Treatment of chronic viral hepatitis - International Medical Press

Antiviral Chemistry & Chemotherapy 9: 449–460

Review

Treatment of chronic viral hepatitis J Main*, B McCarron and HC Thomas General Medicine and Infectious Diseases, Imperial College School of Medicine, St Mary’s Hospital, London W2 1NY, UK

*Corresponding author: Tel: +44 171 886 6312; Fax: +44 171 724 9367

Interferon-α therapy has proved effective for up to 40% of patients with adult-acquired chronic hepatitis B virus (HBV) infection and for 20–25% of those with chronic hepatitis C virus (HCV) infection. Nucleoside analogues, such as lamivudine and famciclovir, are showing promise as antiviral agents for chronic HBV and the combination of

interferon-α and ribavirin is proving to be successful therapy for 40–50% of patients with chronic HCV. In this article we review current therapy and discuss future strategies of the therapy of chronic viral hepatitis. Keywords: Hepatitis B; interferon; hepatitis C

Introduction It is estimated that there are 300 to 400 million carriers of hepatitis B virus (HBV) infection worldwide and 170 million cases of chronic hepatitis C virus (HCV) infection. Chronic viral hepatitis can lead to progressive liver disease with the development of cirrhosis and risks of hepatocellular carcinoma (HCC). The hepatitis carrier can transmit the infection to others and although the spread of HBV can now be limited by vaccination it is likely to be many years before an effective HCV vaccine becomes available. The aims of antiviral therapy are to clear the virus and hopefully thereby prevent the life-threatening complications of chronic viral hepatitis and reduce the risk of viral transmission to others. This review summarizes the progress which has been made in the therapy of chronic hepatitis B and C.

HBV Infection Chronic infection is generally defined as an ongoing infection 6 months after the initial episode. The risk of development of chronic infection depends on the age at the time of infection. It ranges from 5% in otherwise healthy adults to more than 90% in babies born to infected mothers. Host factors are important; underlying human immunodeficiency virus infection, for example, is associated with higher risks of chronicity (Hadler et al., 1991; Bodsworth et al., 1991) and MHC class II type (Thursz et al., 1995) also appears to be important in determining the outcome. The outlook is worse for males with chronic HBV infection who have a 40% lifetime chance of developing life-threatening complications. ©1998 International Medical Press 0956-3202/98/$17.00

Vaccination programmes are in progress; benefits have already been seen in Taiwanese children with reduced disease transmission and reduction in the rates of HCC (Lee & Ko, 1997; Chang et al., 1997).

Laboratory models and cell culture HBV infection of cell cultures has not been successful. However, the HBV-transfected hepatoma cell line 2.2.1.5 supports HBV replication and can be used to screen potential antiviral agents (Sells et al., 1987). Hepadnavirus infection is seen in several animal species. Woodchuck hepatitis B virus (WHBV) and Pekin duck hepatitis B virus (DHBV) are very similar viruses and are again helpful models for increasing our understanding of HBV and screening for new antiviral agents (Tennant & Gerin, 1994). HCC has been observed in woodchucks and this led to the discovery of WHBV (Summers et al., 1978). The lifetime risk of the development of HCC in infected woodchucks is more that 90%. In contrast to humans infected with HBV, where HCC is generally seen in a cirrhotic liver, cirrhosis is unusual in woodchucks and most animals have mild chronic hepatitis. Both male and female animals develop HCC and pulmonary metastases are more commonly seen than in humans with HBV infection. In ducks with chronic DHBV infection, mild hepatitis is common and the development of cirrhosis or HCC is less frequent than in humans. It is thought that there may be environmental factors involved in the development of HCC or cholangiocarcinoma as these complications are uncommon in ducks raised outside China (Duflot et al., 1995). 449

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Figure 1. Molecular structure of adenine arabinoside (araA)

Figure 2. Molecular structure of lamivudine (3TC) NH2

NH2

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S HO

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Interferon-α Interferon-α has been used since the 1970s (Greenberg et al., 1976) and remains first line therapy for chronic HBV infection. Success rates of up to 40% have been reported in those with adult-acquired disease (Brook et al., 1989; Perrillo et al., 1990) but the rates of viral clearance are much lower in those with vertically acquired infection (Lai et al., 1987). A successful response is demonstrated by the sustained clearance of HBeAg and HBV DNA, which is associated with the detection of anti-HBe antibodies. Patients with only a short period of viral infection also clear HBsAg shortly after HBeAg/anti-HBe seroconversion. Long-term follow-up studies of patients clearing HBeAg after therapy show clearance of HBsAg 7 to 10 years later (Korenman et al., 1991). It is only with longer follow-up studies that the full effects of antiviral therapy on the natural history of the disease can be determined. It is evident, however, that clearance of HBeAg following interferon therapy or spontaneous seroconversion is associated with improved survival (Niederau et al., 1996; Lau et al., 1997a). Interferon has several activities which are thought to be important in the treatment of chronic HBV infection. Antiviral actions include the inhibition of viral protein synthesis with stimulation of the intracellular adenylate synthetase enzyme. Interferon also has antiproliferative effects but it is thought that its immunomodulatory effects are particularly important in this setting. Interferon-α increases natural killer cell activity but also facilitates a cytotoxic T cell effect by enhancing MHC class I presentation. Hepatocytes have very little MHC class I display and it is thought that this reduces the host immune recognition of infected hepatocytes and supports the ongoing chronic infection. Enhancement of the MHC class I display by interferon is thought to improve immune recognition of infected cells and promote cell lysis and viral clearance. Thus, successful antiviral therapy involves inhibition of viral replication but also the elimination of infected cells. Interferon-α is given intramuscularly or subcutaneously

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and most patients can be taught self-administration. A typical regimen is 5 to 10 MU/m2 three times weekly for 3 to 4 months. Side-effects include influenza-like symptoms with myalgia and fever. These effects can be minimized by bedtime administration of the interferon and paracetamol, and tend to decrease with ongoing therapy. Myelotoxicity is a major side-effect and regular monitoring of the full blood count is mandatory. It is often possible to continue interferon at a reduced dose with mild degrees of myelotoxicity but particular caution is required in patients with cirrhosis and hypersplenism where there may be low baseline white cell and platelet counts. Depression can be a serious side-effect in patients, particularly where there is a background of premorbid psychiatric disease. Other sideeffects include diarrhoea and transient hair loss.

Nucleoside analogues Nucleoside analogues have been used for several years as therapy for chronic HBV with varying degrees of success. The development of newer antiviral agents such as reverse transcriptase inhibitors as therapy for HIV has led to the availability of several agents that have been shown to also have inhibitory effects on HBV replication. Adenine arabinoside (araA) (Figure 1) was one of the first antiviral agents to be tried as therapy for chronic HBV (Bassendine et al., 1981; Scullard et al., 1981). It is waterinsoluble and has to be given by intravenous administration, which limits its clinical use. Adenine arabinoside monophosphate (araAMP), the monophoshorylated derivative, is water-soluble and can be given by intramuscular injection. Trials confirmed that an inhibitory effect was seen on HBV replication with a decrease in the HBV DNA levels. Clinical trials reported varying rates of sustained response (Perrillo et al., 1985; Trepo et al., 1984). It became apparent that longer term dosing was associated, as reported with several other nucleoside analogues, with significant neurotoxicity and the development of peripheral neuropathy (Garcia et al., 1987). Lamivudine [(-)-β-L-2′,3′dideoxy-3′thiacytidine] (Figure

©1998 International Medical Press

Treatment of chronic viral hepatitis

Figure 3. Molecular structure of famciclovir

NH2

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Figure 4. Molecular structure of adefovir (PMEA)

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2) is a minus enantiomer and it is thought that this may help explain the very low rates of side-effects noted with this agent. Lamivudine was initially developed as an antiHIV agent and is a popular choice in combination therapy regimens for HIV (Eron et al., 1995). It is an inhibitor of reverse transcriptase activity. HBV, although a DNA virus, has reverse transcriptase activity and it is assumed that the efficacy of lamivudine in HBV infection is due to its inhibitory effects on HBV reverse transcriptase (Severini et al., 1995). The first trial of lamivudine in patients with chronic hepatitis B was a multicentre European study comparing the effects of a 1 month treatment period of various doses of drug with placebo. This study showed a rapid decrease in the levels of HBV DNA in treated patients but a return to baseline at the end of therapy (Tyrrell et al., 1993). Subsequent studies (Dienstag et al., 1995; Nevens et al., 1997) with longer treatment periods have confirmed that lamivudine is well tolerated by the majority of patients and that, in contrast to the biochemical response seen with interferon therapy, there is a gradual decline in serum transaminase levels. Even with longer treatment periods, HBeAg clearance and seroconversion is seen in only a small number of patients. Interferon-α therapy has been shown to be of limited benefit for Asian patients unless they have elevated transaminase levels. It is thought that the timing of their infection is an important factor and that there may be some host tolerance to viral antigens as a result of vertical transmission. Prolonged lamivudine therapy is currently being tried in this group of patients. In one large double-blind study (Lai et al., 1998), 358 Chinese patients were randomized to receive lamivudine (25 mg or 100 mg/day) or placebo for 1 year. Lamivudine therapy was associated with an improvement in the hepatic inflammatory activity in about 50% of the patients. HBeAg clearance occurred in

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16% of those who received the higher dose of lamivudine. However, resistant strains of HBV were noted in 14% of patients (Lai et al., 1997). Viral kinetic studies have addressed questions regarding the optimum treatment period of antiviral therapy (Nowak et al., 1996). Clearance of infected cells is likely to be as important as sustained inhibition of viral replication for eradication of infection. One group has found that the rate of decline in HBeAg is useful in predicting the response to lamivudine (Heijtink et al., 1997). Inevitably, prolonged monotherapy is associated with the development of mutations in the HBV genome and viral resistance. This was initially recognized in the setting of liver transplantation (Ling et al., 1996; Bartholomew et al., 1997) where immunosuppressive therapy and higher levels of viral replication form an ideal scenario for escape mutant formation. Resistance has now been reported in immuncompetent patients (Honkoop et al., 1997b; Lai et al., 1997). Four of 14 patients (39%) who received a 6 month course of lamivudine developed viral resistance (Honkoop et al., 1997b). Initial reports describe amino acid changes resulting from mutations in the YMDD motif – the same region in the HIV reverse transcriptase gene where mutations occur with lamivudine therapy. So far results from trials of the combination of interferon α and lamivudine have been disappointing. In vitro studies, however, suggest that the combination of lamivudine and famciclovir may be an alternative approach (Colledge et al., 1997). Famciclovir (Figure 3), the prodrug of penciclovir, is mainly used as therapy for herpesvirus infections such as herpes simplex virus types 1 and 2 and varicella-zoster virus. It requires the presence of the viral thymidine kinase enzyme for the first phosphorylation towards its active triphosphate form. HBV does not possess thymidine kinase activity but a pilot study showed that despite this HBV replication was successfully inhibited by famciclovir (Main et al., 1996). In a larger multicentre study 333 patients were randomized to receive 16 weeks of therapy with famciclovir 500 mg, 250 mg, 125 mg or placebo three times daily (Trepo et al., 1997). All doses of famiclovir led

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to a reduction in the HBV DNA and transaminase values and in the high dose group, 9/64 (14%) patients cleared HBeAg compared with 2/58 (3%) in the placebo group (P=0.04). Studies with DHBV, both in vitro with infected hepatocytes and in vivo with infected ducks have also shown evidence of viral inhibition (K Tsiquaye, D Sutton, M Maung et al., (1993). Pharmacokinetics and antiviral activities of penciclovir and famciclovir in Pekin ducks chronically infected with duck hepatitis B virus. Proceedings of Interscience Conference of Antimicrobial Agents and Chemotherapy Abstract 1594). Further studies are in progress. Famciclovir is well tolerated and may be of benefit as maintenance therapy in the setting of liver (Singh et al., 1997) and other organ transplantation. Viral resistance is being recognized (Aye et al., 1997). The extent of cross resistance with other drug-induced mutants remains to be determined. Studies of penciclovir and lamivudine suggest a synergistic effect in vitro (Colledge et al., 1997) and hopefully trials of combination therapy will show whether a similar in vivo effect is apparent and demonstrate whether resistance can be prevented or at least delayed. Adefovir (9-(2-phoshonylmethoxyethyl)adenine; PMEA) (Figure 4) is an acyclic nucleoside phosphonate analogue with a broad range of antiviral activity. It has inhibitory effects on herpesviruses, retroviruses and hepadnaviruses. Preliminary trials have shown considerable activity against HBV. There have been some concerns regarding toxicity, however, with some reports of abnormal liver function tests in some patients and reports of possible tubular damage in patients receiving more prolonged adefovir therapy.

Other antiviral agents Trials are underway with several nucleoside analogues including lobucavir (Bloomer et al., 1997). Studies of fialuridine (FIAU) (Figure 5) were suspended when several patients developed severe toxicities including lactic acidosis, pancreatitis liver and renal failure (McKenzie et al., 1995). It is thought that these severe side-effects, which were not predicted by short-term treatment studies, are related to the toxic effect of FIAU on host mitochondrial DNA. A similar syndrome has been reported as a rare adverse event with other nucleoside analogues such as zidovudine (Olano et al., 1995). The morphology and function of mitochrondria have been carefully studied in patients receiving lamivudine with no evidence, as yet, of similar phenomena (Honkoop et al., 1997a).

Future treatments Several nucleoside analogues have inhibitory effects on HBV replication and are in clinical trials. Viral resistance is likely to be a limiting factor in prolonged monotherapy regimens and it is likely that combination therapy will be

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Figure 5. Molecular structure of fialuridine (FIAU) O I HN

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increasingly tested in clinical trials. Interferon-β and -γ have been tried as therapy for chronic HBV. Interleukin-2 and interleukin-12 are further approaches (Carreno & Quiroga, 1997). Thymic peptides have also been tried in patients with chronic hepatitis B (Fattovich et al., 1994). It is hoped that a greater understanding of the immune mechanisms involved in spontaneous viral clearance will help to design more effective approaches with cytokines. An effective host Th1 response seems to be important in successful disease resolution, for example (Penna et al., 1997). Adoptive immunity can be effective in clearing chronic HBV and this has been demonstrated in the setting of bone marrow transplantation (Lau et al., 1997b; Brugger et al., 1997).

Cirrhosis and hepatic decompensation High dose interferon regimens are contraindicated in patients with decompensated liver disease. The associated hypersplenism and baseline leukopenia limits the tolerance to the drug and if immune lysis follows HBV clearance, the rapid turnover of infected hepatocytes may have an adverse effect on a liver which is already compromised. In patients with compensated cirrhosis, interferon-α may be beneficial. In one study, clearance rates of 30–40% were reported following a 12 weeks regimen of interferon-α at 10 MU three times weekly (Fattovich et al., 1997). Improved survival was also seen with interferon therapy. In cirrhotic patients with decompensated disease, treatment options are limited and transplantation may be considered. Prolonged interferon regimens have been tried in this group with some success (Marcellin et al., 1997). Other approaches include the use of low dose interferon as a maintenance regimen. Nucleoside analogues have also been tried in this group of patients and there are reports of patients with severe lifethreatening disease who have a considerable improvement in their liver function following administration of lamivudine and other agents. In this group of patients viral erad-



ication is unlikely to occur but long-term suppressive therapy may maintain liver function for some time. Such patients should also be considered for liver transplantation. Following transplantation graft, reinfection and damage are unavoidable for the patient with chronic HBe antigenaemia. Strategies used to minimize this include the administration of interferon at a cautious dose to avoid risk of graft rejection or the administration of specific hepatitis B immunoglobulin (HBIg) to prevent reinfection of the graft (Samuel et al., 1993). Viral escape mutants develop in this setting and in patients with HBs mutants s144 or s145, a less favourable outcome is evident (Protzer-Kolle et al., 1998). Trials are underway with nucleoside analogues. It is unclear at this stage how these agents should be used to best advantage. Starting therapy prior to transplantation has the theoretical benefit of reducing viral load prior to surgery but has the disadvantage that the patient may develop viral resistance and limit the subsequent use of this group of agents as maintenance therapy.

Pre-core variant infection A subgroup of patients who are HBsAg-positive, HBeAg-negative and anti-HBe-positive have evidence of ongoing viral replication and associated liver damage. It was recognized in 1989 (Carman et al., 1989) that these patients were infected with an HBV variant with a stop codon in the pre-core region which prevented transcription of HBeAg. Although the administration of interferon leads to a reduction in the transaminase values and a decrease in the HBV DNA levels there is a high relapse rate following cessation of standard therapy (Hadziyannis et al., 1990; Brunetto et al., 1995). A more recent approach has been the use of a 24 month course of interferon which led to a sustained response in approximately one third of patients (Lampertico et al., 1997). Preliminary studies have been carried out with nucleoside analogues and also demonstrate a high relapse rate following cessation of therapy.

HCV Infection HCV was discovered in 1989 (Choo et al., 1989) but it had been recognized for many years that a viral agent was responsible for many cases of post-transfusion or parenterally transmitted hepatitis. Since 1989 significant progress has been made and recent trials show a 40–50% chance of a sustained response to antiviral therapy. There has also been a greater understanding of the natural history of HCV infection. Between 60 and 80% of those infected become chronic carriers and 20% of those patients develop cirrhosis after 20 years of disease. It is only with longer term follow-up that we can determine whether the majority of patients will eventually develop life-threatening complica-


tions. Healthcare economic issues are of particular interest in this setting. Natural history studies are important in this group of patients as antiviral therapy is expensive. However, treating the complications of chronic HCV is also costly and HCV-related end stage liver disease now accounts for 20–40% of potential candidates for liver transplantation.

Interferon-α Before the identification of HCV, interferon-α had been tried for the therapy of chronic non-A, non-B hepatitis in a pilot study (Hoofnagle et al., 1986) and then in subsequent controlled trials (Jacyna et al., 1989; Brook et al., 1989; Davis et al., 1989 & Di Bisceglie et al., 1989). The biochemical pattern of response to interferon therapy was noted to be different from that seen in the interferon therapy of chronic HBV infection. A fall was seen in the transaminase values but unfortunately this successful response was noted in only a minority of patients. Only 10–20% of patients have a sustained response to interferon monotherapy, which is now generally defined as a combination of a complete virological response with negative PCR for HCV RNA and biochemical response with normalization of the transaminase values sustained for 6 months following cessation of therapy. This is usually associated with a decrease in the inflammatory activity within the liver. Initial studies were generally with 6 months of therapy but subsequent trials supported the use of longer regimens. In a Scandinavian study (Reichard et al., 1994), for example, interferon-α at a dose of 3 MU three times weekly was administered to 40 patients for 60 weeks. At the end of treatment, alanine amino transferase (ALT) values had normalized in 24 (60%) patients and after a follow-up period of up to 24 weeks after discontinuation of therapy, remained normal in 15 patients. HCV RNA levels were negative in 17 of the responders in the follow-up period. Twelve months of interferon therapy proved more successful than 6 months in one study (Jouet et al., 1994). Eighteen months of interferon monotherapy (interferon 3 MU three times weekly) was compared with 6 months and with 6 months of 3 MU three times weekly followed by 1 MU three times weekly for 12 months (Poynard et al., 1995). The highest sustained response was noted in those who received 3 MU three times weekly for 18 months. These and other studies have highlighted host and viral factors that are important in determining response. Patients with cirrhosis are less likely to clear HCV RNA with therapy (Jouet et al., 1994). Favourable host factors include a body weight less than 86 kg, mild histological disease, low levels of serum ferritin and a normal γ-GTP (Davis, 1994). Iron status is important in determining the immune response to several infections. Liver iron seems to

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Table 1. Controlled studies of interferon versus interferon and ribavirin as therapy for chronic hepatitis C Interferon 15 19 50

Regimen (number of patients) Ribavirin Combination 15 – –

15 21 50

Interferon 13 6 18

Sustained response (%)* Ribavirin Combination 0 – –

47 43 36

Reference Chemello et al. (1995) Lai et al. (1996) Reichard et al. (1998)

* Sustained response; negative PCR for HCV RNA 6 months after cessation of therapy.

be important in determining the outcome with antiviral therapy for chronic HCV (Fargion et al., 1997) and venepuncture to reduce iron load has been suggested as an adjunct to therapy (Tsai et al., 1997). Following infection with HCV women are less likely to develop the chronic carrier state and younger women are more likely to respond to therapy than men (Hayashi et al., 1998). It is unclear whether this is related to hormonal patterns or other factors such as iron levels. Viral load and genotype are also relevant (Yoshioka et al., 1992). Patients with high baseline viral loads are less likely to respond (Ide et al., 1997; Colucci & Gitekunst, 1997). In one Italian study (Chemello et al., 1994a) of interferon therapy, 74% (of 19) patients with type 3 HCV infection had a long-term response (normal ALT values for at least 1 year after stopping therapy) compared with only 52% (of 23) of patients with type 2 and 29% (of 65) with type 1 infection. Genotype 1b is associated with a poor chance of response (Kanai et al., 1992). Patients with type 1b infection, however, tend to be older with more advanced disease and it has been suggested that patients with type 1b infection represent a cohort who were infected many years ago. Genotype 4 infection, which is commonly seen in North Africa, is also associated with a reduced chance of responding to interferon monotherapy. Large studies do suggest that viral genotypes are important predictors of response (Bellobuono et al., 1994) and this has already been taken into account in terms of the design of clinical trials with stratification for genotype. Enomoto’s group reported the presence of an interferon-sensitivity determining region in the NS5 region of the HCV genome in Japanese patients (Enomoto et al., 1995). This has not been confirmed in North American or European studies (Hofgartner et al., 1997; Squadrito et al., 1997). Viral kinetics show that the initial antiviral response to interferon may help determine the eventual outcome. Nonresponders who remain HCV RNA-positive after 4 months of interferon monotherapy are unlikely to achieve a sustained response (Booth et al., 1995). Those patients who have a rapid decline in HCV RNA levels with interferon tend to do well. In one small study the viral load response was compared in responders and non-responders. By the end of the second week of therapy HCV RNA was undetectable in 8 of the 10 eventual responders whereas

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only one of the 28 non-responders had a similar early response (Hino et al., 1995). The time until the disappearance of HCV RNA therapy correlated with the pre-treatment viral levels. Other groups have examined the HCV RNA response after 1 month of interferon therapy and found this to be a useful predictor (Gavier et al., 1997). Other centres favour assessing response to therapy after 3 months (Tong et al., 1997). Quantitative viral assays are therefore becoming increasingly important at baseline to determine the pretreatment viral load, during treatment to assess response and at the end of therapy and the follow-up period to determine sustained response. It is hoped that analysis such as this can help limit ineffective therapy and help target therapy to those who are most likely to benefit. Various regimens of interferon have been tried including the use of higher induction dosing, daily dosing and longer term treatment. Another approach has been the use of escalating doses and in one study (Marcellin et al., 1995), 50 patients were prescribed 3 MU three times weekly of interferon α for 8 weeks which was increased to 5 MU three times weekly for 8 weeks if the transaminase values remained abnormal and further increased to 10 MU three times weekly for 8 weeks if transaminases remained elevated. This group was compared with 25 patients who received a constant dosage of 3 MU three times weekly for 24 weeks. A sustained normalization of the transaminase was seen in 16% of those who received the constant dose and in 20% of those who received the escalating regimen. Some patients appear to have no response to interferon despite dosage increases. Of the patients on the escalating regimen who failed to respond to 3 MU, none achieved a sustained response despite the use of higher doses. For those patients who seem to respond initially to interferon therapy and then develop a breakthrough with an increase in the transaminase levels and a rise in HCV RNA levels, the possibility of the development of interferon antibody formation should by considered. In one study (Milella et al., 1993), 15 of 47 patients (31.9%) developed neutralising antibodies which appeared to reduce their chance of eventual response. Patients who fail to respond to interferon are unlikely to respond to repeat courses of interferon. This approach may be beneficial for those who relapse after discontinuation of



Figure 6. Molecular structure of ribavirin O

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therapy (Chemello et al., 1997).

Ribavirin Ribavirin (1-β-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide) (Figure 6) is a broad spectrum antiviral agent which is principally used in a nebulized form for the therapy of severe respiratory syncytial virus (RSV) infection in infants. A Scandinavian study showed that ribavirin, which is also available as an oral preparation, was associated with a biochemical response in patients with chronic HCV infection (Reichard et al., 1991). Transaminase levels increased again following cessation of therapy. Further studies of ribavirin monotherapy followed with similar results (Di Bisceglie et al., 1992, 1995; Bodenheimer et al., 1997). Some patients who failed to respond to interferon nevertheless had a biochemical response when given ribavirin (Camps et al., 1993). Subsequent studies of longer duration of therapy were instigated when quantitative virology was available and again demonstrated consistent decreases in transaminase levels when patients were on therapy but, at most, a modest reduction on the HCV RNA levels and no sustained response. No significant change in viral load or quasispecies was evident in one short study (Lee et al., 1998). The combination of ribavirin and interferon has improved the outlook of the patients with chronic HCV (Chemello et al., 1994b, 1995). The initial pilot study compared monotherapy with interferon or ribavirin with a combination of the two agents and the study, although small, showed an increased response rate in the combination group. Several larger studies have now been performed and have confirmed these initial results (Lai et al., 1996; Reichard et al., 1998) (Table 1). In the Scandinavian study, 100 patients were randomized to receive interferon and ribavirin or interferon and placebo. A sustained virological response was seen in 36% of those who received interferon and ribavirin and in only 18% of those who received the


interferon monotherapy. As with interferon monotherapy the viral load was an important factor in determining the response to therapy. The combination of interferon and ribavirin has also been tried with some success in those who have failed with interferon monotherapy (Brillanti et al., 1994). Ribavirin is generally well tolerated. Mild gastrointestinal upset has been reported but the main limiting sideeffect is haemolysis, with a 1–2 g/dl decrease in the patient’s haemoglobin level. The haemoglobin levels have thus to be carefully monitored and caution must be employed in treating elderly patients or in those with underlying haemolytic disease. Where there is a decrease in the haemoglobin level it is generally possible to continue therapy with a reduced dose of ribavirin.

Amantadine Amantadine is mainly used for prophylaxis and therapy for influenza A virus infection. A study of amantadine monotherapy in patients who had failed interferon therapy suggested that amantadine may also have some inhibitory effects on HCV replication (Smith, 1997). Larger multicentre studies are in progress with amantidine in combination with interferon and also as part of triple therapy regimens with ribavirin.

Targeting therapy With success rates of up to 20–25%, interferon monotherapy is generally prescribed in cases where there are concerns regarding progressive disease. In patients with advanced disease such as cirrhosis the success rates with interferon monontherapy have been very disappointing and less than 10% of patients clear the virus. Several studies have now shown, however, that despite the poor success rates in terms of virological clearance, patients with hepatitis C associated cirrhosis may have a reduced rate of subsequent development of HCC. In one controlled study (Nishiguchi et al., 1995), for example, 90 patients with HCV-associated cirrhosis were randomized to receive either interferon therapy or symptomatic treatment. Although the virological response to therapy was low in the interferon-treated group there appeared to be other potential benefits with improved liver function and less risk of HCC development in the interferon-treated patients. Similar results have now been reported from a large retrospective study of cirrhotic patients (International Interferon-α HCC Study Group, 1998). Interferon α, in addition to its antiviral and immunomodulatory effects, also has anti-proliferative effects and it is only with longterm follow-up that the real benefits of this approach can be determined. For patients with end-stage liver disease, liver transplantation is an option and HCV now accounts for

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20–40% of liver transplantation in Europe and the USA. Reinfection of the graft can occur and various interferon/ribavirin regimens have been tried to suppress viral replication and improve graft survival (Bisollon et al., 1997). High levels of viral replication, immunosupppression and the frequent presence of genotype 1b (Feray et al., 1995) reduce the chance of sustained virological responses in the setting of liver transplantation. The immunomodulatory effects of interferon could be detrimental in the transplantation setting but low dose interferon therapy appears well tolerated in this group. Other approaches includes maintenance therapy with ribavirin or the use of combination therapy with interferon and ribavirin. The long-term toxicities of these regimens are yet to be determined and there are potential concerns that with long-term ribavirin the ongoing haemolysis may lead to intrahepatic iron deposition and result in fibrosis (Di Bisceglie et al., 1994). The use of antiviral therapy in patients with mild disease is a further controversial area. Many patients have evidence of only mild degrees of inflammation and it is not clear at this stage whether all patients will eventually develop fibrosis. There are also reports of patients with very mild liver disease who have developed flares in transaminase levels following interferon therapy and concerns that interferon may have an adverse effect on the host–virus balance in this subgroup of patients (Sangiovanni et al., 1998). Treatment algorithms and guidelines have been developed to help target therapy to the patients who will most benefit (Foster et al., 1997; NIH Consensus Group, 1997). This is a rapidly changing field and treatment algorithms are constantly being updated to take into account the results of clinical trials and particularly the availability of combination therapy. Interferon is generally given to those with moderate disease and multicentre trials are in progress to asssess more fully the benefit of antiviral therapy for those with mild disease and the potential long-term benefits of interferon in those patients with cirrhosis. As with any relatively expensive intervention cost–benefit has become an important issue (Bennett et al., 1997; Kim et al., 1997). Effective antiviral therapy may be preventing expensive disease complications in 20–30 years time and most cost-effectiveness analysis support the use of antiviral therapy in young patients; for older patients the cost–benefit is less evident. Again the calculations will change with the increased success and the increasing availability of combination therapy. Antiviral therapy may be indicated for reasons other than severe liver disease. Many patients with mild liver disease have more major systemic symptoms with chronic fatigue (Foster et al., 1998). Other extrahepatic diseases related to HCV infection include glomerulonephritis, cryoglobulinaemia and vasculitis (Johnson et al., 1993;

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Rollino et al., 1991; Agnello et al., 1992). Individual patients may be concerned regarding transmission of HCV to others and until effective vaccines are developed antiviral therapy is also important in controlling disease spread. Viral kinetics is likely to become of increasing importance in the future. It is now possible in patients receiving interferon therapy to predict the long-term antiviral response from the early changes in the viral load. Targeting therapy towards those who are most likely to respond and stopping ineffective therapy are important factors in determining the cost–benefits of therapy.

Future treatments Research into newer treatments for hepatitis C has been limited by the lack of animal models and in vitro cell culture techniques. Suitable molecular targets for future therapies include the serine proteases and the HCV helicase (reviewed in Bartenschlager, 1997). Further immunomodulatory approaches include the use of thymic peptides and interleukin-12. It is thought that stimulating the host response towards a Th1 rather than a Th2 response may aid viral clearance. It has been suggested that ribavirin may also have a similar effect which may explain its apparent efficacy despite lack of direct antiviral effect.

References Agnello V, Chung RT & Kaplan LM (1992) A role for hepatitis C virus infection in type II cryoglobulinemia. New England Journal of Medicine 327:1490–1495. Aye TT, Bartholomeusz A, Shaw T, Bowden S, Breschkin A & McMillan J (1997) Hepatitis B virus polymerase mutations during antiviral therapy in a patient following transplantation. Journal of Hepatology 26:1148–1153. Bartenschlager R (1997) Molecular targets in inhibition of hepatitis C virus replication. Antiviral Chemistry & Chemotherapy 8:281–301. Bartholomew MM, Jansen RW, Jeffers LJ, Reddy KR, Johnson LC, Bunzendahl H, Condreay L, Tzakis AG, Schiff ER & Brown N (1997) Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 349:20–22. Bassendine MF, Chadwick RG & Salmeron J (1981) Adenine arabinoside therapy in HBsAg-positive chronic liver disease: a controlled study. Gastroenterology 80:1016–1021. Bellobuono A, Mondazzi L, Tempini SGB, Cassara L, Lombino M, Silini E, Bono F, & Ideo G (1994) Efficacy of different regimens of alpha interferon in chronic hepatitis C and relationship between response and HCV genotype. Journal of Hepatology (Suppl.) 21:35. Bennett WG, Inoue Y, Beck JR, Wong JB, Pauker SG & Davis GL (1997) Estimates of the cost-effectiveness of a single course of interferon-alpha 2b in patients with histologically mild chronic hepatitis C. Annals of Internal Medicine 127:855–865. Bisollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M & Baulieux J (1997) Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology 26:500–504.



Bloomer J, Can R, Sherman M, Ingraham P & DeHertog D (1997) A preliminary study of lobucavir for chronic hepatitis B. Hepatology 25:A1199. Bodenheimer HC, Lindsay KL, Davis GL, Lewis JH, Thung SN & Seeff LB (1997) Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 26:473–477.

clovir. Hepatology 26:216–225. Colucci G & Gitekunst K (1997) Development of quantitative PCR assay for monitoring HCV viraemia levels in patients with chronic hepatitis C. Journal of Viral Hepatology 4:75–78. Davis GL (1994) Prediction of response to interferon treatment of chronic hepatitis C. Journal of Hepatology 21:1–3.

Bodsworth NJ, Cooper DA & Donovan B (1991) The influence of human immunodeficiency virus type 1 on the development of the hepatitis B virus carrier state. Journal of Infectious Diseases 163:1138–1140.

Davis GL, Balart LA & Schiff ER (1989) Treatment of chronic hepatitis C with recombinant interferon alpha. New England Journal of Medicine 321:1501–1506.

Booth JCL, Foster GR, Kumar U, Galassini R, Goldin RD, Brown JL & Thomas HC (1995) Chronic hepatitis C virus infection: predictive value of genotype and level of viraemia on disease progression and response to interferon alpha. Gut 36:427–432.

Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, Banks SM & Hoofnagle JH (1989) Recombinant interferon alfa therapy for chronic hepatitis C: a randomized double blind placebo-controlled trial. New England Journal of Medicine 321:1506–1510.

Brillanti S, Garson J, Foli M, Whitby K, Deaville R, Masci C, Miglioli M & Barbara L (1994) A pilot study of combination therapy with ribavirin plus interferon alfa for interferon resistant chronic hepatitis C. Gastroenterology 107:812–817. Brook MG, Chan G, Yap I, Karayiannis P, Lever AM, Jacyna M, Main J & Thomas HC (1989) Randomised controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection. British Medical Journal 299:652–656.

Di Bisceglie AM, Shindo M, Fong T-L, Fried MW, Swain MG, Bergasa NV, Axiotis CA, Waggoner JG, Park Y & Hoofnagle JH (1992) A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16:649–654. Di Bisceglie AM, Bacon BR, Kleiner DE & Hoofnagle JH (1994) Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C. Journal of Hepatolology 21:1109–1112.

Brugger SA, Oesterreicher C, Hofmann J, Kalhs P, Greinix HT & Muller C (1997) Hepatitis B virus clearance by transplantation of bone marrow from hepatitis B immunised donor. Lancet 349:996–997.

Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, ParkY & Yurdaydin C (1995) Ribavirin as therapy for chronic hepatitis C. Annals of Internal Medicine 123:897–903.

Brunetto MR, Oliveri F, Colombatto P, Capalbo M, Barbera C & Bonino F (1995) Treatment of chronic anti-HBe positive hepatitis B with interferon alpha. Journal of Hepatology 22 (Suppl. 1):42–44.

Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C & Rubin M (1995) A preliminary trial of lamivudine for chronic hepatitis B infection. New England Journal of Medicine 333:1657–1661.

Camps J, Garcia N, Riezu-Boj JI, Civeira MP & Prieto J (1993) Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon. Journal of Hepatology 19:408–412. Carman WF, Jacyna MR, Hadziyannis S & Karayiannis P, McGarvey MJ, Makris A & Thomas HC (1989) Mutation preventing formation of hepatitis HB e antigen in chronic hepatitis B virus infection. Lancet ii:588–591. Carreno V & Quiroga JA (1997) Biological properties of interleukin-12 and its therapeutic use in persistent hepatitis B and hepatitis C virus infection. Journal of Viral Hepatitis 4:1419–1425. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY & Chen DS (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. New England Journal of Medicine 336: 1855–1859. Chemello L, Alberti A, Rose K & Simmonds P (1994a) Hepatitis C serotype and response to interferon therapy. New England Journal of Medicine 330:143. Chemello L, Cavaletto L, Bernardinello E, Silvestri E, Benvegnu L, Pontisso P & Alberti A (1994b) Response to ribavirin, to interferon and to a combination of both in patients with chronic hepatitis C and its relation to HCV genotypes. Journal of Hepatology (supplement 1) 21:S12. Chemello L, Cavalletto L, Bernardinello E, Guido M, Pontisso P & Alberti A (1995) The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. Journal of Hepatology 23:8–12 Chemello L, Cavaletto L, Donada C, Bonetti P, Casari P & Urban F (1997) Efficacy of a second cycle of interferon therapy in patients with chronic hepatitis C. Gastroenterology 113:1654–1659. Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley DW & Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–62. Colledge D, Locarnini S & Shaw T (1997) Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penci-


Duflot A, Mehrotra R, Yu SZ, Barraud L, Trepo C & Cova L (1995) Spectrum of liver disease and duck hepatitis B virus infection in a large series of Chinese ducks with hepatocellular carcinoma. Hepatology 21:1483–1491 Enomoto N, Sakuma IYA, Kuorsaki M, Murakami T, Yamamoto C, Izumi N, Marumo F & Sato C (1995) Comparison of fulllength sequences of interferon-sensitive and resistant hepatitis C virus 1b. Journal of Clinical Investigation 96:224–230. Eron JJ, Benoit SL, Jemsek J, MacArthur RD, Santana J, Quinn JB, Kuritzkes DR, Fallon MA & Rubin M (1995) Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. New England Journal of Medicine 333:1662–1669. Fargion S, Fracanzani AL, Sampietro M, Molteni V, Bolorini R & Mattioli M (1997) Liver iron influences the response to interferon alpha therapy in chronic hepatitis C. European Journal of Gastroenterology and Hepatology 9:497–503. Fattovich G, Giustina G, Alberti A, Guido M, Pontisso P, Favarato S, Benvegnu L & Ruol A (1994) A randomised controlled trial of thymopentin therapy in patients with chronic hepatitis B. Journal of Hepatology 21:361–366. Fattovich G, Giustina G, Realdi G, Corrocher R & Schalm SW (1997) European concerted action on viral hepatitis. Long term outcome of hepatitis B e antigen positive patients with compensated cirrhosis treated with interferon alfa. Hepatology 26:1338–1342. Feray C, Gigou M, Samuel D, Paradis V, Mishiro S, Maertens G, Reynes M, Okamoto H, Bismuth H & Brechot C (1995) Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation. Gastroenterology 108:1088–1096. Foster GR, Goldin RD, Main J, Murray-Lyon I, Hargreaves S & Thomas HC (1997) Management of chronic viral hepatitis C; clinical audit of biopsy based management algorithm. British Medical Journal 315:453–458 Foster GR, Goldin RD & Thomas HC (1998) Chronic hepatitis C

457

J Main et al.

virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 27:209–212 Garcia G, Smith CI, Weissberg JI, Eisenberg M, Bissett J, Nair PV, Mastre B, Rosno S, Roskamp D, Waterman K, Pollard RB, Tong MJ, Brown BW, Robinson WS, Gregory PB & Merigan TC (1987) Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B. Annals of Internal Medicine 107:278–285. Gavier B, Martinez-Gonzalez MA, Riezu-Bpj JI, Lasarte JJ, Garcia N, Civeira MP & Prieto J (1997) Viremia after one month of interferon therapy predicts treatment outcome in patients with chronic hepatitis C. Gastroenterology 113:1647–1653. Greenberg HB, Pollard RB, Lutwick LI, Gregory PB, Robinson WS & Merigan TC (1976) Effect of human leucocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. New England Journal of Medicine 295:517–522. Hadler SC, Judson FN, O’Malley PM, Altman NL, Penley K, Buchbinder S, Schable CA, Coleman PJ, Ostrow DN & Francis DP (1991) Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. Journal of Infectious Diseases 163:454–459. Hadziyannis S, Bramou T, Makris A, Moussoulis G, Zignego L & Papaioannou C (1990) Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B. Journal of Hepatology 11:S133–136. Hayashi J, Kishihara T, Ueno K, Yamaji K, Kawakami Y & Furusyo N (1998) Age-related response to inteferon alfa in women vs men with chronic hepatitis C virus infection. Archives of Internal Medicine 158:177–181. Heijtink RA, Kruining J, Honkoop P, Kuhns MC, Hop WCJ, Osterhaus ADME & Schalm SW (1997) Serum HBeAg quantitation during antiviral therapy for chronic hepatitis B. Journal of Medical Virology 53:282–287. Hino K, Okuda M, Konishi T, Ichiko H & Okita K (1995) Serial assay of hepatitis C virus RNA in serum for predicting response to interferon alpha therapy. Digestive Disease Sciences 40:14-20. Hofgartner WT, Polyak SJ, Sullivan DG, Cairthers RL & Gretch DR (1997) Mutations in the NS5A gene of hepatitis C virus in North American patients infected with hepatitis C genotype 1a or 1b. Journal of Medical Virology 53:118–126. Honkoop P, Deman RA, Scholte HR, Zondervan PE, van den Berg JWO, Rademakers LHPM & Schalm SW (1997a) Effect of lamivudine on morphology and function of mitcohondria in patients with chronic hepatitis B. Hepatology 26:211–215. Honkoop P, Niesters HGM, de Man RAM, Osterhaus ADME & Schalm SW (1997b) Lamivudine resistance in immunocompetent chronic hepatitis B – incidence and patterns. Journal of Hepatology 26:1393–1395. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y & Jones EA (1986) Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: a preliminary report. New England Journal of Medicine 315:1575–1578. Ide T, Sata M, Suzuki H, Uchimura Y, Shirachi M, Adachi N & Tanikawa K (1997) Characterisitics of complete responders to interferon among patients with chronic hepatitis C with high serum levels of RNA. Hepatology Research 7:19–27. International Interferon-α Hepatocellular Carcinoma Study Group. (1998). Effect of interferon-α on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 351:1535–1539. Jacyna MR, Brooks MG, Loke RHT, Main J, Murray-Lyon IM & Thomas HC (1989) Randomised controlled trial of interferon alfa (lymphoblastoid interferon) in chronic non-A, non-B hepatitis.

458

British Medical Journal 298:80–82. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Corey L, Wener MH, Alpers CE et al. (1993). Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. New England Journal of Medicine 328:465–470. Jouet P, Roudot-Thorval F, Dhumeaux D, Metreau J-M et Le Groupe Francais pour l’etude du traitement des hepatites chroniques NANB/C (1994) Comparative efficacy of interferon alfa in cirrhotic and non-cirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 106:686–690. Kanai K, Kato M & Okamato H (1992) HCV genotypes in chronic hepatitis C and response to interferon. Lancet 339:1543. Kim WR, Poterucha JJ, Hermans JE, Therneau TM, Dickson ER, Evans RW & Gross JB (1997) Cost-effectiveness of 6 and 12 months of interferon-alpha therapy for chronic hepatitis C. Annals of Internal Medicine 127:866–874. Korenman J, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM & Hoofnagle JH (1991) Long term remissions of chronic hepatitis B after alpha interferon. Annals of Internal Medicine 114:629–634. Lai CL, Lok ASF, Lin HJ et al. (1987) Placebo-controlled trial of recombinant alfa2 interferon (rIFN) in Chinese HBsAg carrier children. Lancet ii:877–880. Lai M-Y, Kao J-H, Yang P-M, Wang J-T, Chen P-J & Chan K-W (1996) Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 111:1307–1312. Lai C-L, Liaw Y-F, Leung N, Deslauriers M, Barnard J, Santhanan L et al. (1997) Genotypic resistance to lamivudine in a prospective, placebo-controlled multicentre study in Asia of lamivudine therapy for chronic hepatitis B infection: incidence, kinetics of emergence and correlation with disease parameters. Hepatology 26:522. Lai C-L, Chien R-N, Leung N, Chang T-T, Guan R, Tai D-I, Ng K-Y, Wu P-C, Dent JC, Barber J, Stephenson SL & Gray DF (1998) A one year trial of lamivudine for chronic hepatitis B. New England Journal of Medicine 339:61–68. Lampertico P, del Nonno E, Manzin A, Donato MF, Rumi MG & Lunghi G (1997) A randomised controlled trial of a 24 month course of interferon afa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 26:1621–1625. Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P & Hoofnagle JH (1997a) Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 113:1660–1667. Lau GKK, Lok ASF, Liang RHS, Lai CL, Chiu EKW & Lau YL (1997b) Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immmunity transfer. Hepatology 25:1497–1501. Lee CL & Ko YC (1997) Hepatitis B vaccinarion and hepatocellular carcinoma in Taiwan. Pediatrics 99:351–353. Lee J-H, von Wagner M, Roth WK, Teuber G, Sarrazin C & Zeuzem S (1998) Effect in ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus. Journal of Hepatology 29:29–35. Ling R, Mutimer D, Ahmed M, Boxall EH, Elias E, Dusheiko G & Harrison TJ (1996) Selection of mutations in the hepatitis B virus polymerase during treatment of transplant recipients with lamivudine. Hepatology 24:711–713. Main J, Brown JL, Howells C, Galassini R, Crossey M, Karayiannis P, Georgiou P, Atkinson G & Thomas HC (1996) A double blind placebo-controlled study to assess the effect of famciclovir in virus replication in patients with chronic hepatitis B virus infection. Journal of Viral Hepatitis 3:211–215. Marcellin P, Giuily N, Loriot MA, Durand F, Samuel D & Bettan



L (1997) Prolonged interferon-alpha therapy of hepatitis B virus related decompensated cirrhosis. Viral Hepatitis 4:21–26. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C, Pruett T, Stotka JL, Straus SE & Hoofnagle JH (1995) Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New England Journal of Medicine 333:1099–1105. Marcellin P, Pouteau M, Martinot-Peignoux M, Degos F, Duchatelle V, Boyer N, Lemonnier C, Degott C, Erlinger S & Benhamou JP (1995) Lack of benefit of escalating dosage of interferon alfa in patients with chronic hepatitis C. Gastroenterology 109:156–165. Milella M, Antonelli G, Santantonio T, Currenti M, Monno L, Mariano N, Angarano G, Dianzani F & Pastore G (1993) Neutralizing antibodies to recombinant alpha-interferon and response to therapy in chronic hepatitis C virus infection. Liver 13:146–150. Nevens F, Main J, Honkoop P, Tyrrell DL, Barber J & Sullivan MT (1997) Lamivudine therapy for chronic hepatitis B; a six month randomised dose-ranging study. Gastroenterology 113:1258–1263. Niederau C, Heintges T, Lange S, Goldman G, Niederau CM, Mohr L & Haussinger D (1996) Long-term follow-up of HBeAg positive patients treated with interferon alfa for chronic hepatitis B. New England Journal of Medicine 334:1422–1427. NIH Consensus Group (1997) National Institute of Health consensus development conference panel statement: management of hepatitis C. Hepatology 26 (Suppl. 1):2S–10S. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S, Seki S, Kobayashi K & Otani S (1995) Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 346:1051–1055 Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC & McDade H (1996) Viral dynamics in hepatitis B virus infection. Proceedings of the National Academy of Sciences, USA 93:4398–4402. Olano JP, Borucki MJ, Wen JW & Haque AK (1995) Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine. Clinical Infectious Diseases 21:973–976. Penna A, del Prete G, Cavalli A, Bertoletti A, D’Elios MM & Sorrentino R (1997) Predominant T-helper cytokine profile of hepatitis B virus nucleocapsid-specific T cellls in acute self-limited hepatitis B. Hepatology 25:1022–1027. Perrillo R, Regenstein F, Bodicky C, Campbell CJ & Sunwoo YC (1985) Comparative efficacy of adenine arabinoside 5′-monophosphate and prednisone withdrawal followed by adenine arabinoside 5′-monophosphate in the treatment of chronic active hepatitis type B. Gastroenterology 88:780–786. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, O’Brien C, Tamburro C, Jacobson IM, Sampliner R, Feit D, Lefkowitch JL, Kuhns M, Meschievitz C, Sanghvi B, Albrecht J & Gibas A (1990) A randomised controlled trial of interferon alfa 2-b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. New England Journal of Medicine 323:295–301. Poynard T, Bedossa P, Chevallier M, Mathurin P, Lemonnier C, Trepo C, Couzigou P, Payen JL, Sajus M, Costa JM, Vidaud M & Chaput JC (1995) A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. New England Journal of Medicine 332:1457–1462. Protzer-Kolle U, Naumann U, Bartenschlager R, Berg T, Hopf U & Meyer zum Buschenfelde KH (1998) Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high dose hepatitis B immune globulin after liver transplantation. Hepatology 27:254–263.


Reichard O, Andersson J, Schvarcz R & Weiland O (1991). Ribavirin treatment for chronic hepatitis C. Lancet 337:1058–1061. Reichard O, Foberg U, Fryden A, Mattson L, Norkrans G, Sonnerborg A, Wejstal R, Yun Z-B & Weiland O (1994) High sustained response rate and clearance of viremia in chronic hepatitis C after treatment with interferon-a2b for 60 weeks. Hepatology 19:280–285. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A & Weiland O (1998) Randomised, double-blind, placebo-controlled trial of interferon alpha 2b with and without ribavirin for chronic hepatitis C. Lancet 352:83–87. Rollino C, Roccatello D, Giachino O, Basolo B & Piccoli G (1991) Hepatitis C virus infection and membranous glomerulonephritis. Nephron 59:319–320. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou J-P & Bismuth H (1993) Liver transplantation in European patients with the hepatitis B surface antigen. New England Journal of Medicine 329:1842–1847. Sangiovanni A, Morales R, Spinzi G, Rumi M, Casraghi A & Ceriani R (1998) Interferon alpha treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomised controlled trial. Hepatology 27:853–856. Scullard GH, Pollard RB, Smith JL, Sacks SL, Gregory PB, Robinson WS & Merigan TC (1981) Antiviral treatment of chronic hepatitis B virus infection. Changes in viral markers with interferon combined with adenine arabinoside. Journal of Infectious Diseases 143:772–783. Sells MA, Chen M & Acs G (1987) Production of hepatitis B virus particles in hepG2 cells transfected with cloned hepatitis B virus DNA. Proceedings of the National Academy of Sciences, USA 84:1005–1009. Severini A, Liu X-Y, Wilson J & Tyrrell D (1995) Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-β-L-2′, 3′ dideoxy-3′-thiacytidine. Antimicrobial Agents and Chemotherapy 39:1430–1435. Singh N, Gayowski T, Wannstedt CF, Wagener CF, Wagener MM & Marino IR (1997) Pretransplant famciclovir as prophylaxis for hepatitis B virus recurrence after liver transplantation. Transplantation 63:1415–1419. Smith JP (1997) Treatment of chronic hepatitis C with amantadine. Digestive Disease Sciences 42:121–129. Squadrito G, Leone F, Sartori M, Nalpas B, Berthelot P & Raimondo G (1997) Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C virus to interferon alfa. Gastroenterology 113:567–572. Summers J, Smolec JM, Snyder R (1978) A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proceedings of the National Academy of Sciences, USA 75:4533–4537 Tennant BC & Gerin GL (1994) The woodchuck model of hepatitis B virus infection. In The Liver: Biology and Pathobiology, pp. 1455–1466. New York: Raven Press. Thursz M, Kwiatowski D, Allsopp CE, Greenwood BM & Thomas HC (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. New England Journal of Medicine 332:1065–1069. Tong MJ, Blatt LM, McHutchison JG, Co RL & Conrad A (1997) Prediction of response during interferon alfa 2b therapy in chronic hepatitic C using viral and biochemical characteristics: a comparison. Hepatology 26:1640–1645. Trepo C, Hantz O, Ouzan D, Fontagnes T et al. (1984) Therapeutic efficacy of adenine arabinoside monophosphate in symptomatic HBeAg positive chronic active hepatitis: a ran-

459

J Main et al.

domised placebo controlled study. Hepatology 4:1055–1061. Trepo C, Jezek P, Atkinson GF & Boon RJ on behalf of the FCV chronic hepatitis B study group. (1997) Long term efficacy of famciclovir (FCV) in chronic hepatitis B: results of a phase IIB study. Journal of Hepatology 26 (Suppl. 1): abstract WP3/22. Tsai NCS, Zuckerman E, Han SH, Goad K, Redeker AG & Fong TL (1997) Effect of iron depletion on long-term response to interferon-alpha therapy in patients with chronic hepatitis C who previously did not respond to interferon therapy. American Journal of

Gastroenterology 92:1831–1834. Tyrrell DLJ, Mitchell MC, De Man RA, Schalm SW, Main J, Thomas HC, Fevery J, Nevens F, Beranek P & Vicary C (1993) Phase II trial of lamivudine for chronic hepatitis B. Hepatology (Suppl.) 18:112A. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, Shibata M & Morishima T (1992). Detection of hepatitis C virus by polymerase chain reaction and response to interferon alpha therapy: relationship to genotypes of hepatitis C virus. Hepatology 16:293–299.

Received 31 July 1998; accepted 17 September 1998

460
