Proton Pump Inhibitors Are Associated With Accelerated Development of Cirrhosis, Hepatic Decompensation and Hepatocellular Carcinoma in Noncirrhotic Patients With Chronic Hepatitis C Infection

Results From ERCHIVES

D. K. Li; P. Yan; A-B. Abou-Samra; R. T. Chung; A. A. Butt


Aliment Pharmacol Ther. 2018;47(2):246-258. 

In This Article



Baseline was defined as the date of HCV treatment initiation. Treatment completion was defined according to the US Food and drug administration approved labels for each drug regimen. Cirrhosis was defined as a FIB-4 score of > 3.5 based on previously published work[18] and was calculated as follows:

Laboratory data were obtained at yearly intervals and the FIB-4 score was recalculated at each interval. An average of two values closest to the selected time point of interest was used for the calculation of FIB-4 scores. Sustained virologic response was defined as undetectable HCV RNA in all follow-up HCV RNA tests after the end of treatment, with at least 1 test more than 12 weeks after the end of initial treatment. Hepatic decompensation was defined as the development of ascites, spontaneous bacterial peritonitis or variceal haemorrhage as evidenced by 1 in-patient or ≥ 2 out-patient ICD-9-CM codes based on a validated algorithm developed in VA populations.[19] The incidence of hepatic encephalopathy and hepatorenal syndrome was not able to be assessed by this algorithm due to relatively poor test characteristics in a validation cohort.[19] Hepatocellular carcinoma was defined as the presence of at least 2 ICD-9-CM for a chronic liver disease plus 2 ICD-9-CM codes for hepatocellular carcinoma based on another validated algorithm developed in VA populations.[20] Patients were defined as having diabetes as previously described using a combination of blood glucose measurement, use of anti-diabetic agents and ICD-9 codes.[21] A history of alcohol or drug abuse/dependence was identified based on the presence of at least 1 in-patient or 2 out-patient ICD-9 diagnoses. The diagnosis of gastro-oesophageal varices was also based on the presence of at least 1 in-patient or 2 out-patient ICD-9 diagnoses. A history of peptic ulcer disease, gastro-oesophageal reflux disease and Helicobacter pylori infection was based on at least one ICD-9 code for each of these diagnoses.

Study Population

Study participants included patients with HCV infection within the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database. ERCHIVES is a large, well-established national cohort of HCV-infected and uninfected veterans and has been described previously.[18,21,22] All HCV-infected veterans observed at any of the nationwide Department of Veterans Affairs (VA) medical facilities, who had a positive HCV antibody test between 2001 and 2015, were identified. Demographic, clinical and laboratory data were obtained from the national patient care database and the corporate data warehouse, and pharmacy information, including all prescriptions written, doses, duration, number of pills, number of refills and date of refills, was retrieved from the pharmacy benefits management database. Data were then merged based on established algorithms.

Patients were included in the study cohort if they received at least 14 days of treatment for HCV. Patients were excluded if they had coinfection with human immunodeficiency virus (HIV), a positive test for hepatitis B surface antigen (HBsAg) or a diagnosis of cirrhosis. Patients were also excluded if they had a hepatic decompensation event prior to baseline or known gastro-oesophageal varices or hepatocellular carcinoma any time before or up to within 6 months of baseline. Patients were also excluded if they were missing a baseline HCV RNA or FIB-4 score and if at least one FIB-4 score was not available at least 24 months after completion of HCV therapy or were exposed to both proton pump inhibitors and histamine-2 receptor antagonists. In addition, patients were excluded if they received their first prescription of proton pump inhibitors after their first diagnosis of cirrhosis.

Exposure to Acid-suppressive Therapy

All patients who were prescribed proton pump inhibitors or histamine-2 receptor antagonists in any VA pharmacy during the study observation period were identified. Analysis was performed on patients who were exposed to either proton pump inhibitors or histamine-2 receptor antagonists, but not both, as described above. Proton pump inhibitor prescriptions included omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole. Histamine-2 receptor antagonist prescriptions included famotidine, ranitidine and cimetidine. Information regarding the dates of prescriptions ordered, number of days prescribed, number of pills per prescription and number of refills ordered were collected. Using this information, the cumulative defined daily dose (cDDD) of proton pump inhibitors or histamine-2 receptor antagonists was calculated for each subject as described previously.[21] Briefly, we collected the dates of prescriptions ordered, the number of days prescribed, number of pills per prescription and number of refills ordered. Using this, the defined daily dose (DDD) of acid-suppressive therapy was calculated. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults and is defined by the World Health Organization for each drug.[23] cDDD was calculated as the total sum of dispensed DDDs of a given medication and was calculated annually for each year of the study observation period. The use of cDDD is recommended by the WHO and is used widely for comparison of drug exposure. Given that previous studies have shown that significant differences in gut microbiota are seen even with daily omeprazole treatment (40 mg) for only 2 weeks,[24] significant exposure to acid-suppressive therapy was defined as > 30 cDDDs prescribed during the study period. Similar information was also collected for statin medications. Statin prescriptions included simvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin.


Primary outcome measures were (1) development of cirrhosis as defined by FIB-4 score ≥ 3.5, (2) development of hepatic decompensation and (3) incident hepatocellular carcinoma.

Statistical Analysis

The study cohort was divided into those who had been exposed to acid-suppressive therapy and those who had not. Baseline demographic and clinical factors were compared between the two groups using Chi-squared test or t test, as appropriate. Predictors of incident cirrhosis, hepatic decompensation and hepatocellular carcinoma were determined using Cox's proportional hazards analysis and generating hazard ratios for each of the predictor variables. In all the Cox models, the assumption of proportionality was met. Mean fibrosis scores were plotted over time by the cDDD of acid-suppressive therapy used. Kaplan-Meier curves were generated to demonstrate time to development of cirrhosis, hepatic decompensation and hepatocellular carcinoma by proton pump inhibitor and histamine-2 receptor antagonist cDDDs. sas (version 9.4, sas Institute Inc., Cary, NC) was used for statistical analyses.