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ART in Earliest Stage of HIV Infection Preserves Cells That Maintain Gut Barrier - reverses activation...."argues for early & aggressive ART"
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Starting antiretroviral therapy (ART) in the earliest stage of acute HIV infection--Fiebig stage 1--prevents loss of mucosal Th17 cells, which are instrumental in preserving the mucosal barrier in the gut, according to results of a comparative study in Thailand [1]. Early ART also fully reversed significant local and systemic immune activation in the gut. But starting ART just a little later, in Fiebig stage 3, did not have these effects.
Left untreated, HIV depletes mucosal Th17 cells within the first 6 months of infection, and long-term therapy does not fully restore them [2]. Loss of these critical cells, the Thai-based investigators of the new study noted, "sets the stage for ongoing immune activation" in people with HIV [3,4]. Because little is known about the precise timing of these changes and how prompt ART may affect them, RV254/Search 010 investigators conducted this study.
Screening 52,767 viral samples turned up 89 people with acute HIV infection, 75 of whom enrolled in the main study protocol and could begin ART. Thirty-four of these 75 agreed to sigmoid colon biopsies and peripheral blood mononuclear cell collection during Fiebig stages 1 and 3. (Fiebig stages 1 through 4 indicate sequential gain in positive HIV-1 clinical diagnostic assays: HIV RNA, p24, p31, and HIV-1-specific antibodies. A higher Fiebig number indicates a later stage of infection.) Twenty-seven people had a follow-up biopsy 6 months after starting ART, and 16 participants had a third biopsy 24 months after starting therapy.
The researchers compared these 34 people to 5 antiretroviral-naive people with chronic HIV infection and to 9 HIV-negative people. In those three groups, median age stood at 29, 24, and 31, and 83%, 100%, and 80% were men who have sex with men. Of the 34 people with acute infection, 13 were in Fiebig stage 1 and 21 in Fiebig stage 3. Median HIV infection duration was 14.5 days in the acute group and 298 days in the chronic group. Median CD4 count stood at 437 in the acute group and 515 in the chronic group. Three quarters of the acute group had HIV-1 CRF01_AE infection.
When clinicians diagnosed acute infection in these people, mucosal Th17-cell frequencies in Fiebig 1 patients were equivalent to those of HIV-negative people and significantly higher than frequencies in people with Fiebig stage 3 (P = 0.05) or chronic HIV infection (P = 0.001). In acutely infected people, Th17-cell frequency correlated inversely with viral load in the colon--the higher the Th17-cell frequency, the lower the viral load.
Mucosal Th17-cell function (indicated by expression of IL-2, IL-22, and interferon-gamma) remained equivalent in Fiebig 1 patients and HIV-negative controls, but significantly lower in Fiebig 3 patients and those with chronic infection (P = 0.01 for both comparisons with Fiebig 1 patients). Mucosal and systemic immune activation (indicated by percentage of HLA-DR/CD38-positive CD8 cells) occurred by Fiebig stage 1 (P = 0.001 versus HIV-negative controls) but at a lower level than at Fiebig stage 3 (P = 0.003) or chronic infection (P = 0.02).
Starting ART in Fiebig stage 1 preserved the Th17-cell frequencies measured before ART, both 6 and 24 months after ART began.
Starting ART in Fiebig stage 1 also preserved mucosal Th17-cell function indicated by expression of IL-2, IL-22, and interferon-gamma. And starting ART at Fiebig 1 fully reversed the local and systemic immune activation recorded during primary infection and resulted in levels similar to those measured in HIV-negative controls. But ART begun in Fiebig stage 3 did not lower CD8-cell activation levels to those measured in HIV-negative people.
The investigators believe their findings "emphasize the importance of strategies to prevent loss of mucosal Th17 cell function and argue for early and aggressive treatment intervention."
Link to webcast:
http://www.croiwebcasts.org/console/player/22154?mediaType=slideVideo&
References
1. Schuetz A, Phuang-Ngern Y, Rerknimitr R, et al. Early ART initiation prevents disruption of the mucosal barrier and subsequent T-cell activation. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 77.
2. Kim CJ, McKinnon LR, Kovacs C, et al. Mucosal Th17 cell function is altered during HIV infection and is an independent predictor of systemic immune activation. J Immunol. 2013;191:2164-2173.
3. Chege D, Sheth PM, Kain T, et al. Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS. 2011;25:741-749.
4. Bixler SL1, Sandler NG, Douek DC, Mattapallil JJ. Suppressed Th17 levels correlate with elevated PIAS3, SHP2, and SOCS3 expression in CD4 T cells during acute simian immunodeficiency virus infection. J Virol. 2013;87:7093-7101.
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