title: Does Hepatitis C Treatment Adherence Affect Risk of Liver Transplantation? A Historical Cohort Study.
abstract: BACKGROUND
  Chronic hepatitis C virus (HCV) is the primary cause of liver failure leading to transplantation, and medication adherence is essential to the therapeutic efficacy of HCV treatments. While there is evidence linking poor adherence with increased utilization and cost, published literature lacks examination of the association between medication adherence and risk of liver transplant. In addition, the impact of HCV treatment on total costs of liver transplantation is not well documented.
  
  
  OBJECTIVE
  To compare (a) the relative risk of liver transplant by adherence in patients treated for HCV and (b) the total health care costs in treated and untreated patients who require liver transplant.
  
  
  METHODS
  This observational, historical cohort study was conducted using administrative data from the Humana Research Database. To be included, patients were required to have a documented HCV diagnosis or treatment between January 1, 2008, and June 30, 2013. Patients were excluded if they had a hepatitis B diagnosis, were not fully insured by a commercial or Medicare Advantage Prescription Drug plan, or were outside the age range of 19-89 years. No minimum pre- or post-index enrollment period was required, and patients were followed for their entire post-index enrollment through December 31, 2013. The study population was divided into treated and untreated groups and then subdivided by presence or absence of a liver transplant. Date of liver transplant was defined as the index date for untreated liver transplant patients; otherwise, the index date was defined as either the date of first observed HCV treatment or diagnosis date (if no treatment or liver transplant). Cox proportional hazards models were used to estimate the relative risk of liver transplant by level of treatment adherence (> 80%, 50%-79%, and < 50%) based on proportion of days covered. General linearized models with log link and gamma distribution were used to compare median total health care costs from index date until end of study period (or death/disenrollment, whichever came first) between treated and untreated liver transplant patients. All costs were converted to 2013 U.S. dollars and reported as total costs per patient and per patient per month (PPPM) to account for varying follow-up periods.
  
  
  RESULTS
  Of the 53,423 patients identified with HCV, 10,377 met exclusion criteria, leaving 43,046 patients (primarily Caucasian, males, mean age of 58 years) in the initial cohort. Only 6.29% (n = 2,708) of the total HCV cohort received HCV treatment, and less than 1% (n = 366, 0.8%) received a liver transplant. Although there were no significant differences in the risk of liver transplant by adherence level, there was an upwards trend in the rate of liver transplant as adherence worsened (> 80%: 1.25%; 50%-79%: 1.30%; and < 50%: 1.99%), and the average days to liver transplant was longer with higher adherence (> 80%: 683; 50%-79%: 623; < 50%: 454). Only 48 (13.11%) patients who received a liver transplant were treated for HCV. Adjusted median total and PPPM health care costs measured from index date until end of the study period were significantly higher for patients who received HCV treatment compared with those who did not (total=$231,139 vs. $86,167, adjusted P < 0.001; PPPM=$20,583 vs. $5,778, adjusted P = 0.008), driven by HCV-related medical costs and total pharmacy costs.
  
  
  CONCLUSIONS
  Adherence with HCV regimens did not affect risk of liver transplant, underscoring the need for further evidence linking treatment adherence to future liver transplant risk. HCV-treated patients who required liver transplant incurred significantly higher health care costs than those without HCV treatment before liver transplant. Introduction of newer all-oral direct-acting antiviral regimens, with higher acquisition costs, will require further research to more accurately assess medication adherence and its relationship with transplantation, as well as with total health care costs.
  
  
  BACKGROUND
  No outside funding supported this research. Ems, Worley, Racsa, Gregory, Anderson, and Holt are employees of Humana. Brill has participated in a physician advisory board at Humana. The authors have no other financial disclosures to report. Study concept and design were contributed by Ems, Racsa, Worley, and Anderson, along with Gregory, Brill, and Holt. Racsa took the lead in data collection, along with Ems and Worley. All authors participated in data interpretation. Anderson, along with the other authors, wrote the manuscript, which was revised by Brill and Holt, with assistance from the other authors.
authors.affiliation: 1 Comprehensive Health Insights, Humana, Louisville, Kentucky.
authors.forename: Derek
authors.initials: D
authors.lastname: Ems
authors.affiliation: 1 Comprehensive Health Insights, Humana, Louisville, Kentucky.
authors.forename: Patrick
authors.initials: P
authors.lastname: Racsa
authors.affiliation: 2 Humana, Louisville, Kentucky.
authors.forename: Chris
authors.initials: C
authors.lastname: Anderson
authors.affiliation: 2 Humana, Louisville, Kentucky.
authors.forename: Fran
authors.initials: F
authors.lastname: Gregory
authors.affiliation: 1 Comprehensive Health Insights, Humana, Louisville, Kentucky.
authors.forename: Karen
authors.initials: K
authors.lastname: Worley
authors.affiliation: 3 Predictive Health, Paradise Valley, Arizona.
authors.forename: Joel V
authors.initials: JV
authors.lastname: Brill
authors.affiliation: 1 Comprehensive Health Insights, Humana, Louisville, Kentucky.
authors.forename: Worthe
authors.initials: W
authors.lastname: Holt
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000191:economics / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000191:economics / Q000601:surgery*; D006801:Humans; D007345:Insurance Claim Review / Q000191:economics / Q000639:trends; D016031:Liver Transplantation / Q000191:economics / Q000639:trends*; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D000998:Antiviral Agents