Treatment of HBeAg-positive patients with nucleos/tide analogues

Authors


Correspondence
Samuel S. Lee, Liver Unit, University of Calgary, 3330 Hospital Drive NW, Calgary, AB,
Canada T2N 4N1
e-mail: samlee@ucalgary.ca

Abstract

The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg.

Chronic hepatitis B affects over 350 million persons worldwide, of whom an estimated 500 000 die annually from hepatitis B virus (HBV)-related liver disease. Effective HBV antiviral treatment is important, given the significant associated global morbidity and mortality from liver-related complications. The immediate goals of treatment in patients with chronic hepatitis B are to reduce the viral load and arrest or reverse hepatic fibrosis. The ultimate aim is to prevent decompensation, cirrhosis and hepatocellular carcinoma (HCC). The approach to the care of patients infected with HBV is rapidly evolving, and considerable progress has been made in the treatment of chronic HBV infection, given the development of more sensitive diagnostic tests and newer antiviral agents. Interferon-α, longer-acting pegylated interferon (peginterferon) and nucleos/tide analogues such as lamivudine, adefovir dipivoxil, entecavir, tenofovir, emtricitabine, clevudine and telbivudine are currently available in most countries for treatment of HBV infection. Challenges to the development of effective treatment regimes include emergence of antiviral-resistant HBV mutants during prolonged monotherapy and although these agents significantly reduce or inhibit viral replication while on therapy, relapse after treatment cessation is common.

Hepatitis B virus molecular virology and antiviral-specific host immune response

Hepatitis B virus is the prototype member of the family Hepadnaviridae and is classified into eight major genotypes (A–H) based on the nucleotide diversity of >8%, which has a distinct global geographical distribution. Genotyping is not necessary in routine clinical practice but may be useful in patients considering interferon therapy. Genotype A is more likely to respond to interferon, whereas genotypes C and D are less likely to respond and have been associated with more severe liver disease (1).

The HBV genome is a partially double-stranded DNA virus with four overlapping open reading frames (ORFs) encoding Core, Surface, X and Polymerase genes. The virus utilizes reverse transcription to copy its DNA genome, and because of a lack of proofreading capacity, it is prone to a 10 times higher mutation rate than other DNA viruses. Mutant HBV genomes or quasispecies continually emerge, and quasispecies with increased replication fitness are readily selected under the selection pressure of antiviral drugs and then emerge as the new dominant population. The genetic overlap of the four HBV ORF makes it possible that HBV polymerase mutants selected during nucleos/tide analogue therapy can cause concomitant changes in the HBV surface gene. Development of antiviral resistance may be associated with relatively rapid increases in viraemia, biochemical breakthrough, severe hepatitic flares and even fatal disease progression. Moreover, HBV surface mutants may behave as vaccine escape mutants, and have the potential to be transmitted, raising public health concerns for HBV vaccination programmes (2–4).

Another important feature of the HBV lifecycle is the formation of a unique replicative intermediate, covalently closed circular DNA (ccc-DNA). This viral minichromosome is formed within the nucleus of the infected host cell acts as the major transcriptional template for new viral particles. The durability and stability of the ccc-DNA pool in the infected hepatocyte is a key factor in the maintenance of chronic HBV infection. While antiviral therapy can significantly affect HBV DNA levels (4–6 log decrease), it is relatively ineffective against HBV ccc-DNA (generally only a 2-log decrease), hindering attempts at viral eradication.

The host immune response, which is not directly cytopathic, is largely responsible for the outcome of HBV infection. In those with self-limited infection, CD4 T-helper cells and CD8 cytotoxic T cells mount a response to HBV antigens, leading to further cytokine production and liver cell injury, viral clearance and then recovery. In individuals who progress to develop chronic infection, the humoral response seems to be more active, with IL-4, IL-5 and IL-10 inducing the production of antibodies; however, there is less viral clearance. In summary, virus persistence occurs because of the presence of an intracellular pool of ccc-DNA, extrahepatic HBV reservoirs, integration of HBV DNA into the host genome and the host antiviral immunological profiles (5).

Who should be treated?

The goals of antiviral therapy are to prevent or delay the complications from chronic HBV infection, including cirrhosis and HCC. Virus eradication is ideal but is impossible to achieve because even in patients achieving HBsAg seroconversion to anti-HBs, occult HBV infection often persists. In general, indications for therapy include the following: (i) evidence of ongoing viral replication; (ii) high levels of HBV DNA for at least 6 months with or without HBeAg; (iii) persistent elevation in alanine aminotransferase (ALT) levels higher than twice the upper limit of normal; and (iv) evidence of hepatic injury on liver biopsy (6–10). These patients are at greatest risk of liver-related complications (11). Patients with cirrhosis, regardless of the ALT level, are recommended for treatment. Sustained loss of the markers of active viral replication (i.e. HBeAg seroconversion and HBV DNA suppression) is associated with biochemical and histological improvement, and thus patients with active replication are most in need of treatment (Table 1).

Table 1.   Summary of anti-hepatitis B virus drugs
DrugAdvantagesDisadvantages
  1. ALT, alanine aminotransferase; HBV, hepatitis B virus; peginterferon, pegylated interferon.

Peginterferon
α-2a
Higher rates of HBeAg seroconversion at 1 year, undetectable HBV DNA and normal ALT
Finite treatment duration
Lack of resistance mutations
Significant side effects
Requires a subcutaneous injection
High cost
Lack long-term off-treatment follow-up data
LamivudineExcellent tolerability even in advanced liver disease
Low cost
HBV resistance in 69% after 5 years
AdefovirWell tolerated even in advanced liver disease
Effective against wild-type & lamivudine-resistant HBV
Low rate of HBV resistance in the first 2 years
Higher cost
Resistant HBV mutants in 29% after 5 years
Nephrotoxic at higher doses
EntecavirWell tolerated
Potent HBV DNA suppression
Low rate of HBV resistance at 2 years (<1% if wild-type HBV)
Higher cost
Higher rate of drug resistance in lamivudine-experienced patients (9% after 2 years)
No long-term data beyond 3 years
TelbivudineWell tolerated
Moderately potent HBV DNA suppression
Modest rate of HBV resistance (18% at 2 years)
Higher cost
Ineffective in some lamivudine-resistant HBV patients
Lack of long-term data (beyond 2 years)
TenofovirWell tolerated, but limited data in HBV patients
Potent HBV DNA suppression
Effective against wild-type and lamivudine-resistant HBV
Higher cost
Risk of nephrotoxicity (incidence unknown)
Lack of long-term data in HBV infection
EmtricitabineWell tolerated
Moderately potent HBV DNA suppression
Moderate risk of HBV-resistant mutants (13% at 1 year)
Ineffective in lamivudine-resistant HBV
ClevudineWell tolerated
Durable off-treatment viral suppression (6 months)
Similar rates of HBeAg conversion to placebo (24 weeks treatment)

However, new evidence is suggesting that these short-term goals may not prevent or delay the development of HCC and cirrhosis. According to the REVEAL-HBV study, the biological gradient of cirrhosis and HCC risk corresponded to the serum HBV DNA levels, even among chronic HBV carriers who were HBeAg seropositive with a normal serum ALT level (12). Therefore, without lowering the serum HBV DNA level, neither seroconversion of HBeAg nor normalization of ALT may be sufficient to protect a patient with chronic hepatitis B from developing end-stage liver disease (12). Recent studies have suggested that some patients with normal ALT may still have significant ongoing inflammation and liver disease, especially if infected with a precore HBV mutant, or have other comorbid liver disease (i.e. alcohol, fatty liver) (13). For this reason, a liver biopsy should be considered in individuals over age 35 years, and treatment should be considered if significant histological disease is present. Some experts also suggest that patients with persistent ALT levels within the upper half of the normal range may still be at risk for liver-related mortality (14). Although we feel there are still insufficient data to support recommendation for therapy in patients with normal ALT values, all patients warrant ongoing disease monitoring. Data previously published by Liaw et al. (15) suggested that treatment of all patients with cirrhosis reduced the risk of HCC. Recently, Lampertico et al. (16) addressed this issue during evaluation of the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B. Although >80% of patients achieved undetectable HBV DNA levels and 90% of patients experienced ALT normalization, 26% (17/63) patients still developed HCC after a median follow-up of 24 months. The investigators concluded that despite viral suppression, the risk for HCC remains relatively high. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the ‘precancerous’ cirrhotic lesions and persistent HBV infection in the liver might explain the continuing risk for HCC.

Duration of treatment

The optimal duration of therapy has not been well defined. In general, for HBeAg-positive patients, treatment until HBeAg seroconversion and then for an additional 6–12 months of consolidation treatment is recommended (6, 7, 10, 17) Seroreversion (reappearance of HBeAg) occurs in approximately 10–25% of patients within 3 years of withdrawal of nucleos/tide treatment. Factors associated with higher rates of seroreversion include a shorter duration of consolidation treatment, older age, a higher HBV DNA level at the time treatment was stopped and infection with HBV genotype C vs. genotype B. Viral relapse and exacerbations of hepatitis may occur after discontinuation of therapy; hence, the exception to discontinue treatment despite HBeAg seroconversion may be in cirrhotic patients in whom recurrence of high-level viral replication might precipitate decompensation. For this reason, it has been suggested in some guidelines that cirrhotic patients should continue treatment indefinitely until they attain HBsAg clearance. Some clinicians are reluctant to discontinue treatment even after 12 additional months of post-seroconversion therapy if residual HBV DNA is detectable (range of 102–103 IU/ml). The AASLD guidelines recommend closely monitoring patients in whom nucleos/tide treatment has been withdrawn (every 1–3 months for the first 6 months, and every 3–6 months thereafter) and note that reinstitution of treatment is usually effective in controlling liver disease progression in patients who have not developed resistance (10).

Recent data also suggest that the durability of therapy-induced HBeAg seroconversion may depend on the age of acquisition of HBV. Patients from western countries are more likely to acquire HBV during adolescence or early adulthood. The majority of patients from Asia and Africa acquire HBV early in life during the neonatal period. Natural history studies have shown that adults with neonatally acquired HBV infection have less durable HBeAg seroconversion rates. In one early study of 34 Korean patients, the cumulative relapse rate was 50% after 2 years of stopping lamivudine (18). Similarly, another study of Indian patients reported a relapse rate of 34% 6 months after stopping lamivudine (19). In contrast, a study of western (European) populations showed that 77% had a durable lamivudine-induced HBeAg seroconversion rate after a median follow-up of 37 months (20). Thus, evidence indicates that HBeAg seroconversion is a dynamic process and should not be considered the sole therapeutic endpoint, especially in patients who acquired HBV in early childhood. An alternative endpoint proposed is treatment cessation 6–12 months after HBeAg seroconversion, provided HBV DNA is undetectable by polymerase chain reaction (PCR) (8, 9).

Overview of anti-hepatitis B virus therapies

The approach to care of HBV patients is rapidly evolving. Until recently, interferon-α was the only improved treatment for chronic hepatitis B. Nowadays, the available drugs for the treatment of chronic HBV infection include longer-acting peginterferon α-2a and several oral nucleos/tide analogues (Table 1). The nucleoside analogues are lamivudine, emtricitabine, entecavir, telbivudine and clevudine. The nucleotide analogues include adefovir dipivoxil and tenofovir. These drugs are generally approved in most countries. Emtricitabine and Tenofovir were initially developed as anti-HIV therapies and have been commonly used for treatment for HIV-HBV co-infected patients, but recent clinical trials have demonstrated that these drugs also show potent antiviral activity in HBV-mono-infected patients (21). Clevudine is approved in some parts of the world and is currently under study in international phase III trials.

Pegylated-interferon

Interferon was approved for treatment of chronic hepatitis B in the early 1990s, but nowadays peginterferon-α is preferred because of the convenience of administration. It is approved for HBV treatment by a subcutaneous injection at doses of 180 mcg once weekly for 48 weeks. Randomized-controlled studies have compared the efficacy of peginterferon α-2a 180 mcg weekly, lamivudine 100 mg daily and combination peginterferon plus lamivudine for 48 weeks, in HBeAg-positive (22) and HBeAg-negative (23) chronic HBV infection. In both studies, peginterferon α-2a was significantly superior to lamivudine in achieving clinical outcomes including ALT normalization, HBeAg seroconversion and a reduction in HBV DNA levels to <400 copies/ml. The advantages of peginterferon compared with the other options are its finite duration of treatment and the absence of selection of resistant mutants. Moreover, treatment can induce HBsAg loss or seroconversion at a rate of 3–8% rate after 1 year of therapy.

The disadvantages are its subcutaneous administration, and side effects from interferon are troubling for many patients, and (less commonly) can be severe. Adverse effects associated with interferon include flu-like symptoms, fever, myalgias, bone marrow suppression, thyroid abnormalities and psychiatric side effects (24). Interferon cannot be used in patients with decompensated disease because of the possibility of further, potentially fatal, decompensation. Results regarding the long-term benefits of peginterferon off treatment follow-up are awaited. Overall, compared with all nucleos/tide analogues, although interferon therapy has been shown to have higher rates of HBeAg seroconversion after 1 year of treatment, seroconversion rates are similar after 2 years (26–32%). However, most patients (70%) do not seroconvert and may require long-term therapy, likely with a nucleos/tide analogue.

The major predictors of treatment response to interferon are female sex, high ALT levels, low HBV DNA levels (<200 pg/ml or <600 × 105 copies/ml) (1 IU=5.26 copies/ml; 1 pg/ml=2.83 × 105 copies/ml) and a greater degree of activity on liver biopsy (22, 25). Infection at birth or early childhood is a negative predictor of response to interferon therapy. Patients with HBV genotype A are most likely to respond and may be a subgroup well suited for interferon therapy (26). Overall, peginterferon can be considered for use as a first-line therapy for chronic hepatitis B in the following clinical situations: HBeAg-positive patients without cirrhosis, patients with genotype A infection, those with relatively low levels of viraemia and active necroinflammation on liver biopsy and in those in whom drug resistance may limit treatment options in the future. Peginterferon may also be an option in women of childbearing age who wish to pursue a finite course of therapy and are concerned about the possible teratogenic risks with nucleos/tide agents.

Nucleos/tide analogues

The advantages of nucleos/tide analogues are the ease of administration (one pill daily), a good safety profile and substantial efficacy with new agents (i.e. entecavir or tenofovir), with 70–90% of patients achieving undetectable HBV DNA (9, 27). The disadvantage of nucleos/tide analogues is that treatment must be continued for many years. In most studies of approved oral agents, loss of HBsAg has been at rates ≤1%. In recent pivotal trials of tenofovir in HBeAg-positive patients, 3% lost HBsAg after 1 year of therapy (28–30). Therefore, although interferon therapy is still marginally superior for achieving HBsAg loss, increasing evidence indicates that the newer oral agents are also able to induce this significant therapeutic endpoint.

Lamivudine

Lamivudine is a cytosine nucleoside analogue, administered 100 mg orally once daily. The drug is well tolerated with few side effects and has proven efficacy in inhibition of viral replication, reduction of liver inflammation and in improvement of liver fibrosis. In large placebo-controlled studies, almost all patients (98%) showed a reduction in the HBV-DNA level after 1 year of treatment, 17–33% on treatment vs. 6% on placebo experienced loss of HBeAg, and >50% of lamivudine-treated patients vs. 20% of controls showed histological improvement (31, 32). Continuous lamivudine treatment for a median duration of 32 months in patients with cirrhosis led to a 50% reduced rate of clinical progression defined by hepatic decompensation and HCC (33). Long-term lamivudine therapy is limited by the emergence of mutations in the YMDD (Tyrosine, Methionine, Aspartate, Aspartate) motif of the HBV polymerase at the rate of 20–25% annually, and approaching 70% after 48 months, leading to drug resistance and virological breakthrough (33, 34). Factors that increase the risk of resistance include high pretherapy serum HBV DNA and ALT levels (creation of replication space) and incomplete suppression of viral replication.

Adefovir dipivoxil

Adefovir dipivoxil is an adenosine nucleotide analogue administered orally at 10 mg daily. Adefovir has efficacy against wild-type and lamivudine-resistant HBV and is indicated for treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B (35). Adefovir 10 mg daily for 48 weeks in patients with HBeAg-positive chronic hepatitis B (compared with untreated patients) resulted in improved liver histology (53 vs. 25%), reduced serum HBV DNA levels <400 copies/ml (21 vs. 0%), normalized ALT levels (48 vs. 16%) and higher rates of HBeAg seroconversion (12 vs. 6%) (36). In HBeAg-negative chronic hepatitis B, 51% patients had reduced serum HBV DNA <400 copies/ml vs. 0% placebo, and ALT levels normalized in 72% vs. only 29% placebo (37). In HBeAg-negative chronic HBV disease, patients had a high rate of virological relapse if treatment was stopped at week 48 (38), but 67% of patients treated for up to 4 years maintained virus suppression, 69% showed ALT normalization and 73% had improved liver histology (39). The drug has potential nephrotoxic side effects (40) but the incidence of renal dysfunction with the 10-mg dose used for HBV infection is very low (6% after 192 weeks of treatment) (38). HBV resistance to adefovir occurs less frequently than resistance to lamivudine. The overall prevalence is around 6% after 3 years, increasing to 29% by 5 years (38, 41). Adefovir-resistant HBV remains sensitive to other antivirals including lamivudine, emtricitabine and entecavir (42, 43).

Entecavir

Entecavir is a deoxyguanosine nucleoside analogue with potent anti-HBV effects. In two multinational studies of mono-infected patients with HBeAg-positive and HBeAg-negative chronic HBV treated with entecavir 0.5 mg daily or lamivudine 100 mg daily for 48 weeks, entecavir was more effective than lamivudine in suppressing viral replication (43, 44). In the treatment of HBeAg-positive chronic HBV, entecavir, compared with lamivudine, had HBeAg seroconversion rates of 21 vs. 18%, suppression of HBV DNA to <0.7 MEq/ml in 91 vs. 65%, normalization of serum ALT in 78 vs. 70% and histological improvement in 72 vs. 62% (43). A similar benefit was noted in the treatment of HBeAg-negative HBV, with entecavir yielding a higher proportion of patients with histological improvement (70 vs. 61%), undetectable HBV DNA by PCR (90 vs. 72%) and ALT normalization (90 vs. 72%) than in the lamivudine group (43). Continued benefit is seen with longer-term entecavir treatment, with 90% of patients achieving complete viral suppression, 80% normalizing ALT and an additional 33% losing HBeAg at 144 weeks of treatment (27, 45).

The efficacy of entecavir in patients who are refractory to lamivudine is less than in treatment-naïve patients. In a study of 286 mono-infected patients with lamivudine refractory HBV infection treated with entecavir (1.0 mg daily) or continued on lamivudine for 48 weeks, the rate of HBeAg loss was higher in the entecavir group (10 vs. 3%), as was the histological improvement (55 vs. 28%), undetectable HBV DNA by PCR (21 vs. 1%) and ALT normalization (75 vs. 23%) (46). However, viral rebound with detection of entecavir-resistant mutations was seen in 9% of patients after 48 weeks. The entecavir mutations occurred only in the presence of preexisting lamivudine-resistance mutations (47).

Telbivudine

Telbivudine is an l-nucleoside analogue of thymidine with potent activity against HBV and the drug most recently approved for treatment of chronic HBV. In a multicentre study of 1367 adults (921 HBeAg positive and 446 HBeAg negative) with chronic HBV treated with telbivudine (600 mg/day orally) or lamivudine (100 mg/day orally) for 2 years, telbivudine was superior to lamivudine (48–50). At week 52, among HBeAg-positive patients, primary outcome measures including HBV DNA <5 log10 copies/ml with HBeAg loss or ALT normalization were observed significantly more often in the telbivudine group (75 vs. 67%). Among HBeAg-negative patients, significantly more patients receiving telbivudine became HBV DNA negative by PCR (88 vs. 71%), but ALT normalization was similar (74 vs. 79%) (49, 50).

Tenofovir

Tenofovir is an acyclic adenosine nucleotide analogue that has activity against both wild-type and lamivudine-resistant HBV. Case reports and pilot studies confirm efficacy in decreasing HBV DNA levels in mono-infected and HIV-co-infected patients (29, 30, 51, 52). The drug was European approved in April 2008 based on results from recent phase III trials for both HBeAg-positive and HBeAg-negative chronic HBV infection (53, 54). In randomized-controlled trials involving 266 patients with HBeAg-positive chronic hepatitis B (53) and 375 patients with HBeAg-negative hepatitis B (54). Patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks all patients on adefovir were switched to tenofovir regardless of the response to adefovir. Tenofovir was associated with HBV DNA levels <400 copies/ml at week 48 in 76% of HBeAg-positive patients and 93% of HBeAg-negative patients (compared with 13% of HBeAg-positive patients and 63% of HBeAg-negative patients treated with adefovir). Both tenofovir and adefovir were associated with biochemical responses and histological improvement.

Emtricitabine

Emtricitabine is a cytosine analogue structurally similar to lamivudine. The results of a phase III randomized placebo-controlled trial of emtricitabine for 48 weeks reported an approximately 4–5 log10 decline in HBV DNA levels, but 13% of patients developed the same YMDD polymerase mutation seen with lamivudine (55). Thus, emtricitabine is not an option for lamivudine-resistant HBV infection. Emtricitabine will likely fill a treatment niche not as monotherapy for chronic HBV but in combination with other drugs. The combination of tenofovir and emtricitabine is already approved for treatment of HIV infection; this combination is recommended in HBV/HIV-coinfected patients.

Clevudine

Clevudine is a pyrmidine analogue with potent in vitro activity against HBV. Recently, two randomized-controlled trials in Korea have compared clevudine 30 mg with placebo for treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B for 24 weeks with an additional 24-week post-observation period (56, 57). In the HBeAg-positive study, at week 24, 59.0% of patients treated with clevudine had an undetectable serum HBV DNA level vs. 0% in the placebo group. Viral suppression in the clevudine group persisted up to 6 months after treatment was stopped. The proportion of patients who achieved normalization of ALT levels was 68% in the clevudine group vs. 17.5% in the placebo group at week 24. Despite the durable viral suppression, at week 48, the rates of HBeAg seroconversion were the same in the treated and the placebo groups (10 and 12%). It is likely that the short duration of treatment, only 24 weeks, was insufficient to show a superiority over placebo in HBeAg seroconversion. Clevudine also showed efficacy in viral suppression in the HBeAg-negative patients. No resistance to clevudine was detected in either study, but the treatment period was short (56, 57). Based on the results of these two trials, clevudine was approved for HBV treatment in Korea. Phase III trials with a larger number of patients and longer duration of treatment are ongoing in other parts of the world. The durable viral suppression after treatment is discontinued is promising and deserves further study; however, the role of clevudine as a monotherapy will depend on the results of the longer-duration phase III trials that are currently ongoing.

Summary of antiviral treatment recommendations (Tables 1 and 2)

Table 2.   General recommendations for treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B virus*
HBeAgHBV DNA
(IU/ml)
ALTTreatment strategy
  • *

    In HBV mono-infected persons.

  • 1 IU/ml=5.26 copies/ml.

  • Severe histological disease: moderate fibrosis (stage 2) or greater and/or significant necroinflammation.

  • Adapted from Keeffe and collegues (8, 9).

  • ALT, alanine aminotransferase; HBV, hepatitis B virus; peginterferon, pegylated interferon.

+≤20 000NormalMonitor q6–12 months, treat if severe histological disease
+≥20 000NormalConsider liver biopsy to assess disease severity if ≥35 years
If treating, use adefovir, tenofovir (alone or in combination with lamivudine), entecavir or peginterferon
+≥20 000ElevatedUse adefovir, tenofovir (alone or in combination with lamivudine), entecavir or peginterferon
<2000NormalMonitor q6–12 months, inactive HBsAg carrier
≥2000NormalConsider liver biopsy, treat if severe histological disease with adefovir, tenofovir (alone or in combination with lamivudine), entecavir or peginterferon preferred
≥2000ElevatedUse adefovir, tenofovir (alone or in combination with lamivudine), or entecavir or peginterferon

For patients with HBeAg-positive chronic hepatitis B who are naïve to treatment, options are peginterferon, lamivudine, adefovir, telbivudine, tenofovir and entecavir. Lamivudine is considered less favourable as the primary therapy because of the risk of selection for antiviral mutants. There is still insufficient evidence to permit even preliminary recommendations on clevudine. In an ideal world, lamivudine use would be extremely limited because of its resistance issues. However, it is far cheaper than the other nucleos/tide analogues and this factor alone leads to its widespread use in many countries where patients and healthcare budgets simply cannot afford the more expensive alternatives.

For compensated cirrhotic patients with HBeAg-positive chronic hepatitis B, nucleos/tide analogues are preferred because interferon-induced hepatitis flares may lead to hepatic failure in patients with cirrhosis. Nucleos/tide analogues that can achieve rapid viral suppression with a low risk of drug resistance are desirable. Treatment options include entecavir, tenofovir or adefovir (9).

Patients with decompensated cirrhosis should be considered for antiviral treatment and referred for liver transplantation. Adefovir and lamivudine are approved first-line therapies, although experts are recommending combination therapy to minimize the risk of resistance and virological breakthrough. Options include combination lamivudine/adefovir, lamivudine/tenofovir and telbivudine/adefovir. There are no published data on use of entecavir in decompensated cirrhosis. Interferon is contraindicated in these patients because of the risk of life-threatening hepatic flares. If adefovir monotherapy is used, HBV DNA levels and liver function should be monitored closely (monthly or more often) and lamivudine should be added if virus suppression is slow or inadequate. Treatment of such patients should be coordinated with a transplant centre.

For those patients failing to achieve an undetectable HBV DNA level with single drug therapy and/or drug resistance, combination antiviral treatment is recommended by expert panels, although none of the drug combinations have been approved for routine use. In patients with lamivudine resistance, the combination of lamivudine or adefovir has been shown to be superior to adefovir monotherapy (16, 58). Therefore, in cases of lamivudine-resistant HBV infection, adding adefovir or tenofovir to lamivudine or switching to emtricitabine plus tenofovir are the primary treatment strategies to consider. In cases of adefovir resistance, addition of entecavir or lamivudine can be considered. For tenofovir resistance, options include addition of entecavir and lamivudine, or changing to tenofovir and emtricitabine (6–10).

Conclusions

Therapy for chronic hepatitis B has made significant advances with the availability of peginterferon and the newer nucleos/tide analogues. Decisions regarding treatment should be based on knowledge of the natural history of HBV, the history of disease flares, hepatic function and the efficacy and safety profiles of each therapeutic option. Prospects for control of chronic HBV infection have never been better, given the development of more sensitive diagnostic tests and ongoing development of newer antiviral agents by the pharmaceutical industry. However, control of HBV mutants will require new drugs, vaccines and treatment strategies, and will become the next major challenge to elimination of HBV infection. Sufficiently potent inhibition of HBV replication should be able to prevent the development of drug resistance.

Conflicts of interest

The authors have not declared any conflicts of interests.

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