Most physicians treating HIV in the U.S. and Europe are all too familiar with antiretroviral drug resistance as a confounder and consequence of the treatment of HIV infection. In sub-Saharan Africa and Asia, the areas in which more than 90% of worldwide cases of HIV infection reside, antiretroviral resistance is likely to be an emerging problem as clinicians and public health authorities wrestle with the implications of use of antiretroviral drugs.

In developing countries, most HIV-infected individuals are not aware of their serostatus, nor, even when voluntary testing and counseling facilities provide access to testing, are they able to initiate antiretroviral therapy. Recommendations for three- or four-drug antiretroviral regimens (often costing thousands of dollars a month) have little bearing on the 30 to 40 million people infected with HIV in countries where the per capita health expenditures are less than $10 and individual or family incomes are, at best, several hundred dollars per month. Furthermore the infrastructure and testing that accompanies antiretroviral drug therapy, including viral load and CD4 measurements, adherence counseling, management of side effects and toxicities, and the capacity to closely monitor patients switching and substituting drugs, are clearly not within the immediate reach of most patients in developing countries. In countries that may be able to afford antiretroviral therapy for some of their HIV-infected citizens, questions about the durability and long-term consequences of therapy and the optimal use of less expensive nuc leoside combinations are complicated by the specter of widespread drug resistance. In general, efforts in less developed countries have focused on testing and counseling as prevention measures, where it is hoped that information, education and communication about HIV will change individual behaviors and slow transmission.

The one use of antiretroviral drugs as part of a structured prevention program is their application to vertical, or mother-to-child transmission. A series of studies completed in Thailand, the Ivory Coast, and Central African Republic provides evidence that 2-3 weeks of zidovudine, administered in late pregnancy and through labor reduces infection in infants by 40-50% [1-3]. The recent findings from the HIVNET 012 study in Uganda show that a single, 200 mg dose of nevirapine administered to the mother at the time of delivery, plus an additional dose provided to the infant in the first day of life, effected a nearly 50% reduction in transmission [4]. The demonstration that a short-course or single-dose prophylactic drug treatment can halve the rate of mother- to-child transmission has been hailed as an important step in the prevention of infant infection and pediatric AIDS. There are, nonetheless, complex issues that emerge as a result of this triumph, including the capacity of social structures to care for uninfected, but potentially orphaned children, the moral dilemma of providing antiretrovirals only for prevention when adults and infants with HIV infection are not able to access treatment, and problems of cost and the logistics of screening all pregnant women and delivering therapy while assuring confidentiality.

New findings from a pilot study of single-dose nevirapine [5] indicate that drug resistance may impact both of these strategies to reduce vertical transmission. Briefly, in a study of 14 women who had received single-dose nevirapine, Becker-Pergola found that 3/14 women studied 6 weeks after therapy had genotypic evidence of high-level nevirapine resistance in their plasma HIV RNA, with a majority or significant fraction of plasma virus containing the K103N mutation. While it is surprising that a single dose of nevirapine was capable of exerting selection pressure on plasma viremia, this is likely a consequence of the extraordinarily long half-life of nevirapine upon initial dosing, before the induction of hepatic enzymes that speed metabolism. Thus, women receiving a single dose experienced a lengthy exposure (perhaps as long as 1-2 weeks) to active, but diminishing concentrations of nevirapine, creating selective pressures similar to those associated with NNRTI monotherapy. These observations are paralleled by a recent paper by Seth Welles and the Women and Infants Transmission Study Group, in which, among women exposed to zidovudine during pregnancy, the investigators found that zidovudine resistance mutations were associated with increased risk for transmission [6].

Neither of these studies suggest that we should slow efforts to implement currently available, low cost tools such as short-course zidovudine or single-dose nevirapine for the reduction of mother-to-child transmission. However they both suggest that long-term follow-up of women exposed to short-course antiretrovirals, particularly to determine their response in subsequent pregnancies, is critical. The nevirapine study in particular should be expanded to track the prevalence and persistence of virus containing the K103N mutation in breast-milk and genital secretions, potential sites for the transmission of resistant virus from women who have received single-dose treatment. Increased understanding of the pharmacokinetics of single-dose nevirapine may help to clarify how selective pressure in a minority of women results in the emergence resistant virus. As in therapy, short courses of combined therapies may be required to reduce maternal virus load, limit exposure of the newborn, and prevent the rapid emergence of resistant virus.

Related HIVresistanceWeb articles:

Is Resistance to Nevirapine a Serious Consideration in Studies of the Prevention of Perinatal Transmission of HIV-1?.