Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: balancing efficacy and infant toxicity

Abstract

Objective: Antiretroviral drugs can prevent mother-to-child transmission of HIV infection, but in-utero antiretroviral exposure may be associated with neurologic symptoms due to mitochondrial toxicity. We sought to identify the currently recommended regimen to prevent mother-to-child transmission that optimally balances risks of pediatric HIV infection and neurologic mitochondrial toxicity.

Design: Published MTCT and mitochondrial toxicity data were used in a decision analytic model of MTCT among women in sub-Saharan Africa.

Methods: We investigated the HIV and mitochondrial toxicity risks associated with no antiretroviral prophylaxis and five recommended regimens ranging from single-dose nevirapine to three-drug antiretroviral therapy (ART). Sensitivity analyses varied all parameters, including infant feeding strategy and the disability of mitochondrial toxicity relative to HIV.

Results: Provision of no antiretroviral drugs is the least effective and least toxic strategy, with 18-month HIV risk of 30.4% and mitochondrial toxicity risk of 0.2% (breastfed infants). With increasing drug number and duration, HIV risk decreases markedly (to 4.9% with three-drug ART), but mitochondrial toxicity risk also increases (to 2.2%, also with three-drug ART). Despite increased toxicity, three-drug ART minimizes total adverse pediatric outcomes (HIV plus mitochondrial toxicity), unless the highest published risks are true for both HIV and mitochondrial toxicity, or the disability from mitochondrial toxicity exceeds 6.4 times that of HIV infection.

Conclusion: The risk of pediatric mitochondrial toxicity from effective regimens to prevent mother-to-child transmission is at least an order of magnitude lower than the risk of HIV infection associated with less-effective regimens. Concern regarding mitochondrial toxicity should not currently limit the use of three-drug ART to prevent mother-to-child transmission where it is available.

Figure 1

Women who did not meet WHO criteria for initiation of ART for their own HIV infections were considered eligible for each ARV and feeding strategy. During the period from 10 weeks of gestation through 18 months postpartum, each of the depicted events occurred based on probabilities derived from the published literature: intrauterine (IU) demise or HIV infection, intrapartum or early postpartum (IP) HIV infection, postpartum (PP) HIV infection, or neurologic mitochondrial toxicity (MT), resulting in the outcomes depicted at the end of each path.

Figure 2

Effect of varying the relative disability of pediatric neurologic MT compared to pediatric HIV infection on total adverse pediatric outcomes (HIV plus MT): base case analysis. On the horizontal axis is the relative disability of MT compared to HIV infection (MT ranging from 0 – 35 times more disabling than HIV). On the vertical axis is the probability of total pediatric morbidity (HIV plus MT). Thresholds are highlighted at which the sdNVP/CBV regimen (open arrow) and the scZDV/sdNVP/CBV regimen (closed arrow) minimize total morbidity compared to 3-drug ART.