Background:
Whether ongoing viral replication occurs in people living with HIV (PLWH) despite antiretroviral therapy (ART) and leads to low-level residual viremia is still debated. Here we report on a study, in which we intensified the ART regimen by doubling dolutegravir (DTG) dosage. We investigated the impact of this strategy on HIV blood and tissue latent reservoirs, residual viremia, immune activation, and inflammation.
Methods:
Twenty HIV-infected adults, who received a triple therapy consisting of DTG 50mg/ABC/3TC and were fully suppressed for at least 2 years, were enrolled in a phase 3 randomized clinical trial. Half of them received an additional 50 mg of DTG as treatment intensification. Peripheral blood mononuclear cells (PBMCs), plasma and rectal biopsies were collected at different time points over 3 months. We quantified total HIV DNA, intact HIV DNA (IPDA), cell-associated unspliced (US) HIV RNA in PBMCs and in tissue. Single copy assay was performed to determine ultrasensitive plasma viral load. Expression of immune activation (HLA-DR, CD38) and exhaustion (PD-1, TIGIT, LAG-3) markers on CD4+ and CD8+ T cells was evaluated. Inflammation was assessed by measuring the levels of several plasma biomarkers including sCD14, IL-4, IL-6, IP-10, usCRP, IFN gamma, and TNF alpha. Concentration of dolutegravir was measured in plasma and in tissue.
Results:
There was no significant difference in total HIV DNA in PBMCs and in tissue between day 0 and day 84 in both groups. However, we observed a significant decrease in US HIV RNA in PBMCs (p=0.020) and in ultrasensitive plasma viral load (p=0.016) between day 0 and day 84 in the intensified group, whereas no such differences were observed in the control group. These results suggest ongoing viral replication prior to intensification, even though we could not detect differences in immune activation or inflammation between the groups. These results should be confirmed in tissue where it would be even more relevant.
Conclusions:
We observed a decrease in US RNA and ultrasensitive plasma viral load following DTG intensification, suggesting ongoing viral replication in some participants. However, it had no measurable impact on chronic inflammation or immune activation. If confirmed in larger clinical trials, these results could have an impact on the clinical management of PLWH.