Abstract
With the scale-up of HIV pre-exposure prophylaxis (PrEP) with tenofovir (TDF) with or without emtricitabine (FTC), we have entered an era of highly effective HIV prevention with a growing pipeline of potential products to be studied. These studies are likely to be randomized trials with an oral TDF/FTC control arm. These studies require comparison of incident infections and can be time and resource intensive. Conventional approaches for design and analysis active controlled trial can lead to very large sample sizes. We demonstrate the important of assumptions about background infections for interpreting trial results and suggest alternative criteria for demonstrating the efficacy and effectiveness of potential PrEP agents.
Funding source: National Institute of Allergy and Infectious Diseases
Award Identifier / Grant number: R01AI143357
Funding statement: This work was supported by the National Institute of Allergy and Infectious Diseases (Funder Id: http://doi.org/10.13039/100000060, Grant Number: R01AI143357)
References
Adimora, A. A., S. R. Cole, and J. J. Eron. 2017. “US Black Women and Human Immunodeficiency Virus Prevention: Time for New Approaches to Clinical Trials.” Clinical Infectious Diseases 65: 324–27.10.1093/cid/cix313Search in Google Scholar
AIDS Vaccine Advocacy Coalition. 2019. “PrEP Watch Country Updates.” Accessed March 15, 2019. https://www.prepwatch.org.Search in Google Scholar
Amico, K. R., M. Mehrotra, V. I. Avelino-Silva, V. McMahan, V. G. Veloso, P. Anderson, J. Guanira, and R. Grant. 2016. “Self-Reported Recent PrEP Dosing and Drug Detection in an Open Label PrEP Study.” AIDS and Behavior 20: 1535–40.10.1007/s10461-016-1360-7Search in Google Scholar
Anderson, P. L., D. V. Glidden, A. Liu, S. Buchbinder, J. R. Lama, J. V. Guanira, V. McMahan, et al. 2012. “Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men.” Science Translational Medicine 4: 151ra125–151ra125.10.1126/scitranslmed.3004006Search in Google Scholar PubMed
Baeten, J. M., R. Heffron, L. Kidoguchi, N. R. Mugo, E. Katabira, E. A. Bukusi, S. Asiimwe, et al. 2016. “Integrated Delivery of Antiretroviral Treatment and Pre-Exposure Prophylaxis to HIV-1–Serodiscordant Couples: A Prospective Implementation Study in Kenya and Uganda.” PLoS Medicine 13: e1002099.10.1371/journal.pmed.1002099Search in Google Scholar
Chan, P. A., L. Mena, R. Patel, C. E. Oldenburg, L. Beauchamps, A. G. Perez-Brumer, S. Parker, K. H. Mayer, M. J. Mimiaga, and A. Nunn. 2016. “Retention in Care Outcomes for HIV Pre-Exposure Prophylaxis Implementation Programmes Among Men Who Have Sex With Men in Three US cities.” Journal of the International AIDS Society 19: 20903.10.7448/IAS.19.1.20903Search in Google Scholar PubMed
Cutrell, A., D. Donnell, D. T. Dunn, D. V. Glidden, A. Grobler, B. Hanscom, B. S. Stancil, R. D. Meyer, R. Wang, and R. L. Cuffe. 2017. “HIV Prevention Trial Design in an Era of Effective Pre-exposure Prophylaxis.” HIV clinical trials 18: 177–188.10.1080/15284336.2017.1379676Search in Google Scholar
Delany-Moretlwe, S., S. Mullick, R. Eakle, and H. Rees. 2016. “Planning for HIV Preexposure Prophylaxis Introduction: Lessons Learned from Contraception.” Current Opinion in HIV and AIDS 11: 87–93.10.1097/COH.0000000000000221Search in Google Scholar PubMed
DISCOVER Protocol Team. 2016. “Safety and Efficacy of Emtricitabine and Tenofovir Alafenamide (F/TAF) Fixed-Dose Combination Once Daily for Pre-exposure Prophylaxis in Men and Transgender Women Who Have Sex With Men and are at Risk of HIV -1 Infection (DISCOVER).” Accessed March 15, 2019. https://clinicaltrials.gov/ct2/show/NCT02842086.Search in Google Scholar
Donnell, D., J. M. Baeten, N. N. Bumpus, J. Brantley, D. R. Bangsberg, J. E. Haberer, A. Mujugira, et al. 2014. “HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention.” Journal of Acquired Immune Deficiency Syndromes 66: 340.10.1097/QAI.0000000000000172Search in Google Scholar
Donnell, D., J. P. Hughes, L. Wang, Y. Q. Chen, and T. R. Fleming. 2013. “Study Design Considerations for Evaluating Efficacy of Systemic Pre-exposure Prophylaxis Interventions.” Journal of Acquired Immune Deficiency Syndromes 63: S130–S134.10.1097/QAI.0b013e3182986facSearch in Google Scholar
Dunn, D. T., D. V. Glidden, O. T. Stirrup, and S. McCormack. 2018. “The Averted Infections Ratio: A Novel Measure of Effectiveness of Experimental HIV Pre-exposure Prophylaxis Agents.” The Lancet HIV 5: e329–e334.10.1016/S2352-3018(18)30045-6Search in Google Scholar
Fleming, T. R., K. Odem-Davis, M. D. Rothmann, and Y. Li Shen. 2011. “Some Essential Considerations in the Design and Conduct of Non-Inferiority Trials.” Clinical Trials 8: 432–39.10.1177/1740774511410994Search in Google Scholar
Fonner, V. A., S. L. Dalglish, C. E. Kennedy, R. Baggaley, K. R. O’reilly, F. M. Koechlin, M. Rodolph, I. Hodges-Mameletzis, and R. M. Grant. 2016. “Effectiveness and Safety of Oral HIV Preexposure Prophylaxis for all Populations.” AIDS 30: 1973–83.10.1097/QAD.0000000000001145Search in Google Scholar PubMed
Grant, R. M., J. R. Lama, P. L. Anderson, V. McMahan, A. Y. Liu, L. Vargas, P. Goicochea, et al. 2010. “Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex With Men.” New England Journal of Medicine 363: 2587–99.10.1056/NEJMoa1011205Search in Google Scholar
Greene, G. J., G. Swann, A. J. Fought, A. Carballo-Diéguez, T. J. Hope, P. F. Kiser, B. Mustanski, and T. Richard. 2017. “Preferences for Long-Acting Pre-Exposure Prophylaxis (PrEP), Daily Oral PrEP, or Condoms for HIV Prevention Among US Men Who Have Sex With Men.” AIDS and Behavior 21: 1336–49.10.1007/s10461-016-1565-9Search in Google Scholar
Hanscom, B., J. P. Hughes, B. D. Williamson, and D. Donnell. 2018. “Adaptive Non-Inferiority Margins Under Observable Non-Constancy.” Statistical Methods in Medical Research. https://doi.org/10.1177/0962280218801134.10.1177/0962280218801134Search in Google Scholar PubMed
HPTN 083 Protocol Team. 2016. “A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure Prophylaxis in HIV -Uninfected Cisgender Men and Transgender Women Who Have Sex With Men.” Accessed March 15, 2019. https://www.hptn.org/research/studies/hptn083.Search in Google Scholar
HPTN 084 Protocol Team. 2017. “A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral tdf/ftc for Pre-Exposure Prophylaxis in HIV -Uninfected Women.” Accessed March 15, 2019. https://www.hptn.org/research/studies/hptn084.Search in Google Scholar
Hung, H. J., S.-J. Wang, and R. O’Neill. 2005. “A Regulatory Perspective on Choice of Margin and Statistical Inference Issue in Non-Inferiority Trials.” Biometrical Journal: Journal of Mathematical Methods in Biosciences 47: 28–36.10.1002/bimj.200410084Search in Google Scholar
Mayer, K., C. Grasso, K. Levine, D. Krakower, V. Powell, S. L. Boswell, and J. L. Marcus. 2018. Increasing PrEP Uptake, Persistent Disparities in at-Risk Patients in a Boston Center, Boston: In Conference on Retroviruses and Opportunistic InfectionsSearch in Google Scholar
McCormack, S., D. T. Dunn, M. Desai, D. I. Dolling, M. Gafos, R. Gilson, A. K. Sullivan, et al. 2016. “Pre-Exposure Prophylaxis to Prevent the Acquisition of HIV -1 Infection (PROUD): Effectiveness Results from the Pilot Phase of a Pragmatic Open-Label Randomised Trial.” The Lancet 387: 53–60.10.1016/S0140-6736(15)00056-2Search in Google Scholar
Meyers, K., K. Rodriguez, A. L. Brill, Y. Wu, M. La Mar, D. Dunbar, B. Koblin, et al. 2017. “Lessons for Patient Education Around Long-Acting Injectable Prep: Findings from a Mixed-Method Study of Phase ii Trial Participants.” AIDS and Behavior 1–8.10.1007/s10461-017-1871-xSearch in Google Scholar PubMed PubMed Central
Molina, J.-M., C. Capitant, B. Spire, G. Pialoux, L. Cotte, I. Charreau, C. Tremblay, et al. 2015. “On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection.” New England Journal of Medicine 373: 2237–46.10.1056/NEJMoa1506273Search in Google Scholar PubMed
Montgomery, E. T., M. Beksinska, N. Mgodi, J. Schwartz, R. Weinrib, E. N. Browne, N. Mphili, et al. 2019. “End-User Preference for and Choice of Four Vaginally Delivered HIV Prevention Methods Among Young Women in South Africa and Zimbabwe: The Quatro Clinical Crossover Study.” Journal of the International AIDS Society 22: e25283.10.1002/jia2.25283Search in Google Scholar PubMed PubMed Central
Mullick, C., and J. Murray. 2019. “Correlations Between HIV Infection and Rectal Gonorrhea Incidence in Men Who Have Sex With Men: Implications for Future HIV Pre-Exposure Prophylaxis Trials.” The Journal of Infectious Diseases. DOI: 10.1093/infdis/jiz037.10.1093/infdis/jiz037Search in Google Scholar PubMed
Rolle, C.-P., E. S. Rosenberg, N. Luisi, J. Grey, T. Sanchez, C. del Rio, J. L. Peterson, P. M. Frew, P. S. Sullivan, and C. F. Kelley. 2017. “Willingness to Use Pre-Exposure Prophylaxis Among Black and White Men Who Have Sex With Men in Atlanta, Georgia.” International Journal of STD & AIDS 28: 849–57.10.1177/0956462416675095Search in Google Scholar PubMed PubMed Central
Ross, J., and J. Stover. 2013. “Use of Modern Contraception Increases When More Methods Become Available: Analysis of Evidence from 1982–2009.” Global Health: Science and Practice 1: 203–12.10.9745/GHSP-D-13-00010Search in Google Scholar PubMed PubMed Central
Ryan, M., A. Bate, C. Eastmond, and A. Ludbrook. 2001. “Use of Discrete Choice Experiments to Elicit Preferences.” BMJ Quality & Safety 10: i55–i60.10.1136/qhc.0100055Search in Google Scholar
Serota, D. P., E. S. Rosenberg, A. M. Lockard, C.-P. M. Rolle, N. Luisi, S. Cutro, C. del Rio, et al. 2018. “Beyond the Biomedical: Preexposure Prophylaxis Failures in a Cohort of Young Black Men Who Have Sex With Men in Atlanta, Georgia.” Clinical Infectious Diseases 67: 965–70.10.1093/cid/ciy297Search in Google Scholar PubMed PubMed Central
Smith, D. K., M. Van Handel, and J. Grey. 2018. “Estimates of Adults With Indications for HIV Pre-Exposure Prophylaxis by Jurisdiction, Transmission Risk Group, and Race/ Ethnicity,United States, 2015.” Annals of Epidemiology 28: 850–57.10.1016/j.annepidem.2018.05.003Search in Google Scholar PubMed
Snapinn, S., and Q. Jiang. 2008. “Preservation of Effect and the Regulatory Approval of New Treatments on the Basis of Non-Inferiority Trials.” Statistics in Medicine 27: 382–91.10.1002/sim.3073Search in Google Scholar PubMed
Sullivan, P. S., R. M. Giler, F. Mouhanna, E. S. Pembleton, J. L. Guest, J. Jones, A. D. Castel, et al. 2018. “Trends in the Use of Oral Emtricitabine/Tenofovir Disoproxil Fumarate for Pre-Exposure Prophylaxis Against HIV Infection, United States, 2012–2017.” Annals of Epidemiology 28: 833–40.10.1016/j.annepidem.2018.06.009Search in Google Scholar PubMed PubMed Central
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