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
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.
|Patients to be considered for therapy||PBS-listed indications CHB in a patient who has:||First-line therapies||PBS streamlined codes (a)|
• 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
• 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
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.
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).
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, 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.
126.96.36.199 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.
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- Liaw YF. Reduction of cirrhosis and hepatocellular carcinoma with antiviral therapy in chronic hepatitis B. Hepatology. 2013.
- Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58(1):98–107.
- EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. Journal of Hepatology. 2012;57(1):167–85.
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- Chan HLY, Wong GLH, Choi PCL, Chan AWH, Chim AML, Yiu KKL, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. Journal of Viral Hepatitis. 2009;16(1):36–44.
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