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  5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
July 19th-22nd 2009
Capetown, South Africa
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Adding Raltegravir to Suppressive Regimen Does Not Cut Low-Level Viremia
  5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Among people with a viral load below 50 copies during antiretroviral therapy, adding the integrase inhibitor raltegravir did not further reduce low-level HIV RNA in a placebo-controlled trial [1]. These results and similar findings in another study [2] argue that low-level viremia does not result from complete cycles of viral replication. If it did, adding raltegravir should drive low HIV RNA levels even lower. Doing that could help dry up latent viral reservoirs fed by complete cycles of covert replication. And draining latent reservoirs is an essential step in viral eradication.
The study involved 53 people taking a standard antiretroviral combination who kept their viral load below 50 copies for 6 months or more. Researchers from several US centers randomized people to add standard-dose raltegravir (400 mg twice daily) or placebo to their regimen for 12 weeks. In the next 12 weeks, people randomized to raltegravir switched to placebo, and people on placebo swapped it for raltegravir. The primary endpoint was viral load determined by a single-copy assay averaged from week 10 through week 12.
Everyone entered the trial with residual viremia above 0.2 copies per milliliter of plasma on the supersensitive assay. Median age, viral load, and CD4 count were 49 years, 1.7 copies, and 589 CD4 cells. Forty-eight study participants (91%) were men, and median time with a viral load under 50 copies was 5.5 years. Two thirds of study participants were taking a nonnucleoside regimen, while the rest were taking a protease inhibitor.
Pill counts during the study showed that participants took 94% to 97% of prescribed doses. Among 49 people who completed the first 12 weeks of study, median viral load at weeks 10-12 did not differ significantly between the 25 in the raltegravir group (1.1 copy) and the 24 in the placebo group (1.7 copy) (P = 0.80). Median change in viral load from week 0 to weeks 10-12 was equivalent in the two groups (-0.3 copy and -0.1 copy, P = 0.52). Virologic results did not change after the 12-week crossover in the 46 people who finished the entire 24 weeks of treatment (medians of 0.9 copy in the group that switched to raltegravir and 1.1 copy in the group that switched to placebo).
From week 0 to week 12, median CD4 count improved in the raltegravir group (+42 cells) while dropping in the placebo group (-44 cells), a result that approached statistical significance (P = 0.082). Why CD4 counts would drop that much in people adding placebo to a stable is unclear. Switching from placebo to raltegravir in the second 12 weeks drove CD4 counts up (+54 cells), and switching from raltegravir to placebo drove them down (-26 cells) (P = 0.088). In the earlier study by some of these same investigators, intensification with efavirenz, lopinavir, or atazanavir also failed to further reduce low-level viremia [2]. These consistent findings suggest that residual viremia reflects viral production from long-lived chronically infected cells, not from covert ongoing rounds of viral replication.
1. Gandhi R, Zheng S, Bosch R, et al. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): results from ACTG A5244. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WELBB104.
2. Dinoso J, Jones J, McMahon D, et al. Antiretroviral intensification does not reduce persistent HIV-1 viremia on therapy. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 10.