Therapy of viral hepatitis

The therapy of viral hepatitis has great medical and socioeconomic impact. Today chronic viral hepatitis is the most important cause for chronic liver disease, liver cirrhosis, and hepatocellular carcinoma. Hepatitis A and E cause acute courses exclusively whereas infection with the hepatitis B, C, and D virus might result in chronic hepatitis as well. The goal of therapy of chronic viral hepatitis has to be a reduction/normalisation of elevated transaminases, decrease of the serologic parameters of active viral replication, improvement of histology and prevention of complications of chronic hepatitis. The only drug with proven benefit in the treatment of chronic viral hepatitis is interferon alpha. This therapy results in a sustained response in 25 to 40% for hepatitis B and 10 to 25% for hepatitis C infection. New developments under clinical evaluation are Lamivudine and Famciclovir in the treatment of HBV-infection and Ribavirin in combination with INFa for chronic HCV-infection.     

Differential sensitivity of hepatitis C virus quasispecies to interferon-alpha therapy

The quasispecies nature of hepatitis C virus was investigated in a patient with chronic hepatitis C virus infection who underwent interferon-alpha therapy. The hepatitis C virus E2/NS1 region was amplified and cloned, and multiple clones were sequenced before and after interferon-alpha therapy. The hepatitis C virus quasispecies can be grouped into three groups by phylogenetic tree analysis. Quasispecies from all the groups were present before interferon-alpha therapy. However, only group 3 remained after interferon-alpha therapy. In addition, only group 3 hepatitis C virus quasispecies were present during the early biochemical relapse. These data indicate that various groups of hepatitis C virus quasispecies may have different sensitivity to interferon-alpha.     

Subjective experience of treatment, side-effects, mental state and quality of life in chronic schizophrenic out-patients treated with depot neuroleptics

Treatment of chronic hepatitis B and C aims to achieve viral eradication. Decreasing the number of carriers subsequently reduces the transmission of the viruses. For an individual patient, therapy is aimed at preventing cirrhosis, liver failure and hepatocarcinoma. Among potential therapies, interferon alfa offers the best results. In one study involving the treatment of children from a region of intermediate endemicity, interferon alfa accelerated the clearance of hepatitis B virus (HBV) replication. In long-term follow-up, the study did not show a significant difference between patients who were treated and those who were not in the rate of disappearance of serum HBV-DNA, normalization of alanine aminotransferase (ALT) levels or seroconversion to antibodies to hepatitis B e antigen. The most important factors in predicting a rapid decrease in HBV replication were AI T levels more than twice normal, low levels of serum HBV-DNA (less than 100 pg/mL) and inflammatory activity on liver biopsy (chronic active hepatitis). A select group of children with HBV infection has thus been shown to benefit from interferon alfa therapy. Treatment should be administered in a dosage of 6 MU/m2 three times each week for 6 months. Chronic active hepatitis, develops in approximately 30% of children with a chronic hepatitis C virus (HCV) infection. Cirrhosis due to HCV appears to be a very rare complication among children. Results of interferon alfa treatment for children with HCV are scarce. A pilot study of 12 children treated with interferon alfa in a dosage of 3 MU/m2 three times each week for 6 months showed that ALT levels normalized in approximately 90% of the patients after 15 months of follow-up. All of the patients had a decrease in the histological activity of the disease. Factors predictive of a favourable response in adults were: low levels of gamma-glutamyl transferase, young age, female sex, short duration of disease, absence of cirrhosis and low histological activity of the disease. Controlled randomized studies are needed to determine the indications for interferon alfa therapy in children infected with HCV. Available data suggest that children may have a better response than adults.     

Prognosis of chronic hepatitis C: results of a large, prospective cohort study

The prognosis of chronic hepatitis C virus (HCV) infection is still ill-defined. The present study prospectively evaluated mortality and complications in a large cohort of patients with chronic hepatitis C. The study included 838 anti-HCV and HCV-RNA-positive patients who were followed for 50.2 +/- 26.9 months (mean +/- SD; range, 6-122 months) in a prospective protocol. During follow-up, 62 patients died (31 from liver disease and 31 from other causes), and 12 patients needed liver transplantation. When compared with a matched general population, hepatitis C increased mortality mainly when cirrhosis was present and in patients who were less than 50 years old at study entry. During follow-up, a further 30 patients developed nonlethal complications of cirrhosis. By multivariate regression, survival was decreased by cirrhosis, long disease duration, history of intravenous drug abuse, and excessive alcohol consumption, whereas interferon therapy improved survival. Alanine transaminase (ALT), bilirubin, sex, and genotype had no effect on survival. The risk of hepatocellular carcinoma (HCC) (n = 17) was increased by cirrhosis and to a lesser degree by long disease duration and high bilirubin, whereas interferon therapy, genotype, and other factors had no effect. Chronic hepatitis C is a disease with considerable mortality and morbidity when cirrhosis is present at diagnosis. Patients who acquire the infection early in life have a markedly increased mortality even when cirrhosis is absent at diagnosis. The age at diagnosis therefore should play a major role in therapeutic considerations. The present data also suggest that interferon therapy has a long-term clinical benefit, although it did not reduce the risk of liver cancer.     

The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C

Since the discovery of hepatitis C virus it has become clear that chronic hepatitis C is a major health problem throughout the world. Because antiviral agents are of limited value in the treatment of chronic hepatitis C, research has focused on the antiviral immune response for the development of both a protective vaccine and effective immunotherapies for established chronic infection. Antiviral antibodies are present in almost all patients with chronic hepatitis C but do not seem to be virus neutralizing, probably due to the high mutational rate of viral envelope proteins. Studies on the antiviral T cell response have revealed the presence of virus-specific CD4+ helper and CD8+ cytotoxic T cells in a substantial proportion of patients with chronic hepatitis C. Recent studies describe an association between strong CD4+ T helper cell activity to certain hepatitis C virus antigens and a self-limited course of acute hepatitis C and possibly also a sustained response to treatment with interferon-alpha. Therapeutic manipulation of the virus-specific T cell response may thus develop into a new approach for prevention and treatment of hepatitis C virus infection.     

Prospective comparison of four lymphoblastoid interferon alpha schedules for chronic hepatitis C. A multivariate analysis of factors predictive of sustained response to treatment

OBJECTIVE: Interferon alpha (IFN-alpha) provides effective treatment in some patients with chronic hepatitis C. Since this drug is costly and causes potentially severe side effects, there is a need for clarification of the optimal dose regimen and treatment duration and of the predictive factors of long-term response to this therapy. DESIGN: Prospective, randomized study in patients with chronic hepatitis C. SETTING: 'Crespi' Division of Medicine and Centre for Liver Diseases, Niguarda Hospital, Milan, Italy. PATIENTS AND METHODS: One hundred and forty-two patients with chronic hepatitis C were randomized to receive IFN-alpha at a dosage of 2-4 mega units/square metre of body surface area thrice weekly for 6-12 months. Eleven baseline variables that might predict sustained response to IFN-alpha were evaluated in this series. Sustained response was defined as normalization of transaminase levels observed by the fourth month of therapy and lasting for at least 6 months after treatment withdrawal. RESULTS: According to univariate analysis, variables significantly associated with sustained response to treatment were: hepatitis C virus (HCV) genotype, treatment duration, serum HCV-RNA level and duration of hepatitis. On multivariate analysis only two of these variables were found to be independently associated with sustained response to IFN-alpha: HCV genotype (P < 0.0001) and treatment duration (P = 0.0015). In the patients infected with genotype 1b, IFN-alpha was effective only when administered at the higher dosage and for the longer period. CONCLUSION: Viral genotype and treatment duration are independently related to sustained response to IFN-alpha in patients with chronic hepatitis C. The patients infected with HCV genotype 1b should receive IFN-alpha at the higher dosage and for the longer period.     

Serum hepatitis G virus RNA in patients with chronic viral hepatitis

OBJECTIVES: The hepatitis G virus (HGV) is a newly described flavivirus that affects a high proportion of patients with chronic viral hepatitis: our objective was to determine what role HGV might play in the course of disease. METHODS: We evaluated stored serum samples from 108 patients with chronic hepatitis B and 99 patients with chronic hepatitis C who participated in trials of alpha-interferon or ribavirin for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA by branched DNA and for the presence of HGV RNA by polymerase chain reaction (PCR), using primers from the NS5 region of the genome. RESULTS: Initially, 20 (19%) patients with hepatitis B and 11 (11%) with hepatitis C had HGV RNA in their serum. Patients with and without HGV infection were similar with regard to clinical features, laboratory tests, and hepatic histology. HGV RNA levels fell during interferon therapy and became undetectable in those receiving the highest doses; however, HGV RNA levels returned to pretreatment values when therapy was stopped. With ribavirin therapy, HGV RNA levels did not change. Two- to 12-yr follow-up serum samples were available from 17 initially HGV RNA-positive patients, of whom only 10 (59%) were still positive. CONCLUSIONS: HGV infection is common among patients with chronic hepatitis B and C but has little effect on the short-term course of disease or response to therapy. HGV RNA levels are suppressed but not eradicated by alpha-interferon and are unaffected by ribavirin treatment. Spontaneous loss of HGV RNA occurs over time in a proportion of patients.     

Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease

Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.     

Therapy of hepatitis C

The purpose of this review is an update of the therapy of hepatitis C especially with Interferon-alpha. From the large number of publications on this topic the established facts were worked out. Taking these facts as a base guidelines for the therapy in practical use were defined. In addition the aspects of therapeutic strategies of chronic hepatitis C which until now can not definitely be judged are discussed. In the relatively few patients in whom hepatitis C is diagnosed already in the acute phase, Interferon-alpha-treatment (3 x 3 million units 3 times a week) for 3 to 4 months increases the percentage of patients in whom HCV-RNA in the serum is eliminated. In patients with chronic hepatitis C, after decision finding for treatment, a standard scheme is recommended which consists of a monotherapy with recombinant Interferon-alpha. The dosage of Interferon-alpha is in the first 12 to 16 weeks 5 up to 6 million units given 3 times a week. For the further therapy 3 million units 3 times a week seems to be appropriate. The recommended duration of Interferon-alpha-therapy is 12 months. A long-term benefit of about 20% can be achieved in unselected groups of patients when judged on the permanent normalisation of serum transaminases and elimination of HCV-RNA in the serum. Important factors which may influence the probability of a sustained response, like HCV genotype, virus titer in serum, duration of the disease, high hepatic iron content and the presence of cirrhosis, are discussed. Up to now there exist no reliable guidelines in the case of a "no change" situation and for patients with a flare-up of inflammatory activity during or after therapy. Combination therapy of Interferon-alpha with other drugs like analogous of nucleotides (for example ribavarin), non steroidal antirheumatic drugs and ursodesoxycholic acid (UDCA) have still to be evaluated in controlled clinical trials.     

Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.     

Chronic hepatitis in children after liver transplantation: role of hepatitis C virus and hepatitis G virus infections

BACKGROUND/AIMS: Chronic graft hepatitis occurs in 20-30% adults after liver transplantation but the prevalence and causes in children are not known. In adults, hepatitis C virus infection is prevalent prior to transplantation and recurrent infection is a frequent cause of graft dysfunction. The significance of the recently described hepatitis G virus infection remains unproven. The aim of this study was to examine the role of hepatitis C virus and hepatitis G virus infection in chronic graft hepatitis after paediatric liver transplantation. METHODS: The prevalence of graft hepatitis and the role of hepatitis C virus and hepatitis G virus infections in 80 children after liver transplantation have been studied, with a median follow up of 4.4 years (range 0.4 to 10.7), and the persistence of hepatitis G infection in the presence of immunosuppression has been determined. RESULTS: Chronic graft hepatitis was diagnosed in 19/80 (24%) children and was most frequently seen in children transplanted for cryptogenic cirrhosis (71%). There was no significant difference in the prevalence of chronic hepatitis in those transplanted before or after donor anti-HCV screening. Hepatitis C infection occurred in three children transplanted prior to donor screening but in only one was associated with chronic hepatitis. Hepatitis G infection was found in 22/79 (28%) transplant recipients but was not associated with graft hepatitis. In 17/21 children hepatitis G infection persisted for a median of 5.2 years after transplantation. CONCLUSION: Chronic hepatitis occurred in 24% of children after liver transplantation, a similar prevalence to that in adults. Cryptogenic liver disease predisposed to graft hepatitis, but neither hepatitis C nor hepatitis G infection was associated. Hepatitis G virus caused a frequent and usually persistent infection after transplantation.     

Overview of nuclides for bone pain palliation

Currently, six distinct types of hepatitis virus have been identified: A, B, C, D, E, and G. Hepatitis A virus infection does not cause a chronic carrier state, and perinatal transmission is extremely uncommon. Hepatitis B can be transmitted perinatally, but immunization of the newborn with hepatitis B immune globulin and hepatitis B vaccine markedly reduces the risk of neonatal infection. Hepatitis D virus is dependent on coinfection with the hepatitis B virus for replication. Immunoprophylaxis against hepatitis B also is effective against hepatitis D. Hepatitis C virus is primarily transmitted by the parenteral route and is particularly likely to cause chronic liver disease. Perinatal transmission of hepatitis C principally occurs in women who have high titers of HCV-RNA or who are coinfected with human immunodeficiency virus. At this time, no immunoprophylaxis for hepatitis C is available. Hepatitis G, a recently described organism, is related to hepatitis C. Its clinical significance remains undetermined. Hepatitis E is transmitted in a manner similar to hepatitis A. Perinatal transmission is unusual, but maternal disease is often severe.     

Seroepidemiologic study of HCV genotypes in the district of Messina and Catania

Aim of the study was to identify the different hepatitis C virus (HCV) genotypes in chronic hepatitis patients living in the districts of Messina and Catania (Sicily, Italy), for epidemiological reasons but also to determine the effect of interferon therapy on therapeutic response of different viral genotypes. Genotyping was carried out by reverse-hybridization after amplification by polymerase chain reaction. The study was conducted on 271 patients with HCV-RNA positive chronic liver disease belonging to categories at risk or not for infection. HCV genotype sub-type 1b was the most common viral genotype identified.     

Comparison of Ottawa ankle rules and current local guidelines for use of radiography in acute ankle injuries

INTRODUCTION: We report the occurrence of non-Hodgkin's lymphoma during the course of chronic hepatitis C treated with alpha-interferon. EXEGESIS: Specific viruses such as Epstein-Barr virus and human T-cell leukemia viruses I and II may be at the origin of various lymphomas in human. The presence of B cell lymphoma in the course of chronic hepatitis C has already been described and could be related to the lymphoid tropism of hepatitis C virus. CONCLUSION: This new report of an association between chronic hepatitis C and B cell lymphoma should lead physicians to search for signs of lymphoma in patients with chronic hepatitis C.     

Comparison of technetium-99m-MIBI and technetium-99m-tetrofosmin uptake by musculoskeletal sarcomas

The development of molecular biology techniques has enabled us to clone the genetic sequence of three new hepatitis viruses, namely, hepatitis C virus, hepatitis E virus and hepatitis G, or GBV-C virus in the last decade. Hepatitis C virus (HCV) is now known to account for the majority of the parenterally transmitted non-A, non-B hepatitis and hepatitis E virus (HEV) is the major cause of the epidemics of enterally transmitted non-A, non-B hepatitis in the less developed countries, mainly through contaminated water supplies. While 80% of those who were infected with HCV will become chronic carriers, there is no known chronic carrier state for HEV. To date, 6 major genotypes of HCV were identified, with various variants of genotype 6 described in Southeast Asia. In Singapore, the majority of our chronic hepatitis C patients are infected with genotype 1. The seroprevalence rate of HEV is 10% to 14% in Singapore. This probably reflects our suboptimal sanitary condition in the past rather than a reflection of a currently high HEV infection rate in our population. However, local cases of acute hepatitis E have been reported. As for the most recently cloned hepatitis G virus, its aetiologic role in the remaining cases of non-A, non-B hepatitis is still unclear. Some preliminary evidence suggests that it may be just an innocent bystander with limited pathogenicity and it certainly cannot account for all the remaining cases of non A-E hepatitis. Hence, the search for yet another hepatitis virus continues.     

Chronic non-A, non-B, non-C hepatitis: is hepatitis G/GBV-C involved?

BACKGROUND: Hepatitis G virus/GBV-C is a recently discovered virus, and its relevance in chronic hepatitis is still debated. METHODS: We have previously described 127 long-term-studied and well-characterized patients with chronic non-A, non-B hepatitis (NANBH). Ninety-one (71.7%) were positive for hepatitis C virus antibodies (anti-HCV) in a first-generation anti-HCV enzyme-linked immunosorbent assay (ELISA). We now reanalyzed the same group of patients and added a third-generation anti-HCV ELISA and recombinant immunoblot assay and, in negative patients, also polymerase chain reactions for hepatitis C virus RNA, hepatitis GBV-C RNA, and hepatitis B virus DNA. Additional tests for autoimmune hepatitis types 2 and 3 were also included. RESULTS: Anti-HCV were detected in 114 of the 123 evaluable patients (92.7%). Of the remaining nine anti-HCV-negative patients one had misdiagnosed primary biliary cirrhosis, and two had autoimmune hepatitis type 3. None of the anti-HCV-negative patients were hepatitis GBV-C RNA-, HCV RNA-, or HBV DNA-positive. Thus, 114 of 120 NANBH patients (95.0%) had chronic hepatitis C. None of the remaining six patients had received blood transfusions or was a drug addict, and two of them were successfully treated with steroids. CONCLUSIONS: Hepatitis G/GBV-C as a single cause of chronic non-A, non-B hepatitis is uncommon, and in all patients with parenteral risk factors hepatitis C was detected.     

GB virus C infection in patients with primary antibody deficiency

Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6 positive CVID and 3 XLA patients had abnormal liver enzymes, explained in 3 by either hepatitis B or C virus infection. Most patients tested had antibodies to the E2 antigen of GBV-C, apparently passively acquired from their immunoglobulin therapy. The high prevalence of GBV-C viremia in CVID and XLA patients is probably explained by their long-term exposure to blood products. Our data indicate that GBV-C does not cause chronic hepatitis in immunocompromised XLA patients and is not the cause of chronic non-B or -C hepatitis in the majority of CVID patients.     

Treatment of chronic viral hepatitis

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.     

Current therapeutic trends in therapy for chronic viral hepatitis

Hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis delta virus (HDV) are associated with clinically significant chronic infection that may lead to the development of cirrhosis or even hepatocellular carcinoma (HCC). Intervention at the earliest possible stage is needed to prevent such untoward sequelae. Currently, interferon (IFN) is the only approved and widely used agent for the treatment of these infections, including in HBV patients with precore mutant hepatitis or decompensated cirrhosis, but its efficacy is far from satisfactory. Corticosteroid priming has been shown to increase the efficacy of IFN therapy in HBV patients with low abnormal serum transaminase levels, but only a few responders will clear serum hepatitis Bs antigen (HBsAg). Ongoing randomized controlled trials of thymosin alpha 1, lamivudine and famcyclovir have demonstrated encouraging preliminary results. Therapeutic vaccines, such as polypeptides with human leucocyte antigen (HLA)-specific hepatitis B core antigen (HBcAg) epitopes, are under phase II/III clinical trial. For HDV infection, the use of IFN in the early phase of acute superinfection tends to prevent chronic progression. For HCV infection, IFN used at higher doses for a longer period of time is associated with a higher sustained response, but overall it is still not satisfactory. The combined use of ribavirin or corticosteroid priming may improve the effect of IFN therapy by enhancing the durability of the response. Interferon in the acute phase of HCV infection may also prevent chronic progression. There is evidence to suggest that IFN therapy, when associated with response, tends to reduce the risk of cirrhosis or HCC and prolongs survival. There is no doubt that satisfactory treatment of chronic viral infection will require more effective agents and demand optimal treatment strategies, many of which are yet to be found.     

Elimination of hepatitis C virus RNA in infected human hepatocytes by adenovirus-mediated expression of ribozymes

Hepatitis C virus (HCV), a positive-strand RNA virus, is the major infectious agent responsible for causing chronic hepatitis. Currently, there is no vaccine for HCV infection, and the only therapy for chronic hepatitis C is largely ineffective. To investigate new genetic approaches to the management of HCV infection, six hammerhead ribozymes directed against a conserved region of the plus strand and minus strand of the HCV genome were isolated from a ribozyme library, characterized, and expressed from recombinant adenovirus vectors. The expressed ribozymes individually or in combination were efficient at reducing or eliminating the respective plus- or minus-strand HCV RNAs expressed in cultured cells and from primary human hepatocytes obtained from chronic HCV-infected patients. This study demonstrates the potential utility of ribozyme therapy as a strategy for the treatment of hepatitis C virus infection.