An HIV treatment succeeds in restoring the microbiome in advanced stages of infection

Nearly 50% of HIV diagnoses are made at advanced stages of infection, a time when the immune system is already compromised and the gut microbiome, made up of the millions of bacteria that inhabit the intestine, is altered as a result of the virus. Now, the journal Nature Communications publishes a study led by IrsiCaixa –a center jointly promoted by the “la Caixa” Foundation and the Department of Health of the Government of Catalonia– showing that initiating antiretroviral treatment with dolutegravir improves the gut microbiome in people diagnosed late with HIV. This improvement is associated with reduced inflammation and lower immune system activation, making the gut microbiome more similar to that of a person without HIV.

The findings come from a clinical trial conducted within the framework of the Advanz-4 project and coordinated by Hospital Clínic, in which all participants received the same background treatment and, depending on the assigned group, were additionally given either dolutegravir or the combination of darunavir and ritonavir. The results are relevant for identifying strategies that enable a more complete recovery of health in people with very advanced HIV infection.

“Knowing which antiretroviral therapy can restore microbiome balance is key to offering the most appropriate treatment to people diagnosed late and improving their long-term health,” says Francesc Català, postdoctoral researcher in bioinformatics at IrsiCaixa and first author of the article.

A more diverse microbiome with beneficial functions

To investigate this, the research team conducted a clinical trial involving 88 people who had been identified at advanced stages of HIV infection. Upon starting antiretroviral therapy, participants were randomly assigned to receive either dolutegravir or the darunavir/ritonavir combination, always together with two other antiretroviral drugs, and were followed for two years.

“Dolutegravir belongs to the integrase inhibitor family and shows better intestinal penetration, whereas the darunavir/ritonavir combination acts as a protease inhibitor and has more limited penetration. These differences already suggested that the two treatments could have distinct effects on the microbiome,” Català explains.

Both treatments successfully fully suppressed HIV and restored CD4+ cell counts, the main immune cells affected by the virus, confirming their effectiveness in controlling the infection. However, only the treatment including dolutegravir was associated with increased richness and diversity of the gut microbiome. “In addition to a more balanced microbiome, these individuals show better immune recovery, lower immune system overactivation, and less inflammation,” explains Roger Paredes, principal investigator at IrsiCaixa and head of the Infectious Diseases Department at Hospital Germans Trias i Pujol and scientific director of the Fight Infections Foundation. “Two years after starting treatment, their microbiome was much more similar to that of people without HIV,” he adds.

Towards full recovery after a late diagnosis

Advanced HIV infection is associated with gut microbiome imbalance, excessive inflammation, persistent immune activation, and increased translocation of bacteria from the intestine to the rest of the body. All these factors may contribute to the development of long-term health problems. Specifically, they promote premature aging, increasing the risk of cardiovascular disease and neurocognitive disorders, as well as greater vulnerability to infections.

“The results indicate that not all antiretroviral treatments have the same impact on intestinal health and that the choice of therapeutic regimen may influence chronic inflammation and the future health of people with HIV,” notes Josep Maria Miró, senior consultant in Infectious Diseases at Hospital Clínic de Barcelona and principal investigator of the Advanz-4 clinical trial. “This study reinforces the importance of considering the gut microbiome as a key element in the comprehensive management of HIV and of moving towards a more complete recovery after advanced infection,” Paredes concludes.