Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption

Abstract

Background: Long-term benefits of combination antiretroviral therapy (cART) initiation during primary HIV-1 infection are debated.

Methods: The evolution of plasma HIV-RNA (432 measurements) and cell-associated HIV-DNA (325 measurements) after cessation of cART (median exposure 18 months) was described for 33 participants from the Zurich Primary HIV Infection Study using linear regression and compared with 545 measurements from 79 untreated controls with clinically diagnosed primary HIV infection, respectively a known date for seroconversion.

Results: On average, early treated individuals were followed for 37 months (median) after cART cessation; controls had 34 months of pre-cART follow-up. HIV-RNA levels one year after cART interruption were -0.8 log₁₀ copies/mL [95% confidence interval -1.2;-0.4] lower in early treated patients compared with controls, but this difference was no longer statistically significant by year three of follow-up (-0.3 [-0.9; 0.3]). Mean HIV-DNA levels rebounded from 2 log₁₀ copies [1.8; 2.3] on cART to a stable plateau of 2.7 log₁₀ copies [2.5; 3.0] attained 1 year after therapy stop, which was not significantly different from cross-sectional measurements of 9 untreated members of the control group (2.8 log₁₀ copies [2.5; 3.1]).

Conclusions: The rebound dynamics of viral markers after therapy cessation suggest that early cART may indeed limit reservoir size of latently infected cells, but that much of the initial benefits are only transient. Owing to the non-randomized study design the observed treatment effects must be interpreted with caution.

Figure 1. The algorithm used to determine the inclusion (in boxes with continuous bounds) and exclusion (in boxes with interrupted bounds) in pre-defined sub-analyses to explore the effect of early started antiretroviral therapy in primary HIV-infected individuals.

Figure 2. Time courses of and correlations between HIV-DNA and HIV-RNA measurements.

Figure 2 depicts time courses of and correlations between HIV-DNA and HIV-RNA measurements obtained before (panels A, B, C), during (panels D, E) and after early antiretroviral therapy initiation (panels F, G, H) in primary HIV-infected individuals. Panels A, B and C show the time dependency of pre-treatment HIV-DNA and -RNA measurements (n = 67 patients). The curves show fits from linear regression including linear and quadratic terms. Final model selection was based on adjusted R² values. Panel A plots plasma HIV-RNA (log₁₀ copies/mL) against time since infection, panel B shows Cell associated HIV-DNA (log₁₀ copies/million cells), and panel C displays the correlation analysis of pre-treatment HIV-RNA and HIV-DNA. Panels D and E depict the dynamics of HIV-RNA (n =  700 measurements) and HIV-DNA (n = 737 measurements) during treatment with combination antiretroviral therapy in 59 patients. Panel D shows longitudinal HIV-RNA measurements during treatment. Note that undetectable HIV-RNA measurements were artificially set to 0. Panel E shows results from non-linear modeling analyses of the longitudinal course of HIV-DNA under antiretroviral therapy. Panels F and G show the evolution of viral marker pairs (HIV-RNA and HIV-DNA; n = 203 measurements) up to 18 months after therapy cessation (n = 33 patients). Curves were fitted with linear mixed models with random intercepts and random slopes. Panel H displays the correlation between post-therapy HIV-RNA and HIV-DNA measurements. The correlation coefficient shown is the median of 33 individual Spearman correlation analyses for each patient.

Figure 3. Long-term evolution of viral markers.

Panel A displays the evolution of HIV-RNA measurements up to 36 months after therapy cessation in 33 individuals with therapy initiation during PHI (n = 432 measurements, light grey symbols) and 79 chronically infected participants of the Swiss HIV Cohort Study (n = 545 measurements, dark symbols). Panel B shows longitudinal HIV-DNA measured in early starters (n = 325 measurements). Note that the dotted line represents the average of 9 randomly selected cross-sectional measurements from control patients.