Safety and Efficacy of Generic Sofosbuvir and Ribavirin for Treatment-naive Genotype 2 Chronic Hepatitis C
Safety and Efficacy of Generic Sofosbuvir and Ribavirin for Treatment-naive Genotype 2 Chronic Hepatitis C
This study aimed to evaluate the safety and efficacy of generic sofosbuvir, an
 investigational anti-hepatitis C virus (HCV) drug, combined with weight-adjusted ribavirin
 for treatment-naive Chinese adults chronically infected with genotype 2 HCV, the second most
 prevalent genotype in China. One hundred and thirty-two (132) subjects, including one hundred
 and twenty (120) non-cirrhotics and twelve (12) compensatory cirrhotics, were medicated with
 sofosbuvir 400 mg daily combined with weight-adjusted ribavirin 1000-1200 mg daily. The
 treatment course lasted 12 successive weeks and thereafter all the study participants entered
 into a 12-week treatment-free follow-up period.
It is estimated that China has a population of over 10 million infected with HCV and also a
 highly variable HCV genotype geographic distribution. Genotype 2 HCV is reported to be the
 second most common type (~25%) in Chinese population and associated with a high risk of acute
 liver disease exacerbation and other extrahepatic diseases. Sofosbuvir is a pan-genotypic HCV
 ribonucleic acid (RNA) polymerase inhibitor directing at HCV RNA replication. Genotype 2
 chronic hepatitis C has a high treatment response to the combined regimen of peginterferon
 and weight-adjusted ribavirin. The all-oral combination regimen of sofosbuvir and ribavirin
 is expected to completely suppress genotype 2 HCV replication in subjects chronically
 infected with HCV and achieve a sustained virologic response, namely, HCV not detected or
 below a predefined limit in plasma, 12 or 24 weeks after cessation of treatment.
Inclusion Criteria:

 -  aged between 18 and 65 years (inclusive) and of either sex

 -  with a body mass index (BMI) between 18 and 30 kg/m^2

 -  chronically infected with genotype 2 HCV, and the diagnosis of chronic hepatitis C
 consistent with the Chinese Guideline for Prevention and Management of Hepatitis C

 -  HCV RNA equaling to or above 10^4 IU/mL and anti-HCV positivity

 -  naive to anti-HCV treatment, defined as being not previously treated with any
 interferon (including interferon alfa or beta or peginterferon), ribavirin, or other
 approved, investigational or any other not approved anti-HCV regimens of any source

 -  with or without cirrhosis, presence or absence of which must be documented as at lease
 one item of the following: 1) liver biopsy confirming presence (e.g., Metavir score =
 4 or Ishak score >=5) or absence of cirrhosis within twelve (12) months before
 screening; 2) FibroScan showing cirrhosis (liver stiffness modulus [LSM]>=12.5 kPa) or
 no cirrhosis (LSM=<9.6 kPa); 3) a subject with a LSM of 9.6-12.5 kPa (exclusive) could
 only be enrolled when the liver biopsy confirmed or excluded presence of cirrhosis

 -  women of childbearing potential without a history of menopause and with a negative
 blood pregnancy test; subjects of childbearing potential (including male subjects and
 their female partners) had no childbearing plan from screening, initiation of
 treatment until six (6) months after the end of treatment and consented to use
 effective contraceptive measures

 -  voluntary participation in the study and being able to understand and sign the
 informed consent form

 Exclusion Criteria:

 -  being infected with mixed-genotype HCV

 -  having previously used any investigational or experimental direct antiviral agents
 against HCV, including protease, nonstructural (NS) protein 5B polymerase or NS5A
 inhibitors, before screening

 -  having received any interferon-based anti-HCV regimens before screening

 -  having been exposed to any systemic potent immunomodulators , such as steroids or
 thymosin alfa (excluding use of nasal, inhalational, topical steroids and/or others)
 for more than two (2) weeks within six (6) months before screening, or anticipated to
 be exposed to these agents during the study period

 -  being coinfected with hepatitis B virus (HBV) or human immunodeficient virus (HIV)

 -  with evidence of decompensatory liver function, including but not limited to total
 serum bilirubin (TBIL) above twice (2) of the upper limit of normal (ULN), serum
 albumin (ALB) below 35 g/L, or prothrombin activity (PTA) below 60%; emergence of
 ascites, upper gastrointestinal bleeding and/or hepatic encephalopathy; with liver
 function reserve Child-Pugh class B or C

 -  with primary liver cancer confirmed or evidenced by serum alfa-fetoprotein above 100
 ng/ml or liver imaging study showing suspected nodules

 -  with a previous history of liver disease of other causes, including alcoholic liver
 disease, nonalcoholic steatohepatitis, drug-induced hepatitis, autoimmune hepatitis
 (anti-nuclear antibody[ANA] titer above 1:100), Wilson disease or hemochromatosis

 -  with serum alaine aminotransferase (ALT) or asparate aminotransferase (AST) above ten
 (10) times of ULN

 -  with white blood cell (WBC) count below 3x10^9 per liter, neutrophil count below
 1.5x10^9 per liter, platelet count below 50x10^9 per liter, or hemoglobin below the
 lower limit of the normal

 -  with serum creatinine clearance (CLcr) below 50 ml/min using the Cockcroft-Gault
 formula

 -  with uncontrolled diabetes mellitus (hemoglobin A1c[HbA1c] above 7.0%)

 -  with psychiatric or neurologic disorders, including previous or family history of
 psychiatric disorders (especially depression, depressive state, epilepsy or hysteria)

 -  with serious cardiovascular disorders, including uncontrolled hypertension (systolic
 blood pressure at or above 160 mmHg and/or diastolic blood pressure at or above 100
 mmHg), heart insufficiency of New York Heart Association class III or above, history
 of myocardial infarction within six (6) months before screening, history of
 percutaneous transluminal coronary angioplasty within six (6) months before screening,
 unstable angina pectoris, or any uncontrolled arrhythmias

 -  with serious hematologic disorders (such as anemia, hemophilia and others)

 -  with serious kidney diseases (such as chronic kidney disease, kidney insufficiency and
 others)

 -  with serious gastrointestinal disorders (such as peptic ulcer, colitis and others)

 -  with serious respirator disorders (such as active pulmonary tuberculosis, lung
 infection, chronic obstructive pulmonary disease, pulmonary interstitial disease and
 others)

 -  with active or suspected malignant tumors or with a previous history of malignant
 tumors (excluding skin basal cell carcinoma or cervical carcinoma in situ) within five
 (5) years before screening

 -  with a history of major organ transplantation

 -  being known to be severely hypersensitive or allergic to any drugs, especially the
 testing medications and other constituents

 -  with a history of active alcohol or drug abuse

 -  being pregnant or lactating

 -  being unable to discontinue prohibited medications as defined by the protocol

 -  having participated in any other clinical studies within three (3) months before
 screening

 -  being unable or unwilling to provide informed consent or unable to follow the protocol
 requirements

 -  any other conditions of excluding a potential participant at the discretion of the
 investigators