Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies

Abstract

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of 'placebo' controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13-25), 21 (IQR:15-28), and 32 (IQR:20-35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.

Fig. 1

Flowchart of literature review.

Fig. 2. Viral kinetics, frequency of control (<50 copies/mL) and time to viremia of 50, 400 and 10,000 copies/mL during 84 days of ATI.

a Individual plasma HIV RNA levels are shown during 84 days of ATI. The bold line represents median plasma HIV RNA of the entire cohort (n = 382). The dotted line indicates plasma HIV RNA of 50 copies/mL. Of note, 86 individuals had at least one plasma HIV RNA measurement above 100,000 copies/mL and 19 individuals had at least one plasma HIV RNA measurement above 1,000,000 copies/mL. b Percentage of individuals (n = 376) with plasma HIV RNA < 50 or >50 copies/mL during 84 days of ATI. c–e Kaplan–Meier curves showing the percentage of individuals (not NNRTI-containing regimen) with first plasma HIV RNA measurement below the following three thresholds 50, 400 and 10,000 copies/mL during 84 days of ATI. The dotted lines indicate median times to reach the specified thresholds. Below each Kaplan-Meier curves are noted the number of individuals at risk. ART antiretroviral therapy, ATI ART interruption, NNRTI non-nucleoside reverse transcriptase inhibitor.

Fig. 3. Post-treatment control (<50 copies/mL) at day 84 of ATI.

a Pie chart showing the percentage of individuals with plasma HIV RNA < 50 or >50 copies/mL at day 84 of ATI among the entire cohort (n = 376). b Pie chart showing the peak plasma HIV RNA level during 84 days of ATI among the post-treatment controllers (n = 14: <50 copies/mL). c Plasma HIV RNA levels for individuals with either sustained or regained post-treatment control (<50 copies/mL) at day 84 day of ATI. Bold and thin lines represent sustained (n = 4) and regained (n = 10) post-treatment controllers, respectively. The dotted line indicates plasma HIV RNA of 50 copies/mL. d Table with characteristics of the post-treatment controllers (n = 14: <50 copies/mL). ART antiretroviral therapy, ATI ART interruption, PI protease inhibitor, PTC post-treatment control, INSTI integrase strand transfer inhibitor.

Fig. 4. Correlations of immunological and virological variables for the ATI participants (not NNRTI-containing regimen).

a Heat map of Spearman’s rank correlations between immunological and virological variables for the ATI participants (not NNRTI-containing regimen). *Asterisks noted at correlations with P values < 0.05. b Correlation between nadir CD4 + T cell count and CD4 + T cell count at ATI start (n = 206). c Correlation between nadir CD4 + T cell count and time to viremia of 50 (circles; n = 208), 400 (squares; n = 206) and 10,000 (triangles; n = 142) copies/mL. d–f Correlations between initial viral doubling time and time to viremia of 50 (d, circles; n = 357), 400 (e, squares; n = 357) and 10,000 (f, triangles; n = 261) copies/mL, respectively. P values were calculated using two-tailed Spearman’s correlation coefficient. ART antiretroviral therapy, ATI ART interruption, NNRTI non-nucleoside reverse transcriptase inhibitor.

Fig. 5. Number of participants needed in future trials to achieve 25%, 35% or 50% post-treatment control (<50 copies/mL) among early-ART and late-ART individuals at day 84 of ATI.

Power calculations to be use for future study designs on how many participants would be needed for either single arm or 1:1 active intervention:placebo randomized controlled trials (RCTs) with 2 groups based on the assumption that the studies would have a power of 90% to detect the indicated differences in post-treatment control (PTC) at a 5% significant level, one-sided. Early-ART (a) and late-ART (b) defined as people who started ART within or beyond 6 months of HIV acquisition. ART antiretroviral therapy, ATI ART interruption, PTC post-treatment control.