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Intensification With Raltegravir Has No Impact on Reservoir of Replicating Virus
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Intensifying standard antiretroviral therapy with the integrase inhibitor raltegravir will not eliminate HIV reservoirs, according to results of an AIDS Clinical Trials Group (ACTG) crossover trial [1]. Instead, the ACTG team suggested, "strategies that directly target latently infected cells may be more likely to eradicate HIV."
The primary goals of the ACTG trial were to gauge the impact of raltegravir intensification on low-level viremia and on 2-LTR circles in peripheral blood mononuclear cells (PMBCs). When a strand-transfer inhibitor like raltegravir blocks viral integration, unintegrated viral DNA accumulates in PBMC nuclei in the form of 1-LTR and 2-LTR circles [2]. Recent work suggested that 2-LTR circles are a marker of recently infected cells [3]. Other researchers proposed that 2-LTR circle monitoring can be "a useful clinical indicator of whether the reservoir of ongoing viral replication in patients on [combination antiretroviral therapy] is stable or enlarging" [4].
The ACTG trial involved 50 people with a viral load below 50 copies/mL while taking a stable antiretroviral regimen. But a single-copy assay could detect circulating virus at a level below 50 in all study participants. The ACTG investigators randomized people to add raltegravir or placebo to their regimen for 12 weeks. At that point, everyone switched their intensification agent. Before study entry and at weeks 12 and 24, the researchers measured 2-LTR circles in 5 million PBMCs, determined single-copy assay values, and estimated T-cell activation as percentage of CD38-positive, HLA-DR-positive T cells. Earlier the ACTG investigators reported that raltegravir intensification did not further reduce low-level viremia in patients taking a currently recommended antiretroviral regimen [5].
Thirteen study participants (26%) had 2-LTR circles detectable before trial entry at a median level of 82 copies per million CD4 cells. People with and without detectable 2-LTR circles at this point had similar times since their first undetectable HIV RNA in plasma (medians of 5 and 6 years), similar single-copy assay values (medians of 2 and 1 copies/mL), and similar levels of CD4-cell and CD8-cell activation (all P > 0.05). Whether a person was taking a protease inhibitor of a nonnucleoside did not affect chances of having detectable 2-LTR circles before entry.
Compared with 33 study participants who never had detectable 2-LTR circles, 17 who had detectable 2-LTR circles at some point did not differ in entry single-copy assay levels or CD4 or CD8 activation.
At study week 12, neither the proportion of 2-LTR-positive cells nor 2-LTR copy number differed between people taking raltegravir and people taking placebo. During raltegravir intensification 3 people (7%) who were initially 2-LTR-negative became 2-LTR-positive, and 5 people (12%) who were initially 2-LTR-positive became 2-LTR-negative. Similar shifts between positive and negative 2-LTR status occurred during the placebo phase. People who became 2-LTR-positive during intensification did not have a greater drop in plasma HIV RNA than those who remained 2-LTR-negative.
The ACTG team concluded that 2-LTR circles do not increase during 12 weeks of raltegravir intensification. "Although we cannot rule out a transient effect of raltegravir on 2-LTR circles," the researchers added, "our results do not find evidence of ongoing HIV replication in circulating cells of patients on suppressive antiretroviral therapy." Such a transient effect (before week 12 of raltegravir intensification) was seen in another placebo-controlled trial [6]. But this study (and others) also found that raltegravir intensification does not further reduce already low-level plasma viremia.
The ACTG results, plus previous reports that intensification with raltegravir or other antiretrovirals has little effect on residual viremia, suggested to the ACTG researchers "that intensification with drugs that block [viral] replication is unlikely to eliminate HIV reservoirs."
References
1. Gandhi R, Coombs R, Chan E, et al. RAL Intensification of patients on long-term suppressive ART does not increase 2-LTR HIV DNA circles in PBMC: results from ACTG A5244. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 51.
2. Cunningham T, Mediavilla J, Pope M, Muesing M. Analysis of 2-LTR circle stability and gene expression in primary human macrophages. 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002, Seattle. Abstract 157.
3. Hatano H, Hayes T, Dahl V, et al. Raltegravir intensification in antiretroviral-treated patients exhibiting a suboptimal CD4+ T cell response. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 101LB.
4. Morlese J, Teo I, Choi JW, Gazzard B, Shaunak S. Longitudinal studies of 2-LTR circles in patients on cART. 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002, Seattle. Abstract 159.
5. Gandhi RT, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010;7(8).pii:e1000321.
6. Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16:460-465.
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