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Delayed HIV Rebound More Frequent After Early Treatment and With NNRTIs
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IDWeek 2014, October 8-12, 2014, Philadelphia
Mark Mascolini
People who began antiretroviral therapy (ART) during acute or early HIV infection proved more likely to have delayed rebounds after ART interruption than people who started treatment during chronic infection, according to results of a six-study AIDS Clinical Trials Group (ACTG) analysis [1]. Among people who started ART during chronic infection, delayed rebounds were more frequent among people taking a nonnucleoside (NNRTI) regimen than among those taking other regimens.
ACTG investigators noted that strategies to achieve ART-free HIV remission need validation in careful treatment interruption trials. They suggested treatment-interruption risks may be minimized if such trials use an intensively monitored antiretroviral pause. Monitoring such treatment breaks may be improved by a better understanding of HIV rebound kinetics after treatment interruption.
The ACTG team described two models of treatment interruption trials, the traditional analytic treatment interruption (ATI) and the monitored antiretroviral pause (MAP). ATI and MAP differ in primary outcome (viral set point versus time to rebound), ART restart trigger (completing the study versus reaching a viral load threshold), treatment interruption duration (12 to 16 weeks versus days to weeks), and whether prolonged viremia is acceptable (yes versus no). The MAP strategy, they explained, may decrease risk to study participants.
The analysis included participants from six ACTG treatment interruption trials who were taking combination ART, had a viral load below 50 copies when they suspended ART, and had no immunologic therapy, such as a therapeutic vaccine. The investigators defined viral rebound threshold as (1) a confirmed viral load at or above 200 copies, or (2) a single viral load at or above 400 or 1000 copies. They stratified participants by timing of initial ART, antiretroviral regimen, and nadir CD4 count.
The study involved 235 people, 155 (66%) who began treatment during chronic infection, 32 (14%) during acute infection, and 48 (20%) during early infection. For all study participants, median age stood at 41, 71% were white, 13% were black, and 14% were Hispanic. Median CD4 count was highest in the acute group (934), followed by the early group (820) and the chronic group (803). The chronic group had a much higher proportion of people taking an NNRTI regimen (61% versus 6% in each of the other two groups).
By interruption week 4, about 35% of trial participants still had an undetectable viral load. By interruption week 8, that proportion fell to about 10%. By week 12 only 6% of participants had a viral load below 200 copies or below 1000 copies. Compared with the group that began ART during chronic infection, the groups that began during acute or early infection had higher proportions of people who maintained viral suppression through week 12 whether the researchers used the 200-copy threshold (13% versus 3%, P = 0.006) or the 1000-copy threshold (11% versus 4%, P = 0.046).
At treatment interruption week 4 among people who started ART during chronic infection, a significantly higher proportion of those taking an NNRTI regimen versus other regimens maintained viral suppression by the 200-copy threshold (44% versus 13%) or the 1000-copy threshold (54% versus 21%) (P < 0.001).
Regardless of whether participants started ART during chronic, early, or acute infection, they lost few CD4 cells during treatment interruptions. Those with a lower nadir CD4 count, however, lost more CD4 cells during treatment breaks than people with higher CD4 nadirs. Participants lost fewer CD4 cells during interruptions in MAP study designs than in traditional ATI studies.
The ACTG team concluded that a small subset of treatment interruption trial participants maintains viral control after 4 weeks without ART. Longer viral suppression proved more frequent among people starting ART during acute or early infection than among those starting during chronic infection. Because people taking NNRTI-based regimens had delayed rebounds during interruptions, the investigators suggested that "standardized ART regimens should be considered for future studies." Finally, they noted, the MAP strategy is associated with smaller CD4-cell drops during ART suspension than is the ATI strategy.
Reference
1. Li J, Aga E, Bosch R, et al. HIV rebound kinetics and CD4+ T-cell loss after treatment interruption: a pooled analysis of six AIDS Clinical Trials Group (ACTG) studies. IDWeek 2014. October 8-12, 2014, Philadelphia. Abstract 541.
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