The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial

Abstract

Background: 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.

Methods and findings: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00515827

Conflict of interest statement

JWM: Gilead Sciences (consultant); Merck (consultant and grant support); Chimerix (consultant); RFS Pharmaceuticals (owns stock options). JJE: Merck, GlaxoSmithKline (consultant and grant support), Bristol-Myers Squibb, Tibotec, Chimerix, Avexa, and Tobira (consultant). RTG: Tibotec (research grant support) and Gilead (grant support). DM: Merck, Bristol-Myers Squibb, and GlaxoSmithKline (consultant and research support); Gilead Sciences (research support and common stock); Chimerix (consultant); Roche, Trimeris, and Tibotec (research support).

Figures

Figure 1. Participant disposition.

Figure 2. Study schema.

Figure 3. No reduction in low-level residual viremia after raltegravir intensification.

(A) HIV-1 RNA values in patients in the raltegravir-first group (red diamonds) compared with participants in the placebo-first group (blue circles). Shaded areas designate time periods during which participants were receiving raltegravir intensification. Open symbols represent results for which one or both single copy assay (SCA) determinations were below the lower limit of quantification. Median SCA values at each time point are reported (horizontal bars). The average HIV-1 RNA level at week 10/12—the primary endpoint of the study—did not differ significantly between the raltegravir-first and the placebo-first groups: median 1.2 vs. 1.7 copies/mL (p = 0.55, Wilcoxon rank sum test). (B) Median HIV-1 RNA levels in participants adding raltegravir-first at week 0 and then crossing over to placebo at week 12 (red solid line) compared with participants adding placebo-first at week 0 and then crossing over to raltegravir at week 12 (blue dashed line). The lines connect medians. The bars represent interquartile ranges (25th and 75th percentiles).