title: Long-term safety of oral nucleos(t)ide analogs for patients with chronic hepatitis B: A cohort study of 53,500 subjects.
abstract: Widespread and long-term use of oral nucleos(t)ide analogs (NAs) to treat chronic hepatitis B (CHB) brings about safety data in a real-life setting. We aimed to determine the risks of renal and bone side effects in patients receiving or who have received NAs as CHB treatment. A territory-wide cohort study using the database from Hospital Authority, the major provider of medical services in Hong Kong, was conducted. We identified CHB patients by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes, diagnosed between 2000 and 2012. The primary events were renal (incident renal failure and renal replacement therapy [RRT]) and bone events (incident hip, vertebral, and all fractures). A 3-year landmark analysis was used to evaluate the relative risk of primary outcome in patients with or without NA treatment. A total of 53,500 CHB patients (46,454 untreated and 7,046 treated), who were event free for 3 years, were included in the analysis. At a median follow-up of 4.9 years, chronic renal failure, RRT, all fractures, hip fractures, and vertebral fractures occurred in 0.6%, 0.2%, 0.7%, 0.1%, and 0.1% of untreated subjects and 1.4%, 0.7%, 1.3%, 0.2%, and 0.2% of treated subjects. After propensity score weighting, NA therapy did not increase the risk of any of the events (hazard ratios [HRs] ranged from 0.79 to 1.31; P = 0.225-0.887). Exposure to nucleotide analogues, compared with nucleoside analogs, increased the risk of hip fracture (HR = 5.69; 95% confidence interval: 1.98-16.39; P = 0.001), but not other events (HR = 0.58-1.44; P = 0.202-0.823).
  
  
  CONCLUSIONS
  NA treatment does not increase the risk of renal and bone events in general. Nucleotide analogs may increase the risk of hip fracture, but the overall event rate is low.
authors.affiliation: Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.|State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Grace Lai-Hung
authors.initials: GL
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Yee-Kit
authors.initials: YK
authors.lastname: Tse
authors.affiliation: Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.|State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Vincent Wai-Sun
authors.initials: VW
authors.lastname: Wong
authors.affiliation: Department of Statistics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Terry Cheuk-Fung
authors.initials: TC
authors.lastname: Yip
authors.affiliation: Big Data Decision Analytics Research Center, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Kelvin Kam-Fai
authors.initials: KK
authors.lastname: Tsoi
authors.affiliation: Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.|State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Henry Lik-Yuen
authors.initials: HL
authors.lastname: Chan
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000453:epidemiology; D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000139:chemically induced / Q000453:epidemiology; D019694:Hepatitis B, Chronic / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D006723:Hong Kong; D006801:Humans; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D009711:Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D009711:Nucleotides