Balancing Statistical Power and Risk in HIV Cure Clinical Trial Design

Abstract Background Analytical treatment interruptions (ATI) are pauses of antiretroviral therapy (ART) in the context of human immunodeficiency virus (HIV) cure trials. They are the gold standard in determining if interventions being tested can achieve sustained virological control in the absence o...

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Veröffentlicht in:The Journal of infectious diseases Jg. 226; H. 2; S. 236 - 245
Hauptverfasser: Lau, Jillian S Y, Cromer, Deborah, Pinkevych, Mykola, Lewin, Sharon R, Rasmussen, Thomas A, McMahon, James H, Davenport, Miles P
Format: Journal Article
Sprache:Englisch
Veröffentlicht: US Oxford University Press 24.08.2022
Schlagworte:
Anti-Retroviral Agents - therapeutic use
Clinical Trials as Topic - methods
HIV Infections - drug therapy
Humans
Research Design
Risk Assessment
Viral Load - statistics & numerical data
Withholding Treatment
analytical treatment interruption
HIV cure
HIV infection
modelling
posttreatment controllers
viral rebound
ISSN:0022-1899, 1537-6613, 1537-6613
Online-Zugang:Volltext
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Zusammenfassung:Abstract Background Analytical treatment interruptions (ATI) are pauses of antiretroviral therapy (ART) in the context of human immunodeficiency virus (HIV) cure trials. They are the gold standard in determining if interventions being tested can achieve sustained virological control in the absence of ART. However, withholding ART comes with risks and discomforts to trial participant. We used mathematical models to explore how ATI study design can be improved to maximize statistical power, while minimizing risks to participants. Methods Using previously observed dynamics of time to viral rebound (TVR) post-ATI, we modelled estimates for optimal sample size, frequency, and ATI duration required to detect a significant difference in the TVR between control and intervention groups. Groups were compared using a log-rank test, and analytical and stochastic techniques. Results In placebo-controlled TVR studies, 120 participants are required in each arm to detect 30% difference in frequency of viral reactivation at 80% power. There was little statistical advantage to measuring viral load more frequently than weekly, or interrupting ART beyond 5 weeks in a TVR study. Conclusions Current TVR HIV cure studies are underpowered to detect statistically significant changes in frequency of viral reactivation. Alternate study designs can improve the statistical power of ATI trials. Mathematical modelling was used to show how HIV cure study design can be improved to maximize statistical power, while minimizing risks to participants. Alternate study designs are also explored and discussed in the context of real-world HIV cure study conduct.
Bibliographie:ObjectType-Article-1
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ISSN:0022-1899
1537-6613
1537-6613
DOI:10.1093/infdis/jiac032