Correspondence: Dr Nancy Leung, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Road,Shatin, Hong Kong. Email: nancyleung@cuhk.edu.hk

ADVANCES IN LIVER DISEASE: HEPATITIS B

Treatment of chronic hepatitis B: Case selection and duration

of therapy

NANCY LEUNG

Prince of W ales Hospital, The Chinese University of Hong Kong, Hong Kong

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 progres-sion 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 100mg 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 pre-treatment 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 Y MDD 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 (par-ticularly 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 con-tinuing 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. Quan-titative 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 var-

may have a better chance of eradicating HBV and its cccDNA in the hepatocytes as the basis for an even-

tual 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 ther-

apeutic 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 sup-

pressive 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 100000viral 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) com-

bination 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

Key words:antiviral treatment, case selection, chronic hepatitis B, combination therapy, interferon,

lamivudine, treatment course.

Real prospects for antiviral therapy of chronic hepatitis

B (CHB) only started to surface in the 1980s. One ear-

lier 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.3,4The 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, lamivu-

dine 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, famiclo-

vir lacks potency and fialuridine causes fatal mitochon-

drial 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. Hepa-

titis 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 seroconver-

sion 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. Solu-

tion hybridization and signal amplification assays have a

lower detection limit of 105−106virus equivalents/mL, but quantitative polymerase chain reaction (PCR)

assays (especially real-time PCR) refine the detection

limit down to 100copies/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 elim-

ination of templates for viral replication (cccDNA) in

the hepatocytes tend to correlate with better outcomes.

The target serum HBV-DNA level may be 104−105virus 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.9Wild-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 immunoreac-tive 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 treat-ment, they will often succumb to complications of cir-rhosis 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 pres-ence or absence of compensated cirrhosis, acute presen-tation with liver failure and the prospect of liver transplantation for decompensated cases. Coinfection with hepatitis C virus, hepatitis delta virus and/or HIVTreatment of chronic hepatitis B411

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 transplanta-tion, 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

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 histol-ogy is rarely mentioned. Different agents and dosage regimens were used. Wong et al. performed a meta-analysis on published trials using adequate dosage (3–5MU/m2, t.i.w) for 3–6 months.6 Compared with con-trols, IFN-treated patients had a significantly higher rate of HBeAg seroconversion (12 vs 33%, respectively; P<0.001), HBsAg seroconversion (2 vs 8%, respec-tively; 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 eth-nic 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 symp-toms 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 dys-function, 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 signifi-

cant reduction in histological activity (histological activ-

ity index (HAI) score by 2 points or more) in 50–60%

of patients. Improvement was seen not only in necroin-

flammatory activity, but fibrosis progression was also

reduced. Extension of therapy increased the total num-

ber of HBeAg seroconversions. Thus, in the Asian mul-

ticenter 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 seroconver-

sion 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 % 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 lami-

vudine; ALT was >500U/L in 6% of patients and there

was associated hyperbilirubinemia in 3%. Reintroduc-

tion of lamivudine allowed control of the disease to be

regained promptly.

Extended periods of monotherapy with lamivudine

are complicated by emergence of drug-resistant Y MDD

mutants. The annual cumulative emergence rates of

YMDD genotypic mutation over 5 years are 17, 40, 55,

66 and 69%.13–17In vi tro studies have demonstrated

that the YMDD mutant HBV has a diminished replica-

tion capacity.18 It is therefore not surprising that CHB

patients who developed YMDD mutants had signifi-

cantly lower serum HBV-DNA and ALT values during

the first year after Y MDD 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, deterio-

ration 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 adefovir412N Leung

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 diffi-

cult 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 emer-

gence of drug-resistant Y MDD mutants and recurrence

of hepatitis activity.20

Lamivudine was well tolerated during 5 years of ther-

apy 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 associ-

ated 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 wait-

ing list.21The benefit of lamivudine in acute hepatic fail-

ure is less well documented, but some data indicate that

delayed introduction of lamivudine until serum biliru-

bin has risen to 20× ULN is seldom able to reverse the downhill trend.22 Conversely, the frequent exacerba-

tions of hepatitis among HBsAg-positive patients dur-

ing 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 lamivu-

dine.19 Adefovir dipivoxil is potent, but is nephrotoxic at

doses higher than 10mg/day. It has the added advantage

of efficacy on YMDD mutant HBV at a renal-tolerable

dose of 10mg 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 conflict-ing 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 con-ducted in an evidence-based manner.

Combination therapy is likely to be the next mile-stone in the therapy of CHB. Preliminary trials indicate a possible synergistic effect between IFN and lamivu-dine,19 but optimal case selection and treatment regi-men 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 effec-tive therapy for a defined duration would be the ideal regimen for the cost-effective control of CHB.

PATIENT SELECTION FOR IFN AND LAMIVUDINE THERAPY

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 100000virus 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 lami-vudine therapy, and in light of possible side-effects and cost, the level of disease activity that provides an indi-cation for cost-effective therapy needs to be somewhat flexible and adaptive. Indications for immediate treat-ment 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 lamivu-dine.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 5–10MU (3MU/m2) t.i.w. for 4–6 months.

•For IFN non-responders, consider treatment with lamivudine.Treatment of chronic hepatitis B413

•Patients with ALT >5× ULN are best treated with lamivudine 100mg daily. There is no consensus on the duration of lamivudine therapy. Either treat until 2–6 months after HBeAg seroconversion to secure durabil-ity 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 treat-ment 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 clin-ical 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 transplan-tation 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 contro-versial. 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 lim-ited transplant opportunities, there is little choice but to start and continue lamivudine.

•The issue of Y MDD 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 fre-quent 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

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. Phy-sicians 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 improve-ments 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

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