User login
Experimental EGFR inhibitor added nothing but rash
SCOTTSDALE, ARIZ. – The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.
The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.
Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.
The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.
"Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge," Dr. Harari said.
"We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition," he said.
Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.
A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.
At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.
Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).
However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.
In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.
Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.
SCOTTSDALE, ARIZ. – The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.
The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.
Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.
The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.
"Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge," Dr. Harari said.
"We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition," he said.
Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.
A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.
At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.
Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).
However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.
In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.
Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.
SCOTTSDALE, ARIZ. – The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.
The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.
Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.
The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.
"Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge," Dr. Harari said.
"We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition," he said.
Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.
A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.
At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.
Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).
However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.
In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.
Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.
AT THE HEAD AND NECK CANCER SYMPOSIUM
Major finding: There were no significant differences in locoregional control, disease-specific survival, or overall survival at 3 years with the addition of zalutumumab to accelerated chemoradiotherapy.
Data source: Open-label, randomized, phase III trial in 619 patients with squamous cell cancers of the head and neck.
Disclosures: The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.
Wait! Put elective surgery on hold after stent placement
SCOTTSDALE, ARIZ. – The presence of a coronary artery stent is not a barrier to noncardiac surgery, but it may change the timing of surgery and perioperative management of the patient, a hospitalist cautions.
Patients who receive bare-metal stents should delay having elective surgery for at least 6 weeks after stent placement, and those who receive a drug-eluting stent should put off elective procedures for at least a year, said Dr. Amir K. Jaffer, professor of medicine and chief of the division of hospital medicine at Rush University Medical Center in Chicago.
The type of stent, its placement, and the time since placement are just some of the key pieces of information that clinicians need to manage patients, Dr. Jaffer said at a meeting on perioperative medicine sponsored by the University of Miami.
"You want to try to get that [information] card if you can from the patient, about where the stents were placed, and if they don’t have the card handy, you really need to go to the procedure note, because the patient may or may not know if it was a drug-eluting stent," he said.
Other vital pieces of the perioperative puzzle are which coronary vessel the stent was implanted in; when the stent was implanted; what drug, if any (sirolimus or paclitaxel) is eluted by the stent; whether there were surgical or postoperative complications; prior history of stent thrombosis; the patient’s comorbidities; duration of dual-antiplatelet therapy; and how the patient has fared on therapy.
Prior to an elective noncardiac procedure, clinicians must consider patient risk factors, including indication for antithrombotic therapy, risk factors for thrombosis or thromboembolism, and type of antithrombotic agent; and surgical risk factors, including type of procedure, bleeding risk, thromboembolism risk, and time off antithrombotic therapy.
When to stop antithrombotic agents
Dr. Jaffer noted that because aspirin is an irreversible inhibitor of platelet cyclooxygenase and the circulating platelet pool is replaced every 7 to 10 days, patients on aspirin as part of their dual-antiplatelet therapy should stop taking the drug from 7 to 10 days before scheduled surgery.
Thienopyridines/P2Y12 receptor antagonists such as clopidogrel (Plavix) and ticagrelor (Brilinta) work by inhibiting adenosine diphosphate (ADP) receptor-mediated platelet activation and aggregation. Dr. Jaffer said that although guidelines recommend stopping these agents 7 days before surgery, there is evidence to suggest that 5 days may be a sufficient window of safety.
It is also important to take into consideration the pharmacokinetic profiles of the specific antiplatelet agents. For example, ticagrelor has a more rapid onset and greater degree of platelet-aggregation inhibition than clopidogrel, although the time from stopping each agent until the return to near-baseline platelet aggregation is similar, on the order of about 120 hours (5 days) or longer, he said.
Risk varies by surgery type
The type of surgery is also important, as certain procedures – such as neurocranial surgery, spinal canal surgery, and procedures performed in the posterior chamber of the eye – carry a high risk for hemorrhage and are likely to require blood transfusions.
Dr. Jaffer noted that in 2007, the American College of Cardiology and American Heart Association issued a joint advisory on antiplatelet therapy and noncardiac surgery, which warned health care providers about the potentially catastrophic risks of stopping thienopyridines prematurely, which could result in acute stent thrombosis, myocardial infarction, and death. The guidelines recommend waiting a minimum of 6 weeks for noncardiac surgery following implantation of a bare-metal stent, and 1 year after a drug-eluting stent.
He pointed to two studies from the Mayo Clinic published in 2008. The first study showed that the risk of major cardiac adverse events among patients with a bare-metal stent undergoing noncardiac surgery within 30 days of stent placement was approximately 10%, but diminished to 2.7% at 91 days after placement (Anesthesiology 2008;109:588-95). The second study showed that the risk of major cardiac adverse events was 6.1% within 90 days after implantation of a drug-eluting stent, with the risk dwindling to 3.1% after 1 year (Anesthesiology 2008;109:596-604).
If urgent surgery such as a hemicolectomy for colon cancer is required within 6 months of drug-eluting stent implantation, the patient should continue on dual-antiplatelet therapy, Dr. Jaffer said. If the surgery is from 6 months to 1 year after implantation in these patients, the patient should be continued on at least 81 mg aspirin, but if the patient is taking clopidogrel, he or she should have the thienopyridine discontinued 5 days before surgery and the drug resumed as soon as possible after surgery with a 300-mg loading dose, followed by 75 mg daily. If the patient is not yet able to eat, the dual-antiplatelet therapy should be delivered via nasogastric tube, he said.
Dr. Jaffer reported serving as a consultant to Boehringer Ingelheim, Janssen Pharmaceuticals, and other companies. Dr. Jaffer also serves on the editorial advisory board of Hospitalist News.
SCOTTSDALE, ARIZ. – The presence of a coronary artery stent is not a barrier to noncardiac surgery, but it may change the timing of surgery and perioperative management of the patient, a hospitalist cautions.
Patients who receive bare-metal stents should delay having elective surgery for at least 6 weeks after stent placement, and those who receive a drug-eluting stent should put off elective procedures for at least a year, said Dr. Amir K. Jaffer, professor of medicine and chief of the division of hospital medicine at Rush University Medical Center in Chicago.
The type of stent, its placement, and the time since placement are just some of the key pieces of information that clinicians need to manage patients, Dr. Jaffer said at a meeting on perioperative medicine sponsored by the University of Miami.
"You want to try to get that [information] card if you can from the patient, about where the stents were placed, and if they don’t have the card handy, you really need to go to the procedure note, because the patient may or may not know if it was a drug-eluting stent," he said.
Other vital pieces of the perioperative puzzle are which coronary vessel the stent was implanted in; when the stent was implanted; what drug, if any (sirolimus or paclitaxel) is eluted by the stent; whether there were surgical or postoperative complications; prior history of stent thrombosis; the patient’s comorbidities; duration of dual-antiplatelet therapy; and how the patient has fared on therapy.
Prior to an elective noncardiac procedure, clinicians must consider patient risk factors, including indication for antithrombotic therapy, risk factors for thrombosis or thromboembolism, and type of antithrombotic agent; and surgical risk factors, including type of procedure, bleeding risk, thromboembolism risk, and time off antithrombotic therapy.
When to stop antithrombotic agents
Dr. Jaffer noted that because aspirin is an irreversible inhibitor of platelet cyclooxygenase and the circulating platelet pool is replaced every 7 to 10 days, patients on aspirin as part of their dual-antiplatelet therapy should stop taking the drug from 7 to 10 days before scheduled surgery.
Thienopyridines/P2Y12 receptor antagonists such as clopidogrel (Plavix) and ticagrelor (Brilinta) work by inhibiting adenosine diphosphate (ADP) receptor-mediated platelet activation and aggregation. Dr. Jaffer said that although guidelines recommend stopping these agents 7 days before surgery, there is evidence to suggest that 5 days may be a sufficient window of safety.
It is also important to take into consideration the pharmacokinetic profiles of the specific antiplatelet agents. For example, ticagrelor has a more rapid onset and greater degree of platelet-aggregation inhibition than clopidogrel, although the time from stopping each agent until the return to near-baseline platelet aggregation is similar, on the order of about 120 hours (5 days) or longer, he said.
Risk varies by surgery type
The type of surgery is also important, as certain procedures – such as neurocranial surgery, spinal canal surgery, and procedures performed in the posterior chamber of the eye – carry a high risk for hemorrhage and are likely to require blood transfusions.
Dr. Jaffer noted that in 2007, the American College of Cardiology and American Heart Association issued a joint advisory on antiplatelet therapy and noncardiac surgery, which warned health care providers about the potentially catastrophic risks of stopping thienopyridines prematurely, which could result in acute stent thrombosis, myocardial infarction, and death. The guidelines recommend waiting a minimum of 6 weeks for noncardiac surgery following implantation of a bare-metal stent, and 1 year after a drug-eluting stent.
He pointed to two studies from the Mayo Clinic published in 2008. The first study showed that the risk of major cardiac adverse events among patients with a bare-metal stent undergoing noncardiac surgery within 30 days of stent placement was approximately 10%, but diminished to 2.7% at 91 days after placement (Anesthesiology 2008;109:588-95). The second study showed that the risk of major cardiac adverse events was 6.1% within 90 days after implantation of a drug-eluting stent, with the risk dwindling to 3.1% after 1 year (Anesthesiology 2008;109:596-604).
If urgent surgery such as a hemicolectomy for colon cancer is required within 6 months of drug-eluting stent implantation, the patient should continue on dual-antiplatelet therapy, Dr. Jaffer said. If the surgery is from 6 months to 1 year after implantation in these patients, the patient should be continued on at least 81 mg aspirin, but if the patient is taking clopidogrel, he or she should have the thienopyridine discontinued 5 days before surgery and the drug resumed as soon as possible after surgery with a 300-mg loading dose, followed by 75 mg daily. If the patient is not yet able to eat, the dual-antiplatelet therapy should be delivered via nasogastric tube, he said.
Dr. Jaffer reported serving as a consultant to Boehringer Ingelheim, Janssen Pharmaceuticals, and other companies. Dr. Jaffer also serves on the editorial advisory board of Hospitalist News.
SCOTTSDALE, ARIZ. – The presence of a coronary artery stent is not a barrier to noncardiac surgery, but it may change the timing of surgery and perioperative management of the patient, a hospitalist cautions.
Patients who receive bare-metal stents should delay having elective surgery for at least 6 weeks after stent placement, and those who receive a drug-eluting stent should put off elective procedures for at least a year, said Dr. Amir K. Jaffer, professor of medicine and chief of the division of hospital medicine at Rush University Medical Center in Chicago.
The type of stent, its placement, and the time since placement are just some of the key pieces of information that clinicians need to manage patients, Dr. Jaffer said at a meeting on perioperative medicine sponsored by the University of Miami.
"You want to try to get that [information] card if you can from the patient, about where the stents were placed, and if they don’t have the card handy, you really need to go to the procedure note, because the patient may or may not know if it was a drug-eluting stent," he said.
Other vital pieces of the perioperative puzzle are which coronary vessel the stent was implanted in; when the stent was implanted; what drug, if any (sirolimus or paclitaxel) is eluted by the stent; whether there were surgical or postoperative complications; prior history of stent thrombosis; the patient’s comorbidities; duration of dual-antiplatelet therapy; and how the patient has fared on therapy.
Prior to an elective noncardiac procedure, clinicians must consider patient risk factors, including indication for antithrombotic therapy, risk factors for thrombosis or thromboembolism, and type of antithrombotic agent; and surgical risk factors, including type of procedure, bleeding risk, thromboembolism risk, and time off antithrombotic therapy.
When to stop antithrombotic agents
Dr. Jaffer noted that because aspirin is an irreversible inhibitor of platelet cyclooxygenase and the circulating platelet pool is replaced every 7 to 10 days, patients on aspirin as part of their dual-antiplatelet therapy should stop taking the drug from 7 to 10 days before scheduled surgery.
Thienopyridines/P2Y12 receptor antagonists such as clopidogrel (Plavix) and ticagrelor (Brilinta) work by inhibiting adenosine diphosphate (ADP) receptor-mediated platelet activation and aggregation. Dr. Jaffer said that although guidelines recommend stopping these agents 7 days before surgery, there is evidence to suggest that 5 days may be a sufficient window of safety.
It is also important to take into consideration the pharmacokinetic profiles of the specific antiplatelet agents. For example, ticagrelor has a more rapid onset and greater degree of platelet-aggregation inhibition than clopidogrel, although the time from stopping each agent until the return to near-baseline platelet aggregation is similar, on the order of about 120 hours (5 days) or longer, he said.
Risk varies by surgery type
The type of surgery is also important, as certain procedures – such as neurocranial surgery, spinal canal surgery, and procedures performed in the posterior chamber of the eye – carry a high risk for hemorrhage and are likely to require blood transfusions.
Dr. Jaffer noted that in 2007, the American College of Cardiology and American Heart Association issued a joint advisory on antiplatelet therapy and noncardiac surgery, which warned health care providers about the potentially catastrophic risks of stopping thienopyridines prematurely, which could result in acute stent thrombosis, myocardial infarction, and death. The guidelines recommend waiting a minimum of 6 weeks for noncardiac surgery following implantation of a bare-metal stent, and 1 year after a drug-eluting stent.
He pointed to two studies from the Mayo Clinic published in 2008. The first study showed that the risk of major cardiac adverse events among patients with a bare-metal stent undergoing noncardiac surgery within 30 days of stent placement was approximately 10%, but diminished to 2.7% at 91 days after placement (Anesthesiology 2008;109:588-95). The second study showed that the risk of major cardiac adverse events was 6.1% within 90 days after implantation of a drug-eluting stent, with the risk dwindling to 3.1% after 1 year (Anesthesiology 2008;109:596-604).
If urgent surgery such as a hemicolectomy for colon cancer is required within 6 months of drug-eluting stent implantation, the patient should continue on dual-antiplatelet therapy, Dr. Jaffer said. If the surgery is from 6 months to 1 year after implantation in these patients, the patient should be continued on at least 81 mg aspirin, but if the patient is taking clopidogrel, he or she should have the thienopyridine discontinued 5 days before surgery and the drug resumed as soon as possible after surgery with a 300-mg loading dose, followed by 75 mg daily. If the patient is not yet able to eat, the dual-antiplatelet therapy should be delivered via nasogastric tube, he said.
Dr. Jaffer reported serving as a consultant to Boehringer Ingelheim, Janssen Pharmaceuticals, and other companies. Dr. Jaffer also serves on the editorial advisory board of Hospitalist News.
EXPERT ANALYSIS FROM THE PERIOPERATIVE MEDICINE SUMMIT
Major finding: Elective noncardiac surgery should be delayed for at least 6 weeks following implantation of a bare-metal stent, and 1 year after implantation of a drug-eluting stent.
Data source: Evidence-based review of data on the risk of adverse events following noncardiac surgery in patients with coronary artery stents.
Disclosures: Dr. Jaffer reported serving as a consultant to Boehringer Ingelheim, Janssen Pharmaceuticals, and other companies. Dr. Jaffer also serves on the editorial advisory board of Hospitalist News.
Strong nerves, teamwork key in managing neurosurgical patients, devices
SCOTTSDALE, ARIZ. – Comanaging neurosurgical patients requires a delicate dance between primary practitioners, surgeons, anesthesiologists, and, in some cases, the makers of implantable neurostimulators, according to perioperative medicine specialists.
Special considerations with patients scheduled for neurosurgical procedures include hypertension, fever, hyponatremia, and risk of deep vein thromboembolism (DVT) and coagulopathies, said Dr. Richard Huh, director of the inpatient medical consultation service at Rush University Medical Center in Chicago, at a meeting on perioperative medicine sponsored by the University of Miami.
For example, hospitalists are typically involved in the management of blood pressure in neurosurgery patients because of the importance of controlling intracranial pressure, Dr. Huh noted.
"The trick is for the blood pressure not to get too high or too low. The Handbook of Neurosurgery suggests a goal of 140 over 90 [mm Hg]," he said.
Patients with acute subarachnoid hemorrhage are at risk for vasospasm, most frequently within 7-10 days of hemorrhage. Hypovolemia is a common cause of vasospasm and should be avoided. Medications such as nimodipine (Nimotop) can help prevent this complication.
Patients undergoing spinal procedures tend to have low blood pressure from acute blood loss or intravenous pain medications, and may require hold parameters on medications to avoid complications from hypotension.
However, on the day following spinal surgery, some patients develop hypertension, and may require additional medications for BP control.
Hyponatremia
The reported prevalence of hyponatremia in hospitalized patients ranges from 1%-7%, and the rate is even higher in neurosurgical patients, possibility because the brain’s response to changes in osmolality. Clinicians managing neurosurgical patients should be aware of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting, Dr. Huh said.
Cerebral salt wasting may be cause by damaged brain cells that affect sympathetic neural input to the kidneys, decreasing sodium resorption and an increase in atrial natriuretic peptide and brain natriuretic peptide.
The syndrome looks similar to SIADH, with high urinary sodium and osmolality, low serum osmolality, and decreased serum uric acid. But cerebral salt wasting is distinguished from SIADH by the presence of hypovolemia. Cerebral salt wasting is treated with saline and/or salt tablets.
DVT
Neurosurgical patients are at increased risk for DVT and pulmonary embolism compared with the general postoperative population. However, 2012 guidelines on antithrombotic therapy from the American College of Chest Physicians recommend against pharmacologic prophylaxis except for high risk patients, such as patients with intracranial masses. Dr. Huh said.
Implantable neurostimulators
Patients with implanted devices such as deep-brain stimulators for control of Parkinson’s disease, hypoglossal nerve stimulators for severe sleep apnea, or vagal nerve stimulators for epilepsy also require special consideration throughout the perioperative period.
Issues to consider when managing a patient with an implantable device include the device site and its proximity to the planned surgical field, indication for the device, comorbidities, and the patient’s goals for treatment, said Dr. Deborah Richman, section chief of preoperative services at Stony Brook (New York) University Medical Center.
"What do we do with device itself? This is a team approach, and we find that it’s best coordinated by our nurses in the preop holding area, because they know what time the surgery is, they have the device company rep’s phone number, they make sure the patient is there on time, and they put everything together to prevent delays on the day of surgery," she said.
In general, device manufacturers recommend turning devices off, and to turn the amplitude down to zero to prevent accidental activation of magnetic on-off switches.
The distance from the surgery to the pulse generator should be a minimum of 20 cm, and electrocautery, if used, should be bipolar rather than monopolar, Dr. Richman said.
Patients with implanted devices will also require prophylactic antibiotics to prevent potential bacterial seeding of the device or leads, she said,
Coordination of perioperative care "is best done with clinical management pathways, so that when you have one of these patients who present to you, you have a checklist that includes the device company’s phone number, and it’s an easy go-to, so that you don’t have to start from scratch each time," she concluded.
Dr. Huh and Dr. Richman reported having no financial disclosures.
SCOTTSDALE, ARIZ. – Comanaging neurosurgical patients requires a delicate dance between primary practitioners, surgeons, anesthesiologists, and, in some cases, the makers of implantable neurostimulators, according to perioperative medicine specialists.
Special considerations with patients scheduled for neurosurgical procedures include hypertension, fever, hyponatremia, and risk of deep vein thromboembolism (DVT) and coagulopathies, said Dr. Richard Huh, director of the inpatient medical consultation service at Rush University Medical Center in Chicago, at a meeting on perioperative medicine sponsored by the University of Miami.
For example, hospitalists are typically involved in the management of blood pressure in neurosurgery patients because of the importance of controlling intracranial pressure, Dr. Huh noted.
"The trick is for the blood pressure not to get too high or too low. The Handbook of Neurosurgery suggests a goal of 140 over 90 [mm Hg]," he said.
Patients with acute subarachnoid hemorrhage are at risk for vasospasm, most frequently within 7-10 days of hemorrhage. Hypovolemia is a common cause of vasospasm and should be avoided. Medications such as nimodipine (Nimotop) can help prevent this complication.
Patients undergoing spinal procedures tend to have low blood pressure from acute blood loss or intravenous pain medications, and may require hold parameters on medications to avoid complications from hypotension.
However, on the day following spinal surgery, some patients develop hypertension, and may require additional medications for BP control.
Hyponatremia
The reported prevalence of hyponatremia in hospitalized patients ranges from 1%-7%, and the rate is even higher in neurosurgical patients, possibility because the brain’s response to changes in osmolality. Clinicians managing neurosurgical patients should be aware of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting, Dr. Huh said.
Cerebral salt wasting may be cause by damaged brain cells that affect sympathetic neural input to the kidneys, decreasing sodium resorption and an increase in atrial natriuretic peptide and brain natriuretic peptide.
The syndrome looks similar to SIADH, with high urinary sodium and osmolality, low serum osmolality, and decreased serum uric acid. But cerebral salt wasting is distinguished from SIADH by the presence of hypovolemia. Cerebral salt wasting is treated with saline and/or salt tablets.
DVT
Neurosurgical patients are at increased risk for DVT and pulmonary embolism compared with the general postoperative population. However, 2012 guidelines on antithrombotic therapy from the American College of Chest Physicians recommend against pharmacologic prophylaxis except for high risk patients, such as patients with intracranial masses. Dr. Huh said.
Implantable neurostimulators
Patients with implanted devices such as deep-brain stimulators for control of Parkinson’s disease, hypoglossal nerve stimulators for severe sleep apnea, or vagal nerve stimulators for epilepsy also require special consideration throughout the perioperative period.
Issues to consider when managing a patient with an implantable device include the device site and its proximity to the planned surgical field, indication for the device, comorbidities, and the patient’s goals for treatment, said Dr. Deborah Richman, section chief of preoperative services at Stony Brook (New York) University Medical Center.
"What do we do with device itself? This is a team approach, and we find that it’s best coordinated by our nurses in the preop holding area, because they know what time the surgery is, they have the device company rep’s phone number, they make sure the patient is there on time, and they put everything together to prevent delays on the day of surgery," she said.
In general, device manufacturers recommend turning devices off, and to turn the amplitude down to zero to prevent accidental activation of magnetic on-off switches.
The distance from the surgery to the pulse generator should be a minimum of 20 cm, and electrocautery, if used, should be bipolar rather than monopolar, Dr. Richman said.
Patients with implanted devices will also require prophylactic antibiotics to prevent potential bacterial seeding of the device or leads, she said,
Coordination of perioperative care "is best done with clinical management pathways, so that when you have one of these patients who present to you, you have a checklist that includes the device company’s phone number, and it’s an easy go-to, so that you don’t have to start from scratch each time," she concluded.
Dr. Huh and Dr. Richman reported having no financial disclosures.
SCOTTSDALE, ARIZ. – Comanaging neurosurgical patients requires a delicate dance between primary practitioners, surgeons, anesthesiologists, and, in some cases, the makers of implantable neurostimulators, according to perioperative medicine specialists.
Special considerations with patients scheduled for neurosurgical procedures include hypertension, fever, hyponatremia, and risk of deep vein thromboembolism (DVT) and coagulopathies, said Dr. Richard Huh, director of the inpatient medical consultation service at Rush University Medical Center in Chicago, at a meeting on perioperative medicine sponsored by the University of Miami.
For example, hospitalists are typically involved in the management of blood pressure in neurosurgery patients because of the importance of controlling intracranial pressure, Dr. Huh noted.
"The trick is for the blood pressure not to get too high or too low. The Handbook of Neurosurgery suggests a goal of 140 over 90 [mm Hg]," he said.
Patients with acute subarachnoid hemorrhage are at risk for vasospasm, most frequently within 7-10 days of hemorrhage. Hypovolemia is a common cause of vasospasm and should be avoided. Medications such as nimodipine (Nimotop) can help prevent this complication.
Patients undergoing spinal procedures tend to have low blood pressure from acute blood loss or intravenous pain medications, and may require hold parameters on medications to avoid complications from hypotension.
However, on the day following spinal surgery, some patients develop hypertension, and may require additional medications for BP control.
Hyponatremia
The reported prevalence of hyponatremia in hospitalized patients ranges from 1%-7%, and the rate is even higher in neurosurgical patients, possibility because the brain’s response to changes in osmolality. Clinicians managing neurosurgical patients should be aware of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting, Dr. Huh said.
Cerebral salt wasting may be cause by damaged brain cells that affect sympathetic neural input to the kidneys, decreasing sodium resorption and an increase in atrial natriuretic peptide and brain natriuretic peptide.
The syndrome looks similar to SIADH, with high urinary sodium and osmolality, low serum osmolality, and decreased serum uric acid. But cerebral salt wasting is distinguished from SIADH by the presence of hypovolemia. Cerebral salt wasting is treated with saline and/or salt tablets.
DVT
Neurosurgical patients are at increased risk for DVT and pulmonary embolism compared with the general postoperative population. However, 2012 guidelines on antithrombotic therapy from the American College of Chest Physicians recommend against pharmacologic prophylaxis except for high risk patients, such as patients with intracranial masses. Dr. Huh said.
Implantable neurostimulators
Patients with implanted devices such as deep-brain stimulators for control of Parkinson’s disease, hypoglossal nerve stimulators for severe sleep apnea, or vagal nerve stimulators for epilepsy also require special consideration throughout the perioperative period.
Issues to consider when managing a patient with an implantable device include the device site and its proximity to the planned surgical field, indication for the device, comorbidities, and the patient’s goals for treatment, said Dr. Deborah Richman, section chief of preoperative services at Stony Brook (New York) University Medical Center.
"What do we do with device itself? This is a team approach, and we find that it’s best coordinated by our nurses in the preop holding area, because they know what time the surgery is, they have the device company rep’s phone number, they make sure the patient is there on time, and they put everything together to prevent delays on the day of surgery," she said.
In general, device manufacturers recommend turning devices off, and to turn the amplitude down to zero to prevent accidental activation of magnetic on-off switches.
The distance from the surgery to the pulse generator should be a minimum of 20 cm, and electrocautery, if used, should be bipolar rather than monopolar, Dr. Richman said.
Patients with implanted devices will also require prophylactic antibiotics to prevent potential bacterial seeding of the device or leads, she said,
Coordination of perioperative care "is best done with clinical management pathways, so that when you have one of these patients who present to you, you have a checklist that includes the device company’s phone number, and it’s an easy go-to, so that you don’t have to start from scratch each time," she concluded.
Dr. Huh and Dr. Richman reported having no financial disclosures.
AT THE PERIOPERATIVE MEDICINE SUMMIT
Major finding: Neurosurgical procedures are associated with increased risk for complications, such as hyponatremia and deep vein thromboembolism, compared with general surgeries.
Data source: Reviews of recommendations on the perioperative management of neurosurgical patients and those with implanted neurostimulating devices.
Disclosures: Dr. Huh and Dr. Richman reported having no financial disclosures.
Hold the immunomodulators for surgery? Maybe yes, maybe no
SCOTTSDALE, ARIZ. – When patients on immunosuppressive therapies need surgery, the risks of disease flare and compromised postoperative recovery and rehabilitation must be weighed against the risk of increased infections and impaired wound healing.
"I’m not sure that there is necessarily a right answer, but I think most people would stop biologic [agents] beforehand," Dr. Paul Grant said at a meeting on perioperative medicine sponsored by the University of Miami.
The decision whether to suspend a disease-modifying antirheumatic drug before surgery may depend on the individual drug and on the patient, said Dr. Grant, director of perioperative and consultative medicine at the University of Michigan Health System in Ann Arbor.
For example, it appears to be safe for patients on methotrexate to continue on therapy during elective orthopedic surgery. Evidence for this comes from a randomized clinical trial in which patients with rheumatoid arthritis (RA) were assigned to either continue on methotrexate (MTX) or suspend taking it for 2 weeks before and 2 weeks after surgery. The study also contained a control of patients with RA who were not on MTX (Ann. Rheum. Dis. 2001;60:214-7).
The investigators found that there were no significant differences in early complication rates or in complications up to 1 year of follow-up between patients who suspended or remained on MTX. Patients who stayed on the drug had significantly lower rates of RA flare.
Additionally, two systematic reviews, one looking at eight studies echoes the findings of the aforementioned randomized trial, and the other looking at four studies, in which the reviewer concluded that "continued MTX therapy appears to be safe perioperatively and seems also to be associated with a reduced risk of flares (Clin. Exp. Rheumatol. 2009;27:856-62) (Clin. Rheumatol. 2008;27:1217-20).None of the examined papers addresses the issue of safety in connection with comorbidities, age, or high doses of methotrexate."
"The bottom line here is that methotrexate should be continued for most surgeries. I think it might be reasonable to hold it in certain situations, for example if the patient has pretty bad kidney or liver disease, or if it’s surgery to treat a major infection," Dr. Grant said.
TNF-alpha antagonists
In contrast, the data on tumor necrosis factor–alpha (TNF-alpha) antagonists are fuzzier, with limited and conflicting information on perioperative use of these agents (etanercept, infliximab, adalimumab, certolizumab, golimumab).
"The major concern with these drugs is infection," Dr. Grant said. He pointed to a meta-analysis published in JAMA in 2006, which showed that taking the drugs doubled the risk of serious infections in general. The study did not specifically look at perioperative use of TNF-alpha antagonists (JAMA 2006;295:2275-85).
A retrospective cohort studyof 127 patients with RA who were undergoing various orthopedic procedures found that there were no differences in surgical site infections but more cases of wound dehiscence in patients who continued on the drugs, compared with those who interrupted their use perioperatively (Clin. Exp. Rheumatol. 2007;25:430-6).
A second, prospective study in 31 patients with RA undergoing foot/ankle surgery found that there were no significant differences in infection or healing between patients who interrupted therapy and those who did not (Foot Ankle Clin. 2007;12:509-24).
Other studies and systematic reviews in patients with RA or Crohn’s disease generally found no significant differences in serious infection rates, but they did detect a higher incidence of skin and soft-tissue infections among patients on anti-TNF-alpha agents vs. other disease-modifying antirheumatic drugs.
The risk of infections tends to be highest at the start of therapy with a TNF-alpha antagonist and stopping therapy is more likely to result in RA flares among patients with established disease, compared with those in the early stages of RA. Therefore, TNF blocker therapy should be restarted as soon as possible after surgery to prevent flare, Dr. Grant said.
The American College of Rheumatology and British Society of Rheumatology recommend holding TNF-alpha antagonists for one dosing cycle before major surgery. For etanercept (Enbrel), that translates to a 1-week before surgery hold, for infliximab (Remicade) 6-8 weeks, and for adalimumab (Humira) 2 weeks. These agents should also be held for 10-14 days after surgery or until wound healing is satisfactory.
"It’s probably safe to continue these medications for minor surgeries," Dr. Grant said.
Other agents
The anti-CD20 agent rituximab (Rituxan) – currently used to treat RA, vasculitis, hematologic malignancies, and other conditions – has a lower risk for bacterial infections than does TNF-alpha antagonists and has been shown to be safe in patients with a history of recurrent bacterial infections.
"Hydroxychloroquine (or Plaquenil) is felt to be safe during the preoperative period. It is recommended to continue this medication without stopping," Dr. Grant said.
There is conflicting information on infection risk with the use leflunomide (Arava), but it may be wise to stop therapy 2-4 weeks before nonurgent surgery in higher-risk patients.
There is consensus that sulfasalazine (Azulfidine) and azathioprine (Imuran) can be safely continued perioperatively, he said, although some advise holding sulfasalazine on the day of surgery.
Regarding perioperative steroids, Dr. Grant recommended determining the patient’s steroid exposure over the past year.
"Stress dose steroids are not routinely needed as long as the patients continue their normal dose. That’s really the important piece: If someone’s taking prednisone every day, make sure they take at least that dose on the day of surgery," he said.
Dr. Grant reported having no financial disclosures.
SCOTTSDALE, ARIZ. – When patients on immunosuppressive therapies need surgery, the risks of disease flare and compromised postoperative recovery and rehabilitation must be weighed against the risk of increased infections and impaired wound healing.
"I’m not sure that there is necessarily a right answer, but I think most people would stop biologic [agents] beforehand," Dr. Paul Grant said at a meeting on perioperative medicine sponsored by the University of Miami.
The decision whether to suspend a disease-modifying antirheumatic drug before surgery may depend on the individual drug and on the patient, said Dr. Grant, director of perioperative and consultative medicine at the University of Michigan Health System in Ann Arbor.
For example, it appears to be safe for patients on methotrexate to continue on therapy during elective orthopedic surgery. Evidence for this comes from a randomized clinical trial in which patients with rheumatoid arthritis (RA) were assigned to either continue on methotrexate (MTX) or suspend taking it for 2 weeks before and 2 weeks after surgery. The study also contained a control of patients with RA who were not on MTX (Ann. Rheum. Dis. 2001;60:214-7).
The investigators found that there were no significant differences in early complication rates or in complications up to 1 year of follow-up between patients who suspended or remained on MTX. Patients who stayed on the drug had significantly lower rates of RA flare.
Additionally, two systematic reviews, one looking at eight studies echoes the findings of the aforementioned randomized trial, and the other looking at four studies, in which the reviewer concluded that "continued MTX therapy appears to be safe perioperatively and seems also to be associated with a reduced risk of flares (Clin. Exp. Rheumatol. 2009;27:856-62) (Clin. Rheumatol. 2008;27:1217-20).None of the examined papers addresses the issue of safety in connection with comorbidities, age, or high doses of methotrexate."
"The bottom line here is that methotrexate should be continued for most surgeries. I think it might be reasonable to hold it in certain situations, for example if the patient has pretty bad kidney or liver disease, or if it’s surgery to treat a major infection," Dr. Grant said.
TNF-alpha antagonists
In contrast, the data on tumor necrosis factor–alpha (TNF-alpha) antagonists are fuzzier, with limited and conflicting information on perioperative use of these agents (etanercept, infliximab, adalimumab, certolizumab, golimumab).
"The major concern with these drugs is infection," Dr. Grant said. He pointed to a meta-analysis published in JAMA in 2006, which showed that taking the drugs doubled the risk of serious infections in general. The study did not specifically look at perioperative use of TNF-alpha antagonists (JAMA 2006;295:2275-85).
A retrospective cohort studyof 127 patients with RA who were undergoing various orthopedic procedures found that there were no differences in surgical site infections but more cases of wound dehiscence in patients who continued on the drugs, compared with those who interrupted their use perioperatively (Clin. Exp. Rheumatol. 2007;25:430-6).
A second, prospective study in 31 patients with RA undergoing foot/ankle surgery found that there were no significant differences in infection or healing between patients who interrupted therapy and those who did not (Foot Ankle Clin. 2007;12:509-24).
Other studies and systematic reviews in patients with RA or Crohn’s disease generally found no significant differences in serious infection rates, but they did detect a higher incidence of skin and soft-tissue infections among patients on anti-TNF-alpha agents vs. other disease-modifying antirheumatic drugs.
The risk of infections tends to be highest at the start of therapy with a TNF-alpha antagonist and stopping therapy is more likely to result in RA flares among patients with established disease, compared with those in the early stages of RA. Therefore, TNF blocker therapy should be restarted as soon as possible after surgery to prevent flare, Dr. Grant said.
The American College of Rheumatology and British Society of Rheumatology recommend holding TNF-alpha antagonists for one dosing cycle before major surgery. For etanercept (Enbrel), that translates to a 1-week before surgery hold, for infliximab (Remicade) 6-8 weeks, and for adalimumab (Humira) 2 weeks. These agents should also be held for 10-14 days after surgery or until wound healing is satisfactory.
"It’s probably safe to continue these medications for minor surgeries," Dr. Grant said.
Other agents
The anti-CD20 agent rituximab (Rituxan) – currently used to treat RA, vasculitis, hematologic malignancies, and other conditions – has a lower risk for bacterial infections than does TNF-alpha antagonists and has been shown to be safe in patients with a history of recurrent bacterial infections.
"Hydroxychloroquine (or Plaquenil) is felt to be safe during the preoperative period. It is recommended to continue this medication without stopping," Dr. Grant said.
There is conflicting information on infection risk with the use leflunomide (Arava), but it may be wise to stop therapy 2-4 weeks before nonurgent surgery in higher-risk patients.
There is consensus that sulfasalazine (Azulfidine) and azathioprine (Imuran) can be safely continued perioperatively, he said, although some advise holding sulfasalazine on the day of surgery.
Regarding perioperative steroids, Dr. Grant recommended determining the patient’s steroid exposure over the past year.
"Stress dose steroids are not routinely needed as long as the patients continue their normal dose. That’s really the important piece: If someone’s taking prednisone every day, make sure they take at least that dose on the day of surgery," he said.
Dr. Grant reported having no financial disclosures.
SCOTTSDALE, ARIZ. – When patients on immunosuppressive therapies need surgery, the risks of disease flare and compromised postoperative recovery and rehabilitation must be weighed against the risk of increased infections and impaired wound healing.
"I’m not sure that there is necessarily a right answer, but I think most people would stop biologic [agents] beforehand," Dr. Paul Grant said at a meeting on perioperative medicine sponsored by the University of Miami.
The decision whether to suspend a disease-modifying antirheumatic drug before surgery may depend on the individual drug and on the patient, said Dr. Grant, director of perioperative and consultative medicine at the University of Michigan Health System in Ann Arbor.
For example, it appears to be safe for patients on methotrexate to continue on therapy during elective orthopedic surgery. Evidence for this comes from a randomized clinical trial in which patients with rheumatoid arthritis (RA) were assigned to either continue on methotrexate (MTX) or suspend taking it for 2 weeks before and 2 weeks after surgery. The study also contained a control of patients with RA who were not on MTX (Ann. Rheum. Dis. 2001;60:214-7).
The investigators found that there were no significant differences in early complication rates or in complications up to 1 year of follow-up between patients who suspended or remained on MTX. Patients who stayed on the drug had significantly lower rates of RA flare.
Additionally, two systematic reviews, one looking at eight studies echoes the findings of the aforementioned randomized trial, and the other looking at four studies, in which the reviewer concluded that "continued MTX therapy appears to be safe perioperatively and seems also to be associated with a reduced risk of flares (Clin. Exp. Rheumatol. 2009;27:856-62) (Clin. Rheumatol. 2008;27:1217-20).None of the examined papers addresses the issue of safety in connection with comorbidities, age, or high doses of methotrexate."
"The bottom line here is that methotrexate should be continued for most surgeries. I think it might be reasonable to hold it in certain situations, for example if the patient has pretty bad kidney or liver disease, or if it’s surgery to treat a major infection," Dr. Grant said.
TNF-alpha antagonists
In contrast, the data on tumor necrosis factor–alpha (TNF-alpha) antagonists are fuzzier, with limited and conflicting information on perioperative use of these agents (etanercept, infliximab, adalimumab, certolizumab, golimumab).
"The major concern with these drugs is infection," Dr. Grant said. He pointed to a meta-analysis published in JAMA in 2006, which showed that taking the drugs doubled the risk of serious infections in general. The study did not specifically look at perioperative use of TNF-alpha antagonists (JAMA 2006;295:2275-85).
A retrospective cohort studyof 127 patients with RA who were undergoing various orthopedic procedures found that there were no differences in surgical site infections but more cases of wound dehiscence in patients who continued on the drugs, compared with those who interrupted their use perioperatively (Clin. Exp. Rheumatol. 2007;25:430-6).
A second, prospective study in 31 patients with RA undergoing foot/ankle surgery found that there were no significant differences in infection or healing between patients who interrupted therapy and those who did not (Foot Ankle Clin. 2007;12:509-24).
Other studies and systematic reviews in patients with RA or Crohn’s disease generally found no significant differences in serious infection rates, but they did detect a higher incidence of skin and soft-tissue infections among patients on anti-TNF-alpha agents vs. other disease-modifying antirheumatic drugs.
The risk of infections tends to be highest at the start of therapy with a TNF-alpha antagonist and stopping therapy is more likely to result in RA flares among patients with established disease, compared with those in the early stages of RA. Therefore, TNF blocker therapy should be restarted as soon as possible after surgery to prevent flare, Dr. Grant said.
The American College of Rheumatology and British Society of Rheumatology recommend holding TNF-alpha antagonists for one dosing cycle before major surgery. For etanercept (Enbrel), that translates to a 1-week before surgery hold, for infliximab (Remicade) 6-8 weeks, and for adalimumab (Humira) 2 weeks. These agents should also be held for 10-14 days after surgery or until wound healing is satisfactory.
"It’s probably safe to continue these medications for minor surgeries," Dr. Grant said.
Other agents
The anti-CD20 agent rituximab (Rituxan) – currently used to treat RA, vasculitis, hematologic malignancies, and other conditions – has a lower risk for bacterial infections than does TNF-alpha antagonists and has been shown to be safe in patients with a history of recurrent bacterial infections.
"Hydroxychloroquine (or Plaquenil) is felt to be safe during the preoperative period. It is recommended to continue this medication without stopping," Dr. Grant said.
There is conflicting information on infection risk with the use leflunomide (Arava), but it may be wise to stop therapy 2-4 weeks before nonurgent surgery in higher-risk patients.
There is consensus that sulfasalazine (Azulfidine) and azathioprine (Imuran) can be safely continued perioperatively, he said, although some advise holding sulfasalazine on the day of surgery.
Regarding perioperative steroids, Dr. Grant recommended determining the patient’s steroid exposure over the past year.
"Stress dose steroids are not routinely needed as long as the patients continue their normal dose. That’s really the important piece: If someone’s taking prednisone every day, make sure they take at least that dose on the day of surgery," he said.
Dr. Grant reported having no financial disclosures.
AT THE PERIOPERATIVE MEDICINE SUMMIT
Major finding: Some immunomodulating agents for inflammatory and autoimmune diseases can be safely continued in the perioperative period.
Data source: A review of evidence on the use of various immunomodulators.
Disclosures: Dr. Grant reported having no financial disclosures.
Defining patients’ risk helps prevent postop urinary retention
SCOTTSDALE, ARIZ. – Early hospital readmissions are not good for patients and can be terrible for a hospital’s bottom line, but at least one cause of readmission – urinary retention after surgery – can be significantly reduced.
"Postoperative urinary retention is a prevalent and mostly avoidable complication," said Dr. Sarita Khemani, a surgical comanagement hospitalist at Stanford (Calif.) University Medical Center.
Postoperative urinary retention can be defined as the inability to void in the presence of symptoms or bladder distension. However, as some patients may retain urine without feeling symptoms or the urge to void, it can also be defined as the inability to void with a bladder volume greater than 500 mL, or the presence of a postvoid residual volume greater than 200 mL on bladder scan, she said at a meeting on perioperative medicine sponsored by the University of Miami.
Identify high-risk patients
"For management, identifying the high-risk patient is very important," said Dr. Khemani.
She and her colleagues are working to develop a scoring system for identifying patients at risk for postoperative retention, she noted.
Depending on the risk factor, patients may require continued use of benign prostatic hyperplasia (BPH) medications (a strategy currently under clinical investigation), multimodal anesthesia, monitoring of IV fluids during and after surgery, and, when necessary, catheterization.
"There is really no consensus as to what is the best catheterization strategy we should use when it comes to urinary retention," Dr. Khemani said.
Low-risk patients undergoing outpatient procedures can be safely sent home without voiding, she said. High-risk patients undergoing ambulatory surgery can be managed with intermittent catheterization.
Patients who are undergoing major but uncomplicated surgery but are at low risk for postoperative retention do not generally need to have Foley catheters placed before surgery. Indwelling catheters should be limited, if possible, to 24 hours after surgery, and the patient can be managed with bladder scans every 6 hours if needed.
Patients scheduled for extensive, complicated procedures and those at high risk may require an indwelling catheter for up to 5 days after surgery. Studies have shown that in these patients early catheter removal actually increases the risk for postoperative urinary retention, Dr. Khemani said.
"It really needs to be followed by bladder scanning very closely, every 6 hours, to try to prevent overdistention and complications after that," she said.
The incidence of postoperative urinary retention among general surgery patients is 3.8%, but can range as high 70% after orthopedic surgery, 50% after anorectal procedures, 40% following spinal surgeries, and 38% after herniorrhaphy, Dr. Khemani said.
Preoperative risk factors for urinary retention after surgery include age over 50; male sex; history of retention; BPH; history of diabetes, stroke, or spinal lesions; or use of drugs such anticholinergic agents or beta-blockers.
Intraoperative and postoperative risk factors include the type and duration of surgery, anesthesia (especially spinal and epidural anethesias), systemic analgesia with opioids (especially patient-controlled analgesia, or PCA), and the use of intraoperative intravenous fluids. High IV fluid infusion causes rapid distention of the bladder detrusor muscles, leading to inability of the muscles to contract after surgery, Dr. Khemani noted.
Complications of postoperative urinary retention can include:
• Autonomic responses to bladder distention, leading to effects such as bradycardia, hypotension, vomiting, and delirium in some elderly patients.
• Infectious complications – urinary tract infections, sepsis, and joint infections.
• Prolonged need for catheterization.
• Bladder dysfunction.
A recent systematic review of drugs for treatment of urinary retention after surgery in adults found that of seven studies involving a total of 494 patients, neither cholinergic agents, alpha blockers, nor sedatives made a significant difference in reducing the incidence of retention. Only prostaglandins, and only when those agents were given intravesically, appeared to offer any benefit, the authors found.
"At this point we definitely need more studies to look at pharmacological alternatives to catheterization for treatment and prevention of this condition," Dr. Khemani concluded.
She reported having no financial disclosures.
SCOTTSDALE, ARIZ. – Early hospital readmissions are not good for patients and can be terrible for a hospital’s bottom line, but at least one cause of readmission – urinary retention after surgery – can be significantly reduced.
"Postoperative urinary retention is a prevalent and mostly avoidable complication," said Dr. Sarita Khemani, a surgical comanagement hospitalist at Stanford (Calif.) University Medical Center.
Postoperative urinary retention can be defined as the inability to void in the presence of symptoms or bladder distension. However, as some patients may retain urine without feeling symptoms or the urge to void, it can also be defined as the inability to void with a bladder volume greater than 500 mL, or the presence of a postvoid residual volume greater than 200 mL on bladder scan, she said at a meeting on perioperative medicine sponsored by the University of Miami.
Identify high-risk patients
"For management, identifying the high-risk patient is very important," said Dr. Khemani.
She and her colleagues are working to develop a scoring system for identifying patients at risk for postoperative retention, she noted.
Depending on the risk factor, patients may require continued use of benign prostatic hyperplasia (BPH) medications (a strategy currently under clinical investigation), multimodal anesthesia, monitoring of IV fluids during and after surgery, and, when necessary, catheterization.
"There is really no consensus as to what is the best catheterization strategy we should use when it comes to urinary retention," Dr. Khemani said.
Low-risk patients undergoing outpatient procedures can be safely sent home without voiding, she said. High-risk patients undergoing ambulatory surgery can be managed with intermittent catheterization.
Patients who are undergoing major but uncomplicated surgery but are at low risk for postoperative retention do not generally need to have Foley catheters placed before surgery. Indwelling catheters should be limited, if possible, to 24 hours after surgery, and the patient can be managed with bladder scans every 6 hours if needed.
Patients scheduled for extensive, complicated procedures and those at high risk may require an indwelling catheter for up to 5 days after surgery. Studies have shown that in these patients early catheter removal actually increases the risk for postoperative urinary retention, Dr. Khemani said.
"It really needs to be followed by bladder scanning very closely, every 6 hours, to try to prevent overdistention and complications after that," she said.
The incidence of postoperative urinary retention among general surgery patients is 3.8%, but can range as high 70% after orthopedic surgery, 50% after anorectal procedures, 40% following spinal surgeries, and 38% after herniorrhaphy, Dr. Khemani said.
Preoperative risk factors for urinary retention after surgery include age over 50; male sex; history of retention; BPH; history of diabetes, stroke, or spinal lesions; or use of drugs such anticholinergic agents or beta-blockers.
Intraoperative and postoperative risk factors include the type and duration of surgery, anesthesia (especially spinal and epidural anethesias), systemic analgesia with opioids (especially patient-controlled analgesia, or PCA), and the use of intraoperative intravenous fluids. High IV fluid infusion causes rapid distention of the bladder detrusor muscles, leading to inability of the muscles to contract after surgery, Dr. Khemani noted.
Complications of postoperative urinary retention can include:
• Autonomic responses to bladder distention, leading to effects such as bradycardia, hypotension, vomiting, and delirium in some elderly patients.
• Infectious complications – urinary tract infections, sepsis, and joint infections.
• Prolonged need for catheterization.
• Bladder dysfunction.
A recent systematic review of drugs for treatment of urinary retention after surgery in adults found that of seven studies involving a total of 494 patients, neither cholinergic agents, alpha blockers, nor sedatives made a significant difference in reducing the incidence of retention. Only prostaglandins, and only when those agents were given intravesically, appeared to offer any benefit, the authors found.
"At this point we definitely need more studies to look at pharmacological alternatives to catheterization for treatment and prevention of this condition," Dr. Khemani concluded.
She reported having no financial disclosures.
SCOTTSDALE, ARIZ. – Early hospital readmissions are not good for patients and can be terrible for a hospital’s bottom line, but at least one cause of readmission – urinary retention after surgery – can be significantly reduced.
"Postoperative urinary retention is a prevalent and mostly avoidable complication," said Dr. Sarita Khemani, a surgical comanagement hospitalist at Stanford (Calif.) University Medical Center.
Postoperative urinary retention can be defined as the inability to void in the presence of symptoms or bladder distension. However, as some patients may retain urine without feeling symptoms or the urge to void, it can also be defined as the inability to void with a bladder volume greater than 500 mL, or the presence of a postvoid residual volume greater than 200 mL on bladder scan, she said at a meeting on perioperative medicine sponsored by the University of Miami.
Identify high-risk patients
"For management, identifying the high-risk patient is very important," said Dr. Khemani.
She and her colleagues are working to develop a scoring system for identifying patients at risk for postoperative retention, she noted.
Depending on the risk factor, patients may require continued use of benign prostatic hyperplasia (BPH) medications (a strategy currently under clinical investigation), multimodal anesthesia, monitoring of IV fluids during and after surgery, and, when necessary, catheterization.
"There is really no consensus as to what is the best catheterization strategy we should use when it comes to urinary retention," Dr. Khemani said.
Low-risk patients undergoing outpatient procedures can be safely sent home without voiding, she said. High-risk patients undergoing ambulatory surgery can be managed with intermittent catheterization.
Patients who are undergoing major but uncomplicated surgery but are at low risk for postoperative retention do not generally need to have Foley catheters placed before surgery. Indwelling catheters should be limited, if possible, to 24 hours after surgery, and the patient can be managed with bladder scans every 6 hours if needed.
Patients scheduled for extensive, complicated procedures and those at high risk may require an indwelling catheter for up to 5 days after surgery. Studies have shown that in these patients early catheter removal actually increases the risk for postoperative urinary retention, Dr. Khemani said.
"It really needs to be followed by bladder scanning very closely, every 6 hours, to try to prevent overdistention and complications after that," she said.
The incidence of postoperative urinary retention among general surgery patients is 3.8%, but can range as high 70% after orthopedic surgery, 50% after anorectal procedures, 40% following spinal surgeries, and 38% after herniorrhaphy, Dr. Khemani said.
Preoperative risk factors for urinary retention after surgery include age over 50; male sex; history of retention; BPH; history of diabetes, stroke, or spinal lesions; or use of drugs such anticholinergic agents or beta-blockers.
Intraoperative and postoperative risk factors include the type and duration of surgery, anesthesia (especially spinal and epidural anethesias), systemic analgesia with opioids (especially patient-controlled analgesia, or PCA), and the use of intraoperative intravenous fluids. High IV fluid infusion causes rapid distention of the bladder detrusor muscles, leading to inability of the muscles to contract after surgery, Dr. Khemani noted.
Complications of postoperative urinary retention can include:
• Autonomic responses to bladder distention, leading to effects such as bradycardia, hypotension, vomiting, and delirium in some elderly patients.
• Infectious complications – urinary tract infections, sepsis, and joint infections.
• Prolonged need for catheterization.
• Bladder dysfunction.
A recent systematic review of drugs for treatment of urinary retention after surgery in adults found that of seven studies involving a total of 494 patients, neither cholinergic agents, alpha blockers, nor sedatives made a significant difference in reducing the incidence of retention. Only prostaglandins, and only when those agents were given intravesically, appeared to offer any benefit, the authors found.
"At this point we definitely need more studies to look at pharmacological alternatives to catheterization for treatment and prevention of this condition," Dr. Khemani concluded.
She reported having no financial disclosures.
AT THE PERIOPERATIVE MEDICINE SUMMIT
Major finding: The incidence of postoperative urinary retention may be as high as 70% after orthopedic procedures.
Data source: Review of evidence on the risk factors, prevention, and treatment of postoperative urinary retention.
Disclosures: Dr. Khemani reported having no financial disclosures.
Rising to the challenge of glucose control before and after surgery
SCOTTSDALE, ARIZ. – Controlling hyperglycemia before and after surgery in patients with diabetes is a balancing act, but when done properly, it can reduce infections and wound complications, according to Dr. David Baldwin.
The key to preoperative planning for patients with diabetes is a full list of medications and an understanding of how well (or how poorly) patients’ glycemia is controlled, said Dr. Baldwin, an endocrinologist at Rush University Medical Center in Chicago.
He discussed strategies for perioperative management of patients with diabetes and thyroid disorders at the Perioperative Medicine Summit 2014."You definitely want to write down exactly what they are and aren’t taking. We find that the medication list for people getting admitted for surgery is often fraught with a lack of little details," he said.
For patients with type 2 diabetes, it’s important to record an accurate description of antidiabetes medications, especially combination oral agents such as Actoplus MET (metformin and pioglitazone) or Janumet (sitagliptin and metformin). For patients with type 1 and 2 diabetes, it is important to record not just the type of insulin but the regimen the patient uses.
Dr. Baldwin noted that many intake staff make the mistake of reporting that patients take "Novolin" or "Humulin," which are brand families of insulin and not specific insulin types.
"We often find, probably at least half of the time, that until we actually go and ask the patients what they take for insulin post-op, the correct information won’t have been in the medical record," he said.
The best way to determine whether a patient has good control of chronic hyperglycemia is with a hemoglobin A1c (HbA1c) level. A value above 6.5% is diagnostic for diabetes; well-controlled patients have HbA1c levels from 6% to 8%. HbA1c values not more than 2 months old should be a routine part of preoperative evaluations for patients with diabetes or newly discovered hyperglycemia, Dr. Baldwin said.
Preoperative medications
The Rush University protocol for the preoperative management of antidiabetic therapies other than insulin notes that sulfonylureas, metformin, pioglitazone, exenatide, liraglutide, sitagliptin, linagliptin, saxagliptin, alogliptin, alpha-glucosidase inhibitors, and canagaflozin may all be taken with food on the eve of surgery, but none should be taken on the morning of surgery.
Specific rules also apply for patients who use insulin, depending on the insulin type, as follows:
• For long-acting insulins (glargine or detemir), the patient should take the full dose on the evening before surgery or the morning of surgery if the dose is prescribed for either morning or evening administration. Patients with prescriptions for a b.i.d. dose should take the full dose both the evening before and the morning of surgery.
• With intermediate-acting insulin (NPH), the patient should take the full dose on the evening before surgery and 80% of the morning dose on the morning of surgery.
• For rapid-acting insulins (aspart, lispro, glulisine, or regular) and premixed insulins (NPH or rapid acting), the patient should take the full dose with dinner the night before, and none on the morning of surgery.
Dr. Baldwin emphasized that except in rare circumstances, patients on subcutaneous insulin pumps should not use the pumps during surgery, and should get special instructions from their endocrinologists.
Ideally, the patient can convert to insulin glargine the night before surgery, with the dose equivalent to the total 24-hour basal insulin dose delivered by the pump. Two hours after the glargine dose is given, the patient should disconnect the pump and leave it at home.
Glycemic control in the hospital
As noted before, poor glycemic control can lead to poor wound healing from impaired leukocyte function, which can lead to decreased chemotaxis, phagocytosis, and bacteriocidal activity.
The risk of bacteremia is especially high among patients who are on total parenteral nutrition with poorly controlled glucose levels, he noted.
Forces conspiring against glucose control in the hospital can include elevated levels of hormones that counterregulate glucose; nausea/vomiting, anorexia, or nothing-by-mouth orders; erratic meal timing due to tests or interventions; intravenous glucose; glucocorticoid therapy; and "physician indifference and lack of attention to required adjustments in therapy," Dr. Baldwin noted.
Evidence from a randomized study showed that in patients with type 2 diabetes undergoing general surgery, basal-bolus treatment with insulin glargine once daily plus insulin glulisine before meals both improved glycemic control and reduced hospital complications compared with sliding-scale insulin therapy, he reported.
Hyper- and hypothyroid patients
Switching endocrinology hats, Dr. Baldwin said that patients who have significant weight loss or resting tachycardia before surgery should be evaluated for hyperthyroidism. A good rule of thumb is that in patients with hyperthyroidism, all but emergency procedures should be postponed until the condition can be controlled with methimazole.
Patients with undiagnosed or untreated hyperthyroidism who undergo anesthesia and surgery are at high risk for thyroid storm, a provoked crisis of multiorgan failure, he said.
If the surgery cannot be delayed until elevated levels of thyroxine are achieved, the team can initiate oral or intravenous beta-blockade, or if the patient is in critical condition, infusion with the beta-1 receptor blocker esmolol (Brevibloc) is preferred, he said.
Patients should also be started on methimazole 30-40 mg/day, and the patient should be given iodine if she has not already received iodinated radiologic contrast. Stress dose glucocorticoids and adequate volume resuscitation may also provide support in this situation.
In contrast, "hypothyroidism is usually not a big deal," Dr. Baldwin said.
Such patients usually tolerate major surgery without significant complications, he said, but patients with hypothyroidism may be more sensitive to sedatives, slower to wean from ventilation, and handle free-water excretion less well than euthyroid patients.
Patients who take levothyroxine (Synthroid and generics) should always have their free T4 and thyroid-stimulating hormone (thyrotropin) levels checked during preoperative evaluation, he said.
Dr. Baldwin reported having no relevant financial conflicts of interest.
SCOTTSDALE, ARIZ. – Controlling hyperglycemia before and after surgery in patients with diabetes is a balancing act, but when done properly, it can reduce infections and wound complications, according to Dr. David Baldwin.
The key to preoperative planning for patients with diabetes is a full list of medications and an understanding of how well (or how poorly) patients’ glycemia is controlled, said Dr. Baldwin, an endocrinologist at Rush University Medical Center in Chicago.
He discussed strategies for perioperative management of patients with diabetes and thyroid disorders at the Perioperative Medicine Summit 2014."You definitely want to write down exactly what they are and aren’t taking. We find that the medication list for people getting admitted for surgery is often fraught with a lack of little details," he said.
For patients with type 2 diabetes, it’s important to record an accurate description of antidiabetes medications, especially combination oral agents such as Actoplus MET (metformin and pioglitazone) or Janumet (sitagliptin and metformin). For patients with type 1 and 2 diabetes, it is important to record not just the type of insulin but the regimen the patient uses.
Dr. Baldwin noted that many intake staff make the mistake of reporting that patients take "Novolin" or "Humulin," which are brand families of insulin and not specific insulin types.
"We often find, probably at least half of the time, that until we actually go and ask the patients what they take for insulin post-op, the correct information won’t have been in the medical record," he said.
The best way to determine whether a patient has good control of chronic hyperglycemia is with a hemoglobin A1c (HbA1c) level. A value above 6.5% is diagnostic for diabetes; well-controlled patients have HbA1c levels from 6% to 8%. HbA1c values not more than 2 months old should be a routine part of preoperative evaluations for patients with diabetes or newly discovered hyperglycemia, Dr. Baldwin said.
Preoperative medications
The Rush University protocol for the preoperative management of antidiabetic therapies other than insulin notes that sulfonylureas, metformin, pioglitazone, exenatide, liraglutide, sitagliptin, linagliptin, saxagliptin, alogliptin, alpha-glucosidase inhibitors, and canagaflozin may all be taken with food on the eve of surgery, but none should be taken on the morning of surgery.
Specific rules also apply for patients who use insulin, depending on the insulin type, as follows:
• For long-acting insulins (glargine or detemir), the patient should take the full dose on the evening before surgery or the morning of surgery if the dose is prescribed for either morning or evening administration. Patients with prescriptions for a b.i.d. dose should take the full dose both the evening before and the morning of surgery.
• With intermediate-acting insulin (NPH), the patient should take the full dose on the evening before surgery and 80% of the morning dose on the morning of surgery.
• For rapid-acting insulins (aspart, lispro, glulisine, or regular) and premixed insulins (NPH or rapid acting), the patient should take the full dose with dinner the night before, and none on the morning of surgery.
Dr. Baldwin emphasized that except in rare circumstances, patients on subcutaneous insulin pumps should not use the pumps during surgery, and should get special instructions from their endocrinologists.
Ideally, the patient can convert to insulin glargine the night before surgery, with the dose equivalent to the total 24-hour basal insulin dose delivered by the pump. Two hours after the glargine dose is given, the patient should disconnect the pump and leave it at home.
Glycemic control in the hospital
As noted before, poor glycemic control can lead to poor wound healing from impaired leukocyte function, which can lead to decreased chemotaxis, phagocytosis, and bacteriocidal activity.
The risk of bacteremia is especially high among patients who are on total parenteral nutrition with poorly controlled glucose levels, he noted.
Forces conspiring against glucose control in the hospital can include elevated levels of hormones that counterregulate glucose; nausea/vomiting, anorexia, or nothing-by-mouth orders; erratic meal timing due to tests or interventions; intravenous glucose; glucocorticoid therapy; and "physician indifference and lack of attention to required adjustments in therapy," Dr. Baldwin noted.
Evidence from a randomized study showed that in patients with type 2 diabetes undergoing general surgery, basal-bolus treatment with insulin glargine once daily plus insulin glulisine before meals both improved glycemic control and reduced hospital complications compared with sliding-scale insulin therapy, he reported.
Hyper- and hypothyroid patients
Switching endocrinology hats, Dr. Baldwin said that patients who have significant weight loss or resting tachycardia before surgery should be evaluated for hyperthyroidism. A good rule of thumb is that in patients with hyperthyroidism, all but emergency procedures should be postponed until the condition can be controlled with methimazole.
Patients with undiagnosed or untreated hyperthyroidism who undergo anesthesia and surgery are at high risk for thyroid storm, a provoked crisis of multiorgan failure, he said.
If the surgery cannot be delayed until elevated levels of thyroxine are achieved, the team can initiate oral or intravenous beta-blockade, or if the patient is in critical condition, infusion with the beta-1 receptor blocker esmolol (Brevibloc) is preferred, he said.
Patients should also be started on methimazole 30-40 mg/day, and the patient should be given iodine if she has not already received iodinated radiologic contrast. Stress dose glucocorticoids and adequate volume resuscitation may also provide support in this situation.
In contrast, "hypothyroidism is usually not a big deal," Dr. Baldwin said.
Such patients usually tolerate major surgery without significant complications, he said, but patients with hypothyroidism may be more sensitive to sedatives, slower to wean from ventilation, and handle free-water excretion less well than euthyroid patients.
Patients who take levothyroxine (Synthroid and generics) should always have their free T4 and thyroid-stimulating hormone (thyrotropin) levels checked during preoperative evaluation, he said.
Dr. Baldwin reported having no relevant financial conflicts of interest.
SCOTTSDALE, ARIZ. – Controlling hyperglycemia before and after surgery in patients with diabetes is a balancing act, but when done properly, it can reduce infections and wound complications, according to Dr. David Baldwin.
The key to preoperative planning for patients with diabetes is a full list of medications and an understanding of how well (or how poorly) patients’ glycemia is controlled, said Dr. Baldwin, an endocrinologist at Rush University Medical Center in Chicago.
He discussed strategies for perioperative management of patients with diabetes and thyroid disorders at the Perioperative Medicine Summit 2014."You definitely want to write down exactly what they are and aren’t taking. We find that the medication list for people getting admitted for surgery is often fraught with a lack of little details," he said.
For patients with type 2 diabetes, it’s important to record an accurate description of antidiabetes medications, especially combination oral agents such as Actoplus MET (metformin and pioglitazone) or Janumet (sitagliptin and metformin). For patients with type 1 and 2 diabetes, it is important to record not just the type of insulin but the regimen the patient uses.
Dr. Baldwin noted that many intake staff make the mistake of reporting that patients take "Novolin" or "Humulin," which are brand families of insulin and not specific insulin types.
"We often find, probably at least half of the time, that until we actually go and ask the patients what they take for insulin post-op, the correct information won’t have been in the medical record," he said.
The best way to determine whether a patient has good control of chronic hyperglycemia is with a hemoglobin A1c (HbA1c) level. A value above 6.5% is diagnostic for diabetes; well-controlled patients have HbA1c levels from 6% to 8%. HbA1c values not more than 2 months old should be a routine part of preoperative evaluations for patients with diabetes or newly discovered hyperglycemia, Dr. Baldwin said.
Preoperative medications
The Rush University protocol for the preoperative management of antidiabetic therapies other than insulin notes that sulfonylureas, metformin, pioglitazone, exenatide, liraglutide, sitagliptin, linagliptin, saxagliptin, alogliptin, alpha-glucosidase inhibitors, and canagaflozin may all be taken with food on the eve of surgery, but none should be taken on the morning of surgery.
Specific rules also apply for patients who use insulin, depending on the insulin type, as follows:
• For long-acting insulins (glargine or detemir), the patient should take the full dose on the evening before surgery or the morning of surgery if the dose is prescribed for either morning or evening administration. Patients with prescriptions for a b.i.d. dose should take the full dose both the evening before and the morning of surgery.
• With intermediate-acting insulin (NPH), the patient should take the full dose on the evening before surgery and 80% of the morning dose on the morning of surgery.
• For rapid-acting insulins (aspart, lispro, glulisine, or regular) and premixed insulins (NPH or rapid acting), the patient should take the full dose with dinner the night before, and none on the morning of surgery.
Dr. Baldwin emphasized that except in rare circumstances, patients on subcutaneous insulin pumps should not use the pumps during surgery, and should get special instructions from their endocrinologists.
Ideally, the patient can convert to insulin glargine the night before surgery, with the dose equivalent to the total 24-hour basal insulin dose delivered by the pump. Two hours after the glargine dose is given, the patient should disconnect the pump and leave it at home.
Glycemic control in the hospital
As noted before, poor glycemic control can lead to poor wound healing from impaired leukocyte function, which can lead to decreased chemotaxis, phagocytosis, and bacteriocidal activity.
The risk of bacteremia is especially high among patients who are on total parenteral nutrition with poorly controlled glucose levels, he noted.
Forces conspiring against glucose control in the hospital can include elevated levels of hormones that counterregulate glucose; nausea/vomiting, anorexia, or nothing-by-mouth orders; erratic meal timing due to tests or interventions; intravenous glucose; glucocorticoid therapy; and "physician indifference and lack of attention to required adjustments in therapy," Dr. Baldwin noted.
Evidence from a randomized study showed that in patients with type 2 diabetes undergoing general surgery, basal-bolus treatment with insulin glargine once daily plus insulin glulisine before meals both improved glycemic control and reduced hospital complications compared with sliding-scale insulin therapy, he reported.
Hyper- and hypothyroid patients
Switching endocrinology hats, Dr. Baldwin said that patients who have significant weight loss or resting tachycardia before surgery should be evaluated for hyperthyroidism. A good rule of thumb is that in patients with hyperthyroidism, all but emergency procedures should be postponed until the condition can be controlled with methimazole.
Patients with undiagnosed or untreated hyperthyroidism who undergo anesthesia and surgery are at high risk for thyroid storm, a provoked crisis of multiorgan failure, he said.
If the surgery cannot be delayed until elevated levels of thyroxine are achieved, the team can initiate oral or intravenous beta-blockade, or if the patient is in critical condition, infusion with the beta-1 receptor blocker esmolol (Brevibloc) is preferred, he said.
Patients should also be started on methimazole 30-40 mg/day, and the patient should be given iodine if she has not already received iodinated radiologic contrast. Stress dose glucocorticoids and adequate volume resuscitation may also provide support in this situation.
In contrast, "hypothyroidism is usually not a big deal," Dr. Baldwin said.
Such patients usually tolerate major surgery without significant complications, he said, but patients with hypothyroidism may be more sensitive to sedatives, slower to wean from ventilation, and handle free-water excretion less well than euthyroid patients.
Patients who take levothyroxine (Synthroid and generics) should always have their free T4 and thyroid-stimulating hormone (thyrotropin) levels checked during preoperative evaluation, he said.
Dr. Baldwin reported having no relevant financial conflicts of interest.
AT THE PERIOPERATIVE MEDICINE SUMMIT 2014
Major finding: Patients with diabetes and thyroid disorder require special handling before, during, and after surgery.
Data source: A review of current practice.
Disclosures: Dr. Baldwin reported having no relevant financial conflicts of interest.
Potential ‘Functional Cure’ for AIDS?
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
FROM CROI 2014
Early study: Potential ‘functional cure’ for AIDS?
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.
The therapy is designed to keep HIV under control without additional antiretroviral drugs.
The technique involves collection of CD4 T cells from patients infected with HIV, genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.
"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.
Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).
In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)–mediated genome editing.
Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/m2, and three received the drug at a dose of 1 g/m2.
Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.
The therapy effectively mimics the CCR5 delta-32 mutation. Patients who are heterozygous for the allele have slower progression of HIV disease, and patients who are homozygous for the deletion are resistant to HIV infection.
The so-called Berlin patient was an HIV-infected man who is HIV free and off of antiretroviral therapy for more than 5 years after receiving a stem cell transplant from a donor who was homozygous for the delta-32 allele.
Dose-escalation study
The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.
The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV.
In addition, two patients at the 500-mg/m2 dose had an approximate reduction of 0.8-1.1 log10 in viral load after a 16-week treatment interruption, and one patient on the 1-g/m2 dose had a 1.9 log10 decrease after 16 weeks off HAART.
Two patients in the highest cyclophosphamide dose group had stable reduced viral loads and remain on treatment interruption.
The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV, Dr. Blick said.
"The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions," commented Dr. Mark A Kay of Stanford (Calif.) University and Dr. Bruce D. Walker of the Ragon Institute of MGH, MIT, and Harvard, in Cambridge, Mass., in an editorial accompanying the study published in the New England Journal of Medicine.
The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay, and Dr. Walker reported having no relevant financial disclosures.
Commentary – ‘Elegant science’ with uncertain future
Dr. Anthony S. Fauci comments: The only way this is really going to be useful is if they in fact completely replace normal T cells ultimately, because as long as you have normal cells getting infected and spitting out virus, you’ve got a problem, and you’ve got a problem because normal cells making virus give you that immune activation that’s a very deleterious part of HIV disease – the aberrant activation associated with virus replication.
Is this elegant science? Yes. Is it an important step in the right direction? Yes. Will this turn out to be a successful approach? I can’t tell you that right now. It might not be.
Dr. Fauci is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
FROM CROI 2014
Major finding: Three of 12 HIV-positive patients treated with modified autologous T cells had viral load reductions between 0.8 and 1.9 log10 after 16 weeks of antiretroviral therapy interruption.
Data source: Phase I/II dose-escalation study in 12 patients.
Disclosures: The study was supported by Sangamo Biosciences. Dr. Blick, Dr.Kay and Dr. Walker reported having no relevant financial disclosures.
Early treatment appears to clear virus in second HIV-infected newborn
An HIV-infected newborn infant started on combined antiretroviral drug therapy just 4 hours after birth had no detectable viral load by 11 days of age and at 9.5 months of treatment appears to be HIV free, investigators have reported.
The case of the unidentified child, born in Los Angeles (L.A.) County, Calif., to a mother with untreated HIV infection, echoes that of the so-called Mississippi child. The latter case made headlines last year when investigators reported that, at the age of 26 months, a girl born with perinatal HIV infection had no detectable virus 10 months after stopping therapy with zidovudine (AZT), zidovudine (3TC), and nevirapine.
Dr. Deborah Persaud from Johns Hopkins Children’s Center in Baltimore, who presented the case of the Mississippi child at the Conference on Retroviruses and Opportunistic Infections (CROI) last year, reported an update on that case and described early results from the aforementioned L.A. child at this year’s CROI meeting.
As she reported in 2013, the Mississippi child was born to an HIV-infected mother with no evidence of antiretroviral therapy or prophylaxis during labor to prevent transmission to the infant.
The child was started on antiretroviral therapy at 31 hours of age with AZT, 3TC, and nevirapine given twice daily at 2 mg/kg per dose.
This regimen differed from the prophylactic regimen used in high transmission–risk situations, in which nevirapine is given in three doses at 0, 48, and 96 hours, Dr. Persaud noted. Investigators are still uncertain as to the optimal nevirapine dose for children under 2 weeks of age, she said.
At the most recent follow-up, the child was 41 months old and had been off combined antiretroviral therapy (cART) for 23 months.
"With respect to the Mississippi child, we can say that this child remains in remission. There’s no replication-competent T-cell reservoir to date, and it supports our hypothesis that very early treatment may prevent formation of critical reservoirs that currently preclude cure," she said.
Despite the apparent clearance of HIV in the Mississippi child, investigators continue to detect HIV proviral DNA in the child’s peripheral blood mononuclear cells.
"We’re not sure whether this is a real signal or really at the assay limits of detection, and it certainly requires continued follow-up and study. It’s important to point out that the clinical relevance of this detection remains unclear, but to date it does not signify impending rebound viremia," she said.
The investigators hypothesized that the residual microviral DNA seen in the child might be explained by maternal microchimerism, that is, residual maternal cells with HIV proviral DNA, but at 40-month follow-up, there was no evidence of maternal chimerism, Dr. Persaud said.
L.A. story
The L.A. child, whose sex was not disclosed, was born to a mother with untreated HIV infection and a high viral load (138,711 copies/mL) and low CD4 count (70 cells/mm3). At 4 hours of age, the child had a blood sample positive for HIV DNA, and at 36 hours, showed HIV RNA at 217 copies/mL.
A cerebrospinal fluid sample taken at 6 days to rule out sepsis showed HIV RNA at 32 copies/mL.
At age 4 hour, the child was started on a regimen of AZT, 3TC, and nevirapine, with the addition of lopinavir/ritonavir (Kaletra) at 2 weeks of age and was continued on this combination for 3.4 months. The child has since been maintained on the initial three-drug regimen.
"What we did find in this case is that by using clinical monitoring the viral load was undetectable by 11 days of age. Sequential samples collected through 9 months of age show undetectable plasma viral load," Dr. Persaud said.
The clinical assay used to diagnose infection found no detectable viral levels by 60 days of age, and the investigators have been unable to recover infectious virus from the child’s resting CD4 T cells at 1, 3, or 9 months.
However, when they looked at the noninduced proviral genome in a culture obtained at 1 month of age, the investigators detected HIV DNA at both days 7 and 14 of culturing, "but not at a level that we could amplify and sequence, so it’s unclear what those signals mean," she said.
Subsequent culture data have shown no detection of non-induced proviral genomes. The proviral DNA remains low. At last testing at 9 months of age, proviral DNA was less than 2 copies/mL in peripheral blood mononuclear cells, and the child had seroreverted and become HIV negative.
"I think we’ve shown that very early treatment, certainly in the Mississippi child, has led to sustained HIV remission now for up to 23 months off cART, and now with the second initiating treatment at 4 hours of life, this has led to rapid clearance of replicating virus and proviral DNA, supporting restriction of HIV spread with very early cART," Dr. Persaud said.
The work was supported by the Center for AIDS Research at Johns Hopkins University, the Foundation for AIDS Research (amfAR), and the National Institute of Allergy and Infectious Diseases.
An HIV-infected newborn infant started on combined antiretroviral drug therapy just 4 hours after birth had no detectable viral load by 11 days of age and at 9.5 months of treatment appears to be HIV free, investigators have reported.
The case of the unidentified child, born in Los Angeles (L.A.) County, Calif., to a mother with untreated HIV infection, echoes that of the so-called Mississippi child. The latter case made headlines last year when investigators reported that, at the age of 26 months, a girl born with perinatal HIV infection had no detectable virus 10 months after stopping therapy with zidovudine (AZT), zidovudine (3TC), and nevirapine.
Dr. Deborah Persaud from Johns Hopkins Children’s Center in Baltimore, who presented the case of the Mississippi child at the Conference on Retroviruses and Opportunistic Infections (CROI) last year, reported an update on that case and described early results from the aforementioned L.A. child at this year’s CROI meeting.
As she reported in 2013, the Mississippi child was born to an HIV-infected mother with no evidence of antiretroviral therapy or prophylaxis during labor to prevent transmission to the infant.
The child was started on antiretroviral therapy at 31 hours of age with AZT, 3TC, and nevirapine given twice daily at 2 mg/kg per dose.
This regimen differed from the prophylactic regimen used in high transmission–risk situations, in which nevirapine is given in three doses at 0, 48, and 96 hours, Dr. Persaud noted. Investigators are still uncertain as to the optimal nevirapine dose for children under 2 weeks of age, she said.
At the most recent follow-up, the child was 41 months old and had been off combined antiretroviral therapy (cART) for 23 months.
"With respect to the Mississippi child, we can say that this child remains in remission. There’s no replication-competent T-cell reservoir to date, and it supports our hypothesis that very early treatment may prevent formation of critical reservoirs that currently preclude cure," she said.
Despite the apparent clearance of HIV in the Mississippi child, investigators continue to detect HIV proviral DNA in the child’s peripheral blood mononuclear cells.
"We’re not sure whether this is a real signal or really at the assay limits of detection, and it certainly requires continued follow-up and study. It’s important to point out that the clinical relevance of this detection remains unclear, but to date it does not signify impending rebound viremia," she said.
The investigators hypothesized that the residual microviral DNA seen in the child might be explained by maternal microchimerism, that is, residual maternal cells with HIV proviral DNA, but at 40-month follow-up, there was no evidence of maternal chimerism, Dr. Persaud said.
L.A. story
The L.A. child, whose sex was not disclosed, was born to a mother with untreated HIV infection and a high viral load (138,711 copies/mL) and low CD4 count (70 cells/mm3). At 4 hours of age, the child had a blood sample positive for HIV DNA, and at 36 hours, showed HIV RNA at 217 copies/mL.
A cerebrospinal fluid sample taken at 6 days to rule out sepsis showed HIV RNA at 32 copies/mL.
At age 4 hour, the child was started on a regimen of AZT, 3TC, and nevirapine, with the addition of lopinavir/ritonavir (Kaletra) at 2 weeks of age and was continued on this combination for 3.4 months. The child has since been maintained on the initial three-drug regimen.
"What we did find in this case is that by using clinical monitoring the viral load was undetectable by 11 days of age. Sequential samples collected through 9 months of age show undetectable plasma viral load," Dr. Persaud said.
The clinical assay used to diagnose infection found no detectable viral levels by 60 days of age, and the investigators have been unable to recover infectious virus from the child’s resting CD4 T cells at 1, 3, or 9 months.
However, when they looked at the noninduced proviral genome in a culture obtained at 1 month of age, the investigators detected HIV DNA at both days 7 and 14 of culturing, "but not at a level that we could amplify and sequence, so it’s unclear what those signals mean," she said.
Subsequent culture data have shown no detection of non-induced proviral genomes. The proviral DNA remains low. At last testing at 9 months of age, proviral DNA was less than 2 copies/mL in peripheral blood mononuclear cells, and the child had seroreverted and become HIV negative.
"I think we’ve shown that very early treatment, certainly in the Mississippi child, has led to sustained HIV remission now for up to 23 months off cART, and now with the second initiating treatment at 4 hours of life, this has led to rapid clearance of replicating virus and proviral DNA, supporting restriction of HIV spread with very early cART," Dr. Persaud said.
The work was supported by the Center for AIDS Research at Johns Hopkins University, the Foundation for AIDS Research (amfAR), and the National Institute of Allergy and Infectious Diseases.
An HIV-infected newborn infant started on combined antiretroviral drug therapy just 4 hours after birth had no detectable viral load by 11 days of age and at 9.5 months of treatment appears to be HIV free, investigators have reported.
The case of the unidentified child, born in Los Angeles (L.A.) County, Calif., to a mother with untreated HIV infection, echoes that of the so-called Mississippi child. The latter case made headlines last year when investigators reported that, at the age of 26 months, a girl born with perinatal HIV infection had no detectable virus 10 months after stopping therapy with zidovudine (AZT), zidovudine (3TC), and nevirapine.
Dr. Deborah Persaud from Johns Hopkins Children’s Center in Baltimore, who presented the case of the Mississippi child at the Conference on Retroviruses and Opportunistic Infections (CROI) last year, reported an update on that case and described early results from the aforementioned L.A. child at this year’s CROI meeting.
As she reported in 2013, the Mississippi child was born to an HIV-infected mother with no evidence of antiretroviral therapy or prophylaxis during labor to prevent transmission to the infant.
The child was started on antiretroviral therapy at 31 hours of age with AZT, 3TC, and nevirapine given twice daily at 2 mg/kg per dose.
This regimen differed from the prophylactic regimen used in high transmission–risk situations, in which nevirapine is given in three doses at 0, 48, and 96 hours, Dr. Persaud noted. Investigators are still uncertain as to the optimal nevirapine dose for children under 2 weeks of age, she said.
At the most recent follow-up, the child was 41 months old and had been off combined antiretroviral therapy (cART) for 23 months.
"With respect to the Mississippi child, we can say that this child remains in remission. There’s no replication-competent T-cell reservoir to date, and it supports our hypothesis that very early treatment may prevent formation of critical reservoirs that currently preclude cure," she said.
Despite the apparent clearance of HIV in the Mississippi child, investigators continue to detect HIV proviral DNA in the child’s peripheral blood mononuclear cells.
"We’re not sure whether this is a real signal or really at the assay limits of detection, and it certainly requires continued follow-up and study. It’s important to point out that the clinical relevance of this detection remains unclear, but to date it does not signify impending rebound viremia," she said.
The investigators hypothesized that the residual microviral DNA seen in the child might be explained by maternal microchimerism, that is, residual maternal cells with HIV proviral DNA, but at 40-month follow-up, there was no evidence of maternal chimerism, Dr. Persaud said.
L.A. story
The L.A. child, whose sex was not disclosed, was born to a mother with untreated HIV infection and a high viral load (138,711 copies/mL) and low CD4 count (70 cells/mm3). At 4 hours of age, the child had a blood sample positive for HIV DNA, and at 36 hours, showed HIV RNA at 217 copies/mL.
A cerebrospinal fluid sample taken at 6 days to rule out sepsis showed HIV RNA at 32 copies/mL.
At age 4 hour, the child was started on a regimen of AZT, 3TC, and nevirapine, with the addition of lopinavir/ritonavir (Kaletra) at 2 weeks of age and was continued on this combination for 3.4 months. The child has since been maintained on the initial three-drug regimen.
"What we did find in this case is that by using clinical monitoring the viral load was undetectable by 11 days of age. Sequential samples collected through 9 months of age show undetectable plasma viral load," Dr. Persaud said.
The clinical assay used to diagnose infection found no detectable viral levels by 60 days of age, and the investigators have been unable to recover infectious virus from the child’s resting CD4 T cells at 1, 3, or 9 months.
However, when they looked at the noninduced proviral genome in a culture obtained at 1 month of age, the investigators detected HIV DNA at both days 7 and 14 of culturing, "but not at a level that we could amplify and sequence, so it’s unclear what those signals mean," she said.
Subsequent culture data have shown no detection of non-induced proviral genomes. The proviral DNA remains low. At last testing at 9 months of age, proviral DNA was less than 2 copies/mL in peripheral blood mononuclear cells, and the child had seroreverted and become HIV negative.
"I think we’ve shown that very early treatment, certainly in the Mississippi child, has led to sustained HIV remission now for up to 23 months off cART, and now with the second initiating treatment at 4 hours of life, this has led to rapid clearance of replicating virus and proviral DNA, supporting restriction of HIV spread with very early cART," Dr. Persaud said.
The work was supported by the Center for AIDS Research at Johns Hopkins University, the Foundation for AIDS Research (amfAR), and the National Institute of Allergy and Infectious Diseases.
FROM CROI 2014
Major finding: Combined antiretroviral therapy in the first hours of life appears to clear HIV from perinatally infected infants.
Data source: Case reports of two children born with HIV infection to untreated mothers.
Disclosures: The work was supported by the Center for AIDS Research at Johns Hopkins University, the Foundation for AIDS Research (amfAR), and the National Institute of Allergy and Infectious Diseases.
Risk of condomless sex low if HIV-positive partner is well controlled on ART
Public health experts do not condone the practice, but it appears that the risk of transmission from an HIV-positive person to an uninfected sex partner during condomless sex is low if the infected partner has good viral control on antiretroviral therapy.
That’s the tentative conclusion investigators in the PARTNER study have drawn from an interim analysis looking at HIV transmission among serodifferent couples in which the positive partner is taking antiretroviral therapy (ART) and has a plasma viral load below 200 copies/mL, said Dr. Alison Rodger from the Research Department of Infection & Population Health at University College London.
"Overall, we had no linked transmissions during eligible follow-up, giving a transmission rate of zero," she reported at the Conference on Retroviruses and Opportunistic Infections.
However, the investigators cannot say with certainty that the actual risk is zero, as the upper limit of the 95% confidence interval was 0.4 per 100 couple-years, translating into a 10-year risk of 4%, Dr. Rodger said.
Although HIV transmissions did occur during the study, the investigators were able to rule out linked transmissions – that is, transmissions that are phylogenetically confirmed to be the same viral strain.
"The uncertainty is particularly advanced for anal sex, where for the moment we do not have sufficient data to exclude that 1 in 10 [HIV-negative partners] would be infected over a 10-year period," commented coinvestigator Dr. Jens Lundgren from the Centre for Viral Diseases and the Copenhagen HIV Programme at the University of Copenhagen.
The investigators plan to continue the study and conduct new analyses each time an additional 1,000 couple-years have been reached, he said at a briefing following the presentation.
The investigators enrolled serodifferent heterosexual and men having sex with men (MSM) couples who reported having had condomless penetrative anal or vaginal sex in the month prior to study entry, and did not use pre- or postexposure HIV prophylaxis.
Every 6 months during follow-up, each partner fills out a sexual behaviors questionnaire, and the seronegative partner is tested for HIV.
The informed consent for the study included information on the need for consistent condom use and explicit reference to the fact that the HIV-negative partners knew that their partner was positive and that there was risk for HIV transmission.
A total of 767 couples have contributed a total of 894 eligible couple follow-up years (586 in heterosexual couples and 308 in MSM) as of November 2013.
Median ART duration at baseline was 4.8 years, and the median duration of condomless sex reported was 2 years.
Although the risk of transmission across all categories of penetrative anal or vaginal sex was zero, as noted before, the upper limit of the confidence interval for receptive anal sex with ejaculation – the type of sex that carries the highest risk of HIV transmission – extends to 4, which translates into 32% risk of transmission at 10 years, Dr. Rodger said.
"Additional follow-up in MSM is needed through PARTNER phase 2, which will extend through 2017 in gay men only to provide more precise estimates for transmission risk to inform policy, and also to involve individual choice on whether to use condoms or not," Dr. Rodger said.
The PARTNER study is supported by the U.K. National Institute for Health Research. Dr. Rodger and Dr. Lundgren reported having no financial conflicts of interest.
Public health experts do not condone the practice, but it appears that the risk of transmission from an HIV-positive person to an uninfected sex partner during condomless sex is low if the infected partner has good viral control on antiretroviral therapy.
That’s the tentative conclusion investigators in the PARTNER study have drawn from an interim analysis looking at HIV transmission among serodifferent couples in which the positive partner is taking antiretroviral therapy (ART) and has a plasma viral load below 200 copies/mL, said Dr. Alison Rodger from the Research Department of Infection & Population Health at University College London.
"Overall, we had no linked transmissions during eligible follow-up, giving a transmission rate of zero," she reported at the Conference on Retroviruses and Opportunistic Infections.
However, the investigators cannot say with certainty that the actual risk is zero, as the upper limit of the 95% confidence interval was 0.4 per 100 couple-years, translating into a 10-year risk of 4%, Dr. Rodger said.
Although HIV transmissions did occur during the study, the investigators were able to rule out linked transmissions – that is, transmissions that are phylogenetically confirmed to be the same viral strain.
"The uncertainty is particularly advanced for anal sex, where for the moment we do not have sufficient data to exclude that 1 in 10 [HIV-negative partners] would be infected over a 10-year period," commented coinvestigator Dr. Jens Lundgren from the Centre for Viral Diseases and the Copenhagen HIV Programme at the University of Copenhagen.
The investigators plan to continue the study and conduct new analyses each time an additional 1,000 couple-years have been reached, he said at a briefing following the presentation.
The investigators enrolled serodifferent heterosexual and men having sex with men (MSM) couples who reported having had condomless penetrative anal or vaginal sex in the month prior to study entry, and did not use pre- or postexposure HIV prophylaxis.
Every 6 months during follow-up, each partner fills out a sexual behaviors questionnaire, and the seronegative partner is tested for HIV.
The informed consent for the study included information on the need for consistent condom use and explicit reference to the fact that the HIV-negative partners knew that their partner was positive and that there was risk for HIV transmission.
A total of 767 couples have contributed a total of 894 eligible couple follow-up years (586 in heterosexual couples and 308 in MSM) as of November 2013.
Median ART duration at baseline was 4.8 years, and the median duration of condomless sex reported was 2 years.
Although the risk of transmission across all categories of penetrative anal or vaginal sex was zero, as noted before, the upper limit of the confidence interval for receptive anal sex with ejaculation – the type of sex that carries the highest risk of HIV transmission – extends to 4, which translates into 32% risk of transmission at 10 years, Dr. Rodger said.
"Additional follow-up in MSM is needed through PARTNER phase 2, which will extend through 2017 in gay men only to provide more precise estimates for transmission risk to inform policy, and also to involve individual choice on whether to use condoms or not," Dr. Rodger said.
The PARTNER study is supported by the U.K. National Institute for Health Research. Dr. Rodger and Dr. Lundgren reported having no financial conflicts of interest.
Public health experts do not condone the practice, but it appears that the risk of transmission from an HIV-positive person to an uninfected sex partner during condomless sex is low if the infected partner has good viral control on antiretroviral therapy.
That’s the tentative conclusion investigators in the PARTNER study have drawn from an interim analysis looking at HIV transmission among serodifferent couples in which the positive partner is taking antiretroviral therapy (ART) and has a plasma viral load below 200 copies/mL, said Dr. Alison Rodger from the Research Department of Infection & Population Health at University College London.
"Overall, we had no linked transmissions during eligible follow-up, giving a transmission rate of zero," she reported at the Conference on Retroviruses and Opportunistic Infections.
However, the investigators cannot say with certainty that the actual risk is zero, as the upper limit of the 95% confidence interval was 0.4 per 100 couple-years, translating into a 10-year risk of 4%, Dr. Rodger said.
Although HIV transmissions did occur during the study, the investigators were able to rule out linked transmissions – that is, transmissions that are phylogenetically confirmed to be the same viral strain.
"The uncertainty is particularly advanced for anal sex, where for the moment we do not have sufficient data to exclude that 1 in 10 [HIV-negative partners] would be infected over a 10-year period," commented coinvestigator Dr. Jens Lundgren from the Centre for Viral Diseases and the Copenhagen HIV Programme at the University of Copenhagen.
The investigators plan to continue the study and conduct new analyses each time an additional 1,000 couple-years have been reached, he said at a briefing following the presentation.
The investigators enrolled serodifferent heterosexual and men having sex with men (MSM) couples who reported having had condomless penetrative anal or vaginal sex in the month prior to study entry, and did not use pre- or postexposure HIV prophylaxis.
Every 6 months during follow-up, each partner fills out a sexual behaviors questionnaire, and the seronegative partner is tested for HIV.
The informed consent for the study included information on the need for consistent condom use and explicit reference to the fact that the HIV-negative partners knew that their partner was positive and that there was risk for HIV transmission.
A total of 767 couples have contributed a total of 894 eligible couple follow-up years (586 in heterosexual couples and 308 in MSM) as of November 2013.
Median ART duration at baseline was 4.8 years, and the median duration of condomless sex reported was 2 years.
Although the risk of transmission across all categories of penetrative anal or vaginal sex was zero, as noted before, the upper limit of the confidence interval for receptive anal sex with ejaculation – the type of sex that carries the highest risk of HIV transmission – extends to 4, which translates into 32% risk of transmission at 10 years, Dr. Rodger said.
"Additional follow-up in MSM is needed through PARTNER phase 2, which will extend through 2017 in gay men only to provide more precise estimates for transmission risk to inform policy, and also to involve individual choice on whether to use condoms or not," Dr. Rodger said.
The PARTNER study is supported by the U.K. National Institute for Health Research. Dr. Rodger and Dr. Lundgren reported having no financial conflicts of interest.
FROM CROI 2014
Major finding: When HIV-infected individuals were well controlled on antiretroviral therapy, the risk of HIV transmission to uninfected sex partners was zero, but confidence intervals indicate that there may still be some transmission risk.
Data source: An observational cohort study in which 767 couples reported 894 couple-years at 75 sites across Europe.
Disclosures: The PARTNER study is supported by the U.K. National Institute for Health Research. Dr. Rodger and Dr. Lundgren reported having no financial conflicts of interest.
