Testing a Real-Time Tenofovir Urine Adherence Assay for Monitoring and Providing Feedback to Preexposure Prophylaxis in Kenya (PUMA): Protocol for a Pilot Randomized Controlled Trial

Paul Drain, Kenneth Ngure, Nelly Mugo, Matthew Spinelli, Purba Chatterjee, Peter Bacchetti, David Glidden, Jared Baeten, Monica Gandhi, Paul Drain, Kenneth Ngure, Nelly Mugo, Matthew Spinelli, Purba Chatterjee, Peter Bacchetti, David Glidden, Jared Baeten, Monica Gandhi

Abstract

Background: The worldwide expansion of preexposure prophylaxis (PrEP) with oral tenofovir-disoproxil-fumarate/emtricitabine will be critical to ending the HIV epidemic. However, maintaining daily adherence to PrEP can be difficult, and the accuracy of self-reported adherence is often limited by social desirability bias. Pharmacologic adherence monitoring (measuring drug levels in a biomatrix) has been critical to interpreting PrEP trials, but testing usually requires expensive equipment and skilled personnel. We have recently developed a point-of-care (POC) immunoassay to measure tenofovir in urine, allowing real-time adherence monitoring for the first time.

Objective: The goal of this study is to examine a point-of-care adherence metric in PrEP to support and increase adherence via a randomized controlled trial.

Methods: The paper describes the protocol for a pilot randomized controlled trial to test the acceptability, feasibility, and impact on long-term adherence of implementing a POC urine test to provide real-time adherence feedback among women on PrEP. Eligible women (n=100) will be HIV-negative, ≥18 years old, and recruited from a clinic in Kenya that provides PrEP. Participants will be randomized 1:1 to the intervention of providing real-time feedback via the assay versus standard of care adherence counseling. Acceptability by participants will be assessed by a quantitative survey, as well as by qualitative data collected via in-depth interviews (n=20) and focus group discussions (n=4 groups, 5-10 women each). Feasibility will be assessed by the proportion of women retained in the study, the mean number of missed visits, the proportion of planned urine assessments completed, and messages delivered, while in-depth interviews with providers (n=8) will explore the ease of administering the urine test. Tenofovir levels in hair will serve as long-term adherence metrics. A linear mixed-effects model will estimate the effect of the intervention versus standard of care on logarithmically transformed levels of tenofovir in hair.

Results: This study has been funded by the National Institute of Health, approved by the Kenya Medical Research Institute Institutional Review Board, and will commence in June 2020.

Conclusions: A novel urine assay to measure and deliver information on adherence to PrEP in real-time will be tested for the first time in this trial planned among women on PrEP in Kenya. Study findings will inform a larger-scale trial assessing the impact of real-time adherence monitoring/feedback on HIV prevention. Improving adherence to PrEP will have long-term implications for efforts to end the HIV epidemic worldwide.

Trial registration: ClinicalTrials.gov NCT03935464; https://ichgcp.net/clinical-trials-registry/NCT03935464.

International registered report identifier (irrid): PRR1-10.2196/15029.

Keywords: Kenya; PrEP; adherence; immunoassay; point of care; real-time monitoring and feedback; tenofovir; trial; urine test; women.

Conflict of interest statement

Conflicts of Interest: DVG has accepted fees from Gilead Sciences.

©Paul Drain, Kenneth Ngure, Nelly Mugo, Matthew Spinelli, Purba Chatterjee, Peter Bacchetti, David Glidden, Jared Baeten, Monica Gandhi. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 02.04.2020.

Figures

Figure 1
Figure 1
The rationale behind the PUMA study. PUMA: Point-of-Care Urine Monitoring of Adherence; PrEP: preexposure prophylaxis; LC-MS: liquid chromatography/tandem mass spectrometry.
Figure 2
Figure 2
Schema for the PUMA study. PUMA: Point-of-Care Urine Monitoring of Adherence; PrEP: preexposure prophylaxis; TFV: Tenofovir.
Figure 3
Figure 3
Schedule of evaluations for participants in the intervention and standard of care arms for the PUMA study. PUMA: Point-of-Care Urine Monitoring of Adherence; PrEP: preexposure prophylaxis; TFV: Tenofovir.
Figure 4
Figure 4
Prototype of point-of-care urine-based tenofovir assay.

References

    1. US Public Health Service Centers for Disease Control and Prevention. 2018. Apr, [2018-04-23]. Preexposure Prophylaxis for the Prevention of HIV in the United States: A Clinical Practice Guideline - 2017 Update .
    1. World Health Organization. 2018. Dec, [2019-03-26]. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance
    1. Amico KR. Adherence to preexposure chemoprophylaxis: the behavioral bridge from efficacy to effectiveness. Curr Opin HIV AIDS. 2012 Nov;7(6):542–8. doi: 10.1097/COH.0b013e3283582d4a.
    1. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, Malahleha M, Owino F, Manongi R, Onyango J, Temu L, Monedi MC, Mak'Oketch P, Makanda M, Reblin I, Makatu SE, Saylor L, Kiernan H, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, Fransen K, Deese J, Crucitti T, Mastro TD, Taylor D. Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2012 Aug 02;367(5):411–422. doi: 10.1056/nejmoa1202614.
    1. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, Palanee T, Nakabiito C, van der Straten A, Noguchi L, Hendrix CW, Dai JY, Ganesh S, Mkhize B, Taljaard M, Parikh UM, Piper J, Mâsse B, Grossman C, Rooney J, Schwartz JL, Watts H, Marzinke MA, Hillier SL, McGowan IM, Chirenje ZM. Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2015 Feb 05;372(6):509–518. doi: 10.1056/nejmoa1402269.
    1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía Martín, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández Telmo, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker L, Mayer KH, Kallás Esper Georges, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng J, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV, iPrEx Study Team Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587–99. doi: 10.1056/NEJMoa1011205.
    1. Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, Chiamwongpaet S, Kitisin P, Natrujirote P, Kittimunkong S, Chuachoowong R, Gvetadze RJ, McNicholl JM, Paxton LA, Curlin ME, Hendrix CW, Vanichseni S, Bangkok Tenofovir Study Group Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013 Jun 15;381(9883):2083–90. doi: 10.1016/S0140-6736(13)61127-7.
    1. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, Henderson FL, Pathak SR, Soud FA, Chillag KL, Mutanhaurwa R, Chirwa LI, Kasonde M, Abebe D, Buliva E, Gvetadze RJ, Johnson S, Sukalac T, Thomas VT, Hart C, Johnson JA, Malotte CK, Hendrix CW, Brooks JT. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med. 2012 Aug 02;367(5):423–434. doi: 10.1056/nejmoa1110711.
    1. Baeten JM, Celum C. Antiretroviral Preexposure Prophylaxis for HIV Prevention. N Engl J Med. 2013 Jan 03;368(1):82–84. doi: 10.1056/nejmc1210464.
    1. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012 Aug 02;367(5):399–410. doi: 10.1056/nejmoa1108524.
    1. Corneli AL, McKenna K, Perry B, Ahmed K, Agot K, Malamatsho F, Skhosana J, Odhiambo J, Van Damme L. The science of being a study participant: FEM-PrEP participants' explanations for overreporting adherence to the study pills and for the whereabouts of unused pills. J Acquir Immune Defic Syndr. 2015 Apr 15;68(5):578–84. doi: 10.1097/QAI.0000000000000525.
    1. van der Straten A, Brown ER, Marrazzo JM, Chirenje MZ, Liu K, Gomez K, Marzinke MA, Piper JM, Hendrix CW, MTN-003 VOICE Protocol Team for Microbicide Trials Network Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) study. J Int AIDS Soc. 2016;19(1):20642. doi: 10.7448/IAS.19.1.20642.
    1. Baker Z, Javanbakht M, Mierzwa S, Pavel C, Lally M, Zimet G, Gorbach P. Predictors of Over-Reporting HIV Pre-exposure Prophylaxis (PrEP) Adherence Among Young Men Who Have Sex With Men (YMSM) in Self-Reported Versus Biomarker Data. AIDS Behav. 2018 Apr;22(4):1174–1183. doi: 10.1007/s10461-017-1958-4.
    1. Agot K, Taylor D, Corneli AL, Wang M, Ambia J, Kashuba ADM, Parker C, Lemons A, Malahleha M, Lombaard J, Van Damme L. Accuracy of Self-Report and Pill-Count Measures of Adherence in the FEM-PrEP Clinical Trial: Implications for Future HIV-Prevention Trials. AIDS Behav. 2015 May;19(5):743–51. doi: 10.1007/s10461-014-0859-z.
    1. Blumenthal J, Haubrich R. Pre-exposure prophylaxis for HIV infection: how antiretroviral pharmacology helps to monitor and improve adherence. Expert Opin Pharmacother. 2013 Sep;14(13):1777–85. doi: 10.1517/14656566.2013.812072.
    1. Hendrix CW, Andrade A, Bumpus NN, Kashuba AD, Marzinke MA, Moore A, Anderson PL, Bushman LR, Fuchs EJ, Wiggins I, Radebaugh C, Prince HA, Bakshi RP, Wang R, Richardson P, Shieh E, McKinstry L, Li X, Donnell D, Elharrar V, Mayer KH, Patterson KB. Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066) AIDS Res Hum Retroviruses. 2016 Jan;32(1):32–43. doi: 10.1089/AID.2015.0182.
    1. Anderson PL, Glidden DV, Liu A, Buchbinder S, Lama JR, Guanira JV, McMahan V, Bushman LR, Casapía M, Montoya-Herrera O, Veloso VG, Mayer KH, Chariyalertsak S, Schechter M, Bekker L, Kallás EG, Grant RM, iPrEx ST. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012 Sep 12;4(151):151ra125. doi: 10.1126/scitranslmed.3004006.
    1. Liu AY, Yang Q, Huang Y, Bacchetti P, Anderson PL, Jin C, Goggin K, Stojanovski K, Grant R, Buchbinder SP, Greenblatt RM, Gandhi M. Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP) PLoS One. 2014;9(1):e83736. doi: 10.1371/journal.pone.0083736.
    1. Castillo-Mancilla JR, Zheng J, Rower JE, Meditz A, Gardner EM, Predhomme J, Fernandez C, Langness J, Kiser JJ, Bushman LR, Anderson PL. Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retroviruses. 2013 Feb;29(2):384–90. doi: 10.1089/AID.2012.0089.
    1. Anderson PL, Liu AY, Castillo-Mancilla JR, Gardner EM, Seifert SM, McHugh C, Wagner T, Campbell K, Morrow M, Ibrahim M, Buchbinder S, Bushman LR, Kiser JJ, MaWhinney S. Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy. Antimicrob Agents Chemother. 2018 Jan;62(1) doi: 10.1128/AAC.01710-17.
    1. van der Straten A, Montgomery ET, Musara P, Etima J, Naidoo S, Laborde N, Hartmann M, Levy L, Bennie T, Cheng H, Piper J, Grossman CI, Marrazzo J, Mensch B, Microbicide Trials Network-003D Study Team Disclosure of pharmacokinetic drug results to understand nonadherence. AIDS. 2015 Oct 23;29(16):2161–71. doi: 10.1097/QAD.0000000000000801.
    1. Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, Hosek S, Mosquera C, Casapia M, Montoya O, Buchbinder S, Veloso VG, Mayer K, Chariyalertsak S, Bekker L, Kallas EG, Schechter M, Guanira J, Bushman L, Burns DN, Rooney JF, Glidden DV, iPrEx study team Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014 Sep;14(9):820–9. doi: 10.1016/S1473-3099(14)70847-3.
    1. Koester KA, Liu A, Eden C, Amico KR, McMahan V, Goicochea P, Hosek S, Mayer KH, Grant RM. Acceptability of drug detection monitoring among participants in an open-label pre-exposure prophylaxis study. AIDS Care. 2015;27(10):1199–204. doi: 10.1080/09540121.2015.1039958.
    1. Landovitz RJ, Beymer M, Kofron R, Amico KR, Psaros C, Bushman L, Anderson PL, Flynn R, Lee DP, Bolan RK, Jordan WC, Tseng C, Dierst-Davies R, Rooney J, Wohl AR. Plasma Tenofovir Levels to Support Adherence to TDF/FTC Preexposure Prophylaxis for HIV Prevention in MSM in Los Angeles, California. J Acquir Immune Defic Syndr. 2017 Dec 15;76(5):501–511. doi: 10.1097/QAI.0000000000001538.
    1. Gandhi M, Bacchetti P, Rodrigues WC, Spinelli M, Koss CA, Drain PK, Baeten JM, Mugo NR, Ngure K, Benet LZ, Okochi H, Wang G, Vincent M. Development and Validation of an Immunoassay for Tenofovir in Urine as a Real-Time Metric of Antiretroviral Adherence. EClinicalMedicine. 2018;2-3:22–28. doi: 10.1016/j.eclinm.2018.08.004.
    1. Gandhi M, Bacchetti P, Spinelli MA, Okochi H, Baeten JM, Siriprakaisil O, Klinbuayaem V, Rodrigues WC, Wang G, Vincent M, Cressey TR, Drain PK. Brief Report: Validation of a Urine Tenofovir Immunoassay for Adherence Monitoring to PrEP and ART and Establishing the Cutoff for a Point-of-Care Test. J Acquir Immune Defic Syndr. 2019 May 01;81(1):72–77. doi: 10.1097/QAI.0000000000001971.
    1. Spinelli MA, Glidden DV, Rodrigues WC, Wang G, Vincent M, Okochi H, Kuncze K, Mehrotra M, Defechereux P, Buchbinder SP, Grant RM, Gandhi M. Low tenofovir level in urine by a novel immunoassay is associated with seroconversion in a preexposure prophylaxis demonstration project. AIDS. 2019 Apr 01;33(5):867–872. doi: 10.1097/QAD.0000000000002135.
    1. Guidelines on Use of Antiretroviral Drugs for Treating and Preventing HIV Infections in Kenya. 2016. Mar 01, [2019-04-20]. .
    1. Celum C, Delany-Moretlwe S, Hosek S, Dye B, Bekker L, Mgodi N, Mabuzz W, Muuyane G, Mukaka S, Donnell D, Pathak S, Noble H, Lennon D, Fogel J, Anderson P. Risk Behavior, Perceptions, and Reasons for PrEP among Young African Women in HPTN 082. 25th Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7; Boston, Massachusetts, United States. 2018.
    1. Gandhi M, Murnane PM, Bacchetti P, Elion R, Kolber MA, Cohen SE, Horng H, Louie A, Kuncze K, Koss CA, Anderson PL, Buchbinder S, Liu A. Hair levels of preexposure prophylaxis drugs measure adherence and are associated with renal decline among men/transwomen. AIDS. 2017 Oct 23;31(16):2245–2251. doi: 10.1097/QAD.0000000000001615.
    1. Koss CA, Bacchetti P, Hillier SL, Livant E, Horng H, Mgodi N, Mirembe BG, Gomez Feliciano K, Horn S, Liu AY, Glidden DV, Grant RM, Benet LZ, Louie A, van der Straten A, Chirenje ZM, Marrazzo JM, Gandhi M. Differences in Cumulative Exposure and Adherence to Tenofovir in the VOICE, iPrEx OLE, and PrEP Demo Studies as Determined via Hair Concentrations. AIDS Res Hum Retroviruses. 2017 Aug;33(8):778–783. doi: 10.1089/aid.2016.0202.
    1. DiFrancesco R, Tooley K, Rosenkranz SL, Siminski S, Taylor CR, Pande P, Morse GD. Clinical pharmacology quality assurance for HIV and related infectious diseases research. Clin Pharmacol Ther. 2013 Jun;93(6):479–82. doi: 10.1038/clpt.2013.62.
    1. Rivest L. Statistical properties of Winsorized means for skewed distributions. Biometrika. 1994;81(2):373–383. doi: 10.1093/biomet/81.2.373.
    1. Marrazzo JM, Scholes D. Acceptability of urine-based screening for Chlamydia trachomatis in asymptomatic young men: a systematic review. Sex Transm Dis. 2008 Nov;35(11 Suppl):S28–33. doi: 10.1097/OLQ.0b013e31816938ca.
    1. Hadland SE, Levy S. Objective Testing: Urine and Other Drug Tests. Child Adolesc Psychiatr Clin N Am. 2016 Jul;25(3):549–65. doi: 10.1016/j.chc.2016.02.005.
    1. Koenig HC, Mounzer K, Daughtridge GW, Sloan CE, Lalley-Chareczko L, Moorthy GS, Conyngham SC, Zuppa AF, Montaner LJ, Tebas P. Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis. HIV Med. 2017 Jul;18(6):412–418. doi: 10.1111/hiv.12518. doi: 10.1111/hiv.12518.
    1. Kearney BP, Ramanathan S, Cheng AK, Ebrahimi R, Shah J. Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration. J Clin Pharmacol. 2005 Aug;45(8):935–40. doi: 10.1177/0091270005278949.
    1. Andriesen J, Bull S, Dietrich J, Haberer JE, Van Der Pol B, Voronin Y, Wall KM, Whalen C, Priddy F. Using Digital Technologies in Clinical HIV Research: Real-World Applications and Considerations for Future Work. J Med Internet Res. 2017 Jul 31;19(7):e274. doi: 10.2196/jmir.7513.
    1. Sullivan PS, Driggers R, Stekler JD, Siegler A, Goldenberg T, McDougal SJ, Caucutt J, Jones J, Stephenson R. Usability and Acceptability of a Mobile Comprehensive HIV Prevention App for Men Who Have Sex With Men: A Pilot Study. JMIR Mhealth Uhealth. 2017 Mar 09;5(3):e26. doi: 10.2196/mhealth.7199.
    1. Biello KB, Marrow E, Mimiaga MJ, Sullivan P, Hightow-Weidman L, Mayer KH. A Mobile-Based App (MyChoices) to Increase Uptake of HIV Testing and Pre-Exposure Prophylaxis by Young Men Who Have Sex With Men: Protocol for a Pilot Randomized Controlled Trial. JMIR Res Protoc. 2019 Jan 07;8(1):e10694. doi: 10.2196/10694.

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