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Hepatitis B

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Prevention and treatment

- Treatment
- Guidelines for epidemic measures
- Future considerations
- WHO goals

The prevention of chronic HBV infection has become a high priority in the global community.²³

Immunization with hepatitis B vaccine is the most effective means of preventing HBV infection and its consequences.^{3, 11, 15, 30, 36} 

HBIG protects by passive immunization if given shortly before or soon after  exposure to HBV. It is also administered in combination with HBV vaccines to newborns of HBsAg positive mothers. The protection is immediate, but of short duration. HBIG is not recommended as a pre-exposure prophylaxis because of high cost, limited availability, and short-term effectiveness.^{11, 15}

Preventing HBV transmission during early childhood is important because of the substantial likelihood of chronic HBV infection and chronic liver disease that occurs when children less than 5 years of age become infected.³

Integrating HB vaccine into childhood vaccination schedules has been shown to interrupt HBV transmission.³

Routine screening of blood donors for HBsAg was mandated in 1972 (USA). The introduction of anti-HBc screening in 1986 (USA) has efficiently excluded those donors who were persistent, low-level carriers, and those in the window period of acute infection.¹⁵

The current overall risk of acquiring HBV after a transfusion is about one in 50 000 per recipient. Unfortunately, donors who are in the early incubation stage of their disease, capable of transmitting HBV, will remain unidentified with current techniques. The objective of no-risk blood supply is therefore not achievable.¹⁵

In order to avoid unnecessary risks of HBV infection, patients who depend on recurrent transfusion should be vaccinated.

Universal precautions should be used when handling human blood and body fluids. Specific precautions include the use of gloves, protective garments, and masks, when handling potentially infectious or contaminated materials.¹⁵

There is no substitute for good personal hygiene, strict surveillance, and appropriate environmental control measures to limit transmission.¹⁵

Autoclaving and the use of ethylene oxide gas are accepted methods for disinfecting metal objects, instruments, or heat-sensitive equipment.¹⁵

The expense and difficulty of treating hepatitis B medically and by hepatic transplantation is in contrast with the fact that the infection can be prevented by vaccination.

Vaccines against hepatitis B were introduced in the early 1980s. Recombinant vaccines became available in the mid 1980s. More than 110 countries have adopted a national policy of immunizing all infants with hepatitis B vaccine.

In endemic areas, mass immunization campaigns are under way mainly in East and South East Asia, the Pacific basin and the Middle East. Some regions in some countries in South America, and some countries in Africa, have started mass immunization.

There are plans to increase coverage in Africa.⁴²

Vaccination campaigns have shown that control of the disease is feasible, even in endemic areas. Some countries incorporate hepatitis B immunoglobulin (HBIG) in their vaccination strategies.

In endemic areas, procurement of low cost vaccine, education and acceptance, vaccine integration in the expanded program of immunization (EPI), prevention of vertical transmission, antibody escape mutations, protective efficacy, long term immunity and natural boosting are important questions and issues.

Since most HBV carriers are unaware of their condition, but pose a significant risk to health care workers and other people exposed to their blood, workers are advised to assume that all patients are potentially infectious, and should practice “universal precautions”.

Click here for: Hepatitis B immunization

Treatment
Currently, there is no treatment available for acute hepatitis B. Symptomatic treatment of nausea, anorexia, vomiting, and other symptoms may be indicated.^{15, 23}

Treatment of chronic hepatitis B is aimed at eliminating infectivity to prevent transmission and spread of HBV, at halting the progression of liver disease and improving the clinical and histologic picture, and at preventing HCC from developing, by losing markers of HBV replication in serum and liver like HBV DNA, HBeAg, and HBcAg. Normalization of ALT activity, resolution of hepatic inflammation and the improvement of a patients’ symptoms usually accompany these virological changes.^{15, 23}

There are two main classes of treatment:

- antivirals: aimed at suppressing or destroying HBV by interfering with viral replication.²³

- immune modulators: aimed at helping the human immune system to mount a defence against the virus.

Neither corticosteroids, which induce an enhanced expression of virus and viral antigens, and a suppression of T-lymphocyte function, nor adenine arabinoside, acyclovir, or dideoxyinosine, have been shown to be beneficial for the treatment of chronic hepatitis B.^{15, 31}

Currently, chronic hepatitis B is treated with interferons.^{11, 15, 23, 31} The only approved ones are interferon-α-2a and interferon-α-2b. Interferons display a variety of properties that include antiviral, immunomodulatory, and antiproliferative effects. They enhance T-cell helper activity, cause maturation of B lymphocytes, inhibit T-cell suppressors, and enhance HLA type I expression. To be eligible for interferon therapy, patients should have infection documented for at least six months, elevated liver enzymes (AST and ALT) and an actively dividing virus in their blood (HBeAg, and/or HBV DNA positive tests). Patients with acute infection, end stage cirrhosis or other major medical problems should not be treated. Interferon-α produces a long-term, sustained remission of the disease in 35% of those with chronic hepatitis B, with normalization of liver enzymes and loss of the three markers for an active infection (HBeAg, HBV DNA, and HBsAg). Complete elimination of the virus is achieved in some carefully selected patients.^{15, 23, 31, 33}

Interferon therapy for patients with HBV-related cirrhosis decreases significantly the HCC rate, particularly in patients with a larger amount of serum HBV DNA. In patients with HBeAg-positive compensated cirrhosis, virological and biochemical remission following interferon therapy is associated with improved survival. In patients with chronic HBV infection, the clearance of HBeAg after treatment with interferon-α is associated with improved clinical outcomes.^{9, 15, 16, 23, 27}

Interferon-α (Intron A (interferon-α-2b), Schering Plough, and Roferon, (interferon-α-2a) Roche Labs) is the primary treatment for chronic hepatitis B, The standard duration of therapy is considered 16 weeks. Patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.^{18, 33}

Permanent loss of HBV DNA and HBeAg are considered a response to antiviral treatment, as this result is associated with an improvement in necro-inflammatory damage, and reduced infectivity.

Interferon in high doses causes fever, fatigue, malaise, and suppression of white blood cell and platelet counts. These effects are reversible when the therapy is stopped.³¹

A new treatment introduced recently for chronic hepatitis B in adults with evidence of HBV viral replication and active liver inflammation is EPIVIR®-HBV (lamivudine, Glaxo Wellcome). The recommended 100 mg once-daily oral dose in form of tablets is easy to take and generally well tolerated, although safety and effectiveness of treatment beyond 1 year have not been established.^{8, 11, 20, 23, 26}

Lamivudine is a 2',3'-dideoxy cytosine analogue that has strong inhibitory effects on the HBV polymerase and therefore on HBV replication in vitro and in vivo. Lamivudine is well tolerated and suppresses HBV replication in HBsAg carriers, but the effect is reversible, if therapy is stopped.^{8, 11, 21, 23, 26}

Combination therapy with interferon-α and lamivudine for patients who failed interferon-α monotherapy is under investigation.

Combination prophylaxis with lamivudine and HBIG prevents hepatitis B recurrence following liver transplantation.^{15, 24} Subjecting hepatitis B patients who develop end-stage liver disease to liver transplantation is very controversial because the graft is inevitably reinfected, especially if the patient is HBV DNA positive. To counteract this problem, the long-term iv administration of HBIG to these patients before the operation and continuously thereafter, helps maintain a minimal level of anti-HBs in the serum at all times. Some patients relapse however when therapy is interrupted.¹⁵

Adoptive transfer of immunity to hepatitis B has been a novel approach to terminating HBV infection in the carrier after bone marrow transplantation from a hepatitis B immune donor.^{11, 15}

Several new agents (e.g. Ritonavir, Adefovir, Dipivoxil, Lobucavir, Famvir, FTC, N-Acetyl-Cysteine (NAC), PC1323, Theradigm-HBV, Thymosin-alpha, Ganciclovir¹⁴) are in development, and some encouraging data are available.

Click here for: Chronic hepatitis B: potential drug therapy
Click here for: Goals of interferon therapy
Click here for: Contraindications for interferon therapy for chronic hepatitis B
Click here for: Side-effects of interferon therapy

Guidelines for epidemic measures

1. When two or more cases occur in association with some common exposure, a search for additional cases should be conducted.

2. Introduction of strict aseptic techniques. If a plasma derivative like antihaemophilic factor, fibrinogen, pooled plasma or thrombin is implicated, the lot should be withdrawn from use.

3. Tracing of all recipients of the same lot in search for additional cases.

4. Relaxation of sterilization precautions and emergency use of unscreened blood for transfusions may result in increased number of cases.

Future considerations
Attaining global immunization coverage is a goal still unmet.

The development of a better and cheaper antiviral therapy should be pursued intensively for chronic HBV infections.³⁰

Strategies to activate appropriate immune responses during chronic virus infections may offer the best approach for terminating such infections.

Attempts at protecting the whole community by vaccinating only high-risk individuals have not been successful.³⁷ Universal vaccination is necessary to control and possibly eradicate hepatitis B. The next step is finding strategies for meeting that goal in countries with different health care structures and financial resources.

WHO goals
WHO aims at controlling HBV worldwide to decrease the incidence of HBV-related chronic liver disease, cirrhosis, and hepatocellular carcinoma. by integrating HB vaccination into routine infant (and possibly adolescent) immunization programmes.^{3, 23, 36} 

Persons infected with HBV during infancy or early childhood are more likely to become infected chronically and to develop life-shortening chronic liver disease such as cirrhosis or even liver cancer than adults. This is one important reason why emphasis should be placed upon preventing HBV among the youngest age groups.

In 1991, the Global Advisory Group of EPI (Expanded Programme on Immunization) set 1997 as the target for integrating the hepatitis B vaccination into national immunization programmes worldwide. The group recommended strategies for implementation and delivery that vary according to epidemiology: advocating integration of the vaccine into immunization programmes by 1995 in countries with a HBV carrier prevalence of 8% or higher, and setting 1997 as the target date for all other countries. WHO endorsed the recommendation in May 1992, and the World Health Assembly added a disease reduction target for hepatitis B in 1994, calling for an 80% decrease in new HBV child carriers by 2001. 

Commitment of public health resources to eliminate the spread of HBV requires recognition of the importance of hepatitis B, persistent efforts to ensure that populations are protected, and patience to achieve the goals of disease reduction.²³

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Introducing hepatitis B vaccine into national immunization services

Immunization strategies⁵¹

Routine infant immunization:

HB immunization of all infants as an integral part of the national immunization schedule should be the highest priority in all countries.

Additional immunization strategies that should be considered depending on the epidemiology of HBV transmission in a particular country are:

• Prevention of perinatal HBV transmission

In order to prevent HBV transmission from mother to infant, the first dose of HB vaccine needs to be given as soon as possible after birth (preferably within 24 hours). In countries where a high proportion of chronic infections is acquired perinatally (e.g. South-east Asia), a birth dose should be given to infants. It is usually most feasible to give HB vaccine at birth when infants are born in hospitals. Efforts should also be made in these countries to give HB vaccine as soon as possible after delivery to infants delivered at home. In countries where a lower population of chronic infections is acquired perinatally (e.g.Africa), the highest priority is to achieve high DTP3 and HB3 vaccine coverage among infants. In these countries, use of a birth dose may also be considered after disease burden, cost-effectiveness, and feasibility are evaluated

• Catch-up vaccination of older persons

In countries with a high prevalence of chronic HBV infection (HBsAg prevalence $8%), catch-up immunization is not usually recommended because most chronic infections are acquired among children <5 years of age, and thus, routine infant vaccination will rapidly reduce HBV transmission. In countries with lower endemicity of chronic HBV infection, a higher proportion of chronic infections may be acquired among older children, adolescents and adults; catch-up immunization for these groups may be considered.

Vaccine formulations

Hepatitis B vaccine is available in monovalent formulations that protect only against HBV infection and also in combination formulations that protect against HBV and other diseases.

·         Monovalent hepatitis B vaccines must be used to give the birth dose of hepatitis B vaccine.

·         Combination vaccines that include hepatitis B vaccine must not be used to give the birth dose of hepatitis B vaccine because DTP and Hib vaccines are not recommended to be given at birth.

·         Either monovalent or combination vaccines may be used for later doses in the hepatitis B vaccine schedule. Combination vaccines can be given whenever all of the antigens in the vaccine are indicated.

Schedule

Hepatitis B vaccine schedules are very flexible; thus, there are multiple options for adding the vaccine to existing national immunization schedules without requiring additional visits for immunization.

Practically, it is usually easiest if the 3 doses of hepatitis B vaccine are given at the same time as the 3 doses of DTP (Option I). This schedule will prevent infections acquired during early childhood, which account for most of the HBV-related disease burden in high endemic countries, and also will prevent infections acquired later in life.

However, this schedule will not prevent perinatal HBV infections because it does not include a dose of hepatitis B vaccine at birth. Two schedule options can be used to prevent perinatal HBV infections: a 3-dose schedule of monovalent hepatitis B vaccine, with the 1^st dose given at birth and the 2^nd and 3^rd doses given at the same time as the 1^st and 3^rd doses of DTP vaccine (Option II); or a 4-dose schedule in which a birth dose of monovalent HepB vaccine is followed by 3 doses of a combination vaccine, e.g. DTP hepatitis B (Option III). The 3-dose schedule (Option II) is less expensive, but may be more complicated to administer, because infants receive different vaccines at the 2^nd immunization visit than at the 1^st and 3^rd visits. The 4-dose schedule (Option III) may be easier to administer in practice, but is more costly, and vaccine supply issues may make it unfeasible.

Administration

Hepatitis B vaccine is given by intramuscular injection in the anterolateral aspect of the thigh (infants) or deltoid muscle (older children). It can be given safely at the same time as other vaccines (e.g. DTP, Hib, measles, OPV, BCG, and yellow fever). If the hepatitis B vaccine is given on the same day as another injectable vaccine, it is preferable to give the two vaccines in different limbs.

Injection equipment

The injection equipment for hepatitis B vaccine is the same type as that for all other  EPI vaccines (except for BCG vaccine):

·         0.5 ml auto-disable (AD) syringes are recommended.

·         If AD syringes are not available, standard disposable syringes (1 ml or 2 ml) must be used ONCE ONLY, and safely disposed of after use.

·         A 25 mm, 22 or 23 gauge needle is recommended.

Dosage

The standard paediatric dose is 0.5 ml.

Presentation

Hepatitis B vaccines are available in liquid single-dose and multi-dose glass vials, and in pre-filled single-dose injection devices (e.g. Uniject™).

Storage and shipping volume

Storage volumes (vial plus packet containing vial plus other packaging) for hepatitis B vaccines supplied through UNICEF are as per the figure below: For comparison, the total storage volume for other EPI vaccines (BCG, DTP, measles, OPV, TT) is about 11.0 cm³ per dose.

Cold chain issues

The storage temperature for hepatitis B vaccine is the same as for DTP vaccine, from 2°C to 8°C. Hepatitis B vaccine should never be frozen. If frozen, hepatitis B vaccine loses its potency.

Adding hepatitis B vaccine to the national immunization schedule will require cold chain assessments at all administrative levels:

·         to assure adequate storage capacity is available, and

·         to assure policies and procedures are in place to prevent freezing of hepatitis B vaccine.

Reducing vaccine wastage

Since hepatitis B vaccines are more expensive than other EPI vaccines, it is important to monitor vaccine wastage and to develop and implement strategies to reduce wastage.

Strategies to reduce wastage include:

·         careful planning of vaccine ordering and distribution;

·         implementation of WHO’s multi-dose vial policy;

·         appropriate use of single-dose and multi-dose vials;

·         careful maintenance of the cold chain;

·         attention to vaccine security; and

·         reducing missed opportunities for immunization.

Injection safety

Hepatitis B vaccine should be supplied with AD syringes and safety boxes.

Managers at each level are responsible for ensuring that adequate supplies are available at all times so that each injection is given with a sterile injection device. Attention should also be given to proper use and disposal of safety boxes to collect these materials.

Revision of immunization forms and materials

An important element of integrating hepatitis B vaccine into national immunization programmes is to revise training and informational materials, immunization cards and forms used to monitor and evaluate immunization services.

Training

Training for health care staff is essential because these staff are responsible for handling and administering hepatitis B vaccine and they are a major source of information for parents and others in the general public.

Advocacy and communication

Advocacy and communication efforts are important in order to generate support and commitment for the new vaccine. The primary target audiences are decision-makers/opinion leaders, health care staff, and the general public (including parents).

What information is needed to assess hepatitis B disease burden?

Adequate seroprevalence data needed to assess hepatitis B disease burden are generally available in all countries, or from adjacent countries with similar HBV endemicity. Thus, additional seroprevalence studies are usually not needed.

How should hepatitis B vaccine be phased into the existing infant immunization services?

A strategy in which hepatitis B vaccine is given to infants who have not yet completed the DTP vaccine series at the time hepatitis B vaccine is introduced is generally the most feasible to implement.

Are monovalent or combination vaccines most suitable?

Issues to consider in choosing a suitable hepatitis B vaccine for national immunization schedules include: flexibility in adding the vaccine to the national immunization schedule; impact on cold chain capacity; the number of injections per visit; vaccine security; impact on local vaccine production; and cost. Use of combination vaccines (e.g. DTP-HB vaccine) may offer certain programmatic advantages. These include:

·         a decreased number of injections required per visit (and thus decrease the number of needles and syringes required); and

·         a decrease in the amount of space required for cold chain storage and transport.

How can the addition of hepatitis B vaccine be used to strengthen national immunization services?

Hepatitis B vaccine introduction should be used as an opportunity to strengthen existing immunization services. Issues needing particular attention include stock management, reducing vaccine wastage, injection safety, and monitoring coverage.

Budgeting for the introduction of hepatitis B vaccine

Capital and recurrent costs related to the introduction of hepatitis B vaccine should be estimated and included in the annual immunization budget. Additional capital costs might include investment in cold chain equipment and information campaigns targeted to the general public. Additional recurrent costs include vaccines, AD syringes, training, safe disposal of waste, and evaluation of the impact of immunization.

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Chronic hepatitis B: potential drug therapy

Agent	Effective	Ineffective	Toxic	Under evaluation
Interferon	interferon-α	interferon-γ		Interferon-β
Antiviral	lamivudine famciclovir	acyclovir dideoxyinosine azudothymidine foscarnet	fialuridine adenine arabinoside	ribavirin lamivudine (long term) famciclovir (long term) adefovir entecavir
Immunomodulatory		prednisone interleukin-2 thymosin levamisole		adoptive immune transfer

Adopted from: Gitlin N. Hepatitis B: diagnosis, prevention, and treatment. Clinical Chemistry, 1997, 43:1500-1506,¹¹ with permission.

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Goals of interferon therapy

Goal	Implication
Loss of HBeAg	Significant decrease of infectious potential accompanied by clinical benefit
Loss of HBV DNA	Loss of ability of HBV to replicate
Return to normal ALT levels	Cessation of hepatic inflammation and interruption of progression of liver injury
Loss of HBsAg	Eradication of HBV

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Contraindications for interferon therapy for chronic hepatitis B

Hepatic decompensation	albumin <3.0 g/l bilirubin >51.3 μ mol/l (30 mg/l) prolonged prothrombin time >3.0 s
Portal hypertension	variceal bleed ascites encephalopathy
Hypersplenism	leukopenia (<2 x 109/l) thrombocytopenia (<7 x 107/l)
Psychiatric depression	severe, suicide attempt
Autoimmune disease	polyarteritis nodosa, rheumatoid arthritis, thyroiditis
Major system impairment	cardiac failure obstructive airways disease uncontrolled diabetes
Pregnancy
Current intravenous drug abuse

From: Gitlin N. Hepatitis B: diagnosis, prevention, and treatment. Clinical Chemistry, 1997, 43:1500-1506,¹¹ with permission.

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Side-effects of interferon therapy

Constitutional	flu-like illness fever rigors arthralgia myalgia fatigue
Haematologic	leukopenia thrombocytopenia
Alopecia
Neuropsiachiatric	depression insomnia irritability
Weight loss
Ocular
Autoimmune	hypothyroidism diabetes

From: Gitlin N. Hepatitis B: diagnosis, prevention, and treatment. Clinical Chemistry, 1997, 43:1500-1506,¹¹ with permission.