Tenofovir Alafenamide(TAF) Reduces the Risk of Hepatocellular Carcinoma(HCC) Recurrence

Study Overview
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Brief Summary
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Hepatocellular carcinoma(HCC) is prevalent in the hepatitis B virus(HBV) infection endemic areas. For early stage of HCC, surgical resection, radiofrequency ablation (RFA) or microwave ablation (MWA) are the main treatment options. However, the risk of recurrence is as high as 50% in 5 years by surgical resection or 60-70% in 5 years by RFA. In average, the recurrence rate of HCC at 2 years is 30%. Many factors are associated with the HCC recurrence, including HBV viral load, cirrhotic stage, tumor size, tumor number, vascular invasion, alpha-fetoprotein(AFP) level and so on. Of them, high HBV viral load is associated with the risk of HCC recurrence after surgical resection, especially on late recurrence. In one previous randomized controlled trial, patients who received lamivudine, adefovir dipivoxil, or entecavir had significantly decreased early recurrence of HCC, however, whether nucleos(t)ide analogues(NUCs) can further reduce the risk of recurrence in patients with low viral loads (<2000 IU/ml) is still unclear. In EASL 2017 guideline, all patients with compensated or decompensated cirrhosis need antiviral treatment, with any detectable HBV DNA level and regardless of alanine aminotransferase(ALT) levels. In Taiwan, even in chronic hepatitis B(CHB) infection patients with HCC, NUC is not reimbursed if their HBV viral load was less than 2000 IU/ml. It is an important unmet medical need to understanding the role of TAF in reducing the risk of recurrence in HBV-HCC patients with low HBV viral load (HBV DNA<2000 IU/ml) and significant liver fibrosis after curative treatment (The definition of significant liver fibrosis was based on reference. In our recent retrospective study, the risk of recurrence and survival are comparable between patients with and without NUCs treatment before HCC development only if NUCs treatment can be provided after curative treatment of HCC. However, a higher risk of recurrence was observed in cirrhotic patients with prior NUCs treatment before HCC occurrence. It would be interesting to investigate the incidence of recurrence by switching to tenofovir alafenamide(TAF) after curative treatment of HCC in patients already on NUCs treatment.

Official Title
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Decreasing Risk of Recurrence by TAF in HCC Patients After Curative Treatment With Low HBV Viral Load

Conditions
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HCC Patients After Curative Treatment With Low HBV Viral Load

Intervention / Treatment
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* Drug: Vemlidy® (Tenofovir Alafenamide; TAF)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HBsAg-positive for more than 6 months. HCC after curative treatment (eight by surgical resection or RFA or MWA) with significant liver fibrosis (either by Ishak≧2, Metavir≧2, Knodell≧3) or cirrhosis and HBV DNA<2,000 IU/ml. The duration of curative treatment of HCC to study enrollment should be less than 90 days. Curative treatment is confirmed by contrast-enhanced CT or MR after the surgery/RFA/MWA. Exclusion Criteria: Child-Pugh class B8-C. Active EV bleeding within 4 weeks. History of hepatic encephalopathy or intractable ascites. BCLC C or D.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: NUC-naïve patients will be randomization into tenofovir alafenamide(TAF) or placebo arm in 1:1 ratio. Part 2: NUCs-treated patients will be switched to tenofovir alafenamide(TAF) treatment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>NUC-naïve patients will be randomization into Tenofovir Alafenamide(TAF) treatment. | Drug: Vemlidy® (Tenofovir Alafenamide; TAF)<br>* Dosage form: Oral Tablets; Dosage: 25mg; Frequency: One tablet with meals, once daily(QD).<br>|
| Placebo Comparator: Arm 2<br>NUC-naïve patients will be randomization into placebo arm. | Drug: Placebo<br>* Dosage form: Oral Tablets; Dosage: N/A; Frequency: One tablet with meals, once daily(QD).<br>|
| Active Comparator: Arm 3<br>NUCs-treated patients will be switched to Tenofovir Alafenamide(TAF) treatment. | Drug: Vemlidy® (Tenofovir Alafenamide; TAF)<br>* Dosage form: Oral Tablets; Dosage: 25mg; Frequency: One tablet with meals, once daily(QD).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Hepatocellular carcinoma(HCC) recurrence | Incidence of HCC recurrence | Up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatocellular carcinoma(HCC) recurrence | HCC recurrence | Up to 3 years. | 
| Hepatocellular carcinoma(HCC) recurrence in NUCs-treated patients after switched to TAF treatment | HCC recurrence in NUCs-treated patients after switched to TAF treatment | Up to 2 years. | 
| Dynamic (kinetics) changes in the bio-markers related to hepatitis B virus(HBV) infection | HBV DNA, HBsAg, HBV RNA, HBcrAg, etc. | Up to 3 years. | 
| Changes in the renal function | eGFR | Up to 3 years. | 
| Changes in the bone density | Dual-energy X-ray absorptiometry(DEXA) scan | Up to 3 years. | 
| Regression of liver fibrosis | Fibroscan | Up to 3 years. |