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ID Week 2013: Antiretroviral Therapy
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Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
The NNRTI efavirenz (EFV) has been in clinical use since 1998 and serves as the anchor drug in some of the most effective antiretroviral therapy (ART) regimens. It has for many years been the only NNRTI granted preferred status in HIV treatment guidelines. The fixed-dose combination of EFV, tenofovir DF and emtricitabine is the most frequently prescribed ART regimen in developed countries. Its success came despite the frequent occurrence of neuropsychiatric adverse effects that typically include transient dizziness, somnolence, vivid dreams and clouded mentation, although some patients experience persistent symptoms. Uncommonly, it can cause more severe acute symptoms such as hallucinations, behavioral or personality changes or psychosis. Controversy exists as to whether long-term EFV exacerbates depression. Suicidality has been reported in patients on EFV, but also occurs at an increased rate in the HIV-infected individuals not using EFV. To determine if EFV use is associated with an increased risk of suicidality, Mollan et al. collected all reports of suicidal ideation, suicide attempt or completed suicide among individuals participating in four ACTG trials that randomized patients to an EFV-containing or EFV-free ART [1]. The analysis was large (EFV n=3241; EFV-free n=2091) and the two groups were well balanced for baseline characteristics that might affect suicide risk. There were 47 events (8.08/1,000 patient-years) in the EFV group and 15 events (3.66/1,000 patient-years) in the EFV-free group. A Cox proportional hazards model yielded a hazard ratio (HR) of 2.28 (95% CI 1.27-4.10, p=0.006) for suicidality. When only attempted and completed suicide was considered, there were 17 and 5 events in the EFV and EFV-free groups, respectively (HR 2.58, 95% CI 0.94-7.06, p=0.06). Combined deaths attributed to suicide, accident, substance abuse, homicide or unknown causes were increased in EFV recipients (HR 2.46, p=0.03) while deaths due to other causes were not. Factors significantly associated with suicidality were randomization to EFV, age <30, history of IDU and prior psychiatric history.
The findings of this study are bolstered by its size and randomized assignment to therapy. Limitations include lack of blinding in 3 or the 4 studies and lack of standardized reporting of suicidality. Although attempted or completed suicide was reported uncommonly in this study (less than 0.5% on EFV), EFV use appeared to increase the risk 2-2.5-fold. Deaths due to suicide plus accidents, overdose or unknown causes appeared to be increased, suggesting the possibility that some suicides may be misclassified or that EFV treatment may in other ways contribute to accidental deaths. Patients with a psychiatric history are at greatest risk. Alternative regimens should be considered in these cases.
However, only one of the 5 regimens included in the EFV-free comparison group in this study is currently considered a guidelines preferred regimen. Other, simple, effective EFV-free regimens are now available. Analyses similar to this one should be conducted with these agents to assess the risk of suicidality.
For initial ART in patient for whom efavirenz is not a suitable choice, including those with an increased risk for suicidality, one of two ritonavir boosted protease inhibitors (atazanavir or darunavir) or the integrase inhibitor raltegarvir may be used. Other NNRTIs, nevirapine and rilpivirine are given alternate guidelines status, and neither is ideal due to problems with toxicity, potency or both. Etravirine (ETR) is an NNRTI developed for use in NNRTI-experienced patients because it retains activity against certain common NNRTI resistance mutations. In that patient population, it has a favorable safety and potency profile when dosed at 200 mg twice daily, but was not adequately studied or FDA-approved for treatment-naive patients. Floris-Moore et al. reported 24 week results of a planned 96 week, single arm, open-label study of ETR 400 mg once daily combined with tenofovir DF and emtricitabine in 80 treatment-naive patients [2]. The median baseline CD4 was 382/mm3 and the HIV RNA 4.52 logs. Twenty patients had baseline HIV RNA >100,000/mL. Eighty-six percent achieved HIV RNA <50 copies/ mL. The increase in CD4 from baseline was 156/mm3 . There were 5 premature discontinuations, including 2 for rash, 1 missing data and 5 with virologic failure. Only a single case of emergent resistance was documented. Neuropsychiatric adverse effects were reported in only 2 patients. Grade 2 AST/ALT elevations were seen in 5 participants and grade 3/4 in one with hepatitis B co-infection. This study is small, unblinded, non-comparative, the baseline viral load is fairly low and the reported data is an interim analysis. Nevertheless, the preliminary findings are consistent with a previously published randomized, double-blind, 48 week, phase II study (Sense Trial) comparing once-daily ETR to EFV. That study demonstrated non-inferior efficacy and low rates of neuropsychiatric adverse events. A large, well powered comparative trial would be needed for definitive proof that ETR-based ART is equivalent to current standard of care, but this trial adds to already suggestive evidence that ETR may be a reasonable alternative to EFV-based ART.
1. Mollan K, Smurzynski M, Na L, et al. Hazard of Suicidality in Patients Randomly Assigned to Efavirenz for Initial Treatment of HIV-1: a Cross-Study Analysis Conducted by the AIDS Clinical Trials Group (ACTG). ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 670
2. Floris-Moore M, Mollan K, Wilkin AM et al. Antiretroviral Activity and Safety of Once-daily Etravirine in Treatment-naïve HIV-infected Adults. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 170.
ID Week: Low Risk but Twice Higher Risk of Suicidal Thoughts or Acts on First-Line Efavirenz
ID Week: Once-Daily Etravirine Effective Through 24 Weeks in Three-Center Study
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ID Week HIV Articles...
ID Week
October 2-6, 2013
San Francisco
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