Hepatitis B virus (HBV) is a hepatotropic non-cytopathic DNA virus which is transmitted percutaneously, sexually and perinatally. Worldwide, it is estimated that two billion people have been infected with hepatitis B virus. Chronic infection by the HBV is a major cause of liver disease worldwide, ranking as a substantial cause of cirrhosis and hepatocellular carcinoma (HCC). An estimated 350 to 400 million people worldwide are living with chronic HBV infection which accounts annually for 1 million deaths worldwide from cirrhosis, liver failure, and hepatocellular carcinoma. Current estimates suggest that it causes 30% of cirrhosis and approximately 50% of HCC worldwide.
Available antiviral treatments, especially BARACLUDE® (entecavir) and VIREAD® (tenofovir), have shown to induce a remarkable and fast drop of HBV viral load as measured by viral DNA. However even after long-term antiviral therapy with these powerful drugs the percentage of patients reaching HBsAg seroconversion remains extremely low and the viral load increases at the end of treatment. HBsAg seroconversion is the ultimate goal of therapy for patients with CHB and on-treatment quantification of HBsAg in patients with HBeAg-negative chronic hepatitis B (CHB) treated with peginterferon alfa-2a may help identify those likely to be cured by this therapy and optimize treatment strategies.
During a meeting of the European Association for the Study of the Liver (EASL) held in April 2009, HBsAg loss was considered as the ideal surrogate marker of CHB healing for the following reasons: it is easy to measure; it is correlated to the liver concentration of ccc-DNA; it reflects the infection of the liver cells; it is the closest marker to cure.
The failure of healing of the disease explains why experts are trying to boost the long-term immunological response by vaccinating patients. Up to now the results obtained with different schemes of vaccination are encouraging but insufficient to fully control the disease. It is expected that the addition of IL-7 (CYT107) may improve the results observed with the antiviral treatments and the vaccines such as GenHevac B Pasteur®.
In the CONVERT study, the combination of three factors may result in producing a protective immune response against the HBV virus in a significant proportion of patients:
- The severe drop in viral load due to entecavir or tenofovir treatment will decrease the frequency of PD-1 expressing T cells and rescue them from exhaustion, leaving room for protective T cells expressing the IL-7 receptor (CD127+)
- The repeated administration of GenHevac B Pasteur® vaccine should support the production of anti-HBV specific T cells, including central memory T cells
- The cycle of CYT107 treatment should both facilitate the production of naïve CD4 and CD8 T cells available for specific antigen response and support the production of long lived central memory specific T cells
The restoration of specific immune response should translate into HBe- and/or HBsAg seroconversion together with direct viral elimination of residual HBV DNA. Moreover the antifibrotic effects of CYT107 may prevent or slow the evolution to cirrhosis. In this early investigative study, the aim will be to better understand how to optimize this combined therapeutic approach to favor a protective and long lasting immune response.