The Efficacy and Safety of 12-week SOF/VEL Regimen Combined With Prophylactic Use of TAF for Treatment-naïve Genotype 1-6 HCV/HBV Co-infection Adult Patients With or Without Compensated Cirrhosis in China

The Efficacy and Safety of 12-week SOF/VEL Regimen Combined With Prophylactic Use of TAF for Treatment-naïve Genotype 1-6 HCV/HBV Co-infection Adult Patients With or Without Compensated Cirrhosis in China : a Mutil-center,Prospective,Single-arm,Open-label Trial

Subjects can be classified into two groups, Group 1 include non-cirrhotic patients, Group 2 include cirrhotic patients.

All the patients will be received prophylactically TAF for 4 weeks before using SOF/VEL once daily for 12 weeks. In total, Group 1 patients will be discontinued TAF once daily therapy at the end of week 28 if no HBV reactivation occurs during treatment , Group 2 patients will be received TAF once daily for 64 weeks. In this study, after week 64, Group 2 patients will continue NUC treatment but pay by themselves. For those who is GT3 cirrhosis patients, RBV added simultaneously with SOF/VEL for 12 weeks. For patients weighing < 75 kg, the dose is 500 mg twice; for patients weighing ≥ 75 kg, the dose is 600 mg twice.

Subjects can be classified into two groups, Group 1 include non-cirrhotic patients, Group 2 include cirrhotic patients.

All the patients will be received prophylactically TAF for 4 weeks before using SOF/VEL once daily for 12 weeks. In total, Group 1 patients will be discontinued TAF once daily therapy at the end of week 28 if no HBV reactivation occurs during treatment , Group 2 patients will be received TAF once daily for 64 weeks. In this study, after week 64, Group 2 patients will continue NUC treatment but pay by themselves. For those who is GT3 cirrhosis patients, RBV added simultaneously with SOF/VEL for 12 weeks. For patients weighing < 75 kg, the dose is 500 mg twice; for patients weighing ≥ 75 kg, the dose is 600 mg twice.

The primary objective of this study is:

•To evaluate efficacy and safety of SOF/VEL in HBsAg-positive patients with HCV (GT1-6) co-infection.

The secondary objectives of this study are:

• To evaluate the proportion of subjects with HBV reactivation during the treatment and after cessation of treatment.
• To evaluate the proportion of subjects with virologic failure (virological breakthrough/ viral relapse)of HCV/ HBV.

Inclusion Criteria:

1. Willing and able to provide written informed consent

2. Male or female, age≥18 years

3. Bodyweight≥40 kg

4. HCV RNA positive (15 IU/mL )at Screening

5. HCV genotype 1, 2, 3, 4, 5, 6, or indeterminate as assessed at Screening by the Central Laboratory

6. Chronic HBV/HCV coinfection (≥ 6 months) documented by prior medical history or liver biopsy. For non-cirrhotic patients, and for HBeAg positive patients, HBV DNA<20000IU/ml. For HBeAg negative patients, HBV DNA<2000IU/ml.

   For cirrhosis patients, HBV DNA was dectable or undectable. Cirrhosis Determination (approximately 20% of subjects may have cirrhosis)

   • Cirrhosis by B Ultrasound/CT/ MRI.
   • Cirrhosis is defined as Fibroscan® with a result of ≥ 17.5 kPa
   • Absence of cirrhosis is defined as Fibroscan with a result of <10.6 kPa within ≤ 6 months of Day 1

7. Classification as treatment naïve for CHC patients Treatment naïve is defined as having never been exposed to approved or experimental HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or ribavirin

8. Individuals must not be taking or requiring treatment with HBV antiviral therapy at screening. For participants that are HBV treatment experienced, the most recent treatment must have been completed at least 6 months prior to Day 1.

9. Patients with HBsAg positive as least 6 month without decompensated cirrhosis.

10. Liver imaging within 6 months of Day 1 is required in cirrhotic patients only to exclude hepatocellular carcinoma (HCC)

11. Females of childbearing potential (as defined in Appendix 4) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment

12. Male subjects and female subjects of childbearing potential who engage in heterosexualinter course must agree to use protocol specified method(s) of contraception as described in Appendix 4

13. Lactating females must agree to discontinue nursing before the study drug is administered

14. Subject must be of generally good health, with the exception of chronic HBV/HCV infection, as determined by the Investigator

15. Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study -

Exclusion Criteria:

1. Any direct antiviral drugs (DAAs) used before screening, including non-structural proteins NS3/4A inhibitor, NS5A inhibitor or NS5B polymerase inhibitor.

2. Patients who received hepatitis B antiviral therapy within 6 months.

3. Diagnosis of primary liver cancer or support for the following evidence: alpha-fetoprotein (AFP) >100 ng/ml or cirrhosis imaging studies of the liver revealed suspicious nodules in the liver

4. A history of malignant tumors within 5 years prior to screening, except for specific cancers that have been cured by surgical resection (eg.Basal cell skin cancer, etc.), or patients suspected of having malignant tumors

5. Current or previous evidence of liver decompensation, including but not limited to: Child-Pugh score Grade B or C, ascites, or hepatic encephalopathy, variceal bleeding or diuretics for the treatment of ascites.

6. A current or previous history of a major medical condition or any other major medical disorder that may interfere with the individual's treatment, assessment or compliance program.

   1. Clinically significant disease (except HBV, HCV) or any other major disease that may interfere with subject treatment, assessment, or protocol compliance; subjects that are currently undergoing assessment of a potentially clinically significant disease (except HBV，HCV) are also excluded.
   2. Gastrointestinal disease, or the condition after surgery may interfere with the absorption of the study drug.
   3. Difficulty in collecting blood and/or poor venous access for blood collection.
   4. Solid organ transplantation.
   5. Severe lung disease, severe heart disease or porphyria.
   6. Psychiatric hospitalization, attempted suicide and/or a period of disability due to mental illness in the past 5 years. Subjects with psychiatric illness (without previously mentioned conditions) who are well-controlled or who have not needed medication for the past 12 months before Day 1 may Will be included in the study.
   7. Serious drug allergies (such as allergic reactions or hepatotoxicity).

7. Pregnant or lactating women.

8. HIV or HDV infection.

9. Screening ECG for clinically significant abnormalities

10. Subjects have the following laboratory test parameters at screening:

    1. ALT > 10 Upper Limit of Normal (ULN)
    2. AST > 10 ULN
    3. Direct bilirubin > 1.5 ULN
    4. platelets < 50,000/L
    5. HbA1c > 8.5%
    6. eGFR < 30 mL/min/1.73 m2，estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation，eGFR will be calculated by the Cockcroft-Gault method: eGFRCG (mL/min) = [(140 - age (yrs))× weight (kg) × (0.85 if female)] / (serum creatinine (mg/dL) × 72), where weight is total body mass in kilograms.
    7. Female subjects with hemoglobin < 11 g/dL; male subjects with hemoglobin < 12 g/dL
    8. albumin < 3 g/dL
    9. INR > 1.5 x ULN unless the subject has known hemophilia or remains stable for anticoagulant therapy affecting INR

11. Chronic liver disease other than HCV pathogens (eg hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cholangitis).

12. Known hypersensitivity to SOF/VEL, TAF and RBV (only for GT 3 cirrhosis patients).

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