Residual HIV RNA in Plasma Continues to Decline for at Least 11 Years on Treatment

March 28, 2016

Residual plasma viremia continued to decay up to 11 years after suppressive antiretroviral therapy (ART) began, according to results of a 64-person AIDS Clinical Trials Group (ACTG) analysis using a single-copy HIV RNA assay. These findings contrasts with the results of other studies, which found a plateau in low-level viremia after initial ART-induced drops.

ART that drives plasma viremia to levels below the cutoffs of routinely used clinical assays cannot eradicate HIV because viral DNA becomes integrated into long-living resting T cells. Residual low-level viremia (< 50 copies/mL) in patients taking an effective regimen probably reflects intermittent expression of nonreplicating virus from resting T cells, according to the ACTG team that conducted this study. Previous modeling indicated that residual viremia reaches a plateau with no further decline and with a half-life exceeding seven years. ACTG investigators conducted this analysis of patients in the ACTG Longitudinal Linked Randomized Trials (ALLRT) study to refine estimates and identify predictors of residual viremia.

Study participants began their first antiretroviral regimen in an ACTG trial and had a viral load < 50 copies/mL from treatment week 32 through the last follow-up. Participants also had frozen plasma samples available at ART weeks 192 and 208. A subset of individuals had frozen samples from approximately 7, 10 and 12 years after they started ART. A single lab measured HIV RNA in these samples with a single-copy assay. The researchers used logistic regression to identify factors associated with plasma viremia ≥ 1 copy/mL versus < 1 copy/mL. A random-effects model estimated longitudinal viral decay in patients with samples at 7, 10 and 12 years of ART.

Most of the 334 study participants (82%) were men. Median pre-ART age stood at 40 years, pre-ART CD4+ count at 248 cells/mm3, and pre-ART viral load at 4.7 log10 copies/mL. Most study participants began ART with a nonnucleoside (61%) or a protease inhibitor (28%). Pretreatment viral load was positively associated with single-copy assay results at treatment week 192 (r = 0.18, P = .004) and week 208 (r = 0.20, P = .001).

An analysis adjusted for pretreatment viral load identified two factors independently associated with residual plasma viremia ≥ 1 copy/mL at weeks 192 and 208: Every 100-cell higher CD8+-cell count during treatment raised the odds of residual viremia (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.01 to 1.11, P = .014) and every 0.5 higher (better) CD4+/CD8+-cell ratio during treatment lowered the odds (OR 0.78, 95% CI 0.63 to 0.98, P = .031). Factors not associated with persistent low-level viremia included age; sex, race/ethnicity; antiretroviral regimen; and pre-ART CD4+ count, CD8+ count or CD4+/CD8+ ratio.

Among the 64 participants in the longitudinal analysis, median time between starting ART and last single-copy assay was 11.2 years, while the minimum interval was 8.1 years. Most participants with detectable residual viremia in treatment year four had residual viremia ≥ 1 copy/mL at year seven (65%) or 10 (56%). But few people with undetectable residual viremia in year four had detectable residual viremia at year seven (14%) or 10 (9%). Random effects modeling estimated that plasma viremia continued to decay at a rate of 6% yearly through follow-up, corresponding to a half-life of 11.5 years (95% confidence interval 6.2 to 83).

The ACTG team noted that their analysis, which is larger and longer than previous studies addressing this issue, "provides the first evidence of slow but ongoing decay of plasma viremia level after 4 years of suppressive ART." This slow but steady viral decay suggested to the authors "that [resting] cells capable of expressing HIV-1 do not persist indefinitely."

Mark Mascolini writes about HIV infection.

Copyright © 2016 Remedy Health Media, LLC. All rights reserved.

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