7.0 Treatment of chronic hepatitis B virus infection

  • Patients in the immune clearance and immune-escape phase of infection should be considered for antiviral therapy. Treatment is indicated for those with any of the following: – high hepatitis B virus (HBV) DNA – elevated alanine aminotransferase levels or evidence of inflammation – fibrosis on liver biopsy or marked fibrosis on FibroScan®.
  • All patients with cirrhosis are candidates for treatment.
  • Patient and doctor attention to the issue of adherence by patient is critical for the success of therapy.
  • Entecavir and tenofovir are first-line treatment options for oral antiviral therapy.
  • Pegylated interferon is an alternative option in some patients.

The goal of therapy is to prevent, halt or even reverse the progression of liver injury towards cirrhosis, liver decomposition and liver cancer, which are the major causes of death in older patients with hepatitis B virus (HBV) infection (1). This is achieved by controlling viral replication, either with direct acting anti-viral therapy or indirectly using interferon (IFN) to stimulate immune control. Control of viral replication reverses decompensated liver disease and reduces the risk of hepatocellular cancer (2, 3). The challenge for the clinician is to determine the phase of infection and anticipated natural history for an individual patient, so that therapy can be tailored to those likely to benefit. The phase of infection can be determined using the standard narrative (see Chapter 4). In communicating information to patients about their treatment choices for hepatitis B, language, literacy and culture are important considerations. Patient resources are available to aid communication; for example, the hepatitis B bear, or the Hepatitis B story (see Appendix 1 and Appendix 2 for patient factsheets and other resources).

Aims of treatment
  • Limit liver damage due to immune-mediated inflammation and fibrosis.
  • Achieve sustained suppression of viral replication.
  • Achieve clearance (hepatitis B surface antigen [HBsAg] seroconversion) – rare.
  • Reduce risk of progression to cirrhosis and hepatocellular carcinoma.
  • Reduce morbidity and mortality.
  • Minimise toxicity, minimise resistance, maximise adherence.

The decision to commence antiviral therapy is based on a number of factors, including the patient’s age, serum HBV DNA concentration, extent of hepatic fibrosis, alanine transaminase (ALT) levels, hepatitis B e antigen (HBeAg) status and the risk of hepatocellular carcinoma (HCC). Barriers to treatment adherence need to be considered (Table 7.1), because liver damage can be worsened by stopping and starting treatment. Many guidelines are available on this subject, but there are no absolute rules (4). A recent review summarises the variance in international consensus guidelines for treatment initiation and the art of decision making in the clinic (5). Previously, a liver biopsy demonstrating necroinflammation consistent with chronic hepatitis B (CHB) was a necessary prerequisite for reimbursed access to antiviral therapy in Australia.

A liver biopsy is no longer mandatory for reimbursement; however, in some settings, it may still have a role in decision making. Non-invasive techniques to indirectly measure the extent of liver fibrosis may be used to assist decision making in the absence of liver biopsy (6, 7) (see Chapter 6).

There are two main classes of therapy for CHB:

  • direct antiviral agents, which inhibit the function of the viral polymerase and thus prevent viral replication
  • the IFNs, which are synthetic cytokines that act via multiple different intracellular biological pathways to eradicate viral infection.
Table 7.1 Potential barriers to treatment adherence (8, 9)
The patient Understanding of disease or reason for antiviral treatment
Cultural health beliefs, literacy or health literacy
Competing priorities (e.g. health, employment and family issues)
Other social issues (e.g. substance use, poverty and housing)
Distance, time and cost to attend appointments (including lost work time)
Doctor–patient interaction Poor communication, including inadequate use of culturally appropriate resources or interpretation services (or both) when needed
Failure to appreciate barriers to adherence, and to employ strategies and appropriate one-to-one education
Health system Geographical and system barriers to treatment access, including specialist availability, local availability of antiviral therapy for ongoing supply, hospital outpatient waiting lists and outpatient appointment waiting time
Nature of disease Hepatitis B is asymptomatic
People feel well, so may discontinue treatment
Long-term therapy leads to treatment fatigue

In practical terms, once the decision to commence antiviral therapy has been made, the physician should choose one of the three agents that are currently approved by the Australian Government’s Therapeutic Goods Administration (TGA) and reimbursed under the Pharmaceutical Benefits Scheme (PBS) for the initial treatment of CHB in Australia. These agents are pegylated IFN (PEG-IFN) alfa-2a (180 μg/week), tenofovir (300 mg/day) and entecavir (0.5 mg/day) (Table 7.2). Several other oral agents – including lamivudine, adefovir and telbivudine – have been registered for the treatment of CHB, but are not preferred due to inferior potency or inferior barrier to resistance.

When choosing the most appropriate anti-HBV therapy, it is important to consider the advantages and disadvantages of each treatment option. The choice of therapy must take into account the drug’s efficacy, safety, chance of achieving desired endpoints, anticipated duration of therapy and the likelihood of developing resistance.

7.3.1 Hepatitis B e antigen (HBeAg) positive patients

Patients who are positive for HBeAg should be considered for antiviral therapy if they also have elevated serum ALT (i.e. >30 IU/L for males and >19 IU/L for females) that is persistent (i.e. 3–6 months without an alternative cause), and a serum HBV DNA level of greater than 20,000 IU/mL (10). In contrast, those with a persistently normal ALT level are often in the immune tolerance phase of their illness, and treatment is usually not of benefit.

Table 7.2 Treatment indications and recommended antiviral agents for patients with chronic hepatitis B
Patients to be considered for therapy

PBS-listed indications CHB in a patient who has:First-line therapiesPBS streamlined codes (a)
HBeAg-positive patients
• Persistent (at least 3–6 months) elevated ALT‡
• HBV DNA >20,000 IU/mL
Elevated HBV DNA levels(1) and evidence of chronic liver injury(2)

Tablet 300 mg
Tablet 0.5 mg
HBeAg-negative patients
• HBV DNA >2,000 IU/mL WITH
• Persistent (at least 3–6 months) elevated ALT‡
• evidence of accumulated liver damage (e.g. fibrosis, or moderate to severe inflammation)
Patients with advanced
fibrosis or cirrhosis, irrespective of ALT (e.g. Schueur score of 3) or 4 on biopsy, or FibroScan >~10k Pa
Cirrhosis and detectable HBV DNA Tenofovir
Tablet 300 mg
Tablet 0.5 mg
Failed HBV therapy and has cirrhosis and detectable HBV DNA Tenofovir
Tablet 300 mg
Failed HBV therapy and has evidence of treatment failure(3) 4490
Failed lamivudine and has cirrhosis and detectable HBV DNA Entecavir
Tablet 1.0 mg
Failed lamivudine and has evidence of treatment failure(3) 5044
‡ Note: Elevated ALT
‘Elevated’ serum ALT varies between guidelines, but would usually be considered as >2 × ULN ALT ULN for men >30
ALT ULN for women >19
  1. >20,000 IU/mL (100,000 copies/mL) if HBeAg positive, or >2,000 IU/mL (10,000 copies/mL) if HBeAg negative
  2. As determined by: (a) confirmed elevated serum ALT; or (b) liver biopsy
  3. (a) Repeatedly elevated serum ALT levels while on concurrent antihepadnaviral therapy of ≥6 months duration in conjunction with documented chronic hepatitis B infection; or (b) Repeatedly elevated HBV DNA levels one log greater than the nadir value or failure to achieve a 1 log reduction in HBV DNA within 3 months, while on previous antihepadnaviral therapy except in patients with evidence of poor compliance.
All persons with Child’s class B or C cirrhosis (ascites, variceal bleeding, encephalopathy, albumin <30 g/L, bilirubin >30 μmol/L) should have their treatment discussed with a transplant unit before therapy is started.

a PBS Streamlined codes – GP HBV s100 prescribers accredited to prescribe by their state or territory through the public hospital system can use streamlined codes. The streamlined authority process is designed to reduce the administrative burden on prescribers, because it removes the need for prior telephone or written approval from the DHS or the DVA to prescribe some PBS Authority required items. To prescribe a streamlined authority item, a prescriber is required to include a ‘streamlined authority code’ on the authority prescription. Streamlined codes may be updated from time to time, see www.pbs.gov.au/info/browse/publications. For information on general practitioner prescribing see www.ashm.org.au
ALT, alanine aminotransferase; CHB, chronic hepatitis B; DHS, Australian Government Department of Human Services; DVA, Australian Government Department of Veterans’ Affairs; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IU, international unit; PBS, Pharmaceutical Benefits Scheme; ULN, upper limit of normal

Patients in the immune tolerance phase should be monitored every 6 months, to identify when they shift from the immune tolerance phase to the immune clearance phase of the disease, at which point treatment would be considered.

Older patients with significant viraemia but only mildly elevated ALT levels may have significant liver injury from a prior phase of CHB (11). A liver biopsy or other assessment of liver fibrosis (e.g. transient elastography) will assist in determining the need for therapy. Patients with advanced fibrosis or cirrhosis, irrespective of ALT (e.g. a Schueur score of 3 or 4 on biopsy, or a FibroScan® of >~10 kPa or equivalent) should be considered for antiviral therapy (see Chapter 8).

7.3.2 Hepatitis B e antigen (HBeAg) negative patients

Patients who are HBeAg negative and are thus in the immune escape phase of infection are often older, with ALT levels and serum HBV DNA levels lower than in patients with HBeAg-positive CHB. Nevertheless, the former are at greater risk of liver injury and worse outcomes than younger patients with HBeAg-positive disease. It is therefore recommended that the threshold serum HBV DNA level for initiating antiviral therapy should be 2,000 IU/mL, in combination with either an elevated ALT, or evidence of accumulated significant liver damage (e.g. fibrosis, or moderate or severe inflammation), or both (12). Assessment by an invasive technique (liver biopsy) or a non-invasive technique (elastography) can greatly assist decision making. In general, other recommendations for therapy in HBeAg-negative patients are similar to those for HBeAg-positive disease.

7.3.3 Women of child-bearing age

Female patients interested in starting a family should consider the safety profile of various treatment options, and restricted access to treatment under PBS Section 100 criteria. Management decisions for patients initiated on treatment who later fall pregnant must be individualised. The abundant safety data for lamivudine and tenofovir in HIV-treated patients may facilitate a discussion on the risks and benefits of treatment; this discussion should also include the possibility of a flare of disease activity during pregnancy, and the likelihood of vertical transmission despite immunoprophylaxis in pregnant women with a viral load of more than 7 log10 IU/mL (11). There is limited data on the safety of entecavir in pregnancy, and its use is not recommended. Initiating a patient prior to family planning with PEG-IFN could be an alternative option because this treatment is limited to a defined duration.

7.4.1 Interferons

The use of conventional IFN has been supplanted by the use of PEG-IFN, which has the advantage of weekly dosing and (probably) of improved efficacy. The recommended standard dosing of PEG-IFN alfa-2a is 180 μg, given weekly for 48 weeks. The side effects are similar to conventional IFN (e.g. influenza-like symptoms, fatigue, leukopenia, irritability, sleep disturbance and depression), but are neither universal nor easy to predict. In HBeAg-positive patients, HBe seroconversion occurred in 32% of patients up to 6 months after the end of treatment. Baseline predictors of response include genotype A infection, lower HBV DNA (<9 log copies/mL) and higher ALT levels (>2 × ULN). A small but significant proportion of patients treated with IFN also achieve hepatitis B surface antigen (HBsAg) seroconversion. This is seen particularly in genotype A, and is uncommon in Asian patients. Genotype D HBV patients have the lowest response rates to PEG-IFN therapy. Given the expense and side-effect profile of IFNs, it would be helpful to identify non-responders early, although rules for stopping IFN have not been clearly established. Failure to suppress the virus by 6 months is usually indicative of non-response, and treatment may be discontinued. A change in HBsAg titres has been suggested as a useful predictor of response, but the test is not widely available in Australia, and its applicability across different genotypes requires further evaluation (13, 14).

PEG-IFN also has a role in the treatment of HBeAg-negative patients. Sustained control of viral replication (<2,000 IU/mL) is seen in 20% of patients after completion of therapy (15). Control of viral loads to these levels should reduce progression to clinically significant liver disease.

The main advantage of PEG-IFN is the fixed duration of therapy (which is particularly attractive to younger patients), and the chance for HBsAg seroconversion. The main disadvantage is the side-effect profile. Flares of viral hepatitis resulting from enhanced immune clearance can be seen in up to 18% of patients, and can be severe in those with advanced underlying liver disease. IFNs are contraindicated in patients with decompensated cirrhosis.

PEG-IFN is generally contraindicated in pregnancy and breastfeeding (see Chapter 10).

Treatment options
  • Direct antiviral agents can be chosen according to their potency, their side effects and the chance of resistance. For treatment-naive patients, entecavir or tenofovir is the best currently available antiviral therapy. For lamivudine-resistant patients, tenofovir added to lamivudine therapy is most effective.
  • Pegylated interferon has a different mechanism but comparable efficacy to antiviral agents, with the disadvantage of increased side effects and the advantage of a shorter, fixed-duration therapy without drug resistance. Interferon is not the best choice in patients with cirrhosis.
  • Therapy should be individualised.

7.4.2 Antiviral therapy

Long-lasting, treatment-maintained suppression of HBV DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off-treatment response is uncommon, and long-term therapy should be anticipated (16), particularly in patients in the HBeAg-negative phase of infection. Entecavir

Entecavir, a purine-derived nucleoside analogue, is a highly effective inhibitor of viral replication. Long-term (at least 3 years) entecavir therapy appears to result in the reversal of fibrosis and cirrhosis, and continued improvement in liver histology (17). It has few side effects, the most common being headache (2–4%) and fatigue (1–3%). The rate of HBeAg clearance with entecavir is similar to that seen with other antiviral agents. Entecavir is recommended at a dose of 0.5 mg for treatment-naive subjects. HBV drug resistance in that clinical scenario is extremely uncommon; it was reported in only 1.2% of cases after 5 years of study. Entecavir is not the best choice of therapy for patients with established lamivudine resistance. Even with a higher dose (1.0 mg daily), 50% of such patients develop entecavir resistance in 5 years. This is due to partial cross-resistance between lamivudine and entecavir.

Entecavir is contraindicated in pregnancy and thus is not a good choice in young women who might be planning to or may accidentally become pregnant.

Entecavir absorption is affected by food, and it should be taken on an empty stomach 2 hours before or after a meal. This food requirement should be discussed with the patient before therapy is started. Tenofovir disproxil fumarate

Tenofovir disoproxil fumarate (TDF, tenofovir), like adefovir, is an acyclic adenine nucleotide with potent activity against HBV. It has been used extensively in the treatment of human immunodeficiency virus (HIV) infection. The recommended dose of tenofovir is 300 mg daily. No patient included in the initial registration trial has developed tenofovir resistance after 5 years of follow up (18). Nephrotoxicity, including Fanconi Syndrome, has been reported in patients receiving tenofovir, although is much less common than in the setting of HIV (19) (17). The risk of renal toxicity is low; however, on treatment, monitoring of renal function (estimated glomerular filtration rate, eGFR) and serum phosphate concentration is important to avoid progressive renal injury. Tenofovir is the agent of choice for patients with lamivudine resistance, because lamivudine and tenofovir have different mutational pathways to resistance. Although adefovir and tenofovir have similar pathways to resistance, the latter is highly effective in patients with prior adefovir resistance, with 60–90% of patients receiving tenofovir having undetectable HBV DNA after 1 year of therapy (20).

7.4.3 Other agents and combinations

Lamivudine, adefovir and telbivudine are no longer recommended as first-line therapies in Australia; however, they may still be widely prescribed in lower-middle income countries.

Lamivudine was the first antiviral agent made available for the treatment of CHB in Australia. It is an oral nucleoside analogue, well tolerated and without significant side effects. It produced substantial early inhibition of viral replication in most patients which resulted in improved liver histology, and improved liver function in decompensated cirrhosis. Unfortunately prolonged therapy with lamivudine resulted in high rates of viral resistance occurring in 14–32% of patients after 1 year of therapy, and 60–70% of patients after 5 years of therapy (21).

Adefovir is an acyclic nucleotide analogue and an effective antiviral agent. The recommended dose of 10 mg restricted adefovir’s antiviral potency, but nephrotoxicity at higher doses was a limiting factor. In the United States, adefovir was made available for first-line therapy; however, its role in Australia as guided by PBS reimbursements was limited to the treatment of lamivudine resistance. Initially adefovir was used as monotherapy in patients with lamivudine resistance, but the development of resistance to adefovir was common in this situation and it quickly became apparent that combination therapy provided much better control of viral replication (22). Adefovir has largely been replaced by tenofovir due to the latter’s superior antiviral activity.

Telbivudine is also a highly effective antiviral agent, but its utility is limited by the rather rapid emergence of resistance variants of HBV (30% in 3 years). A specific side effect of telbivudine is myopathy, and patients on treatment should be monitored for muscle symptoms. Telbivudine has a pregnancy category B listing.

For patients naive to therapy, it might be predicted that dual direct antiviral therapy might be superior to single agent therapy (as is the case for HIV), although to date no benefit has been demonstrated (23). Combining IFN with direct acting antiviral therapy has also not been shown to be superior although studies in this area are ongoing.

In summary, both nucleos(t)ide analogues and PEG-IFN can be prescribed as first-line treatment options for CHB. However, PEG-IFN should only be considered for patients with a high chance of response based on pretreatment and on-treatment factors.

In patients on antiviral agents, a rising ALT or HBV DNA level may indicate viral resistance or non-adherence. In patients on older antiviral agents, a switch to one of the new agents or the addition of a new agent to the original drug must be undertaken.

While on therapy, patients should be monitored regularly to document virological response to treatment, detect adverse events early in their evolution, identify the emergence of viral resistance and encourage adherence. Monitoring of patients should be more frequent in patients treated with PEG-IFN compared to oral agents, because of the risk of bone marrow suppression, neuropsychological side effects and other complications of IFN-based therapies. For patients treated with PEG-IFN, frequent monitoring is recommended until treatment dose is stabilised. Patients can then reduce the frequency of their visits to every 4–6 weeks. Particular attention should be paid to the full blood count, white cell count differential and platelet count at each visit, and dosing adjusted as needed.

In patients on direct antiviral therapies, baseline assessment should include renal measures, particularly assessment for proteinuria, eGFR and (if tenofovir therapy is planned) fasting serum phosphate level. On-treatment monitoring is recommended 3-monthly for the first year. Full blood count, liver and renal function (and fasting serum phosphate for patients on tenofovir) and HBV serology (for patients who are HBeAg positive) and HBV DNA is recommended. Dose adjustments may be required, depending on renal dysfunction. After the first year, or when complete virological control has been achieved, 6-monthly monitoring is reasonable with entecavir and tenofovir, given their low rates of drug resistance in pivotal studies and in the clinical situation (24). One risk of such infrequent monitoring is reduced adherence to therapy. Shared attention to the issue of adherence by patient, specialist and general practitioner is critical for the success of therapy.

Monitoring on treatment
  • Regular monitoring is required to identify virological response, resistance and hepatitis flares, and to encourage adherence.
Pegylated interferon
  • Frequent monitoring until treatment dose stabilised, then every 4–6 weeks. Particular attention: FBC, white cell count differential and platelet count at each visit; adjust dosing as necessary.
Direct antiviral therapies
  • Three-monthly for the first year, then 6-monthly. FBC, liver and renal function (and fasting serum phosphate for those on TDF) and HBV serology (for HBeAg positive) and HBV DNA is recommended. 
FBC, full blood count; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; TDF, tenofovir

In HBeAg-positive patients, nucleos(t)ide analogue therapy can be used in an attempt to cease antiviral therapy after a sustained period of complete HBeAg seroconversion and undetectable HBV DNA. However, a proportion of patients will relapse after treatment is stopped. The longer the period of consolidation after the HBeAg seroconversion and before cessation of therapy, the less likely the patient is to relapse. Most guidelines recommend a 6–12 month consolidation period before stopping therapy. In HBeAg-negative patients, the risk of virological relapse after stopping therapy is high, and patients usually continue lifelong therapy unless they undergo loss of HBsAg (28).

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Miriam T Levy, Department of Medicine, The University of New South Wales, South Western Sydney Clinical School, and Liverpool Hospital, Liverpool, NSW

& Darrell HG Crawford, School of Medicine, University of Queensland, Greenslopes Private Hospital, and Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD