Clinical trials of antiretroviral treatment interruption in HIV-infected individuals

Lau, Jillian S.Y.; Smith, Miranda; Lewin, Sharon R.; McMahon, James

doi:10.1097/qad.0000000000002113

Cited by 43 publications

(40 citation statements)

References 188 publications

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“…However, all 16 selected participants rebounded within eight weeks after ATI, which is similar to what has been observed in other ATI studies using less stringent criteria [28,29]. In line with most ATI studies, however, no major AEs were recorded and all reservoir measures returned to baseline after treatment restart [5,28,30].…”

Section: Discussionsupporting

confidence: 85%

“…Participants were followed for 48 weeks or until ART resumption criteria were reached. In line with other treatment interruption studies , these criteria included two consecutive viral loads >1000 copies/mL measured at least three days apart, a single viral load >10,000 copies/mL, CD4+ T‐cell count drop to <350 cells/µL at two consecutive measurements at least two weeks apart or a drop of more than 50% compared to baseline, any new significant clinical condition, a new sexually transmitted infection, pregnancy or participant withdrawal from the study.…”

Section: Methodsmentioning

confidence: 99%

“…This causes most patients to experience viral rebound within weeks after treatment interruption [2]. Viral remission after analytical treatment interruption (ATI), termed post-treatment control (PTC), has been described in a small proportion of patients [3][4][5]. Although PTC has been associated with early treatment initiation [6], we and others showed that some PTCs initiated ART in the chronic phase [4,7].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Its main advantage is that by reducing its duration, it may prevent potential complications. The conceivable downside of this approach is that it will reduce the capacity to test the effectiveness of interventions that aim to work through immunological mechanisms and, consequently, might prevent the identification of virological controllers [ 8 , 10 , 14 ]. MAP are thus useful in assessing strategies aiming to reduce reservoir size [ 15 ].…”

Section: Types Of Ati: Virological Outcome Measuresmentioning

confidence: 99%

“…These findings indicate that ATI may be a safe strategy as part of HIV-1 cure trials by closely monitoring for viral rebound [ 7 ]. In addition, a systematic review of 159 clinical studies published from 2000–2017 performed by Lau et al [ 10 ] concluded that ATI in recent intervention studies conducted since 2014 were more closely monitored, had more conservative thresholds to restart ART, and had a shorter treatment interruption duration compared with older studies. Both metanalyses found that the incidence of treatment interruption related AEs was low and did not cause irreparable harm to study participants.…”

Section: Potential Adverse Effectsmentioning

confidence: 99%

Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response

et al. 2020

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A functional Human immunodeficiency Virus (HIV) cure has been proposed as an alternative to antiretroviral treatment for life, and therapeutic vaccines represent one of the most promising approaches. The goal of therapeutic vaccination is to augment virus-specific immune responses that have an impact on HIV viral load dynamics. To date, the agreed feature to evaluate the effects of these therapeutic interventions is analytical antiretroviral treatment interruption (ATI), at least until we find a reliable biomarker that can predict viral control. Different host, immunologic, and virologic markers have been proposed as predictors of viral control during ATI after therapeutic interventions. This review describes the relevance of ATI and the different surrogate markers of virological control assessed in HIV therapeutic vaccine clinical trials.

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The Essential Need for Trust When Transmission Risk Cannot Be Eliminated in HIV‐Remission Trials

Rennie

Henderson

Phanuphak

et al. 2023

Ethics & Human Research

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Analytic treatment interruption (ATI) is scientifically necessary in HIV‐remission (“cure”) studies to test the effects of new interventions. However, stopping antiretroviral treatment poses risks to research participants and their sexual partners. Ethical debate about whether and how to conduct such studies has largely centered on designing risk‐mitigation strategies and identifying the responsibilities of research stakeholders. In this paper, we argue that because the possibility of HIV transmission from research participants to partners during ATI cannot practicably be eliminated—that is, it is ineliminable—the successful conduct of such trials ultimately depends on relationships of trust and trustworthiness. We describe our experiences with conducting and studying HIV‐remission trials with ATI in Thailand to examine the strengths, complexities, and limitations of the risk‐mitigation and responsibility approaches and to explore ways in which the building of trust—and trustworthiness—may help enhance the scientific, practical, and ethical dimensions of these trials.

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Clinical trials of antiretroviral treatment interruption in HIV-infected individuals

Cited by 43 publications

References 188 publications

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

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

Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response

The Essential Need for Trust When Transmission Risk Cannot Be Eliminated in HIV‐Remission Trials

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