The proposed research plan is a laboratory-based epidemiologic study to determine the role of ZDV-resistant HIV-1 in maternal-infant transmission. Specimens from the NIAID-supported, Women and Infants HIV-l Transmission Study (WITS) will be assayed to estimate the magnitude of maternal ZDV- resistance with perinatal transmission, to determine the prevalence of ZDV resistant HIV- l among mothers treated with ZDV during pregnancy, to evaluate potential predictors of ZDV-resistant HIV-l in ZDV-treated mothers, to determine the incidence of ZDV-resistant HIV transmission to the infants, and to determine virologic, immunologic, and clinical impact of ZDV-resistant HIV transmission in the pathogenesis of pediatric AIDS. The recent success in the AIDS Clinical Trials Group (ACTG) protocol 076 suggests that ZDV treatment during pregnancy and the perinatal period is highly efficient at decreasing mother to infant HIV-l transmission. However, this study did not address the effectiveness of ZDV in women with CD4 < 200 cells/mu L or in women who may be infected with ZDV-resistant HIV-l variants. Preliminary resistance data on five maternal-infant pairs from ZDV treated mothers have been examined for the presence of the T215Y mutation in the HIV-l pol gene known to be associated with ZDV-resistance. Two of the three mothers who were treated with longer than or equal to 12 months of ZDV had mutant T2l5Y codon present. One of these mothers transmitted HIV-l with the T215Y mutation to her infant. The hypotheses to be tested are l.) that among mothers on ZDV treatment during pregnancy, the prevalence of ZDV-resistant HIV-l is higher in the transmitting women compared to the non-transmitting women; 2.) that ZDV resistance is more common among women with higher viral load, more advanced HIV disease, lower CD4, longer duration of prior ZDV therapy, and higher cumulative dose of prior ZDV therapy; 3.) that among children whose mothers were treated with ZDV during pregnancy, ZDV-resistant HIV-1 will be detected sooner than in infants whose mothers were not treated with ZDV; 4.) and finally, that there is a more rapid progression of HIV disease in children whose mothers received ZDV treatment during pregnancy as a consequence to the rapid emergence of ZDV-resistant HIV- l.
The aims of the project will be carried out by linking the WITS database with the data generated in this study; namely, the detection of specific HIV-l mutations known to confer ZDV resistance in virus isolates from mother-infant pairs. The increased use of ZDV by pregnant women as a result of ACTG 076 combined with increased ZDV use in the general HIV- infected population may lead to increased prevalence of ZDV-resistant HIV in the United States. If ZDV resistance was to increase, and was associated with a higher rate of perinatal HIV transmission, alternative strategies for the prevention of perinatal transmission would be needed.
| Welles, Seth L; Bauer, Greta R; LaRussa, Philip S et al. (2007) Time trends for HIV-1 antiretroviral resistance among antiretroviral-experienced and naive pregnant women in New York City during 1991 to early 2001. J Acquir Immune Defic Syndr 44:329-35 |
| Bauer, Greta R; Colgrove, Robert C; Larussa, Philip S et al. (2006) Antiretroviral resistance in viral isolates from HIV-1-transmitting mothers and their infants. AIDS 20:1707-12 |
| Colgrove, Robert C; Millet, Amy; Bauer, Greta R et al. (2005) Gag-p6 Tsg101 binding site duplications in maternal-infant HIV infection. AIDS Res Hum Retroviruses 21:191-9 |
| Bauer, Greta R; Welles, Seth L; Colgrove, Robert R et al. (2003) Zidovudine resistance phenotype and risk of perinatal HIV-1 transmission in zidovudine monotherapy-treated mothers with moderately advanced disease. J Acquir Immune Defic Syndr 34:312-9 |
