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Size of active HIV reservoir predicts rebound when antiretroviral therapy stops
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
webcast:
http://www.croiwebcasts.org/console/player/25707?mediaType=slideVideo&
Levels of cell-associated HIV RNA and residual viremia detected with a 1-copy assay predicted time to viral rebound after treatment interruption in a 124-person study [1]. Cell-associated HIV DNA did not predict rebound in this 5-trial analysis.
Jonathan Li and colleagues at Harvard and other centers proposed that strategies aimed at suspending antiretroviral therapy (ART) "will ultimately be judged by their ability to show clinically meaningful results in HIV treatment interruption trials." Because researchers do not have the time or resources to test every ART-suspension strategy clinically, they will benefit from defining biomarkers of viral rebound that can be tracked in early-phase studies. Identifying such biomarkers, the researchers suggested, could speed development of cure strategies.
With those goals in mind, Li and coworkers analyzed HIV RNA rebound in a pool of patients enrolled in one of 5 AIDS Clinical Trials Group treatment-interruption studies. Participants in this retrospective analysis had to be on combination ART with HIV RNA below 50 copies at treatment interruption. The investigators defined rebound as (1) confirmed HIV RNA at or above 200 copies or (2) a single HIV RNA at or above 400 or 1000 copies. The research team measured two reservoirs before ART suspension: (1) the active HIV reservoir calculated as cell-associated HIV RNA (CA-RNA) or residual viremia (determined by a single-copy assay) and (2) cell-associated HIV DNA (CA-DNA).
The study group included 104 people with chronic HIV infection and 20 with acute or early infection. Median ages of the chronic and acute groups were 42 and 35, 69% and 65% were white, and median on-treatment CD4 counts stood at 843 and 828. While 63% of people with chronic infection were taking a nonnucleoside (NNRTI) regimen, none with acute/early infection took an NNRTI combination.
Two thirds of study participants lost viral suppression 4 weeks after interrupting ART, but about 20% maintained an undetectable viral load about 6 weeks after stopping therapy, while about 10% remained rebound-free through 8 weeks. Compared with the chronic infection group, people treated during acute/early infection had higher proportions with viral suppression at week 12 with the 200-copy threshold (13% versus 3%) or the 1000-copy threshold (11% versus 4%). Among people with chronic HIV infection, those taking an NNRTI-based combination had a significantly delayed rebound 4 weeks after interruption (44% versus 13% at the 200-copy threshold and 54% versus 21% at the 1000-copy threshold, P < 0.001).
Compared with people treated in chronic infection, those treated in acute/early infection had significantly lower preinterruption CA-RNA (about 1 versus 2 log copies per million cells, P < 0.001) but not significantly lower CA-DNA. Preinterruption CA-RNA or CA-DNA did not differ between people taking an NNRTI and those taking a PI.
Higher CA-RNA (but not CA-DNA) at treatment interruption predicted a faster viral rebound after ART stopped. At the 200-copy rebound cutoff, group CA-RNA was 1.83 log in people who rebounded within 4 weeks of interruption, 1.68 log in those who rebounded between 5 and 8 weeks, and below 1.58 log in those who rebounded after 8 weeks (P = 0.001 vs 4-week group and P = 0.04 versus 5-to-8-week group).
Higher proportions of participants with residual HIV RNA detectable with the 1-copy assay before treatment interruption rebounded within 4 weeks (47%) or 5 to 8 weeks (29%) than after 8 weeks (8%) (P = 0.02).
Li and colleagues concluded that the size of the active HIV reservoir (CA-RNA and residual viremia) predicts how fast viremia rebounds after ART stops. This finding, they believe, suggests that "quantification of the active HIV reservoir has the potential to serve as biomarkers of efficacy for therapies that aim to achieve ART-free remission."
The finding of significantly lower CA-RNA in people treated during acute versus chronic infection, the researchers proposed, could mean "a smaller active HIV reservoir may mediate delayed viral rebound in participants treated during early infection."
Reference
1. Etemad B, Ahmed H, Aga E, et al. The size of the active HIV reservoir predicts timing of viral rebound. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 110LB.
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