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Intact Proviral HIV DNA Drops During Long-Term Suppressive ART
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CROI 2020, March 8-11, 2020, Boston
Mark Mascolini
While total proviral DNA levels hardly budge through years of successful antiretroviral therapy (ART), new work from the AIDS Clinical Trials Group (ACTG) shows that intact proviral DNA does decline when ART keeps viral load undetectable year after year [1]. Waning intact proviral DNA "implies that cells containing replication-competent HIV . . . are being lost," the ACTG team proposed.
HIV researchers now use an intact proviral DNA assay (IPDA), which separately measures intact and defective proviral HIV DNA and gives them a better fix on levels of replication-competent virus. Intact plus defective proviral DNA adds up to total proviral DNA. ACTG researchers conducted this study to learn more about whether intact proviral DNA levels fall over time in people taking suppressive ART and whether levels of intact proviral DNA correlate with other gauges of HIV persistence or activation.
The investigators picked 50 people from the ACTG HIV Reservoir Cohort (ACTG A5321) who began ART in an ACTG trial and had a well-documented sustained undetectable viral load. After these people took ART for a median 7.1 years, researchers measured intact proviral DNA (timepoint 1), then did so again a median 3.7 years later (timepoint 2). They compared results of the intact proviral DNA assays with three other measures of viral persistence in blood: (1) HIV-1 RNA by integrase single-copy assay, (2) HIV pol DNA, and (3) cell-associated unspliced HIV pol RNA. They also measured various markers of inflammation, T-cell activation or proliferation, and T-cell exhaustion.
Among the 50 people recruited, 37 (74%) were men, 26 (52%) white, 14 (28%) Hispanic, and 10 (20%) black.
Total HIV DNA remained stable from timepoint 1 to timepoint 2 (median 821 and 836 copies/million CD4 cells), as did cell-associated RNA (51 and 45 copies/million CD4 cells), and proportions of participants with HIV RNA below 0.3 copies/mL by single-copy assay (55% and 55%).
But intact proviral DNA levels dropped as suppressive ART continued, from 65 copies/million CD4 cells at timepoint 1 to 53 copies/million CD4 cells at timepoint 2. Between the two timepoints, 83% of participants had falling intact proviral DNA levels, while those levels rose in the other 17%. Median intact proviral DNA half-life measured 7.1 years (95% confidence interval [CI] 4.7 to 18 years). The researchers found no evidence that intact proviral DNA decay differed by age, sex, or pre-ART or on-ART measures of inflammation or activation.
Defective proviral DNA did not wane over time on suppressive ART. As a result, median half-life for total proviral DNA (intact plus defective) stood at a sluggish 30 years (95% CI 12 to 81).
Higher intact proviral DNA correlated positively with cell-associated HIV DNA (Spearman 0.61, P < 0.001), cell-associated RNA (0.57, P < 0.001), and HIV-1 RNA by integrase single-copy assay (0.53, P < 0.001). Higher pre-ART HIV DNA was associated with higher on-ART intact proviral DNA levels (r = 0.43, P = 0.005), even after statistical adjustment for pre-ART HIV RNA.
Intact proviral DNA did not correlate with inflammation during ART measured by 7 markers, after adjustment for pre-ART HIV RNA and years on ART at timepoint 1. The investigators turned up no evidence tying intact proviral DNA to T-cell activation or exhaustion markers.
The ACTG team proposed that the "more dynamic nature of the intact proviral DNA landscape" compared with levels of total proviral DNA supports measuring this variable to track the impact of strategies targeting the HIV reservoir.
Reference
1. Gandhi RT, Cyktor J, Bosch R, et al. Intact proviral DNA levels decline in people with HIV on antiretroviral therapy. Conference on Retroviruses and Opportunistic Infections (CROI). March 8-11, 2020. Boston. Abstract 75.
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