A case for preART-adjusted endpoints in HIV therapeutic vaccine trials |
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| Affiliation: | 1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3. Department of Global Health, University of Washington, Seattle, WA, USA;4. S-cubed Biometrics Ltd, Oxfordshire, United Kingdom;5. Bionor Pharma ASA, Oslo, Norway;6. Lausanne University Hospital, Lausanne, Switzerland;1. Department of Internal Medicine & Gastroenterology, Spaarne Gasthuis, Haarlem, The Netherlands;2. Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands;3. Department of Medical Microbiology & Virology, University Medical Center Utrecht, Utrecht, The Netherlands;1. Indiana University School of Medicine, Indianapolis, IN, USA;2. Case Western Reserve University, Cleveland, OH, USA;3. JOSHA Research, Bloemfontein, South Africa;4. Hospital Nacional Cayetano Heredia, Lima, Peru;5. Desmond Tutu HIV Foundation, Cape Town, South Africa;6. HIV-NAT, Thai Red Cross AIDS Research Centre and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;7. Triple O Research Institute, West Palm Beach, FL, USA;8. Centro Glucomedi, Mexico City, Mexico;9. Bristol-Myers Squibb, Princeton, CT, USA;10. Bristol-Myers Squibb, Wallingford, NJ, USA;1. Hospital Vall d’Hebrón, Universitat Autónoma de Barcelona, Barcelona, Spain;2. CIBEREHD, Barcelona, Spain;3. Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain;4. Hospital de Cruces, University of the Basque Country, Bilbao, Spain;5. Hospital Universitario Reina Sofía-IMIBIC, Córdoba, Spain;6. Hospital Universitario Ramón y Cajal-IRYCIS, Madrid, Spain;7. Hospital Universitario Doce de Octubre, Madrid, Spain;8. Hospital de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain;9. Hospital Universitari La Fe, Valencia, Spain;10. Hospital General Universitario Gregorio Marañón, Madrid, Spain;11. Hospital Universitario Central de Asturias, Oviedo, Spain;12. Hospital Universitario Virgen del Rocío, Sevilla, Spain;13. Complejo Hospitalario Universitario, A Coruña, Spain;14. Hospital Universitario de Santiago de Compostela, La Coruña, Spain;15. Organización Nacional de Trasplantes, Madrid, Spain;16. Hospital Universitario La Paz-IdiPaz, Madrid, Spain;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3. Department of Biostatistics, University of Washington, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Department of Global Health, University of Washington, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3. Department of Biostatistics, University of Washington, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA;3. Department of Medicine, University of Washington, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Department of Global Health, University of Washington, Seattle, WA, USA;3. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA;4. Department of Medicine, University of Washington, Seattle, WA, USA;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3. Department of Biostatistics, University of Washington, Seattle, WA, USA;1. Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea;2. Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea;3. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea;1. Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA |
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| Abstract: | BackgroundIn a randomized, double-blind, placebo-controlled phase 2 clinical trial of Vacc-4x, a peptide-based therapeutic HIV-1 p24Gag vaccine candidate, 135 HIV-infected participants (vaccine:placebo = 92:43) received a series of six immunizations while on combination antiretroviral therapy (cART). At week 28, all participants underwent an analytical treatment interruption (ATI) for up to 24 weeks. preART VL appeared to be higher among Vacc-4x recipients. Based on a previous analysis, during ATI viral load (VL) appeared to be lower in Vacc-4x recipients, but no difference in CD4 level was observed between Vacc-4x and placebo groups. We propose fold-change-based endpoints and report comparative analyses accounting for imbalanced preART VL and missing data.MethodsAll analyses included per-protocol (PP) participants who received the full immunization and underwent ATI. Linear regression models were used to identify predictors of study endpoints and to estimate the vaccine effect based on fold changes in CD4 counts or VL over preART values at week 40 or at set-point (geometric mean over weeks 48 and 52 values). We adjusted for potential baseline factors and used a multiple imputation approach to account for missing endpoints due to cART resumption or dropout. P-values were adjusted for multiple comparisons using q-values.ResultspreART VL and CD4 count were significant predictors of study endpoints. The vaccine recipients had a higher fold change in week 40 CD4 counts (vaccine vs. placebo mean fold-change difference = 0.08; p = 0.02; q = 0.03), a higher fold change in CD4 count set-point (0.06; p = 0.06; q = 0.07), a lower fold change in week 40 VL (−0.47; p = 0.03; q = 0.05), and a lower fold change in VL set-point (−0.50; p = 0.02; q = 0.03).ConclusionsThese exploratory analyses consistently suggested that Vacc-4x provided positive effects on both CD4 counts and VL. Future HIV therapeutic vaccine studies may adopt similar preART-adjusted endpoints and missing data imputation methods in vaccine effect evaluations. |
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| Keywords: | Analytical treatment interruption Fold-change HIV-infected Missing data preART Statistical power |
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