Recent studies (HIVNET 012) have shown that the use of nevirapine (NVP) as a single dose to HIV-infected pregnant women at time of onset of labor, followed by a single dose to the infant on the day of birth, could reduce the vertical transmission of HIV by more than 50%. Moreover, this regimen is extremely cost-effective, and can be priced at approximately $4 per mother-child pair. The low cost and high effectiveness of NVP in this context, when compared to the higher costs of other regimens, such as AZT in an ACTG 076-like protocol, argue that NVP should be the drug of choice to prevent perinatal transmission of HIV. Moreover, some advocates have suggested that all pregnant mothers in HIV-endemic areas be treated in this way to avoid the expense and difficulty of screening women in endemic rural areas for HIV seropositivity.

Against this background, HIVNET scientists recently reported that 3 of 14 women who were followed in the study had developed NVP-resistant strains of HIV in their blood by 6 weeks after delivery [1]. This occurred in spite of the fact that the women had only received the drug on the one occasion. The question is, then, whether the development of such resistance overshadows the benefits of using NVP in the maternal-offspring setting. The answer is that the use of NVP should continue to be encouraged. Let us consider some of the reasons why.

First, multiple studies have now shown that drug-resistant viruses are commonly not as replication-competent as are wild-type viruses. This means that the NVP-resistant viruses in the women in whom NVP resistance was observed should be fairly quickly overgrown by wild-types. The fact that resistance to NVP was selected at all in this cohort is testimony to the potent anti-viral effect of NVP as well as its long half-life. Hence, resistant viruses were selected by this drug because it continued to be present in the body over long periods of time. Conceivably, the persistence of NVP may even have been increased by body changes associated with the perinatal and post-natal state. In any event, the NVP-resistant viruses (which contained the K103N mutation) should be overgrown, in time, by wild-type viruses, since the pregnant women in question will not continue to be treated with antiviral drugs after pregnancy. Ostensibly, this means that NVP should be made available to these women as a viable prophylactic agent during future pregnancies as well as for future therapy (should improved drug access in the developing country setting become a reality).

This does not mean, however, that other potential complications of NVP resistance should not be taken into account. There is a growing consensus that HIV-infected women should not breast-feed their infants, so as to avoid the transmission of HIV through breast milk. This consideration becomes even stronger in the context of women whose milk might contain NVP-resistant strains of HIV. Nonetheless, one should also remember that only 20% of the women studied had NVP-resistant viruses in their blood after 6 weeks of follow-up. Clearly, long-term studies are needed to determine the duration of time over which these NVP-resistant viruses will persist in the absence of drug pressure.

An additional point is that the women in the HIVNET 012 study, which was conducted in Uganda, had been infected by subtype A variants of HIV. We have little or no information on whether different subtypes or clades of HIV will develop resistance to NVP at the same rate and as a result of the same mutations. Comparative studies of viruses of different clades are urgently needed in this regard. In general, the K103N mutation is seen with relative infrequency among patients with clade B viruses who develop resistance to NVP during combination antiretroviral therapy. Whether the K103N mutation is more likely to arise among clade A viruses, as a consequence of monotherapy, and/or in peri- and post-natal women who receive NVP as monotherapy are subjects that merit priority attention.

Related HIVresistanceWeb articles:

Vertical Transmission and Antiretroviral Drug Resistance in Developing Countries.
(David Katzenstein, M.D.; May 2000)