HIV This Week

Ciaranello AL, Seage GR 3rd, Freedberg KA, Weinstein MC, Lockman S, Walensky RP. Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: balancing efficacy and infant toxicity. AIDS. 2008;22(17):2359-69.

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. Ciaranello and colleagues 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. Published mother-to-child transmission and mitochondrial toxicity data were used in a decision analytic model of mother-to-child transmission among women in sub-Saharan Africa. The authors 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. Sensitivity analyses varied all parameters, including infant feeding strategy and the disability of mitochondrial toxicity relative to HIV. 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 antiretroviral therapy), but mitochondrial toxicity risk also increases (to 2.2%, also with three-drug antiretroviral therapy). Despite increased toxicity, three-drug antiretroviral therapy 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. The risk of paediatric 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 antiretroviral therapy to prevent mother-to-child transmission where it is available.

Editors’ note: This modelling showed that protease inhibitor (PI) based 3 drug antiretroviral regimens (ZDV, 3TC, PI) resulted in fewer paediatric infections, slightly more cases of paediatric mitochondrial toxicity, and substantially fewer adverse paediatric outcomes than less toxic but less effective regimens. The true prevalence and severity of infant neurological dysfunction related to mitochondrial toxicity remains unknown. Such toxicity is thought to be due primarily to in utero exposure to NRTI (nucleoside reverse transcriptase inhibitors), however maternal HIV viraemia also appears to be an independent risk factor for foetal mitochondrial dysfunction. Whether there will be next generation effects for the foetuses exposed to NRTI, as was seen for women whose mothers used diethylstilbestrol in the 1950s to prevent threatened abortions and unknowingly placed their daughters at higher risk of vaginal cancer, will not be known for a decade or two.