title: Analytical Advances in the Ex Vivo Challenge Efficacy Assay.
abstract: The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaLex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.
authors.affiliation: 1 Alpha StatConsult, LLC , Damascus, Maryland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.affiliation: 1 Alpha StatConsult, LLC , Damascus, Maryland.|2 School of Mathematical Sciences, Rochester Institute of Technology , Rochester, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Parody
authors.affiliation: 3 Department of Medicine, David Geffen School of Medicine at UCLA, Center for HIV Prevention Research, UCLA AIDS Institute , Los Angeles, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Anton
authors.affiliation: 4 School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Magee Womens Research Institute , Pittsburgh, Pennsylvania.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: 6 CONRAD, Eastern Virginia Medical School , Norfolk and Arlington, Virginia.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Doncel
authors.affiliation: 6 CONRAD, Eastern Virginia Medical School , Norfolk and Arlington, Virginia.
authors.forename: Andrea Ries
authors.initials: AR
authors.lastname: Thurman
authors.affiliation: 7 Division of Infectious Diseases, Faculty of Medicine, Imperial College , London, United Kingdom .
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
authors.affiliation: 8 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Southern California , Los Angeles, California.
authors.forename: Kattayoun
authors.initials: K
authors.lastname: Kordy
authors.affiliation: 9 Guys and St. Thomas' NHS Foundation Trust , London, United Kingdom .
authors.forename: Julie
authors.initials: J
authors.lastname: Fox
authors.affiliation: 3 Department of Medicine, David Geffen School of Medicine at UCLA, Center for HIV Prevention Research, UCLA AIDS Institute , Los Angeles, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Tanner
authors.affiliation: 10 Advanced Bioscience Laboratories , Gaithersburg, Maryland.
authors.forename: Glenn
authors.initials: G
authors.lastname: Swartz
authors.affiliation: 4 School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Magee Womens Research Institute , Pittsburgh, Pennsylvania.
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002584:Cervix Uteri / Q000821:virology; D018890:Chemoprevention / Q000379:methods; D003625:Data Collection / Q000379:methods*; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D005260:Female; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development*; D006801:Humans; D065129:Pre-Exposure Prophylaxis / Q000379:methods; D012007:Rectum / Q000821:virology; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013048:Specimen Handling / Q000379:methods*; D016896:Treatment Outcome; D014621:Vagina / Q000821:virology
chemical_list: D000890:Anti-Infective Agents; D016655:HIV Core Protein p24
keywords: HIV; HIV prevention; bioinformatics; drug discovery