HIV-1 chemoprophylaxis and archived drug resistance in infants

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DESCRIPTION (provided by applicant): Nearly three million children worldwide have human immunodeficiency virus type 1 (HIV-1)/AIDS, and most live in sub-Saharan Africa where access to antiretroviral drugs is limited. Highly active antiretroviral therapy (HAART) reduces disease progression and mortality, but in low-income countries often the only HAART option is combination therapy with nevirapine (NVP). Single-dose NVP (SD-NVP) is also commonly used to prevent peripartum HIV-1 transmission, but it causes rapid selection of NVP-resistant (NVP-R) HIV-1 in up to 80% of subtype C infected women and infants. Within a year this chemoprophylaxis- induced NVP-R HIV-1 decays from the plasma and replicating cellular pools and is replaced with drug-sensitive wild-type HIV-1, providing a rationale for reusing NVP in HAART. We have shown in children that drug-resistant HIV-1 arising during non-suppressive antiretroviral therapy is archived in replication competent forms in resting CD4+T cells and is continuously activated to produce low level viremia even when viral loads are <50 copies/ml on HAART, precluding reuse of drugs from failed regimens. We will test the hypothesis that NVP reuse in subtype C infected infants with SD-NVP exposure causes selection of NVP-R variants and subsequent rebound viremia despite decay of NVP-R from plasma and even when virus replication had been controlled. In the context of two ongoing clinical trials using different approaches to reusing NVP to treat HIV-1 infected African infants (Neverest and PACTG P1060), we will use sensitive molecular and genotyping assays to analyze plasma and cellular samples to: 1. Quantify the extent of NVP-R HIV-1 cellular reservoirs in subtype C infected infants exposed to prophylactic SD-NVP. 2. Determine persistence of NVP-R HIV-1 variants in plasma of SD-NVP exposed infants whose first suppressive HAART regimen lacks an NNRTI, and emergence of lamivudine-resistance in these infants after re-exposure to NVP. 3. Characterize the kinetics and prevalence of NVP and lamivudine-resistant HIV-1 variants in subtype C infected infants during the first month of therapy with NVP-based HAART that includes lamivudine. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations.