Abstract
Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. ClinicalTrials.gov NCT00515827
Highlights
Currently recommended antiretroviral therapy (ART) lowers plasma human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) levels to below the detection limit of commercial assays, most patients have persistent low-level viremia when tested with more sensitive methods [1]
In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells
Baseline Characteristics One hundred twenty-five patients were screened for the study, of whom 75 (60%) had detectable plasma HIV-1 RNA by single copy assay (SCA) (Figure 1)
Summary
Currently recommended antiretroviral therapy (ART) lowers plasma HIV-1 RNA levels to below the detection limit of commercial assays (generally ,50 copies/mL), most patients have persistent low-level viremia when tested with more sensitive methods [1]. Prior intensification studies of patients on suppressive three-drug antiretroviral regimens did not observe reductions in plasma HIV-1 RNA levels after the addition of antiretroviral drugs that block new replication cycles, including inhibitors of reverse transcriptase (RT), protease, and integrase [5,6]. These studies were small, single-arm trials of short duration that were not randomized or placebo-controlled and had limited power to detect changes in residual viremia. In industrialized countries, the life expectancy of HIV-infected patients treated with ART is similar to that of people with diabetes and other chronic conditions
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