Combination antiretroviral therapy (ART) with either efavirenz (EFV) or nevirapine (NVP), both nonnucleoside reverse transcriptase inhibitors (NNRTIs), and two nucleoside reverse transcriptase inhibitors (NRTI) is recommended by the WHO as first-line therapy in resource-limited countries . Compared with NVP, EFV is easier to monitor, is relatively well tolerated, has less frequent and less severe rash and hepatic toxicity than NVP, and can be administered once daily. Whereas NVP and EFV have generally comparable clinical and virologic efficacy [2–5], because of lower drug–drug interactions, EFV-based ART is associated with superior virologic outcome compared with NVP-based ART in individuals with tuberculosis (TB) receiving anti-TB therapy containing rifampicin. Therefore, efavirenz is the NNRTI antiretroviral drug of choice of TB-coinfected individuals [6–9]. However, there have been concerns regarding potential for central nervous system birth defects with first-trimester exposure to EFV based on studies in pregnant rhesus macaques and retrospective case reports in humans that have limited EFV use in women of childbearing age. This is a problem in many resource-limited settings, where women constitute 50% or more of HIV-infected individuals and TB is endemic, but there is limited access to contraception or women may wish to become pregnant.
In this issue, Ouattara and colleagues use a computer simulation model to evaluate the risks and benefits of using EFV and NVP in women of childbearing age in resource-limited countries . Using the previously validated Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model, the authors simulated the trade-off between potential excess birth defects and potential long-term clinical benefits for women starting EFV-based versus NVP-based ART in Cote d’Ivoire. In a ‘hypothetical’ cohort of 100 000 women starting ART with EFV, the authors found that a drug with lower toxicity and requiring less regimen switching led to approximately 911 more women alive after 10 years compared with those starting with NVP, an improvement in survival of approximately 1%. However, over the same period, there were 59 more birth defects in women initiating EFV-based ART than those starting with NVP. The authors concluded that in Cote d’Ivoire, initiating ART with EFV instead of NVP is likely to substantially increase the number of women alive at 10 years, at the expense of a small number of infants born with birth defects. A similar analysis from the CEPAC investigators using data from the U.S. Women's Interagency HIV Study also demonstrated a potential benefit of initial therapy with EFV, finding survival was 0.89 years greater (28.91 versus 28.01 years) for women receiving EFV-based ART than for women receiving non-EFV-based initial therapy at the risk of a small increase (4.8 per 100 000) of teratogenic events .
The excess mortality associated with NVP in resource-limited settings is due to higher rates of acute toxicity requiring earlier switching, and possibly also to lower effectiveness in patients who are concurrently receiving rifampin-based TB treatment. Indeed, TB is the leading opportunistic infection seen with HIV in these settings. The concomitant use of rifampicin with first-line NVP-based or EFV-based ART may cause a reduction in the plasma NNRTI concentrations. The reduction in the concentration of EFV is more modest (25%) when compared with that of NVP (65–70%), and there are a number of observational studies showing better ART outcomes in HIV/TB-coinfected patients with EFV [6,9]. The CARINEMO-ANRS 12146 randomized trial compared the efficacy and safety of NVP versus EFV for treatment of HIV-TB co-infected patients in Mozambique and reported better viral suppression to less than 50 copies/ml at 48 weeks in patients on EFV (195/285, 68.4%) compared with NVP (171/285, 60%); more patients receiving NVP than EFV switched therapy (5.3 versus 2.1%), although mortality was similar (16 patients, 5.6% on EFV and 18 patients, 6.3% on NVP) .
Among the shortcomings of the Ouattara study is the fact that the effectiveness data used for the modelling are based mostly on observational studies that may not be directly comparable. Selection bias is inherently built into cohort studies. In addition, the authors did not consider cost of EFV versus NVP. Indeed, the relative lower cost of NVP and its availability as a generic fixed-dose ART combination is another major reason for its wide use in sub-Saharan Africa. Therefore, there is an urgent need for well conducted cost-effectiveness studies comparing EFV versus NVP-based ART in such settings. The investigators also used the risk of overall birth defects in their calculations; however, the concern with EFV is neural tube defects, which have a low incidence in the general population (0.1–0.4%) but can be associated with significant morbidity and mortality. One recent systematic review of 16 studies found no increased risk of overall birth defects among women on EFV during the first trimester of pregnancy compared with those on other ARV agents . However, given the low underlying incidence of neural tube defects in the general population, birth defect data from over 2000 well documented first-trimester EFV exposures are needed to be able to rule out three-fold increase in risk . In an update of the systemic review including 1248 first-trimester EFV exposures, the incidence of neural tube defects remained low, 0.07% [95% confidence interval 0.002–0.38) . These data can likely rule out a 10-fold or higher increased risk, but larger numbers are needed to rule out a doubling or tripling of the risk of neural tube defects with first-trimester exposure. Neural tube defects, while low incidence, are highly likely to be fatal in infants born with this defect in resource-limited countries.
Better information regarding the teratogenic risk of EFV is critically needed to inform decision-making. With increasing use of triple antiretroviral drug regimens in resource-limited countries in pregnant women for treatment and prevention of mother-to-child transmission (PMTCT) of HIV, including EFV-based ART, the development of prospective surveillance systems in resource-limited settings to allow systemic recording of birth outcomes of women receiving ART during pregnancy and assess the incidence of rare birth defects is essential to provide evidence-based guidance to providers. Additionally, decreasing antiretroviral cost and increasing the availability of alternative drugs with lower toxicity and less teratogenicity concerns (and with efficacy against NNRTI-resistant viruses) for first-line therapy in low-resource settings, such as rilpivirine tablet (now available in a fixed dose combination tablet given once daily) would be important to optimize treatment and PMTCT, and improve outcomes for both the mother and her infant.
J.B.N. is supported by US NIH-FIC/HRSA/PEPFAR Grant Award, T84HA21652-01-00 for Medical Education Partnership Initiative (MEPI); The European Developing Countries Clinical Trial Partnership (EDCTP) Senior Fellowship Award: TA-08-40200-021 and the Wellcome Trust Southern Africa Consortium for Research Excellence (SACORE). J.B.N. is a former John McGoldrick Fellow, Center for Biostatistics in AIDS Research at Harvard School of Public Health, Boston, Massachusetts, USA.
Comments and views of the author(L.M.M.) do not necessarily represent the views of the National Institutes of Health or Department of Health and Human Services.
Conflicts of interest
There are no conflicts of interest.
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