title: Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175).
abstract: BACKGROUND
  Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings.
  
  
  METHODS
  This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups.
  
  
  RESULTS
  Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001).
  
  
  CONCLUSIONS
  TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.
authors.affiliation: The Miriam Hospital, Providence, Rhode Island, USA Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: F
authors.initials: F
authors.lastname: Touzard Romo
authors.affiliation: Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Smeaton
authors.affiliation: University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Campbell
authors.affiliation: Institut Nacional de Laboratoire et Recherches, Port-au-Prince, Haiti.
authors.forename: C
authors.initials: C
authors.lastname: Riviere
authors.affiliation: University of KwaZulu-Natal, Durban, South Africa.
authors.forename: R
authors.initials: R
authors.lastname: Mngqibisa
authors.affiliation: College of Medicine - Johns Hopkins Research Project, Blantyre, Malawi.
authors.forename: M
authors.initials: M
authors.lastname: Nyirenda
authors.affiliation: Chiang Mai University, Chiang Mai, Thailand.
authors.forename: K
authors.initials: K
authors.lastname: Supparatpinyo
authors.affiliation: YRG Centre for AIDS Research and Education, Chennai, India.
authors.forename: N
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
authors.forename: J G
authors.initials: JG
authors.lastname: Hakim
authors.affiliation: The Miriam Hospital, Providence, Rhode Island, USA Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Flanigan
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced*; D016015:Logistic Models; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced*; D008875:Middle Aged
chemical_list: D019380:Anti-HIV Agents
keywords: antiretrovirals; metabolic toxicity; renal toxicity; tenofovir; zidovudine