The overall objective of the study in this revised application is to improve clinical decision-making regarding the appropriate time to initiate highly active antiretroviral therapy (HAART) among persons with early HIV infection. Current guidelines suggest that antiretroviral therapy be considered for HIV-infected people who are identified within the first 6-12 months of infection. However, there are no randomized studies that have provided data supporting early treatment of HIV infection as a valid therapeutic strategy for the long-term management of the disease, nor are there are data to justify a cut-off that would establish how """"""""early"""""""" infection should be best defined for the purposes of this strategy. Therefore, Specific Aim 1 of this application is to conduct a randomized trial of HAART vs. no therapy in people who are identified as HIV-infected within one year of becoming infected, and divided into periods of acute (<2 months) and early (2-12 months) infection, to determine whether therapy is superior to no therapy in terms of subsequent virologic control of HIV and whether treatment within 2 months of infection is superior to treatment with 2-12 months. In response to reviewers' concern about our statistical power to address these questions, we have increased the number of sites at which we will accrue participants from two to five (Baltimore, MD and Vancouver, BC, Victoria, BC, Montreal, PQ, and Toronto, ON, Canada) and the anticipated enrollment from 120 to 180 subjects over a 2-year period, yielding substantially improved statistical power. Enrollees will be randomized to receive HAART for one year or no therapy. After the initial year of follow-up, subjects will be followed for up to 4 more years and the principal study endpoint will be a comparison of the plasma viral load 24 months after initial presentation in all treated vs. untreated subjects. If our hypothesis is correct, early treatment will lead to viral suppression and preservation of host immune responses that will be reflected in lower viral loads in subsequent years. (These lower viral loads would be expected to translate into improved AIDS-free survival and time remaining therapy-free according to current guidelines for therapy of chronic HIV infection, although these endpoints because they would likely occur later than the 5-year term of this application.) Such findings would have a major impact on treatment of and surveillance for acute and early HIV infection and would result in reduced costs and morbidity of therapy as well as a much-needed databased approach to treatment of acute/early HIV infection for a limited period of time. Since our study population will also include a high proportion of injecting drug users (IDUs), the findings will also help in the design of new approaches for treatment of acute/early HIV infection in this important group of people at risk for HIV infection.
In Specific Aim 2, we will monitor the prevalence of primary drug resistance in all study subjects and monitor its stability over time in untreated subjects. Comparison with untreated subjects carrying susceptible isolates will allow us to evaluate the contribution (positive or negative) of primary drug resistance on HIV disease progression.
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