A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least 2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴ TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵ Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.

A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least 2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴ TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵ Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.

A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least 2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴ TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵ Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.

Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716. 

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2 

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi. 

Details of the study 

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely. 

As a caveat to their research, the authors noted that: 

1. transcription levels do not always correlate with protein expression 
2. it is possible that a noncanonical cell-entry mediator facilitates entry 
3. individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2. 

Study strengths and limitations 

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings. 

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰ 

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses. 

Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716. 

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2 

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi. 

Details of the study 

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely. 

As a caveat to their research, the authors noted that: 

1. transcription levels do not always correlate with protein expression 
2. it is possible that a noncanonical cell-entry mediator facilitates entry 
3. individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2. 

Study strengths and limitations 

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings. 

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰ 

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses. 

Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716. 

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2 

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi. 

Details of the study 

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely. 

As a caveat to their research, the authors noted that: 

1. transcription levels do not always correlate with protein expression 
2. it is possible that a noncanonical cell-entry mediator facilitates entry 
3. individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2. 

Study strengths and limitations 

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings. 

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰ 

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses. 

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

Upfront treatment with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab “significantly and meaningfully” improves survival in metastatic colorectal cancer when compared with chemotherapy doublets plus bevacizumab, investigators reported in the Journal of Clinical Oncology.

In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.

FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.

“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
 

Patient characteristics and treatment

The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).

About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.

In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).

The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
 

Efficacy and safety

At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.

The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).

The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).

The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).

Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
 

Patient selection is ‘critical’

Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.

FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”

For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.

“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.

There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.

aotto@mdedge.com

SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.

Upfront treatment with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab “significantly and meaningfully” improves survival in metastatic colorectal cancer when compared with chemotherapy doublets plus bevacizumab, investigators reported in the Journal of Clinical Oncology.

In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.

FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.

“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
 

Patient characteristics and treatment

The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).

About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.

In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).

The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
 

Efficacy and safety

At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.

The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).

The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).

The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).

Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
 

Patient selection is ‘critical’

Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.

FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”

For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.

“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.

There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.

aotto@mdedge.com

SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.

Upfront treatment with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab “significantly and meaningfully” improves survival in metastatic colorectal cancer when compared with chemotherapy doublets plus bevacizumab, investigators reported in the Journal of Clinical Oncology.

In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.

FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.

“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
 

Patient characteristics and treatment

The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).

About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.

In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).

The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
 

Efficacy and safety

At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.

The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).

The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).

The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).

Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
 

Patient selection is ‘critical’

Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.

FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”

For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.

“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.

There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.

aotto@mdedge.com

SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.

The COVID-19 pandemic has affected private medical practices on so many levels, not least of which is the loss of employees to illness, fear of illness, early retirement, and other reasons. With so many practices forced to hire replacements, basically at the same time, it’s not surprising to see a significant and frustrating increase in ghosting.

ismagilov/iStock/Getty Images Plus

If you’re not hip to the slang, “ghosting” is the situation in which an employee disappears without any warning, notice, or explanation. It usually occurs after a candidate accepts a job offer, and you schedule their first day of work. That day dawns, but the new hire never arrives. Less commonly, an employee who has been with you for some time simply stops showing up and cannot be contacted.

Many employers think of ghosting as a relatively new phenomenon, and blame it on the irresponsibility of younger age groups – millennials, in particular. In fact, it has been an issue for many years across all age groups, and employers often share more of the responsibility than they think.

While total prevention is impossible, there are steps you can take as an employer to minimize ghosting in your practice.

• Your hiring process needs to be efficient. If you wait too long to schedule an interview with a promising candidate or to offer them the job, another job offer could lure them away. At the very least, a lengthy process or a lack of transparency may make the applicant apprehensive about accepting a job with you, particularly if other employers are pursuing them.
• Keep applicants in the loop. Follow up with every candidate; let them know where they are in your hiring process. Applicants who have no clue whether they have a shot at the job are going to start looking elsewhere. And make sure they know the job description and starting salary from the outset.
• Talk to new hires before their first day. Contact them personally to see if they have any questions or concerns, and let them know that you’re looking forward to their arrival.
• Once they start, make them feel welcome. An employee’s first few days on the job set the tone for the rest of the employment relationship. During this time, clearly communicate what the employee can expect from you and what you expect from them. Take time to discuss key issues, such as work schedules, timekeeping practices, how performance is measured, and dress codes. Introduce them to coworkers, and get them started shadowing more experienced staff members.
• Take a hard look at your supervision and your supervisors. Business people like to say that employees don’t quit their job, they quit their boss. If an employee quits – with or without notice – it may very well be because of a poor working relationship with you or the supervisor. To be effective, you and your supervisors need to be diligent in setting goals, managing performance, and applying workplace rules and policies. Numerous third-party companies provide training and guidance in these areas when needed.
• Recognize and reward. As I’ve written many times, positive feedback is a simple, low-cost way to improve employee retention. It demonstrates that you value an employee’s contributions and sets an excellent example for other employees. Effective recognition can come from anyone – including patients – and should be given openly. (Another old adage: “Praise publicly, criticize privately.”) It never hurts to catch an employee doing something right and acknowledge it.
• Don’t jump to conclusions. If a new hire or employee is absent without notice, don’t just assume you’ve been ghosted. There may be extenuating circumstances, such as an emergency or illness. In some states, an employee’s absence is protected under a law where the employee may not be required to provide advance notice, and taking adverse action could violate these laws. Establish procedures for attempting to contact absent employees, and make sure you’re complying with all applicable leave laws before taking any action.

If an employee does abandon their job, think before you act. Comply with all applicable laws. Act consistently with how you’ve handled similar situations in the past. Your attorney should be involved, especially if the decision involves termination. Notify the employee in writing. As with all employment decisions, keep adequate documentation in case the decision is ever challenged, or you need it to support future disciplinary decisions.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. He has no disclosures related to this column. Write to him at dermnews@mdedge.com.

The COVID-19 pandemic has affected private medical practices on so many levels, not least of which is the loss of employees to illness, fear of illness, early retirement, and other reasons. With so many practices forced to hire replacements, basically at the same time, it’s not surprising to see a significant and frustrating increase in ghosting.

ismagilov/iStock/Getty Images Plus

If you’re not hip to the slang, “ghosting” is the situation in which an employee disappears without any warning, notice, or explanation. It usually occurs after a candidate accepts a job offer, and you schedule their first day of work. That day dawns, but the new hire never arrives. Less commonly, an employee who has been with you for some time simply stops showing up and cannot be contacted.

Many employers think of ghosting as a relatively new phenomenon, and blame it on the irresponsibility of younger age groups – millennials, in particular. In fact, it has been an issue for many years across all age groups, and employers often share more of the responsibility than they think.

While total prevention is impossible, there are steps you can take as an employer to minimize ghosting in your practice.

• Your hiring process needs to be efficient. If you wait too long to schedule an interview with a promising candidate or to offer them the job, another job offer could lure them away. At the very least, a lengthy process or a lack of transparency may make the applicant apprehensive about accepting a job with you, particularly if other employers are pursuing them.
• Keep applicants in the loop. Follow up with every candidate; let them know where they are in your hiring process. Applicants who have no clue whether they have a shot at the job are going to start looking elsewhere. And make sure they know the job description and starting salary from the outset.
• Talk to new hires before their first day. Contact them personally to see if they have any questions or concerns, and let them know that you’re looking forward to their arrival.
• Once they start, make them feel welcome. An employee’s first few days on the job set the tone for the rest of the employment relationship. During this time, clearly communicate what the employee can expect from you and what you expect from them. Take time to discuss key issues, such as work schedules, timekeeping practices, how performance is measured, and dress codes. Introduce them to coworkers, and get them started shadowing more experienced staff members.
• Take a hard look at your supervision and your supervisors. Business people like to say that employees don’t quit their job, they quit their boss. If an employee quits – with or without notice – it may very well be because of a poor working relationship with you or the supervisor. To be effective, you and your supervisors need to be diligent in setting goals, managing performance, and applying workplace rules and policies. Numerous third-party companies provide training and guidance in these areas when needed.
• Recognize and reward. As I’ve written many times, positive feedback is a simple, low-cost way to improve employee retention. It demonstrates that you value an employee’s contributions and sets an excellent example for other employees. Effective recognition can come from anyone – including patients – and should be given openly. (Another old adage: “Praise publicly, criticize privately.”) It never hurts to catch an employee doing something right and acknowledge it.
• Don’t jump to conclusions. If a new hire or employee is absent without notice, don’t just assume you’ve been ghosted. There may be extenuating circumstances, such as an emergency or illness. In some states, an employee’s absence is protected under a law where the employee may not be required to provide advance notice, and taking adverse action could violate these laws. Establish procedures for attempting to contact absent employees, and make sure you’re complying with all applicable leave laws before taking any action.

If an employee does abandon their job, think before you act. Comply with all applicable laws. Act consistently with how you’ve handled similar situations in the past. Your attorney should be involved, especially if the decision involves termination. Notify the employee in writing. As with all employment decisions, keep adequate documentation in case the decision is ever challenged, or you need it to support future disciplinary decisions.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. He has no disclosures related to this column. Write to him at dermnews@mdedge.com.

The COVID-19 pandemic has affected private medical practices on so many levels, not least of which is the loss of employees to illness, fear of illness, early retirement, and other reasons. With so many practices forced to hire replacements, basically at the same time, it’s not surprising to see a significant and frustrating increase in ghosting.

ismagilov/iStock/Getty Images Plus

If you’re not hip to the slang, “ghosting” is the situation in which an employee disappears without any warning, notice, or explanation. It usually occurs after a candidate accepts a job offer, and you schedule their first day of work. That day dawns, but the new hire never arrives. Less commonly, an employee who has been with you for some time simply stops showing up and cannot be contacted.

Many employers think of ghosting as a relatively new phenomenon, and blame it on the irresponsibility of younger age groups – millennials, in particular. In fact, it has been an issue for many years across all age groups, and employers often share more of the responsibility than they think.

While total prevention is impossible, there are steps you can take as an employer to minimize ghosting in your practice.

• Your hiring process needs to be efficient. If you wait too long to schedule an interview with a promising candidate or to offer them the job, another job offer could lure them away. At the very least, a lengthy process or a lack of transparency may make the applicant apprehensive about accepting a job with you, particularly if other employers are pursuing them.
• Keep applicants in the loop. Follow up with every candidate; let them know where they are in your hiring process. Applicants who have no clue whether they have a shot at the job are going to start looking elsewhere. And make sure they know the job description and starting salary from the outset.
• Talk to new hires before their first day. Contact them personally to see if they have any questions or concerns, and let them know that you’re looking forward to their arrival.
• Once they start, make them feel welcome. An employee’s first few days on the job set the tone for the rest of the employment relationship. During this time, clearly communicate what the employee can expect from you and what you expect from them. Take time to discuss key issues, such as work schedules, timekeeping practices, how performance is measured, and dress codes. Introduce them to coworkers, and get them started shadowing more experienced staff members.
• Take a hard look at your supervision and your supervisors. Business people like to say that employees don’t quit their job, they quit their boss. If an employee quits – with or without notice – it may very well be because of a poor working relationship with you or the supervisor. To be effective, you and your supervisors need to be diligent in setting goals, managing performance, and applying workplace rules and policies. Numerous third-party companies provide training and guidance in these areas when needed.
• Recognize and reward. As I’ve written many times, positive feedback is a simple, low-cost way to improve employee retention. It demonstrates that you value an employee’s contributions and sets an excellent example for other employees. Effective recognition can come from anyone – including patients – and should be given openly. (Another old adage: “Praise publicly, criticize privately.”) It never hurts to catch an employee doing something right and acknowledge it.
• Don’t jump to conclusions. If a new hire or employee is absent without notice, don’t just assume you’ve been ghosted. There may be extenuating circumstances, such as an emergency or illness. In some states, an employee’s absence is protected under a law where the employee may not be required to provide advance notice, and taking adverse action could violate these laws. Establish procedures for attempting to contact absent employees, and make sure you’re complying with all applicable leave laws before taking any action.

If an employee does abandon their job, think before you act. Comply with all applicable laws. Act consistently with how you’ve handled similar situations in the past. Your attorney should be involved, especially if the decision involves termination. Notify the employee in writing. As with all employment decisions, keep adequate documentation in case the decision is ever challenged, or you need it to support future disciplinary decisions.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. He has no disclosures related to this column. Write to him at dermnews@mdedge.com.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Dermatology residency can feel like drinking from a firehose, in which one is bombarded with so much information that it is impossible to retain any content. This article provides an overview of available resources and a guide on how to tailor studying throughout one’s training.

Prior to Residency

There are several resources that provide an introduction to dermatology and are appropriate for all medical students, regardless of intended specialty. The American Academy of Dermatology offers a free basic dermatology curriculum (https://www.aad.org/member/education/residents/bdc), with a choice of a 2- or 4-week course consisting of modules such as skin examination, basic science of the skin, dermatologic therapies, and specific dermatologic conditions. VisualDx offers LearnDerm (https://www.visualdx.com/learnderm/), which includes a 5-part tutorial and quiz focused on the skin examination, morphology, and lesion distribution. Lookingbill and Marks’ Principles of Dermatology¹ is a book at an appropriate level for a medical student to learn about the fundamentals of dermatology. These resources may be helpful for residents to review immediately before starting dermatology residency (toward the end of intern year for most).

First Year

During the beginning of dermatology residency (postgraduate year [PGY] 2 for most), the fire hose of information feels most daunting. During this time, studying should focus on engendering a broad overview of dermatology. Most residencies maintain a textbook reading schedule, which provides a framework from which residents may structure their studying. Selection of a textbook tends to be program dependent. Even if the details of reading the textbook do not stick when reading it the first time, benefits include becoming familiar with what information one is expected to learn as a dermatologist and developing a strong foundation upon which one may continue to build. Based on my informal discussions with current residents, some reported that reading the textbook did not work well for them, citing too much minutiae in the textbooks and/or a preference for a more active learning approach. These residents instead focused on reading a review book for a broad overview, accompanied by a textbook or VisualDx when a more detailed reference is necessary. Table 1 provides a list of textbooks and mobile applications (apps) that residents may find helpful.

First-year residents may begin their efforts in synthesizing this new knowledge base toward the end of the year in preparation for the BASIC examination. The American Board of Dermatology provides a content outline as well as sample questions on their website (https://www.abderm.org/residents-and-fellows/exam-of-the-future-information-center.aspx#content), which may be used to guide more focused studying efforts during the weeks leading up to the examination.

Second Year

For second-year residents (PGY-3 for most) studying should focus on deepening and consolidating the broad foundation that was established during their first year. For many, this pursuit involves rereading the textbook chapters alongside more active learning measures, such as taking notes and quizzing oneself using flashcard apps and question banks (Table 2). Others may benefit from listening to podcasts (Table 3) or other sources utilizing audiovisual content, including attending conferences and other lectures virtually, which is becoming increasingly available in the setting of the coronavirus disease 2019 pandemic (Table 4). Because there are so many resources available to support these efforts, residents should be encouraged to try out a variety to determine what works best.

Toward the end of second year, studying may be tailored to preparing for the CORE examinations using the resources of one’s choice. Based on my discussions with current residents, a combination of reading review books, reviewing one’s personal notes, and quizzing through question banks and/or flashcard apps could be used.

In addition to maintaining a consistent and organized study schedule, second-year residents should continue to read in depth on topics related to patients for whom they are caring and stay on top of the dermatology literature. Table 5 provides a list of medical journals that dermatology residents should aim to read. The Journal of the American Academy of Dermatology’s continuing medical education series (https://www.jaad.org/content/collection-cme) may be particularly helpful to residents. In this series, experts review a variety of dermatologic topics in depth paired with quiz questions.

Third Year

As a third-year resident (PGY-4 for most), studying should focus on deepening one’s knowledge base and beginning preparation for the boards examination. At this point, residents should stick to a limited selection of resources (ie, 1 textbook, 1 review book, 1 question bank) for in-depth study. More time should be spent on active learning, such as note-taking and question banks. Boards review courses historically have been available to dermatology residents, namely the Barron Board Review course and a plenary session at the American Academy of Dermatology Annual Conference (Table 4).

Consistent Habits

Studying strategies can and should differ throughout dermatology residency, though consistency is necessary throughout. It is helpful to plan study schedules in advance—yearly, monthly, weekly—and aim to stick to them as much as possible. Finding what works for each individual may take trial and error. For some, it may mean waking up early to study before work, whereas others may do better in the evenings. It also is helpful to utilize a combination of longer blocks of studying (ie, weekend days), with consistent shorter blocks of time during the week. Many residents also learn to take advantage of time spent commuting by listening to podcasts in the car or reading while on public transportation.

Final Thoughts

There are many resources available to support residents in their learning such as textbooks, journals, podcasts, flashcards, question banks, and more. The path to mastery will be individualized for each resident, likely using a unique combination of resources. The beginning of residency is a good time to explore a variety of resources to see what works best, whereas at the end studying becomes more targeted.

Dermatology residency can feel like drinking from a firehose, in which one is bombarded with so much information that it is impossible to retain any content. This article provides an overview of available resources and a guide on how to tailor studying throughout one’s training.

Prior to Residency

There are several resources that provide an introduction to dermatology and are appropriate for all medical students, regardless of intended specialty. The American Academy of Dermatology offers a free basic dermatology curriculum (https://www.aad.org/member/education/residents/bdc), with a choice of a 2- or 4-week course consisting of modules such as skin examination, basic science of the skin, dermatologic therapies, and specific dermatologic conditions. VisualDx offers LearnDerm (https://www.visualdx.com/learnderm/), which includes a 5-part tutorial and quiz focused on the skin examination, morphology, and lesion distribution. Lookingbill and Marks’ Principles of Dermatology¹ is a book at an appropriate level for a medical student to learn about the fundamentals of dermatology. These resources may be helpful for residents to review immediately before starting dermatology residency (toward the end of intern year for most).

First Year

During the beginning of dermatology residency (postgraduate year [PGY] 2 for most), the fire hose of information feels most daunting. During this time, studying should focus on engendering a broad overview of dermatology. Most residencies maintain a textbook reading schedule, which provides a framework from which residents may structure their studying. Selection of a textbook tends to be program dependent. Even if the details of reading the textbook do not stick when reading it the first time, benefits include becoming familiar with what information one is expected to learn as a dermatologist and developing a strong foundation upon which one may continue to build. Based on my informal discussions with current residents, some reported that reading the textbook did not work well for them, citing too much minutiae in the textbooks and/or a preference for a more active learning approach. These residents instead focused on reading a review book for a broad overview, accompanied by a textbook or VisualDx when a more detailed reference is necessary. Table 1 provides a list of textbooks and mobile applications (apps) that residents may find helpful.

First-year residents may begin their efforts in synthesizing this new knowledge base toward the end of the year in preparation for the BASIC examination. The American Board of Dermatology provides a content outline as well as sample questions on their website (https://www.abderm.org/residents-and-fellows/exam-of-the-future-information-center.aspx#content), which may be used to guide more focused studying efforts during the weeks leading up to the examination.

Second Year

For second-year residents (PGY-3 for most) studying should focus on deepening and consolidating the broad foundation that was established during their first year. For many, this pursuit involves rereading the textbook chapters alongside more active learning measures, such as taking notes and quizzing oneself using flashcard apps and question banks (Table 2). Others may benefit from listening to podcasts (Table 3) or other sources utilizing audiovisual content, including attending conferences and other lectures virtually, which is becoming increasingly available in the setting of the coronavirus disease 2019 pandemic (Table 4). Because there are so many resources available to support these efforts, residents should be encouraged to try out a variety to determine what works best.

Toward the end of second year, studying may be tailored to preparing for the CORE examinations using the resources of one’s choice. Based on my discussions with current residents, a combination of reading review books, reviewing one’s personal notes, and quizzing through question banks and/or flashcard apps could be used.

In addition to maintaining a consistent and organized study schedule, second-year residents should continue to read in depth on topics related to patients for whom they are caring and stay on top of the dermatology literature. Table 5 provides a list of medical journals that dermatology residents should aim to read. The Journal of the American Academy of Dermatology’s continuing medical education series (https://www.jaad.org/content/collection-cme) may be particularly helpful to residents. In this series, experts review a variety of dermatologic topics in depth paired with quiz questions.

Third Year

As a third-year resident (PGY-4 for most), studying should focus on deepening one’s knowledge base and beginning preparation for the boards examination. At this point, residents should stick to a limited selection of resources (ie, 1 textbook, 1 review book, 1 question bank) for in-depth study. More time should be spent on active learning, such as note-taking and question banks. Boards review courses historically have been available to dermatology residents, namely the Barron Board Review course and a plenary session at the American Academy of Dermatology Annual Conference (Table 4).

Consistent Habits

Studying strategies can and should differ throughout dermatology residency, though consistency is necessary throughout. It is helpful to plan study schedules in advance—yearly, monthly, weekly—and aim to stick to them as much as possible. Finding what works for each individual may take trial and error. For some, it may mean waking up early to study before work, whereas others may do better in the evenings. It also is helpful to utilize a combination of longer blocks of studying (ie, weekend days), with consistent shorter blocks of time during the week. Many residents also learn to take advantage of time spent commuting by listening to podcasts in the car or reading while on public transportation.

Final Thoughts

There are many resources available to support residents in their learning such as textbooks, journals, podcasts, flashcards, question banks, and more. The path to mastery will be individualized for each resident, likely using a unique combination of resources. The beginning of residency is a good time to explore a variety of resources to see what works best, whereas at the end studying becomes more targeted.

Dermatology residency can feel like drinking from a firehose, in which one is bombarded with so much information that it is impossible to retain any content. This article provides an overview of available resources and a guide on how to tailor studying throughout one’s training.

Prior to Residency

There are several resources that provide an introduction to dermatology and are appropriate for all medical students, regardless of intended specialty. The American Academy of Dermatology offers a free basic dermatology curriculum (https://www.aad.org/member/education/residents/bdc), with a choice of a 2- or 4-week course consisting of modules such as skin examination, basic science of the skin, dermatologic therapies, and specific dermatologic conditions. VisualDx offers LearnDerm (https://www.visualdx.com/learnderm/), which includes a 5-part tutorial and quiz focused on the skin examination, morphology, and lesion distribution. Lookingbill and Marks’ Principles of Dermatology¹ is a book at an appropriate level for a medical student to learn about the fundamentals of dermatology. These resources may be helpful for residents to review immediately before starting dermatology residency (toward the end of intern year for most).

First Year

During the beginning of dermatology residency (postgraduate year [PGY] 2 for most), the fire hose of information feels most daunting. During this time, studying should focus on engendering a broad overview of dermatology. Most residencies maintain a textbook reading schedule, which provides a framework from which residents may structure their studying. Selection of a textbook tends to be program dependent. Even if the details of reading the textbook do not stick when reading it the first time, benefits include becoming familiar with what information one is expected to learn as a dermatologist and developing a strong foundation upon which one may continue to build. Based on my informal discussions with current residents, some reported that reading the textbook did not work well for them, citing too much minutiae in the textbooks and/or a preference for a more active learning approach. These residents instead focused on reading a review book for a broad overview, accompanied by a textbook or VisualDx when a more detailed reference is necessary. Table 1 provides a list of textbooks and mobile applications (apps) that residents may find helpful.

First-year residents may begin their efforts in synthesizing this new knowledge base toward the end of the year in preparation for the BASIC examination. The American Board of Dermatology provides a content outline as well as sample questions on their website (https://www.abderm.org/residents-and-fellows/exam-of-the-future-information-center.aspx#content), which may be used to guide more focused studying efforts during the weeks leading up to the examination.

Second Year

For second-year residents (PGY-3 for most) studying should focus on deepening and consolidating the broad foundation that was established during their first year. For many, this pursuit involves rereading the textbook chapters alongside more active learning measures, such as taking notes and quizzing oneself using flashcard apps and question banks (Table 2). Others may benefit from listening to podcasts (Table 3) or other sources utilizing audiovisual content, including attending conferences and other lectures virtually, which is becoming increasingly available in the setting of the coronavirus disease 2019 pandemic (Table 4). Because there are so many resources available to support these efforts, residents should be encouraged to try out a variety to determine what works best.

Toward the end of second year, studying may be tailored to preparing for the CORE examinations using the resources of one’s choice. Based on my discussions with current residents, a combination of reading review books, reviewing one’s personal notes, and quizzing through question banks and/or flashcard apps could be used.

In addition to maintaining a consistent and organized study schedule, second-year residents should continue to read in depth on topics related to patients for whom they are caring and stay on top of the dermatology literature. Table 5 provides a list of medical journals that dermatology residents should aim to read. The Journal of the American Academy of Dermatology’s continuing medical education series (https://www.jaad.org/content/collection-cme) may be particularly helpful to residents. In this series, experts review a variety of dermatologic topics in depth paired with quiz questions.

Third Year

As a third-year resident (PGY-4 for most), studying should focus on deepening one’s knowledge base and beginning preparation for the boards examination. At this point, residents should stick to a limited selection of resources (ie, 1 textbook, 1 review book, 1 question bank) for in-depth study. More time should be spent on active learning, such as note-taking and question banks. Boards review courses historically have been available to dermatology residents, namely the Barron Board Review course and a plenary session at the American Academy of Dermatology Annual Conference (Table 4).

Consistent Habits

Studying strategies can and should differ throughout dermatology residency, though consistency is necessary throughout. It is helpful to plan study schedules in advance—yearly, monthly, weekly—and aim to stick to them as much as possible. Finding what works for each individual may take trial and error. For some, it may mean waking up early to study before work, whereas others may do better in the evenings. It also is helpful to utilize a combination of longer blocks of studying (ie, weekend days), with consistent shorter blocks of time during the week. Many residents also learn to take advantage of time spent commuting by listening to podcasts in the car or reading while on public transportation.

Final Thoughts

There are many resources available to support residents in their learning such as textbooks, journals, podcasts, flashcards, question banks, and more. The path to mastery will be individualized for each resident, likely using a unique combination of resources. The beginning of residency is a good time to explore a variety of resources to see what works best, whereas at the end studying becomes more targeted.

To the Editor:

Severe dystrophic calcinosis cutis is a debilitating disease with no universally accepted therapeutic options. This case demonstrates the benefit of intravenous (IV) sodium thiosulfate in alleviating the calcified lesions as well as the associated pain and disability. This application of IV sodium thiosulfate with a favorable outcome is new and should be considered for the treatment of generalized dystrophic calcinosis cutis, especially when topical, procedural, or surgical options are not feasible.

A 54-year-old woman with a history of well-controlled dermatomyositis and systemic lupus erythematosus presented with diffuse, hard, calcified lesions on the legs, arms, clavicular region, and neck that had slowly progressed over at least a 10-year period (Figure 1). The lesions were consistent with dystrophic calcinosis cutis. The patient was started on 12.5 g of IV sodium thiosulfate 3 times weekly infused over 30 minutes. Drastic diminution of the cutaneous calcification was observed at 3-month follow-up (Figure 2). She reported decreased pain and burning as well as increased overall functionality and improved sleep. The patient completed 8 months of therapy, but the treatment was stopped secondary to suspicion of a lupuslike flare, and the lesions recurred with more widespread involvement, including the trunk, tendons, bony prominences, and supraclavicular soft tissue. The patient reported burning pain and pruritus that resulted in impairment of daily activities such as getting dressed. Sodium thiosulfate was restarted once weekly, which again resulted in reduction of the dystrophic calcinosis cutis.

Intravenous sodium thiosulfate has been widely used for the treatment of calciphylaxis secondary to end-stage renal failure and tumoral calcinosis.² It also has been reported to be effective in iatrogenic calcinosis cutis secondary to extravasation of calcium-containing solutions in a patient with T-cell acute lymphoblastic leukemia.³ However, reports of its use in treating dystrophic calcinosis cutis are limited. Intravenous sodium thiosulfate—10 g 3 times weekly for 2 weeks, followed by 15 g twice weekly for the next 3 months—was used with abatacept for treatment of dystrophic calcinosis cutis in a patient with juvenile dermatomyositis.⁴ Other formulations of sodium thiosulfate have been reported to result in clearance of calcified lesions, including a topical application compounded in zinc oxide⁵ and intradermal injection at the base of a nodule.⁶ We used 12.5 g over 30 minutes 3 times weekly; however, the dose can be increased to 25 g over 60 minutes if 3 to 4 treatments are tolerated, with nausea being the only notable side effect. Its mechanism of action in treating dystrophic calcinosis cutis is unclear, but it likely is due to its ability to chelate and dissolve calcium deposits. Topical and intradermal therapy is impractical for widespread, dystrophic calcinosis cutis as in our patient.

Our case highlights the successful use of IV sodium thiosulfate as a stand-alone treatment modality for generalized dystrophic calcinosis cutis in an adult patient. Both our patient and a child in a previously reported case who received the same treatment⁴ had dermatomyositis, but we suspect IV sodium thiosulfate also may be effective for dystrophic calcinosis cutis associated with other diseases. Sodium thiosulfate should be considered as a treatment for patients who experience tremendous pain and disability. It is safe, inexpensive, and easy to administer and is especially helpful in patients for whom topical, intradermal, or procedural therapy is not possible.

To the Editor:

Severe dystrophic calcinosis cutis is a debilitating disease with no universally accepted therapeutic options. This case demonstrates the benefit of intravenous (IV) sodium thiosulfate in alleviating the calcified lesions as well as the associated pain and disability. This application of IV sodium thiosulfate with a favorable outcome is new and should be considered for the treatment of generalized dystrophic calcinosis cutis, especially when topical, procedural, or surgical options are not feasible.

A 54-year-old woman with a history of well-controlled dermatomyositis and systemic lupus erythematosus presented with diffuse, hard, calcified lesions on the legs, arms, clavicular region, and neck that had slowly progressed over at least a 10-year period (Figure 1). The lesions were consistent with dystrophic calcinosis cutis. The patient was started on 12.5 g of IV sodium thiosulfate 3 times weekly infused over 30 minutes. Drastic diminution of the cutaneous calcification was observed at 3-month follow-up (Figure 2). She reported decreased pain and burning as well as increased overall functionality and improved sleep. The patient completed 8 months of therapy, but the treatment was stopped secondary to suspicion of a lupuslike flare, and the lesions recurred with more widespread involvement, including the trunk, tendons, bony prominences, and supraclavicular soft tissue. The patient reported burning pain and pruritus that resulted in impairment of daily activities such as getting dressed. Sodium thiosulfate was restarted once weekly, which again resulted in reduction of the dystrophic calcinosis cutis.

Intravenous sodium thiosulfate has been widely used for the treatment of calciphylaxis secondary to end-stage renal failure and tumoral calcinosis.² It also has been reported to be effective in iatrogenic calcinosis cutis secondary to extravasation of calcium-containing solutions in a patient with T-cell acute lymphoblastic leukemia.³ However, reports of its use in treating dystrophic calcinosis cutis are limited. Intravenous sodium thiosulfate—10 g 3 times weekly for 2 weeks, followed by 15 g twice weekly for the next 3 months—was used with abatacept for treatment of dystrophic calcinosis cutis in a patient with juvenile dermatomyositis.⁴ Other formulations of sodium thiosulfate have been reported to result in clearance of calcified lesions, including a topical application compounded in zinc oxide⁵ and intradermal injection at the base of a nodule.⁶ We used 12.5 g over 30 minutes 3 times weekly; however, the dose can be increased to 25 g over 60 minutes if 3 to 4 treatments are tolerated, with nausea being the only notable side effect. Its mechanism of action in treating dystrophic calcinosis cutis is unclear, but it likely is due to its ability to chelate and dissolve calcium deposits. Topical and intradermal therapy is impractical for widespread, dystrophic calcinosis cutis as in our patient.

Our case highlights the successful use of IV sodium thiosulfate as a stand-alone treatment modality for generalized dystrophic calcinosis cutis in an adult patient. Both our patient and a child in a previously reported case who received the same treatment⁴ had dermatomyositis, but we suspect IV sodium thiosulfate also may be effective for dystrophic calcinosis cutis associated with other diseases. Sodium thiosulfate should be considered as a treatment for patients who experience tremendous pain and disability. It is safe, inexpensive, and easy to administer and is especially helpful in patients for whom topical, intradermal, or procedural therapy is not possible.

To the Editor:

Severe dystrophic calcinosis cutis is a debilitating disease with no universally accepted therapeutic options. This case demonstrates the benefit of intravenous (IV) sodium thiosulfate in alleviating the calcified lesions as well as the associated pain and disability. This application of IV sodium thiosulfate with a favorable outcome is new and should be considered for the treatment of generalized dystrophic calcinosis cutis, especially when topical, procedural, or surgical options are not feasible.

A 54-year-old woman with a history of well-controlled dermatomyositis and systemic lupus erythematosus presented with diffuse, hard, calcified lesions on the legs, arms, clavicular region, and neck that had slowly progressed over at least a 10-year period (Figure 1). The lesions were consistent with dystrophic calcinosis cutis. The patient was started on 12.5 g of IV sodium thiosulfate 3 times weekly infused over 30 minutes. Drastic diminution of the cutaneous calcification was observed at 3-month follow-up (Figure 2). She reported decreased pain and burning as well as increased overall functionality and improved sleep. The patient completed 8 months of therapy, but the treatment was stopped secondary to suspicion of a lupuslike flare, and the lesions recurred with more widespread involvement, including the trunk, tendons, bony prominences, and supraclavicular soft tissue. The patient reported burning pain and pruritus that resulted in impairment of daily activities such as getting dressed. Sodium thiosulfate was restarted once weekly, which again resulted in reduction of the dystrophic calcinosis cutis.

Intravenous sodium thiosulfate has been widely used for the treatment of calciphylaxis secondary to end-stage renal failure and tumoral calcinosis.² It also has been reported to be effective in iatrogenic calcinosis cutis secondary to extravasation of calcium-containing solutions in a patient with T-cell acute lymphoblastic leukemia.³ However, reports of its use in treating dystrophic calcinosis cutis are limited. Intravenous sodium thiosulfate—10 g 3 times weekly for 2 weeks, followed by 15 g twice weekly for the next 3 months—was used with abatacept for treatment of dystrophic calcinosis cutis in a patient with juvenile dermatomyositis.⁴ Other formulations of sodium thiosulfate have been reported to result in clearance of calcified lesions, including a topical application compounded in zinc oxide⁵ and intradermal injection at the base of a nodule.⁶ We used 12.5 g over 30 minutes 3 times weekly; however, the dose can be increased to 25 g over 60 minutes if 3 to 4 treatments are tolerated, with nausea being the only notable side effect. Its mechanism of action in treating dystrophic calcinosis cutis is unclear, but it likely is due to its ability to chelate and dissolve calcium deposits. Topical and intradermal therapy is impractical for widespread, dystrophic calcinosis cutis as in our patient.

Our case highlights the successful use of IV sodium thiosulfate as a stand-alone treatment modality for generalized dystrophic calcinosis cutis in an adult patient. Both our patient and a child in a previously reported case who received the same treatment⁴ had dermatomyositis, but we suspect IV sodium thiosulfate also may be effective for dystrophic calcinosis cutis associated with other diseases. Sodium thiosulfate should be considered as a treatment for patients who experience tremendous pain and disability. It is safe, inexpensive, and easy to administer and is especially helpful in patients for whom topical, intradermal, or procedural therapy is not possible.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.