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Comparative Safety and Neuropsychiatric Adverse Events Associated With Efavirenz Use in First-Line Antiretroviral Therapy

A Systematic Review and Meta-Analysis of Randomized Trials

Ford, Nathan MPH, PhD*; Shubber, Zara MBBCh, MSc; Pozniak, Anton MD; Vitoria, Marco MD*; Doherty, Meg MD, PhD*; Kirby, Catherine MBChB§; Calmy, Alexandra MD, PhD

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1, 2015 - Volume 69 - Issue 4 - p 422-429
doi: 10.1097/QAI.0000000000000606

Abstract

INTRODUCTION

Efavirenz (EFV) has been widely used as part of triple-combination first-line therapy for over 15 years and is recommended by the World Health Organization (WHO)1 and national guidelines in both low- and high-income countries2,3 as a preferred antiretroviral drug for the treatment of antiretroviral-naive HIV-positive individuals. This preference is justified by its high virological efficacy,4 availability as a fixed-dose combination and once-daily administration, compatibility with tuberculosis treatment,5 reassuring data regarding its safety in pregnancy,6 and better safety profile compared with the widely used alternative, nevirapine.7

With the recent development of new drugs with potentially improved efficacy and safety, the preference given to EFV in initial HIV therapy has come into question. Results of several trials comparing EFV with recently developed antiretroviral agents have suggested inferiority,8–10 and this has led to calls to challenge EFV as the preferred drug for first-line antiretroviral therapy (ART).11–13 Nevertheless, EFV is a widely used drug in both high- and low-income settings, and the risk of severe adverse events overall is not well characterized.

We conducted this systematic review to comprehensively evaluate the safety of EFV compared with other antiretroviral agents in first-line therapy and to describe the frequency of neuropsychiatric adverse events among patients exposed to EFV.

METHODS

This review and meta-analysis was conducted after a predefined protocol (see Appendix, Supplemental Digital Content, http://links.lww.com/QAI/A669) and followed criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group.14

Eligibility Criteria

We included randomized and quasi-randomized trials that compared EFV irrespective of dose against non-EFV–based regimens as part of an identical backbone combination therapy for the treatment of antiretroviral-naive HIV-positive adults and children. We excluded switch studies (ie, studies that compare different regimens in patients once they have achieved virological suppression) and studies that only included patients with specific comorbidities that may influence outcomes, such as patients with underlying neuropsychiatric disorders or substance misuse. No geographical, age, or language restrictions were applied.

Search Strategy and study Selection

Using a sensitive search strategy including terms for adverse drug events,15 randomized trials, and EFV, the following databases were searched from inception to October 1, 2014: MEDLINE through PubMed, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials. Bibliographies of review articles and included studies were also screened. One investigator (N.F.) screened initial searches by title, and abstract and final inclusions were verified by a second investigator (Z.S.).

Data Extraction

Data were abstracted using a prepiloted data extraction form by 1 investigator (N.F.) and verified by a second investigator (Z.S., C.K.). The primary outcome was drug discontinuation as a result of any adverse event; secondary outcomes were severe (grade, 3–4) clinical adverse events, severe laboratory adverse events, and toxicity-related mortality. Severity was defined according to study definitions; where this was lacking, and where possible, the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events was applied.16 Because of the specific concern regarding neuropsychiatric adverse events associated with EFV, the proportion of patients experiencing neuropsychiatric adverse events was estimated by event for all patients receiving EFV. Data on the following specific neuropsychiatric adverse events were extracted: dizziness, insomnia, somnolence, abnormal dreams, impaired concentration, depression, anxiety, headache, and suicidality. Data on study characteristics and relevant indicators of potential risk of bias were also extracted according to the Cochrane risk of bias tool for randomized trials,17 and the overall quality of the evidence was assessed using the GRADE framework.18

Data Analysis

Point estimates and 95% confidence intervals (95% CIs) were calculated for the proportion of patients experiencing each outcome. For the comparison of EFV and non-EFV based regimens, we calculated the relative risk (RR), risk difference (RD), and corresponding 95% CIs for each outcome and pooled data using random-effects meta-analysis.19 For the RR assessment, comparator drugs no longer recommended by the WHO guidelines for ART were dropped from the analysis (aplaviroc, fosamprenavir, indinavir, lersivirine, nelfinavir, and stavudine)1; however, the EFV arms of these trials were retained for the assessment of the proportion of neuropsychiatric adverse events associated with EFV. For this analysis, proportions were pooled using random-effects meta-analysis after appropriate transformation of the data.20,21 Publication bias was assessed for the primary outcome of treatment discontinuation by funnel plot and the Eggers test for small study effects.22 Heterogeneity was assessed using the I2 statistic, which describes the percentage of variation across studies that is due to heterogeneity rather than due to chance.23

All analyses were conducted using Stata version 12.0 (StataCorp LP, College Station, TX) and GRADE Pro (www.gradeworkinggroup.org).

RESULTS

Characteristics of Included Studies

From an initial screen of 651 titles and abstracts, 42 trials were taken through for review (Fig. 1). Studies were published between 2002 and 2014, trial size ranged from 47 to 1771 participants (mean, 303), and trial duration ranged from 12 to 280 weeks (mean, 78 weeks). Overall, the systematic review provided information on 8466 adult patients exposed to EFV and 9631 adult patients exposed to the comparator drug. Trials compared EFV against 19 different comparator drugs across 5 different classes, most frequently nevirapine (9 studies) and ritonavir-boosted lopinavir (7 studies). Seventeen studies were single-country trials of which 8 were conducted in low- and middle-income settings while the remainder were multisite trials. Six trials compared EFV against comparator drugs that are no longer recommended by WHO guidelines24–28 or drugs whose development has been discontinued,29,30 and these were excluded from the RR analysis. One trial that compared abacavir against EFV published different combinations of results in 3 separate articles,4,31,32 but only one of these provided data could be evaluated against our inclusion criteria (EFV vs comparator with identical backbone regimen).31 Two studies compared standard dose EFV (600 mg) against a reduced dose, either as an initial stepped-dose33 or throughout the duration of the trial.34 No pediatric trials were identified that met our inclusion criteria.

FIGURE 1
FIGURE 1:
Study selection process.

Study quality was rated as moderate for the primary outcome of discontinuations. Most studies (81%) failed to report on approach to allocation concealment, and only a third of studies (33%) blinded participants and patients. Loss to follow-up was less than 10% for the majority (74%) of studies and in most instances was nondifferential (79%); and for the majority of trials (86%), there was no evidence of selection bias or outcome reporting (86%). There was some statistical evidence of publication bias (0.06 using Egger test for funnel plot asymmetry). Included studies are listed in Table S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A669).

Risk and Frequency of Adverse Events

Primary Outcome: Treatment discontinuations

Thirty-seven studies5,8–10,25,33,34,35–66 comprising 7734 patients exposed to EFV and 842 patients exposed to a comparator ARV drug contributed to the assessment of discontinuations due to adverse events. A lower risk of discontinuations due to adverse drug reactions was seen with EFV compared with nevirapine (RR: 0.7, 95% CI: 0.5 to 0.9; RD: −3.6, 95% CI: −6.6 to −0.6). Discontinuations were greater for EFV compared with low-dose EFV (RR: 3.1, 95% CI: 1.3 to 7.7; RD: 4.0, 95% CI: 1.0 to 7.0), rilpivirine (RR: 2.0, 95% CI: 1.0 to 3.8; RD: 4.1, 95% CI: 1.3 to 6.8), tenofovir (RR: 3.6, 95% CI: 1.4 to 9.6; RD: 7.7, 95% CI: 2.4 to 13.0), atazanavir (RR: 1.4, 95% CI: 1.1 to 1.8; RD: 2.6, 95% CI: 0.6 to 4.6), and maraviroc (RR: 3.3, 95% CI: 1.9 to 5.7; RD: 9.4, 95% CI: 5.3 to 13.5). The RR of discontinuation was greater for EFV compared with dolutegravir (RR: 4.3, 95% CI: 2.2 to 8.3) and raltegravir (RR: 2.7, 95% CI: 1.1 to 6.9), but absolute risks were not significantly different. These results are summarized in Figure 2 and Table 1.

FIGURE 2
FIGURE 2:
Relative and absolute risk of treatment discontinuation comparing efavirenz- and non-efavirenz based regimens.
TABLE 1
TABLE 1:
Relative and Absolute Risk of Adverse Events Associated With Efavirenz Versus Comparator

Severe Adverse Events

There was no statistically significant difference in the risk of severe clinical adverse events for any drug comparison. The absolute risk of severe laboratory adverse events was lower comparing EFV with atazanavir/r (RD: −77.1, 95% CI: −91.9 to −62.4) and higher comparing EFV with dolutegravir (2.8, 95% CI: 0.2 to 5.3), but relative differences were not significant for these comparisons and no other differences were observed.

Ten deaths reported by 5 trials were considered to be at least possibly related to study drug. EFV was associated with 7 deaths: 3 deaths were attributed to severe lactic acidosis among 3 overweight women (body mass index >25 kg/m2)64; 1 patient died of hepatotoxicity 14 weeks after treatment initiation55; 1 patient died of sepsis 5 weeks after treatment initiation that was considered possibly related to study drug34; 1 patient died of lactic acidosis25; and 1 patient died of hepatic steatosis associated with hepatitis C coinfection.25 The other 3 deaths were all associated with nevirapine and resulted from fulminant hepatitis secondary to hospitalization after Steven–Johnsons syndrome,62 lactic acidosis,25 and progressive neuropathic syndrome.25

Neuropsychiatric Adverse Events

Neuropsychiatric adverse events of any grade were common, affecting 29.6% of patients (95% CI: 21.9% to 37.3%), and 6.1% of these events (95% CI: 4.3% to 7.9%) were considered to be severe. With the exception of dizziness, fewer than 10% of patients experienced any specific type of neuropsychiatric adverse event; 12.8% of patients experienced dizziness (95% CI: 9.1% to 16.5%), and this was the only event that was found in subgroup analysis to occur more frequently in the first 48 weeks compared with a longer duration of follow-up (16.2, 95% CI: 11.0% to 21.3% vs 5.1, 95% CI: 1.2% to 9.0%). Severe neuropsychiatric adverse events were more common for EFV compared with atazanavir/r (RR: 2.4, 95% CI: 1.5 to 3.8; RD: 3.7, 95% CI: 1.8 to 5.5), dolutegravir (RR: 16.7, 95% CI: 2.0 to 137.8; RD: 3.0, 95% CI: 1.4 to 4.6), and maraviroc (RR: 5.3, 95% CI: 1.6 to 18.1; RD: 3.6, 95% CI: 1.3 to 5.9), and absolute differences were also higher for EFV compared with abacavir (RD: 6.0, 95% CI: 2.4 to 9.6). No other differences were observed. The proportion of neuropsychiatric adverse events is summarized in Figure 3.

FIGURE 3
FIGURE 3:
Proportion of CNS events experienced by patients receiving Efavirenz-containing regimens.

DISCUSSION

This systematic review found that over 90% of patients remained on an EFV-based first-line regimen after an average follow-up time of 78 weeks. The RR of discontinuations due to adverse events however was higher for patients on EFV compared with other first-line options that included tenofovir, abacavir, dolutegravir, raltegravir, or rilpivirine as a third component of the regimen, and when compared with low-dose EFV. The absolute difference in discontinuations was low, with less than 5% for most comparisons. No difference in severe clinical adverse events was found for any comparison.

Consistent with expectations, neuropsychiatric adverse events were more common, with almost a third of patients receiving EFV experiencing a neuropsychiatric adverse event of any grade of severity, mainly dizziness and abnormal dreams. This underscores the need for adherence counseling to prepare patients for the possibility of occurrence of such events, which are mild and short-term in most patients, and to provide alternatives in case of intolerance.67

The low rate of suicidality in this review contrasts with a recent study that reported a 2-fold increased hazard of suicidality associated with EFV use (1.5 vs 0.7 for non-EFV regimens in intent-to-treat analysis).68 This study reanalyzed data from 4 clinical trials, 3 of which are included in this review31,40,55; the forth trial was excluded from this review because backbone regimens were not comparable.69 Although this remains a concern, the rate of suicide ideation reported by this review was low (0.6%) and no completed suicides were reported in any of the evaluated studies, similar to the recent findings from a multisite cohort study documenting adverse events among patients on ART across Europe, Australia, and the United States.70

This review used a broad search strategy across several databases that allowed for the evaluation of outcomes for almost 9000 patients exposed to EFV. The fact that this review was limited to data from randomized trials is both strength and limitation. Well-conducted randomized trials are the most reliable way to limit the influence of bias and confounding in the interpretation of results; however, trials are often underpowered to assess adverse events, and this is reflected in the wide CIs around the majority of individual estimates. Trials may impose inclusion criteria on trial participants that could limit the generalizability of findings (for example by excluding patients considered the most at risk of adverse events; in this case patients with depression, pre-existing central nervous system [CNS] disease, and so on), and although there was little evidence of patient selection that could influence outcomes of interest, moderate heterogeneity was apparent and may reflect underlying differences in trial populations.71 It should be noted that the majority of trials included in this review were done in white populations and differences in metabolism in African and Asian populations may lead to a higher rate of CNS adverse events,72 although in a post hoc subgroup analysis there was no apparent difference in the proportion of severe adverse events by geographic region. Finally, adverse event reporting in clinical trials of antiretrovirals is subject to large variability and a lack of standardization in the reporting of type and severity of adverse events73 and this was a limitation for this review, particularly with respect to the consistency and quality of reporting of CNS events. Finally, the comparative evaluations for specific drugs were limited by the amount of information available for certain comparisons, and lack of statistical significance may for some comparisons be the result of insufficient power to detect differences in rare events.

In conclusion, this review finds that EFV use is associated with a higher risk of treatment discontinuation compared with a number of other antiretroviral drugs, with a greater (and expected) frequency of CNS events. Although most CNS events were mild, and suicide ideation is rare, even mild adverse events are a concern from a public health perspective because they may lead to decreased adherence to treatment.74 Future decisions about keeping or replacing EFV in first-line therapy, particularly in low- and middle-income settings, should take into account other factors, such as the good virological efficacy, low cost, availability as once-daily combination, compatibility with tuberculosis drugs, and wide experience of using this antiretroviral drug.

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Keywords:

central nervous system events; efavirenz; neuropsychiatric adverse events; randomized trials; suicide

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