Short‐Course Raltegravir Intensification Does Not Reduce Persistent Low‐Level Viremia in Patients with HIV‐1 Suppression during Receipt of Combination Antiretroviral Therapy

Abstract

Background Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short (28d) course antiretroviral intensification of standard combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma viremia in patients on suppressive antiretroviral therapy. Methods Subjects (N=10) with long term HIV-1 suppression on combination antiretroviral regimens were intensified for 4 weeks with raltegravir. Plasma viremia was determined prior to, during, and following the 4-week intensification period using a sensitive HIV-1 RNA assay (limit of detection of 0.2 copies HIV-1 RNA/ml plasma). A four week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (c. 1-14 d) half-lives. Results There was no evidence in any subject of decline in HIV-1 RNA levels during the period of raltegravir intensification or rebound after discontinuation. Median levels of HIV-1 RNA prior to (0.17 log10 copies/ml), during (0.04 log10 copies/ml), and following (0.04 log10 copies/ml) raltegravir intensification (p >0.1 for all comparisons in parametric analyses). HPLC/mass spectroscopy studies confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification. Conclusions Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects on suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches.

Baseline Cellular HIV DNA Load Predicts HIV DNA Decline and Residual HIV Plasma Levels during Effective Antiretroviral Therapy

“…This residual viremia was not reduced by treatment intensification (10,11,18). However, these results are under debate (8), as it has been suggested that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells.…”

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

“…Through in-depth phylogenetic analyses, we determined that the HIV-1 reservoir in these cells from eight patients is kept stable during long-term cART and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes. (30,31), suggesting that cART is effective in preventing viral replication in these anatomical sites. In contrast, increased numbers of 2-long terminal repeat circles in peripheral blood mononuclear cells and decreased amounts of unspliced HIV-1 RNA in CD4 + T cells isolated from the terminal ileum have been reported during raltegravir intensification, supporting the concept that some viral replication can occur despite suppressive cART (32,33).…”

HIV Pathogenesis: Dynamics and Genetics of Viral Populations and Infected Cells

“…The level of viremia is not affected by the inclusion of another drug. Several studies have been performed in which a suppressive three-drug regimen was intensified by the addition of a fourth inhibitor of a class previously unseen by the patient (Dinoso et al 2009;Gandhi et al 2010;McMahon et al 2010). Despite some differences in design and inhibitors used, all studies gave the same result: There was no difference in the amount of virus during and after the intensification period as compared with before.…”