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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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Direct-Acting Antiviral Therapy and Risk of Hepatocellular Carcinoma Recurrence in Patients with Chronic Hepatitis C

Chang Hun Lee and In Hee Kim

Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea

Correspondence to:In Hee Kim
ORCID https://orcid.org/0000-0003-3863-7907
E-mail ihkimmd@jbnu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2021; 15(3): 327-328

Published online May 15, 2021 https://doi.org/10.5009/gnl210191

Copyright © Gut and Liver.

Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection showed high rates (>95%) of sustained virologic response (SVR) with good safety. SVR after DAA therapy may result in improved liver dysfunction in patients with hepatocellular carcinoma (HCC), but its impact on the risk of HCC recurrence has been the subject of controversy. In this issue of Gut and Liver, Ahn et al.1reported that HCV-related HCC patients with complete response (CR) to treatment achieved acceptable SVR (88%) with DAA therapy, and 37% experienced HCC recurrence during the median follow-up period of 15.8 months (range, 4.4 to 29.9 months). Unfortunately, this study did not include a control group, which made it difficult to ascertain whether DAA therapy itself could increase or decrease the risk of HCC recurrence.

In 2016, Reig et al.2sparked a debate by reporting an unexpectedly high HCC recurrence rate in HCV-infected patients following DAA therapy. Since then, studies evaluating the impact of DAA therapy on the risk of HCC recurrence after CR have produced conflicting data, and some studies have suggested a decreased risk of HCC recurrence, while others have shown the opposite results. A meta-analysis also showed that the use of DAA therapy was associated with a >60% lower risk of HCC recurrence compared to patients without DAA treatment (odds ratio, 0.36; 95% confidence interval, 0.27 to 0.47; p<0.001).3However, most relevant studies had several limitations including heterogeneity between the cohorts in terms of stage of HCC, different HCC treatment options, multiple HCC treatments, the time interval between CR to HCC treatment and the initiation of DAA therapy, surveillance protocols after DAA therapy, the duration of follow-up, and variability in the analytical methods used. Therefore, there are still no conclusive data that DAA therapy is associated with the risk of recurrent HCC in patients with CR to HCC treatment and the controversy continues.

Apart from these debates, it is evident that the risk of recurrent HCC continues in HCV-infected patients with CR to HCC treatment after DAA therapy even achieving an SVR. The major risk factors for HCC recurrence are male gender, older age, non-SVR, advanced liver fibrosis, cirrhosis, and higher posttreatment alpha-fetoprotein levels. The time interval between curative therapy and DAA therapy has been suggested as a risk factor for HCC recurrence after HCC CR.4Tsai et al.5found that the recurrence rate was significantly higher among patients with a timespan of <4 months (54.6%) between HCC treatment and DAA therapy compared to those with a timespan of >4 months (21.3%, p=0.026). Singal et al.6revealed that the risk of early recurrence could differ according to the initiation time of DAA therapy. The proportion of patients with HCC recurrence was 44.0% for those with a duration from HCC CR to DAA initiation of fewer than 3 months, 50.0% for those with a duration from HCC CR to DAA initiation of 4 to 6 months, and 36.9% for those with a duration of more than 6 months. However, these values did not achieve statistical significance. In multivariate analysis, Ogawa et al.7reported that the time between previous HCC treatment and DAA exposure within 1 year (hazard ratio, 3.20; 95% confidence interval, 1.29 to 9.65; p=0.0011) was significantly associated with HCC recurrence. In this issue of Gut and Liver, Ahn et al.1also reported that a short last HCC treatment durability before DAA therapy (<12 months) was an independent risk factor of HCC recurrence in both a multicenter Korean cohort and a nationwide cohort from the Korean Health Insurance Review and Assessment Service database. The authors defined last HCC treatment durability as the time between the final HCC treatment and the start of DAA therapy.

The delay of DAA therapy can provide a longer time for immune surveillance to work and allow a longer time to verify HCC CR, thereby minimizing the chance of misclassification bias.4Meanwhile, SVR with DAA therapy can result in fibrosis regression and improvements in portal hypertension and liver dysfunction, which is the major cause of mortality in patients with HCC CR and untreated HCV infections. Singal et al.8reported that patients with prior HCC had a median time from HCC CR to DAA initiation of 7.7 months, and DAA therapy was associated with a significant reduction in the risk of death (hazard ratio, 0.54; 95% confidence interval, 0.33 to 0.90). In a systematic review with a meta-analysis, Saraiya et al.9suggested an acceptable HCC recurrence rate after DAA therapy that was delayed at least 6 months after the HCC CR. However, the appropriate timing of DAA initiation after CR in HCV-related HCC patients remains controversial. The American Gastroenterological Association expert review suggested that DAA therapy should not be withheld from patients with CR to HCC therapy, but DAA therapy can be deferred 4 to 6 months to confirm response to HCC therapy.10However, even after SVR with DAA therapy in patients with HCC CR, clinicians and patients should be vigilant for HCC recurrence and require regular surveillance.


No potential conflict of interest relevant to this article was reported.

  1. Ahn YH, Lee H, Kim DY, et al. Independent risk factors for hepatocellular carcinoma recurrence after direct-acting antiviral therapy in patients with chronic hepatitis C. Gut Liver 2021;15:410-419.
    Pubmed CrossRef
  2. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016;65:719-726.
    Pubmed CrossRef
  3. Lui FH, Moosvi Z, Patel A, et al. Decreased risk of hepatocellular carcinoma recurrence with direct-acting antivirals compared with no treatment for hepatitis C: a meta-analysis. Ann Gastroenterol 2020;33:293-298.
    Pubmed KoreaMed CrossRef
  4. Gao X, Zhan M, Wang L, Ding Y, Niu J. Timing of DAA initiation after curative treatment and its relationship with the recurrence of HCV-related HCC. J Hepatocell Carcinoma 2020;7:347-360.
    Pubmed KoreaMed CrossRef
  5. Tsai PC, Huang CF, Yu ML. Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: issue of the interval between HCC treatment and antiviral therapy. J Hepatol 2017;66:464.
    Pubmed CrossRef
  6. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a Multicenter North American Cohort Study. Gastroenterology 2019;156:1683-1692.
    Pubmed KoreaMed CrossRef
  7. Ogawa E, Furusyo N, Nomura H, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther 2018;47:104-113.
    Pubmed CrossRef
  8. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019;157:1253-1263.
    Pubmed KoreaMed CrossRef
  9. Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther 2018;48:127-137.
    Pubmed KoreaMed CrossRef
  10. Singal AG, Lim JK, Kanwal F. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review. Gastroenterology 2019;156:2149-2157.
    Pubmed KoreaMed CrossRef

Article

Editorial

Gut and Liver 2021; 15(3): 327-328

Published online May 15, 2021 https://doi.org/10.5009/gnl210191

Copyright © Gut and Liver.

Direct-Acting Antiviral Therapy and Risk of Hepatocellular Carcinoma Recurrence in Patients with Chronic Hepatitis C

Chang Hun Lee and In Hee Kim

Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea

Correspondence to:In Hee Kim
ORCID https://orcid.org/0000-0003-3863-7907
E-mail ihkimmd@jbnu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection showed high rates (>95%) of sustained virologic response (SVR) with good safety. SVR after DAA therapy may result in improved liver dysfunction in patients with hepatocellular carcinoma (HCC), but its impact on the risk of HCC recurrence has been the subject of controversy. In this issue of Gut and Liver, Ahn et al.1reported that HCV-related HCC patients with complete response (CR) to treatment achieved acceptable SVR (88%) with DAA therapy, and 37% experienced HCC recurrence during the median follow-up period of 15.8 months (range, 4.4 to 29.9 months). Unfortunately, this study did not include a control group, which made it difficult to ascertain whether DAA therapy itself could increase or decrease the risk of HCC recurrence.

In 2016, Reig et al.2sparked a debate by reporting an unexpectedly high HCC recurrence rate in HCV-infected patients following DAA therapy. Since then, studies evaluating the impact of DAA therapy on the risk of HCC recurrence after CR have produced conflicting data, and some studies have suggested a decreased risk of HCC recurrence, while others have shown the opposite results. A meta-analysis also showed that the use of DAA therapy was associated with a >60% lower risk of HCC recurrence compared to patients without DAA treatment (odds ratio, 0.36; 95% confidence interval, 0.27 to 0.47; p<0.001).3However, most relevant studies had several limitations including heterogeneity between the cohorts in terms of stage of HCC, different HCC treatment options, multiple HCC treatments, the time interval between CR to HCC treatment and the initiation of DAA therapy, surveillance protocols after DAA therapy, the duration of follow-up, and variability in the analytical methods used. Therefore, there are still no conclusive data that DAA therapy is associated with the risk of recurrent HCC in patients with CR to HCC treatment and the controversy continues.

Apart from these debates, it is evident that the risk of recurrent HCC continues in HCV-infected patients with CR to HCC treatment after DAA therapy even achieving an SVR. The major risk factors for HCC recurrence are male gender, older age, non-SVR, advanced liver fibrosis, cirrhosis, and higher posttreatment alpha-fetoprotein levels. The time interval between curative therapy and DAA therapy has been suggested as a risk factor for HCC recurrence after HCC CR.4Tsai et al.5found that the recurrence rate was significantly higher among patients with a timespan of <4 months (54.6%) between HCC treatment and DAA therapy compared to those with a timespan of >4 months (21.3%, p=0.026). Singal et al.6revealed that the risk of early recurrence could differ according to the initiation time of DAA therapy. The proportion of patients with HCC recurrence was 44.0% for those with a duration from HCC CR to DAA initiation of fewer than 3 months, 50.0% for those with a duration from HCC CR to DAA initiation of 4 to 6 months, and 36.9% for those with a duration of more than 6 months. However, these values did not achieve statistical significance. In multivariate analysis, Ogawa et al.7reported that the time between previous HCC treatment and DAA exposure within 1 year (hazard ratio, 3.20; 95% confidence interval, 1.29 to 9.65; p=0.0011) was significantly associated with HCC recurrence. In this issue of Gut and Liver, Ahn et al.1also reported that a short last HCC treatment durability before DAA therapy (<12 months) was an independent risk factor of HCC recurrence in both a multicenter Korean cohort and a nationwide cohort from the Korean Health Insurance Review and Assessment Service database. The authors defined last HCC treatment durability as the time between the final HCC treatment and the start of DAA therapy.

The delay of DAA therapy can provide a longer time for immune surveillance to work and allow a longer time to verify HCC CR, thereby minimizing the chance of misclassification bias.4Meanwhile, SVR with DAA therapy can result in fibrosis regression and improvements in portal hypertension and liver dysfunction, which is the major cause of mortality in patients with HCC CR and untreated HCV infections. Singal et al.8reported that patients with prior HCC had a median time from HCC CR to DAA initiation of 7.7 months, and DAA therapy was associated with a significant reduction in the risk of death (hazard ratio, 0.54; 95% confidence interval, 0.33 to 0.90). In a systematic review with a meta-analysis, Saraiya et al.9suggested an acceptable HCC recurrence rate after DAA therapy that was delayed at least 6 months after the HCC CR. However, the appropriate timing of DAA initiation after CR in HCV-related HCC patients remains controversial. The American Gastroenterological Association expert review suggested that DAA therapy should not be withheld from patients with CR to HCC therapy, but DAA therapy can be deferred 4 to 6 months to confirm response to HCC therapy.10However, even after SVR with DAA therapy in patients with HCC CR, clinicians and patients should be vigilant for HCC recurrence and require regular surveillance.

CONFLICTS OF INTEREST


No potential conflict of interest relevant to this article was reported.

References

  1. Ahn YH, Lee H, Kim DY, et al. Independent risk factors for hepatocellular carcinoma recurrence after direct-acting antiviral therapy in patients with chronic hepatitis C. Gut Liver 2021;15:410-419.
    Pubmed CrossRef
  2. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016;65:719-726.
    Pubmed CrossRef
  3. Lui FH, Moosvi Z, Patel A, et al. Decreased risk of hepatocellular carcinoma recurrence with direct-acting antivirals compared with no treatment for hepatitis C: a meta-analysis. Ann Gastroenterol 2020;33:293-298.
    Pubmed KoreaMed CrossRef
  4. Gao X, Zhan M, Wang L, Ding Y, Niu J. Timing of DAA initiation after curative treatment and its relationship with the recurrence of HCV-related HCC. J Hepatocell Carcinoma 2020;7:347-360.
    Pubmed KoreaMed CrossRef
  5. Tsai PC, Huang CF, Yu ML. Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: issue of the interval between HCC treatment and antiviral therapy. J Hepatol 2017;66:464.
    Pubmed CrossRef
  6. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a Multicenter North American Cohort Study. Gastroenterology 2019;156:1683-1692.
    Pubmed KoreaMed CrossRef
  7. Ogawa E, Furusyo N, Nomura H, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther 2018;47:104-113.
    Pubmed CrossRef
  8. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019;157:1253-1263.
    Pubmed KoreaMed CrossRef
  9. Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther 2018;48:127-137.
    Pubmed KoreaMed CrossRef
  10. Singal AG, Lim JK, Kanwal F. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review. Gastroenterology 2019;156:2149-2157.
    Pubmed KoreaMed CrossRef
Gut and Liver

Vol.15 No.3
May, 2021

pISSN 1976-2283
eISSN 2005-1212

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