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, I 2 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.
1. Anon. Scaling up antiretroviral therapy in resource-limited settings. Guideline for a public health approach. 2002. Geneva; WHO,
2. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study
. Lancet 2004; 363:1253–1263.
3. Patel AK, Pujari S, Patel K, Patel J, Shah N, Patel B, et al. Nevirapine versus efavirenz based antiretroviral treatment in naive Indian patients: comparison of effectiveness in clinical cohort
. J Assoc Physicians India 2006; 54:915–918.
4. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E. Myelomeningocele in a child with intrauterine exposure to efavirenz
. AIDS 2002; 16:299–300.
5. Tang MW, Kanki PJ, Shafer RW. A review of the virological efficacy of the 4 World Health Organization-recommended tenofovir-containing regimens for initial HIV therapy
. Clin Infect Dis 2012; 54:862–875.
6. Amoroso A, Etienne-Mesubi M, Edozien A, Ojoo S, Sheneberger R, Obiefune M, et al. Treatment outcomes of recommended first-line antiretroviral regimens in resource-limited clinics
. J Acquir Immune Defic Syndr 2012; 60:314–320.
7. Ford N, Mofenson L, Kranzer K, Medu L, Frigati L, Mills EJ, et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts
. AIDS 2010; 24:1461–1470.
8. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis
. AIDS 2011; 25:2301–2304.
9. Williams I, Churchill D, Anderson J, Boffito M, Bower M, Cairns G, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012
. HIV Med 2012; 13 (Suppl 2):1–6.
11. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement
. PLoS Med 2009; 6:6.
12. Golder S, Loke Y. Search strategies to identify information on adverse effects: a systematic review
. J Med Libr Assoc 2009; 97:84–92.
13. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Table for Grading the Severity of Adult and Pediatric Adverse Events. 2004. Bethesda, Maryland: National Institutes of Health;
14. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations
. BMJ 2008; 336:924–926.
15. Freeman MF, Tukey JW. Transformations related to the angular and the square root
. Ann Inst Stat Mathematics 1950; 21:607–611.
16. Sheehe PR. Combination of log relative risk in retrospective studies of disease
. Am J Public Health Nations Health 1966; 56:1745–1750.
17. Fleiss JL. The statistical basis of meta-analysis
. Stat Methods Med Res 1993; 2:121–145.
18. Golder S, Loke YK, Bland M. Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview
. PLoS Med 2011; 8:e1001026.
19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses
. BMJ 2003; 327:557–560.
21. Boulle A, Van Cutsem G, Cohen K, Hilderbrand K, Mathee S, Abrahams M, et al. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy
. JAMA 2008; 300:530–539.
22. Bruck S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine
. Eur J Med Res 2008; 13:343–348.
23. Castelnuovo B, Kiragga A, Kamya MR, Manabe Y. Stavudine toxicity in women is the main reason for treatment change in a 3-year prospective cohort of adult patients started on first-line antiretroviral treatment in Uganda
. J Acquir Immune Defic Syndr 2011; 56:59–63.
24. Elzi L, Marzolini C, Furrer H, Ledergerber B, Cavassini M, Hirschel B, et al. Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008
. Arch Intern Med 2010; 170:57–65.
25. Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, et al. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment
. Lancet 2006; 367:1335–1342.
26. Forna F, Liechty CA, Solberg P, Asiimwe F, Were W, Mermin J, et al. Clinical toxicity of highly active antiretroviral therapy in a home-based AIDS care program in rural Uganda
. J Acquir Immune Defic Syndr 2007; 44:456–462.
27. Gaytan JJA, de la Garza ERZ, Garcia MC, Chavez SBV. Nevirapine or efavirenz in combination with nucleoside analogues in patients infected with HIV without previous treatment
. Med Int Mex 2004; 20:24–28.
28. George C, Yesoda A, Jayakumar B, Lal L. A prospective study evaluating clinical outcomes and costs of three NNRTI-based HAART regimens in Kerala, India
. J Clin Pharm Ther 2009; 34:33–40.
29. Haddow LJ, Wood CW, Ainsworth JG. Discontinuation of nonnucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy due to nucleoside analogue reverse transcriptase inhibitor-related metabolic toxicity
. Int J STD AIDS 2007; 18:343–346.
30. Jena A, Sachdeva RK, Sharma A, Wanchu A. Adverse drug reactions to nonnucleoside reverse transcriptase inhibitor-based antiretroviral regimen: a 24-week prospective study
. J Int Assoc Physicians AIDS Care (Chic) 2009; 8:318–322.
31. Kalyesubula R, Kagimu M, Opio KC, Kiguba R, Semitala CF, Schlech WF, et al. Hepatotoxicity from first line antiretroviral therapy: an experience from a resource limited setting
. Afr Health Sci 2011; 11:16–23.
32. Khalili H, Dashti-Khavidaki S, Mohraz M, Etghani A, Almasi F. Antiretroviral induced adverse drug reactions in Iranian human immunodeficiency virus positive patients
. Pharmacoepidemiol Drug Saf 2009; 18:848–857.
33. Kumarasamy N, Venkatesh KK, Cecelia AJ, Devaleenal B, Lai AR, Saghayam S, et al. Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients
. AIDS Patient Care STDs 2008; 22:337–344.
34. Manfredi R, Calza L. Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with female sex, and a baseline CD4 cell count greater than 250 cells/microl
. AIDS 2006; 20:2233–2236.
35. Mankhatitham W, Lueangniyomkul A, Manosuthi W. Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing antituberculosis regimen
. Southeast Asian J Trop Med Public Health 2011; 42:651–658.
36. Messou E, Anglaret X, Duvignac J, Konan-N’dri E, Komena E, Gnokoro J, et al. Antiretroviral treatment changes in adults from Cote d’Ivoire: the roles of tuberculosis and pregnancy
. AIDS 2010; 24:93–99.
37. Modayil RR, Harugeri A, Parthasarathi G, Ramesh M, Prasad R, Naik V, et al. Adverse drug reactions to antiretroviral therapy (ART): an experience of spontaneous reporting and intensive monitoring from ART centre in India
. Pharmacoepidemiol Drug Saf 2010; 19:247–255.
38. Nunez M, Soriano V, Martin-Carbonero L, Barrios A, Barreiro P, Blanco F, et al. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals
. HIV Clin Trials 2002; 3:186–194.
39. Obiako R, Muktar H, Garko S, Tobi-Ajayi E, Olayinka A, Iyanda M, et al. Adverse reactions associated with antiretroviral regimens in adult patients of a university teaching hospital HIV program in Zaria, northern Nigeria: an observational cohort study
. J Antivir Antiretrovir 2012; 4:1.
40. Ritchie MD, Haas DW, Motsinger AA, Donahue JP, Erdem H, Raffanti S, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity
. Clin Infect Dis 2006; 43:779–782.
41. Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects
. J Infect Dis 2005; 191:825–829.
42. Sivadasan A, Abraham OC, Rupali P, Pulimood SA, Rajan J, Rajkumar S, et al. High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment
. J Assoc Physicians India 2009; 57:384–388.
43. Sreenivasan S, Dasegowda V. Adverse effects after HAART initiation in resource-limited settings: a prospective study from Mysore, India
. J Infect Dev Ctries 2010; 4:750–753.
44. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections
. Hepatology 2002; 35:182–189.
45. Swaminathan S, Padmapriyadarsini C, Venkatesan P, Narendran G, Ramesh Kumar S, Iliayas S, et al. Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial
. Clin Infect Dis 2011; 53:716–724.
46. van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons
. HIV Clin Trials 2008; 9:324–336.
47. Wester CW, Thomas AM, Bussmann H, Moyo S, Makhema JM, Gaolathe T, et al. Nonnucleoside reverse transcriptase inhibitor outcomes among combination antiretroviral therapy-treated adults in Botswana
. AIDS 2010; 24 (Suppl 1):S27–S36.
48. Zhou J, Phanupak P, Kiertiburanakul S, Ditangco R, Kamarulzaman A, Pujary S. Highly active antiretroviral treatment containing efavirenz or nevirapine and related toxicity in the TREAT Asia HIV Observational Database
. J Acquir Immune Defic Syndr 2006; 43:501–503.
49. Kumarasamy N, Venkatesh KK, Devaleenol B, Poongulali S, Mothi SN, Solomon S. Safety, tolerability and effectiveness of generic HAART in HIV-infected children in South India
. J Trop Pediatr 2009; 55:155–159.
50. Tukei VJ, Asiimwe A, Maganda A, Atugonza R, Sebuliba I, Bakeera-Kitaka S, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda
. J Acquir Immune Defic Syndr 2012; 59:274–280.
51. Ibadova G, Atakhodjieva K. Evaluation of frequency of ARVT side effects in children of Uzbekistan.
AIDS 2010 – XVIII International AIDS Conference:Abstract CDB0233
52. Kampiire L, Garone D, Giddy J, Rabie H, Wood R, Moultrie H, et al. Substitutions to initial antiretroviral therapy in children in South Africa: the international epidemiological database to evaluate AIDS, Southern Africa (IeDEA-SA) Collaboration
. 2012. XVIV International AIDS Conference, Washington, Abstract TUPE092.
53. Lee L, Lim P, Fahey P, Yunihastuti E. Predictors of nevirapine and efavirenz toxicity in HIV infected patients: updated analysis from the TREAT Asia HIV Observational Database (TAHOD).
6th IAS Conference on HIV Pathogenesis and Treatment: Abstract no. CDB486.
54. Hartmann M, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Comparison of efavirenz and nevirapine in HIV-infected patients (NEEF Cohort)
. Int J STD AIDS 2005; 16:404–409.
55. Elzi L, Erb S, Furrer H, Ledergerber B, Cavassini M, Hirschel B, et al. Choice of initial combination antiretroviral therapy in individuals with HIV infection: determinants and outcomes
. Arch Intern Med 2012; 70:1–9.
56. Al-Dakkak I, Patel S, McCann E, Gadkari A, Prajapati G, Maiese EM. The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-analysis.
AIDS Care 2012. [Epub ahead of print]
57. Phanuphak N, Apornpong T, Teeratakulpisarn S, Chaithongwongwatthana S, Taweepolcharoen C, Mangclaviraj S, et al. Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women
. HIV Med 2007; 8:357–366.
58. Aaron E, Kempf MC, Criniti S, Tedaldi E, Gracely E, Warriner A, et al. Adverse events in a cohort of HIV infected pregnant and nonpregnant women treated with nevirapine versus nonnevirapine antiretroviral medication
. PLoS One 2010; 5:e12617.
59. Jamisse L, Balkus J, Hitti J, Gloyd S, Manuel R, Osman N, et al. Antiretroviral-associated toxicity among HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens
. J Acquir Immune Defic Syndr 2007; 44:371–376.
60. Ford N, Calmy A, Andrieux-Meyer I, Hargreaves S, Mills EJ, Shubber Z. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis.
AIDS 2013. [Epub ahead of print]