Dolutegravir restores gut microbiota in late-stage HIV-1 unlike darunavir: an open-label, randomized clinical trial.

Both dolutegravir and darunavir/ritonavir regimens achieved similar HIV-1 suppression rates and CD4+ T cell recovery over two years.

• 88 antiretroviral-naïve individuals with advanced HIV-1 infection were enrolled in a multicenter, open-label, randomized clinical trial (NCT02337322)
• Participants had a median CD4+ T cell count of 34 cells/mm3 at baseline
• Participants were randomized 1:1 to lamivudine/abacavir plus either dolutegravir or ritonavir-boosted darunavir
• Follow-up duration was 2 years
• HIV-1 suppression rates and CD4+ T cell recovery were similar between the two treatment groups

Dolutegravir-based therapy led to increased gut microbial richness and diversity compared to darunavir/ritonavir.

• Treatment with dolutegravir resulted in increased gut microbial richness and diversity
• These changes did not occur with darunavir/ritonavir treatment
• The trial enrolled individuals with late-stage HIV-1 infection defined by median CD4+ T cells of 34 cells/mm3
• Microbial diversity changes were observed over the 2-year follow-up period

Dolutegravir treatment led to enrichment of specific microbial taxa and metabolic pathways not observed with darunavir/ritonavir.

• Specific microbial taxa were enriched in the dolutegravir group
• Specific metabolic pathways were also enriched in the dolutegravir group
• These enrichments were not observed in the darunavir/ritonavir group
• The changes occurred in the context of late-stage HIV-1 infection with advanced immunosuppression

Microbiota changes in the dolutegravir group were associated with reduced inflammation and lower immune activation.

• Increased gut microbial richness and diversity in the dolutegravir group were associated with reduced inflammation
• These changes were also associated with lower immune activation
• Reduced inflammation and immune activation did not occur with darunavir/ritonavir treatment
• Late presentation of HIV-1 infection is linked to excess inflammation, immune activation, and increased morbidity and mortality

After two years, participants on dolutegravir-based therapy had gut microbiota profiles more closely resembling those of people without HIV compared to individuals taking darunavir/ritonavir.

• The comparison was made after 2 years of antiretroviral therapy
• Dolutegravir-treated participants' microbiota profiles more closely resembled HIV-negative individuals
• Darunavir/ritonavir-treated participants did not show comparable normalization of gut microbiota
• This finding suggests that the choice of antiretroviral regimen influences the degree of gut microbiota restoration

Late presentation of HIV-1 infection is linked to gut dysbiosis, impaired immune reconstitution, excess inflammation, immune activation, and increased morbidity and mortality.

• This relationship between late HIV presentation and gut dysbiosis provided the rationale for the study
• It was unclear prior to this trial whether antiretroviral therapy initiation could reverse HIV-associated gut dysbiosis
• It was also unclear whether specific antiretroviral regimens would be more effective in restoring gut microbiota than others
• The study enrolled individuals with advanced HIV-1 infection with a median CD4+ T cell count of 34 cells/mm3