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ART REDUCES T CELL ACTIVATION AND IMMUNE EXHAUSTION MARKERS IN HIV CONTROLLERS
Jonathan Z. Li1, Florencia P. Segal1, Ronald Bosch2, Christina Lalama2, Randall Tressler3, Cornelius N. Van Dam4, Michael Keefer5, Mary Carrington6, Mathias Lichterfeld1, Daniel R. Kuritzkes1, Xu G. Yu7, Alan Landay8, Paul E. Sax1
1Brigham and Women's Hospital, Boston, MA, USA,2Harvard University, Boston, MA, USA,3NIAID, Bethesda, MD, USA,4University of North Carolina Greensboro, Greensboro, NC, USA,5University of Rochester, Rochester, NY, USA,6NIH, Frederick, MD, USA,7Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA,8Rush University Medical Center, Chicago, IL, USA
Despite low or undetectable plasma HIV RNA, many HIV controllers (HCs) have detectable viral replication and elevated systemic inflammation. We assessed the effect of ART on HIV suppression, viral reservoir, immune activation, markers of inflammation, and quality of life in HCs.
A5308 is a prospective, open-label study of RPV/FTC/TDF in ART-naive HCs with viral loads (VLs) <500 cp/mL for ≥12 months. After 48 weeks of ART, HCs had the option to be followed for an additional 48 weeks with optional ART. The primary outcome was the change in %CD38+HLA-DR+ CD8+ T cells after 24-48 weeks of ART. Outcomes were evaluated by repeated measures GEE models. Immune phenotyping was performed by flow cytometry. Soluble inflammatory markers were measured by ELISA. Residual viremia (RV) was measured by the integrase single-copy assay (iSCA); reservoir size by levels of total HIV DNA in CD4+ cells. Quality of life (QoL) was measured by the EQ-5D questionnaire.
Thirty-five HCs completed ≥24 weeks of ART and were analyzed. Before ART, HCs with undetectable VL by the iSCA had higher CD4+ counts than those with detectable VL (median 1128 vs. 659 cells/mm3, P=0.03) and lower levels of both CD8+ (median 19.4% vs. 26.5%, P=0.04) and CD4+ cell activation (2.3% vs. 2.9%, P=0.04). RPV/FTC/TDF was well tolerated, resulting in a modest, but significant improvement in self-reported QoL; two-thirds of HCs elected to continue ART through 96 weeks. ART was effective in further reducing RV: 81% of HCs had detectable RV pre-ART vs. 6% after 24-48 weeks of ART (P<0.001). ART use resulted in a significant decline in the %CD38+HLA-DR+CD8+ cells at 24-48 (-4.0%, P=0.001) and 72-96 (-7.2%, P<0.001) weeks after ART initiation. After ART initiation, several markers of immune exhaustion (%PD1+, %TIGIT+, %CD160+ on CD8+ cells and %CD160 on CD4+ cells) declined. ART use decreased IP-10 levels, but increased levels of sCD163. There were no significant changes in the CD4+ counts or levels of total HIV DNA. Four HCs discontinued ART with ≥10 weeks of subsequent follow-up. All 4 HCs maintained VL<40 copies/mL at the last study time point, a median of 26 weeks after stopping ART.
One year of ART reduced T cell activation and markers of immune exhaustion in HIV controllers, in some cases with further decreases after two years of ART. ART was well tolerated and did not adversely affect controller status when discontinued. These results provide additional support for ART in HIV controllers.