title: Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study.
abstract: As pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine for the prevention of HIV infection is rolled out internationally, strategies to maintain effectiveness and to minimise adverse effects merit consideration. In this study, we aimed to assess reductions in renal function and predictors of renal toxicity in a large open-label study of PrEP.
  
  
  
  As part of the iPrEx open-label extension (OLE) study, men who have sex with men or transgender women aged 18-70 years who were HIV negative and had participated in three previous PrEP trials from Brazil, Ecuador, Peru, South Africa, Thailand, and the USA were enrolled into an open-label PrEP study. There were no restrictions on current renal function for enrolment into iPrEx OLE, in which participants were given combination tablets of tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) and advised to take one tablet per day. At follow-up sessions every 12 weeks, participants' creatinine clearance on PrEP was estimated and in a subset of participants, hair samples were collected to measure tenofovir and emtricitabine concentrations (a measure of adherence and exposure) via liquid-chromatography-tandem-mass-spectrometry. Reductions in creatinine clearance from baseline were calculated and predictors of decline were identified by use of multivariate models. iPrEx is registered with ClinicalTrials.com, number NCT00458393.
  
  
  
  Baseline characteristics were similar between all participants in iPrEx-OLE (1224 participants with 7475 person-visits) and those participating in the hair substudy (220 participants with 1114 person-visits). During a median of 72 weeks, the mean decline in creatinine clearance was -2·9% (95% CI -2·4 to -3·4; ptrend<0·0001), but declines were greater for those who started PrEP at older ages: participants aged 40-50 years at baseline had declines of -4·2% (95% CI -2·8 to -5·5) and participants older than 50 years at baseline had declines of -4·9% (-3·1 to -6·8). In multivariate models, age and baseline creatinine clearance less than 90 mL/min predicted declines in renal function. We identified a monotonic association between percentage decrease in creatinine clearance and the number of doses of tenofovir disoproxil fumarate and emtricitabine taken per week, as estimated by hair concentrations of tenofovir and emtricitabine (ptrend=0·008).
  
  
  
  Our data suggest that the frequency of safety monitoring for PrEP might need to be different between age groups and that pharmacological measures can monitor for toxic effects as well as adherence.
  
  
  
  National Institutes of Health.
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, USA. Electronic address: monica.gandhi@ucsf.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Gandhi
authors.affiliation: Department of Biostatistics and Epidemiology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.affiliation: Fenway Health, Boston, MA, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Projeto Praça Onze, Hospital Escola Sâo Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mauro
authors.initials: M
authors.lastname: Schechter
authors.affiliation: San Francisco Department of Public Health, San Francisco, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.affiliation: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS, Rio De Janeiro, Brazil.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Grinsztejn
authors.affiliation: Department of Psychiatry, Stroger Hospital of Cook County, Chicago, IL, USA.
authors.forename: Sybil
authors.initials: S
authors.lastname: Hosek
authors.affiliation: Asociacion Civil Selva Amazonica (ACSA) CRS, Iquitos, Peru.
authors.forename: Martin
authors.initials: M
authors.lastname: Casapia
authors.affiliation: Investigaciones Médicas en Salud, Lima, Peru.
authors.forename: Juan
authors.initials: J
authors.lastname: Guanira
authors.affiliation: Desmond Tutu Health Foundation, Faculty of Health Sciences, Cape Town, South Africa.
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Louie
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Horng
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.affiliation: HIV Prevention Intervention Studies Bridge HIV, San Francisco, CA, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grant
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000367:Age Factors; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use; D001938:Brazil / Q000453:epidemiology; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D004484:Ecuador / Q000453:epidemiology; D000068679:Emtricitabine / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use; D006197:Hair / Q000737:chemistry; D015658:HIV Infections / Q000517:prevention & control / Q000821:virology; D007677:Kidney Function Tests; D055118:Medication Adherence; D010568:Peru / Q000453:epidemiology; D065129:Pre-Exposure Prophylaxis; D013019:South Africa; D000068698:Tenofovir / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use; D013785:Thailand / Q000453:epidemiology
chemical_list: D019380:Anti-HIV Agents; D003404:Creatinine; D000068679:Emtricitabine; D000068698:Tenofovir