Early ART Reduces Potential HIV Reservoir

By Will Boggs MD

March 15, 2020

NEW YORK (Reuters Health) - Antiretroviral therapy (ART) early in the course of acute HIV infection markedly reduces blood and tissue levels, researchers report.

"The total pool of cells in people treated very early on is around 100 times smaller than in people starting ART in chronic infection," said Dr. Nicolas Chomont of the University of Montreal, Canada.

"Another interesting aspect of the work is that we found that the early infected cells are not stable," he told Reuters Health by email. "They are rapidly cleared when therapy is started, which gives a window of opportunity to start ART very early on to limit the establishment of stable, long-lived reservoirs."

A persistent viral reservoir is established early in HIV infection and is the source of viral rebound upon ART cessation. The timing and location of the establishment of this viral reservoir remain unclear.

Dr. Chomont and colleagues used longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection to identify the compartments in which the HIV reservoir is seeded and persists during ART.

The frequency of productively infected cells reached their maximal frequencies in tissues as early as Fiebig stage II, with infected cells and lymph nodes likely contributing to the high levels of plasma viremia measured in acutely infected individuals.

Initiation of ART within a few days after diagnosis resulted in a rapid decay in the frequency of cells harboring integrated HIV DNA in blood and tissues, suggesting that the early pool of such cells is short-lived, the researchers report in Science Translational Medicine.

HIV primarily infects and persists in CD4+ T cells displaying a memory phenotype, and most of these cells harboring HIV DNA are cleared when ART is initiated during Fiebig stages II and III of acute infection.

In contrast, infected memory CD4+ T cells from Fiebig IV/V and chronically infected individuals have a greater ability to persist during ART.

"In this study, it is clear that not one (patient) was cured," Dr. Chomont said. "Even though the reservoir was much reduced, it is still there. But we believe early treatment is a big step towards a cure, since their reservoirs are much smaller, and thus, probably will be 'easier' to eradicate."

"It will be important to combine early treatment with another therapeutic strategy to target and eliminate these small reservoirs," he said.

"For optimistic people (like me) who think we will have a strategy to eliminate (these reservoirs) in the future, these early treated people will be the first to benefit from these new approaches," Dr. Chomont said. "As such, early ART is not only good from a public health perspective (since it reduces transmission), but it is also good for the immune system and good for future eradication strategies."

Dr. Zabrina L. Brumme of the British Columbia Center for Excellence in HIV/AIDS at Simon Fraser University, in Burnaby, Canada, who studies HIV, told Reuters Health by email, "In my opinion, the most important message to reinforce to physicians and people at risk of HIV infection is the importance of early HIV diagnosis and immediate ART treatment. That is: test often and treat early!"

"This paper adds one more reason why early diagnosis and immediate HIV treatment initiation is important," she said.

"This paper also adds to the growing body of evidence that very early treatment will also substantially limit the size of the HIV reservoir," said Dr. Brumme, who was not involved in the study. "That is, early treatment will profoundly limit the number of HIV-infected cells that continue to persist in the body. This is important because, the smaller an individual's HIV reservoir, the more feasible it may be to achieve ART-free remission or even an HIV cure, once strategies to achieve these goals become available."

Dr. Louise Kuhn from Mailman School of Public Health at Columbia University, in New York City, recently found that achieving long-term remission is elusive even with early ART. She told Reuters Health by email that the new findings "support the concept that earlier is better in terms of the amount and persistence of HIV. However, one interpretation of their results is that the magnitude of the viral reduction observed with very early treatment is not sufficient to lead to post-treatment control/remission in the majority of people even if ART is started very early."

The study had no commercial funding. Two of Dr. Chomont's coauthors report ties to companies selling HIV treatment.

SOURCE: https://bit.ly/2IE28Kx Science Translational Medicine, online March 4, 2020.