insurers in 2018, meaning that patients in those counties could be without marketplace options.
“For 2018, at least 13,008 Americans currently enrolled for health coverage on the exchanges live in the counties projected to be without coverage in 2018,” according to the CMS announcement. “In addition to overall issuer participation, increasing rates have also been a concern for the health insurance exchanges. ... A number of insurers in several states requested rate increases of 30% or more. Consumers in the 39 healthcare.gov states have already seen their premiums increase more than 100% since 2013.”
Unmentioned however, is that the number of potential “bare counties” has dropped in half from about a month ago. A similar map by the Kaiser Family Foundation shows that in June, 44 counties were at risk of having no marketplace insurer in 2018, a number that fell to 17 counties as of Aug. 4, according to Kaiser’s most recent map.
Kristine Grow, senior vice president of communications for America’s Health Insurance Plans (AHIP), noted that based on CMS’ projections thus far, the overall percentage of enrollees without an insurer for 2018 is 0.15%.
“We’re talking pretty small numbers, that’s about 15,000 people out of 10 million or so who get their coverage through an exchange,” Ms. Grow said in an interview. “It’s important for those people to have options, so the health plans have been working very hard to try to get into those counties.”
4. Work for Medicaid recipients
Potential work requirements for Medicaid beneficiaries may harm the Medicaid expansions that were part of the ACA.
On March 14, the HHS sent a letter to 50 U.S. governors encouraging states to come up with innovative ideas for their Medicaid programs, including the possibility of work requirements. The letter included specific suggestions, such as introducing plans that include health savings account–like features, encouraging Medicaid patients to secure employer-provided insurance, and requiring small premiums or other contributions from patients to encourage personal responsibility. The letter noted that the HHS would be open to states proposing work requirements for some Medicaid recipients, an approach that has “produced proven results for Americans enrolled in other federal, state, and local programs.”
Four states – Arizona, Indiana, Kentucky, and Pennsylvania – have formally submitted waiver requests to the HHS that would require work as an eligibility condition. To date, none has been approved. Arkansas also recently announced that it would seek changes to its waiver, including a work requirement.
Imposing work requirements would hurt access to Medicaid for patients who need health assistance, but who cannot work, Dr. Forman said. Under the ACA, 31 states and the District of Columbia have expanded their Medicaid coverage to people previously uncovered. Dr. Forman stresses that the bulk of Medicaid funding is spent on elderly, disabled, and mentally ill patients.
5. Withhold cost sharing reduction payments
For months, President Trump has threatened to stop making cost saving reduction (CSR) payments to insurers in the marketplace, a move that analysts say would raise premiums and cause insurers to exit the marketplaces. Most recently, the President on July 29 tweeted, “If a new HealthCare Bill is not approved quickly, BAILOUTS for Insurance Companies and BAILOUTS for Members of Congress will end very soon!”
Under the ACA, the federal government provides CSR payments to insurers to offset the costs for providing discount plans to patients who earn up to 200% of the federal poverty level. Plans on the individual exchanges are required to cover a package of essential benefits with pricing limitations to ensure that out-of-pocket costs are low enough for poorer patients. Because insurers lose money on these plans, the ACA provides about $7 billion to insurers through CSR payments.
Republican members of the House of Representatives sued the HHS over the CSR payments under the Obama administration, claiming the funding was illegal because it was never appropriated by Congress. A court ruled in favor of the House in 2016, but an appeal filed by the Obama administration allowed the CSR payments to continue.
President Trump has not indicated whether he plans to drop the appeal or carry on the case. But if he fails to continue the suit, the move would immediately end the CSR payments.
“If the funding for the CSR benefits goes away, premiums will go up, taxpayer dollars will go up, and choices will go down,” Ms. Grow of AHIP said in an interview. “The benefits as we understand them are still required to be offered on the exchanges. In order to cover those benefits, the premiums for everybody in the individual market will have to go up, and they will go up by about 20%.”
While the federal government would save money by ending the CSR payments, it would face increased costs for tax credits that subsidize premiums for marketplace enrollees with incomes that are 100% to 400% of the poverty level, according to an analysis by the Kaiser Family Foundation.
Following President Trump’s most recent threat to stop the CSR payments, AHIP issued a joint statement with the American Academy of Family Physicians, the American Medical Association, and several others underscoring the importance of the payments.
“Cost-sharing reductions are used to help those who need it most – low- and moderate-income consumers,” the associations said in the Aug. 2 statement. “Without these funds, consumers’ access to care is jeopardized, their premiums will increase dramatically, and they will be left with even fewer coverage options ... As medical professionals, insurers providing health care services and coverage to hundreds of millions of Americans, and business leaders concerned with maintaining a stable health insurance marketplace for consumers, we believe it is imperative that the administration fund the cost-sharing reduction program.”
agallegos@frontlinemedcom.com
On Twitter @legal_med
Menopause in HIV-Infected Women
From the University of Maryland School of Medicine, Baltimore, MD.
Abstract
- Objective: To review the current literature on menopause in HIV-infected women.
- Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
- Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
- Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.
Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.
Effect of HIV on the Menstrual Cycle
Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].
As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].
The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.
Age at Menopause
Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20]. These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].
As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].
Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].
There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].
In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.
HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm3 had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm3. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm3, 46.0 years in women with CD4 cell counts between 200 cells/mm3 and 500 cells/mm3, and 46.5 years in women with CD4 cell counts > 500 cells/mm3 [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm3 to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm3 [41]. De Pommerol et al studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm3 were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm3 [37].
Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].
Menopause-Associated Symptoms
The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].
It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.
Vasomotor Symptoms
In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].
Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].
Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm3 were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.
Genitourinary Symptoms
With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.
Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].
Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia
Psychiatric Symptoms
Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].
In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].
Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].
Other Symptoms
Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].
Treatment
For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].
Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].
Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].
Cardiovascular Risk
Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].
HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.
Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.
Osteoporosis
Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].
Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].
Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].
Cognition
The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].
Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].
Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].
Cervical Dysplasia
As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.
In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].
Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.
HIV Acquisition and Transmission
The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.
In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.
In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].
HIV Progression
Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.
Conclusion
As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.
There still remain significant gaps in our understanding of menopause in HIV-infected women. As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.
Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, lfantry@medicine.umaryland.edu.
Financial disclosures: None.
1. CASCADE Collaboration. Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 2000;355:1158–9.
2. Brooks JT, Buchaz K, Gebo KA, Mermin J. HIV infection and older Americans: the public health perspective. Am J Pub Health 2012;102:1516–26.
3. Munster K, Helm P, Schmidt L. Secondary amenorrhea: Prevalence and medical contract–A cross sectional study from a Danish county. Br J Obstet Gynecol 1992;99:430–3.
4. Vyver E, Steinegger C, Katzman DK, et al. Eating disorders and menstrual dysfunction in adolescents. Ann N Y Acad Sci 2008;1135:253–64.
5. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000;85:2215–22.
6. Pelosi MA, Sama JC, Caterini H, et al. Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am J Obstet Gynecol 1974;118:966–70.
7. Bai J, Greenwald E, Caterini H, et al. Drug-related menstrual aberrations. Obstet Gynecol 1974;44:713–9.
8. Chirgwin KD, Feldman J, Muneyyirci-Delale O, et al. Menstrual function in HIV-infected women without AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:489–94.
9. Clark RA, Mulligan K, Stamenovic E, et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 2001;184:1325–7.
10. Watts DH, Spino C, Zaborski L. Comparison of gynecologic history and laboratory results in HIV-positive women with CDR+ lymphocyte counts between 200 and 500 cells/µl and below 100 cells/ µl. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:455–62.
11. Ellerbrock TV, Wrig TC, Bush TJ, et al. Characteristics of menstruation in women infected with HIV. Obstet Gynecol 1996;87:1030–4.
12. Shah PN, Smith JR, Wells C, et al. Menstrual symptoms in women infected by the HIV. Obstet Gynecol 1994;83:397–400.
13. Harlow SC, Schuman P, Cohen M, et al. Effect of HIV infection on menstrual cycle length. J Acquir Immune Defic Syndr Hum Retrovirol 2000;24:68–75.
14. Grinspoon S, Corocran C, Miller K, et al. Bone composition and endocrine function in women with AIDS wasting. J Clin Edocrinol Metab 1997;82:1332–7.
15. Research on the menopause in the 1990s. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1996;866:1–107.
16. Cejtin HE, Kalinowski A, Bacchetti P. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol 2006;108:1423–31.
17. Freeman EW, Sammel MD, Garcia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
18. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.
19. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
20. Thomas F, Renaud F, Benefice E, et al. International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol 2001;73:271–90.
21. Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65:161–6.
22. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404–11.
23. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the multi-ethnic study of atherosclerosis. Menopause 2012;19:1081–7.
24. Rocca WA, Grossardt BR, Miller VM, et al. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012;19:272–7.
25. Svejme O, Ahlborg HG, Nilsson JA, et al. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG 2012;119:810–6.
26. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology 1999;10:771–3.
27. Luoto R, Kaprio J, Uutela A. Age at natural menopause and socioeconomic status in Finland. Am J Epidemiol 1994;139:64–76.
28. Bromberger JT, Matthews KA, Kuller LH, et al. Prospective study of the determinants of age at menopause. Am J Epidemiol 1997;145:24–33.
29. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
30. Tziomalos K, Charsoulis F. Endocrine effects of tobacco smoking. Clin Endocrinol 2004;61:664–74.
31. Potter DA, Moreno A, Luther MF, et al. Effects of follicular-phase cocaine administration on menstrual and ovarian cyclicity in rhesus monkeys. Am J Obstet Gynecol 1998;178:118–25.
32. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: Cross-sectional survey. Ann Intern Med 2015;162:335–44.
33. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥ 18 years–United States, 2005-2010. MMWR Morb Mortal Wkly Rep 2011;60:1207–12.
34. Feldman J, Mikoff H, Schneider M, et al. Association of cigarette smoking with HIV prognosis among women in the HAART era: A report from the Women’s Interagency HIV study. Am J Public Health 2006:96:1060–5.
35. Centers for Disease Control and Prevention. Estimated HIV incidence among adults and adolescents in the United States, 2007–2010. HIV Surveillance Supplemental Report 2012;17(4).
36. Galea S, Ahren J, Vlahov D. Contextual determinants of drug use risk behavior: a theoretical framework. J Urban Health 2003;80:50–8.
37. de Pommerol M, Hessamfar M, Lawson-Ayayi S, et al. Menopause and HIV infection: age at onset and associated factors, ANRS CO3 Aquitaine cohort. Int J STD AIDS 2011;22:67–72.
38. Ferreira CE, Pinto-Neto AM, Conde DM, et al. Menopausal symptoms in women infected with HIV: prevalence and associated factors. Gynecol Endocrinol 2007;23:198–205.
39. Clark RA, Cohn SE, Jarck C, et al. Perimenopausal symptomatology among HIV infected women at least 40 years of age. J Acquir Immune Defic Syndr Hum Retrovirol 2000;23:99–100.
40. Fantry L, Zhan M, Taylor G, et al. Age at menopause and menopausal symptoms in HIV-infected women. AIDS Patient Care STD 2005;19:703–11.
41. Calvet G, Grinsztejn G. Predictors of early menopause in HIV infected women: a prospective cohort study. Am J Obstet Gynecol 2015;212:765.
42. Boonyanurak P, Bunupuradah T, Wilawan K, et al. Age at menopause and menopause-related symptoms in human immunodeficiency virus-infected Thai women. Menopause 2012;19:820–4.
43. Cejtin SH, Taylor R, Watts DH. Assessment of menopausal status among women in the Women’s Interagency HIV study (WIHS). Proceedings of the 57th International AIDS Conference 2004; Bangkok, Thailand.
44. WIHS Data Management and Analysis Center (WDMAC). Women’s Interagency HIV Study (WIHS) Dossier. October 2014. Available at https://statepiaps.jhsph.edu/wihs/invest-info/dossier.pdf.
45. Schoenbaum E, Hartel D, Lo Y, et al. HIV infection, drug use, and onset of natural menopause. Clinical Infect Dis 2005;41:1517–24.
46. Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002;9:32–40.
47. Miro F, Parker SW, Aspinall LJ, et al. Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study. J Clin Endocrinol Metab 2004;89:4910–5.
48. Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012;97:1159–68.
49. Freeman EW, Sammel MD, Gracia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
50. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008;15:603–12.
51. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103–15.
52. Szoeke CE, Cicuttini F, Guthrie J, Dennerstein L. Self-reported arthritis and the menopause. Climacteric 2005;8:49–55.
53. Blümel JE, Chedraui P, Baron G, et al. Menopause could be involved in the pathogenesis of muscle and joint aches in mid-aged women. Maturitas 2013;75:94–100.
54. Woods NF, Mitchell ES. Symptoms interference with work and relationships during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause 2011;18:654–61.
55. Johnson TM, Cohen HW, Howard AA, et al. Attribution of menopause symptoms in human immunodeficiency virus–infected or at-risk drug-using women Menopause 2008;15:551–7.
56. Miller SA, Santoro N, Lo Y. Menopausal symptoms in HIV-infected and drug-using women. Menopause 2005;12:348–56.
57. Looby S, Shifren J, Corless I. Increased hot flash severity and related interference in perimenopausal HIV-infected women. Menopause 2014;21:403–9.
58. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the Study of Women’s Health across the Nation. Obstet Gynecol Clin North Am 2011;38:489–501.
59. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med 2005;118 Suppl 12B:14.
60. Maki PM, Rubin LH, Cohen M, et al. Depressive symptoms are increased in the early perimenopausal stage in ethnically diverse human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Menopause 2012;19:1215–33.
61. Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351–8.
62. Palma F, Volpe A, Villa P, et al. Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: The AGATA study. Maturitas 2015 Sep 14.
63. Cutler WB, Garcia CR, McCoy N. Perimenopausal sexuality. Arch Sex Behav 1987;16:225–34.
64. Moreira ED, Glasser DB, Nicolosi A, et al. GSSAB Investigators’ Group. Sexual problems and help-seeking behavior in adults in the United Kingdom and continental Europe. BJU Int 2008;101:1005–11.
65. MacBride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010;85:87–94.
66. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas 2010;67:233–8.
67. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009;6:2133–42.
68. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active post-menopausal women. Menopause 2008;15(4 Pt 1):661–6.
69. Cumming GP, Currie HD, Moncur R, Lee AJ. Web-based survey on the effect of menopause on women’s libido in a computer-literate population. Menopause Int 2009;15:8–12.
70. Valadares AL, Pinto-Neto AM, Conde DM, et al. A population-based study of dyspareunia in a cohort of middle-aged Brazilian women. Menopause 2008;15:1184–90.
71. Latthe P, Migini L, Gray R, et al. Factors predisposing women to chronic pelvic pain: a systemic review. BMJ 2006;332:749–55.
72. Valadares AL, Pinto-Neto AM, Gomes D, et al. Dyspareunia in HIV-positive and HIV-negative middle-aged women: a cross-sectional study. BMJ Open 2014;4:e004974.
73. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health 2001;91:1435–42.
74. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4:214–20.
75. Cohen LS, Soares CN, Joffe H. Diagnosis and management of mood disorders during the menopausal transition. Am J Med 2005;118 Suppl 12B:93–7.
76. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63:375–82.
77. Eller LS, Corless I, Bunch EH, et al. Self-care strategies for depressive symptoms in people with HIV disease. J Adv Nurs 2005;51:119–30.
78. Fuh JL, Wang SJ, Lee SJ, et al. A longitudinal study of cognition change during early menopausal transition in a rural community. Maturitas 2006;53:447–53.
79. Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72:1850–7.
80. Hinkin CH, Castellon SA, Atkinson JH, et al. Neuropsychiatric aspects of HIV infection among older adults. J Clin Epidemiol 2001;54:S44–52.
81. Kravitz HM, Ganz PA, Bromberger J, et al. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause 2003;10:19–28.
82. Freedman RR, Roehrs TA. Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance. Menopause 2006;13:576–83.
83. Erlik Y, Tataryn IV, Meldrum DR, et al. Association of waking episodes with menopausal hot flushes. JAMA 1981; 245:1741–4.
84. Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause 2007;14:826–9.
85. Lui-Filho JF, Valadares AR, Gomes D, et al. Menopausal symptoms and associated factors in HIV-positive women. Maturitas 2013;76:172–8.
86. Aberg JA, Gallant JE, Ghanem KG, et al, Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis 2014;58:e1–34.
87. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14:357–69.
88. Dorr MB, Nelson AL, Mayer PR, et al. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis. Fertil Steril 2010;94:2365–8.
89. El-Ibiary SY, Cocohoba JM. Effects of antiretrovirals on the pharmacokinetics of hormonal contraception. Eur J Contracept Reprod Health Care 2008;13:123–32.
90. Tittle V, Bull L, Boffito M, Nwokolo N. Pharmacokinetic and pharmacodynamics drug interactions between antiretrovirals and oral contraceptives. Clin Pharmacokinet 2015;54:23–34.
91. Thurman AR, Anderson S, Doncel G. Effects of hormonal contraception on anti-retroviral drug metabolism, pharmacokinetics and pharmacodynamics. Am J Reprod Immunol 2014:71:523–30.
92. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US. Department of Health and Human Services. Availabe at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
93. Berg G, Mesch V, Boero L, et al. Lipid and lipoprotein profile in menopausal transition: effects of hormones, age and fat distribution. Hormone Metab Res 2004;36:215–20.
94. Sower M, Zheng H, Tomey K, et al. Changes in body composition in women over six years at midlife: ovarian and chronological aging. J Clin Endocrin Metab 2007;92:895–901.
95. Flooris-Moore M, Howard AA, Lo Y, et al. Increased serum lipids are associated with higher CD4 lymphocyte count in HIV-infected women. HIV Med 2006;7:421–30.
96. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 2009;23:1841–9.
97. Palacios R, Alonso I, Hidalgo A, et al. Peripheral arterial disease in HIV patients older than 50 years of age. AIDS Res Hum Retroviruses 2008;24:1043–6.
98. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001;32:130–9.
99. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrin Metab 2007;92:2506–12.
100. Dolan SE, Frontera W, Librizzi J et al. The effects of a supervised home based aerobic and progressive resistance training regimen in HIV-infected women: randomized trial. Arch Intern Med 2006;166:1225–31.
101. Grinspoon S, Carr A. Cardiovascular risk and body fat abnormalities in HIV-infected adults. N Engl J Med 2005;352:48–62
102. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr 2006;42:562–71.
103. Jaff NG, Norris SA, Snyman T, et al. Body composition in the study of women entering and in Endocrine Transition (SWEET): A perspective of African women who have a high prevalence of obesity and HIV infection. Metabolism 2015;64:1031–41.
104. Akhter MP, Lappe JM, Davies KM, et al. Transmenopausal changes in the trabecular bone structure. Bone 2007;41:111–6.
105. Cassetti I, Madruga JV, Suleiman JM, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials 2007;8:164–72.
106. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203:1791–801.
107. Hansen AB, Obel N, Nielsen H, et al. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: Data from a randomized trial. HIV Med 2011;12:157–65.
108. Yin MT, Zhang CA, McMahon DJ, et al. Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study. J Clin Endocrinol Metab 2012;97:554–62.
109. Sharma A, Flom PL, Rosen CJ, et al. Racial differences in bone loss and relation to menopause among HIV-infected and uninfected women. Bone 2015;77:24–30.
110. Caputo BV, Traversa-Caputo GC, Costa C, et al. Evaluation of bone alterations in the jaws of HIV-infected menopausal women. Braz Oral Res 2013;27:231–7.
111. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int 2005;26:1345–52.
112. Yin MT, Mcmahon DJ, Ferris DC, et al. Low bone mass and high bone turnover in postmenopausal human immunodeficiency virus-infected women. J Clin Endocrinol Metab 2010;95:620–9.
113. Gibellini D, De Crignis E, Ponti C. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNF-alpha activation. J Med Virol 2008;80:1507–14.
114. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000;14:F63–7.
115. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy)propyl] adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004;48:1469–87.
116. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006;20:2165–74.
117. Dao CN, Patel P, Overton ET, Rhame F, et al. Study to understand the natural history of HIV and AIDS in the era of effective therapy (SUN) investigators. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011;52:396–405.
118. Jacobson DL, Spiegelman D, Know TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the nutrition for healthy living study. J Acquir Immune Defic Syndr Hum Retrovirol 2008;49:298–308.
119. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporosis Int 2005;16:581–9
120. Pedrazzoni M, Vescovi L, Maninetti M, et al. Effects of chronic heroine abuse on bone and mineral metabolism. Acta Endocrinol 1993;129:42–5.
121. Lo Re V 3rd, Guaraldi G, Leonard MB, et al. Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men. AIDS 1990;23:2191–8.
122. Yin MT, Modarresi R, Shane E, et al. Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporos Int 2011;22:1459–66.
123. Sharma A, Cohen HW, Freeman R, et al. Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss. Maturitas 2011;70:295–301.
124. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008;93:3499–504.
125. Womack JA, Goulet JL, Gibert C, et al. Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One Feb 16 2011;6:e17217.
126. Young B, Dao CN, Buchacz K, et al, HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006. Clin Infect Dis 2011;52:1061–8.
127. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011; 154:356–64.
128. Aberg JA, Kaplan JE, Libman H, et al; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651–81.
129. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis 2014. Washington, DC: National Osteoporosis Foundation; 2014.
130. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis 2010;51:937–46.
131. McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007;21:2473–82.
132. Lin D, Rieder MJ. Interventions for the treatment of decreased bone mineral density associated with HIV infection. Cochrane Database Syst Rev 2007:CD005645.
133. Haring B, Leng X, Robinson J. Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women’s Health Initiative Memory Study. J Am Heart Assoc 2013;2:e000369.
134. Soares CN, Maki PM. Menopausal transition, mood, and cognition: an integrated view to close the gaps. Menopause 2010;17:812–4.
135. Greendale GA, Derby CA, Maki PM. Perimenopause and cognition. Obstet Gynecol Clin North Am 2011;38:519–35.
136. Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. Am J Epidemiol 2010;171:1214–24.
137. Price RW. Neurological complications of HIV infection. Lancet 1996;348:445–52.
138. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789–99.
139. Gisslén M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 2011;11:356.
140. Rubin LH, Sundermann EE, Cook JA, et al. An investigation of menopausal stage and symptoms on cognition in HIV-infected women. Menopause 2014;21:997–1006.
141. Cook JA, Cohen MH, Burke J, et al. Effects of depressive symptoms and mental health quality of life on use of highly active antiretroviral therapy among HIV-seropositive women. J Acquir Immune Defic Syndr 2002;30:401–9.
142. Cook JA, Grey D, Burke J, et al. Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Pub Health 2004;94:1133–40.
143. Kim SC, Messing S, Shah K, et al. Effects of highly active antiretroviral therapy (HAART) and menopause on risk of progression of cervical dysplasia in human immune deficiency virus (HIV) infected women. Infect Dis Obstet Gynecol 2013;2013:784718.
144. Ceccaldi PF, Ferreira C, Coussy F, et al. Cervical disease in postmenopausal HIV-1 infected women. J Gynecol Obstet Biol Reprod 2010;39:466–70.
145. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992;304:809–13.
146. Meditz AL, Moreau KL, MaWhinney S, et al. CCR5 expression is elevated on endocervical CD4+ T cells in healthy postmenopausal women. J Acquir Immune Defic Syndr 2012;59:221–8.
147. Chappell CA, Isaacs CE, Xu W, et al. The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 2015;213:204.
148. Melo KC, Melo MR, Ricci BV, Segurado AC. Correlates of human immunodeficiency virus cervicovaginal shedding among postmenopausal and fertile-aged women. Menopause 2012;19:150–6.
149. Viard JP, Mocroft A, Chiesi A, et al. Influence of age of CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the Euro SIDA study. J Infect Dis 2001;193:1290–4.
150. Grabar S, Kousignian I, Sobel A, et al. Immunological and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004;18:2029–38.
151. Cuzin L, Delpierre C, Gerard S, et al. Immunologic and clinical responses to highly active antiretroviral therapy in patients with HIV infection aged >50 years. Clin Infect Dis 2007;45:654–7.
152. Patterson KB, Cohn SE, Uynik J, et al. Treatment responses in antiretroviral treatment-naïve premenopausal and postmenopausal HIV-1 infected women: an analysis from AIDS clinical trials group studies. Clin Infect Dis 2009;49:473–6.
153. van Benthem BH, Vernazza P, Coutinho RA, et al. The impact of pregnancy and menopause on CD4 lymphocyte count in HIV-infected women. AIDS 2002;16:919–24.
From the University of Maryland School of Medicine, Baltimore, MD.
Abstract
- Objective: To review the current literature on menopause in HIV-infected women.
- Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
- Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
- Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.
Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.
Effect of HIV on the Menstrual Cycle
Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].
As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].
The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.
Age at Menopause
Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20]. These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].
As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].
Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].
There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].
In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.
HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm3 had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm3. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm3, 46.0 years in women with CD4 cell counts between 200 cells/mm3 and 500 cells/mm3, and 46.5 years in women with CD4 cell counts > 500 cells/mm3 [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm3 to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm3 [41]. De Pommerol et al studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm3 were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm3 [37].
Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].
Menopause-Associated Symptoms
The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].
It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.
Vasomotor Symptoms
In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].
Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].
Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm3 were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.
Genitourinary Symptoms
With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.
Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].
Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia
Psychiatric Symptoms
Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].
In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].
Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].
Other Symptoms
Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].
Treatment
For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].
Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].
Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].
Cardiovascular Risk
Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].
HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.
Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.
Osteoporosis
Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].
Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].
Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].
Cognition
The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].
Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].
Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].
Cervical Dysplasia
As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.
In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].
Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.
HIV Acquisition and Transmission
The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.
In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.
In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].
HIV Progression
Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.
Conclusion
As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.
There still remain significant gaps in our understanding of menopause in HIV-infected women. As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.
Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, lfantry@medicine.umaryland.edu.
Financial disclosures: None.
From the University of Maryland School of Medicine, Baltimore, MD.
Abstract
- Objective: To review the current literature on menopause in HIV-infected women.
- Methods: We searched PubMed for articles published in English using the search terms HIV and menopause, HIV and amenorrhea, HIV and menopause symptoms, HIV and vasomotor symptoms, HIV and vaginal dryness, HIV and dyspareunia, HIV and menopause and cardiovascular disease, HIV and menopause and osteoporosis, HIV and menopause and cognition, HIV and menopause and cervical dysplasia, menopause and HIV transmission, and menopause and HIV progression. Major studies on menopause in other populations were also reviewed to provide background data.
- Results: While studies on the age of menopause in HIV-infected women give conflicting results, immuno-suppression associated with HIV appears to contribute to an earlier onset of menopause. HIV-infected women experience menopausal symptoms, especially vasomotor symptoms, earlier and in greater intensity. In addition, menopause and HIV infection have additive effects on one another, further increasing the disease risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. The effects of menopause on HIV infection itself seems limited. While some data suggest an increased risk of acquisition in non–HIV-infected menopausal women, menopause has no effect on the transmission or progression of HIV in menopausal HIV-infected women.
- Conclusion: As HIV-infected individuals live longer, practitioners will encounter an increasing number of women entering menopause and living into their postmenopausal years. Future studies on the age of menopause, symptoms of menopause, and the effects of menopause on long term comorbidities such as cognitive decline, cardiovascular disease, and bone density loss are necessary to improve care of this expanding population of women living with HIV.
Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decrease in morbidity and mortality worldwide among individuals living with human immunodeficiency virus (HIV) [1]. It is projected that by the year 2020, half of persons living with HIV infection in the United States will be over the age of 50 years [2]. For HIV-infected women, this longer survival translates into an increased number of women entering into menopause and living well beyond menopause. Enhancing our knowledge about menopause in HIV-infected women is important since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality. Symptoms associated with menopause can be mistaken for symptoms suggestive of infections, cancers, and drug toxicity. Furthermore, changes in cognition, body composition, lipids, glucose metabolism, and bone mass are influential factors determining morbidity and mortality in later years.
Effect of HIV on the Menstrual Cycle
Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].
As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].
The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.
Age at Menopause
Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20]. These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].
As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].
Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].
There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].
In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.
HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm3 had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm3. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm3, 46.0 years in women with CD4 cell counts between 200 cells/mm3 and 500 cells/mm3, and 46.5 years in women with CD4 cell counts > 500 cells/mm3 [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm3 to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm3 [41]. De Pommerol et al studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm3 were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm3 [37].
Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].
Menopause-Associated Symptoms
The perimenopausal period, which begins on average 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles. Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches [46–53]. Such menopausal symptoms can be distressing, negatively impacting quality of life [54].
It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in HIV-infected women as they have multiple potential reasons for these symptoms, such as antiretroviral therapy, comorbidities, and HIV infection itself [55]. However, several studies clearly show that there are symptoms that occur more commonly in the perimenopausal period and that HIV-infected women experience these symptoms earlier and with greater intensity [38–40,42,56,57]. In a cross-sectional study of 536 women among whom 54% were HIV-infected, Miller et al found that menopausal symptoms were reported significantly more frequently in HIV-infected women compared with non–HIV-infected women [56]. As symptoms can occur in greater intensity and impair quality of life, it is important that providers be able to recognize, understand, and appropriately treat menopausal symptoms in HIV-infected women.
Vasomotor Symptoms
In the United States the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women [58,59]. Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American [19]. As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal HIV-infected women found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women [40,42]. In addition, a comparison of HIV-infected and non–HIV-infected women demonstrated a higher prevalence of hot flashes among HIV-infected women [38,56]. Ferreira et al found that 78% of Brazilian HIV-infected women reported vasomotor symptoms compared to 60% of non–HIV-infected women [38]. Similarly, Miller et al reported that 64% of HIV-infected women reported vasomotor symptoms compared to 58% of non–HIV-infected women [56].
Vasomotor symptoms can be severely distressing with hot flashes contributing to increased risk of depression [56,60]. In a cross-sectional analysis of 835 HIV-infected and 335 non–HIV-infected women from the WIHS, persistent vasomotor symptoms predicted elevated depressive symptoms in both HIV-infected and non-HIV-infected women [60]. In a similar cross-sectional analysis of 536 women, among whom 54% were HIV positive and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms [56].
Oddly enough, higher CD4 cell counts appear to be associated with increased prevalence of vasomotor symptoms [39,56]. Clark et al demonstrated that menopausal HIV-infected women with CD4 cell counts > 500 cells/mm3 were more likely to report hot flashes [39]. Similarly, Miller et al observed a reduction in the prevalence of menopausal symptoms as CD4 cell counts declined among HIV-infected non-HAART users [56]. The rationale behind this is unclear but some experts postulated that it may be due to the effects of HAART.
Genitourinary Symptoms
With estrogen deficiency, which accompanies the perimenopausal period, vulvovaginal atrophy (VVA) occurs leading to symptoms of vaginal dryness, itching, burning, urgency, and dyspareunia (painful intercourse) [59,61,62]. Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated [63]. Furthermore, these symptoms are often underreported and underdiagnosed [64,65]. Several studies using telephone and online surveys have found that the prevalence of symptoms of VVA is between 43% and 63% in postmenopausal women [66–69]. Even higher rates were found in the Agata Study in which pelvic exams in 913 Italian women were performed to obtain objective signs of VVA [62]. The prevalence of VVA was 64% 1 year after menopause and 84% 6 years after menopause. Vaginal dryness was found in 100% of participants with VVA or 82% of total study participants. In addition, 77% of women with VVA, or 40% of total study participants, reported dyspareunia.
Genitourinary symptoms are most common among women who are African American, have an increased BMI, are from lower socioeconomic class, use tobacco [19], have prior history of pelvic inflammatory disease, and have anxiety and depression [70,71]. Similarly to hot flashes, many of these predisposing factors are more common in HIV-infected women. Fantry et al found that 49.6% of HIV-infected women had vaginal dryness. Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels [7,31] was associated with a higher frequency of vaginal dryness [40].
Similarly, dyspareunia is also common among HIV-infected women. In a cross-sectional study of 178 non–HIV-infected and 128 HIV-infected women between 40 and 60 years of age, Valadares et al found that the frequency of dyspareunia in HIV-infected women was high at 41.8% [72]. However, this was not significantly higher compared to the prevalence of 34.8% in non–HIV-infected women. HIV infection itself was not associated with the presence of dyspareunia
Psychiatric Symptoms
Anxiety and depression are also common symptoms in perimenopausal women [73–76]. Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal than premenopausal women [76].
In a study by Miller et al that focused on 536 HIV-infected women, among whom 37% were perimenopausal, 89% reported psychological symptoms [56]. Ferreira et al found that HIV-infected perimenopausal women had an increased incidence of psychological symptoms compared to non–HIV-infected women [38]. Whether this increased prevalence of psychological symptoms seen in HIV-infected women can be attributed to menopause is unclear since one third to one half of men and women living with HIV experience symptoms of depression [77]. However, in the WIHS, which compared 835 HIV-infected with 335 non-HIV-infected women from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period [60]. There was no increased incidence of such symptoms during the premenopausal or postmenopausal period, suggesting the contribution of menopause to depressive symptoms during the perimenopausal period [60].
Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies [56,60] suggesting the importance of appropriately identifying and treating menopausal symptoms. In addition, cognitive decline associated with menopause contributes to depression [78–80].
Other Symptoms
Sleep disturbances are also common among perimenopausal women, with prevalence estimated to be between 38% and 46% [81–84]. Hot flashes, anxiety, and depression appear to be contributing factors [81–84]. In a cross-sectional study of 273 HIV-infected and 264 non-HIV-infected women between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal HIV-infected women. HIV-infected women had the same prevalence of insomnia compared to non–HIV-infected women [85]. Joint aches are also commonly reported in the perimenopausal period, with prevalence as high as 50% to 60% among perimenopausal women in the United States [52,53]. In HIV-infected women, Miller et al found that 63% of menopausal women reported arthralgia [56].
Treatment
For women experiencing severe hot flashes and vaginal dryness, short-term menopausal hormone therapy (MHT) is indicated to relieve symptoms. MHT should be limited to the shortest period of time at the lowest effective dose as MHT is associated with increased risks of breast cancer, cardiovascular disease, thromboembolism, and increased morbidity [86]. Despite the increased severity of menopausal symptoms experienced among HIV-infected women, the prevalence of the use of MHT in this population is lower compared to non–HIV-infected women [85].
Topical treatment is recommended for women who are experiencing solely vaginal atrophy. First-line treatment is topical nonhormonal therapy such as moisturizers and lubricants [87]. If symptoms are not relieved, then topical vaginal estrogen therapy is recommended [87]. Although topical therapy can result in estrogen absorption into the circulation, it is to a much lesser extent than systemic estrogen therapy [88].
Overall, there is lack of data on the potential interactions between MHT and HAART. Much of the potential interactions are inferred from pharmacokinetic and pharmacodynamics studies between HAART and oral contraceptives. Hormone therapy, protease inhibitors (PIs), colbicistat, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized by the CYP3A4 enzyme [89–91]. Current evidence suggests that concomitant use of hormone therapy with NNRTIs and PIs does not significantly alter the pharmacokinetics of HAART or the clinical outcomes of HIV [91]. However, there is evidence that concomitant use of nevirapine and PIs boosted with ritonavir leads to decrease in estrogen levels so higher doses of MHT may have to be used to achieve symptomatic relief [91]. There is no data on the interaction between PIs boosted with colbicistat and estrogen [92]. Integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and the CCR5 antagonist maraviroc have no significant interactions with estrogen containing compounds [89,90,92].
Cardiovascular Risk
Estrogen deficiency resulting from menopause leads to several long-term effects, including cardiovascular disease and osteoporosis. The loss of protective effects of estrogen leads to an increased risk of cardiovascular disease particularly with changes in lipid profiles [93]. Perimenopausal women experience changes in body composition with increased fat mass and waist circumference, as well as dyslipidemia and insulin resistance, all of which are associated with higher risk of cardiovascular disease [94].
HIV infection also incurs a higher risk of cardiovascular disease [95–99]. The inflammatory effects of HIV, HAART, and traditional risk factors including dyslipidemia all contribute to cardiovascular disease but the degree to which each factor contributes to elevated risk is unknown [95,98]. In addition, modifiable risk factors for cardiovascular disease such as decreased fitness and smoking are more commonly seen in HIV-infected women [100]. Even prior to menopause, HIV-infected women experience lipodystrophy syndrome with increase in truncal visceral adiposity and decrease in subcutaneous fat and muscle mass [101,102]. Whether such changes in body composition are exacerbated during the perimenopausal period remain unclear. In the SWEET study, which focused on 702 South African women among whom 21% were HIV-infected, there was lower lean mass but minimal difference in the fat mass of postmenopausal women compared to premenopausal women [103]. As the study was based in South Africa with only 21% HIV-infected, the results of this study should be viewed with caution. While changes in body composition were not observed in postmenopausal women in the SWEET study, increased truncal adiposity seen in premenopausal HIV-infected women is likely to pose an additional risk for cardiovascular disease during the menopause transition.
Several studies have been conducted to demonstrate an increased risk of cardiovascular disease, especially among young HIV-infected men [95–99]. However, no study has focused specifically on the risk of cardiovascular disease in postmenopausal HIV-infected women to date. Despite the lack of studies, it is plausible that the increased risk of cardiovascular disease seen in HIV infection is likely to be compounded with the increased risk seen during menopause. Postmenopausal HIV-infected women may be at significantly higher risk of cardiovascular disease. Appropriate measures such as lipid control, antiplatelet therapy, smoking cessation, and other lifestyle changes should be initiated as in any other population. Further studies are necessary focusing on the effects of menopause on cardiovascular disease risk in HIV-infected women.
Osteoporosis
Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].
Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].
Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].
Cognition
The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].
Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].
Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].
Cervical Dysplasia
As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.
In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].
Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.
HIV Acquisition and Transmission
The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.
In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.
In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].
HIV Progression
Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.
Conclusion
As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.
There still remain significant gaps in our understanding of menopause in HIV-infected women. As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.
Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, lfantry@medicine.umaryland.edu.
Financial disclosures: None.
1. CASCADE Collaboration. Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 2000;355:1158–9.
2. Brooks JT, Buchaz K, Gebo KA, Mermin J. HIV infection and older Americans: the public health perspective. Am J Pub Health 2012;102:1516–26.
3. Munster K, Helm P, Schmidt L. Secondary amenorrhea: Prevalence and medical contract–A cross sectional study from a Danish county. Br J Obstet Gynecol 1992;99:430–3.
4. Vyver E, Steinegger C, Katzman DK, et al. Eating disorders and menstrual dysfunction in adolescents. Ann N Y Acad Sci 2008;1135:253–64.
5. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000;85:2215–22.
6. Pelosi MA, Sama JC, Caterini H, et al. Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am J Obstet Gynecol 1974;118:966–70.
7. Bai J, Greenwald E, Caterini H, et al. Drug-related menstrual aberrations. Obstet Gynecol 1974;44:713–9.
8. Chirgwin KD, Feldman J, Muneyyirci-Delale O, et al. Menstrual function in HIV-infected women without AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:489–94.
9. Clark RA, Mulligan K, Stamenovic E, et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 2001;184:1325–7.
10. Watts DH, Spino C, Zaborski L. Comparison of gynecologic history and laboratory results in HIV-positive women with CDR+ lymphocyte counts between 200 and 500 cells/µl and below 100 cells/ µl. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:455–62.
11. Ellerbrock TV, Wrig TC, Bush TJ, et al. Characteristics of menstruation in women infected with HIV. Obstet Gynecol 1996;87:1030–4.
12. Shah PN, Smith JR, Wells C, et al. Menstrual symptoms in women infected by the HIV. Obstet Gynecol 1994;83:397–400.
13. Harlow SC, Schuman P, Cohen M, et al. Effect of HIV infection on menstrual cycle length. J Acquir Immune Defic Syndr Hum Retrovirol 2000;24:68–75.
14. Grinspoon S, Corocran C, Miller K, et al. Bone composition and endocrine function in women with AIDS wasting. J Clin Edocrinol Metab 1997;82:1332–7.
15. Research on the menopause in the 1990s. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1996;866:1–107.
16. Cejtin HE, Kalinowski A, Bacchetti P. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol 2006;108:1423–31.
17. Freeman EW, Sammel MD, Garcia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
18. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.
19. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
20. Thomas F, Renaud F, Benefice E, et al. International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol 2001;73:271–90.
21. Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65:161–6.
22. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404–11.
23. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the multi-ethnic study of atherosclerosis. Menopause 2012;19:1081–7.
24. Rocca WA, Grossardt BR, Miller VM, et al. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012;19:272–7.
25. Svejme O, Ahlborg HG, Nilsson JA, et al. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG 2012;119:810–6.
26. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology 1999;10:771–3.
27. Luoto R, Kaprio J, Uutela A. Age at natural menopause and socioeconomic status in Finland. Am J Epidemiol 1994;139:64–76.
28. Bromberger JT, Matthews KA, Kuller LH, et al. Prospective study of the determinants of age at menopause. Am J Epidemiol 1997;145:24–33.
29. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
30. Tziomalos K, Charsoulis F. Endocrine effects of tobacco smoking. Clin Endocrinol 2004;61:664–74.
31. Potter DA, Moreno A, Luther MF, et al. Effects of follicular-phase cocaine administration on menstrual and ovarian cyclicity in rhesus monkeys. Am J Obstet Gynecol 1998;178:118–25.
32. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: Cross-sectional survey. Ann Intern Med 2015;162:335–44.
33. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥ 18 years–United States, 2005-2010. MMWR Morb Mortal Wkly Rep 2011;60:1207–12.
34. Feldman J, Mikoff H, Schneider M, et al. Association of cigarette smoking with HIV prognosis among women in the HAART era: A report from the Women’s Interagency HIV study. Am J Public Health 2006:96:1060–5.
35. Centers for Disease Control and Prevention. Estimated HIV incidence among adults and adolescents in the United States, 2007–2010. HIV Surveillance Supplemental Report 2012;17(4).
36. Galea S, Ahren J, Vlahov D. Contextual determinants of drug use risk behavior: a theoretical framework. J Urban Health 2003;80:50–8.
37. de Pommerol M, Hessamfar M, Lawson-Ayayi S, et al. Menopause and HIV infection: age at onset and associated factors, ANRS CO3 Aquitaine cohort. Int J STD AIDS 2011;22:67–72.
38. Ferreira CE, Pinto-Neto AM, Conde DM, et al. Menopausal symptoms in women infected with HIV: prevalence and associated factors. Gynecol Endocrinol 2007;23:198–205.
39. Clark RA, Cohn SE, Jarck C, et al. Perimenopausal symptomatology among HIV infected women at least 40 years of age. J Acquir Immune Defic Syndr Hum Retrovirol 2000;23:99–100.
40. Fantry L, Zhan M, Taylor G, et al. Age at menopause and menopausal symptoms in HIV-infected women. AIDS Patient Care STD 2005;19:703–11.
41. Calvet G, Grinsztejn G. Predictors of early menopause in HIV infected women: a prospective cohort study. Am J Obstet Gynecol 2015;212:765.
42. Boonyanurak P, Bunupuradah T, Wilawan K, et al. Age at menopause and menopause-related symptoms in human immunodeficiency virus-infected Thai women. Menopause 2012;19:820–4.
43. Cejtin SH, Taylor R, Watts DH. Assessment of menopausal status among women in the Women’s Interagency HIV study (WIHS). Proceedings of the 57th International AIDS Conference 2004; Bangkok, Thailand.
44. WIHS Data Management and Analysis Center (WDMAC). Women’s Interagency HIV Study (WIHS) Dossier. October 2014. Available at https://statepiaps.jhsph.edu/wihs/invest-info/dossier.pdf.
45. Schoenbaum E, Hartel D, Lo Y, et al. HIV infection, drug use, and onset of natural menopause. Clinical Infect Dis 2005;41:1517–24.
46. Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002;9:32–40.
47. Miro F, Parker SW, Aspinall LJ, et al. Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study. J Clin Endocrinol Metab 2004;89:4910–5.
48. Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012;97:1159–68.
49. Freeman EW, Sammel MD, Gracia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
50. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008;15:603–12.
51. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103–15.
52. Szoeke CE, Cicuttini F, Guthrie J, Dennerstein L. Self-reported arthritis and the menopause. Climacteric 2005;8:49–55.
53. Blümel JE, Chedraui P, Baron G, et al. Menopause could be involved in the pathogenesis of muscle and joint aches in mid-aged women. Maturitas 2013;75:94–100.
54. Woods NF, Mitchell ES. Symptoms interference with work and relationships during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause 2011;18:654–61.
55. Johnson TM, Cohen HW, Howard AA, et al. Attribution of menopause symptoms in human immunodeficiency virus–infected or at-risk drug-using women Menopause 2008;15:551–7.
56. Miller SA, Santoro N, Lo Y. Menopausal symptoms in HIV-infected and drug-using women. Menopause 2005;12:348–56.
57. Looby S, Shifren J, Corless I. Increased hot flash severity and related interference in perimenopausal HIV-infected women. Menopause 2014;21:403–9.
58. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the Study of Women’s Health across the Nation. Obstet Gynecol Clin North Am 2011;38:489–501.
59. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med 2005;118 Suppl 12B:14.
60. Maki PM, Rubin LH, Cohen M, et al. Depressive symptoms are increased in the early perimenopausal stage in ethnically diverse human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Menopause 2012;19:1215–33.
61. Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351–8.
62. Palma F, Volpe A, Villa P, et al. Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: The AGATA study. Maturitas 2015 Sep 14.
63. Cutler WB, Garcia CR, McCoy N. Perimenopausal sexuality. Arch Sex Behav 1987;16:225–34.
64. Moreira ED, Glasser DB, Nicolosi A, et al. GSSAB Investigators’ Group. Sexual problems and help-seeking behavior in adults in the United Kingdom and continental Europe. BJU Int 2008;101:1005–11.
65. MacBride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010;85:87–94.
66. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas 2010;67:233–8.
67. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009;6:2133–42.
68. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active post-menopausal women. Menopause 2008;15(4 Pt 1):661–6.
69. Cumming GP, Currie HD, Moncur R, Lee AJ. Web-based survey on the effect of menopause on women’s libido in a computer-literate population. Menopause Int 2009;15:8–12.
70. Valadares AL, Pinto-Neto AM, Conde DM, et al. A population-based study of dyspareunia in a cohort of middle-aged Brazilian women. Menopause 2008;15:1184–90.
71. Latthe P, Migini L, Gray R, et al. Factors predisposing women to chronic pelvic pain: a systemic review. BMJ 2006;332:749–55.
72. Valadares AL, Pinto-Neto AM, Gomes D, et al. Dyspareunia in HIV-positive and HIV-negative middle-aged women: a cross-sectional study. BMJ Open 2014;4:e004974.
73. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health 2001;91:1435–42.
74. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4:214–20.
75. Cohen LS, Soares CN, Joffe H. Diagnosis and management of mood disorders during the menopausal transition. Am J Med 2005;118 Suppl 12B:93–7.
76. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63:375–82.
77. Eller LS, Corless I, Bunch EH, et al. Self-care strategies for depressive symptoms in people with HIV disease. J Adv Nurs 2005;51:119–30.
78. Fuh JL, Wang SJ, Lee SJ, et al. A longitudinal study of cognition change during early menopausal transition in a rural community. Maturitas 2006;53:447–53.
79. Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72:1850–7.
80. Hinkin CH, Castellon SA, Atkinson JH, et al. Neuropsychiatric aspects of HIV infection among older adults. J Clin Epidemiol 2001;54:S44–52.
81. Kravitz HM, Ganz PA, Bromberger J, et al. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause 2003;10:19–28.
82. Freedman RR, Roehrs TA. Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance. Menopause 2006;13:576–83.
83. Erlik Y, Tataryn IV, Meldrum DR, et al. Association of waking episodes with menopausal hot flushes. JAMA 1981; 245:1741–4.
84. Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause 2007;14:826–9.
85. Lui-Filho JF, Valadares AR, Gomes D, et al. Menopausal symptoms and associated factors in HIV-positive women. Maturitas 2013;76:172–8.
86. Aberg JA, Gallant JE, Ghanem KG, et al, Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis 2014;58:e1–34.
87. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14:357–69.
88. Dorr MB, Nelson AL, Mayer PR, et al. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis. Fertil Steril 2010;94:2365–8.
89. El-Ibiary SY, Cocohoba JM. Effects of antiretrovirals on the pharmacokinetics of hormonal contraception. Eur J Contracept Reprod Health Care 2008;13:123–32.
90. Tittle V, Bull L, Boffito M, Nwokolo N. Pharmacokinetic and pharmacodynamics drug interactions between antiretrovirals and oral contraceptives. Clin Pharmacokinet 2015;54:23–34.
91. Thurman AR, Anderson S, Doncel G. Effects of hormonal contraception on anti-retroviral drug metabolism, pharmacokinetics and pharmacodynamics. Am J Reprod Immunol 2014:71:523–30.
92. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US. Department of Health and Human Services. Availabe at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
93. Berg G, Mesch V, Boero L, et al. Lipid and lipoprotein profile in menopausal transition: effects of hormones, age and fat distribution. Hormone Metab Res 2004;36:215–20.
94. Sower M, Zheng H, Tomey K, et al. Changes in body composition in women over six years at midlife: ovarian and chronological aging. J Clin Endocrin Metab 2007;92:895–901.
95. Flooris-Moore M, Howard AA, Lo Y, et al. Increased serum lipids are associated with higher CD4 lymphocyte count in HIV-infected women. HIV Med 2006;7:421–30.
96. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 2009;23:1841–9.
97. Palacios R, Alonso I, Hidalgo A, et al. Peripheral arterial disease in HIV patients older than 50 years of age. AIDS Res Hum Retroviruses 2008;24:1043–6.
98. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001;32:130–9.
99. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrin Metab 2007;92:2506–12.
100. Dolan SE, Frontera W, Librizzi J et al. The effects of a supervised home based aerobic and progressive resistance training regimen in HIV-infected women: randomized trial. Arch Intern Med 2006;166:1225–31.
101. Grinspoon S, Carr A. Cardiovascular risk and body fat abnormalities in HIV-infected adults. N Engl J Med 2005;352:48–62
102. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr 2006;42:562–71.
103. Jaff NG, Norris SA, Snyman T, et al. Body composition in the study of women entering and in Endocrine Transition (SWEET): A perspective of African women who have a high prevalence of obesity and HIV infection. Metabolism 2015;64:1031–41.
104. Akhter MP, Lappe JM, Davies KM, et al. Transmenopausal changes in the trabecular bone structure. Bone 2007;41:111–6.
105. Cassetti I, Madruga JV, Suleiman JM, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials 2007;8:164–72.
106. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203:1791–801.
107. Hansen AB, Obel N, Nielsen H, et al. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: Data from a randomized trial. HIV Med 2011;12:157–65.
108. Yin MT, Zhang CA, McMahon DJ, et al. Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study. J Clin Endocrinol Metab 2012;97:554–62.
109. Sharma A, Flom PL, Rosen CJ, et al. Racial differences in bone loss and relation to menopause among HIV-infected and uninfected women. Bone 2015;77:24–30.
110. Caputo BV, Traversa-Caputo GC, Costa C, et al. Evaluation of bone alterations in the jaws of HIV-infected menopausal women. Braz Oral Res 2013;27:231–7.
111. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int 2005;26:1345–52.
112. Yin MT, Mcmahon DJ, Ferris DC, et al. Low bone mass and high bone turnover in postmenopausal human immunodeficiency virus-infected women. J Clin Endocrinol Metab 2010;95:620–9.
113. Gibellini D, De Crignis E, Ponti C. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNF-alpha activation. J Med Virol 2008;80:1507–14.
114. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000;14:F63–7.
115. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy)propyl] adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004;48:1469–87.
116. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006;20:2165–74.
117. Dao CN, Patel P, Overton ET, Rhame F, et al. Study to understand the natural history of HIV and AIDS in the era of effective therapy (SUN) investigators. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011;52:396–405.
118. Jacobson DL, Spiegelman D, Know TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the nutrition for healthy living study. J Acquir Immune Defic Syndr Hum Retrovirol 2008;49:298–308.
119. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporosis Int 2005;16:581–9
120. Pedrazzoni M, Vescovi L, Maninetti M, et al. Effects of chronic heroine abuse on bone and mineral metabolism. Acta Endocrinol 1993;129:42–5.
121. Lo Re V 3rd, Guaraldi G, Leonard MB, et al. Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men. AIDS 1990;23:2191–8.
122. Yin MT, Modarresi R, Shane E, et al. Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporos Int 2011;22:1459–66.
123. Sharma A, Cohen HW, Freeman R, et al. Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss. Maturitas 2011;70:295–301.
124. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008;93:3499–504.
125. Womack JA, Goulet JL, Gibert C, et al. Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One Feb 16 2011;6:e17217.
126. Young B, Dao CN, Buchacz K, et al, HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006. Clin Infect Dis 2011;52:1061–8.
127. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011; 154:356–64.
128. Aberg JA, Kaplan JE, Libman H, et al; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651–81.
129. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis 2014. Washington, DC: National Osteoporosis Foundation; 2014.
130. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis 2010;51:937–46.
131. McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007;21:2473–82.
132. Lin D, Rieder MJ. Interventions for the treatment of decreased bone mineral density associated with HIV infection. Cochrane Database Syst Rev 2007:CD005645.
133. Haring B, Leng X, Robinson J. Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women’s Health Initiative Memory Study. J Am Heart Assoc 2013;2:e000369.
134. Soares CN, Maki PM. Menopausal transition, mood, and cognition: an integrated view to close the gaps. Menopause 2010;17:812–4.
135. Greendale GA, Derby CA, Maki PM. Perimenopause and cognition. Obstet Gynecol Clin North Am 2011;38:519–35.
136. Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. Am J Epidemiol 2010;171:1214–24.
137. Price RW. Neurological complications of HIV infection. Lancet 1996;348:445–52.
138. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789–99.
139. Gisslén M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 2011;11:356.
140. Rubin LH, Sundermann EE, Cook JA, et al. An investigation of menopausal stage and symptoms on cognition in HIV-infected women. Menopause 2014;21:997–1006.
141. Cook JA, Cohen MH, Burke J, et al. Effects of depressive symptoms and mental health quality of life on use of highly active antiretroviral therapy among HIV-seropositive women. J Acquir Immune Defic Syndr 2002;30:401–9.
142. Cook JA, Grey D, Burke J, et al. Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Pub Health 2004;94:1133–40.
143. Kim SC, Messing S, Shah K, et al. Effects of highly active antiretroviral therapy (HAART) and menopause on risk of progression of cervical dysplasia in human immune deficiency virus (HIV) infected women. Infect Dis Obstet Gynecol 2013;2013:784718.
144. Ceccaldi PF, Ferreira C, Coussy F, et al. Cervical disease in postmenopausal HIV-1 infected women. J Gynecol Obstet Biol Reprod 2010;39:466–70.
145. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992;304:809–13.
146. Meditz AL, Moreau KL, MaWhinney S, et al. CCR5 expression is elevated on endocervical CD4+ T cells in healthy postmenopausal women. J Acquir Immune Defic Syndr 2012;59:221–8.
147. Chappell CA, Isaacs CE, Xu W, et al. The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 2015;213:204.
148. Melo KC, Melo MR, Ricci BV, Segurado AC. Correlates of human immunodeficiency virus cervicovaginal shedding among postmenopausal and fertile-aged women. Menopause 2012;19:150–6.
149. Viard JP, Mocroft A, Chiesi A, et al. Influence of age of CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the Euro SIDA study. J Infect Dis 2001;193:1290–4.
150. Grabar S, Kousignian I, Sobel A, et al. Immunological and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004;18:2029–38.
151. Cuzin L, Delpierre C, Gerard S, et al. Immunologic and clinical responses to highly active antiretroviral therapy in patients with HIV infection aged >50 years. Clin Infect Dis 2007;45:654–7.
152. Patterson KB, Cohn SE, Uynik J, et al. Treatment responses in antiretroviral treatment-naïve premenopausal and postmenopausal HIV-1 infected women: an analysis from AIDS clinical trials group studies. Clin Infect Dis 2009;49:473–6.
153. van Benthem BH, Vernazza P, Coutinho RA, et al. The impact of pregnancy and menopause on CD4 lymphocyte count in HIV-infected women. AIDS 2002;16:919–24.
1. CASCADE Collaboration. Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 2000;355:1158–9.
2. Brooks JT, Buchaz K, Gebo KA, Mermin J. HIV infection and older Americans: the public health perspective. Am J Pub Health 2012;102:1516–26.
3. Munster K, Helm P, Schmidt L. Secondary amenorrhea: Prevalence and medical contract–A cross sectional study from a Danish county. Br J Obstet Gynecol 1992;99:430–3.
4. Vyver E, Steinegger C, Katzman DK, et al. Eating disorders and menstrual dysfunction in adolescents. Ann N Y Acad Sci 2008;1135:253–64.
5. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000;85:2215–22.
6. Pelosi MA, Sama JC, Caterini H, et al. Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am J Obstet Gynecol 1974;118:966–70.
7. Bai J, Greenwald E, Caterini H, et al. Drug-related menstrual aberrations. Obstet Gynecol 1974;44:713–9.
8. Chirgwin KD, Feldman J, Muneyyirci-Delale O, et al. Menstrual function in HIV-infected women without AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:489–94.
9. Clark RA, Mulligan K, Stamenovic E, et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 2001;184:1325–7.
10. Watts DH, Spino C, Zaborski L. Comparison of gynecologic history and laboratory results in HIV-positive women with CDR+ lymphocyte counts between 200 and 500 cells/µl and below 100 cells/ µl. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:455–62.
11. Ellerbrock TV, Wrig TC, Bush TJ, et al. Characteristics of menstruation in women infected with HIV. Obstet Gynecol 1996;87:1030–4.
12. Shah PN, Smith JR, Wells C, et al. Menstrual symptoms in women infected by the HIV. Obstet Gynecol 1994;83:397–400.
13. Harlow SC, Schuman P, Cohen M, et al. Effect of HIV infection on menstrual cycle length. J Acquir Immune Defic Syndr Hum Retrovirol 2000;24:68–75.
14. Grinspoon S, Corocran C, Miller K, et al. Bone composition and endocrine function in women with AIDS wasting. J Clin Edocrinol Metab 1997;82:1332–7.
15. Research on the menopause in the 1990s. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1996;866:1–107.
16. Cejtin HE, Kalinowski A, Bacchetti P. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol 2006;108:1423–31.
17. Freeman EW, Sammel MD, Garcia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
18. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.
19. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
20. Thomas F, Renaud F, Benefice E, et al. International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol 2001;73:271–90.
21. Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65:161–6.
22. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404–11.
23. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the multi-ethnic study of atherosclerosis. Menopause 2012;19:1081–7.
24. Rocca WA, Grossardt BR, Miller VM, et al. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012;19:272–7.
25. Svejme O, Ahlborg HG, Nilsson JA, et al. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG 2012;119:810–6.
26. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology 1999;10:771–3.
27. Luoto R, Kaprio J, Uutela A. Age at natural menopause and socioeconomic status in Finland. Am J Epidemiol 1994;139:64–76.
28. Bromberger JT, Matthews KA, Kuller LH, et al. Prospective study of the determinants of age at menopause. Am J Epidemiol 1997;145:24–33.
29. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013;178:70–83.
30. Tziomalos K, Charsoulis F. Endocrine effects of tobacco smoking. Clin Endocrinol 2004;61:664–74.
31. Potter DA, Moreno A, Luther MF, et al. Effects of follicular-phase cocaine administration on menstrual and ovarian cyclicity in rhesus monkeys. Am J Obstet Gynecol 1998;178:118–25.
32. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: Cross-sectional survey. Ann Intern Med 2015;162:335–44.
33. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥ 18 years–United States, 2005-2010. MMWR Morb Mortal Wkly Rep 2011;60:1207–12.
34. Feldman J, Mikoff H, Schneider M, et al. Association of cigarette smoking with HIV prognosis among women in the HAART era: A report from the Women’s Interagency HIV study. Am J Public Health 2006:96:1060–5.
35. Centers for Disease Control and Prevention. Estimated HIV incidence among adults and adolescents in the United States, 2007–2010. HIV Surveillance Supplemental Report 2012;17(4).
36. Galea S, Ahren J, Vlahov D. Contextual determinants of drug use risk behavior: a theoretical framework. J Urban Health 2003;80:50–8.
37. de Pommerol M, Hessamfar M, Lawson-Ayayi S, et al. Menopause and HIV infection: age at onset and associated factors, ANRS CO3 Aquitaine cohort. Int J STD AIDS 2011;22:67–72.
38. Ferreira CE, Pinto-Neto AM, Conde DM, et al. Menopausal symptoms in women infected with HIV: prevalence and associated factors. Gynecol Endocrinol 2007;23:198–205.
39. Clark RA, Cohn SE, Jarck C, et al. Perimenopausal symptomatology among HIV infected women at least 40 years of age. J Acquir Immune Defic Syndr Hum Retrovirol 2000;23:99–100.
40. Fantry L, Zhan M, Taylor G, et al. Age at menopause and menopausal symptoms in HIV-infected women. AIDS Patient Care STD 2005;19:703–11.
41. Calvet G, Grinsztejn G. Predictors of early menopause in HIV infected women: a prospective cohort study. Am J Obstet Gynecol 2015;212:765.
42. Boonyanurak P, Bunupuradah T, Wilawan K, et al. Age at menopause and menopause-related symptoms in human immunodeficiency virus-infected Thai women. Menopause 2012;19:820–4.
43. Cejtin SH, Taylor R, Watts DH. Assessment of menopausal status among women in the Women’s Interagency HIV study (WIHS). Proceedings of the 57th International AIDS Conference 2004; Bangkok, Thailand.
44. WIHS Data Management and Analysis Center (WDMAC). Women’s Interagency HIV Study (WIHS) Dossier. October 2014. Available at https://statepiaps.jhsph.edu/wihs/invest-info/dossier.pdf.
45. Schoenbaum E, Hartel D, Lo Y, et al. HIV infection, drug use, and onset of natural menopause. Clinical Infect Dis 2005;41:1517–24.
46. Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002;9:32–40.
47. Miro F, Parker SW, Aspinall LJ, et al. Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study. J Clin Endocrinol Metab 2004;89:4910–5.
48. Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012;97:1159–68.
49. Freeman EW, Sammel MD, Gracia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
50. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008;15:603–12.
51. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103–15.
52. Szoeke CE, Cicuttini F, Guthrie J, Dennerstein L. Self-reported arthritis and the menopause. Climacteric 2005;8:49–55.
53. Blümel JE, Chedraui P, Baron G, et al. Menopause could be involved in the pathogenesis of muscle and joint aches in mid-aged women. Maturitas 2013;75:94–100.
54. Woods NF, Mitchell ES. Symptoms interference with work and relationships during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause 2011;18:654–61.
55. Johnson TM, Cohen HW, Howard AA, et al. Attribution of menopause symptoms in human immunodeficiency virus–infected or at-risk drug-using women Menopause 2008;15:551–7.
56. Miller SA, Santoro N, Lo Y. Menopausal symptoms in HIV-infected and drug-using women. Menopause 2005;12:348–56.
57. Looby S, Shifren J, Corless I. Increased hot flash severity and related interference in perimenopausal HIV-infected women. Menopause 2014;21:403–9.
58. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the Study of Women’s Health across the Nation. Obstet Gynecol Clin North Am 2011;38:489–501.
59. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med 2005;118 Suppl 12B:14.
60. Maki PM, Rubin LH, Cohen M, et al. Depressive symptoms are increased in the early perimenopausal stage in ethnically diverse human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Menopause 2012;19:1215–33.
61. Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351–8.
62. Palma F, Volpe A, Villa P, et al. Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: The AGATA study. Maturitas 2015 Sep 14.
63. Cutler WB, Garcia CR, McCoy N. Perimenopausal sexuality. Arch Sex Behav 1987;16:225–34.
64. Moreira ED, Glasser DB, Nicolosi A, et al. GSSAB Investigators’ Group. Sexual problems and help-seeking behavior in adults in the United Kingdom and continental Europe. BJU Int 2008;101:1005–11.
65. MacBride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010;85:87–94.
66. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas 2010;67:233–8.
67. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009;6:2133–42.
68. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active post-menopausal women. Menopause 2008;15(4 Pt 1):661–6.
69. Cumming GP, Currie HD, Moncur R, Lee AJ. Web-based survey on the effect of menopause on women’s libido in a computer-literate population. Menopause Int 2009;15:8–12.
70. Valadares AL, Pinto-Neto AM, Conde DM, et al. A population-based study of dyspareunia in a cohort of middle-aged Brazilian women. Menopause 2008;15:1184–90.
71. Latthe P, Migini L, Gray R, et al. Factors predisposing women to chronic pelvic pain: a systemic review. BMJ 2006;332:749–55.
72. Valadares AL, Pinto-Neto AM, Gomes D, et al. Dyspareunia in HIV-positive and HIV-negative middle-aged women: a cross-sectional study. BMJ Open 2014;4:e004974.
73. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health 2001;91:1435–42.
74. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4:214–20.
75. Cohen LS, Soares CN, Joffe H. Diagnosis and management of mood disorders during the menopausal transition. Am J Med 2005;118 Suppl 12B:93–7.
76. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63:375–82.
77. Eller LS, Corless I, Bunch EH, et al. Self-care strategies for depressive symptoms in people with HIV disease. J Adv Nurs 2005;51:119–30.
78. Fuh JL, Wang SJ, Lee SJ, et al. A longitudinal study of cognition change during early menopausal transition in a rural community. Maturitas 2006;53:447–53.
79. Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72:1850–7.
80. Hinkin CH, Castellon SA, Atkinson JH, et al. Neuropsychiatric aspects of HIV infection among older adults. J Clin Epidemiol 2001;54:S44–52.
81. Kravitz HM, Ganz PA, Bromberger J, et al. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause 2003;10:19–28.
82. Freedman RR, Roehrs TA. Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance. Menopause 2006;13:576–83.
83. Erlik Y, Tataryn IV, Meldrum DR, et al. Association of waking episodes with menopausal hot flushes. JAMA 1981; 245:1741–4.
84. Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause 2007;14:826–9.
85. Lui-Filho JF, Valadares AR, Gomes D, et al. Menopausal symptoms and associated factors in HIV-positive women. Maturitas 2013;76:172–8.
86. Aberg JA, Gallant JE, Ghanem KG, et al, Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis 2014;58:e1–34.
87. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14:357–69.
88. Dorr MB, Nelson AL, Mayer PR, et al. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis. Fertil Steril 2010;94:2365–8.
89. El-Ibiary SY, Cocohoba JM. Effects of antiretrovirals on the pharmacokinetics of hormonal contraception. Eur J Contracept Reprod Health Care 2008;13:123–32.
90. Tittle V, Bull L, Boffito M, Nwokolo N. Pharmacokinetic and pharmacodynamics drug interactions between antiretrovirals and oral contraceptives. Clin Pharmacokinet 2015;54:23–34.
91. Thurman AR, Anderson S, Doncel G. Effects of hormonal contraception on anti-retroviral drug metabolism, pharmacokinetics and pharmacodynamics. Am J Reprod Immunol 2014:71:523–30.
92. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US. Department of Health and Human Services. Availabe at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
93. Berg G, Mesch V, Boero L, et al. Lipid and lipoprotein profile in menopausal transition: effects of hormones, age and fat distribution. Hormone Metab Res 2004;36:215–20.
94. Sower M, Zheng H, Tomey K, et al. Changes in body composition in women over six years at midlife: ovarian and chronological aging. J Clin Endocrin Metab 2007;92:895–901.
95. Flooris-Moore M, Howard AA, Lo Y, et al. Increased serum lipids are associated with higher CD4 lymphocyte count in HIV-infected women. HIV Med 2006;7:421–30.
96. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 2009;23:1841–9.
97. Palacios R, Alonso I, Hidalgo A, et al. Peripheral arterial disease in HIV patients older than 50 years of age. AIDS Res Hum Retroviruses 2008;24:1043–6.
98. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001;32:130–9.
99. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrin Metab 2007;92:2506–12.
100. Dolan SE, Frontera W, Librizzi J et al. The effects of a supervised home based aerobic and progressive resistance training regimen in HIV-infected women: randomized trial. Arch Intern Med 2006;166:1225–31.
101. Grinspoon S, Carr A. Cardiovascular risk and body fat abnormalities in HIV-infected adults. N Engl J Med 2005;352:48–62
102. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr 2006;42:562–71.
103. Jaff NG, Norris SA, Snyman T, et al. Body composition in the study of women entering and in Endocrine Transition (SWEET): A perspective of African women who have a high prevalence of obesity and HIV infection. Metabolism 2015;64:1031–41.
104. Akhter MP, Lappe JM, Davies KM, et al. Transmenopausal changes in the trabecular bone structure. Bone 2007;41:111–6.
105. Cassetti I, Madruga JV, Suleiman JM, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials 2007;8:164–72.
106. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203:1791–801.
107. Hansen AB, Obel N, Nielsen H, et al. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: Data from a randomized trial. HIV Med 2011;12:157–65.
108. Yin MT, Zhang CA, McMahon DJ, et al. Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study. J Clin Endocrinol Metab 2012;97:554–62.
109. Sharma A, Flom PL, Rosen CJ, et al. Racial differences in bone loss and relation to menopause among HIV-infected and uninfected women. Bone 2015;77:24–30.
110. Caputo BV, Traversa-Caputo GC, Costa C, et al. Evaluation of bone alterations in the jaws of HIV-infected menopausal women. Braz Oral Res 2013;27:231–7.
111. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int 2005;26:1345–52.
112. Yin MT, Mcmahon DJ, Ferris DC, et al. Low bone mass and high bone turnover in postmenopausal human immunodeficiency virus-infected women. J Clin Endocrinol Metab 2010;95:620–9.
113. Gibellini D, De Crignis E, Ponti C. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNF-alpha activation. J Med Virol 2008;80:1507–14.
114. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000;14:F63–7.
115. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy)propyl] adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004;48:1469–87.
116. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006;20:2165–74.
117. Dao CN, Patel P, Overton ET, Rhame F, et al. Study to understand the natural history of HIV and AIDS in the era of effective therapy (SUN) investigators. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011;52:396–405.
118. Jacobson DL, Spiegelman D, Know TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the nutrition for healthy living study. J Acquir Immune Defic Syndr Hum Retrovirol 2008;49:298–308.
119. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporosis Int 2005;16:581–9
120. Pedrazzoni M, Vescovi L, Maninetti M, et al. Effects of chronic heroine abuse on bone and mineral metabolism. Acta Endocrinol 1993;129:42–5.
121. Lo Re V 3rd, Guaraldi G, Leonard MB, et al. Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men. AIDS 1990;23:2191–8.
122. Yin MT, Modarresi R, Shane E, et al. Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporos Int 2011;22:1459–66.
123. Sharma A, Cohen HW, Freeman R, et al. Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss. Maturitas 2011;70:295–301.
124. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008;93:3499–504.
125. Womack JA, Goulet JL, Gibert C, et al. Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One Feb 16 2011;6:e17217.
126. Young B, Dao CN, Buchacz K, et al, HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006. Clin Infect Dis 2011;52:1061–8.
127. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011; 154:356–64.
128. Aberg JA, Kaplan JE, Libman H, et al; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651–81.
129. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis 2014. Washington, DC: National Osteoporosis Foundation; 2014.
130. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis 2010;51:937–46.
131. McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007;21:2473–82.
132. Lin D, Rieder MJ. Interventions for the treatment of decreased bone mineral density associated with HIV infection. Cochrane Database Syst Rev 2007:CD005645.
133. Haring B, Leng X, Robinson J. Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women’s Health Initiative Memory Study. J Am Heart Assoc 2013;2:e000369.
134. Soares CN, Maki PM. Menopausal transition, mood, and cognition: an integrated view to close the gaps. Menopause 2010;17:812–4.
135. Greendale GA, Derby CA, Maki PM. Perimenopause and cognition. Obstet Gynecol Clin North Am 2011;38:519–35.
136. Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. Am J Epidemiol 2010;171:1214–24.
137. Price RW. Neurological complications of HIV infection. Lancet 1996;348:445–52.
138. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789–99.
139. Gisslén M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 2011;11:356.
140. Rubin LH, Sundermann EE, Cook JA, et al. An investigation of menopausal stage and symptoms on cognition in HIV-infected women. Menopause 2014;21:997–1006.
141. Cook JA, Cohen MH, Burke J, et al. Effects of depressive symptoms and mental health quality of life on use of highly active antiretroviral therapy among HIV-seropositive women. J Acquir Immune Defic Syndr 2002;30:401–9.
142. Cook JA, Grey D, Burke J, et al. Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Pub Health 2004;94:1133–40.
143. Kim SC, Messing S, Shah K, et al. Effects of highly active antiretroviral therapy (HAART) and menopause on risk of progression of cervical dysplasia in human immune deficiency virus (HIV) infected women. Infect Dis Obstet Gynecol 2013;2013:784718.
144. Ceccaldi PF, Ferreira C, Coussy F, et al. Cervical disease in postmenopausal HIV-1 infected women. J Gynecol Obstet Biol Reprod 2010;39:466–70.
145. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992;304:809–13.
146. Meditz AL, Moreau KL, MaWhinney S, et al. CCR5 expression is elevated on endocervical CD4+ T cells in healthy postmenopausal women. J Acquir Immune Defic Syndr 2012;59:221–8.
147. Chappell CA, Isaacs CE, Xu W, et al. The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 2015;213:204.
148. Melo KC, Melo MR, Ricci BV, Segurado AC. Correlates of human immunodeficiency virus cervicovaginal shedding among postmenopausal and fertile-aged women. Menopause 2012;19:150–6.
149. Viard JP, Mocroft A, Chiesi A, et al. Influence of age of CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the Euro SIDA study. J Infect Dis 2001;193:1290–4.
150. Grabar S, Kousignian I, Sobel A, et al. Immunological and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004;18:2029–38.
151. Cuzin L, Delpierre C, Gerard S, et al. Immunologic and clinical responses to highly active antiretroviral therapy in patients with HIV infection aged >50 years. Clin Infect Dis 2007;45:654–7.
152. Patterson KB, Cohn SE, Uynik J, et al. Treatment responses in antiretroviral treatment-naïve premenopausal and postmenopausal HIV-1 infected women: an analysis from AIDS clinical trials group studies. Clin Infect Dis 2009;49:473–6.
153. van Benthem BH, Vernazza P, Coutinho RA, et al. The impact of pregnancy and menopause on CD4 lymphocyte count in HIV-infected women. AIDS 2002;16:919–24.
ALLOZITHRO trial: HSCT patients fared worse with azithromycin
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
FROM JAMA
Key clinical point:
Major finding: The 2-year airflow decline–free survival rates were 32.8% and 41.3% in the azithromycin and placebo groups, respectively (hazard ratio, 1.3).
Data source: The randomized, placebo-controlled ALLOZITHRO trial of 480 patients.
Disclosures: The ALLOZITHRO trial was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
California study indicates increased melanoma incidence is real
A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.
The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.
“Our findings support a true real rise in incidence of melanoma across all thicknesses and stages, and not just thinner, more indolent tumors that may be due to increased screening or diagnosis,” lead researcher Susan Swetter, MD, said in an interview. The study was published online in the Journal of Investigative Dermatology (J Invest Dermatol. 2017 Jul 20. pii: S0022-202X(17)31867-5. doi: 10.1016/j.jid.2017.06.024).
Overall, the incidence rose 25% in men from 1998-2002 to 2008-2012 (an average annual age-adjusted incidence of 34.7 to 43.5 per 100,000 person-years), and by 21% in women between those two time periods (from 21.7 to 26.2 per 100,000). Melanoma incidence rate ratios (IRR) increased across all SES classes: by 27% among men in the highest SES neighborhoods, and by 12% among men in the lowest SES neighborhoods. For women, the rates increased by 28% and 13% respectively.
The highest increases in the incidence of regional and distant disease occurred in the lowest SES neighborhoods, nearly doubling in men (distant disease IRR, 1.87; 95% CI, 1.39-2.53; regional disease IRR, 1.93; 95% CI, 1.51-2.47). Women in these neighborhoods also experienced a significant increase in regional disease (IRR, 1.44; 95% CI, 1.00-2.08), but not distant disease.
Incidence of diagnosis with the thickest tumors (greater than 4 mm) rose significantly in most neighborhood SES quartiles, with the exception of the men in the lowest SES quartiles, who had a lower increase that was of borderline significance.
The results solidify the evidence that melanoma incidence is truly increasing, but they also have public health implications. The rising incidence of more advanced disease suggests a heightening health care burden from melanoma in the coming years, but also points to strategies for prevention, according to Dr. Swetter. “It’s important that we focus not only on primary prevention. We need methods to enhance early detection, especially in areas where there is lower access to dermatologists and even primary care providers, who can assist in this effort,” she said.
The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.
A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.
The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.
“Our findings support a true real rise in incidence of melanoma across all thicknesses and stages, and not just thinner, more indolent tumors that may be due to increased screening or diagnosis,” lead researcher Susan Swetter, MD, said in an interview. The study was published online in the Journal of Investigative Dermatology (J Invest Dermatol. 2017 Jul 20. pii: S0022-202X(17)31867-5. doi: 10.1016/j.jid.2017.06.024).
Overall, the incidence rose 25% in men from 1998-2002 to 2008-2012 (an average annual age-adjusted incidence of 34.7 to 43.5 per 100,000 person-years), and by 21% in women between those two time periods (from 21.7 to 26.2 per 100,000). Melanoma incidence rate ratios (IRR) increased across all SES classes: by 27% among men in the highest SES neighborhoods, and by 12% among men in the lowest SES neighborhoods. For women, the rates increased by 28% and 13% respectively.
The highest increases in the incidence of regional and distant disease occurred in the lowest SES neighborhoods, nearly doubling in men (distant disease IRR, 1.87; 95% CI, 1.39-2.53; regional disease IRR, 1.93; 95% CI, 1.51-2.47). Women in these neighborhoods also experienced a significant increase in regional disease (IRR, 1.44; 95% CI, 1.00-2.08), but not distant disease.
Incidence of diagnosis with the thickest tumors (greater than 4 mm) rose significantly in most neighborhood SES quartiles, with the exception of the men in the lowest SES quartiles, who had a lower increase that was of borderline significance.
The results solidify the evidence that melanoma incidence is truly increasing, but they also have public health implications. The rising incidence of more advanced disease suggests a heightening health care burden from melanoma in the coming years, but also points to strategies for prevention, according to Dr. Swetter. “It’s important that we focus not only on primary prevention. We need methods to enhance early detection, especially in areas where there is lower access to dermatologists and even primary care providers, who can assist in this effort,” she said.
The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.
A new analysis in non-Hispanic whites suggests that rising melanoma rates are real, not attributable to increased levels of detection, and that the burden of the disease could rise significantly in the coming years.
The incidence of melanoma in light-skinned individuals has been rising worldwide in recent years, but it remains unclear whether that trend is due to an increase in the disease, or better screening and diagnosis. The new results are drawn from California, and track incidence and stage at diagnosis of melanoma across different socioeconomic status (SES) groups. Across all groups, the researchers found increases not only in incidence, but also in advanced disease.
“Our findings support a true real rise in incidence of melanoma across all thicknesses and stages, and not just thinner, more indolent tumors that may be due to increased screening or diagnosis,” lead researcher Susan Swetter, MD, said in an interview. The study was published online in the Journal of Investigative Dermatology (J Invest Dermatol. 2017 Jul 20. pii: S0022-202X(17)31867-5. doi: 10.1016/j.jid.2017.06.024).
Overall, the incidence rose 25% in men from 1998-2002 to 2008-2012 (an average annual age-adjusted incidence of 34.7 to 43.5 per 100,000 person-years), and by 21% in women between those two time periods (from 21.7 to 26.2 per 100,000). Melanoma incidence rate ratios (IRR) increased across all SES classes: by 27% among men in the highest SES neighborhoods, and by 12% among men in the lowest SES neighborhoods. For women, the rates increased by 28% and 13% respectively.
The highest increases in the incidence of regional and distant disease occurred in the lowest SES neighborhoods, nearly doubling in men (distant disease IRR, 1.87; 95% CI, 1.39-2.53; regional disease IRR, 1.93; 95% CI, 1.51-2.47). Women in these neighborhoods also experienced a significant increase in regional disease (IRR, 1.44; 95% CI, 1.00-2.08), but not distant disease.
Incidence of diagnosis with the thickest tumors (greater than 4 mm) rose significantly in most neighborhood SES quartiles, with the exception of the men in the lowest SES quartiles, who had a lower increase that was of borderline significance.
The results solidify the evidence that melanoma incidence is truly increasing, but they also have public health implications. The rising incidence of more advanced disease suggests a heightening health care burden from melanoma in the coming years, but also points to strategies for prevention, according to Dr. Swetter. “It’s important that we focus not only on primary prevention. We need methods to enhance early detection, especially in areas where there is lower access to dermatologists and even primary care providers, who can assist in this effort,” she said.
The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point: Increased incidences of more advanced disease suggest a rising health care burden.
Major finding: Between 1998-2002 and 2008-2012, incidence rate ratios rose by 25% in men and 21% in women.
Data source: A retrospective study of over 58,000 melanoma cases.
Disclosures: The Stanford Cancer Institute funded the study. Dr. Swetter reported having no financial disclosures.
Colonic microbiota encroachment linked to diabetes
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Microbiota encroachment into colonic mucosa characterizes type 2 diabetes in humans.
Major finding: Regardless of whether they were obese or normal weight, patients with diabetes had bacterial-epithelial colonic distances that were one-third of those in euglycemic individuals (P less than .001).
Data source: A study of 42 Veterans Affairs patients with and without type 2 diabetes mellitus.
Disclosures: Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.