Annotated Abstracts of Journal Articles
2014, 3rd Quarter
Annotations by Oliver Freudenreich, MD, FAPM and Mary Ann Cohen, MD, FAPM
Also of interest:
Gandhi and Gandhi (we learned that they are sibling ID doctors, one practicing on the West coast and one on the East coast) provide a clinically helpful summary of single-pill treatment options for patients with HIV infection. Since publishing their article, a forth single-pill regimen they discuss as pending FDA approval has been approved by the FDA in August of this year (Triumeq which combines the integrase inhibitor dolutegravir with abacavir and lamivudine).
The July 23-30, 2014 issue of JAMA features HIV/AIDS in a mostly topical journal issue. Special communications include the 2014 Recommendations of the International Antiviral Society – USA Panel (IAS-USA) for HIV prevention in clinical care settings and for antiretroviral treatment of adult HIV infection (as well as several viewpoints and editorials).
A brief report on the efforts of the field to figure out how to best screen for HIV-associated neurocognitive disorder (HAND), including in aging patients with HIV/AIDS whose numbers are increasing as patients with HIV survive longer and longer. For patients older than age 60, the MOCA, which includes measure of executive function, showed only moderate performance characteristics (sensitivity of 72% and specificity of 67%). Still, the MOCA is much preferred over the MMSE which should not be used to screen for HAND.
Mollan KR, Smurzynski M, Eron JJ, et al
Ann Intern Med 2014 Jul 1; 161(1):1-10
ANNOTATION (Freudenreich & Cohen)
The Finding: Using data from four AIDS Clinical Trial Group studies of treatment-naive patients with HIV who commenced on randomized treatment with a cART regimen, the risk of suicidality (defined as suicidal ideation or attempted or completed suicide) was twice as high for patients randomly assigned to an efavirenz-containing regimen compared to efavirenz-free regimens. Eight of the observed nine suicides were in the efavirenz group.
Strength and Weaknesses: This is the first analysis using data about suicidality from random assignment to treatment regimens with or without efavirenz. Still, 3 of the 4 trials were open label; with suicide already listed in the prescribing information as a complication, reporting bias is possible. Suicidality was further not assessed with a standard rating scale, and patients deemed at higher risk for suicidality might not have been referred to these four trials to begin with. Last, efavirenz was not compared to regimens containing other NNRTIs or integrase inhibitors.
Relevance: The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (brand name Sustiva) has been an important cornerstone medication for the treatment of HIV/AIDS because of its excellent antiretroviral efficacy. It is also included in the most widely used single-pill regimen (brand name Atripla). However, its use has always been complicated by a higher rate of neuropsychiatric side effects and anecdotal observations of serious events like suicidality. This analysis using date from randomized trials provides the best evidence yet that these clinical observations are true and that there is in fact some risk of suicidality (including death from suicide) due to the use of efavirenz. Careful clinical monitoring for psychiatric problems is thus needed for patients starting efavirenz. Next-generation NNRTIs like relpivirine (brand name Edurant, also in single-pill regimen Complera) seem to have a lower risk for neuropsychiatric complications and might eventually become preferred over efavirenz, at least in a setting where the higher cost of newer (non-generic) medications can be absorbed.
Background: The relationship between efavirenz use and suicidality is not well-defined.
Objective: To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV.
Design: Participant-level data were analyzed from 4 AIDS Clinical Trials Group, antiretroviral-naive studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n = 3241) or efavirenz-free (n = 2091) regimen. (ClinicalTrials.gov: NCT00013520 [A5095], NCT00050895 [A5142], NCT00084136 [A5175], and NCT00118898 [A5202]).
Setting: AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States.
Patients: Antiretroviral-naive participants.
Intervention: Efavirenz versus efavirenz-free regimens.
Measurements: Suicidality was defined as suicidal ideation or attempted or completed suicide. Groups were compared with a hazard ratio and 95% CI estimated from a Cox model, stratified by study.
Results: Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 [95% CI, 1.27 to 4.10]; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 [CI, 0.94 to 7.06]; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported.
Limitation: There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies.
Conclusion: Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz.
ANNOTATION (Freudenreich & Cohen)
The Finding: Using previously collected data from the HIV-CAUSAL Collaboration, the authors were able to prospectively assess the risk of developing four AIDS-defining neurological conditions (HIV dementia, toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy) as a function of the selected antiretroviral treatment regimen (based on treatments with low, medium, or high so-called CPE scores that provide a summary score for the ability of antiretroviral regimens to penetrate into the CNS). Unexpectedly, the incidence of HIV dementia increased by over 70% if treatment was initiated with a high CPE score regimen compared to a low CPE score regimen. It was hoped that high CPE-score regimens would have a protective effect.
Strength and Weaknesses: While the largest study to date, the number of events (235 cases of HIV dementia in the data set of over 60,000 patients) was still small which leads to large confidence intervals. As in any observational study, confounding variables and selection bias could lead to spurious results. The authors did not detect confounding by indication effects in secondary analyses.
Relevance: Preventing HIV-associated neurocognitive disorders (HAND) is one remaining frontier in the long-term management of patients with HIV/AIDS. The title of the editorial that accompanies this article says it all: Berger JR, Clifford DB: The relationship of CPE to HIV dementia: slain by an ugly fact?, Neurology 2014; 83(2):109-110. It would have been nice if this study had found a protective effect regarding the development of HIV dementia by using cART regimens with a high CPE score. At this point, selecting cART regimens based on CPE scores for the prevention of HAND is premature. More work is needed to develop the best cART regimen (perhaps using next-generation CPE scores) to prevent the full spectrum of HAND.
Objective: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown.
Methods: HIV-infected, antiretroviral therapy-naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8-9), or high (>9) CPE score. We estimated “intention-to-treat” hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up.
Results: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58).
Conclusions: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.