HIV-1 DNA decay dynamics in early treated individuals: practical considerations for clinical trial design

Background: Initiation of combination antiretroviral therapy (cART) soon after HIV-1 infection limits the establishment of viral reservoirs. Thus, early treated individuals are preferred candidates to evaluate novel viral remission strategies. However, their cART-dependent HIV-1 DNA decay dynamics are still poorly defined. This can hamper the design and interpretation of results from clinical trials intended to further reduce viral reservoirs. Objectives: To clarify the duration of cART needed for the HIV-1 reservoir to be stabilized in early treated individuals. Methods: We characterized the longitudinal decline of total HIV-1 DNA levels by droplet digital PCR in 21 individuals initiating cART within 6months after estimated HIV-1 acquisition. Measurements were taken at cART initiation, after 6months and annually until Year 4. Correlations between virological and clinical parameters were statistically analysed. Statistical modelling was performed applying a mixed-effects model. Results: Total HIV-1 DNA experienced a median overall decrease of 1.43 log10 units (IQR = 1.17-1.69) throughout the 4 years of follow-up. Baseline levels for total HIV-1 DNA, viral load, absolute CD4! T cell count and CD4!/ CD8! ratio correlate with final HIV-1 DNA measurements (R-2 = 0.68, P < 0.001; R-2 = 0.54, P = 0.012; R-2 =#0.47, P = 0.031; and R-2 =#0.59, P = 0.0046, respectively). Statistical modelling shows that after 2 years on cART the viral reservoir had reached a set point. Conclusions: A waiting period of 2 years on cART should be considered when designing interventions aiming to impact latent HIV-1 reservoir levels and viral rebound kinetics after cART discontinuation, in order to facilitate interpretation of results and enhance the chance of viral control.