title: Use of agent-based simulations to design and interpret HIV clinical trials.
abstract: In this study, we illustrate the utility of an agent-based simulation to inform a trial design and how this supports outcome interpretation of randomized controlled trials (RCTs). We developed agent-based Monte Carlo models to simulate existing landmark HIV RCTs, such as the Partners in Prevention HSV/HIV Transmission Study. We simulated a variation of this study using valacyclovir therapy as the intervention, and we used a male circumcision RCT based on the Rakai Male Circumcision Trial. Our results indicate that a small fraction (20%) of the simulated Partners in Prevention HSV/HIV Transmission Study realizations rejected the null hypothesis, which was no effect from the intervention. Our results also suggest that an RCT designed to evaluate the effectiveness of a more potent drug regimen for HSV-2 suppression (valacyclovir therapy) is more likely to identify the efficacy of the intervention. For the male circumcision RCT simulation, the greater biological effect of the male circumcision yielded a major fraction (81%) of RCT realizations' that rejects the null hypothesis, which was no effect from the intervention. Our study highlights how agent-based simulations synthesize individual variation in the epidemiological context of the RCT. This methodology will be particularly useful for designing RCTs aimed at evaluating combination prevention interventions in community-based RCTs, wherein an intervention׳s effectiveness is challenging to predict.
authors.affiliation: Infectious Disease Epidemiology Group, Weill Cornell Medical College in Qatar, Cornell University, Qatar Foundation, Education City, Doha, Qatar; Department of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, NY, USA. Electronic address: dfc2002@qatar-med.cornell.edu.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Cuadros
authors.affiliation: Infectious Disease Epidemiology Group, Weill Cornell Medical College in Qatar, Cornell University, Qatar Foundation, Education City, Doha, Qatar; Department of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, NY, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
authors.forename: Laith J
authors.initials: LJ
authors.lastname: Abu-Raddad
authors.affiliation: Infectious Disease Epidemiology Group, Weill Cornell Medical College in Qatar, Cornell University, Qatar Foundation, Education City, Doha, Qatar.
authors.forename: Susanne F
authors.initials: SF
authors.lastname: Awad
authors.affiliation: Department of Biology, University of Kentucky, Lexington, USA.
authors.forename: Gisela
authors.initials: G
authors.lastname: García-Ramos
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives; D019380:Anti-HIV Agents / Q000627:therapeutic use; D002944:Circumcision, Male / Q000379:methods; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D015658:HIV Infections / Q000517:prevention & control* / Q000628:therapy*; D006558:Herpes Genitalis / Q000188:drug therapy / Q000517:prevention & control; D018258:Herpesvirus 2, Human; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D009010:Monte Carlo Method; D012107:Research Design; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir
keywords: Agent-based simulation; Clinical trial; HIV; HIV treatment and prevention; Mathematical modeling