Efficacy and Tolerance of Naked DNA Vaccine in Patients With Chronic B Hepatitis (VAC-ADN)

Randomised, Opened, Multicentre Phase I/II Trial in Patients With Chronic Hepatitis B With HBV VL < 12 IU/ml and Under Treatment With NRTI, Which Evaluated Efficacy and Tolerance of Vaccination With Naked DNA on Viral Replication After Analogs' Treatment Interruption. ANRS HB02 VAC-ADN

The purpose of this study is to determine if DNA vaccination of chronic HBV patients under treatment with NRTI can restore T-cell responsiveness and delay virologic reactivation after treatment discontinuation.

Despite the availability of effective vaccines against hepatitis B, over 370 million people worldwide remain persistently infected with HBV. Persistent infection is associated with chronic liver disease that can lead to the developement of cirrhosis and hepatocellular carcinoma in two-third of persons. Treatment of chronic hepatitis B relies on the use of analogs such as lamivudine, adefovir, entecavir or immunostimulators such as interferons. Although analogs are efficient, genotypic resistance occurs after one year of treatment and the rate of virologic relapse is high after treatment discontinuation. HBV is a non cytopathic virus and liver damage is caused by immune response against infected hepatocytes and to a non specific inflammatory response. Immune response contributes to the virus clearance. In acute hepatitis B infection, T cell response is polyclonal, specific and vigorous, whereas in patients with chronic infection, responses remain weak, less specific and hardly detectable in peripheral blood. T cell responses could be induced or restored by antigenic stimulation such as vaccination. In a previous phase I clinical trial, we showed that DNA vaccination with plasmid pCMVS2.S is safe and can specifically, but transiently activate T-cell responses in chronic HBV-carriers not responding to current antiviral therapies. Analogs such as lamivudine and adefovir were shown to enhance T cell responses concomitantly with viral load decrease. In this phase I/II clinical trial, we would like to determine if DNA vaccination of chronic HBV patients under treatment with NRTI can restore T-cell responsiveness and delay virologic reactivation after treatment discontinuation.

Primary endpoint is virologic failure defined by 1) reactivation after analogs' treatment interruption, 2) virologic breakthrough during treatment with analogs, 3) the impossibility for the patients to interrupt treatment at week 48

Inclusion Criteria: chronic hepatitis B with or without AgHBe no cirrhosis and no hepatocellular carcinoma treatment with NRTI unchanged for at least 3 months undetectable HBV viral load for 12 months HBV viral load < 12 IU/ml at screening sGPT < 5N tetanus immunization or booster dose for less than 8 years accurate birth control or menopausal women or sterility sickness insurance signed informed consent Exclusion Criteria: HLA-DR 15/16 coinfections with HDV, HCV and/or HIV treatment with immunomodulators immunosuppressors long-term corticotherapy (over 4 weeks) active intravenous drug-users prolonged and excessive consumption of alcohol (men > 40g/day ; women > 30g/day ; for more than 5 years) medical history of autoimmune disease or presence of autoantibodies previous immunization by HBV vaccine of less than 5 years previous immunization by DNA vaccine against HBV personal or family medical history of demyelinising diseases uncontrolled hypophosphatemia renal failure, renal transplantation, haemodialysis pregnancy, breast-feeding

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