Daily oral tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis (PrEP) is recommended as an HIV prevention strategy for at-risk persons globally. Preventative strategies in general must be safe, as they are provided to otherwise healthy persons to prevent a condition that they may or may not otherwise acquire. In clinical trials, TDF-based PrEP was associated with small nonprogressive declines in estimated glomerular filtration rate,1–3 a commonly used measure of kidney function, but severe kidney dysfunction was very rare (<2%).3–5
In clinical trials of PrEP efficacy, kidney function, as estimated by creatinine clearance, was assessed every 3 months; follow on PrEP demonstration projects, designed to include procedures that were close to “real world” settings, have used a variety of monitoring schedules, including both less and more frequently than the trials.6–14 Currently, the US Centers for Disease Control and Prevention recommends kidney monitoring every 6 months while on PrEP, and the World Health Organization recommends quarterly monitoring for the first 12 months of PrEP use and then annually thereafter; neither suggests differential monitoring based on specific risk factors. Studies have not formally investigated the optimal timing of kidney function monitoring while on PrEP or the potential for less frequent monitoring for some PrEP users.
As PrEP is delivered more widely, especially in resource-limited settings, it is important to define the optimal frequency of kidney safety monitoring that balances the clinical need to identify kidney dysfunction against the costs, complexity, and availability of laboratory testing. Using data from 2 prospective PrEP studies in East Africa which enrolled a generally young healthy population, we investigated whether 6-monthly kidney function monitoring could be as safe as 3-monthly monitoring.
Data were from 2 large prospective PrEP studies, the Partners PrEP Study and the follow on Partners Demonstration Project. Details of study design, recruitment, and primary outcomes of the 2 studies are reported elsewhere.7,8 Briefly, the Partners PrEP Study was a randomized clinical trial of the efficacy and safety of daily oral TDF and emtricitabine-TDF PrEP for HIV prevention among HIV-uninfected members of African heterosexual HIV serodiscordant couples conducted between 2008 and 2012 at 9 clinical sites in Kenya and Uganda (Clinicaltrials.gov number NCT00557245).7 Monitoring of kidney function was conducted every 3 months. The follow on study, Partners Demonstration Project, was an open-label, delivery study of integrated PrEP for HIV-uninfected partners and antiretroviral therapy for the HIV-infected partners among high-risk HIV serodiscordant African couples conducted in 4 clinical sites in Kenya and Uganda (Clinicaltrials.gov number NCT02775929).8 In this study, which was designed to demonstrate a scalable public health delivery model for PrEP, kidney function monitoring was routinely conducted every 6 months. In both studies, abnormal results were followed with confirmatory testing within approximately 1 week and PrEP was withheld if clinically indicated.
For both studies, eligible HIV-uninfected participants at entry were 18 years or older, did not have active hepatitis B infection, were not pregnant or breastfeeding, had Cockcroft–Gault calculated creatinine clearance of ≥60 mL/min, were not receiving ongoing therapy with agents with known significant nephrotoxic potential, and did not have diabetes requiring hypoglycemic medication or active and clinically significant cardiac disease. In both studies, PrEP adherence was very high (>80%).7,8 Protocols for both studies were approved by the University of Washington Human Subjects Division and by ethics review committees at each of the participating study sites. All participants provided written informed consent, and study progress for each study was reviewed by independent data monitoring committees.
Criteria for Permanent Study Drug Discontinuation
Permanent study drug discontinuation occurred under the following circumstances: (1) at completion of scheduled follow-up on study medication, (2) in participants who seroconverted to HIV infection, (3) in participants who experienced a confirmed grade 2 or higher serum creatinine abnormality (a Cockcroft–Gault calculated creatinine clearance, 50 mL/min). For participants with a recorded graded creatinine-related drug adverse event, serum creatinine was monitored weekly until the abnormality resolved or stabilized.
For both study cohorts, kidney function monitoring consisted of serum creatinine testing and calculation of creatinine clearance using the Cockoft–Gault equation with ideal body weight, at baseline and during follow-up. Serum creatinine was measured by local site laboratories which participated in regular proficiency testing for quality control and quality assurance before and during collection of biological specimens.
The current analysis included persons who initiated PrEP and had at least 1 postenrollment serum creatinine measurement. The primary outcome was the frequency of decline in calculated creatinine clearance to a level <60 mL/min; a decline of this magnitude is a frequently used measure for kidney dysfunction and is the recommended threshold by WHO and CDC guidelines. Additional analysis considered the occurrence of 1.5-fold serum creatinine increase from baseline and a composite outcome of creatinine clearance <60 mL/min or a 1.5-fold serum creatinine increase; a 1.5-fold increase in serum creatinine compared with baseline is a conservative measure often used in the context of acute kidney injury. Results were summarized at an individual level as an unconfirmed or confirmed creatinine event. Cumulative frequency and patterns of occurrence of each creatinine outcome were determined separately for each study and are descriptively compared between the 2 cohorts. Cox proportional hazards regression models stratified by site were used to explore baseline factors independently associated with creatinine clearance <60 mL/min.
Overall, 5358 participants were included in this analysis: 4404 (82% of all participants) from the Partners PrEP Study and 954 (94% of all participants) from the Partners Demonstration Project. Most participants were aged 30 years and older (mean age: 35 and 32 years for the Partners PrEP Study and the Demonstration project, respectively) and approximately two-thirds were men in both studies. The baseline mean creatinine clearance was 111 mL/min (110 mL/min in the Partners PrEP Study and 116 mL/min in Demonstration project), and 22% of participants in the Partners PrEP Study and 13% in the Demonstration Project had a baseline creatinine clearance between 60 and 90 mL/min. Mean baseline weight was 61 kg, and 22% of participants in the Partners PrEP Study and 9% in the Partners Demonstration Project weighed ≤55 kg.
Creatinine Clearance Decline <60 mL/min
The primary analysis considered the cumulative proportion of participants experiencing CrCl decline to <60 mL/min during the first 12 months of PrEP use. In the clinical trial with 3-monthly monitoring, 1.4% of participants experienced a creatinine clearance level <60 mL/min at the first quarterly check, but fewer than 25% of these were confirmed on repeat testing (ie, 0.4% experienced a confirmed event). At month 6, 0.5% of participants experienced a confirmed event, and at month 12, 0.7% of participants had a confirmed event (Table 1). In the study with 6-monthly monitoring, 0.2% of participants experienced a confirmed creatinine clearance level <60 min/mL both at month 6 and month 12.
Frequency of 1.5-fold Creatinine Elevation Compared With Baseline
We observed a similar pattern when the analysis was based on a 1.5-fold creatinine elevation from baseline: At 6 months, 0.5% of participants in the clinical trial using 3-monthly creatinine monitoring and 0.3% of participants in the demonstration project using 6-monthly monitoring experienced a 1.5-fold creatinine elevation from baseline. At 12 months, 0.8% of participants in the clinical trial and 0.4% of participants in the demonstration project experienced a 1.5-fold creatinine elevation. Similar patterns were observed when the analysis was based on a composite outcome (confirmed CrCl level <60 mL/min or 1.5-fold creatinine elevation from baseline).
Creatinine-Related PrEP Hold and Baseline Factors Associated With CrCl Decline <60 mL/min
Overall, 31 participants had confirmed creatinine clearance levels <60 mL/min within 12 months of PrEP initiation. An additional 21 experienced a confirmed event during 24 months of follow-up. For these 52 persons, 27 had a level between 50 and 60 mL/min and continued PrEP as per the protocol-specified safety management plan, 13 had PrEP temporarily withheld but restarted after resolution of the abnormality, 9 had PrEP withheld and were not able to restart within the prespecified study follow-up time, and in 3 persons the abnormality resolved but PrEP hold was continued because of other protocol specifications (pregnancy, HIV seroconversion, or study exit). Specifically, in the Demonstration Project, 2 people experienced confirmed CrCl decline <60 mL/min on repeat testing. First, a 64-year-old man with baseline CrCl of 64 mL/min, experienced decline to 56 (serum creatinine: 1.05 mg/dL) at month 6. Study drug was discontinued and never restarted. CrCl at study exit was 52 mL/min. Second, a 29-year-old woman experienced decline from a baseline of 61–53 mL/min at month 18. She continued on drug and CrCl was 59 mL/min at exit.
Overall, declines in creatinine clearance <60 mL/min were more likely to occur in participants who were older than 45 years [adjusted hazard ratio (aHR) 3.18, 95% confidence interval (CI): 1.76 to 5.75], weighed ≤55 kg (aHR 2.01, 95% CI: 1.13 to 3.57), elevated blood pressure (aHR 2.57, 95% CI: 0.98 to 6.78; P = 0.06), and those who had a baseline creatinine clearance between 60 and 90 mL/min (aHR 22.50, 95% CI: 7.78 to 65.07). These factors were all independently associated with experiencing creatinine clearance decline to below 60 mL/min (Table 2). Women appeared to be marginally more likely to experience events compared with men, but this difference may be driven by sex-related physiological differences and lower muscle mass in women rather than underlying pathophysiological differences. Notably, even among those with at least one of these characteristics, only a minority (ie, <5%) ever experienced a confirmed creatinine clearance <60 mL/min during 24-month follow-up: baseline creatinine clearance between 60 and 90 mL/min = 4.3%; weighed ≤55 kg = 1.9%; and ≥45 years = 3.4% (Table 2).
In these 2 large cohorts of HIV-uninfected participants with high adherence to daily TDF-based PrEP, the identification of moderate declines in creatinine clearance to a level <60 mL/min was not qualitatively different based on a 3-monthly or 6-monthly monitoring schedule. Overall, creatinine elevations were rare and most were not confirmed on repeat testing (<1% of participants had confirmed elevations). Thus, these data suggest that creatinine clearance monitoring on a 6-month schedule could be equally safe as a 3-month schedule and require fewer resources for most persons receiving PrEP for up to 24 months. More frequent monitoring may be indicated for those with specific risk factors associated with high propensity for declines in creatinine clearance (eg, age >45 years, baseline CrCl <90 mL/min, hypertension, and/or weight <55 kg); these characteristics have also been associated with increased likelihood of kidney dysfunction in other populations.15,16
These data are encouraging for PrEP implementation programs, particularly in resource-limited settings, where laboratory testing may be a burden to health systems. For example, in Kenya, recent Ministry of Health guidelines regarding PrEP are permissive of less frequent kidney monitoring,17 recommending baseline and then annual serum creatinine but permitting PrEP to be initiated and continued without kidney testing if laboratory testing is not available. In these guidelines, testing for individuals older than 45 years, weight <55 kg, with diabetes or hypertension, or other risk factors for renal disease is still strongly recommended. Guidelines that tailor the type of service, location and provider of service, and frequency of service to the differing needs of distinct patient groups will not only improve efficiency but are consistent with the differentiated care approach, which has gained interest in antiretroviral therapy programs.
Less frequent kidney monitoring may also be appealing to PrEP users. Given the epidemiology of HIV, persons for whom PrEP is most useful are likely to find it challenging to frequently undergo laboratory-based safety monitoring. Moreover, PrEP acceptability may be complicated by negative attitudes toward health systems and providers and by higher costs stemming from frequent safety monitoring and confirmatory testing. Thus, developing evidenced-based PrEP delivery models that minimize consumer burden is a priority for PrEP implementation. Approaches to maintain PrEP user interest by improving the efficiency of PrEP delivery may involve using point-of-care creatinine testing, reducing the frequency of kidney safety monitoring, incorporating HIV self-testing,18 and offering 6-monthly PrEP refill.
We qualitatively observed a slightly higher number of creatinine-related abnormalities in the protocol implementing 3-monthly testing than in 6-monthly which is likely driven by high volume of testing as only a minority of these events were confirmed with subsequent testing. We have previously reported that severe kidney toxicities are very rare (<2%) with TDF-based PrEP and that even the small declines in kidney function occurring in a minority of persons quickly resolve within weeks of discontinuing PrEP.3–5 Our data, thus, are in agreement with the US Centers for Disease Control and Prevention recommendation for routine kidney monitoring every 6 months while using PrEP,19 and models that incorporate kidney monitoring even less frequently than biannually among healthy persons merit investigation.
This analysis has limitations. First, the 2 studies analyzed here were not specifically conducted to compare the frequency of kidney function testing. Nonetheless, the studies were conducted in similar populations during relatively similar time frames, and kidney function testing was performed by protocol in both studies. In addition, the low frequency of moderate declines in creatinine clearance even under exceptionally high adherence to daily dosing lends confidence to our findings. Second, this study only considered declines in creatinine clearance <60 mL/min and not other changes that could be considered clinically relevant, such as a decline from normal to a creatinine clearance <90 mL/min. Changes in creatinine clearance above 60 mL/min are subject to limitations of the estimating equation and may not have triggered confirmatory testing in all cases. Third, both study populations were generally healthy, and optimal kidney function monitoring in persons with comorbid conditions such as diabetes, hypertension, or use of nephrotoxic medications is unknown. Fourth, follow-up time was limited to 24 months, and studies in HIV-infected persons suggest that TDF toxicity is cumulative; as a result, this analysis does not provide guidance on the optimal frequency of kidney function monitoring in persons who plan to take TDF-based PrEP for longer periods. Finally, this study did not consider the frequency or necessity of monitoring for proximal tubular dysfunction with TDF-based PrEP. Although we previously demonstrated no statistically significant difference in the incidence of proximal tubular dysfunction between participants randomized to TDF-based PrEP versus placebo,4 we did identify a single case of overt proximal tubular dysfunction in the clinical trial population; this participant was identified on the basis of routine creatinine clearance testing during the trial.4
In conclusion, in these 2 large cohorts of HIV-uninfected persons using PrEP, moderate decline in creatinine clearance was rare over up to 24 months of follow-up, and the pattern of identification was not qualitatively different based on 3-monthly or 6-monthly safety monitoring. Delivery of PrEP to most healthy persons can likely be implemented with 6-monthly and the potential for less frequent kidney safety monitoring can be explored through routine data collected through PrEP delivery programs.
The authors thank the HIV serodiscordant couples who participated in these 2 studies for their invaluable contributions, and the teams at the study sites and at the University of Washington for work on data and sample collection and management.
Members of the Partners PrEP Study Team and Partners Demonstration Project Team Partners PrEP Study Team
University of Washington Coordinating Center and Central Laboratories, Seattle, USA: Connie Celum (principal investigator, protocol co-chair), J.M.B. (medical director, protocol co-chair), Deborah Donnell (protocol statistician), Robert W. Coombs, Lisa Frenkel, Craig W. Hendrix, Jairam R. Lingappa, and M. Juliana McElrath.
Study sites and site principal investigators: Eldoret, Kenya (Moi University, Indiana University): Kenneth H. Fife and Edwin Were; Kabwohe, Uganda (Kabwohe Clinical Research Center): Elioda Tumwesigye; Jinja, Uganda (Makerere University, University of Washington): Patrick Ndase and E.K.; Kampala, Uganda (Makerere University): E.K. and A.R.; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): Elizabeth Bukusi and Craig R. Cohen; Mbale, Uganda (The AIDS Support Organization, CDC-Uganda): Jonathan Wangisi, James D. Campbell, and Jordan W. Tappero; Nairobi, Kenya (University of Nairobi, University of Washington): James Kiarie, Carey Farquhar, and Grace John-Stewart; Thika, Kenya (University of Nairobi, University of Washington): Nelly R. Mugo; Tororo, Uganda (CDC-Uganda, The AIDS Support Organization): James D. Campbell, Jordan W. Tappero, and Jonathan Wangisi.
Data management was provided by DF/Net Research, Inc. (Seattle, USA) and site laboratory oversight was provided by Contract Laboratory Services (CLS) of the Wits Health Consortium (University of the Witwatersrand, Johannesburg, South Africa).
Partners Demonstration Project Team
Coordinating Center (University of Washington) and collaborating investigators (Harvard Medical School, Johns Hopkins University, Massachusetts General Hospital): J.B. (protocol chair), Connie Celum (protocol co-chair), R.H. (project director), Deborah Donnell (statistician), Ruanne Barnabas, Jessica Haberer, Harald Haugen, Craig Hendrix, Lara Kidoguchi, Mark Marzinke, Susan Morrison, Jennifer Morton, Norma Ware, and Monique Wyatt.
Project sites: Kabwohe, Uganda (Kabwohe Clinical Research Centre): Stephen Asiimwe and Edna Tindimwebwa; Kampala, Uganda (Makerere University): E.K. and Nulu Bulya; Kisumu, Kenya (Kenya Medical Research Institute): Elizabeth Bukusi and Josephine Odoyo; Thika, Kenya (Kenya Medical Research Institute, University of Washington): Nelly Rwamba Mugo and Kenneth Ngure.
Data management was provided by DF/Net Research, Inc. (Seattle, WA). PrEP medication was donated by Gilead Sciences.
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