Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

Abstract

Introduction Viral remission after analytical treatment interruption (ATI), termed post‐treatment control, has been described in a small proportion of HIV‐positive patients. This phenomenon has been separately associated to both low levels of HIV‐1 proviral DNA as well as cell‐associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). Methods We conducted an open single‐arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV‐1 RNA copies/mL for more than two years, more than 500 CD4 cells/µL for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV‐1 DNA (t‐DNA) and fewer than 10 copies cell‐associated HIV‐1 unspliced RNA (US‐RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV‐1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t‐DNA and US‐RNA after TI. Results All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t‐DNA and US‐RNA increased after TI but returned to pre‐ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. Conclusions The combination of low levels of t‐DNA and US‐RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.

Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

“…Evidence thus far indicates that brief ATIs of 4-6 weeks do not meaningfully increase the absolute size of the RCVR based on comparison of pre-ATI and post-ATI surrogate measures of RCVR size, including total HIV-1 vDNA concentrations, cell-associated viral RNA, and frequency of resting CD4+ T cells harboring inducible replication-competent virus as assessed using quantitative viral growth assays (QVOA) [16][17][18][19]. However, these ex vivo assays do not directly assess the size of the persisting vDNA population that can lead to recrudescent viremia after ART interruption, and are not in general predictive of time-to-rebound [19][20][21][22], which is considered the most relevant measure of the size of the RCVR. Total HIV-1 vDNA levels based on viral gag gene quantification are difficult to interpret because they are typically dominated by defective proviruses that do not contribute to viral rebound, particularly if ART is initiated during the chronic phase of HIV-1 infection, and therefore tend to greatly overestimate the size of the RCVR [8,23,24].…”

Extremely low viral reservoir in treated chronically HIV-1-infected individuals

“…This finding differs from the main factors associated with elite and post-treatment controller cohorts. In addition, various studies suggest that having low amounts of HIV-1 DNA does not prevent early and consistent viral rebound if therapy is interrupted in infected individuals receiving long-term treatment [20,47,48]. Therefore, a very low reservoir is not necessarily associated with spontaneous control of viral replication, as might be the case in elite controllers or post-treatment controllers.…”

Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?

“…It would therefore seem logical that ATI performed in a group of ARTtreated individuals with low reservoir measures may result in HIV remission in a substantial proportion of cases. This has indeed been attempted by several groups (Chun et al, 2010;Calin et al, 2016;Colby et al, 2018;Pannus et al, 2020), but the absolute majority of cases experienced a quick viral rebound, suggesting that a low reservoir alone is insufficient for HIV remission and that other factors need to be considered. Here it must be noted that our understanding of the HIV reservoirs and their importance for the prediction of the posttreatment remission is still largely limited to the peripheral blood, whereas tissue reservoirs might play an even more important role.…”