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Very Early Antiretroviral Therapy Does Not Prevent Immune Activation

People who started antiretroviral therapy (ART) during acute HIV infection and experienced sustained viral suppression saw a substantial decrease in immune activation markers on their CD8 T-cells after 2 years of treatment, but often not to the level seen in HIV negative individuals, according to a report in the April 15, 2013, Journal of Acquired Immune Deficiency Syndromes.

Ever since the development of effective combination ART, some researchers have held out hope that starting treatment very early might limit viral reservoirs and reduce the persistent immune activation and inflammation that accompany even well-controlled HIV infection. Smaller reservoirs and less activation could be important components of a "functional cure" that lets people with HIV stay off treatment without disease progression.

Michael Vinikoor from the University of North Carolina at Chapel Hill and colleagues looked at longitudinal changes in immune activation markers on CD8 T-cells from acutely infected people who started ART early. The presence of CD38+ and HLA-DR+ markers together on CD4+ or CD8+ cells is a signature of ongoing activation.

The analysis included 31 participants who rapidly accessed care and started ART during acute infection (median 43 days since exposure) and maintained viral suppression through 96 weeks.

Results

• Before starting ART, participants had a median of 72.6% CD8 cells bearing the CD38+HLA-DR+ signature markers.
• CD8 cell activation decreased substantially during the first 12 weeks on ART, but the rate of decline then slowed.
• By 96 weeks on treatment, the median activation level fell to 15.6%.
• However, immune activation remained significantly higher overall than that of HIV negative control subjects, who had a median level of 8.9%.
• 40% of people with suppressed HIV never reached a normal activation level during 96 weeks of therapy.
• People who took less time to achieve viral suppression on ART had lower immune activation levels at 96 weeks.
• Among 4 participants also underwent viral reservoir measurements, there was a "positive but non-significant correlation" between the number of latently infected cells, or reservoir size, and CD8 cell activation at 96 weeks.

"Although not fully understood, immune activation seems to play a central role in HIV pathogenesis, and this study builds on the existing evidence in [chronic HIV infection] that immune activation persists in many patients," the study authors wrote.

"In the early stages of HIV infection, virus-host interactions result in steady states of HIV RNA and CD8+ activation. These parameters determine the rate at which HIV progresses and may be associated with the risk of death from non-AIDS-associated conditions," they continued. "In this study, we found that initiation of ART during acute HIV-1 infection failed to prevent the persistence of immune activation at 96 weeks of suppressive therapy. These results suggest that the early pathogenesis of HIV disease leaves a long-lasting imprint on host immune function."

"One possible explanation for persistence of immune activation is the extensive and rapid depletion of gut associated lymphoid tissue, which may result in a state of chronic hyperactivation and inadequate immune restoration," they suggested.

While longer-term ART might eventually normalize activation of immune cells in peripheral blood, they added, these peripheral blood lymphocytes "represent only a tiny fraction of all lymphocytes, and gut associated lymphoid tissue may be a better (but more logistically challenging) site for examination of the overall immunological status of HIV-infected individuals."

5/15/13

Reference

MJ Vinikoor, A Cope, CL Gay, et al. Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T cell activation. Journal of Acquired Immune Deficiency Syndromes 62(5):505-508. April 15, 2013.