Antiretroviral therapy in pregnancy - A focus on safety

Antiretroviral compounds differ from most other new pharmaceutical agents i n that they have become widely prescribed in pregnancy in the absence of pr oof of safety. They are prescribed for the treatment of the mother and to r educe the risk of transmission of HIV to the fetus. In the animal models te sted to date, no increased risk of malformations has been demonstrated for some compounds whereas others have been associated with malformations or de velopmental abnormalities in rats, mice or rabbits and, in the case of efav irenz, monkeys. Zidovudine monotherapy is still prescribed to reduce the risk of mother-to- child transmission of HIV. Combinations of 3 or more compounds are recommen ded when treatment of the mother is deemed necessary because of advanced HI V infection. Until recently, in vitro toxicity studies relevant to pregnanc y were restricted to single agents; no animal teratogenicity or carcinogene sis studies of combination therapy have been published. Despite many thousands of women having taken antiretroviral therapy to redu ce the risk of transmission, documented experience in human pregnancy remai ns sadly lacking, with the possible exception of zidovudine which has been prescribed in clinical trials to several hundred mother-infant pairs. For o ther compounds and for the numerous permutations of combination therapy, da ta are available only from small phase I/II studies, from retrospective inv estigations and from the prospective arm of the Antiretroviral Pregnancy Re gister (i.e. pregnancies in women taking antiretrovirals who were registere d before delivery and then followed up). Antiretroviral monotherapy and combination therapy is widely prescribed in pregnancy because: (i) with appropriate management, which includes antiretr oviral therapy, the risk of mother-to-child transmission can be reduced fro m 15 to 25% to less than 1%; (ii) pregnant women with advanced HIV infectio n require therapy; (iii) combination therapy with at least 3 compounds sign ificantly reduces morbidity and mortality compared with dual or monotherapy ; and (iv) the benefits of therapy for both the mother and the infant outwe igh the risk. The choice of antiretroviral therapy in pregnancy may be influenced by the indication (prevention of transmission or maternal treatment), past antiret roviral therapy exposure/drug resistance, effects of pregnancy on the pharm acokinetics of the drug and factors influencing tolerability and adherence. In pregnancy, tolerability may be even more important than usual, especial ly if therapy exacerbates common complications of pregnancy, such as vomiti ng and glucose intolerance.