Hepatitis B: treatments now available for primary care

Chronic hepatitis B infection affects more than 100,000 adults in New Zealand¹

The hepatitis B virus (HBV) is acquired via perinatal transmission from mother to child, sexual contact or blood-borne transmission. Almost all people with HBV infection in New Zealand were infected at birth or in early childhood, via incidental blood transmission from other infected children, before hepatitis B vaccination was included in the National Immunisation Schedule.¹ Immigrants from countries with a high incidence of hepatitis B and unvaccinated travellers to those countries are the other main risk groups in New Zealand. People who are infected with HBV as adults, e.g. via sexual contact, are less likely to proceed to chronic infection (see: “Acute vs chronic hepatitis B).

Large ethnic disparities in chronic HBV infection and its consequences exist in New Zealand; chronic HBV infection affects approximately:^1–3

• 8–9% of people of Chinese or South East Asian ethnicity
• 7% of people of Pacific ethnicity
• 6% of people of Māori ethnicity
• ≤ 1% of people of European or Indian ethnicity

Immigrants belonging to other ethnic groups, such as people from the Middle East, Africa or Latin American, may also have higher rates of chronic HBV infection due to a high prevalence in their country of birth. However, data for these groups are not available.

People living in socioeconomically deprived communities experience worse overall health outcomes as a result of HBV infection.³ In particular, liver disease due to HBV infection disproportionately affects Māori and Pacific peoples. For example, a study in Middlemore hospital found that chronic HBV infection was the leading cause of cirrhosis in Māori or Pacific peoples, contributing to 53–76% of cases, compared to approximately 5% of cases in people of European ethnicity.⁴ The incidence of hepatocellular carcinoma is three to five times higher among Māori than Europeans in New Zealand, and approximately half of Māori with hepatocellular carcinoma have hepatitis B infection compared to approximately one-quarter of European people.^{5, 6}

People born in New Zealand prior to 1988 are at risk

Hepatitis B vaccination was first introduced in New Zealand in 1988 (see: “HBV vaccination”). The current National Immunisation Schedule includes HBV vaccination as part of the DTaP-IPV-HepB/Hib vaccine given at age 6 weeks, 3 months and 5 months¹. Between 85–95% of children who receive a full vaccination course develop lifelong immunity, with no requirement for booster doses.¹ Additional steps to prevent transmission to a newborn if the mother has HBV infection include antiviral treatment for the mother and hepatitis B immunoglobulins and a vaccine dose administered to the infant within 24 hours of birth. Due to these preventive measures, most people born in New Zealand from 1988 onwards are not at risk of HBV infection.

Immigrants of any age and unvaccinated travellers are at higher risk

People who have migrated from countries with a high prevalence of HBV, and limited access to vaccination and perinatal preventive measures, e.g. the Pacific Islands, South East Asia and China, are at higher risk of chronic HBV infection. An assessment of immigrant children resettled in New Zealand between 2007–2011 found that approximately one-third had serology results suggesting they had not previously been vaccinated.⁷ People from New Zealand who are unvaccinated and regularly visit countries with a high prevalence of HBV are at increased risk, particularly if they stay with people who are infected or have unprotected sex. Vaccination is recommended, but not funded, for travellers to high prevalence countries (see: “HBV vaccination”).

Sexual transmission and blood contact

HBV is highly infectious and can be transmitted via fresh or dried blood or sexual fluids. It can remain on surfaces for up to one week.¹ Therefore transmission can occur through activities such as unprotected sexual contact, sharing drug injecting equipment, incidental transfer of blood to open wounds or broken skin (e.g. during play or sports), tattooing, piercing or cosmetic services such as hairdressing or manicures using improperly sterilised equipment and sharing items such as razor blades.¹

Other people at risk include those with a higher occupational risk of needlestick injury or blood contact, e.g. healthcare workers, ambulance personnel, police, or people who undergo multiple percutaneous medical procedures, e.g. renal dialysis.

Most adults who contract HBV infection via sexual or blood contact will have acute infection only (see: “Acute vs chronic hepatitis B infection").

Vaccination is recommended for people at high risk of infection; many will be eligible for funded vaccination (see: “HBV vaccination”).

Acute vs chronic hepatitis B

Infection with HBV begins with an acute phase. Detection of acute HBV infection is relatively rare; approximately 30 cases per year were notified^* in New Zealand between 2016 - 2020.⁸

Approximately 70% of adults develop acute icteric hepatitis which is characterised by jaundice and other symptoms such as fever, nausea, vomiting and abdominal pain, with marked elevations in liver enzymes. Symptoms usually occur after a subclinical period of one and a half to six months following infection.^{1, 9} Children are usually asymptomatic following acute infection.

Management of patients diagnosed in the acute phase of infection is typically supportive, however, some patients may require referral to secondary care due to the development of severe hepatitis symptoms; fulminant hepatitis with hepatic necrosis occurs in less than 1% of patients following acute HBV infection.⁹

In most cases, adults who have acquired acute HBV infection will not progress to chronic infection.

^* Acute HBV infection is a notifiable disease; chronic infection is not

Chronic HBV infections usually arise from perinatal or childhood exposures

Chronic HBV infection is defined as an infection lasting six months or longer.¹ Younger people are less likely to clear HBV infection from their body during the acute stage of infection, and have higher rates of progression to chronic infection:¹

• Approximately 90% of infants aged less than one year who acquire HBV progress to chronic infection
• Approximately 30% of children aged one to four years who acquire HBV progress to chronic infection
• Less than 5% of adults who acquire HBV progress to chronic infection

People with chronic infection are at increased risk of liver disease

Most people with childhood-acquired chronic HBV infection will enter a long-term inactive phase associated with persistently normal serum ALT and low serum HBV DNA levels, which may last up to 30 years.¹⁰ However, some people will enter an active phase of infection, which is associated with persistently elevated ALT levels, high levels of viral activity, liver inflammation and progressive liver fibrosis.

Depending on viral and patient characteristics:

• 13-38% of adults with untreated chronic hepatitis B will develop cirrhosis over a five year period.¹⁰
• Of those with cirrhosis, approximately 4% per year develop liver failure (i.e. decompensated cirrhosis), with complications of jaundice, ascites, hepatic encephalopathy and gastroesophageal variceal haemorrhage.¹¹
• Approximately 1-4% of people with HBV-related cirrhosis develop hepatocellular carcinoma each year.¹¹
• The risk of liver disease increases with age, with males aged over 40 years more likely to develop cirrhosis or hepatocellular carcinoma.¹¹

It is estimated that approximately 40% of patients presenting with advanced HBV-related hepatocellular carcinoma in New Zealand are unaware that they have an HBV infection.³

Treatment is not curative

None of the current treatment options for chronic HBV are curative. Treatment reduces viral replication, improves liver function and reduces the risk of future complications. All current oral antiviral treatments suppress viral activity. However, a reservoir of HBV remains in the nucleus of hepatocytes, which can lead to viral reactivation after treatment has stopped. The aims of treatment for patients with chronic HBV infection therefore differ in important ways from patients with chronic hepatitis C infection (see: “Know your ABCs”).

Testing for HBV infection

There are two main groups of people who should be tested for hepatitis B infection: those who may have been exposed during birth or early childhood and therefore now have chronic hepatitis B infection, and those with a potential exposure as an adult, which may have resulted in acute hepatitis B infection but in most cases will not proceed to chronic infection.

Consider testing people with risk factors for HBV infection, including:^1,13,16

• Incomplete or unknown childhood vaccination status, particularly in people of Māori, Pacific, South East Asian or Chinese ethnicity*
• Age over 30 years*
• People born in countries with a high HBV prevalence, e.g. Pacific Islands, China, South East Asia, Middle East and Africa, or travellers to those countries
• Mother or close family or household member with HBV infection
• Unprotected sex with an HBV-infected person
• Current or previous injecting drug user
• Chronic liver disease or incidental abnormal liver function tests
• Tattoo, piercing or other cosmetic procedure received using unsterile equipment, e.g. in prison, in locations with few safety standards
• Higher risk sexual activity, such as sex workers, men who have sex with men or unprotected sex while travelling in a country with high prevalence
• Following exposure to blood, e.g. sports, assault, needlestick injury

^* In addition to other risk factors from the list

How to test for HBV infection

The three main initial tests to determine hepatitis B infection are:

• HBsAg – hepatitis B surface antigen; shows current HBV infection and is always detected in chronic infection
• Anti-HBs or HBsAb – hepatitis B surface antibody, which is produced in response to the HBsAg; this shows whether there is immunity to HBV either from vaccination or infection
• Anti-HBc or HBcAb – hepatitis B core antibody, which is produced in response to the hepatitis B core antigen (HBcAg); this shows whether exposure to HBV has ever occurred. It is detected in people with current infection and previous acute infection that has now resolved, but not in those who are immune through vaccination.

A combination of HBsAg, anti-HBs and anti-HBc can be used to assess whether a patient is infected, their immune status and whether an infection is in the acute or chronic stage (Table 2). Additional tests are usually added reflexively by the laboratory depending on results of initial tests. Include clinical information regarding the reasons for ordering HBV serology to assist the laboratory in interpreting results.

NB. Testing for hepatitis B e antigen (HBeAg) and its corresponding antibody (anti-HBe) is useful to assess HBV activity, the stage of infection and corresponding risk of liver complications. However, this is not required to make an initial diagnosis. For more information, see: “An overview of HBV management for primary care”.

If patients test positive for HBV infection

Inform all patients who test positive how HBV is transmitted and steps they can take to reduce the risk to sexual partners and others in their household (see: “Advice for patients after an HBV diagnosis”).

Sexual partners and household contacts of infected individuals should undergo testing to check if they have become infected or if they are immune. If a patient is diagnosed in the acute stage of infection, rather than chronic, only household members or sexual partners who have had contact with the patient within the previous three weeks need to be tested.¹⁸

Acute HBV infection is a notifiable disease; follow advice from the Ministry of Health’s Communicable Disease Control Manual: www.health.govt.nz/our-work/diseases-and-conditions/communicable-disease-control-manual/hepatitis-b.

Arrange follow-up for patients with chronic HBV infection

Patients with chronic HBV infection should be referred to the Hepatitis Foundation, secondary care^*, or treated within primary care.

The Hepatitis Foundation has a national contract to provide clinical support and management in partnership with primary and secondary care, including:¹⁹

• Initial evaluation after a diagnosis has been made
• Organising ongoing monitoring tests, including blood tests and liver elastography (Fibroscan) assessments
• Patient support, education and access to a community hepatitis nurse

Patients can be referred by:

• Calling the Hepatitis Foundation: 0800 33 20 10
• Completing an online form: https://www.hepatitisfoundation.org.nz/node/16

Maintaining up to date contact details is particularly important for patients with chronic HBV infection, since monitoring and treatment is lifelong. If patients are referred to the Hepatitis Foundation, ensure its staff are informed of any change of address or phone number. Consider setting up a register of patients enrolled in your practice with chronic HBV infection.

If patients are being managed in primary care, set up recalls for regular monitoring (see: “An overview of management in primary care”).

Table 2: Interpreting serology for HBV infection. Adapted from Ministry of Health and the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine.^1,17

Serology markers*				Interpretation**
HBsAg	anti-HBs	anti-HBc
		Total	IgM
				Patient is not infected and not immune; recommend vaccination if at risk
				Either (1) early acute HBV infection or (2) transient positivity after vaccination (for up to 18 days post-vaccination on average, or for up to 52 days in patients undergoing haemodialysis)
				Acute HBV infection
	or			Acute HBV infection which is resolving
	or			Immune due to previous infection†
				Immune due to previous vaccination†
				Chronic HBV infection

Management of chronic HBV infection

Initial tests are required for patients with chronic HBV infection in order to assess the presence or severity of liver disease and the stage of infection (see: “An overview of management in primary care”). These tests can be arranged in primary or secondary care or by the Hepatitis Foundation.

All patients with chronic HBV infection require regular monitoring to assess the stage of infection and check for the development of liver fibrosis or cirrhosis (see: “An overview of management in primary care”). Patients at high risk of liver cancer, which includes those with severe fibrosis or cirrhosis or a family history of hepatocellular carcinoma, require regular liver ultrasound or CT scans to assess the development of hepatocellular carcinoma, ideally at six month intervals.¹³

Genotype testing is not required for chronic HBV infection: Different genotypes of the hepatitis B virus exist, however, genotype testing is not necessary for patients with chronic HBV infection as the results do not influence initial management.²³ Further investigation may be undertaken for some patients if treatment is unsuccessful, to test for the presence of genetic variants associated with resistance to hepatitis B treatments.

Many patients will now receive treatment with oral medicines in the community

The recommended first-line oral antiviral treatments for chronic HBV infection are tenofovir disoproxil or entecavir. These medicines were previously funded with Special Authority approval for the treatment of chronic HBV infection. However, since 1 June, 2018, tenofovir disoproxil^* and entecavir have been funded without restriction, allowing them to be prescribed more widely, including by general practitioners. As a result, more patients have been able to recieve treatment for chronic HBV infection in the community. Pegylated interferon, which is administered by subcutaneous injection, is also used for some patients.

Lamivudine is another oral medicine which is indicated and funded for the treatment of chronic HBV infection.²⁴ However, lamivudine is no longer recommended as a first-line treatment as HBV often develops resistance to this medicine.¹³ Adefovir dipivoxil was previously funded for the treatment of chronic HBV infection, however, it is no longer being manufactured and was delisted from the New Zealand Pharmaceutical Schedule in March, 2021.

^* Tenofovir disoproxil is also used in combination with other antiviral medicines for the treatment of HIV infection. It remains funded with Special Authority approval when used for this indication.²⁵

Treatment suppresses viral activity and is likely to reduce the risk of future complications

Unlike the management of chronic hepatitis C, where all patients eligible for treatment with approved medicines should receive treatment at diagnosis, treatment may not necessarily be required at diagnosis for patients with chronic HBV infection. Oral antiviral treatment is recommended for patients during stages of infection which are associated with liver damage, guided by the patient’s risk factors, such as age, and the results of ALT and HBV DNA tests (see: “An overview of management in primary care”).^{13, 14}

First line antiviral treatments result in suppression of HBV DNA levels in 61–93% of patients.¹³ Approximately 70–90% of patients treated with tenofovir disoproxil or entecavir have a normalisation of elevated ALT levels after three months of treatment, and approximately 35–50% of patients treated with pegylated interferon after eighteen months of treatment.¹³ There is less evidence available regarding the long-term effects of treatment, however, analyses to date suggest that antiviral treatment reduces, but does not eliminate, the risk of complications such as hepatocellular carcinoma.²⁶ A meta-analysis including 8,060 patients who had received curative treatment for HBV-related hepatocellular carcinoma (e.g. via surgical resection or liver transplantation) demonstrated that post-treatment with tenofovir disoproxil or entecavir reduced the three-year risk of hepatocellular carcinoma recurrence by 37%.²⁷

Most patients taking tenofovir disoproxil or entecavir experience adverse effects such as headache, nasopharyngitis, nausea and fatigue.²⁸ However, most adverse effects are mild and do not require patients to stop treatment. Tenofovir disoproxil can cause small reductions in eGFR and bone mineral density and monitoring of calcium, phosphate and creatinine levels is recommended.¹³

Reductions in dose frequency are required for patients with renal impairment

Tenofovir disoproxil and entecavir are dosed based on renal function, as measured by creatinine clearance (Table 3). Rare cases of lactic acidosis, sometimes fatal, have been reported for both tenofovir disoproxil and entecavir, and in some of these cases renal impairment may have been a contributing factor.^{13, 25}

Prescribe “tenofovir disoproxil 245mg” not tenofovir disoproxil fumarate or tenofovir disoproxil succinate

Tenofovir disoproxil is available in several different salt forms in New Zealand and other forms may be introduced. These are all clinically equivalent and currently available tablets all contain 245 mg of tenofovir disoproxil.²⁹ Prescribers should not record the salt form on the prescription, e.g. “tenofovir disoproxil fumarate” but instead prescribe “tenofovir disoproxil 245 mg” as this will allow pharmacists to dispense the funded medicine.^{25, 29}

Table 3: Recommended dose frequencies of tenofovir disoproxil and entecavir for patients with renal impairment.

^* Dose is 1 mg in patients with decompensated liver disease or resistance to lamivudine

^** Doses are stated as 245 mg of tenofovir disoproxil; see above regarding tenofovir disoproxil salts

Prophylactic antiviral treatment is recommended if patients initiate some immunosuppressive medicines

The use of immunosuppressive medicines such as chemotherapy, TNF inhibitors, or courses of oral corticosteroids equivalent to prednisone ≥ 10 mg/day for four weeks or more, are associated with an increased risk of hepatitis flares in patients with chronic HBV infection, occurring either during treatment or after the immunosuppressive medicine is stopped.^{28, 32}

Due to this increased risk, prophylactic treatment with tenofovir disoproxil or entecavir is recommended when some immunosuppressive medicine regimens are initiated (Table 4). The risks of HBV reactivation and an appropriate length of prophylactic treatment can be discussed with the clinician managing the patient’s HBV treatment; use of tenofovir disoproxil or entecavir is often required for six months or longer after the immunosuppressive medicine has been stopped.¹³

The Hepatitis Foundation of New Zealand is currently developing updated advice to assist clinicians who will be managing patients with HBV in primary care. For further information, see: https://www.hepatitisfoundation.org.nz/healthcare-professionals/hepatitis-b-health-professionals

Table 4: When to initiate antiviral prophylaxis in patients taking immunosuppressive medicines.³²