Plasma, Intracellular and Lymph node Antiretroviral Concentrations and HIV DNA Change During Primary HIV Infection: Results from the INACTION P25 Study

: Despite its high effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV-DNA reservoir, which establishes early during primary infection (PHI) and is maintained by latency, homeostatic T-cells proliferation, and residual replication: this can be associated with low drug exposure in lymphoid tissues and/or suboptimal adherence to antiretroviral drugs (ARVs). Aim of this study was to assess ARVs concentrations in plasma, peripheral blood mononuclear cells (PBMC) and lymph nodes (LN), and their association to HIV-RNA and DNA decay during PHI. Participants were randomized to receive standard doses of darunavir/cobicistat (arm I), dolutegravir (arm II) or both (arm III), with a backbone of tenofovir alafenamide and emtricitabine. Total HIV-DNA was measured by digital-droplet PCR in PBMC at baseline, 12 and 48 weeks. Plasma and PBMC drugs concentrations were determined at 2, 12 and 48 weeks (LN at 12 weeks) by UHPLC-MS/MS. Seventy-two participants were enrolled, mostly male (n=68), median age 34 years and variable Fiebig stages (V-VI 57.7%, I-II 23.9%, and III-IV 18.3%). Twenty-six patients were assigned to Arm I, 27 to Arm II and 19 to Arm III. After 48 weeks, most patients had undetectable viremia, with minor between-arms differences in HIV-RNA decay. Patients with Fiebig I-II showed faster HIV-RNA and HIV-DNA decay. Intracellular-tissue penetration was high for nucleoside analogues and low-moderate for darunavir and dolutegravir. Only tenofovir diphosphate concentrations in PBMC showed correlation with HIV-DNA decay. Overall, this study suggests the timing of treatment initiation and intracellular tenofovir penetration as primary and secondary factors affecting HIV reservoir.