DAA in the Risk of Recurrence After Curative Treatment of HCC

Study Overview
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Brief Summary
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For early stage of HCC, surgical resection or radiofrequency ablation (RFA) is the mainstay curative treatments. However, recurrence is still a major issue after the surgery or RFA. Only selected patients are eligible and tolerable to IFN-based treatment after surgical resection and the sustained virological response varied. Harvoni for genotype 1 HCV and sovaldi plus ribavirin for genotype 2 HCV can achieve high SVR and being recommended by AASLD and EASL. Mixed HCV genotype infection accounts for 10% of CHC patients in Taiwan. Sovaldi-based treatment plus ribavirin should be as effective as Sovaldi plus rivavirin in the treatment of genotype 2 HCV, as well as mixed genotype 1 and 2 HCV infection. As genotype 1 and 2 are the leading HCV genotypes in Taiwan, It can simplify the regimen of anti-HCV treatment in Taiwan by using Harvoni plus ribavirin, not only for genotype 1 and 2 HCV but also for mixed genotype 1 and 2 HCV infection. Although an unexpected high recurrence rate in HCC patients under DAA treatment was reported once. However, one recent study showed a low risk of HCC recurrence after DAA treatment. In this study, the investigators plan to enroll 130 HCV-HCC patients after confirming curative treatment for their HCC, either by surgery or RFA. For the cases fulfilling the inclusion/exclusion criteria, a 12 weeks Harvoni plus ribavirin treatment will be provided for all cases (single armed design). The primary objective of the study is annual recurrence-free survival after curative resection of HCV-HCC for up to 5 years. A hospital-based cohorts of HCV-related HCC undergoing surgical resection or RFA from Taipei Veterans General Hospital and Investigated Sites will be recruited as historical controls.

Detailed Description
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Chronic hepatitis C virus (HCV) infection is a major etiology of hepatocellular carcinoma (HCC). For early stage of HCC, surgical resection or radiofrequency ablation (RFA) is the mainstay curative treatments. However, recurrence is still a major issue after the surgery or RFA. According to our previous report, the cumulated recurrence rate for small HCV-HCC was 72.4% at 5 year. PEG-interferon plus RBV treatment is the standard of care for chronic hepatitis C (CHC) in Taiwan. NHIRD data showed that PEG-IFN plus RBV treatment can reduce 12% of recurrence rate in 5 years (64% vs 52%) after curative resection of HCC. However, only selected patients are eligible and tolerable to IFN-based treatment after surgical resection and the sustained virological response varied. Harvoni for genotype 1 HCV and sovaldi plus ribavirin for genotype 2 HCV can achieve high SVR and being recommended by AASLD and EASL. All-oral regimen, being more tolerable and effective for HCC patients after curative treatment than IFN-based treatment. Mixed HCV genotype infection accounts for 10% of CHC patients in Taiwan. Sovaldi-based treatment plus ribavirin should be as effective as Sovaldi plus rivavirin in the treatment of genotype 2 HCV, as well as mixed genotype 1 and 2 HCV infection. As genotype 1 and 2 are the leading HCV genotypes in Taiwan, It can simplify the regimen of anti-HCV treatment in Taiwan by using Harvoni plus ribavirin, not only for genotype 1 and 2 HCV but also for mixed genotype 1 and 2 HCV infection. Although an unexpected high recurrence rate in HCC patients under DAA treatment was reported once. However, one recent study showed a low risk of HCC recurrence after DAA treatment. Harvoni is an all-oral regimen, being more tolerable and effective for HCC patients after surgery than IFN-based treatment. The all oral regimen would be beneficial in eradicating HCV viral load and subsequently reduce the risk of recurrence after curative resection of HCV-HCC. In this study, the investigators plan to enroll 130 HCV-HCC patients after confirming curative treatment for their HCC, either by surgery or RFA. For the cases fulfilling the inclusion/exclusion criteria, a 12 weeks Harvoni plus ribavirin treatment will be provided for all cases (single armed design). The primary objective of the study is annual recurrence-free survival after curative resection of HCV-HCC for up to 5 years. The secondary objectives of the study are SVR 4/12/24 by DAA, regression of fibrosis, incidence of liver-related complications (EV bleeding, ascites) after DAA treatment, and overall survival for 5 years. A hospital-based cohorts of HCV-related HCC undergoing surgical resection or RFA from Taipei Veterans General Hospital and Investigated Sites will be recruited as historical controls. The historical controls include HCV-HCC undergoing curative treatment without Peg-interferon plus ribavirin treatment (cohort 1) or with Peg-interferon plus ribavirin treatment (cohort 2) after curative treatment (surgical resection or RFA) for HCC.

Official Title
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The Role of DAA in Reducing the Risk of Recurrence After Curative Treatment of HCC in Patients With Chronic Hepatitis C and Early Stage HCC

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Ledipasvir 90mg/Sofosbuvir 400 mg
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Anti-HCV positive and HBsAg-negative HCV genotype 1 or 2 infection, mixed infection GT 1 & 2 is allowed HCV RNA ≥ 10,000 IU/ml at the time of screening Age > 20 y/o BCLC stage 0 or A HCC confirmed by pathology and receiving the first time of curative treatment No recurrence of HCC confirmed by contrast-enhanced image studies (CT or MRI) within 3 months post the curative treatment. Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 Child-Pugh score ≤7 Exclusion Criteria: HBV, or HIV coinfection Co-existing other malignancy Intolerance to ribavirin Marked decompensated liver cirrhosis (CTP score>7) Uremia or renal impaired patients (eGFR<30)

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: DAA treatment arm<br>Active DAA treatment ('Ledipasvir 90mg/Sofosbuvir 400 mg plus Ribavirin' ) for HCV-HCC patients after curative resection or ablation. | Drug: Ledipasvir 90mg/Sofosbuvir 400 mg<br>* A 12 week Harvoni (Ledipasvir 90mg/Sofosbuvir 400 mg ) plus ribavirin will be provided after confirmation of curative treatment.<br>* Other names: DAA;Drug: Ribavirin<br>* A 12 week Harvoni (Ledipasvir 90mg/Sofosbuvir 400 mg ) plus ribavirin will be provided after confirmation of curative treatment.<br>* Other names: rebetol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of the study is annual recurrence-free survival after curative resection of HCV-HCC for up to 5 years. | The primary objective of the study is annual recurrence-free survival after curative resection of HCV-HCC for up to 5 years. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SVR 4/12/24 by DAA | SVR: sustained virological response. DAA: direct antiviral agent. SVR 4/12/24 means undetectable HCV viral load 4/12/24 weeks after completing DAA treatment. | up to 5 years | 
| Regression of fibrosis | Regression of fibrosis | up to 5 years | 
| Incidence of liver-related complications (EV bleeding, ascites) after DAA treatment | Incidence of liver-related complications (EV bleeding, ascites) after DAA treatment | up to 5 years | 
| Overall survival | Overall survival | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis C, Hepatocellular Carcinoma, Direct-acting antiviral (DAA), Recurrence