Analysis of HIV-1 Replication During Antiretroviral Therapy

Combination antiretroviral therapy for human immunodeficiency virus serotype 1 (HIV-1) infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. How drug resistance emerges during suppressive antiretroviral therapy remains poorly understood. Investigating the characteristics of HIV-1 replication during suppressive antiretroviral therapy will yield important insights in understanding the emergence resistance, and requires patients who have suppressed viral RNA levels. Prior National Institutes of Health (NIH) protocols have made important observations regarding the kinetics of HIV-1 decline in response to therapy, the levels of HIV-1 viremia during suppressive therapy, and the nature of HIV-1 genetic diversity prior to and following initiation of antiretroviral therapy. In the process, these studies have generated a useful cohort of patients with suppressed viral RNA levels, who have been extensively characterized from a virologic and immunologic standpoint. Similarly, patients from other NIH protocols have been followed for prolonged periods before and after therapy has been initiated, and they also have stored sample sets that would be useful in new studies of HIV replication. The HIV Drug Resistance Program (DRP) has studied samples from protocols 00-I-0110 and 97-I-0082 to develop a number of new, sensitive laboratory techniques to measure and quantitate genetic variation and to investigate immune response parameters. To further advance understanding of HIV-1 replication during suppressive antiretroviral therapy and the emergence of drug resistance, we propose a new protocol to study these 2 patient cohorts (from the above cited protocols) and selected patients in other protocols with a new series of studies. The primary objective of this protocol is to investigate the virologic and immunologic characteristics of HIV-infected individuals undergoing antiretroviral therapy. Upon implementation, this new protocol will provide human subjects protection for samples collected under the two prior protocols, whether patients enroll in the new study or not.

• INCLUSION CRITERIA:

Inclusion criteria

for this protocol comprise all of the following conditions:

• Age greater than or equal to 18 years.
• HIV infection with documented reactive ELISA and positive western blot.
• Prior enrollment in 00-I-0110, 97-I-0082 OR patients with long term evaluation at NIH for whom additional sampling will be useful for protocol objectives, including:

• Available stored specimens from pretherapy period.
• Ongoing suppression of viremia with bDNA less than 50 copies/mL, OR
• Suppression of viremia to less than 50 copies/mL followed by rebound viremia during therapy.
• Patients must have a private physician for routine medical care.

Exclusion criteria

Any prospective study subject who has been previously withdrawn from any prior study for inability to comply with study procedures will be considered ineligible for this study.