Summary

Four hundred million people are chronically infected with hepatitis B worldwide and they carry a high risk of developing cirrhosis and hepatocellular carcinoma. In recent years, approved therapies including interferon, pegylated interferon, lamivudine, adefovir, entecavir are available for treatment. Long term suppression, rarely eradication, of the virus by these therapies will undoubtedly reduce the progression of the disease. More new potent antiviral agents are under evaluation and various combination therapies are being designed for future therapy.

摘要

全球有四億人仕患有慢性乙型肝炎。因肝炎而出現肝硬化和肝癌的風險頗高。在近年，受認可的治療藥物包括干擾素、長效干擾素、拉米夫定、亞德福韋、Entecavir等。這些藥物雖難根除病毒，但可將它長期抑制，無疑可減慢病情惡化。更多新而有效的藥物正在研制，多種混合使用的治療方法也正被計劃供未來應用。

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Introduction

There are four hundred million people infected with hepatitis B virus (HBV) worldwide, 70% of them reside in Asian countries. Since the implementation of the hepatitis B vaccination programme in the 1980's and 1990's, the number of new infections has dropped dramatically in recent years. However, there still remains a large pool of chronic hepatitis B (CHB) carrier, having been infected prior to the era of hepatitis B vaccination. Among the chronic carriers, they have a 25% lifetime risk of developing cirrhosis and hepatocellular carcinoma (HCC). Treatment of chronic hepatitis B infection has been shown to reduce the risk of developing cirrhosis and HCC.

Goal of therapy

It is ideal to have an antiviral agent which is potent enough that can totally eradicate the virus during a short course of treatment. Such ideal regime is simple and user friendly. However, hepatitis B virus is notoriously difficult to eradicate because the covalently closed circular DNA (ccc DNA), a replication intermediate of HBV, persists in the hepatocyte nuclei and is not targeted by the current antiviral agents. The currently available therapies are not ideal, they can suppress but rarely eradicate the virus, and the viral response is often suboptimal, not to mention the associated problem of adverse effects of drug therapy, the development of drug resistance and the cost of treatment. However, sustained suppression of HBV replication has been shown to be associated with a reduction in the risk of morbidity and mortality of chronic liver disease. Evidence had shown that treatment of hepatitis B cirrhosis with lamivudine, which suppresses the viral replication, can retard the progression of cirrhosis and reduce the risk of developing HCC.¹ Furthermore, prospective studies of hepatitis B carriers in China and Taiwan have shown that low viral load is associated with decreased mortality from chronic liver disease and HCC.^2,3 Because the current therapy available has its limitations in terms of suboptimal response, adverse effects and drug resistance, treatment should be offered to selected patients who can benefit most from the therapy. The goal of treatment is to suppress the virus indefinitely, leading to reduction in hepatic necroinflammation and fibrosis, and in the long run, prevent hepatic decompensation and prevent progression to cirrhosis and HCC.

Assessment of response to therapy

The response of therapy can be categorized into three groups.

1. Virological response
   Three parameters are used in assessing virological response, namely HBeAg, HBVDNA and HBsAg. HBeAg seroconversion in HBeAg+ CHB, indicating a decrease in viral replication, is often associated with reduced disease activity and reduced long term liver related complications. HBVDNA is often used as end point of treatment in both HBeAg+ and HBeAg- CHB. A cut off level of 10⁵ copies/ml is often used arbitrarily in HBV studies, and a level below 10⁵ copies/ml is assumed to be associated with reduced hepatic necroinflammation and fibrosis. However, it is known that patients with persistent low level viraemia (HBVDNA 10² -10³ copies/ml) are not completely free of developing complications, and significant sequelae like HCC have been reported in this group of patients.⁴ Hence, there is no known cut off level of HBVDNA, below which there is no disease progression. There are various types of HBVDNA assay in the market, however PCR assay is preferable because the detection limit can reach as low as 50-200 copies/ml, which is important in monitoring and assessing response to treatment in CHB infection. HBVDNA is measured before therapy as baseline, during therapy for assessing response and detecting resistant mutant, and post therapy for assessing durability of response and detecting any relapse. Finally, HBsAg loss or serosonversion indicates resolution of the disease; however, this is rarely achieved in Asian patients.
2. Biochemical response
   This means decrease of ALT level to within normal range suggesting resolution of necroinflammation.
3. Histological response
   This means decrease in necroinflammation and fibrosis on liver biopsy findings. Often a decrease in >2 points in histological activity index is used as the end point in hepatitis B trial.

Treatment of chronic hepatitis B infection

Interferon a2, Peginterferon a2a, Peginterferon a2b, lamivudine, adefovir, entecavir are the currently approved therapies for treatment in CHB. However, entecavir, which was approved by the FDA in March 2005, has not yet been registered in Hong Kong. Each therapeutic agent will be discussed under different categories of CHB, namely HBeAg+ CHB, HBeAg- CHB, cirrhosis, because the treatment strategy is different among different catogories.

Treatment in HBeAg+ CHB

Table 1 summarizes the clinical data of each antiviral agent in HBeAg+ CHB. Interferon a had been studied extensively in 1980's and a meta-analysis in 1993, which included 15 randomised controlled studies, showed in patients treated with interferon a, there were 33% HBeAg loss (12% in control) and 37% HBVDNA (bDNA) loss (17% in control).⁵ Nevertheless, Asian studies showed that Asian patients were less responsive to interferon a compared with the Western patients. This phenomenon is probably explained by the fact that most Asian patients acquired their infection during birth and early childhood, and hence they are more refractory to treatment. Interferon is given by subcutaneous injection three times a week and is associated with side effects consisting of flu like illness, depression, leukopenia, thrombocytopenia and thyroid dysfunction. In recent years, pegylated interferon, a drug produced by adding a polyethylene glycol molecule to the conventional interferon, has been shown to have an improved pharmacological profile, prolonged plasma half-life, reduced renal clearance and also enhanced biological activity. The advantages of pegylated interferon over conventional interferon are i) injection can be given once a week instead of three times a week and ii) higher efficacy, a combined treatment response (HBeAg loss, HBVDNA < 500,000 copies/ml, ALT normalization) of 26% in pegylated interferon compared with 12% in conventional interferon.⁶ The side effect profile of pegylated interferon is the same as in conventional interferon. There are two commercially available pegylated interferon in the market, namely peginterferon a2a (P egasys) and peginterferon a2b (Pegintron). Phase 3 study of pegylated interferon revealed a HBeAg seroconversion rate of 32%, HBVDNA loss (< 100,000 copies/ml) of 32% and HBsAg loss of 3%.⁷

Lamivudine is a nucleoside analog which inhibits HBV-DNA polymerase. The dosage is 100mg daily and the side effects are minimal. The reduction of hepatic necroinflammation and fibrosis on lamividine therapy is well shown in several studies.^8,9 The e-seroconversion rate is around 18% after one year of lamivudine therapy and increases with increased duration of treatment. However, the post treatment e-seroconversion is less durable in treatment with lamivudine compared with interferon. Moreover, higher pretreatment baseline ALT level will predict a higher e-seroconversion response, suggesting an intrinsic host mediated immune response on infected hepatocyte is important for achieving higher response in lamivudine treatment. Based on these data, it is recommended to initiate lamivudine therapy only when ALT is >2 x upper limit of normal (ULN). Long term treatment of lamivudine is associated with the emergence of drug resistance, which is due to mutation in the YMDD motif of polymerase gene resulting in reduced susceptibility to lamivudine. The mutant is rarely detected in first nine months of treatment of patients and the incidence of mutant increases with duration of therapy, being 20% at end of one year therapy and up to 70% at end of 5 year therapy. Fortunately, the lamivudine resistant mutant is fully susceptible to, and can be treated with, adefovir.

Adefovir dipivoxil is a nucleotide analog of adenosine monophosphate and it inhibits HBV-DNA polymerase. It has a slower onset of action than lamivudine, and is effective against both wild type and lamivudine resistant HBV. Phase 3 study of adefovir in HBeAg+ CHB patients showed favourable response (HBVDNA loss, ALT normalization, HBeAg loss and e-seroconversion) compared with placebo.¹⁰ Furthermore, the response continues to improve with continuing treatment with adefovir. The dosage is 10mg daily orally and the side effects are: i) potential renal toxicity and ii) hypophosphataemia. Mutant resistant to adefovir does emerge but at a much lower rate compared with lamivudine, 0%, 2%, 7% and 15% at end of 1 year, 2 years, 3 years and 4 years respectively. Table 2 summarizes the recommendation for treatment in HBeAg+ CHB.

Treatment in HBeAg- CHB

HBeAg- CHB is a mutant selected during the immun clearance phase, in which it is unable or is diminished in producing HBeAg. Two types of HBeAg- mutants occur, namely precore mutant and core promoter mutant. Patients with HBeAg- CHB often have gone through multiple flares in the immune clearance phase and the clinical significance of HBeAg- CHB are i) the liver disease is more severe and progressive, ii) the patients are more likely to develop cirrhosis, hepatocellular carcinoma, iii) spontaneous remission is rare, and iv) the disease is more difficult to treat than HBeAg+ CHB. Treatment with interferon for 24 weeks in HBeAg- CHB, a similar regime used in HBeAg+ CHB, often fails to achieve sustained viral response because of high relapse rate (50-90%) after cessation of treatment. Studies in the Mediterranean area, where 90% of CHB are HBeAg-ve, had clearly shown that it needs at least one year of interferon treatment, rather than the conventional 4 to 6 months treatment, in order to achieve an end viral response of 40-90% and sustained viral response of around 24%.¹¹ Treatment with peginterferon a 2a for one year in HBeAg- CHB showed a sustained viral response of 42% (HBVDNA < 20,000 copies/ml) and HBsAg loss of 4% one year after end of treatment.¹²

Lamivudine therapy produces high response at the end of treatment in HBeAg- CHB but relapse is common (~90%) when the therapy is stopped.¹³ Moreover, prolonged lamivudine treatment for over one year will result in increasing incidence of lamivudine resistant mutants.

Treatment with adefovir in HBeAg- CHB for 48 weeks results in favourable treatment response, 72% ALT normalization, 51% HBVDNA < 400 copies/ml, 64% histological improvement.¹⁴ However, relapse is common after withdrawal of treatment. Continuing treatment with adefovir for over one year is associated with further improvement in treatment response (ALT normalization, HBVDNA reduction). However, resistance to adefovir emerges, but at a lower incidence compared with lamivudine. The incidence of adefovir resistance mutation at the end of 1,2,3 and 4 years was 0%, 3%, 11% and 18% respectively. Table 3 summarizes the recommendation for treatment in HBeAg- CHB.

Treatment in hepatitis B cirrhosis

Interferon treatment is contraindicated in decompensated cirrhosis because of the risk of developing hepatic failure. However, in compensated cirrhotic patients, interferon must be used cautiously and with frequent monitoring. Patients with significant fibrosis and compensated cirrhosis were also included in the phase 3 studies of peginterferon a 2a in HBeAg+ and HBeAg- CHB, and these studies showed favourable response of peginterferon a 2a in this group of patients.

An Asian multicenter study of lamivudine in hepatitis B patients with significant fibrosis or compensated cirrhosis (CALM study, Cirrhosis Asian Lamivudine Multicenter), involving 651 patients, demonstrated that lamivudine reduces disease progression (7.8% vs 17.7% control) and development of HCC (3.9% vs 7.4% control).¹ Because of such favourable results, the study originally planned for 5 years, was terminated after a median duration of treatment of 32.4 months. Furthermore, lamivudine treatment in decompensated hepatitis B cirrhosis also showed reduction in ascites, improvement in albumin level and prothrombin time.¹⁵ The Child Pugh score improved and some patients were even delisted from liver transplantation.

Adefovir was also studied in decompensated cirrhosis and showed improvement in Child Pugh scores.¹⁶ Table 4 summarizes the recommendation for treatment in compensated and decompensated hepatitis B cirrhosis. Table 5 summarizes the different therapies in the treatment of CHB.

Monitoring of CHB

Monitoring should be done before, during and after treatment accordingly. Before treatment, one needs to check baseline HBVDNA, HBeAg status, liver function and possibly perform liver biopsy, if indicated, to grade and stage the liver disease. One can monitor the ALT level and consider starting treatment when ALT level is elevated. During treatment, one needs to monitor ALT, HBeAg and/or HBVDNA at least every 3 months. Renal function should be checked if adefovir is used. After stopping treatment, ALT, HBeAg and/or HBVDNA should be monitored monthly for first 3 months and then every 3 to 6 months, for assessing the durability of treatment response and detecting any early relapse. Furthermore, surveillance for HCC, including a fetoprotein level and ultrasonogram of liver, is mandatory, even in those who respond to treatment and those who are inactive carriers.

Development of drug resistance

The incidence of drug resistant mutants increases with prolonged duration of antiviral treatment. The currently available drugs, lamivudine and adefovir, fortunately, have no cross resistance. The lamivudine resistant HBV can be treated with adefovir, and vice versa. When switching lamivudine to adefovir without overlapping, sometimes hepatitic flare may occur due to the slower onset of action of adefovir. Therefore, it is recommended to overlap both drugs for a period of three months during switching.

Future therapy

Many new antiviral agents are under evaluation for treatment in chronic hepatitis B. An ideal antiviral agent should have strong viral suppressive effect, minimal drug resistance, minimal adverse effect and reasonable cost. Entecavir, telbivudine and clevudine are briefly discussed.

Entecavir, a carbocyclic analog of 2'-deoxyguanosine, inhibits HBV DNA polymerase and is effective against both wild type and lamivudine resistant mutant. At the end of 48-week treatment, entecavir resulted in HBV-DNA suppression of 7 logs compared with 5.5 logs in lamivudine. No resistance to entecavir is detected at the end of 48 week. Entecavir was approved by FDA in March 2005 and will be registered in Hong Kong soon. Carcinogenicity was reported in animal model using high dosage of entecavir. Long term data is lacking in human study. Nevertheless, because of its strong potency, it certainly will play a role in the treatment of CHB.

Telbivudine is a thymidine in b-L configuration. Study in woodchuck showed it has strong potency against woodchuck hepatitis virus (WHV), with WHVDNA level dropped by 8 logs. Human study showed telbivudine is more potent than lamivudine but, because of cross resistance between telbivudine and lamivudine, it is not effective against lamivudine resistant mutant.

Clevudine, a pyrimidine analog, suppresses HBVDNA by 3 logs after treatment for 28 days. Clevudine is shown to have prolonged viral suppressive effect after cessation of treatment, probably related to its long half-life.

The trend of future treatment in CHB will focus on the application of combination therapy which we have learned well in HIV and TB therapy. The combination therapy can combine two or more antiviral drugs which can target various steps in the viral replication cycle. The combination can also include immunomodulatory agent which, besides antiviral, may target the existing pool of cccDNA in the hepatocyte nuclei. Theoretically, the combination therapy has the advantage of synergistic or additive effect, less drug resistance and less side effects. Current studies on combination therapy, for example, peginterferon plus lamivudine, lamivudine plus adefovir, telbivudine plus lamivudine do not show any synergistic or additive effect. However, in the group, peginterferon plus lamivudine, lamivudine plus adefovir, there is reduction in the emergence of lamivudine resistant mutant. Future studies on exploration of different combination therapies are awaited.

Conclusion

Chronic hepatitis B infection is a life long illness in most Asians who acquired the disease during birth and in early childhood, and they carry a high risk of developing cirrhosis and HCC. Chronic hepatitis B infection is notoriously difficult to treat, because the current therapy available can suppress, but rarely eradicates, the virus, and this is due to the persistence of cccDNA in hepatocyte. Long term suppression of the virus is the goal of treatment, but long term administration of antiviral therapy is challenged by the problems of drug resistance and side effects. Hence, therapy should be offered only to those patients who can derive most benefit from the treatment. Recommendations for treatment are discussed in this article. For further details, one can refer to Asian Pacific consensus,¹⁷ NIH consensus,¹⁸ EASL international consensus.¹⁹ The future direction is to develop more potent antiviral agents, design various combination therapy, so treatment can be offered to all patients, even those in the early stage of the disease - the immunotolerant phase, to prevent disease progression and to prevent cirrhosis and HCC.

Key messages

1. People infected with chronic hepatitis B carry a 25 % lifetime risk of developing cirrhosis and hepatocellular carcinoma.
2. The goal of treatment is to suppress the virus indefinitely, leading to reduction in hepatic necroinflammation and fibrosis, and in the long run, prevent hepatic decompensation, prevent progression to cirrhosis and HCC.
3. The current therapies include interferon a, pegylated interferon a , lamivudine, adefovir and entecavir. These therapies can suppress but rarely eradicate the virus, and are associated with suboptimal viral response, adverse effects, development of drug resistance in nucleoside/nucleotide analog, and the high cost of treatment.
4. Pegylated interferon is preferable to conventional interferon because of more convenient injection scheme and higher treatment response rate.
5. Lamivudine treatment in hepatitis B patients with significant fibrosis or compensated cirrhosis would reduce disease progression and development of HCC.
6. Lamivudine resistant HBV is susceptible to and can be treated with adefovir and vice versa.
7. The future direction is to develop more potent antiviral agents, design various combination therapy, so treatment can be effective and offered to all patients, even those in the immunotolerant phase.

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References