Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

doi:10.1016/S2352-3018(19)30052-9

. 2019 Apr;6(4):e259-e268.

doi: 10.1016/S2352-3018(19)30052-9. Epub 2019 Mar 15.

Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

Boris Julg¹, Lynda Dee², Jintanat Ananworanich³, Dan H Barouch⁴, Katharine Bar⁵, Marina Caskey⁶, Donn J Colby⁷, Liza Dawson⁸, Krista L Dong⁹, Karine Dubé¹⁰, Joseph Eron¹¹, John Frater¹², Rajesh T Gandhi¹³, Romas Geleziunas¹⁴, Philip Goulder¹⁵, George J Hanna¹⁶, Richard Jefferys¹⁷, Rowena Johnston¹⁸, Daniel Kuritzkes¹⁹, Jonathan Z Li¹⁹, Udom Likhitwonnawut²⁰, Jan van Lunzen²¹, Javier Martinez-Picado²², Veronica Miller²³, Luis J Montaner²⁴, Douglas F Nixon²⁵, David Palm²⁶, Giuseppe Pantaleo²⁷, Holly Peay²⁸, Deborah Persaud²⁹, Jessica Salzwedel²⁰, Karl Salzwedel⁸, Timothy Schacker³⁰, Virginia Sheikh³¹, Ole S Søgaard³², Serena Spudich³³, Kathryn Stephenson⁴, Jeremy Sugarman³⁴, Jeff Taylor³⁵, Pablo Tebas³⁶, Caroline T Tiemessen³⁷, Randall Tressler⁸, Carol D Weiss³¹, Lu Zheng³⁸, Merlin L Robb³, Nelson L Michael³, John W Mellors³⁹, Steven G Deeks⁴⁰, Bruce D Walker⁴¹

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA. Electronic address: bjulg@mgh.harvard.edu.
² AIDS Action Baltimore, Baltimore, MD, USA.
³ US Military HIV Research Program, Henry Jackson Foundation, Bethesda, MD, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁵ Department of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
⁶ Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
⁷ Thai Red Cross AIDS Research Center, Bangkok, Thailand.
⁸ National Institute of Allergy and Infectious Diseases, Fishers ln Rockville, MD, USA.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; University of KwaZulu Natal, Durban, South Africa.
¹⁰ Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
¹¹ Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA.
¹² Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford National Institute of Health Research Biomedical Research Centre, Oxford, UK.
¹³ Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Gilead Sciences, Foster City, CA, USA.
¹⁵ Department of Paediatrics, University of Oxford, Oxford, UK.
¹⁶ Merck, Kenilworth, NJ, USA.
¹⁷ Treatment Action Group, New York, NY, USA.
¹⁸ amfAR, New York, NY, USA.
¹⁹ Division of Infectious Diseases, Brigham and Women's Hospital, Cambridge, MA, USA.
²⁰ AVAC: Global Advocacy for HIV Prevention, New York, NY, USA.
²¹ ViiV Healthcare, Brentford, UK.
²² AIDS Research Institute IrsiCaixa, Barcelona, Spain; Catalan Institution for Research and Advanced Studies, Barcelona, Spain; University of Vic-Central University of Catalonia, Barcelona, Spain.
²³ Forum for Collaborative Research, Washington, DC, USA.
²⁴ The Montaner Laboratory, The Wistar Institute, Philadelphia, PA, USA.
²⁵ Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York City, NY, USA.
²⁶ Global HIV Prevention, and Treatment Clinical Trials Unit, University of North Carolina, Chapel Hill, NC, USA.
²⁷ Service Immunology and Allergy, and Swiss Vaccine Research Institute, Centre Hospitalier Universitaire, Lausanne, Switzerland.
²⁸ Research Triangle Institute, Research Triangle Park, NC, USA.
²⁹ Pediatrics Infectious Disease, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
³⁰ Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA.
³¹ Division of Antiviral Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
³² Department of Infectious Diseases, Aarhus University, Aarhus, Denmark.
³³ Department of Neurology, Yale University, New Haven, CT, USA.
³⁴ Berman Institute of Bioethics, University of North Carolina, Chapel Hill, NC, USA.
³⁵ Collaboratory for AIDS Researchers for Eradication, University of North Carolina, Chapel Hill, NC, USA.
³⁶ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Cell Biology Research Laboratory, Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁹ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁰ School of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 30885693
PMCID: PMC6688772
DOI: 10.1016/S2352-3018(19)30052-9

Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

Boris Julg et al. Lancet HIV. 2019 Apr.

. 2019 Apr;6(4):e259-e268.

doi: 10.1016/S2352-3018(19)30052-9. Epub 2019 Mar 15.

Authors

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA. Electronic address: bjulg@mgh.harvard.edu.
² AIDS Action Baltimore, Baltimore, MD, USA.
³ US Military HIV Research Program, Henry Jackson Foundation, Bethesda, MD, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁵ Department of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
⁶ Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
⁷ Thai Red Cross AIDS Research Center, Bangkok, Thailand.
⁸ National Institute of Allergy and Infectious Diseases, Fishers ln Rockville, MD, USA.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; University of KwaZulu Natal, Durban, South Africa.
¹⁰ Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
¹¹ Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA.
¹² Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford National Institute of Health Research Biomedical Research Centre, Oxford, UK.
¹³ Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Gilead Sciences, Foster City, CA, USA.
¹⁵ Department of Paediatrics, University of Oxford, Oxford, UK.
¹⁶ Merck, Kenilworth, NJ, USA.
¹⁷ Treatment Action Group, New York, NY, USA.
¹⁸ amfAR, New York, NY, USA.
¹⁹ Division of Infectious Diseases, Brigham and Women's Hospital, Cambridge, MA, USA.
²⁰ AVAC: Global Advocacy for HIV Prevention, New York, NY, USA.
²¹ ViiV Healthcare, Brentford, UK.
²² AIDS Research Institute IrsiCaixa, Barcelona, Spain; Catalan Institution for Research and Advanced Studies, Barcelona, Spain; University of Vic-Central University of Catalonia, Barcelona, Spain.
²³ Forum for Collaborative Research, Washington, DC, USA.
²⁴ The Montaner Laboratory, The Wistar Institute, Philadelphia, PA, USA.
²⁵ Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York City, NY, USA.
²⁶ Global HIV Prevention, and Treatment Clinical Trials Unit, University of North Carolina, Chapel Hill, NC, USA.
²⁷ Service Immunology and Allergy, and Swiss Vaccine Research Institute, Centre Hospitalier Universitaire, Lausanne, Switzerland.
²⁸ Research Triangle Institute, Research Triangle Park, NC, USA.
²⁹ Pediatrics Infectious Disease, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
³⁰ Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA.
³¹ Division of Antiviral Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
³² Department of Infectious Diseases, Aarhus University, Aarhus, Denmark.
³³ Department of Neurology, Yale University, New Haven, CT, USA.
³⁴ Berman Institute of Bioethics, University of North Carolina, Chapel Hill, NC, USA.
³⁵ Collaboratory for AIDS Researchers for Eradication, University of North Carolina, Chapel Hill, NC, USA.
³⁶ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Cell Biology Research Laboratory, Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁹ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁰ School of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 30885693
PMCID: PMC6688772
DOI: 10.1016/S2352-3018(19)30052-9

Abstract

Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.

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Conflict of interest statement

Conflict of interest statements: All other authors report no competing interests.

Figures

**Figure 1.**
Key recommendations. Additional or more stringent criteria may be required based on known toxicities of the study drug(s) or expected risks of the study intervention(s). Inclusion and exclusion criteria, monitoring and ART restart criteria may differ in children depending on age.

See this image and copyright information in PMC

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References

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[1] Sneller MC, Justement JS, Gittens KR, Petrone ME, Clarridge KE, Proschan MA, et al. A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Science translational medicine 2017;9(419). - PMC - PubMed

[2] Sneller MC, Justement JS, Gittens KR, Petrone ME, Clarridge KE, Proschan MA, et al. A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Science translational medicine 2017;9(419). - PMC - PubMed

[3] Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nature communications 2015;6:8495. - PMC - PubMed

[4] Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nature communications 2015;6:8495. - PMC - PubMed

[5] Li JZ, Etemad B, Ahmed H, Aga E, Bosch RJ, Mellors JW, et al. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. Aids 2016;30(3):343–53. - PMC - PubMed

[6] Li JZ, Etemad B, Ahmed H, Aga E, Bosch RJ, Mellors JW, et al. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. Aids 2016;30(3):343–53. - PMC - PubMed

[7] Tanner Z, Lachowsky N, Ding E, Samji H, Hull M, Cescon A, et al. Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort. BMC Infect Dis 2016;16(1):590. - PMC - PubMed

[8] Tanner Z, Lachowsky N, Ding E, Samji H, Hull M, Cescon A, et al. Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort. BMC Infect Dis 2016;16(1):590. - PMC - PubMed

[9] Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife 2014;3:e03821. - PMC - PubMed

[10] Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife 2014;3:e03821. - PMC - PubMed

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Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

Affiliations

Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

Authors

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Conflict of interest statement

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