Current Papers in Liver Disease - November, 1996

By Howard J. Worman, M. D.
Columbia University

This is a past issue of Current Papers in Liver Disease.

Click here for information on Current Papers and the current issue.

Tanaka, E., Alter, H. J., Nakatsuji, Y., Shih, W.-K., Kim, J. P., Matsumoto, A., Kobayashi, M., and Kiyosawa, K. 1996. Effect of hepatitis G virus infection on chronic hepatitis C. Annals of Internal Medicine. 125:740-743.

Hepatitis G virus (HGV) is a flavivirus related to the hepatitis C virus (HCV). In this paper, the authors retrospectively studied 189 randomly selected patients from a university hospital in Japan with chronic hepatitis C. Of these 189 patients, 21 (11%) were co-infected with HGV as determined by serum reverse transcription-polymerase chain reaction. On average, patients with serum HGV RNA were slightly younger but similar in other demographic and clinical features to those without HGV. Patients with and without HGV co-infection were infected with similar distributions of HCV genotypes. Ten of 101 patients treated with interferon-alpha for chronic hepatitis C had HGV co-infection, and the rate of sustained response to therapy in this small sample was similar to that for patients without HGV. Serum HGV RNA levels decreased during therapy with interferon-alpha in 9 patients in whom in was measured, with HGV as determined by serum reverse transcription-polymerase chain reaction. On average, patients with serum HGV RNA were slightly younger but similar in other demographic and clinical features to those without HGV. Patients with and without HGV co-infection were infected with similar distributions of HCV genotypes. Ten of 101 patients treated with interferon-alpha for chronic hepatitis C had HGV co-infection, and the rate of sustained response to therapy in this small sample was similar to that for patients without HGV. Serum HGV RNA levels decreased during therapy with interferon-alpha in 9 patients in whom in was measured, however, in most of these patients, HGV RNA was again detectable after therapy was stopped. In summary, this retrospective analysis suggests that patients with chronic HCV and HGV co- infection do not differ from patients with only HCV infection. It also appears that HGV is sensitive to therapy with interferon-alpha.

Zein, N. N., Rakela, J., Krawitt, E. L., Reddy, K. R., Tominaga, T., Persing, D. H., and the Collaborative Study Group. 1996. Hepatitis C virus genotype in the United States: epidemiology, pathogenicity, and response to interferon therapy. Annals of Internal Medicine. 125:634-639.

Hepatitis C virus is classified into multiple genotypes based on sequence differences in the viral genome. In this study, the investigators retrospectively studied 179 patients in the United States with chronic hepatitis C to determine how genotype related to epidemiology, pathogenicity and response to therapy. Fifty-eight percent of patients had genotype 1a, 21% had 1b, 2% had 2a, 13% had 2b, 5% had 3a and 1% had 4a. There was no association between genotype and mode of acquisition of infection. Patients with genotypes 1a and 1b had more severe hepatitis. Twenty-eight percent of patients with genotype 1a based on sequence differences in the viral genome. In this study, the investigators retrospectively studied 179 patients in the United States with chronic hepatitis C to determine how genotype related to epidemiology, pathogenicity and response to therapy. Fifty-eight percent of patients had genotype 1a, 21% had 1b, 2% had 2a, 13% had 2b, 5% had 3a and 1% had 4a. There was no association between genotype and mode of acquisition of infection. Patients with genotypes 1a and 1b had more severe hepatitis. Twenty-eight percent of patients with genotype 1a and 26% of patients with genotype 1b had a complete biochemical response to treatment with interferon-alpha for six months. In contrast, 71% of patients with genotype 2a or 2b had a complete response to interferon therapy. This study confirms that 1a and 1b are the most predominant hepatitis C virus genotypes in the United States and that patients infected with these viral genotypes generally have more severe liver disease and lower rates of response to interferon therapy than patients infected with genotypes 2a or 2b.

Lai, M.-Y., Kao, J.-H., Yang, P.-M., Wang, J.-T., Chen, P.-J., Chan, K.-W., Chu, J.-S., and Chen, D.-S. 1996. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology. 111:1307-1312.

Interferon alpha is effective in the treatment of chronic hepatitis C, however, only about 20% of treated patients have a lasting response characterized by normal serum ALT activities and undetectable serum viral RNA levels. This unblinded, pilot study compared treatment with interferon alpha alone to treatment with interferon alpha plus ribavirin, another antiviral agent. Sixty noncirrhotic patients with chronic hepatitis C, who had not previously received interferon, were randomly assigned to three groups. Group 1 received 3 million units of interferon alpha-2a three times a week plus 1200 mg of ribavirin daily. Group 2 received 3 million units of interferon alpha-2a three times a week. Group 3 received no treatment. After 24 weeks of treatment, 76% of patients in Group 1 had a complete response compared to 32% of patients in Group 2 (P<0.025) and no patients in Group 3. Ninety-six weeks after stopping the drugs, 43% of patients in Group 1 had a lasting response compared to 6% of patients in Group 2 (P<0.017). The results of this pilot study suggest that combination therapy with interferon alpha plus ribavirin may be superior to interferon alpha alone in inducing a long-term response in patients with chronic hepatitis C.

Kim, J. L., Morgenstern, K. A., Lin, C., Fox, T., Dwyer, M. D., Landro, J. A., Chambers, S. P., Markland, W., Lepre, C. A., O'Malley, E. T., Harbeson, S. L., Rice, C. M., Murcko, M. A., Caron, P. R., and Thomson, J. A. 1996. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell. 87:343-355.

and

Love, R. A., Parge, H. E., Wickersham, J. A., Hostomsky, Z., Habuka, N., Moomaw, E. W., Adachi, T., and Hostomska, Z. 1996. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell. 87:331-342.

The hepatitis C virus (HCV) genome encode a polyprotein of approximately 3000 amino acids that is proteolytically processed in structural and non-structural viral polypeptides. The structural (core and envelope) polypeptides are generated by cleavages by cellular proteases. The non-structural polypeptides are generated by cleavages by viral proteases. A serine protease located within the HCV non-structural protein 3 (NS3) is responsible for four site-specific cleavages that generate other non-structural proteins. The NS3 protease requires a cofactor polypeptide, NS4A, for activity and is considered essential for viral replication. Inhibitors of the NS3 protease, or its interaction with NS4A, could therefore be clinically useful anti-viral agents. In these two papers, the three-dimensional structures of the NS3 protease and the NS3 protease-NS4A complex have been solved. The paper by Love et al. reports on work done primarily at Agouron Pharmaceuticals, Inc. These investigators showed that the NS3 protease folds as a trypsin-like protease with two beta-barrels and a catalytic triad of histidine, aspartate and serine at the active site. The active site has a structure consistent with the cleavage specificities of the enzyme. These workers also identify a zinc-binding site, likely involved in structural stability, and a long amino-terminus that may interact with neighboring molecules. The paper by Kim et al. reports on work done primarily at Vertex Pharmaceuticals, Inc. These investigators also identified a chymotrypsin-like fold with critical histidine, aspartate and serine residues and a tetrahedrally coordinated zinc binding site distal to the active site. This group also described in detail the interaction between the NS3 protease and its NS4A cofactor. The results reported in these two papers provide critical information necessary for the rational design of drugs to inhibit a viral enzyme essential for HCV replication.

Council of State and Territorial Epidemiologists (CDC). 1996. Ten leading nationally notifiable infectious diseases - United States, 1995. Mobidity and Mortality Weekly Report. 45:883-884.

This brief paper presents the most commonly reported notifiable diseases in the United States for 1995. The data come from the National Notifiable Diseases Surveillance System (NNDSS), a passive surveillance system comprising 52 infectious diseases designated by the Council of State and Territorial Epidemiologists as reportable to the Centers for Diseases Control and Prevention (CDC). Of the ten most commonly reported diseases, hepatitis A was number five and hepatitis B number ten. The top four reported diseases were chalamydia, gonorrhea, acquired immunodeficiency syndrome (AIDS) and salmonellosis. Although these findings reflect only diseases that are diagnosed by health-care or laboratory workers and are reported to state and local health departments, who then report to the CDC (probably underestimates), they are useful for monitoring trends and for determining relative disease burdens.

Brazas, R., and Ganem, D. 1996. A cellular homolog of hepatitis delta antigen: implications for viral replication and evolution. Science. 274:90-94.

The hepatitis D virus (HDV) causes severe liver injury in patients infected with the hepatitis B virus. HDV contains a 1700-nucleotide, single-stranded, circular RNA genome that encodes one known protein termed hepatitis delta antigen (HDAg). HDAg is required for HDV genome replication. The remainder for the HDV genome resembles those of viroids, small naked infections RNA molecules that produce diseases in plants. In this study, the authors used the yeast two-hybrid assay to identify a cellular protein that interacts with HDAg. This protein, which the called DIPA for delta-interacting protein A, had 24% amino acid sequence identity to HDAg and 56% similarity. DIPA also showed similarity to the transcription factor FRA1 consistent with it being a nucleic acid binding protein. Overexpression of DIPA inhibited HDV replication in cells and specifically down-regulated HDV RNA synthesis. HDAg overexpression reversed DIPA inhibition of HDV replication. These findings suggest that DIPA is a potent cellular inhibitor of HDV replication and that HDAg functions to reverse this inhibition in infected cells. Furthermore, this study has implications for the evolution of HDV suggesting that it may have arisen from a viroidlike RNA capture of a cellular RNA transcript.

Poynard, T., Leroy, V., Cohard, M., Thevenot, T., Mathurin, P., Opolon, P., and Zarski, J. P. 1996. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C. effects of dose and duration. Hepatology. 24:778-789.

Many previous studies have shown that interferon is effective in the treatment of patients with chronic hepatitis C. The standard interferon regimen for this disease is 3 million units (MU) three times a week for 6 months, however, some studies have suggested that higher doses or longer treatment durations may improve the response rate. In this study, a meta-analysis of was performed on 17 trials in which interferon was compared to controls and 16 trials comparing different doses of interferon. Standard regimen of 3 MU three times a week for six months was associated with an increase in the number of patients who normalized serum ALT activities (45%) and had sustained normalization (21%) compared to controls (2%). There were also significant dose and duration effects upon the sustained response rates with 6 MU three times a week superior to 3 MU and 12 months of treatment superior to 6 months. In acute hepatitis C, 3 months of interferon treatment showed superior efficacy than control. The best efficacy/risk ration was in favor of 3 MU three times a week for 12 months in patients with chronic hepatitis C who had never been treated with interferon. Hence, this meta-analysis suggests that patients with chronic hepatitis C may benefit from longer duration treatment with interferon.

Chen, H.-L., Chang, M.-H., Ni, Y.-H., Hsu, H.-Y., Lee, P.-I., Lee, C.-Y., and Chen, D.-S. 1996. Seroepidemiology of hepatitis B infection in children. Ten years of mass vaccination in Taiwan. Journal of the American Medical Association. 276:906-908.

Hepatitis B virus (HBV) infection is endemic in much of Asia and is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Effective vaccines are available for the prevention of HBV infection. In this cross-sectional study, the authors examined the seroepidemiology of HBV infection in children 10 years after a mass vaccination program was begun in Taiwan in 1984. Serum samples from 1515 healthy children less than 12 years of age, 87% of whom had received at least three doses of HBV vaccine, were tested for serological markers of viral infection. The results were compared to those obtained in similar studies conducted in 1984, just before the vaccination program was launched, and in 1989. The overall prevalence rate of hepatitis B surface antigen (present in HBV infected individuals) significantly decreased from 9.8% in 1984 to 1.3% in 1994. The overall prevalence of hepatitis B core antibody (present in individuals with persistent or past infection) was 26% in 1984, 15% in 1989 and 4.0% in 1994. The prevalence rate for hepatitis B surface antibody (present in individuals who have been vaccinated or some of whom have been infected in the past) was 79% in 1994. These results show that mass vaccination is a successful method to control HBV infection in an endemic area.