ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia

Abstract

Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50–75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy. Combination antiretroviral therapy is effective in reducing, but not eliminating, HIV-1 replication. Residual viremia during suppressive antiretroviral therapy may arise from a number of sources, including reservoirs of long-lived virus-producing cells, or ongoing complete cycles of viral replication. Here, we used a new, more sensitive assay of HIV-1 RNA to measure residual viremia in a large cohort of patients with prolonged suppression on antiretroviral therapy. We found a persistent, stable level of viremia in patients on prolonged therapy that correlated with pretherapy levels of HIV-1. Over 80% of patients had viremia ≥1 copy/ml plasma, and the level of viremia was independent of the drug regimen patients were taking. These data strongly suggest that persistent viremia on antiretroviral therapy is likely derived from reservoirs of long-lived virus-producing cells that are not affected by currently available drugs that target new cycles of viral replication. New antiviral strategies that eradicate this reservoir will be necessary to cure HIV-1 infection.