Antiretroviral Therapy in Pregnancy

Abstract

Antiretroviral compounds differ from most other new pharmaceutical agents in that they have become widely prescribed in pregnancy in the absence of proof of safety. They are prescribed for the treatment of the mother and to reduce the risk of transmission of HIV to the fetus. In the animal models tested to date, no increased risk of malformations has been demonstrated for some compounds whereas others have been associated with malformations or developmental abnormalities in rats, mice or rabbits and, in the case of efavirenz, monkeys. Zidovudine monotherapy is still prescribed to reduce the risk of mother-to-child transmission of HIV. Combinations of 3 or more compounds are recommended when treatment of the mother is deemed necessary because of advanced HIV infection. Until recently, in vitro toxicity studies relevant to pregnancy were restricted to single agents; no animal teratogenicity or carcinogenesis studies of combination therapy have been published. Despite many thousands of women having taken antiretroviral therapy to reduce the risk of transmission, documented experience in human pregnancy remains sadly lacking, with the possible exception of zidovudine which has been prescribed in clinical trials to several hundred mother—infant pairs. For other compounds and for the numerous permutations of combination therapy, data are available only from small phase I/II studies, from retrospective investigations and from the prospective arm of the Antiretroviral Pregnancy Register (i.e. pregnancies in women taking antiretrovirals who were registered before delivery and then followed up). Antiretroviral monotherapy and combination therapy is widely prescribed in pregnancy because: (i) with appropriate management,which includes antiretroviral therapy, the risk of mother-to-child transmission can be reduced from 15 to 25% to less than 1%; (ii) pregnant women with advanced HIV infection require therapy; (iii) combination therapy with at least 3 compounds significantly reduces morbidity and mortality compared with dual or monotherapy; and (iv) the benefits of therapy for both the mother and the infant outweigh the risk. The choice of antiretroviral therapy in pregnancy may be influenced by the indication (prevention of transmission or maternal treatment), past antiretroviral therapy exposure/drug resistance, effects of pregnancy on the pharmacokinetics of the drug and factors influencing tolerability and adherence. In pregnancy, tolerability may be even more important than usual, especially if therapy exacerbates common complications of pregnancy, such as vomiting and glucose intolerance.