Optimizing the frequency of kidney safety monitoring in

Optimizing the frequency of kidney safety monitoring in

Optimizing the frequency of kidney safety monitoring in HIV-uninfected persons using daily oral tenofovir disoproxil fumarate PrEP Kenneth Mugwanya, Renee Heffron, Christina Wyatt, Nelly Mugo, Connie Celum, Elly Katabira, James Kiarie, Alan Ronald, and Jared M. Baeten for the Partners PrEP Study and Partners Demonstration Project Teams PARTNERS DEMONSTRATION PROJECT Conflicts of Interest I have received research funding from the National Institutes of Health. I am the Principal Investigator of a study that received donated emtricitabine/tenofovir from Gilead. Clinically relevant kidney toxicity is rare with TDF-based PrEP In clinical trials, TDF-based PrEP has been associated with small non-progressive and clinically insignificant declines in creatinine clearance, a commonly used measure of overall kidney function. Clinically relevant events are very rare and quickly resolve within weeks of PrEP discontinuation. 2.5% of people randomized to FTC/TDF in the Partners PrEP Study experienced a decline in eGFR >25% of their baseline eGFR value (Mugwanya et al 2015 JAMA Intern Med) Optimal frequency of kidney safety

monitoring is a key knowledge gap As PrEP is bought to scale, defining the optimal frequency of kidney safety monitoring is a key knowledge gap This is particularly important for regions with limited resources and/or less developed laboratory infrastructure PrEP implementation guidance recommend periodic creatinine monitoring (when feasible) Clinical trials monitored creatinine clearance every 3 months Demonstration projects have used a variety of monitoring schedules, from monthly to 6-monthly US CDC recommends monitoring 6-monthly Research objective To investigate whether 6-monthly kidney function monitoring could be as safe as 3-monthly monitoring Data sources Partners PrEP Study Partners Demonstration Project Randomized clinical trial of PrEP efficacy and safety Routine 3-monthly creatinine monitoring; confirmatory testing

of any abnormal results was conducted within ~1 week Open-label delivery study of integrated PrEP and ART Routine 6-monthly creatinine monitoring; confirmatory testing of any abnormal results was conducted within ~1 week Both studies HIV uninfected participants were members of heterosexual HIV serodiscordant couples Creatinine clearance >60 mL/min was required for study entry PrEP adherence was high (>80% by tenofovir blood measurements) PrEP was not discontinued unless there was a confirmed creatinine toxicity Methods Analysis included people who initiated PrEP and had at least one post-enrollment serum creatinine measurement Outcomes 1. Occurrence of clinically relevant decline in creatinine clearance, defined as creatinine clearance <60 mL/minute 2. Occurrence of 1.5-fold creatinine increase from baseline Descriptive methods used to summarize creatinine events Cox proportional hazards regression used to determine factors associated with the incidence of creatinine

clearance falling below 60mL/minute Participant baseline characteristics Partners Partners PrEP Study Demonstration Project (N=4404) (N=955) Mean SD or % Mean SD or % Age, years 35 9 32 9 Male 63% 67% 0.77 0.15 0.77 0.15 110 25 116 25 Creatinine clearance 60-90 mL/min

22% 13% Weight 55kg 22% 9% Systolic blood pressure 140 mmHg 5% 5% Serum creatinine, mg/dL Creatinine clearance, mL/min Cumulative proportion of persons with CrCl <60 mL/min 3-monthly monitoring (Partners PrEP Study) N=4404 6-monthly monitoring (Partners Demo) N=955

Months after study enrollment Unconfirmed measurement Confirmed measurement* 3 6 12 6 12 1.4% 2.5% 2.7% 0.7% 1.1% 63/4404 90/4404 120/4404

7/955 10/955 0.4% 0.5% 0.7% 0.2% 0.2% 16/4404 21/4404 * Decline confirmed on repeating testing 29/4404 2/955 2/955 Cumulative proportion of persons with 1.5-fold increase in creatinine 3-monthly monitoring (Partners PrEP)

N=4404 6-monthly monitoring (Partners Demo) N=955 Months after study enrollment Unconfirmed measurement Confirmed measurement 3 6 12 6 12 1.3% 1.9% 2.8% 1.4% 1.8%

57/4404 85/4404 123/4404 13/955 17/955 0.4% 0.5% 0.8% 0.3% 0.4% 18/4404 23/4404 * Increase confirmed on repeating testing 33/4404 3/955

4/955 Baseline covariates associated with CrCl <60 mL/min within 12 months of starting PrEP Age 45 years % with confirmed CrCl <60 mL/min in 12 months Adjusted HR 3.4% (23/676) 2.5 (95% CI) p-value (1.3-4.9) Age <45 years 0.6% (30/4685) p=0.0008 CrCl 60-90 mL/min

4.3% (35/812) 74.4 CrCl >90 mL/min 0.1% (4/4256) Weight 55 kg 2.3% (25/1105) Weight >55kg 0.7% (32/4549) (9.8-567.2) p<0.001 2.7 (1.4-5.2) p=0.004 *Model includes variables listed plus systolic blood pressure and PrEP treatment (TDF/ FTC or TDF) and stratification by site and gender. Other demographic and medical factors were not significantly associated with CrCl <60mL/min. Results summary The frequency of clinically relevant decline in creatinine

clearance was rare in these 2 large cohorts with high adherence to TDF-based PrEP Overall, <1% of people in the 2 cohorts experienced a confirmed decline in CrCl to <60 mL/min within 12 months of starting PrEP The occurrence and pattern was not qualitatively different whether creatinine clearance monitoring was based on 3monthly or 6-monthly monitoring More than 75% of creatinine elevations or declines in creatinine clearance were unconfirmed on repeat testing Implications These data support US CDC recommendations for 6-monthly creatinine monitoring for people using PrEP These data also suggest that less frequent testing may be possible for a majority of persons using PrEP, requiring fewer resources Reduced creatinine clearance was extremely rare among persons with baseline levels >90 mL/ min, younger than age 45, and weighing >55kg. Monitoring might be able to target those with defined risk factors. Partners PrEP Study Team Sites:

Eldoret, Kenya (Moi U, Indiana U): Edwin Were (PI), Ken Fife (PI), Cosmas Apaka Jinja, Uganda (Makarere U, UW); Patrick Ndase (PI), Elly Katabira (PI), Fridah Gabona Kabwohe, Uganda (KCRC): Elioda Tumwesigye (PI), Rogers Twesigye Kampala, Uganda (Makarere U): Elly Katabira (PI), Allan Ronald (PI), Edith Nakku-Joloba Kisumu, Kenya (KEMRI, UCSF): Elizabeth Bukusi (PI), Craig Cohen (PI), Josephine Odoyo Mbale, Uganda (TASO, CDC): Jonathan Wangisi (PI), Akasiima Mucunguzi Nairobi, Kenya (KNH/U Nairobi, UW): James Kiarie (PI), Carey Farquhar (PI), Grace John-Stewart (PI), Harrison Tamooh Thika, Kenya (KNH/U Nairobi, UW): Nelly Mugo (PI), Kenneth Ngure Tororo, Uganda (CDC, TASO): Jim Campbell (PI), Jordan Tappero (PI), Aloysious Kakia University of Washington Coordinating Center: Connie Celum (PI and Co-Chair), Jared Baeten (Co-Chair and Medical Director), Deborah Donnell (Statistician), Justin Brantley, Robert Coombs, Carlos Flores, Lisa Frenkel, Harald Haugen, Ting Hong, Jim Hughes, Erin Kahle, Becky Karschney, Lara Kidoguchi, Meighan Krows, Jai Lingappa, Toni Maddox, Angela McKay, Julie McElrath, Allison Mobley, Susan Morrison, Kelly Moutsos, Apollo Odika, Hilda OHara, Dana Panteleeff, Marothodi Semenya, John Sparkman, Katherine Thomas Adherence Ancillary Study: David Bangsberg, Jessica Haberer, Norma Ware, Monique Wyatt, Steve Safren, Christina Psaros, Craig Hendrix, Namandj Bumpus

DF/Net (data center): Lisa Ondrejcek, Darryl Pahl, Jae Chong CLS (laboratory oversight): Wendy Stevens, Charlotte Ingram, Ute Jentsch, Mukthar Kader, Nombulelo Gqomane, Feroza Bulbulia, Jan van den Heuvel ClinPhone/Perceptive Informatics (randomization) Gilead (study drug donation): Jim Rooney Bill & Melinda Gates Foundation (study funder): Stephen Becker HIV serodiscordant couples who tested, screened, & participated Partners Demonstration Project Team Investigators University of Washington Coordinating Center: Jared Baeten (protocol chair), Connie Celum (protocol co-chair), Renee Heffron (project director), Deborah Donnell (protocol statistician),

Ruanne Barnabas, ICRC Operations, Data and Administration teams Kabwohe, Uganda (KCRC): Stephen Asiimwe, Edna Tindimwebwa Kampala, Uganda (Makerere University): Elly Katabira, Nulu Bulya Kisumu, Kenya (KEMRI): Elizabeth Bukusi, Josephine Odoyo Thika, Kenya (KEMRI): Nelly Mugo, Kenneth Ngure MGH/Harvard: Jessica Haberer, Norma Ware Johns Hopkins: Craig Hendrix, Mark Marzinke DF/Net Research (data management) Funders US National Institutes of Health (grants R01 MH095507, R01 MH100940, R01 MH 101027, R21 AI104449, K99 HD076679, R00 HD076679) Bill & Melinda Gates Foundation (grants OPP47674, OPP1056051) US Agency for International Development (contract AID-OAA-A-12-00023) Research participants The Partners Demonstration Project is made possible by the United States National Institutes of Health, the Bill and Melinda Gates Foundation, and the generous support of the American people through the United States Agency for International Development. The contents are the responsibility of the University of Washington and study partners and do not necessarily reflect the views of any of the study sponsors or the United States Government.

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