Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study

• Published in: PloS one Vol. 11; no. 9; p. e0161821
• Main Authors: Berden, Floor A C, de Knegt, Robert J, Blokzijl, Hans, Kuiken, Sjoerd D, van Erpecum, Karel J L, Willemse, Sophie B, den Hollander, Jan, van Vonderen, Marit G A, Friederich, Pieter, van Hoek, Bart, van Nieuwkerk, Carin M J, Drenth, Joost P H, Kievit, Wietske
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-09-2016; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Anemia; Anemia - complications; Anemia - drug therapy; Anemia - virology; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Biology and Life Sciences; Cardiovascular Diseases - complications; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - virology; Clinical medicine; Clinical trials; Cohort analysis; Coronary artery disease; Criteria; Drug therapy; Drugs; Eligibility Determination - methods; Female; Gastroenterology; Genotype & phenotype; Heart diseases; Hepacivirus - drug effects; Hepacivirus - growth & development; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Hepatology; Humans; Infections; Interferon-alpha - administration & dosage; Interferon-alpha - adverse effects; Internal medicine; Liver cancer; Liver diseases; Male; Malignancy; Medical research; Medicine; Medicine and Health Sciences; Middle Aged; Morbidity; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - virology; Netherlands; Neutropenia; Neutropenia - complications; Neutropenia - drug therapy; Neutropenia - virology; Patient Selection; Patients; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - adverse effects; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Registration; Regression Analysis; Research and Analysis Methods; Retrospective Studies; Ribavirin - administration & dosage; Ribavirin - adverse effects; Risk assessment; Risk Factors; Safety; Safety and security measures; Sensitivity analysis; Testing; Toxicity; World population; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0161821

Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials.
We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes.
In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used.
Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.