9. Hepatitis B

The HBV antigens and their associated antibodies are serological markers of HBV infection or vaccination (Table 9.1). At least one serological marker is present during the different phases of infection (Table 9.2).

The virus preferentially infects liver cells, multiplying in the liver and releasing large amounts of HBsAg, which is present in the blood of people with active infection. The incubation period varies between 45 and 180 days and is commonly 60 to 90 days.

HBV is not directly cytopathic; the host’s immune response leads to death of infected liver cells. Most infected people mount an effective immune response that leads to eradication of infection over a period of several months. Approximately 80 percent of adults with acute infection have symptomatic hepatitis, and the remaining 20 percent can be asymptomatic (but these proportions vary).[2]

The common symptoms of acute hepatitis B illness are fever, jaundice, malaise, anorexia, nausea, vomiting, myalgia and abdominal pain. Jaundice usually develops within two weeks of onset of the illness, and dark urine and/or clay coloured stools might appear up to five days before clinical jaundice. Clinical signs and symptoms of acute hepatitis B usually resolve one to three months later.[1]

There is a small risk of liver failure (less than 1 percent) with acute infection; if failure occurs, almost half will die or require emergency liver transplantation.

The main burden of HBV disease occurs in people with chronic HBV infection. Chronically infected people are identified by presence and persistence of HBsAg in their serum for at least six months. The age of acquisition of HBV is strongly associated with the risk of developing chronic HBV infection. Approximately 90 percent of those infected perinatally or in infancy develop chronic HBV infection, compared with 30 percent of children infected between ages 1 and 4 years and less than 5 percent of people infected as adults.

Infants seldom mount an immune response to HBV infection, and infection in infancy is often asymptomatic. Asymptomatic chronic infection stimulates persistent immune responses that may eventually lead to cirrhosis (decades later); cirrhosis and chronic infection increase the risk of development of hepatocellular carcinoma.

HBV is usually transmitted through contact with infected blood or body fluids during childbirth, contact with broken skin, sexual intercourse or intravenous drug use. Although HBV can be found in all body fluids, blood has the highest concentration and saliva the lowest. HBV in dried blood remains infective for at least one week.[4]

Perinatal (vertical) transmission

The primary source of HBV infection is perinatal exposure from mothers with chronic HBV infection. Transmission usually occurs at the time of birth. The in utero transmission of HBV is relatively rare, accounting for less than 2 percent of infections transmitted from mother to infant.[5]

If no prophylaxis is given to the infant, the baby of an HBeAg positive mother has a 70–90 percent risk of infection, while the baby of an HBeAg negative HBsAg positive carrier mother has a 5–20 percent risk of infection. Over 90 percent of infants who acquire infection perinatally become chronic carriers.

Person-to-person (horizontal) transmission

Non-sexual person-to-person transmission probably occurs from inadvertent percutaneous or mucosal contact with blood or infectious body fluids among people in close daily contact (household members).

The main sources of transmission are:

• sexual contact with an infected individual
• percutaneous exposure to blood or infectious body fluids
• needle-stick injuries or sharing needles.

Those travelling to high endemic countries are at higher risk of exposure (see below).

Approximately two billion people worldwide had been exposed to HBV in 1995. In 2015, based on serological data, around 3.5 percent of the general population globally were infected with HBV and more than 250 million people were estimated to have chronic infection and these people remain at risk of developing cirrhosis and hepatocellular carcinoma.[6, 7] More than 90 percent of individuals with chronic HBV resided in the Asia–Pacific region, where most countries have high prevalence rates of HBV infection (the population rate of HBsAg positivity is between 5 and 20 percent) and more than 99 percent of HBV-infected people in this region acquired infection through vertical transmission from their mother (usually at the time of delivery) or in early childhood.[8] As an example of this risk, 22.8 million out of 80 million people living in China with chronic HBV infection are women of child-bearing age.[9] Acquisition of HBV during adulthood (usually via sexual transmission or injecting drug use) is associated with a high rate of symptomatic hepatitis but a low rate of chronic infection.

The introduction of universal childhood HBV immunisation has changed the epidemiology of chronic infection in many countries, but it will be several decades (one to two human generations) before the full benefits are realised. In China, for example, within 20 years since the introduction of HBV immunisation, mother-to-child transmission has been cut by 97 percent; 120 million new HBV infections and 28 million chronic infections have been averted.[9] Thirty years after the introduction of a HepB immunisation programme for newborns in Taiwan, infant fulminant hepatitis mortality and, in those aged 5 to 29 years, chronic liver disease and hepatocellular carcinoma mortality had all decreased by more than 90 percent.[10]

The world can be divided into regions with high (8 percent and over), high-moderate (5–7 percent), low-moderate (2–4 percent) and low (less than 2 percent) prevalence of chronic infection, defined as the presence of HBsAg in serum.[11, 12] In regions with a high prevalence of chronic infection, the lifetime risk of exposure to HBV is almost 80 percent, with most infections occurring in the first decade of life. The Pacific Islands and most of Asia (except Japan and India) are high-prevalence regions. Other high-prevalence regions include Sub-Saharan Africa and Latin America.[12] In contrast, in countries with a low HBsAg prevalence, the lifetime risk of HBV exposure is less than 20 percent, with most infections acquired in adulthood. New Zealand has a low overall prevalence of hepatitis B carriage but contains certain populations with high prevalence (see section 9.3.2 below).

Before the introduction of HBV immunisation in New Zealand, HBV transmission was common among preschool and school-aged children. The exact mode of transmission is uncertain, but is thought to be related to close contact. In the eastern Bay of Plenty region almost half of the population were infected by age 15 years.[13, 14] Even after the introduction of universal HepB in 1988 (see Appendix 1), there were regions in New Zealand where children were still at risk of HBV infection due to poor immunisation coverage rates.[15, 16, 17]

Acute HBV infection

Only acute hepatitis B is a notifiable disease in New Zealand; notification rates do not describe the burden of chronic HBV infections.

The HBV notification rate in 2019 was 0.6 per 100,000 population (28 cases), similar to the 2018 rate (0.7 per 100,000, 33 cases). The highest notification rate was in the 30–39 years age group (1.1 per 100,000) followed by 50–59 years and 70 years and over (both 0.8 per 100,000). The notification rate was higher for males (0.9 per 100,000) than for females (0.3 per 100,000) (ESR, 8 June 2020).

Ethnicity was recorded for all cases. The Māori (1.3 per 100,000) ethnic group had the highest hepatitis B notification rate followed by the Asian (0.7 per 100,000) ethnic group.

The most common reported risk factors were overseas travel, migration and sexual contact with a confirmed case or carrier.

Hepatitis B notifications have declined from 609 cases in 1984 to 28 cases in 2019 (see Figure 9.1). While difficult to quantify accurately, the introduction of universal infant immunisation in 1988 has contributed to the dramatic decline in the number of newly notified cases of HBV infection. 

Figure 9.1: Notifications of hepatitis B, 1997–2019

The specific monovalent and combination HepB vaccines licensed (approved for use) and available (marketed) in New Zealand contain recombinant HBsAg (HepB).

Funded vaccines

Other vaccines

HepA-HepB (hepatitis A and hepatitis B vaccine): Twinrix and Twinrix Junior (GSK) (see also section 8.4.1).

Clinical trials in high-risk groups have shown a vaccine efficacy of 85–95 percent for HepB vaccines.[8]

See also section 15.4.2 for information about the DTaP-IPV-HepB/Hib vaccine.

Immunogenicity

Serum anti-HBs antibody ≥10 IU/L, measured 1–2 months after immunisation, is considered by WHO as a correlate of long-term protection.[8] In the primary care setting, individuals who have had a documented seroconversion after three injections are expected to have lifelong immunity with no need for further boosters, even if circulating antibody is subsequently not detectable.

Smoking, obesity, HIV infection and chronic disease (including renal failure) all reduce vaccine efficacy, but age is the primary factor affecting the response. At least 98 percent of infants, 95 percent of children and 90 percent of adolescents develop protective levels of antibody after three doses of vaccine. Some non-responders will not produce adequate antibody levels to the initial vaccination course, but most respond to further vaccine doses.

However, some people are persistent non-responders. Persistent non-responders often have an impaired immune system, such as organ transplant recipients and those with HIV infection or chronic disease, including advanced cirrhosis, renal failure or those undergoing haemodialysis. A small percentage (approximately 2–3 percent) of the immunocompetent population may also fail to elicit an antibody response. High-risk individuals who fail to respond adequately are recommended further vaccinations (see section 9.5.7).

Effectiveness of birth dose given to babies born to HBsAg‑positive mothers

Infants vaccinated at birth born to infected mothers were 3.5 times less likely to be infected with HBV than those who did not receive a birth vaccination.[8, 23] For babies of HBeAg-positive mothers, controlled trials have shown that vaccine at birth provides 75 percent protection from infection, while administration of HBIG in addition to vaccination provides 85–95 percent protection against transmission.[23, 24] Protection is reduced to less than 80 percent when the mother’s HBV DNA level (viral load) is greater than 10⁸ IU/mL (or 10⁸ copies/mL).[25] In this situation, administration of tenofovir (an antiviral agent) to the mother during the last trimester is recommended and funded.

Duration of immunity

The development of anti-HBs antibodies after a primary vaccination course (three injections and seroconversion) indicates development of immune memory. The quantity of antibody in serum is thought to determine the length of time the antibody titre can be detected in the blood, although any reading ≥10 IU/L post-vaccination course is considered protective.[26, 27] Children who are given booster doses up to 12 years after the primary series show strong anamnestic (secondary) responses, indicating that booster is unnecessary once a seroprotective level is reached after the three-dose primary vaccination course.[26, 27]

Long-term protection from clinical infection, despite loss of detectable neutralising antibody, is thought to reflect a strong cellular memory immune response following HBV vaccination.[28] Even though a large proportion of vaccine recipients may have undetectable antibody within seven years of vaccination, there is evidence from Germany,[28] Taiwan,[29] Alaska[30] and Hawaii[31] that boosters of HepB are unnecessary following completion of infant immunisation.

Sustained immune memory, including circulating memory B and T cells, and long-term protection have been shown 20–30 years after complete primary immunisation of immune competent adults in the absence of natural or artificial boosting.[24]

In general, vaccine recipients who are subsequently infected with HBV do not develop clinical illness but may have anti-HBc present in plasma.[1]

Impact on chronic HBV infection

In all populations, where it has been measured, immunisation has led to a dramatic drop in HBV chronic infection.[32] For example, chronic HBV infection dropped from 16 percent to zero in Alaska as a result of 96 percent immunisation coverage. In Taiwan, the incidence of hepatocellular carcinoma also decreased as a result of the immunisation programme in children.[33, 34] Adolescents and adults who were offered universal HBV vaccination in infancy had more than 75 percent lower prevalence of HBV infection and anti-HBc prevalence than those for whom immunisation was unavailable.[35]

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store at +2°C to +8°C. Do not freeze. DTaP-IPV-HepB/Hib and HepB vaccines should be stored in the dark.

DTaP-IPV-HepB/Hib

Each 0.5 mL dose of DTaP-IPV-HepB/Hib (Infanrix-hexa) vaccine contains 10 μg of HBsAg, and is administered by intramuscular injection (see section 2.2.3).

HepB

The dose of HepB vaccine varies according to the vaccine manufacturer, the age of the individual and/or their health status (see section 9.5 for recommendations):

• Engerix-B 20 μg (GSK): 20 μg HBsAg per 1.0 mL
• Engerix-B paediatric 10 μg (GSK): 10 μg per 0.5 mL.

HepB vaccine is administered by intramuscular injection. It can be also administered by subcutaneous injection, if indicated for bleeding disorders (see section 2.2.3).

Co-administration with other vaccines

Hepatitis B vaccines may be given at the same time as all other vaccines on the Schedule, including measles, mumps and rubella (MMR) vaccine.

If a course of vaccine is interrupted, it may be resumed without repeating prior doses (see Appendix 2).

A primary course of hepatitis B vaccination is given as three doses of DTaP-IPV-HepB/Hib at ages 6 weeks, 3 months and 5 months (Table 9.5). If a course of immunisation is interrupted for any reason, it may be resumed without repeating prior doses (see section 9.5.3 and Appendix 2).

The routine schedule for these infants is a birth dose of monovalent HepB plus HBIG, then three routine doses of DTaP-IPV-HepB/Hib at ages 6 weeks, 3 months and 5 months.

All pregnant women should receive antenatal screening for hepatitis B infection by testing for HBsAg. Infants of HBsAg-positive mothers are to be notified at birth using the form HE1446: Consent for hepatitis B vaccine and hepatitis B immunoglobulin and notification to the Medical Officer of Health, available from the Health Ed website or the local authorised health education resource provider or public health unit.

HepB is recommended and funded for everyone aged under 18 years. If HepB is not given during the first year of life, three doses of vaccine are recommended given 0, 1 and 6 months.

For adolescents aged 10–15 years, an alternative two-dose hepatitis B catch-up schedule may be considered using the monovalent HepB with the second dose given six months after the first.

See Appendix 2 for catch-up schedules.

Children and adolescents with liver or kidney disease

HepB vaccine is funded for liver or kidney transplant patients (recommend six months post-transplant) and for dialysis patients.

See Figure 9.3 and Figure 9.4 for serological testing and vaccination recommendations. If non-immune, children aged under 16 years should receive three doses of HepB; those aged 16 years and older should receive four doses of HepB given at 0, 1, 2 and 12 months. If there is an inadequate immune response to the initial three-dose HepB series (see Figure 9.4), give a further three doses, as appropriate for age.

See also ‘Solid organ transplantation’ in section 4.3.11, ‘Chronic kidney disease’ in section 4.4 and ‘Chronic liver disease’ in section 4.5.

HepB may be given during pregnancy and while breastfeeding. Acute HBV infection in pregnant women may result in severe acute hepatitis for the mother, with associated increased risk of fetal loss or neonatal infection. Vaccination should not be withheld from a susceptible pregnant woman at increased risk of acquiring hepatitis B (eg, the sexual partner of an injecting drug user, or known infected male).

Hepatitis B-containing vaccines are funded for vaccination and revaccination of eligible children, as follows. See also sections 4.2 and 4.3.

DTaP-IPV-HepB/Hib (Infanrix-hexa)

An additional four doses (as appropriate) of DTaP-IPV-HepB/Hib are funded for vaccination or revaccination of children aged under 10 years:

• post-HSCT or chemotherapy
• pre- or post-splenectomy
• pre- or post-solid organ transplant
• undergoing renal dialysis
• prior to planned or following other severely immunosuppressive regimens.

Up to five doses of DTaP-IPV-HepB/Hib are funded for children aged under 10 years receiving solid organ transplantation.

Monovalent HepB

HepB is funded for children aged under 18 years who are considered not to have achieved a positive serology and require additional vaccination.

Screening for chronic infection

Screening for the antigen (HBsAg) is useful where there is increased likelihood of the individual already being infected.

The Hepatitis Foundation of New Zealand recommends that the following individuals are most at risk of HBV:[43]

• people of Māori, Pacific or Asian ethnicity, unless fully vaccinated with HepB vaccine as an infant
• people born in an area of high hepatitis B endemicity, including Asia, the Pacific Islands, Africa, the Middle East, southern Europe or the northern or eastern parts of New Zealand’s North Island
• people born to a mother or who have a close family member who has chronic HBV infection
• people who live with someone who has HBV
• people who have had unprotected sexual contact with an HBV-infected person
• people who have ever injected drugs
• people who have received a tattoo using unsterile equipment.

Screening for HBsAg is also part of routine antenatal care (see section 9.5.2).

All HBsAg-positive individuals should be offered follow-up under the Hepatitis Foundation Hepatitis B Follow-up Programme to enable early diagnosis and treatment of the complications of severe liver disease and hepatocellular carcinoma. Vaccination is funded for household or sexual contacts of HBsAg-positive people (ie, contacts of people with acute or chronic HBV infection).

To confirm chronic HBV status, repeat testing after 6 months and if still positive, refer patient to The Hepatitis Foundation.

Serological testing for high-risk groups

Figure 9.3: Flow diagram for serological testing for hepatitis B

Minor side-effects – including local tenderness and redness, nausea, diarrhoea, general malaise and fever – are more common in adults than in children and, except for local reactions, occur at rates close to those seen with a placebo. Minor reactions reported after receiving the vaccine include a temperature >37.7°C in 1–6 percent; pain in 3–29 percent; and erythema, headache or swelling in 3 percent of vaccine recipients.

Allergic reactions have been reported but are rare. Anaphylaxis following vaccination is extremely rare (estimated to be 1.1 cases per million doses).[47]

A number of studies have examined and failed to find disease events linked to hepatitis B immunisation.[48] These studies have documented no increased risk of multiple sclerosis,[49, 50, 51] diabetes, chronic fatigue syndrome,[52] encephalomyelitis or hair loss.[53] Rarely, transient thrombocytopenia[54] and myalgia and arthralgia[55, 56] have been reported after HepB vaccination.

HBIG is prepared from donated blood plasma and contains high levels of anti-HBs antibody (see Appendix 6). It is given after exposure to HBV and provides passive anti-HBs antibody protection against acute and chronic HBV disease. HBIG prophylaxis should be given in combination with the HepB to confer both passive and active immunity after exposure.

The efficacy of HBIG alone in preventing clinical hepatitis B infection is about 75 percent in adults, but the protection lasts only for a few months.[1]

Whenever immediate protection is required, immunisation with a vaccine should be combined with simultaneous administration of HBIG at a different site. It has been shown that passive immunisation with HBIG does not suppress the active immune response to vaccination. A single dose of HBIG is sufficient (usually 400 IU for adults, 100–110 IU for newborns).[59] If infection has already occurred at the time of the first immunisation, virus replication is unlikely to be inhibited completely, but severe illness and, more importantly, the development of chronic HBV infection may be prevented, particularly in the infants of HBsAg-positive mothers.

The management of contacts is summarised in Table 9.8.

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