The Body PRO Covers: The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy

Prevention of HIV Infection, Epidemiology and the Changing Face of HIV/AIDS (Poster Session 020)

December 16, 2001

  • Comparison of Nevirapine Resistance (NVPR) Mutations in Women vs. Infants Receiving Single Dose NVP Prophylaxis to Prevent HIV-1 Vertical Transmission (HIVNET 012)
    Abstract 234
    Authored by Susan H. Eshleman (The Johns Hopkins Med. Inst., Baltimore, MD), M. Deseyve (Fred Hutchinson Cancer Res. Ctr., Seattle, WA), L.A. Guay (The Johns Hopkins Med. Inst., Baltimore, MD), M. Mracna (The Johns Hopkins Med. Inst., Baltimore, MD), M. Furtado (Applied Biosystems, Foster City, CA), P. Musoke (Makerere Univ., Kampala, Uganda), F. Mmiro (Makerere Univ., Kampala, Uganda), J.B. Jackson (The Johns Hopkins Med. Inst., Baltimore, MD)
    View the original abstract

The HIVNET 012 study was a landmark study, demonstrating that a single dose of nevirapine given to a pregnant woman in labor, combined with a single dose for the neonate within 48 hours of birth, was about twice as effective as a short-course AZT regimen at preventing mother-to-child transmission. The promise of a simple, practical and inexpensive treatment raised hopes for making a dramatic impact on mother-to-child transmission.

The reality has been more complex, as usual. Political and organizational hurdles have made it hard to begin programs. Relatively few women have had access to programs using nevirapine, even though the drug is available for free to programs in developing countries.

Resistance is an issue that requires careful attention as well. In the HIVNET 012 study, nineteen percent of the women who had received nevirapine, and who were tested at six to eight weeks post partum, had evidence of nevirapine-resistant mutations.

At 48 weeks, these mutations could not be detected in any of the women, but we would expect them to be archived. Only 24 infants were infected and available for resistance testing at four to six weeks, but 49% had resistant virus. Although many women and infants in Africa currently have no chance of receiving HAART therapy, the emergence of nevirapine resistance could compromise their chance of responding to treatment when it becomes available.

Dr. Eshelman reported on the genotypic resistance patterns in the mothers and children with nevirapine resistance in HIVNET 012. Remarkably, the mothers and infants had different patterns of resistance mutations, demonstrating that resistance evolved independently in mother and child. Of 18 women, 15 had the K103N mutation, either alone or with other mutations. In contrast, most of the infants had Y181C.

The implications of this are not yet clear. It is likely that the different selection pressure based on persistence of drug levels leads to different resistance patterns. Because the drug is metabolized slowly, infants maintain nevirapine levels for up to two weeks. This may provide some protection against transmission through breast milk, but seems to increase the selection for resistance.

For physicians in the developed world, it means that if nevirapine is to be used for a woman with no prenatal care or with a persistent viral load, it should be combined with additional drugs to prevent the emergence of resistance. AZT, 3TC and nevirapine might be a reasonable choice when therapy is begun during labor.

In the developing world, it means that trials combining nevirapine with other agents for short, effective therapy are urgently needed. We need to be able to preserve the mother's chance of response to therapy. Candidate regimens might include nevirapine and AZT begun at the onset of labor and continued for three days (see abstract 232) or AZT and 3TC. The use of tenofovir, which has been remarkably effective in a monkey model of mother-to-child transmission, needs to be evaluated.

The problem of breast-feeding HIV transmission is not addressed by these regimens. In many ways, the obvious solution is to treat the mother with HAART after birth. This would give the uninfected child a healthy mother, perhaps the most important therapy of all.

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