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Keywords:

  • antiviral treatment;
  • case selection;
  • chronic hepatitis B;
  • combination therapy;
  • interferon;
  • lamivudine;
  • treatment course

Abstract

  1. Top of page
  2. Abstract
  3. Therapeutic agents: review of clinical data
  4. Patient selection for IFN and lamivudine therapy
  5. Concluding remarks
  6. References

Abstract  Hepatitis B viral (HBV) infection is a major health burden in the Asia–Pacific region. The seriousness of chronic hepatitis B (CHB) is often realized at a late stage. The resultant morbidity and mortality from cirrhosis complications is considerable, with a high human cost. The most affected patients are men aged 40 years or older. Two decades ago, the prognosis for the 300 million ‘Australia antigen’-positive people (people with chronic HBV infection) was gloomy, with no effective intervention. Twenty years on, research and development have changed their outlook. Chronic hepatitis should now be diagnosed early, at the asymptomatic stage. Proper assessment and judicial introduction of therapy can suppress replication of HBV and resolve liver inflammation, thereby preventing the silent progression of chronic liver disease to end-stage cirrhosis. Interferon (IFN) monotherapy has been available for nearly 20 years, but various limitations restrict its general application. Injection-based therapies are inconvenient, the response rate is low (33% hepatitis B e antigen (HBeAg) seroconversion rate among optimal cases), side-effects are many, and some serious, and the cost is unaffordable for most people. However, in non-cirrhotic patients with mild to moderate disease activity, IFN is still a worthwhile option because the treatment course is shorter, mutation seems less of a problem and most responses are permanent and reduce or abolish late complications. Lamivudine, an oral nucleoside analog with potent antiviral effects, has been approved in many countries. Daily dosing of 100 mg reduces serum HBV-DNA to below detectable levels within 6 weeks. In HBeAg-positive patients, approximately 16% of treated patients seroconverted with the first year. This was associated with significant improvement in liver histology. Long-term treatment induces further HBeAg seroconversion, but overall clinical benefit is undermined by continuous emergence of drug-resistant YMDD mutants. In an Asian multicentre study, 58 patients on 5 years lamivudine therapy showed annual cumulative HBeAg seroconversion rates at 1, 2, 3, 4 and 5 years of 22, 29, 40, 47 and 50%, respectively. The best predictor of response is pretreatment alanine aminotransferase (ALT). Among patients with ALT > 2× the upper limit of normal (ULN), annual HBeAg seroconversion is increased to 38, 42, 65, 73 and 77%, respectively. However, emergence of YMDD mutants occurred at a cumulative rate of 15, 38, 55, 67 and 69%, respectively. The impact of this emergence on disease activity is unpredictable. Thus, while continued disease suppression, or even HBeAg seroconversion, still occurred in some patients, in others hepatitis may relapse and liver failure has been reported despite continuation of lamivudine. While the duration of lamivudine therapy is difficult to define, the best strategy may be to define only active CHB with major ALT elevation (par­ticularly ALT > 5× ULN) for a duration of 1 year or less. Lamivudine can be stopped in responders. The response is durable in approximately 80% of responders. Non-responders should be monitored closely for rebound off treatment. Therapy can be re-instituted if ALT is over 5× ULN. Management of patients with YMDD mutants can be challenging, but there is no clear evidence to recommend stopping or continuing lamivudine, or to add other possible effective agents, such as adefovir dipivoxil. More data are required to help draw up guidelines. Hepatitis B e antigen-negative CHB has been less well studied. Both IFN and lamivudine can suppress disease activity, but permanent responses are few. Without a distinct marker as an end-point for response, the duration of treatment is even more difficult to define. Quantitative polymerase chain reaction for low viral levels may give a clue, but definitive studies are required. Monotherapy is clearly not the answer for the majority of CHB patients with active disease. Combination therapy has the theoretical advantage of additional or synergistic efficacy. Preliminary results on IFN and lamivudine are promising and further clinical trials are ongoing. Emtricitabine (FTC), adefovir dipivoxil, entecavir, BL-thymidine (L-dT), DAPD, clevudine (l-FMAU), thymosin, therapeutic vaccines and various herbal medicines are potential candidates. Antiviral action in conjunction with immune modulation may have a better chance of eradicating HBV and its cccDNA in the hepatocytes as the basis for an eventual successful outcome. The key points are: (i) approved therapeutic agents for chronic hepatitis B (CHB) are IFN, lamivudine and thymosin (in a few countries only); (ii) indications for IFN therapy are viremia in compensated CHB patients with moderately raised ALT; (iii) lamivudine has broader therapeutic indications: it is effective in subgroups of CHB patients with compensated or decompensated liver diseases, but generally works better if patients have raised ALT; (iv) lamivudine has a potent suppressive action on HBV replication, including HBeAg-negative variants, but cannot eliminate cccDNA; this is the reason for the relapse of disease after discontinuing treatment, unless HBeAg seroconversion is obtained; (v) successful use of lamivudine aims at HBeAg seroconversion or profound suppression of HBV-DNA to serum levels of less than 100 000 viral copies/mL, in order to prevent emergence of drug-resistant YMDD mutants (which commences from 6 months onward); (vi) YMDD mutants may cause a flare of hepatitis, resulting in deterioration of liver histology and, occasionally, liver failure; (vii) combination therapy of lamivudine with IFN (standard or pegylated) or other nucleoside analogs should be the next advance. Preliminary data from IFN and lamivudine combination therapy show some promise, but there are conflicting results.

© 2002 Blackwell Publishing Asia Pty Ltd

Real prospects for antiviral therapy of chronic hepatitis B (CHB) only started to surface in the 1980s. One earlier agent, the nucleoside analog adenine arabinoside monophosphate,1 had unacceptable neuromyotoxicity. Interferon (IFN) has direct actions on viral replication and indirect actions via immune modulation.2 In the mid-1980s, IFN became the first approved therapy for CHB.3,4 The emergence of human immunodeficiency virus (HIV) infection facilitated the search for effective and safe antiviral agents. Lamivudine, famiclovir and fialuridine were three promising candidates for the treatment of CHB. After clinical assessment, lamivudine was shown to have significant clinical efficacy and a good safety profile.5,6 In 1998, the US Food and Drug Administration registered lamivudine for CHB therapy, another therapeutic milestone. Unfortunately, famiclovir lacks potency and fialuridine causes fatal mitochondrial toxicity, so that clinical trials of these two drugs were abandoned.7,8

Much has been learnt about the virology of hepatitis B virus (HBV) and the natural history of CHB. Hepatitis B e antigen (HBeAg) can be used as a serological marker of active viral replication (see Liaw, this issue of the Journal). Hepatitis B e antigen loss, or seroconversion to anti-HBe, is still being used as the end-point of antiviral therapy, but assay of serum HBV-DNA levels improves the assessment of therapeutic potency. Solution hybridization and signal amplification assays have a lower detection limit of 105−106 virus equivalents/mL, but quantitative polymerase chain reaction (PCR) assays (especially real-time PCR) refine the detection limit down to 100 copies/mL. Accurate measurements of viral levels in the blood have revealed important information on viral dynamics during therapy: the rate of suppression and, more importantly, the rate of elimination of templates for viral replication (cccDNA) in the hepatocytes tend to correlate with better outcomes. The target serum HBV-DNA level may be 104−105 virus equivalents/mL which, in most instances, means that the therapy should be able to reduce serum HBV-DNA by 4–5 log units.

Another revelation from HBV molecular biology is the discovery of HBeAg-negative, anti-HBe-positive CHB.9 Wild-type HBV sometimes undergoes point mutations in CHB patients. The natural history of these ‘precore’ and core promoter HBV mutants is not entirely clear but, at present, therapy is similar to that for wild-type infections and assessment of efficacy data is under close investigation.

Asian people are estimated to account for 75% of the 400 million individuals with chronic HBV infection worldwide.10 In Asian people, HBV is mostly acquired at birth by vertical transmission from CHB mothers or in infancy by close physical contact. In early life, immune tolerance to HBV is the rule, with normal serum alanine aminotransferase (ALT) levels, despite high HBV-DNA levels. Then follows an immunoreactive phase, with fluctuating viral levels and periodic or persistent elevation of serum ALT levels. Up to three-quarters of Asian CHB patients undergo spontaneous HBeAg seroconversion. This is followed by disease quiescence and a good prognosis. The remaining one-quarter of patients have a protracted immune clearance process, eventually resulting in cirrhosis. Without treatment, they will often succumb to complications of cirrhosis or hepatocellular carcinoma. Adults who acquire CHB are more common among non-Asian patients, the routes of infection being parenteral or sexual. They tend to have active liver disease.

Consideration of therapy for CHB must take into account the different stages of liver disease, the intensity of disease activity and genetic variability of the virus and host. Thus, the treatment plan will vary according to the different immune phase and to the viral load, the presence or absence of compensated cirrhosis, acute presentation with liver failure and the prospect of liver transplantation for decompensated cases. Coinfection with hepatitis C virus, hepatitis delta virus and/or HIV may be common in certain high-risk groups; this requires tailored therapy. Few data are available on the management of patients with extrahepatic HBV-related problems, including glomerulonephritis. Patients with CHB who are immunocompromised, for example, those undergoing chemotherapy or organ transplantation, comprise another important subgroup that needs separate management guidelines.

At the beginning of the 21st century, how can we manage our CHB patients in order to benefit most from the recent advances? Are the guidelines likely to be relevant and affordable to all CHB patients in the Asia–Pacific region?

Therapeutic agents: review of clinical data

  1. Top of page
  2. Abstract
  3. Therapeutic agents: review of clinical data
  4. Patient selection for IFN and lamivudine therapy
  5. Concluding remarks
  6. References

Interferon

Interferon was the only approved treatment for nearly 10 years and, until 4 years ago, most studies monitored HBeAg seroconversion, a few reported on HBV-DNA levels, but the impact of IFN treatment on liver histology is rarely mentioned. Different agents and dosage regimens were used. Wong et al. performed a meta-analysis on published trials using adequate dosage (3–5 MU/m2, t.i.w) for 3–6 months.6 Compared with controls, IFN-treated patients had a significantly higher rate of HBeAg seroconversion (12 vs 33%, respectively; P < 0.001), HBsAg seroconversion (2 vs 8%, respectively; P < 0.001) and suppression of HBV-DNA (17 vs 37%, respectively; P < 0.001).

This meta-analysis also addressed the concern about unfavorable responses among Asian patients. The results indicated that raised ALT levels rather than ethnic origin are more important in determining treatment outcome. The immune modulatory action of IFN appears to be the more important factor and the agent works better in patients with moderately raised ALT levels. A few subsequent publications demonstrated the long-term benefits of HBeAg seroconversion on the prevention of complications and extension of the complication -free survival.11

Interferon treatment is associated with flu-like symptoms in most patients during the early part of therapy. This is controllable with prophylactic paracetamol, acetaminophen. Some patients experience weight loss, bone marrow suppression, an increased risk of sepsis (particularly those with cirrhosis), alopecia, thyroid dysfunction, depression and other psychiatric disorders. Specialist experience is required in managing patients on IFN therapy.7,11

Lamivudine

Lamivudine is the first oral therapy for the treatment of CHB.5,6,12 It is effective in a broad range of patients and has minimal safety issues. Phase III clinical trials on patients with HBeAg-positive, compensated CHB showed that 1 year of lamivudine therapy significantly increased HBeAg seroconversion to 16–18%, compared with placebo (4–6%) and IFN controls (19%).6,13 Assessment of paired liver biopsies indicated a significant reduction in histological activity (histological activity index (HAI) score by 2 points or more) in 50–60% of patients. Improvement was seen not only in necroinflammatory activity, but fibrosis progression was also reduced. Extension of therapy increased the total number of HBeAg seroconversions. Thus, in the Asian multicenter lamivudine study, the cumulative rate of HBeAg seroconversion at each successive year of therapy was 22, 29, 40, 47 and 50% in a subgroup of 58 patients randomized to 5 years of continuous therapy.13–16 The single most important predictor of HBeAg seroconversion is the baseline ALT level. After 1 year of lamivudine therapy in patients with ALT > 2× upper limit of normal (ULN), 38% underwent HBeAg seroconversion; this increased to 64% if the ALT was > 5× ULN. Among cases treated with extended lamivudine therapy, HBeAg seroconversion was predominantly seen in patients with moderately raised (> 2× ULN) and was 38, 42, 65, 73 and 77% over 5 years. These observations indicate that, as for IFN therapy, the immune status of the host is an important determinant of a successful outcome during lamivudine treatment.14

Alanine aminotransferase levels decrease gradually during the first year of lamivudine treatment. Among patients randomized to placebo in the second year of the Asian multicenter lamivudine study, relapse of hepatitis always occurred if the patients had not achieved HBeAg seroconversion. Return of viremia and rebound of serum ALT occurred 2–3 months after stopping lamivudine; ALT was > 500 U/L in 6% of patients and there was associated hyperbilirubinemia in 3%. Reintroduction of lamivudine allowed control of the disease to be regained promptly.

Extended periods of monotherapy with lamivudine are complicated by emergence of drug-resistant YMDD mutants. The annual cumulative emergence rates of YMDD genotypic mutation over 5 years are 17, 40, 55, 66 and 69%.13–17In vitro studies have demonstrated that the YMDD mutant HBV has a diminished replication capacity.18 It is therefore not surprising that CHB patients who developed YMDD mutants had significantly lower serum HBV-DNA and ALT values during the first year after YMDD emergence relative to baseline values. Furthermore, some patients with YMDD mutants continued to achieve HBeAg seroconversion or underwent such seroconversion for the first time. A few patients also lost the YMDD mutant form(s), with a return to detectable wild-type isolates.15–17

Patients with YMDD mutants have a variable degree of ALT elevation. The ALT profile changes with time, but is unpredictable. Individual patient profiles range from persistently normal ALT, transient ALT elevation and persist ALT elevation. Acute exacerbations (flares), sometimes with hepatic decompensation, have been observed and fatalities have been reported.19 Among a subgroup of Asian patients who underwent liver biopsy at baseline and after 1 and 3 years of therapy, deterioration was seen more often among patients who had harbored YMDD mutants for a longer period of time.16 Therapy with other nucleoside analogs, such as adefovir dipivoxil and entecavir, is currently being assessed in phase III clinical trials. Data on lamivudine therapy in HBeAg-negative CHB are less substantial. Clinical trials so far indicate that viral suppression is similar to wild-type infections. Lack of a serological marker for a therapeutic end-point makes management more difficult and relapse is common after stopping therapy at 12 months.14 In the future, sensitive HBV-DNA assays may help guide therapy. Extended therapy for 2 years or longer has been associated with difficulties of the emergence of drug-resistant YMDD mutants and recurrence of hepatitis activity.20

Lamivudine was well tolerated during 5 years of therapy in the Asian multicenter study.13–17 Elevated ALT levels were observed in some patients, especially during the initial phase, and this was attributed to a rebound host immune response associated with the rapid fall of HBV-DNA. Such elevations in ALT were rarely associated with hyperbilirubinemia.

The role of lamivudine in decompensated CHB and during acute exacerbations has been explored. In many patients with decompensated cirrhosis waiting for liver transplantation, treatment with lamivudine has been associated with improvement of liver function and some patients were even able to come off the transplant waiting list.21 The benefit of lamivudine in acute hepatic failure is less well documented, but some data indicate that delayed introduction of lamivudine until serum bilirubin has risen to 20× ULN is seldom able to reverse the downhill trend.22 Conversely, the frequent exacerbations of hepatitis among HBsAg-positive patients during chemotherapy and after organ transplantation warrant prophylactic lamivudine therapy to cover the at-risk period.17,18

Other potential therapeutic agents

A number of potential HBV antivirals are being assessed in phase II and III clinical trials. Emtricitabine (FTC) showed potent viral suppression and an increased HBeAg seroconversion rate with a good safety profile, but emergence of YMDD variants could be expected to be similar to the closely related lamivudine.19 Adefovir dipivoxil is potent, but is nephrotoxic at doses higher than 10 mg/day. It has the added advantage of efficacy on YMDD mutant HBV at a renal-tolerable dose of 10 mg daily. Entecavir is effective in suppressing YMDD mutant CHB, and phase III trials start in 2002. Phase II results on BL-thymidine (L-dT) are also encouraging. There are also newer agents, such DAPD and clevudine (l-FMAU).23 Thymosin-α1, an immune modulator, is available in some countries, but has failed to gain a strong therapeutic position because of conflicting results from clinical trials.24 Therapeutic vaccines are theoretically attractive, but confirmation of efficacy is awaited. Finally, herbal medicine has much intrinsic appeal in Asian countries among the population, where traditional medicine remains part of present day culture and it is more affordable. The number of herbs used is plentiful, but a formal randomized study has not been conducted and so no definite conclusion can be drawn on the efficacy of herbal medicines until studies are conducted in an evidence-based manner.

Combination therapy is likely to be the next milestone in the therapy of CHB. Preliminary trials indicate a possible synergistic effect between IFN and lamivudine,19 but optimal case selection and treatment regimen have not yet been clarified; the possible benefits of pegylated IFN and lamivudine in combination will be of great interest. Many other combinations are being tested, such as adefovir and lamivudine. Two or more agents used together are more likely to suppress HBV, thereby both eradicating cccDNA in hepatocytes and decreasing the emergence of drug resistance. An effective therapy for a defined duration would be the ideal regimen for the cost-effective control of CHB.

Patient selection for IFN and lamivudine therapy

  1. Top of page
  2. Abstract
  3. Therapeutic agents: review of clinical data
  4. Patient selection for IFN and lamivudine therapy
  5. Concluding remarks
  6. References

Bearing in mind that therapy should improve prognosis, the current indications for treatment are focused on patients with active liver disease (i.e. with detectable HBV-DNA by bDNA or sensitive hybridization assays that have a lower limit of detection of 100 000 virus equivalents/mL, together with raised ALT). This applies both to HBeAg-positive and -negative patients. In view of the relatively low response with either IFN or lamivudine therapy, and in light of possible side-effects and cost, the level of disease activity that provides an indication for cost-effective therapy needs to be somewhat flexible and adaptive. Indications for immediate treatment are histological evidence of moderate to severe necroinflammatory changes with a fibrosis score of 2 on Metavir or similar 0–4 scoring systems. Viremic patients with decompensated liver disease should be treated if liver transplantation is not appropriate. Data are scarce for treating CHB at extremes of age, but children have been successfully treated with either IFN or lamivudine.25 Elderly patients may have concomitant diseases and the risk/benefit of therapy has to be individualized.

These treatment options can be summarized as follows.

Chronic hepatitis B with normal or minimally elevated ALT (2× ULN)

  • • Responds poorly to IFN and lamivudine.

  • • 
    Monitor and watch for an opportunity to treat.

Chronic hepatitis B with raised ALT

  • • ALT > 2× ULN: IFN or lamivudine (note: IFN is preferably confined to patients without cirrhosis with ALT 2–5× ULN because ALT flare during treatment may precipitate liver failure).

  • • 
    The dose of IFN is 5–10 MU (3 MU/m2) t.i.w. for 4–6 months.
  • • 
    For IFN non-responders, consider treatment with lamivudine.
  • • 
    Patients with ALT > 5× ULN are best treated with lamivudine 100 mg daily. There is no consensus on the duration of lamivudine therapy. Either treat until 2–6 months after HBeAg seroconversion to secure durability of response or stop lamivudine in patients who have not seroconverted despite 1 year of therapy. This will minimize the chance of emergence of YMDD. This can be justified because more effective therapy is likely to become available in the near future. Relapse after treatment is stopped, which is almost inevitable unless HBeAg seroconversion has occurred, and patients can be successfully retreated with lamivudine until HBeAg seroconversion occurs. Alternatively, experimental clinical trial protocols can be considered. It is very difficult to define the optimal duration of lamivudine treatment. It is advisable for all patients who failed to undergo HBeAg seroconversion after 1 year of therapy to be reviewed by an experienced specialist.

Active cirrhosis (Child’s A)

  • • Prompt lamivudine treatment to halt the progression of the disease; YMDD mutation may emerge with reduced therapeutic benefit or worsening disease, especially with flares that can lead to hepatic decompensation .

  • • 
    Interferon has been used successfully in compensated Child’s A cirrhosis with reduced dosage. Alanine aminotransferase flare and bone marrow suppression aggravating hypersplenism are major concerns. These patients must be managed by experienced specialists. The decision has to be made according to availability of experimental drugs and/or efficiency of liver transplantation facilities in local settings. Maximize the response by frequently monitoring ALT to detect an optimal opportunity to commence therapy. Whether lamivudine can be stopped after HBeAg seroconversion is controversial. It appears advisable to continue therapy in the long term based on available data.21

Active cirrhosis (Child’s B and C)

  • • These patients should be treated in specialist centers.

  • • 
    Because Asian countries generally have extremely limited transplant opportunities, there is little choice but to start and continue lamivudine.
  • • 
    The issue of YMDD in this group poses a considerable dilemma; while improvement may help them come off the liver transplantation list, development of YMDD may jeopardize their chance of a successful transplant.
  • • 
    Availability of adefovir, entecavir and other agents effective against YMDD mutant HBV may eventually alter the outcome.

Acute exacerbations (flares) of CHB

  • • When patients present with an acute exacerbation and icteric decompensation, the prognosis is poor. Exclude other causes, especially acute hepatitis A, E and C, drugs (paracetamol) and herbs.

  • • 
    Lamivudine should be started promptly; reported series show clinical benefit compared with historical controls .22
  • • 
    Long-term lamivudine therapy may be advisable.

Chemotherapy and organ transplantation in people with CHB

  • • The occurrence of reactivation or acute flares in HBsAg-positive patients during chemotherapy is frequent enough to warrant prophylactic lamivudine therapy for the duration of chemotherapy.

  • • 
    HBsAg-positive organ transplant recipients on immune suppressive agents often have reactivation of hepatitis; ongoing immune suppression necessitates long-term lamivudine therapy.
  • • 
    The risk of YMDD mutant emergence and hepatitis reactivation is a management dilemma.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Therapeutic agents: review of clinical data
  4. Patient selection for IFN and lamivudine therapy
  5. Concluding remarks
  6. References

Therapy for CHB is making advances in leaps and bounds but, to date, only IFN and lamivudine have been approved for use outside clinical trials. Both agents have distinct advantages and shortcomings. Physicians must assess patients properly and weigh the pros and cons of ‘to treat’ or ‘not to treat’, what agent and the treatment course. Discussion with patients must be open, making sure that the person understands the complicated issues involved with efficacy, safety (flares and adverse effects) and drug resistance in relation to natural history. Information on hepatitis B therapy, both accurately or erroneously portrayed, is readily available to the general public, making the role of a clinician more challenging. The state of play on CHB therapy is still at an early phase and future improvements are likely in the next few years. Available therapy with IFN and lamivudine is beneficial only for patients with active liver disease and detectable serum HBV-DNA with raised serum ALT levels. Lamivudine is appealing to many patients who may ‘demand’ therapy, but its inappropriate use will result in many patients infected with YMDD mutants; they are likely to be less responsive to combination therapy in the future. Those with less active disease may best be recruited to clinical trials to search for better therapy.

References

  1. Top of page
  2. Abstract
  3. Therapeutic agents: review of clinical data
  4. Patient selection for IFN and lamivudine therapy
  5. Concluding remarks
  6. References
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