Hepatitis B

Hepatitis B

David J Mutimer, MBBS, MD, FRCP; Ye Htun Oo, MBBS, PhD, MRCP

atitis B virus (HBV) infection is a global health problem. Around 400 million people are chronically infected with HBV, which is a major cause of liver cirrhosis and liver failure. The interaction between the virus and host immune responses defines the clinical course of infection. The natural history of HBV is not linear, and the clinical spectrum varies from an asymptomatic carrier state to fulminant hepatic failure. Immunization programmes have resulted in a dramatic decline in the incidence and prevalence of chronic hepatitis B infection in many countries. For those with infection, the timing of treatment and the choice of antiviral therapy depend on the patient profile. The main goal of antiviral therapy is to prevent liver cirrhosis. Antiviral treatment is with interferon or nucleoside analogues. Nucleoside analogues are potent oral antiviral drugs that can suppress viral replication to undetectable levels. However, the viral genome can persist in hepatocytes despite sustained and potent suppression. For selected patients with decompensated liver cirrhosis, liver transplantation may be appropriate.

Epidemiology

Hepatitis B virus (HBV) infection is an important global health problem and is one of the most common chronic viral infections. Approximately 350–400 million persons havAe chronic infection,¹ and more than 1 million deaths annually are due to end-stage liver disease or hepatocellular cancer (HCC). HCC is the fifth most common cancer in the world and third leading cause of cancer-related death. HBV infection is highly prevalent in Asia, Africa, and parts of southern and eastern Europe. In the UK, more than 300,000 people may have chronic HBV infection.² Prevalence is low in most affluent countries, so it is not a leading indication for liver transplantation. In the UK, for instance, HBV is the indication for transplantation in only 5% of transplant cases.

However, migration from countries of high to countries of low prevalence influences the distribution, incidence and prevalence of HBV infection in low-prevalence countries, especially in western Europe, North America and Australia. Worldwide prevalence of HBV is described in Figure 1.

Virology

Human HBV is a member of the Hepadnaviridae family, and humans and higher primates are the only hosts for HBV infection. The intact viron comprises the viral DNA surrounded by a nucleocapsid (core protein or antigen) and an outer layer comprising the HBV surface protein or antigen (HBsAg). The viral genome is a 3.2-kb partially double-stranded DNA with four overlapping reading frames. The viral genome encodes the viral polymerase (which includes the reverse transcriptase function), the core and surface proteins, and the non-structural proteins (HBV e antigen [HBeAg] and X protein). The covalently closed circular (ccc) DNA, which acts as the major transcriptional template for the virus, is central to the durability of HBV infection and persists as an episome in infected hepatocytes. It can persist after antiviral therapy and even after the apparent clearance of infection.

There are eight distinct HBV genotypes, which have well-defined geographical distribution (see Figure 1). They differ in some important respects, including their natural history and response to interferon (IFN)-based antiviral therapy. In Europe, genotypes A and D are most common. In eastern Asia, genotypes B and C are prevalent.

Pathogenesis and Natural History

The pathogenesis of liver disease in HBV infection is related to the persistence and magnitude of viral replication. The course of viral infection and the severity of liver damage are determined by the balance between viral replication and host immune defence mechanisms. HBV-specific cytotoxic CD8 T-cells play a critical role in HBV clearance. However, suppressor or regulatory T-cells (T_reg) inhibit HBV-specific CD8 T-cell function in chronic HBV infection. This contributes to viral persistence. Large numbers of T_reg are found in both the circulation and in the liver of chronic HBV patients.³

The natural history of chronic HBV is diverse and non-linear. Chronically infected patients range from inactive carriers with low levels of replication to those patients with higher levels of virus and active inflammation, which may progress to cirrhosis and HCC.

Following acute HBV infection of adults, 95% recover spontaneously with viral clearance not needing treatment. Intrauterine infection and infection at a young age are strongly associated with failure to clear the virus and with the development of chronic infection. Chronic infection is defined as the persistence of HBsAg in serum for at least 6 months after infection with hepatic inflammation.

Liver inflammation requires both high levels of replication and targeted inflammatory responses. Chronic infection may be associated with production and secretion by infected hepatocytes of the HBeAg. In that case, the level of viral replication is almost invariably very high. Eventually, the production of HBeAg usually stops. At this stage, the level of viral replication may be low or high. When HBeAgnegativity is associated with high levels of replication, the associated hepatitis may be referred to as e-negative hepatitis. Under that circumstance, sequencing of the viral DNA frequently shows that specific mutations have emerged in the pre-core or core promoter regions of the viral DNA. Thus, e-negative hepatitis is also known as pre-core mutant hepatitis (see Figure 2).

Classically, four phases of chronic HBV infection have been described. They are the immune tolerant phase, the immune reactive phase, the inactive/resolution phase and reactivation phase.

High levels of replication (usually more than 10 million IU/mL) may be observed in the absence of inflammatory response (normal alanine aminotransferase [ALT] with minimal or no inflammation on liver biopsy), the so-called immune tolerant phase. Immune tolerance is more frequently associated with HBeAg-positive infection and is seen most often in those infected at birth or at a young age. However, this phase is seldom maintained for life. The majority of patients with high levels of replication sustained for a long duration will develop progressive liver damage leading to cirrhosis and/or HCC. During this phase, there is no cytotoxic T-cell reaction to virus.

When the virus is recognized as foreign antigen by the immune system, the immune reactive phase occurs and is characterized by elevated or fluctuating ALT, HBeAg-positivity and moderate to severe inflammation on liver biopsy. During this phase, serum HBV DNA falls and HBeAg secretion may stop (called HBeAg seroconversion).

After HBeAg seroconversion, the majority of patients will become inactive hepatitis B carriers with HBeAg-negativity, low serum HBV (< 2,000 IU/mL) and normal ALT. This phase may persist for life with sustained and effective cytotoxic T-cell responses. For those that remain inactive, 1–3% per annum will achieve resolution phase with clearance of HBsAg from serum. These HBsAgnegative patients may still have detectable HVB DNA in the liver but not in serum.

However, some patients revert from the inactive phase to a reactivation phase, with reappearance of higher levels of virus despite HBeAg-negativity (sequencing may demonstrate pre-core or core promoter mutations). There is resumed liver inflammation and progressive fibrosis.

This natural history of HBV can be transformed by antiviral agents.

Successful treatment prevent s progressive fibrosis and hepatic decompensation, reduces the risk for HCC and prevents liver-related deaths. Hepatitis serology, HBV DNA titres, serum ALT and expected liver histology findings in different phases of HBV infection are shown in Figure 3. 

Clinical Presentation and Diagnosis

Infection can be diagnosed during acute or chronic phases. Acute infection is characterized by arthralgia, fever, urticaria and flu-like symptoms, followed by jaundice. More than 90% recover with acquired immunity; fulminant hepatitis is rare, but a small proportion is persistently infected.

Globally, however, most infection is acquired at a very young age, the majority of infection is asymptomatic, and a high proportion becomes chronic. Thus, the majority of diagnoses are made in asymptomatic carriers when blood tests are performed for HBV screening or for other reasons. First presentation in middle age with cirrhosis, which is either compensated (features of chronic liver disease) or decompensated (ascites, hepatic encephalopathy, and variceal bleed), is not uncommon.

Investigations

Viral Serology

Those patients who present with acute hepatitis typically have both HBsAg and immunoglobulin M (IgM) antibodies to HBV in serum (IgM reactivity to the core antigen is typically measured). Chronic HBV patients who present to clinics should be checked for HBsAg, HBeAg and HBV DNA level. HBV DNA quantification is a key determinant for selection of patients for therapy, and its measurement is necessary to monitor response to antiviral therapy (Table 1). HBV infection can be associated with hepatitis delta virus (HDV) infection, so HDV serology should be routinely performed. HBV/HDV infection has a different natural history and different treatment to HBV mono-infection.

Liver Biochemistry

Assessment of liver damage requires routine biochemical liver function tests, including serum albumin, and international normalized ratio.

Assessment of Fibrosis

A liver biopsy can determine the degree of hepatic necroinflammation (grading) and fibrosis (staging).⁴ The use of non-invasive methods such as serum markers and transient elastography may provide a measurement of liver fibrosis, and some centres use these as an alternative to liver biopsy.

Monitoring Cirrhosis and Surveillance of HCC

Liver ultrasound demonstrates cirrhosis and features of portal hypertension (splenomegaly, ascites and varices) and monitors the appearance of primary liver cancer. It should be performed at first assessment for all patients and every 6 months for patients with high risk of liver cancer.

Management

The management of HBV has improved during recent years with the use of IFN and with the development of safe and potent oral antiviral nucleoside/nucleotide analogues. The goal of therapy is to prevent the progression to cirrhosis and to reduce risk of HCC. Antiviral efficacy is measured by the degree of HBV DNA suppression and rates of HBeAg and HBsAg loss, and is reflected by improvement in liver histology.

When to Start Treatment

HBV treatment is recommended for those patients who have moderate hepatic necroinflammation or fibrosis and high serum HBV DNA. Patients with established cirrhosis should receive oral antiviral therapy regardless of HBV DNA titre.⁵

Treatment Strategy

The choice between nucleoside/ nucleotide or IFN depends on patient and viral characteristics. IFN therapy has both immunomodulatory and antiviral effects. It is of finite duration, and the ideal candidate is the young patient with HBeAg-positivity who is infected with HBV genotype A (the genotype most sensitive to IFN treatment). Successful outcome for this patient is defined as HBeAg loss, acquisition of antibody to HBeAg, and low serum HBV DNA (all sustained after cessation of treatment). Occasional patients will lose serum HBsAg.

IFN is not recommended for treatment of patients with cirrhosis, and adverse effects can be significant.

Nucleoside/nucleotide analogues are oral antiviral agents that inhibit HBV DNA synthesis by acting as DNA chain terminators and are well tolerated. They fall into three groups as shown in Table 2.

Recommended first-line therapy for the treatment-naive non-cirrhotic patient is either IFN or an oral antiviral. Entecavir and tenofovir both have potent antiviral activity (90% of treated patients have undetectable serum HBV DNA at 12 months of therapy), good safety profiles, and very low rates of emergence of resistance. Lamivudine and telbivudine should not be used as first-line therapy because the risk of drug resistance is high. Adefovir has a good resistance profile, but lacks potency (50% undetectable HBV DNA at year 1). Thus, entecavir and tenofovir are the superior oral agents.

Patients taking oral antiviral therapy need to understand the importance of treatment adherence to prevent disease progression and to minimize the risk of drug resistance. In normal practice, the emergence of drug resistance is recognized by a rise in viral load of at least 1 log10 IU/mL from nadir titre in a compliant patient. HBV resistance can be confirmed by genetic sequencing of the virus (Figure 4).

Follow-up and HCC Surveillance

It is estimated that more than 50% of liver cancers worldwide are due to HBV, and 89% of these HBV-related HCC are from developing countries. African or Asian ethnicity, male gender, age over 40 years, family history of HCC, high HBV DNA titre and co-infection with other viruses are the risk factors which are associated with increased risk of HCC development.^6–8 Most cancer is seen after development of cirrhosis, so prevention of cirrhosis dramatically reduces the risk of cancer.

HBV Infection in Special Circumstances

Pregnancy

Vaccination of the offspring of carrier mothers prevents neonatal infection in the majority of cases. Occasional vaccine failure is observed, most commonly in association with very high maternal viral titre. Antiviral therapy for the pregnant mother with very high titres may further reduce the risk of transmission to the baby. Current recommendations suggest that either lamivudine (Category C) or tenofovir (Category B) can be taken by the pregnant mother during the third trimester to further reduce the risk of transmission to the developing fetus and neonate.

Breastfeeding by an HBV-positive mother is safe, and there is a low risk of infection (so long as the baby has been vaccinated).

Infants and Children

HBV infection is seldom associated with significant liver damage during childhood years. Antivirals can be used under specialist care.

Health-care Worker

Health-care workers who undertake exposure-prone procedures (eg, surgeons, obstetricians) can be given antivirals to reduce the risk of transmission from doctor to patient.

Co-infection

HBV and HDV co-infection is not uncommon. Around 5% of HBV carriers are co-infected with HDV. IFN is the treatment of choice for HBV/ HDV infection. In patients with HBV and HCV co-infection, treatment is recommended to target the dominant virus and IFN has the advantage of being active against both viruses.

HIV and HBV co-infection is frequently observed. Inclusion of tenofovir in the HIV treatment regimen ensures excellent suppression of the HBV.

Immunosuppressed Patients

Reappearance of HBV DNA in a patient with previous resolved or inactive HBV infection is sometimes observed in immunosuppressed states. cccDNA, which resides within the infected hepatocytes, plays a significant role in reactivation of HBV during cancer chemotherapy, during the use of some biological agents (particularly anti-CD20 rituximab) and following organ transplantation. Under these circumstances, pro phylaxis with oral antiviral drugs is frequently indicated.

Prevention

HBV Vaccination

Vaccination is the most effective way to achieve global HBV control and to prevent cirrhosis, liver failure and liver cancer. Most countries include HBV vaccination as part of the routine universal childhood vaccination schedule. Universal vaccination has been shown to reduce the incidence of HBV infection, to reduce the frequency of childhood chronic infection, and to reduce the risk of childhood liver cancer. The HBV vaccine has been available for two decades. Most deaths from chronic HBV occur in middle age. Thus, it is too soon to observe an impact of vaccination on death from the complications of chronic liver disease, but a dramatic impact is predicted.

Some low-prevalence countries have not implemented universal vaccination, but prefer to target vaccination to specific high-risk groups. Most countries undertake maternal screening for HBsAg, and vaccinate the neonate born to the HBV carrier mother.⁹

If a person is detected with HBV infection, family members should be screened and vaccination should be offered to household members and close contacts who are HBsAg-negative.

Liver Transplantation

Liver transplantation is the preferred treatment for HBV-infected individuals who present with fulminant liver failure, decompensated liver disease and HBV-related HCC. Oral antiviral therapy alone or in combination with hyperimmune immunoglobulin can prevent graft reinfection.^10,11

Conclusion

Currently, HBV causes nearly 1 million deaths per annum globally. HBV vaccination will have a major impact on prevalence of infection. For those with established chronic infection and evidence of liver damage, antiviral treatment should be started early to prevent the development of HBV-related cirrhosis, liver failure and liver cancer.

Declaration of Interests

David J Mutimer has acted as advisor to Gilead and BMS, the manufacturers of tenofovir and entecavir, respectively. Ye Htun Oo: None.

References

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6. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678–686.

7. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129–1133.

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9. Department of health guidelines J2. Hepatitis B testing in pregnancy, information to midwives; 2011.

10. Freshwater DA, Dudley T, Cane P, Mutimer DJ. Viral persistence after liver transplantation for hepatitis B virus: a cross-sectional study. Transplantation 2008;85:1105–1111.

11. Mutimer D. Hepatitis B after transplantation: competition between the recipient virus and the donor virus. Liver Transpl 2010;16:1225–1227.

© 2011 Elsevier Ltd. Initially published in Medicine 2011;39(9):545–549.

About the Authors

David J Mutimer is a Consultant Hepatologist at the Queen Elizabeth Hospital Liver Unit, and Reader in Hepatology at the University of Birmingham, UK. His main interests include viral hepatology and liver transplantation. Ye Htun Oo is Specialist Registrar in Hepatology at the Queen Elizabeth Hospital Liver Unit, UK. His research interests include viral hepatitis, liver transplantation, and hepatic immune tolerance.

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