Drug discontinuations due to adverse events were reported by 18 studies (17 512 patients). For patients on NVP, the proportion of patients discontinuing treatment due to any adverse event ranged from 1.3% (95% CI 0.9–1.7)  to 30.5% (95% CI 21.3–40.5%) , with an overall pooled proportion of 8.7% (95% CI 6.7–10.6%). For patients receiving EFV, this proportion ranged from 0.18% (95% CI 0.16–1.5%) to 22.6% (95% CI 16.7–29.2%), with a pooled proportion of 5.8% (95% CI 4.2–7.4%). Patients on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95% CI 1.9–2.6, I2 70.5%).
There was a tendency toward a higher frequency of discontinuations among patients on NVP with a higher CD4 cell count (16.9% at CD4 ≥250 cells/μl versus 7.2% at CD4<250 cells/μl, P = 0.08); this association was not seen for EFV. A higher frequency of treatment discontinuations was also reported by studies with a follow-up time of greater than 1 year compared to studies with a follow-up time of less than 1 year (P <0.001), and for studies carried out in upper-income countries compared to lower-income countries (P = 0.02). All other subgroup findings were not statistically significant. No differences were found in the frequencies of treatment discontinuations reported by cohort studies and RCTs.
Patients receiving NVP were more likely to experience any grade of hepatotoxicity (OR 1.5, 95% CI 1.3–1.8) or severe hepatotoxicity (OR 3.3, 95% CI 2.5–4.2) compared to patients on EFV. They were also more likely to experience any grade of skin toxicity (1.8, 95% CI 1.5–2.2), severe skin toxicity (OR 3.9, 95% CI 2.5–5.4), and severe hypersensitivity reactions (OR 2.4, 95% CI 1.9–2.9) compared to patients receiving EFV. Seven studies [2,26,32,33,39,42,45] reported 64 cases of Stevens–Johnson syndrome among 7391 patients exposed to NVP, giving a pooled proportion of 0.7% (95% CI 0.5–0.9%).
In contrast, patients receiving EFV were more likely to experience any CNS-related adverse event (OR 2.1, 95% CI 1.9–2.4) and severe CNS-related adverse events (OR 3.4, 95% CI 2.1–5.4). There were no differences between the two drugs in the occurrence of other neurological events (OR 0.9, 95% CI 0.6–1.2) and lipid-associated adverse events (OR 0.9, 95% CI 0.6–1.2). Deaths attributed to toxicity were rare (<1%) for both NVP (14 deaths among 5835 patients) and EFV (three deaths among 1380 patients).
Four prospective cohort studies reported adverse drug outcomes in children. In the first study, from India , the frequency of rash was found to be higher for NVP (20%, 95% CI 13.1–30.0%) compared to EFV (14%, 95% CI 5.8–26.7%); differences in hepatotoxicity were not statistically significant. In the second study, from Uganda , 11 patients on NVP (6.4%, 95% CI 3.3–11.2) developed lipodystrophy resulting in antiretroviral drug substitution; no patients on EFV developed this adverse event. The occurrence of CNS-associated adverse events was lower among patients on NVP (7.6%, 95% CI 4.1–12.6%) compared to EFV (14.1%, 95% CI 9.4–20.1%); one patient on EFV changed treatment for this reason. The third study, a conference abstract from Uzbekistan , reported a greater frequency of rash among children receiving NVP (7.5%) compared to EFV (3.8%). The final study, from South Africa, found that children were seven times more likely to discontinue NVP-based first-line antiretroviral therapy compared to EFV-based therapy (OR 7.1, 95% CI 3.3–15.4) .
Adverse drug events are an important concern in the provision of antiretroviral therapy. They can cause significant patient morbidity and are potentially fatal, are a common cause of drug discontinuations , and are associated with poorer patient adherence to treatment . Poor adherence to treatment and regimen changes complicate patient management, decrease future treatment options, and may increase costs.
This systematic review supports prior findings of individual studies reporting a greater frequency of both liver and skin toxicities associated with NVP compared to EFV, and a greater frequency of CNS toxicity associated with EFV compared to NVP. Importantly, the number of deaths attributed to toxicity was rare for both drugs.
Drug discontinuation due to any adverse drug event was chosen as our primary outcome as a measure of the frequency of both clinically important and potentially life-threatening adverse drug events. We found that patients on NVP-based first-line ART were more than twice as likely to switch regimens due to any adverse drug event compared to patients on EFV-based therapy. Although CNS events were more frequent for EFV, these events infrequently led to a drug substitution.
We used a broad search strategy that allowed us to retrieve data for over 26 000 patients. A strength of such a sensitive search strategy is that a more precise estimate of both the frequencies and the risks of occurrence of a broad range of adverse events were obtained from a diversity of settings. There was moderate-to-high statistical heterogeneity across studies, and subgroup analyses highlighted some differences in outcomes reported by different studies. Higher income settings reported a higher frequency of treatment discontinuations compared to low-income settings, which may be due to more intensive laboratory monitoring in higher income settings, more frequent switching in specific situations of suspected risk (e.g., high CD4 cell counts), and increased therapeutic options for drug substitutions. Drug discontinuations were also more common in studies with a longer duration of follow-up suggesting that not all clinically important adverse events occur early. Our exploration of potential sources of heterogeneity was limited by the inconsistent reporting by the studies. Higher toxicity-driven discontinuations appeared to be associated with higher CD4 cell counts, a finding that is consistent with other reports [57,58]. Other variables that may explain heterogeneity in adverse drug outcomes but which were not adequately reported by studies include baseline disease status (as defined by the CD4 cell count or viral load), or the contribution of other drugs in the regimen. Only a minority of studies reported the average time to occurrence of adverse event, but those that did report this found that adverse events generally occurred within the first 5 months. Finally, this review sought to compare adverse events between the two most commonly used nonnucleoside reverse transcriptase inhibitors. Because EFV has been contraindicated in pregnancy, our search strategy did not include pregnant women. As NVP toxicity remains a concern for pregnant women , this question has been reviewed separately . Finally, we pooled data from RCTs and observational studies, both of which have limitations in the reporting of adverse events. Although adequately conducted RCTs provide stronger evidence of outcomes compared to cohort evaluations, observational studies are more likely to identify events that are rare in occurrence as well as events within populations that may not be represented in RCTs (for example, children, those with comorbidities, and the elderly).
Our review highlights several areas for future research. First, the diversity of monitoring strategies implemented among the studies for the diagnosis of adverse drug events (both the type and the frequency of monitoring) highlights the need for research to better rationalize toxicity monitoring. Second, a better ascertainment of the timing of clinically important adverse events would help better define monitoring requirements. Third, the exclusion of a large number of studies from this review due to a lack of or incomplete adverse drug event data is a missed opportunity. Finally, the scarcity of reports of adverse events among children underscores the need for more consistent reporting of adverse drug events in children.
NVP will likely continue to be an important drug for the management of HIV-infected individuals, and CNS-associated side-effects associated with EFV remain a concern, particularly for specific patient groups such as postnatal women and patients with psychiatric comorbidities. Nevertheless, the overall benefit in terms of reduced toxicity-driven drug substitution, better compatibility with TB drugs, and potentially superior efficacy of EFV compared to NVP, supports the move toward tenofovir, lamivudine or emtricitabine, and EFV as the preferred first-line regimen for scale up of ART.
The authors would like to thank Jonathan Ainsworth, Xavier Anglaret, Kathryn Chu, Mary-Anne Davies, Lewis Haddow, Robert Kalyesubula, Laetitia Kampiire, Nagalingeswaran Kumarasamy, and Roberto Manfredi for providing additional data. Finally, they thank Teri Roberts for assistance with data verification.
N.F., Z.S., I.A.M., and A.C. designed the review. N.F. and Z.S. undertook literature searches, extracted data from the studies, and contacted authors for data verifications. I.A.M. and S.H. undertook additional data extractions. N.F. and Z.S. performed the statistical analyses and wrote the first draft. All authors supported the interpretation of results, provided comments on subsequent drafts, and approved the final version.
This work was supported by funds from the WHO.
There are no conflicts of interest.
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