Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection.

Genevieve E Martin,Morgane Gossez,Wolfgang Stöhr,Philip Goulder,Jodi Meyerowitz,Kholoud Porter,Sarah Fidler,Ellen M Leitman,John Frater,James P Williams

doi:10.1097/qad.0000000000001382

Abstract

An HIV cure will impose aviraemia that is sustained following the withdrawal of antiretroviral therapy (ART). Understanding the efficacy of novel interventions aimed at curing HIV requires characterization of both natural viral control and the effect of ART on viral control after treatment interruption. Analysis of transient viral control in recent seroconverters in the Short Pulse AntiRetroviral Therapy at Acute Seroconversion trial. We compared untreated and treated HIV seroconverters (n = 292) and identified periods of control (plasma HIV RNA < 400 copies/ml for ≥16 weeks off therapy) in 7.9% of ART-naive participants, and in 12.0% overall. HIV DNA was measured by qPCR, and HIV-specific CD8 responses were measured by enzyme-linked immunosorbent spot assay (ELISpot). T-cell activation and exhaustion were measured by flow cytometry. At baseline, future controllers had lower HIV DNA, lower plasma HIV RNA, higher CD4 : CD8 ratios (all P < 0.001) and higher CD4 cell counts (P < 0.05) than noncontrollers. Among controllers, the only difference between the untreated and those who received ART was higher baseline HIV RNA in the latter (P = 0.003), supporting an added ART effect. Consideration of spontaneous remission in untreated individuals will be critical to avoid overestimating the effect size of new interventions used in HIV cure studies.

Highlights

Strategies to achieve an HIV cure by implementing interventions to deplete the HIV reservoir – a pool of latently infected cells containing transcriptionally repressed viral DNA – are entering clinical trials
Transient control of viraemia is evident in untreated primary HIV infection Most studies of virological control have focused on ‘elite’ and posttreatment controllers (PTCs) [17,26,27]
We set out to explore a different question – are there individuals who experience transient viral control during untreated primary HIV infection (PHI), and how does this compare with post-antiretroviral therapy (ART) remission?

Summary

Introduction

Strategies to achieve an HIV cure by implementing interventions to deplete the HIV reservoir – a pool of latently infected cells containing transcriptionally repressed viral DNA – are entering clinical trials. In the absence of a validated biomarker to prove cure, a key outcome measure in these studies is the time to detection of viral RNA, or ‘viral rebound’, in plasma after stopping antiretroviral therapy (ART) in an analytic treatment interruption [1,2,3,4,5]. To understand the impact of ART – or any other intervention – on remission requires characterization of the time from seroconversion to a detectable HIV plasma viral load in untreated patients. We must turn to high-quality historical data to assist interpretation of treatment interruption studies

Methods

Results

Conclusion