immunotherapy with tg4040 in treatment-naïve patients chronically infected with hepatitis c virus

Conditions: Hepatitis C, Chronic

Summary: the primary objective is to determine the safety of sub-cutaneous (sc) injections of tg4040 in non-cirrhotic, treatment-naïve patients chronically infected with hcv (genotype 1). patients will be sequentially treated at an escalting dose of tg4040. all patients will be followed up to at least 6 months after his/her first injection. in addition, all patients treated at the highest dose will receive a tg4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period.

the first nine patients will be sequentially treated in three cohorts of three patients, i.e. they will receive 3 sc injections of tg4040 on days 1, 8 and 15, at the dose of 10e6 pfu (first cohort), 10e7 pfu (second cohort), or 10e8 pfu (third cohort). there will be a one-week safety interval between the first injection of the patients of a given cohort, and a two-week safety interval between the last injection of the last patient of a given cohort and the first injection of the first patient of the next one. there will be also a two-week safety observation period after the last injection of the last patient of the third cohort. if the dose of 10e8 pfu does not raise safety problems, then 6 patients will be further enrolled, without safety intervals between patients. they will receive 3 sc injections of tg4040 at the dose of 10e8 pfu, on days 1, 8 and 15. all patients will be followed up to at least 6 months after his/her first injection. in addition, all patients treated at the dose of 10e8 pfu will receive a tg4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period. three additional cohorts of 9 patients will receive a boost injection either at 2, 4 or 6 months.

Eligibility criteria:
inclusion criteria: * informed consent obtained and signed; * male or female patients; * with chronic hepatitis c (genotype 1) evidenced by hcv positive serology detectable for more than 6 months; * patients with fibrosis status graded f0 or f1 according to the metavir grading system; patients with a f2 fibrosis stage could be enrolled on a case-by-case basis after being sure that they have a contraindication to be treated with an ifn-based standard hcv treatment; patients with f3 or f4 fibrosis stage will not be enrolled; this will be assessed either on the liver biopsy performed less than 18 months prior to baseline or on a fibrotest® and a fibroscan® performed within 2 months prior to first tg4040 injection; in case of discordant results, a liver biopsy will be performed prior to tg4040 treatment;; * treatment-naïve patients: patients who have never received ifn-based treatment; * patients must have compensated liver disease, with: * no history of ascites, hepatic encephalopathy or bleeding from esophageal varices; * laboratory tests values: * serum alanine aminotransferase (alt)less then 2 folds the upper limit of normal (uln); * serum bilirubin and international normalized ratio (inr) values within normal range (except in patients with gilbert syndrome where serum bilirubin may be as high as 3.0 mg/dl); and * other laboratory parameters of grade 0 or 1 (ctc criteria); * for women of child-bearing potential, i.e. with no history of hysterectomy or tubal ligation, a negative pregnancy test at study entry and adequate protection against pregnancy during the conduct of the study and until 3 months after last tg4040 injection. additionnal cohorts: * patients with high alt level (2 folds uln\<alt\<5 folds uln in the 2 months before inclusion) and fibrosis not higher than f2. exclusion criteria: patients will be excluded from the study for any of the following reasons: * co-infection with hbv (indicated by the presence of hepatitis b surface antigen (hbsag) in serum; patients with anti-hepatitis b core antibody response (anti-hbc) will not be excluded) or hiv (anti-hiv antibodies in serum); patients with hiv positive sexual partner (by history) will not be included; * current hcv therapies; * active iv drug or alcohol abuse; * serious, concomitant disorder, including: * primary biliary cirrhosis or sclerosing cholangitis; * auto-immune disease such as symptomatic cryoglobulinemia, polyarthritis, multiple sclerosis; a broad auto-immune testing will be performed at baseline; * proven or suspected immunosuppressive disorder; * active systemic infection; if the patient has acute febrile illness ( \> 38°c) on the day of vaccination, it will be delayed by at least one week after complete recovery; * malignancy within the last 5 years; patients with history of squamous cell skin cancer or basal cell skin cancer will be enrolled, unless the history of skin cancer is at the vaccination site; * systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs (e.g. cyclosporine) within 2 months prior to first study drug injection; corticosteroid nasal sprays, inhaled steroids for asthma and/or topical steroids are permissible; * participation in another experimental protocol during the study period (last intake of investigational drug within 6 months prior to baseline); * breast-feeding women; * receipt of any inactivated vaccine 14 days prior to vaccination or for the duration of the study; receipt of any live attenuated vaccine within 30 days prior to vaccination or for the duration of the study; * allergy to eggs; * patient unable to comply with the protocol requirements; * any condition that, in the opinion of the investigator, might interfere with study objectives.