Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis (PrEP) has demonstrated protection against HIV acquisition in diverse geographical and at-risk populations.1–4 The World Health Organization and the US Centers for Disease Control and Prevention (CDC) recommend TDF-based PrEP as part of a comprehensive package to prevent HIV infection in high-risk individuals.5,6 Although generally well tolerated, TDF exposure has been associated with small but statistically significant decline in estimated glomerular filtration rate (eGFR) in HIV-infected adults receiving TDF-containing antiretroviral regimens7–9 and in HIV-uninfected persons receiving TDF-based PrEP for HIV prevention.10,11 Among HIV-infected adults, kidney function returns to baseline level in a majority who discontinue TDF, but cases of less than optimal recovery have been reported.9,12 In PrEP trials,1–4,13 renal adverse events based on serum creatinine levels and calculated creatinine clearance generally resolved with TDF discontinuation, but detailed data on the reversibility of TDF-related eGFR decline after PrEP discontinuation, are limited. We assessed the reversibility of eGFR decline in HIV-uninfected adults discontinuing TDF-based PrEP in the Partners PrEP Study, a randomized, double-blind, placebo-controlled trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African heterosexual HIV serodiscordant couples (Clinicaltrials.gov number NCT00557245).1 Adherence to PrEP was very high in the Partners PrEP study (tenofovir was detected in 82% of random sample of participants),14,15 making it an important source of evidence for changes in kidney function during and after stopping PrEP.
Study Design and Participants
The design, recruitment, procedures, and primary results for the Partners PrEP study are reported elsewhere.1 Briefly, between July 2008 and November 2010, 4747 heterosexual HIV serodiscordant couples were enrolled at 9 sites in Kenya and Uganda. Eligible HIV-uninfected participants were ≥18 years of age, did not have active hepatitis B infection, had normal renal function (defined by serum creatinine ≤1.3 mg/dL for men/≤1.1 mg/dL for women and 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 clinically significant cardiac disease. Participants were randomized in a 1:1:1 ratio to one of the 3 study groups: TDF, FTC-TDF, or placebo. In July 2011, the study's independent Data and Safety Monitoring Board recommended early discontinuation of the placebo arm because of definitive demonstration of PrEP efficacy against HIV acquisition. Thereafter, the 2 active arms continued blinded follow-up to garner additional data on safety and efficacy of FTC-TDF versus TDF.16 The present analysis presents data including the additional follow-up of the 2 active PrEP arms with the placebo group follow-up truncated at July 2011. The study protocol, including the post-study drug visits, was approved by the University of Washington Human Subjects Review Committee and ethics review committees at each of the study sites. All participants provided written informed consent.
Participant Follow-up and Procedures
TDF and FTC were dosed at 300 and 200 mg daily, respectively; these doses are also the standard for treatment of HIV.17 HIV-uninfected partners were followed monthly up to 36 months with HIV testing, study medication refill for 30 days, collection of the previous month's unused medication, and adverse event assessment. After completing follow-up on study drug, HIV-uninfected participants completed 2 additional post-study drug visits 4 and 8 weeks after study drug was discontinued at the final visit. Study medication was withheld in women who became pregnant for the duration of pregnancy and breastfeeding. Serum creatinine was measured at baseline, month 1, and quarterly thereafter up to 36 months, and at the 2 poststudy drug visits, 4 and 8 weeks after stopping study drug, by site laboratories which participated in regular proficiency testing for quality control and quality assurance.
Study medication was temporarily withheld if a participant had an increase in serum creatinine to 1.1 times the upper limit of normal or to >1.5-fold times the baseline creatinine value, even if still within the normal range; an abnormal result needed to be confirmed with repeat testing, scheduled within 7 days of the first abnormal result, for the temporary study medication hold to be initiated. For participants with a recorded graded creatinine-related drug adverse event, serum creatinine was monitored weekly until the abnormality resolved or stabilized. Once held, study drug could be restarted if serum creatinine returned to within normal limits or, in a >1.5-fold increase in creatinine from baseline, decreased to within 1.3-fold of the baseline value. 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 (defined as ≥1.4 times the upper limit of serum creatinine normal or a Cockcroft–Gault calculated creatinine clearance <50 mL/min), regardless of whether serum creatinine returned to baseline on withdrawal of the study medication.
Assessment of GFR
For the present analysis, eGFR was calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation,18 although the Cockcroft–Gault equation was used for safety monitoring during the study, as described above. The Chronic Kidney Disease Epidemiology Collaboration equation is validated in African populations and provides more accurate estimates for eGFR values in the normal range than both the Modification of Diet in Renal Disease Study and Cockcroft–Gault equations when compared with a direct measure of GFR by iohexol clearance.19,20 For the present analysis, the primary assessment measure of renal function recovery was predefined as mean eGFR after the last on-study drug date. The predefined secondary outcome of eGFR reversibility was a return to >75% of the baseline eGFR level, confirmed by repeat testing. The cutoff of reversibility to >75% of baseline was used because it is the reciprocal of a ≥25% decline in eGFR, which is an established criterion for the diagnosis of acute kidney injury21 and has been associated with increased morbidity and mortality.22–24
The primary outcome was mean eGFR after the last on-study drug date and the primary analysis included all participants who had any protocol-defined post-study drug serum creatinine obtained within 12 weeks of scheduled study drug discontinuation (ie, generally at 4 and 8 weeks visits after study drug discontinuation, and accounting for late visits that occurred at up to 12 weeks). To estimate the total effects of study drug discontinuation on mean eGFR, we used linear regression to compare mean eGFR, separately, at the last on-treatment visit and the first poststudy drug visit, Kaplan–Meier methods to estimate the cumulative probability, and cox proportional hazards regression to compare the time to post-study eGFR reversibility >75% of baseline between active PrEP versus placebo group. In multivariate analyses, we adjusted for duration of drug exposure, sex, baseline age, eGFR, and indicators for body mass index (BMI) and systolic blood pressure. We performed a sensitivity analysis considering all persons with any creatinine measurement taken after the last on-study drug date (ie, regardless of whether the post-study drug phase serum creatinine was obtained within 12 weeks of scheduled study discontinuation); this approach minimized potential exclusions of participants with early drug holds for creatinine-related abnormality or pregnancy and provided the opportunity for longer observation period after study drug discontinuation beyond the 8-week protocol-defined post-study phase (ie, participants with early study drug hold for safety or pregnancy continued follow-up in the study and could potentially be observed for up to 36 months after drug discontinuation). Analyses were conducted using SAS software (version 9.3; SAS Institute Inc., Cary, NC) and Stata version 12.
Of the 4747 HIV-uninfected persons enrolled and followed in the Partners PrEP Study, 3924 (83%) had serum creatinine measured within 12 weeks after study drug was discontinued: 1271 in the TDF group, 1308 in the FTC-TDF group, and 1345 in placebo group. Of these 3924, 65% were men, with median age of 35 years (range, 18–64), and baseline characteristics were comparable across the 3 exposure groups (Table 1). Median duration of study drug exposure was 33 months overall [interquartile range (IQR) 25–36]; 36 months (IQR 30–36) for TDF and FTC-TDF, and 25 months (IQR 18–30) for placebo. Participants were observed for a median of 8 weeks (range, 1–12) after study drug discontinuation; median duration to the first post-study drug creatinine measurement was 4 weeks (range, 1–12). An additional 436 participants (165 TDF, 137 FTC-TDF, and 134 placebo) had ≥1 creatinine measured after the last on-study drug date but not within 12 weeks (ie, due to study drug hold or early discontinuation); thus, a total of 4360 participants were included in the sensitivity analysis. The remaining 387 participants (148 TDF, 134 FTC-TDF, and 105 placebo) did not have a post-study drug creatinine measurement, mostly due to missed visits, post-HIV seroconversion, and refusal of study procedures; they tended to be males of younger age and higher baseline eGFR compared with those included in the analysis (excluded versus included persons; P < 0.05 for all comparison: age-years: 33 versus 35; men: 67% versus 62%; and baseline eGFR: 133 versus 129 mL·min−1·1.73 m−2) but were comparable on all other baseline characteristics.
Mean Last On-Treatment and Post-study Drug Discontinuation eGFR
Mean eGFR at entry into the randomized trial was 129.3 mL·min−1·1.73 m−2 for TDF, 128.8 mL·min−1·1.73 m−2 for FTC-TDF, and 128.6 mL·min−1·1.73 m−2 for placebo (P > 0.05 for both TDF and FTC-TDF versus placebo). As reported previously,10 TDF and FTC-TDF use was associated with a small, nonprogressive decline in eGFR, and in the current analysis, crude mean eGFR was 2–3 mL·min−1·1.73 m−2 lower in the active PrEP arms (representing annual eGFR loss of ≤1 mL·min−1·1.73 m−2·yr−1) compared with placebo at the last on-study drug visit: 129 mL·min−1·1.73 m−2 for TDF and 128 mL·min−1·1.73 m−2 for FTC-TDF versus 131 mL·min−1·1.73 m−2 for placebo (Table 2; P < 0.01 for both TDF and FTC-TDF versus placebo). By 4 weeks after study drug discontinuation, mean eGFR was similar across the 3 groups (Fig. 1): 130.1 mL·min−1·1.73 m−2 for TDF, 129.9 mL·min−1·1.73 m−2 for FTC-TDF, and 130.1 mL·min−1·1.73 m−2 for placebo (P > 0.05 for both TDF and FTC-TDF versus placebo). Multivariate analyses adjusting for duration of drug exposure, sex, baseline age, eGFR, BMI, and systolic blood pressure yielded similar patterns (Data not shown). Notably, the proportion of persons with <90 mL·min−1·1.73 m−2 at the last post-drug visit was similar to that observed at study entry (≤2%), and mean eGFR recovery after drug discontinuation was not modified by either having or not having a baseline eGFR <90 mL·min−1·1.73 m−2 (P > 0.05). Overall, younger age, normal BMI, female sex, baseline eGFR ≥90 mL·min−1·1.73 m−2, and shorter duration of drug exposure were independently associated with quicker mean eGFR recovery after drug discontinuation (P < 0.05 for all) with comparable rates across treatment groups (P > 0.05). Sensitivity analysis including all participants with ≥1 creatinine measurement after the last on-study drug date yielded qualitatively consistent patterns to the primary analysis (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A761).
Frequency of eGFR Reversibility to >75% of Baseline Levels After Study Drug Discontinuation
Overall, eGFR returned to >75% of baseline level in >70% of subjects by 4 weeks after discontinuation of study drug, >96% by 8 weeks, and 100% at 12 weeks in the primary analysis (ie, limited to participants with a post-study drug creatinine measurement within 12 weeks of the last on-study drug visit), and these proportions were similar across the 3 treatment groups (Table 2; P > 0.10 for both TDF and FTC-TDF versus placebo). Additional analysis with cut offs of 90% eGFR reversibility yielded similar patterns across treatment groups. Similarly, >98% of persons had eGFR ≥90 mL·min−1·1.73 m−2 at last visit after drug discontinuation. In the sensitivity analysis (ie, considering all persons with any creatinine measurement after the last on-study drug date, including participants with early creatinine abnormality-related drug discontinuation, n = 4360), the proportion of participants with a post-study drug eGFR >75% reversibility was >74% by 4 weeks, >91% by 8 weeks, and >95% by 12 weeks after discontinuation of study drug; median time to >75% eGFR reversibility was qualitatively similar in the 3 groups but statistically significantly quicker in those assigned placebo versus PrEP (PrEP versus placebo: 4 versus 3 weeks, P < 0.05; see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A761). In the sensitivity analysis, there were 161 participants whose eGFR had not reversed to >75% of baseline level by 12 weeks after study drug discontinuation (54 in TDF, 66 in FTC-TDF, and 41 in placebo); of these, the final poststudy drug eGFR rebounded to >75% of their baseline eGFR level in all but 4 (3 in placebo and 1 in TDF group). In the 4 participants, the final recorded eGFR was >60 mL·min−1·1.73 m−2 (specifically, >86 mL·min−1·1.73 m−2) in all but 1 participant, a 46-year-old male in the TDF group with acute HIV seroconversion and a creatinine clearance of 36 mL·min−1·1.73 m−2 at the last on-treatment visit. Detailed description of these 4 participants is provided in the Supplemental Digital Content (http://links.lww.com/QAI/A761).
Frequency of Creatinine-Related Study Drug Interruption and Drug Rechallenge
Study drug interruption triggered by any creatinine-related abnormality was recorded in 62 (1.2%) participants: 22 for TDF, 25 for FTC-TDF, and 15 for placebo; median time of drug exposure to the first recorded creatinine-related study drug interruption was 12 months (range 1–35) in the 2 active PrEP groups. For 57 (92%) participants (20 TDF, 23 FTC-TDF, and 14 placebo), the creatinine abnormality resolved after temporary drug withdrawal during study follow-up; these participants were rechallenged with study medication per the protocol. In 2 rechallenged participants (1 each for the TDF and placebo group), the creatinine abnormality recurred on more than 2 occasions and study drug was not re-established per protocol. First, a 30-year-old, 45 kg woman in the TDF group with baseline eGFR of 135 mL·min−1·1.73 m−2 (serum creatinine: 0.7 mg/dL), had eGFR of 98 mL·min−1·1.73 m−2 (serum creatinine: 0.9 mg/dL) and 111 mL·min−1·1.73 m−2 at the last on-treatment (month 18) and poststudy drug visit, respectively. Second, a 35-year-old, 71 kg man in the placebo group with baseline eGFR of 146 mL·min−1·1.73 m−2 (serum creatinine: 0.65 mg/dL), had a >1.5-fold increase in serum creatinine compared with baseline (serum creatinine of 1.05 mg/dL) at the last on-treatment visit (month 18) that did not resolve by the end of final study follow-up visit. Throughout the poststudy drug phase, the participant's eGFR was ≥90 mL·min−1·1.73 m−2 (108 mL/min at the final visit). As previously reported,10 permanent study drug discontinuation occurred in 5 persons with ≥grade 2 creatinine abnormalities during follow-up (Table 3): 2 each in the TDF and FTC-TDF groups and 1 in placebo. In a sixth participant, a 30-year-old, 45 kg woman in the TDF group, with baseline eGFR of 134 mL·min−1·1.73 m−2 (serum creatinine 0.7 mg/dL), experienced ≥25% eGFR decline from baseline (eGFR 98 mL·min−1·1.73 m−2, serum creatinine 0.9 mg/dL; Table 3). Overall, among participants with creatinine abnormality-related drug discontinuation, median time to eGFR recovery after drug discontinuation (ie, eGFR return to >75% of baseline level) was 4 weeks, similar across the 3 treatment groups (P > 0.1 for TDF and FTC-TDF versus placebo).
In this longitudinal analysis among HIV-uninfected African men and women receiving and then discontinuing daily oral TDF-based PrEP, the decline in eGFR associated with TDF exposure was small and rapidly resolved after discontinuation of study medication, including in individuals having treatment-emergent creatinine elevations resulting in temporary discontinuations of study medication. Our study has many strengths: a prospective design, high adherence to PrEP (with tenofovir detected in 82% of random sample of participants),14,15 a placebo comparison, a large sample size of men and women across a broad range of ages, and regular measurement of eGFR, and thus, this study provides robust evidence on the reversibility of eGFR decline in HIV-uninfected persons.
PrEP is a potentially powerful biomedical intervention with the potential to significantly impact the global HIV epidemic if rolled-out to scale and taken with high adherence among key at-risk populations. However, for any preventive intervention, tolerance of adverse effects in healthy persons is low compared with therapeutic interventions. We recently reported that TDF exposure was associated with a small but nonprogressive eGFR decline in men and women in the Partners PrEP Study, and that clinically relevant eGFR decline (≥25%) was rare and no more frequent in the active than the placebo group.10 These results were consistent with those from the iPrEx study among men who have sex with men.11 The current analysis builds on those data to report that recovery of eGFR decline after TDF discontinuation is robust in healthy persons, even in the minority of participants who developed a clinically relevant decline in eGFR on PrEP.
The intracellular mechanism by which TDF induces nephrotoxicity is not well understood, but is hypothesized to result from the direct tubulo-cytotoxicity effects mediated through mitochondrial DNA injury. In case series of HIV-infected persons with potential TDF-related nephrotoxicity,25 light microscopic and ultrastructural evaluations have documented acute tubular necrosis with varying degrees of chronic tubulointerstitial scarring, which may account for less than optimal reversibility reported in a minority of cases. However, extrapolating results from these studies among HIV-infected persons to the PrEP context may be limited by the lack of a truly nonactive comparator and the potential confounding effects by other risk factors for kidney injury, including HIV infection26,27 and use of other antiretroviral medications by persons taking TDF for HIV treatment, decreased body mass, pre-existing decrease in kidney function, other comorbidities, and concomitant use of other potentially nephrotoxic drugs, which are all common in HIV-infected persons.24 Nonetheless, comparatively more studies have given credence to robust resolution of TDF-associated nephrotoxicity in HIV-infected persons, including recovery from profound kidney injury requiring renal replacement therapy.25 The US CDC has issued guidelines for the delivery of PrEP in clinical settings, and guidelines for other settings have been developed or are in development. US CDC guidelines recommend renal monitoring at 3 months after starting PrEP and semi-annually thereafter.5 Our findings might suggest that renal monitoring for oral TDF-based PrEP could potentially be less frequent than in the CDC guidelines, unless there are comorbidities or longer term use than 36 months.
Although this is the largest prospective study of the reversibility of TDF-related eGFR decline in HIV-uninfected adults, this study has limitations. First, the trial only enrolled persons with baseline creatinine clearance ≥60 mL/min, and reversibility of eGFR decline among subpopulations with lower baseline eGFR, co-morbid risk factors for kidney disease, or concurrent nephrotoxic medications should be evaluated. Second, creatinine-based GFR estimates are less accurate in persons with low creatinine generation, including those with low muscle mass, muscle wasting, or reduced animal protein intake, which may be more common in African individuals. Third, we did not routinely evaluate proteinuria and changes in proximal tubular function, another potential consequence of TDF exposure.
In conclusion, in this large secondary analysis of a placebo-controlled trial of daily oral TDF-based PrEP among HIV-uninfected African men and women with a median TDF exposure of 36 months, declines in eGFR rapidly resolved within weeks after study drug discontinuation. These findings are encouraging for the delivery of PrEP in clinical settings.
The authors the HIV serodiscordant couples who participated in this study 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.
Partners PrEP Study Team:
University of Washington Coordinating Center and Central Laboratories, Seattle, WA: C. Celum (principal investigator, protocol co-chair), J. M. Baeten (medical director, protocol co-chair), D. Donnell (protocol statistician), Robert W. Coombs, Lisa Frenkel, Craig W. Hendrix, Jairam R. Lingappa, M. Juliana McElrath.
Study Sites and Site Principal Investigators: Eldoret, Kenya (Moi University, Indiana University): Kenneth H. Fife, Edwin Were; Kabwohe, Uganda (Kabwohe Clinical Research Center): Elioda Tumwesigye; Jinja, Uganda (Makerere University, University of Washington): Patrick Ndase, Elly Katabira; Kampala, Uganda (Makerere University): Elly Katabira, A. Ronald; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): Elizabeth Bukusi, Craig R. Cohen; Mbale, Uganda (The AIDS Support Organization, CDC-Uganda): Jonathan Wangisi, James D. Campbell, Jordan W. Tappero; Nairobi, Kenya (University of Nairobi, University of Washington): J. Kiarie, Carey Farquhar, 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, Jonathan Wangisi. Data management was provided by DF/Net Research, Inc. (Seattle, WA) and site laboratory oversight was provided by Contract Laboratory Services (CLS) of the Wits Health Consortium (University of the Witwatersrand, Johannesburg, South Africa).
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eGFR decline reversibility; tenofovir disoprfoxil fumarate; pre-exposure prophylaxis; eGFR recovery after TDF discontinuation
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