Dolutegravir Restores Gut Microbiota in Late-stage HIV-1 Unlike Darunavir: An Open-Label, Randomized Clinical Trial

Late HIV-1 presentation is linked to impaired immune reconstitution, excess inflammation, immune activation, and increased morbidity and mortality. It also leads to gut dysbiosis, which is believed to worsen all such conditions. It is not clear if antiretroviral therapy initiation can reverse HIV-associated gut dysbiosis at all, or if specific antiretroviral regimens with higher intestinal penetration are more effective in restoring the gut microbiota than others, which has important implications for the long-term health of individuals with HIV. In this multicenter, open-label, randomized clinical trial (NCT02337322), 88 antiretroviral-naïve individuals with advanced HIV-1 infection (median CD4+ 34 cells/mm3) were randomized (1:1) to initiate lamivudine/abacavir plus either dolutegravir or ritonavir-boosted darunavir, and were followed for 2 years. Both groups achieved similar HIV-1 suppression and CD4+ count recovery. However, subjects starting dolutegravir experienced increases in gut microbial diversity and enrichment of beneficial commensal taxa and functional microbial pathways, which correlated with reductions in systemic inflammation and immune activation. These changes were not observed with darunavir/ritonavir treatment. In conclusion, treatment regimens that include dolutegravir are more likely to restore at 2 years the architecture and function of the gut microbiota in individuals with advanced HIV compared to those that include darunavir/ritonavir and should therefore be prioritized.