Australian consensus recommendations for the management of hepatitis B

This consensus statement was developed by the Gastroenterological Society of Australia (GESA), the peak body in gastrointestinal and liver health and diseases, to provide a list of contemporary recommendations for health professionals involved in the care of patients living with hepatitis B infection. The endorsing institutions are listed in the online Supporting Information. This statement is applicable to all clinicians involved in the management of people with hepatitis B, including specialist and general physicians, general practitioners, nurses, health coordinators, hospital administrators and policymakers. It covers six main topics that include epidemiology, natural history, diagnosis and monitoring, treatment and complications, and specific subgroups, such as people with viral coinfection, immunosuppressed individuals, those with renal impairment and pregnant women, especially with regard to preventing vertical transmission.

One of the primary objectives is to provide a consensus statement to inform clinical decisions and to set a standard of care, with particular reference to the Australian health care setting, thus providing a local context for management recommendations. The expected benefits of this consensus statement include a standardised approach to the management of hepatitis B across varied health care settings in Australia. At a community level, the benefits of producing locally relevant guidance are ultimately to improve the health care, experience and outcomes of people living with hepatitis B.

These recommendations summarise the complete consensus statement found at https://www.gesa.org.au/education/clinical‐information/hbv‐consensus‐statement.

Methods

This consensus statement was developed applying the principles outlined by the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.1 Consensus was determined using the modified Delphi approach, comprising three online questionnaires and a hybrid (combined face‐to‐face and online) meeting on 14 May 2021.2 Sixty‐eight experts in hepatitis B virus (HBV) infection management as well as consumer representatives, including those with lived experience, were invited to participate in the modified Delphi process, with online completion rates of 97% (66/68), 100% (66/66) and 98.5% (65/66) in rounds 1, 2 and 3 respectively.

Each recommendation has been graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. For each recommendation, the quality of the evidence has been classified as one of four levels — high (A), moderate (B), low (C) or very low (D) — and the strength of recommendation as either strong (1) or weak (2) (Box 1).

(Box 2)(Box 3)(Box 4)(Box 5)(Box 6) are all referenced in Box 1.

Recommendations

Prevalence, transmission and priority populations (R1–R2)

In 2020 an estimated 222 559 people in Australia were living with chronic hepatitis B, representing 0.9% of the population.3 Since the introduction of immunisation in the 1980s and universal vaccination in 2000, the incidence and prevalence of HBV infection in younger Australians has fallen.

Hepatitis B is transmitted through blood and body fluids. In Australia, 46.3% of people with chronic hepatitis B were born in the Asia–Pacific region, most frequently in China, Vietnam and the Philippines.4 Aboriginal and Torres Strait Islander peoples also have higher prevalence, representing 7% of people with chronic hepatitis B.3 As most people living with chronic hepatitis B come from culturally and linguistically diverse communities, it is essential that pre‐testing and post‐diagnosis discussions are held with an accredited interpreter when necessary.

Australia has committed to the National Hepatitis B Strategy goals, aiming to improve diagnosis, treatment and care and therefore reduce attributable mortality. We remain well short of reaching targets, with an estimated 27% of chronic hepatitis B cases remaining undiagnosed, 22.6% receiving care (target 50%) and just 10.7% of people being treated (target 20%).5,6 With more than 1700 preventable deaths anticipated as a consequence, at the current rate of progress, Australia is projected to reach the National Strategy 2022 targets in 2045 for the proportion in care (target 50%) and in 2046 for the proportion receiving treatment (target 20%).7

Identification of people living with HBV infection is a pivotal step in the management of chronic hepatitis B, and all health care workers should be aware of high risk groups and the importance of implementing appropriate testing (Box 2). Although the threshold of ≥ 2% prevalence is the commonly accepted cut‐off for HBV screening, there are cost‐effectiveness data from similar settings to Australia (United States and Netherlands) supporting the application of a threshold below Australia’s average prevalence of 0.9%.8,9 Consequently, many experts suggest universal screening could be extended to Australian adults (aged 20–79 years) in whom hepatitis B status has not been documented.10

Natural history (R3–R4)

Chronic hepatitis B is recognised as comprising four phases that reflect the dynamic interplay between virus and host immune response. Traditionally, these phases were described as i) immune tolerant, ii) immune clearance, iii) immune control, and iv) immune escape. Recent nomenclature changes that more aptly reflect the level of HBV replication and degree of host immune response have been proposed, and these phases are now described according to hepatitis B e antigen (HBeAg) status (positive or negative) and the absence or presence of hepatic inflammation (infection or hepatitis) (Box 7). Hence, evaluation requires knowledge of HBeAg status, degree of necroinflammation (alanine aminotransferase [ALT]), and level of viraemia (HBV DNA level), all of which are important predictors of long term outcomes. Defining normal ALT is important not only for defining the phase of chronic hepatitis B but also for determining thresholds for antiviral therapy. There is compelling epidemiological evidence to support a revised ALT upper limit of normal of 19 IU/L in women and 30 IU/L in men.11,12 As the phases of chronic hepatitis B are determined by the complex interplay between virus and host, it is essential that repeated assessments be performed to accurately determine the phase of chronic hepatitis B and the need for antiviral therapy.

Other factors contributing to elevated ALT should be considered in patients with low HBV DNA, including coinfection with other blood‐borne viruses and commonly occurring liver diseases such as metabolic‐associated fatty liver disease (MAFLD) and alcohol‐related liver disease. These may only become apparent after initiation of antiviral therapy and failure of ALT to normalise.

Diagnosis and monitoring (R5–R6)

Appropriate testing for people at risk of chronic hepatitis B should include three qualitative serological tests (hepatitis B surface antigen [HBsAg], hepatitis B core antibody [anti‐HBc], and hepatitis B surface antibody [anti‐HBs]) to determine infection, exposure and immunity respectively, with addition of anti‐HBc IgM if an acute or recent infection or flare is suspected (Box 8). Although the strict definition of chronic hepatitis B requires persistence of HBsAg for 6 months or more,13,14 in the absence of history or serology indicating recent acute infection, people presenting for the first time with positive HBsAg can be diagnosed with chronic hepatitis B infection without waiting to repeat the serology after 6 months and delaying initial management.13

In newly diagnosed people with chronic hepatitis B, we recommend assessing the presence of coinfection with other blood‐borne viruses (hepatitis delta virus [HDV], hepatitis C virus [HCV] and human immunodeficiency virus [HIV]) and additional comorbidities (eg, alcohol, smoking, obesity, diabetes, MAFLD or other causes of chronic liver disease) as well as testing for hepatitis A virus serology to advise immunisation. The phase of chronic hepatitis B and the non‐invasive evaluation of hepatic fibrosis determine the need for treatment and ongoing hepatocellular carcinoma (HCC) surveillance. Liver biopsy is infrequently performed and should only be considered when the results are likely to affect management; for example, in the setting of potential comorbidities.

Chronic hepatitis B is a dynamic infection with changes over time, so all people living with chronic hepatitis B need ongoing monitoring with yearly assessment of HBV DNA, liver function tests every 6–12 months, full blood examination, HBeAg status (if initially positive), and HCC surveillance every 6 months if indicated. Periodic, non‐invasive assessment of fibrosis is advised in order to determine if there is progression.

Patients with prior exposure to HBV may have persistent viral HBV DNA in the liver in the form of covalently closed circular DNA (cccDNA). The cccDNA is a template for HBV transcription, and HBV reactivation can occur in the setting of profound immunosuppression. Rarely, people have detectable HBV DNA (in serum or liver) without detectable HBsAg, which is defined as occult hepatitis B.

Antiviral therapy (R7–R14)

Treatment of HBV infection is achieved through sustained viral suppression with the goals of reducing i) liver disease progression, ii) HCC development, and iii) HBV infectivity. Two oral nucleos(t)ide analogues, both with high barrier to resistance, are commonly used in Australia: entecavir and tenofovir disoproxil, together accounting for 92% of prescribed antiviral therapy for HBV infection. Pegylated interferon is reserved for selected patients and only accounts for 0.4% of prescribed antiviral therapy.15

Antiviral therapy is recommended in all HBsAg positive patients with cirrhosis. Otherwise, antiviral therapy is generally reserved for HBeAg positive or negative hepatitis (formerly immune clearance and immune escape phases). There are certain circumstances in people with HBeAg positive infection (immune tolerant) where antiviral therapy may also be considered (Box 3).

In clinical trials comparing entecavir and tenofovir disoproxil, there was no significant difference in HBV DNA suppression (> 90%), HBeAg seroconversion (12–34%), or HBsAg loss (< 1%).16 By 48 weeks, more than two‐thirds of patients treated with either drug will achieve a biochemical response (ie, normalisation of transaminases). Long term viral suppression can result in histological improvement (including regression of cirrhosis) and a reduction in the incidence of cirrhosis, decompensated liver disease, HCC and the need for liver transplantation. A sustained response off treatment is uncommon, and long term therapy should be anticipated, particularly among HBeAg negative individuals. The choice of nucleos(t)ide analogue should consider patient factors (Box 9), including liver disease stage, pregnancy or family planning, prior nucleos(t)ide analogue exposure, and comorbidities. It is clear that treatment with nucleos(t)ide analogues reduces the risk of HCC among people with HBV infection, and despite recent debate, a systematic review and meta‐analysis suggests that HCC risk reduction is likely to be equivalent for both tenofovir disoproxil and entecavir.17

Complications (R15–R20)

Chronic hepatitis B conveys a lifetime risk of HCC ten‐ to 25‐fold higher than uninfected individuals.18 It is estimated that over 50% of global HCC cases are attributable to HBV.19 The development of HCC is dependent on a combination of viral, host and environmental factors. Men have up to a fourfold higher risk than women. A first degree family history of HCC confers a twofold increase in risk, which is synergistic at each stage of HBV infection.20 Other patient factors that increase HCC‐risk include age, cigarette smoking, alcohol consumption, obesity and diabetes mellitus.21 Viral factors that increase risk for HCC include high HBV DNA levels, positive HBeAg status, high HBsAg levels, genotype C, HBV mutations, and viral coinfection (HDV, HCV or HIV). Although the risk of HCC is attenuated by effective viral suppression with antiviral therapy, it is not eliminated.22 Unlike most other liver diseases, in chronic hepatitis B, cirrhosis is not a prerequisite for the development of HCC, and risk evaluation and implementation of appropriate HCC surveillance in people at risk is paramount (Box 4).

Decompensated cirrhosis is characterised by ascites, hepatic encephalopathy, variceal bleeding or jaundice. In untreated HBV cirrhosis, the risk of decompensation is 20% over 5 years,18 with 68–71% survival at one‐year, reducing to 14–35% at 5 years.23 After antiviral therapy, one‐year transplant‐free survival increases to over 90%.24 Therefore, patients with an episode of decompensation should be treated with antiviral therapy and be considered for liver transplantation referral. Uncommonly, HBV can cause acute liver failure (rapid onset syndrome of jaundice, encephalopathy and liver synthetic dysfunction) or acutely decompensated cirrhosis. Both complications are medical emergencies and are associated with high mortality in the absence of urgent liver transplantation.

Special groups (R21–R32)

Pregnancy and mother‐to‐child transmission. In regions of the world where infant HBV vaccination is not standard, mother‐to‐child transmission occurs frequently, and leads to chronic infection in the infant — an incurable lifelong problem with serious clinical sequelae.25 In Australia, universal HBV infant vaccination delivers an effective means of preventing mother‐to‐child transmission except in the setting of high maternal viral load (ie, > 200 000 IU/mL), where up to 10% of vaccinated infants still develop chronic hepatitis B.26 Therefore, it is recommended that HBV DNA is assessed early in the second trimester and if > 200 000 IU/mL, antiviral therapy should be commenced from the 28th week of pregnancy to minimise mother‐to‐child transmission. Tenofovir disoproxil is the preferred antiviral therapy as it has a well established safety profile in pregnancy, high potency and no documented resistance. While the optimal time to cease tenofovir disoproxil post partum is not established, usual practice is to stop between birth and 12 weeks post partum.

Immunosuppression. Immunosuppressive drugs allow unimpeded HBV replication. Cessation of immunosuppressive therapy or periodic administration (eg, cycles of cancer chemotherapy) may result in immune reconstitution and a vigorous immune response to HBV. Reactivation of hepatitis B is defined as a greater than tenfold increase in HBV DNA from baseline27 or HBsAg seroreversion (transition from HBsAg negative to positive status) in an individual with past HBV infection (ie, anti‐HBc positive with or without anti‐HBs). All HBsAg‐positive patients receiving immunosuppressive cancer chemotherapy require prophylactic antiviral therapy,27 and even patients with past exposure require evaluation for risk of reactivation (Box 6). In the setting of immunosuppression for non‐malignant conditions, therapeutic regimens need to be classified according to the likely risk of HBV reactivation (Box 5).28 All clinicians prescribing immunosuppressive therapy should be aware of the risk of HBV reactivation and should implement appropriate screening strategies to identify individuals at risk. No matter the underlying condition, all patients receiving highly immunosuppressive therapies should be screened for HBV as the consequences of reactivation can be fatal.

Hepatitis B coinfection.

1. ▪ Coinfection with HCV. About 6% of people diagnosed with HBV infection in Australia are coinfected with HCV,29 which leads to accelerated progression of liver disease.30 Direct‐acting antiviral (DAA) therapy for HCV may lead to HBV reactivation,31 and monitoring for this event is recommended.32 Clinically significant HBV reactivation in people who are HBsAg negative, anti‐HBc positive is extremely rare, and these people do not require HBV therapy.33
2. ▪ Coinfection with HDV. HDV is reliant on HBV, and specifically, HBsAg for replication. It affects about 5% of people with chronic hepatitis B in Australia,34,35 and people at increased risk include men who have sex with men, people who inject drugs,35 and those from regions endemic for HDV, including Africa (West Africa, Horn of Africa), Asia (Central and Northern Asia), Pacific Islands, the Middle East, Eastern Europe and the Amazonian Basin.34 Testing for HDV should be performed in all people who are positive for HBsAg using HDV antibody initially, and if positive, followed by confirmatory polymerase chain reaction (PCR) for HDV RNA. Pegylated interferon is the only drug available in Australia with proven antiviral efficacy against chronic HDV infection.36 Suppression of HDV RNA during treatment occurs in up to 50% of people during 48 weeks of pegylated interferon therapy.37 However, HDV viraemia can fluctuate during treatment and may not predict post‐treatment response, with relapse occurring in up to 50% after on‐treatment suppression.37,38
3. ▪ Coinfection with HIV. About 27 500 Australians are currently living with HIV infection, of whom 5% are coinfected with HBV.39,40 The natural history of HBV is modified by HIV coinfection; HBV DNA levels, rates of HBeAg persistence, development of chronic HBV infection, and liver disease‐related mortality are higher than those in HBV monoinfection.41,42 Without treatment, progression of fibrosis is more rapid and development of cirrhosis more common,43 although the risk of liver disease is significantly reduced in people on long term suppression with tenofovir‐based anti‐retroviral therapy.44,45 Tenofovir alafenamide fumarate is available in Australia for people living with HIV infection, and is associated with reduced rates of renal disease and osteopenia46 and is preferred over tenofovir disoproxil in people with HIV–HBV coinfection.

Renal impairment. Pre‐existing renal disease may affect dosing of antiviral therapy and some of the agents, and in particular tenofovir disoproxil, are known to be nephrotoxic, with risk of reduced glomerular filtration rate, hypophosphataemia and rarely Fanconi syndrome.47,48,49 All people with chronic hepatitis B should undergo baseline assessment of renal function, and this should be monitored during antiviral therapy.

Although tenofovir disoproxil primarily undergoes renal excretion and is associated with an increased risk of renal tubular damage in patients with HIV–HBV coinfection, the risk remains low in the setting of HBV monoinfection and is similar to the risk seen with long term entecavir. Tenofovir alafenamide fumarate is associated with less renal toxicity than tenofovir disoproxil in HIV–HBV coinfection.50 It is currently only available in Australia for patients with HIV–HBV coinfection, but could be considered in patients with tenofovir‐related renal disease.

Conclusion

These recommendations aim to improve awareness of chronic hepatitis B among clinicians and to increase detection of cases that currently remain undiagnosed. In Australia, all clinicians need to recognise groups at increased risk of HBV infection and implement appropriate screening strategies. Once identified, monitoring and timely commencement of treatment significantly reduces complications of chronic hepatitis B. In addition, it is imperative that clinicians understand that in chronic hepatitis B, cirrhosis is not a prerequisite for development of HCC, and non‐cirrhotic people with chronic hepatitis B require risk evaluation and, where appropriate, should be enrolled into a HCC surveillance program.

Box 7 – Natural history of chronic hepatitis B

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ALT = alanine aminotransferase; ULN = upper limit of normal. The new and old (grey shade) nomenclature for hepatitis phases are shown at the top. To ascertain the phase of chronic hepatitis B, three determinants are required: hepatitis B serology, viral load, and ALT. In general, treatment is indicated for patients in either e antigen positive or negative chronic hepatitis phases (formerly called the immune clearance and immune escape phases) depicted in red shade. Although the phases are conceptualised as sequential steps in the evolution of chronic hepatitis B, there is movement between adjacent phases; therefore, repeated assessment is required to ascertain risk of fibrosis (green ticks) and need for antiviral therapy. The values for viral load (red line) and ALT (blue line) provide an indication of values that may be seen.