Background
The A5324 trial investigated intensification with dolutegravir (DTG) +/- maraviroc (MVC) on neuropsychological performance (NP) in persons with HIV (PWH) and neurocognitive impairment (NCI) on suppressive ART. Intensification with these drug classes does not reduce the reservoir size or residual viremia, but changes in other virological parameters have been observed. For example, intensification with integrase strand transfer inhibitors (INSTIs) may increase early (2-4 week) cell-associated 2-LTR circle (CA-2LTR). MVC intensification may also increase CA-2LTR as well as cell-associated unspliced RNA (CA-RNA). We investigated the impact of the first 12 weeks of intensification with DTG +/- MVC versus dual placebo on these virologic measures in the large randomized, double-blind, placebo-controlled A5324 study.
Methods
Eligibility criteria for the A5324 included PWH with plasma HIV RNA < 50 copies/mL, ART regimens without INSTI or MVC, and with NCI on NP screening. This analysis focused on samples collected at baseline and weeks 2, 4, and 12, after randomization. HIV-1 virological markers were measured by ddPCR from total PBMC: cell-associated DNA (CA-DNA), CA-RNA, CA-2LTR. Residual plasma HIV RNA was measured by a low copy assay (LoD of 7 copies/mL).
Results
168 participants (70% assigned male sex at birth; 64% non-White) were enrolled and randomized to dual placebo (n=58), DTG+placebo (n=57), or DTG+MVC (n=53). CA-DNA and CA-RNA were detectable at both baseline and 12 weeks in 97% and 77% of participants, respectively, and did not differ between arms in change over 12 weeks (Wilcoxon rank-sum, P values > 0.2). In contrast, HIV-1 CA-2LTR was only detectable at both baseline and 12 weeks in 49% of participants. CA-2LTR was less frequently detected post-baseline in the DTG+MVC arm (58.5%) compared to placebo (29.3%) or DTG+placebo (31.6%) (Figure, Chi-square; vs. DTG, P = 0.03; vs. placebo, P = 0.02).
Conclusions
Unlike some prior studies of INSTI intensification, we did not observe an early increase in CA-2LTR with DTG intensification. Unexpectedly, DTG+MVC intensification appeared to decrease CA-2LTR detection without affecting other virologic measures. One limitation of this finding is that the DTG+MVC arm exhibited a lower percentage of CA-2LTR detectable at baseline, despite randomization (Figure). The reduction of CA-2LTR detection with DTG+MVC may indicate suppression of residual replication, but other mechanisms are possible like altered migration of CA-2LTR-postive CD4+ T cells.
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