Absence of HIV-1 evolution in early-treated individuals with HIV switching to dolutegravir monotherapy during 48 weeks. The Journal of Infectious Diseases
Jörimann et al. evaluated the impact of dolutegravir (DTG) monotherapy on the dynamics and the evolution of the viral reservoir among people with acute HIV infection. Specifically, the authors tested the hypothesis of ongoing low-level HIV replication as a mechanism for HIV-1 reservoir maintenance, which may lead to an increase in genetic distance, viral diversity or the occurrence of drug resistance mutations (DRM) in HIV-1 proviruses.
The study included participants from the Early Simplified Study (ESS), in which people with acute HIV infection who received standard antiretroviral therapy (ART) for at least one year were randomized to either receiving DTG monotherapy or continuing standard ART. For the present work, peripheral blood mononuclear cells (PBMCs) or co-culture virus from ESS participants were collected at multiple time points, and near full-length HIV-1 PCR with next-generation sequencing (NGS) was performed to assess the viral diversity, genetic distance and to detect DRMs.
Sequences were obtained from 210/297 samples (71%), and 163 NGS sequences were selected from 43 ESS participants with longitudinal data (25 on DTG monotherapy, 18 on standard ART). After filtering for APOBEC-induced hypermutations (which occur frequently but do not indicate proviral evolution), the median pairwise genetic distance over the study period was 0.50% (IQR 0.06-1.50), and did not differ between the two groups (p = 0.56). Similarly, average pairwise viral diversity assessed for the 3 genomic regions pol, gag, and env were similar in both groups, and did not change over time. Finally, after filtering for APOBEC signature mutations, one single proviral DRM emerged in an individual after receiving 48 weeks of DTG monotherapy. Importantly, this individual did not develop viral failure during a total of four years of DTG monotherapy.
Taken together, the study shows that DTG monotherapy among individuals who entered HIV care during primary HIV infection did not lead to an increase in genetic distance, viral diversity or accumulation of DRMs. These findings argue against ongoing low-level HIV replication in those individuals, and highlight that a better understanding of HIV-1 reservoir dynamics is important to inform future ART simplification strategies.