icon-    folder.gif   Conference Reports for NATAP  
  Conference on Retroviruses
and Opportunistic Infections
Will be Virtual
Boston USA
March 6-10, 2021
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  CROI 2021 March 6-10 Reported by Jules Levin
Michele B . Daly1, Mara Sterling1, Kenji Nishiura1, Angela Holder1, Chuong Dinh1, Alison Swaims Kohlmeier1, Sunita Sharma1, Jillian Condrey1, Rex A. Howard1, Patrick Mills1, James Mitchell1, Veerle Van Eygen2, William R. Spreen3, Walid Heneine1, Gerardo Garcia-Lerma1 1Centers for Disease Control and Prevention, Atlanta, GA, USA, 2Janssen, Beerse, Belgium, 3ViiV Healthcare, Research Triangle Park, NC, USA
Background: Early initiation of antiretroviral therapy (ART) does not cure HIV in humans or SIV in macaques due to rapid viral reservoir establishment. Here, we investigated in macaques if a novel ART regimen, designed to have robust penetration in virus reservoir sites, can result in virus remission after treatment cessation.
Methods: The ART regimen included daily tenofovir alafenamide (TAF; 1.5 mg/ kg), and emtricitabine (FTC; 20 mg/kg), and monthly rilpivirine long-acting (RPV LA; 200 mg/kg), and cabotegravir long-acting (CAB LA; 50 mg/kg) for 6 months followed by 6 months of CAB LA/RPV LA maintenance therapy. TAF was selected to enhance tenofovir-diphosphate (TFV-DP) levels in lymphoid tissues (LT). CAB LA and RPV both distribute in the central nervous system. TAF/FTC were given at human-equivalent doses and administered orally to mimic drug biodistribution in humans. CAB LA/RPV LA were given intramuscularly at doses that maintain human therapeutic drug levels. Macaques were infected intrarectally with RT-SHIV and initiated treatment at day 5-6 post infection (n=4) or were untreated (n=2). SHIV RNA in plasma was monitored by RT-PCR (LOQ=12.5 copies/ml) during 1 year of ART and a 20-month period of no treatment which included in vivo CD8+ cell depletion with monoclonal antibody MT807R1 at month 16. Drug concentrations were measured by HPLC-MS/MS.
Results: Peak viremia in treated animals was 3.4 [range=2.7-4.3] log10RNA copies/ml compared to 6.8-7.0 in untreated controls. Treated macaques achieved viral suppression 14-22 days after treatment initiation and remained aviremic during 1 year of ART and the 20-month follow-up period. Median plasma CAB levels during treatment were 2.11 ug/ml and became undetectable 3 months after the last dose. RPV testing is ongoing. Median concentrations of TFV-DP in PBMCs, LT, and RT were 1427 and 367 fmol/10^6 cells, and 14.6 fmol/ mg of tissue, respectively. Median FTC-TP levels were 498 and 260 fmol/10^6 cells in PBMCs and LT, respectively, and were undetectable in RT.
Treatment with MT807R1 effectively depleted >99.9% of CD8+ T cells in blood. Plasma SHIV RNA remained undetectable during and 4 months after CD8 depletion.
Conclusion: We identified in macaques a suppressive ART regimen that results in virus remission following early treatment. The lack of viral rebound 20 months after treatment cessation and CD8 depletion is encouraging and highlights the need to further define the effect of optimized early ART regimens on virus remission.