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

  • Jessie Torgersen
    Correspondence
    Corresponding author. Address: Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, 51 N. 39th Street, Medical Arts Building, Suite 103B, Philadelphia, PA 19104, USA. Tel.: +267 588 2164; fax: 215 243 3272.
    Affiliations
    Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Tamar H. Taddei
    Affiliations
    VA Connecticut Healthcare System, West Haven, CT, USA

    Department of Medicine, Yale School of Medicine, New Haven, CT, USA
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  • Vincent Lo Re III
    Affiliations
    Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Published:March 10, 2022DOI:https://doi.org/10.1016/j.jhep.2022.02.025

      Linked Article

      To the Editor:
      We thank Drs. Wong and Nguyen for their interest in our study.
      • Wong Y.J.
      • Nguyen M.H.
      Is it safe to treat chronic hepatitis C patients with decompensated cirrhosis with PI-based DAA?.
      They raise several considerations and provide an opportunity to clarify some of the aspects of our article.
      We agree with Drs. Wong and Nguyen that our study’s findings should not be generalized beyond the FDA-approved treatment indications for direct-acting antivirals (DAAs). Indeed, our study was never designed to address the question of whether it is safe to treat chronic HCV-infected patients who have decompensated cirrhosis with protease inhibitor (PI)-based DAA regimens. Since PI-based DAAs are currently contraindicated for use among patients with decompensated cirrhosis, these patients were excluded from our analyses.
      • Mak L.Y.
      • Seto W.K.
      • Lai C.L.
      • Yuen M.F.
      An update on the toxicological considerations for protease inhibitors used for hepatitis C infection.
      ,

      America Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Accessed at: https://www.hcvguidelines.org. [Accessed on February 3, 2022].

      Patients with prevalent acute liver injury (ALI) outcomes, including hepatic decompensation, within 2 years prior to DAA initiation were excluded from the analysis (n = 6,794 in Fig. 1)
      • 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.
      to ensure that incident ALI events following DAA initiation could be ascertained and attributed to the PI or non-PI cohorts. This included 837 patients who were excluded due to a recent history of hepatic decompensation.
      Although some of the exclusions we implemented may affect the generalizability of our study, these exclusions increased our study’s internal validity. We required at least 2 years in the VA system prior to DAA initiation to ensure we could adequately ascertain the variables that influence clinicians’ decisions to prescribe PI vs. non-PI-based DAA therapy and which might affect risk of ALI. We excluded patients with prevalent ALI to enable determination of the risk of incident ALI events, decreasing the potential for erroneous attribution of prevalent ALI events to the exposure under evaluation in this real-world cohort.
      The FIB-4 index was employed in our study to identify patients with advanced hepatic fibrosis/cirrhosis, a stratification approach now recommended in the simplified pretreatment evaluation by the American Association for the Study of Liver Diseases and the Infectious Disease Society of America.

      America Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Accessed at: https://www.hcvguidelines.org. [Accessed on February 3, 2022].

      Since cirrhosis is a clinically silent disease process, requiring radiologic or histologic evidence to ascertain its presence may not be practical since: i) not all patients undergo liver biopsy or radiographic imaging prior to DAA initiation, and ii) ultrasound, the most commonly utilized radiographic modality, is insensitive for the diagnosis of cirrhosis.
      • Yen Y.H.
      • Kuo F.Y.
      • Chen C.H.
      • Hu T.H.
      • Lu S.N.
      • Wang J.H.
      • et al.
      Ultrasound is highly specific in diagnosing compensated cirrhosis in chronic hepatitis C patients in real world clinical practice.
      Transient elastography, while ideal for point-of-care assessment of fibrosis, was not widely available in the VA during the course of the study period.
      Drs. Wong and Nguyen noted that patients with cirrhosis in our study were not stratified by Child-Pugh class. We elected not to classify patients according to Child-Pugh class because PI-based DAAs are contraindicated in patients with Child-Pugh class B and C cirrhosis, who were excluded from our study by design.
      • Mak L.Y.
      • Seto W.K.
      • Lai C.L.
      • Yuen M.F.
      An update on the toxicological considerations for protease inhibitors used for hepatitis C infection.
      In contrast, our use of the model for end-stage liver disease score aimed to provide further information on compensated cirrhosis severity.
      Finally, our presentation of sustained virologic response (SVR) at 12 weeks following completion of DAA therapy served as a descriptive display only as our study design evaluated risk of ALI events and not effectiveness of treatment. In our observational cohort where patients may be lost to care or have SVR assessment obtained beyond our defined study period, standardized SVR assessment was not performed. Of the 126 patients who had alanine aminotransferase >200 U/L (Table 4), 69 (54.8%) developed the event when a DAA refill was expected. However, only 16 of these 69 patients (23.2%) did not have a subsequent DAA dispensed, suggesting that the majority of these events did not result in treatment discontinuation.
      We appreciate the opportunity to clarify these important points. Our study demonstrated comparable hepatic safety of PI-based and non-PI-based DAA therapies among chronic HCV-infected persons without decompensated cirrhosis. Further studies are needed to understand the real-world safety of PI-based DAA regimens among people with decompensated cirrhosis.

      Abbreviations

      ALI, acute liver injury; DAA, direct-acting antiviral; PI, protease inhibitor; SVR, sustained virologic response.

      Financial support

      No funding was required for this work.

      Authors’ contributions

      All authors contributed equally to development of this manuscript.

      Conflict of interest

      All authors declare no conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

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        Is it safe to treat chronic hepatitis C patients with decompensated cirrhosis with PI-based DAA?.
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        An update on the toxicological considerations for protease inhibitors used for hepatitis C infection.
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      1. America Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Accessed at: https://www.hcvguidelines.org. [Accessed on February 3, 2022].

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        Ultrasound is highly specific in diagnosing compensated cirrhosis in chronic hepatitis C patients in real world clinical practice.
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