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Is it safe to treat chronic hepatitis C patients with decompensated cirrhosis with PI-based DAAs?

  • Yu Jun Wong
    Affiliations
    Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore

    Duke-NUS Medical School, Singapore
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  • Mindie H. Nguyen
    Correspondence
    Corresponding author. Address: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 780 Welch Road, Rm CJ250K, Palo Alto, CA 94304-1509, USA.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA

    Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, USA
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Published:January 21, 2022DOI:https://doi.org/10.1016/j.jhep.2021.12.037

      Linked Article

      To the Editor:
      We read the recent study published by Torgerson and colleagues with great interest.
      • Torgersen J.
      • Newcomb C.W.
      • Carbonari D.M.
      • Rentsch C.T.
      • Park L.S.
      • Mezochow A.
      • et al.
      Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.
      In this large Veteran Affairs cohort study, the authors conclude that protease inhibitor (PI) direct-acting antivirals (DAAs) are safe and do not increase the risk of hepatic decompensation compared to non-PI DAAs. We would like to highlight several considerations before these findings can be applied to clinical practice.
      First, we noted in the methods section that patients with decompensated cirrhosis were not included in this study, but in the patient flow diagram, there was no mention as to how many patients were excluded from the original cohort due to having decompensated cirrhosis or having a history of decompensated cirrhosis.
      Second, we noted that about 22% of the included cohort (15,568/71,391) were excluded owing to unknown baseline status or because they may have been at a higher risk of aminotransferase elevations or hepatic decompensation with PI-based DAAs (namely those with acute liver injury within 2 years of study index, those with hepatocellular carcinoma, and those with missing lab data). However, since many of these patients are no longer considered as being at high risk of decompensation following PI-based DAA treatment, as shown in prior studies,
      • Gane E.
      • Poordad F.
      • Zadeikis N.
      • Valdes J.
      • Lin C.W.
      • Liu W.
      • et al.
      Safety and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1-6 hepatitis C virus infections and compensated liver disease.
      this exclusion limits the generalizability of the findings beyond currently approved treatment indications.
      • Saleem N.
      • Miller L.S.
      • Dadabhai A.S.
      • Cartwright E.J.
      Using vibration controlled transient elastography and FIB-4 to assess liver cirrhosis in a hepatitis C virus infected population.
      Additionally, some patients in the “high-risk” group in this study may not even have cirrhosis because FIB-4 >3.25 indicates stage 3-4 fibrosis. Given the recent study which questioned the performance of FIB-4 to rule-in the presence of cirrhosis among patients with HCV,
      EASL recommendations on treatment of hepatitis C: final update of the series.
      we suggest that the diagnosis of cirrhosis should be refined using radiological or histological evidence of cirrhosis, or liver stiffness measurement.
      Furthermore, patients with cirrhosis were not stratified based on Child-Pugh class. The risk of hepatic decompensation is higher in those with clinically significant portal hypertension as measured by liver stiffness measurement
      • Pons M.
      • Augustin S.
      • Scheiner B.
      • Guillaume M.
      • Rosselli M.
      • Rodrigues S.G.
      • et al.
      Non-invasive diagnosis of portal hypertension in patients with compensated advanced chronic liver disease.
      or other measures. While matching was done for model for end-stage liver disease (MELD) score, the results were largely driven by patients with a low MELD score (70% had MELD <10, and only <2% of the total cohort had an MELD ≥15), in whom the risk of hepatic decompensation was likely to be low. Together, these characteristics suggest that the overall study population had a low baseline risk of developing the adverse outcomes of interest. This is an important consideration before concluding the safety of PI-based DAAs among high-risk patients with cirrhosis.
      Lastly, we found the reported sustained virologic response (SVR) rates potentially misleading. Although the authors noted in Table 4’s footnote that the SVR rates were calculated only for those tested for SVR, we would like to clarify the patient selection for SVR testing, specifically, whether all patients with HCV treatment interrupted due to acute liver injury were offered an SVR test, despite incomplete treatment. This is important clinical information as about 30% of patients did not undergo SVR testing.
      Nonetheless, we would like to congratulate the authors as the current study validates the real-world tolerability of PI-based DAAs and the current EASL guidelines.
      EASL recommendations on treatment of hepatitis C: final update of the series.
      However, as highlighted by the author, more studies are needed to better examine the impact of PI-based DAAs on the risk of hepatic decompensation among patients with prior or current decompensated cirrhosis.

      Financial support

      No external funding to disclose.

      Authors’ contributions

      Guarantor of article: Mindie H. Nguyen. Specific author contributions: Study design, data collection, data analysis, data interpretation, and drafting of the article: All authors. Study concept and study supervision: Mindie H. Nguyen.

      Conflict of interest

      WYJ: Invited speaker: Gilead. MHN: Research support: Pfizer, Enanta, Gilead, Exact Sciences, Vir Biotech, Helio Health, National Cancer Institute, Glycotest, B.K. Kee Foundation; Consulting and/or Advisory Board: Intercept, Exact Science, Gilead, GSK, Eli Lilly, Laboratory of Advanced Medicine, Janssen.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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