Early Antiretroviral Therapy During Primary HIV-1 Infection Results in a Transient Reduction of the Viral Setpoint upon Treatment Interruption

Abstract

BackgroundLong-term benefits of combination antiretroviral therapy (cART) initiation during primary HIV-1 infection are debated.MethodsThe 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.ResultsOn 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]).ConclusionsThe 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.

Early Initiation of Antiretroviral Therapy Can Functionally Control Productive HIV-1 Infection in Humanized-BLT Mice

“…Other animal studies showed that HIV-1 always rebounded after ART was withdrawn in these setting 19,20 . However, our study showed that hu-BLT mice which received ART at 6 hours post-infection had undetectable PVL measured by the sensitive ddPCR after ART was stopped.…”

“…Several studies have shown that ART administration within days of post-infection (p.i.) often resulted in a rebound of viremia during treatment interruption 19,20 . In contrast, the Mississippi infant case initiated ART at ∼30 hours after birth was able to suppress viremia for 2 years without ART 6,7 .…”

Considerations in the development of nonhuman primate models of combination antiretroviral therapy for studies of aids virus suppression, residual virus, and curative strategies

“…Indeed, a recent RT-SHIV mne EFV monotherapy study using an ultrasensitive allele-specific PCR method demonstrated that EFV drug resistance mutations existed at low frequencies within the circulating virus population at 13 weeks postinfection, prior to the initiation of therapy [31*]. Early cART initiation has been shown to impact the magnitude of later, off-treatment viremia rebound, however, suggesting that cART timing may influence the seeding and establishment of the latent viral reservoir and/or the development of antiviral immune responses [37,61,64–68], similar to findings for humans treated during acute infection [69–71*]. It remains possible that initiating therapy later in infection might benefit from the additive impact of adaptive immune responses, and several studies have demonstrated good virologic suppression when cART was initiated later in infection [8,9,14,59*].…”

Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs

“…Administration of antiretroviral therapy in very early acute infection appears to result in a lower post-treatment total and integrated DNA and HIV-RNA levels, suggesting aggressive treatment can limit the size of the viral reservoir 1, 7–9 . Although early treatment can substantially reduce the total reservoir size, a stable population of latently infected CD4 cells exists that transits in to the long-lived latent reservoir and is relatively unaffected by early cART 10 .…”