Over the last 15 years there has been a dramatic improvement in our ability to treat chronic viral hepatitis, with interferon emerging as the mainstay of therapy for both hepatitis B and C infections. Researchers more recently have focused on improving the current interferon regimens as well as on developing combination therapies of interferon with other antiviral agents: the results in hepatitis C, following combination treatment with interferon a-2b and ribavirin, have been especially promising. The near future will bring the development of totally new therapeutic agents that may lead to novel strategies for the eradication of these two important viral pathogens. In this article, I will summarize the data from pivotal trials in both hepatitis C and B, and also outline the newer therapeutic agents currently under investigation.
- 1 Treatment of Chronic Hepatitis B Infection
- 2 Treatment of Chronic Hepatitis C Infection
- 3 Summary
Treatment of Chronic Hepatitis B Infection
Lamivudine (3TC) is an antivital drug developed in Canada, with wide use in the treatment of HIV infection. It was originally shown to dramatically reduce viral replication in Peking ducks infected with duck hepatitis virus. Although the virus almost always re-emerged on discontinuation of treatment, lamivudine’s ability to suppress viral replication warranted trials in HBV infected patients.
Results of a one year study in Chinese patients with HBeAg positive chronic HBV infection were recently reported.14 This is the largest but most difficult group of patients with chronic HBV infection to treat: most were infected at birth, and tend to respond poorly to standard interferon therapy. In this study of 358 patients, 142 were randomly assigned to receive 25 mg of lamivudine, 143 to receive 100 mg and 73 were given placebo.
The parameters studied included transaminases, HBeAg seroconversion, HBV DNA levels, and hepatic inflammation and fibrosis (Knodell’s score).
However, this is end of treatment data only and at present, we have no information on the sustainability of these responses. Unpublished data indicates that in patients with HBeAg and HBV DNA loss, the beneficial response is maintained 97% of the time.
The medication was well-tolerated, with no serious adverse effects observed. No patients had a significant deterioration in liver function. However, 14% of patients developed a mutation in the polymerase gene which makes the virus, although less virulent, 1000 times more resistant to lamivudine. Whether the mutation rate will change with longer duration treatment or whether these mutations will lead to significant clinical problems down the road, remains to be documented.
The results at 6 months or one year after stopping treatment are not given and whether worrisome flares in hepatic inflammation will occur in some patients on discontinuation of therapy remains a major concern. In fact, many of these patients continued on treatment for another year, with excellent results. However, three important questions arise: 1. Is life-long treatment required? 2. Is there risk to stopping lamivudine? 3. Will the rate of drug-induced mutants increase with prolonged therapy?
We do not have the answers to these questions at present and until we do we should not be treating all patients with chronic hepatitis B with lamivudine. At present we should certainly consider lamivudine treatment for patients with significant fibrosis or cirrhosis who are heading in the direction of needing a liver transplant. To the best of our knowledge, these patients must continue lamivudine therapy long-term once it has been started. Patients with less advanced disease should still be initially considered for standard interferon treatment which in carefully selected individuals has a 33% success rate.2 Patients with mild disease should continue to be observed until long-term data on lamivudine treatment are available. An important concern with lamivudine therapy is the development of resistance, estimated to occur in 11% to 15% of patients after one year of therapy, and more than 30% after two years.
Lamivudine is, without doubt, useful in the hepatitis B patient requiring a liver transplant. Lamivudine, with or without hepatitis B immunoglobulin, has been shown to reduce the incidence of posttransplant hepatitis B infection and the associated severe cholestasis.3 Long- term studies are also required in this population, but the current results are most promising. Some patients treated with lamivudine while waiting for a liver transplant have improved so much they were taken off the transplant waiting list.
Because of the development of lamivudine resistant mutants in both the transplant and non-transplant settings, there is interest in combination therapy as is used in HIV infection. Thus far, lamivudine and penciclovir have been used successfully in treating duck hepatitis with the combination therapy showing synergy and better results than either agent alone.4 Studies in HBV infected patients are ongoing and such combination treatment looks promising.
Several other nucleoside analogues with similarities to lamivudine are currently being investigated in both animal models and humans with HBV infection. Famciclovir, adefovir, dipivoxil and lobucavir are other nucleoside analogues which inhibit the HBV polymerase enzyme and have variable degrees of success in reducing the amount of closed circular DNA, often the cause of posttreatment rebound infection. These drugs induce mutations different from those observed in lamivudine-treated patients and offer the real possibility that combination therapy may be superior to single agent therapy.
Thymosin a1 (Ta) is an immunomodulatory peptide produced by the thymus and other cells. It stimulates T-cell maturation, antigen recognition, natural killer cell activity and the production of native interferons. Pilot studies showed some benefit in chronic HBV infection and as a result a therapeutic trial was undertaken in 98 Chinese patients to assess its efficacy and tolerability.5 Eighteen months after entry, 40.6% of patients receiving 1.6 mg sc bid for 26 weeks had cleared HBV DNA and HBeAg compared with 26.5% in the group receiving 52 weeks of the same treatment and 9.4% in the untreated control group. None cleared HBsAg. No significant side-effects were observed. Although this is only a single study, results are encouraging as they are significantly better than those observed with either lamivudine or IFN in this patient population.
Other Potential Therapies for Chronic HBV Infection
Several other lines of investigation are being taken in the approach to treatment of chronic HBV infection. As with other viral agents, vaccination with antigenic epitopes are being investigated. Antisense oligonucleotides and ribozymes have some theoretical potential and are being studied.6 Recently, an inhibitor of the endoplasmic reticulum a-glucosidase, which prevents proper folding and transport of the hepadnavirus glycoproteins, has been reported to be successful in the woodchuck hepatitis model.7 Human studies are planned.
Ultimately, we may use a cocktail of antiviral drugs as is currently the norm in the treatment of HIV infection, with the hope of reducing resistance and improving response rates.
Treatment of Chronic Hepatitis C Infection
Interferon and Ribavirin
The use of interferon (IFN) monotherapy for chronic hepatitis C infection has been the subject of a great deal of research attention. However, even with the use of different types of interferon, different dosages, and different durations of treatment, sustained virological and biochemical responses were seen typically in less than a quarter of patients. These unsatisfactory long-term results with single-agent therapy led to the examination of combination therapy using ribavirin. Ribavirin, a guanosine analogue, had previously been shown to be ineffective in HCV infection when used as a solo agent, although a transient improvement in transaminases was often observed. In combination with interferon however, results are significantly better.
The first of the trials of combination therapy in the treatment of HCV infection was reported early in 1998.8 In a double-blind study, 50 naive patients (previously untreated with interferon) were treated with IFN a-2b 3 mu tiw plus placebo or ribavirin 1000 to 1200 mg orally, for 24 weeks. Follow-up was carried out at 24 weeks and 1 year posttreatment.
Of the 50 patients treated in this study, 33 had genotype 3a, which is quite rare in most of Canada. The sustained response in type 3a patients was 53% compared with only 13% in those with type 1b and 36% in those with type 1a. The side-effects observed were typical of IFN, with significant hemolytic anemia observed in the group receiving ribavirin. The anemia is commonly seen with ribavirin treatment and responds well to dosage reduction, but close monitoring of these patients is required. This is especially true for patients with other conditions who could not tolerate significant anemia.
Two larger randomized trials, one from the United States and one from Europe, were recently published.9, 10 These investigators compared IFN a-2b plus ribavirin, either for 24 or 48 weeks, with IFN a-2b plus placebo for 48 weeks (the American trial also had a 24-week IFN a-2b plus placebo arm). The American trial enrolled 912 naive patients, of whom 72% had genotype 1.9 In the European trial, with 832 patients, 59% had genotype 1, 36% genotype 2 or 3, and 6% had other genotypes.10
More detailed analyses in these two large trials showed that in patients with genotype 1, sustained responses were much better after 48 weeks of combination treatment, than after 24 weeks of therapy (28% vs 16% in the American study, 31% vs 18% in the European study, which included genotypes 1,4,5, and 6 in a pooled analysis). However, for patients with genotype 2 or 3, there was no significant difference with the prolonged combination therapy compared with the shorter duration (66% vs 69% in one study, 64% and 64% in the other). This finding, along with similar results concerning viral load, raises the intriguing possibility that patients may be identified who do not require a full year of therapy in order to achieve good results.
Similar trials have been conducted to examine the use of combination therapy in chronic hepatitis C patients who have relapsed after previous successful interferon monotherapy. In one study, the response rate in the combination group was 42%, compared with a response rate in the IFN-only group of 3%.11
The results of these large trials have now clearly established combination therapy, with IFN a-2b and ribavirin, as the standard of treatment for chronic hepatitis C. However, it remains to be determined as to whether the duration of treatment should be determined by the genotype of the virus.
Other Interferon Regimens
As the combination trials with IFN a-2b and ribavirin were being conducted, other investigators were working to clarify dosing regimens for IFN monotherapy. Although combination therapy is more effective than monotherapy, these trials offer some interesting information about the use of IFN.
Multiple interferon trials have shown that 1 year and 18 months of therapy with Intron® (interferon a-2b) is more effective in maintaining a long-term response than a 6 month course of treatment, but is less well tolerated. A recently published trial compared 6 months of lymphoblastoid IFN, a-n1 vs recombinant IFN a-2b in 1071 patients.12 At 48 weeks after treatment completion, the sustained ALT response was somewhat higher in the lymphoblastoid group (10.3% vs 6.5%) and 38/383 patients were HCV RNA negative in the lymphoblastoid group compared with 21/367 in the recombinant IFN group (p=0.04). Most of the apparent benefit of the lymphoblastoid IFN was secondary to a 50% reduction in the posttreatment relapse. This finding remains unexplained.
Consensus interferon (CIFN), is a genetically engineered molecule designed to incorporate the most common amino acid structures of naturally occurring alpha-interferons. Tong reported the results of a randomized controlled trial of CIFN 3µg or 9µg tiw for 24 weeks vs 3 mu IFN a-2b in 704 chronic HCV patients.13 CIFN 9 µg was superior to the lower dose of consensus interferon, but the results were virtually identical to that observed in the group treated with recombinant IFN a-2b, with 20.3% normalizing ALT and 12.1% with a sustained negative HCV RNA. The side-effect profile was similar to that observed with other interferons.
Another trial used CIFN in 337 patients who had either not responded to previous IFN therapy or who had relapsed after treatment.14 The patients were treated with 15 µg of CIFN for 48 weeks, a dose equivalent to 6 to 9 mu of standard IFN. The CIFN resulted in a sustained ALT response in 17% (10/59) of previous non-responders, but a 52% (22/42) response in relapsers. The sustained HCV RNA response was 13% (9/69) in non-responders but 58% (19/33) in relapsers. Whether these results reflect an intrinsic improved efficacy of CIFN itself or predominantly a response to higher dose and longer duration treatment, requires further assessment.
Investigation of a longer acting form of interferon, pegylated interferon, which only requires weekly injections, is underway. Because of its prolonged antiviral activity, it has the potential for enhanced efficacy and perhaps a reduction in the development of resistant virus.
Interferon and Thymosin a-1
Combination therapy using 26 weeks of thymosin a-1 and IFN a-2b showed improved end-of-treatment results in the combination group compared with IFN treatment alone in a trial with 109 patients.15 The rate of normalization of ALT was 37% (13/35) in the combination group vs 16.2% (6/37) in the IFN treated group and negative HCV RNA was observed in 37% (13/35) and 19% (7/37) respectively. However, in this study relapsers were retreated and therefore the sustained response to treatment is not reported. The side-effect profile was similar in both groups.
There has been some interest in amantadine, an antiviral agent, sometimes used in the treatment of influenza A. Its exact mechanism of action is unknown, but in some viral models it can interfere with viral uncoating or transcription. This year Smith reported the results of her pilot study of amantadine 100 mg po bid for 6 months in 22 IFN nonresponders.16 Two patients withdrew from the study because of side-effects. Of the remaining 20 patients, four developed a sustained negative HCV RNA level and six normal transaminases. However, two negative studies have also been reported, although only in abstract form. This medication warrants further investigation, possibly in conjunction with IFN or other antiviral agents.
As with hepatitis B, newer therapeutic agents such as ribozymes, antisense oligonucleotides and antigenic vaccines are potential agents. Protease and helicase inhibitors are being investigated as are dominant negative mutants but it will be several years before these agents are in clinical use. Research in HCV would be greatly expedited by an improved cell culture system for growing and manipulating the virus, or by an easier laboratory animal model such as we have in the woodchuck model of HBV infection. Currently, only chimpanzees can be infected with HCV, and they do not have the same high carrier rate observed in humans.
Headway is being made in the treatment of these two viral pathogens. With increased worldwide use of the hepatitis B vaccine, chronic HBV infection should eventually become less of a health problem. HCV infection, even now, is seldom transmitted by blood and blood products and thus the number of new infections may decline. However, with intravenous drug use so rampant, there may not be any obvious change in incidence of HCV infection in the near future. In addition, there are a huge number of patients currently infected with hepatitis C, who will ultimately require liver transplant if successful therapy is not available in the next ten years. We can realistically hope that our search for improved therapeutic regimens for HCV will be successful within the next decade.
Linda J. Scully, MD
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