Kidney Function in Oral Pre-Exposure Prophylaxis Users: A Systematic Literature Review and Individual Patient Data Meta-Analysis

Background: Previous World Health Organization (WHO) guidance on tenofovir disoproxil fumarate (TDF)-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards. Creatinine screening may represent barriers to PrEP implementation and uptake. We systematically reviewed published literature on renal toxicity among PrEP users and conducted an individual patient data meta-analysis (IPDMA) on kidney function among PrEP users in a global data set.  Methods: Meta-analyses were conducted on published data to estimate pooled relative risks of grade 1+ and 2+ kidney-related adverse events among PrEP users. The IPDMA included data on PrEP users from 19 PrEP programmes. Estimated creatinine clearance at baseline and change in creatinine clearance after PrEP initiation were described by age, gender, and comorbidities. Random-effects regressions estimated risk in decline in creatinine clearance to <60ml/min.  Findings: Eleven randomised controlled trials on oral PrEP were identified in the literature review. Pooled odds ratio (OR) for grade 1+ and grade 2+ renal adverse events was 1.51 (95% confidence interval [CI]=1.17-1.94) and 2.57 [0.97-6.77], respectively. The IPDMA included 18,676 individuals from 15 countries and 0.42% had abnormal baseline estimated creatinine clearance (<60ml/min) (increasing proportions with increasing age). Longitudinal analyses included 14,368 PrEP users and 2.43% experienced a decline to <60ml/min creatine clearance, with higher risk associated with increasing age and a baseline creatinine clearance of 60-89.99ml/min (adjusted hazard ratio [HR]=8.06 [6.44-11.2]) and <60ml/min (aHR=20.8 [12.8-33.8]).  Interpretation: Few people screened for TDF-based oral PrEP had a <60ml/min creatinine clearance and renal adverse evets were rare. Older age and baseline creatinine clearance of <90ml/min were associated with clinically significant declines in creatinine clearance. Less frequent or optional screening among younger individuals without kidney-related comorbidities may be appropriate and may reduce barriers to PrEP implementation and use.  Funding Information: Unitaid, Bill & Melinda Gates Foundation, WHO Declaration of Interests: The authors declare no conflict of interests.