This is a proposal to continue and extend the longitudinal studies of HIV therapy, adherence to therapy and drug resistance in the REACH cohort of HIV-positive homeless and marginally housed persons. The cohort will be augmented by a third wave of sampling in the study population, all subjects will be followed for three years, and subjects on Highly Active Therapy (HAART) will be followed monthly with intensive measurement of adherence levels and monthly plasma storage for genotyping. The specific aims of the proposed research are: 1. Once-a-day therapy. To study the penetration and impact of once-a- day HAART in the REACH cohort, including its effects on adherence to therapy and the development of resistance. 2. Biology of incomplete adherence. To divide subjects by adherence level and test four hypotheses on the biology of incomplete adherence to therapy, including hypotheses on the relationship between adherence level and viral fitness and the relationship between adherence level and immune response to therapy. These studies are collaborative with Drs M. McCune, S. Deeks, and R. Grant at UCSF. 3. Mortality and progression to AIDS, the effect of adherence to therapy on mortality and progression to AIDS, and the changing population prevalence of anti-retroviral resistance. 4. Hepatitis C Virus (HCV) co-infection. To study the penetration of and adherence to HCV therapy in the homeless and the effect of HCV co- infection on progression of HIV infection and mortality. The REACH cohort is the only representative cohort of HIV-positive persons recruited from the urban indigent, an increasingly important reservoir of HIV infection in the United States. This population is at high risk for adherence and the development of drug resistance. The proposed research will assist in the development of both behavioral and therapeutic strategies to extend treatment and reduce the risk of drug resistance in this important population.