Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

It is widely believed that the hepatitis B virus (HBV) is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes (CTLs) during acute viral hepatitis. We now demonstrate that traces of HBV are often detectable in the blood for many years after clinical recovery from acute hepatitis, despite the presence of serum antibodies and HBV-specific CTLs, which can be present at acute-stage levels. The strength of the CTL response to HBV following clinical recovery correlates with persistence of HBV DNA. It is of particular interest that HBV-specific CTLs from patients studied up to 23 years after clinical and serological recovery expressed activation markers (HLA-DR, CD69) indicating recent contact with antigen. These results suggest that sterilizing immunity to HBV frequently fails to occur after recovery from acute hepatitis and that traces of virus can maintain the CTL response for decades following clinical recovery, apparently creating a negative feedback loop that keeps the virus under control, perhaps for life.

Transgenic mice that overproduce the hepatitis B virus large envelope polypeptide and accumulate toxic quantities of hepatitis B surface antigen (HBsAg) within the hepatocyte develop severe, prolonged hepatocellular injury that initiates a programmed response within the liver, characterized by inflammation, regenerative hyperplasia, transcriptional deregulation, and aneuploidy. This response inexorably progresses to neoplasia. The incidence of hepatocellular carcinoma in this model corresponds to the frequency, severity, and age of onset of liver cell injury, which itself corresponds to the intrahepatic concentration of HBsAg and is influenced by genetic background and sex. Thus, the inappropriate expression of a single structural viral gene is sufficient to cause malignant transformation in this model. These results suggest that severe, prolonged cellular injury induces a preneoplastic proliferative response that fosters secondary genetic events that program the cell for unrestrained growth.

This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

The HLA class I-restricted cytotoxic T Iymphocyte (CTL) response is a major defense mechanism in viral infections. It has been suggested that the CTL response may contribute to viral clearance and liver cell injury during hepatitis C virus (HCV) infection. To test this hypothesis requires an understanding of the characteristics of HCV-specific cytotoxic effector cells and identification of the target antigens to which they respond. To begin this process we stimulated peripheral blood mononuclear cells (PBMC) from a group of HLA-A2 positive patients with chronic hepatitis C with a panel of 130 HCV-derived peptides containing the HLA-A2 binding motif. Effector cells were tested for their capacity to lyse HLA-A2-matched target cells that were either sensitized with peptide or infected with a vaccinia virus construct containing HCV sequences. Using this approach we have identified nine immunogenic peptides in HCV, three of which are derived from the putative core protein, three from the nonstructural (NS) 3 domain, two from NS4 and one from NS5. Selected responses were shown to be HLA-A2 restricted, mediated by CD8+ T cells and to recognize endogenously synthesized viral antigen. Unexpectedly, peptide-specific CTL responses could also be induced in seronegative individuals, suggesting in vitro activation of naive CTL precursors. The precursor frequency of peptide-specific CTL was 10 to 100-fold higher in infected patients compared to uninfected controls, and the responses were greatly diminished by removal of CD45 RO + (memory) T cells. Further quantitative studies are clearly required to establish whether a correlation exists between the HCVspecific CTL response and the clinical course of this disease. Definition of the molecular targets of the human CTL response to HCV creates this opportunity, and may also contribute to the development of a T cell-based HCV vaccine.(J. Clin. Invest. 1995. 95:521-530.)