Prof Howard Thomas highlights the importance of identification, treatment, and vaccination in an overview of chronic hepatitis B

Chronic hepatitis B covers a spectrum of disease characterised by the presence of hepatitis B surface antigen (HBsAg) in the blood or serum for a period longer than 6 months.1 Estimates of the 
number of individuals in the UK 
with chronic hepatitis B infection
vary between 180,000 and 325,000 people.2 
 
Some individuals may not experience significant health problems from chronic hepatitis B, but in others, it can cause chronic inflammation and liver cell necrosis (chronic hepatitis) leading to liver fibrosis, and death from decompensated cirrhosis and hepatocellular carcinoma (HCC).1
 
The risk of developing progressive liver disease and HCC is proportional to the level of viraemia, as indicated by hepatitis B virus (HBV) DNA levels in the blood.1,3 Without antiviral treatment, the 5-year cumulative incidence of cirrhosis ranges from 8% to 20% and 5-year survival rates among people with untreated decompensated cirrhosis may be as low as 15%. Prolonged antiviral treatment can significantly reduce the incidence of hepatic decompensation and the risk of hepatocellular carcinoma.4
 
Chronic hepatitis B can be divided into HBe antigen (HBeAg)-positive or HBeAg-negative disease based on the presence or absence of this
antigen. Its presence is typically associated with higher rates of viral replication and therefore increased infectivity.

Natural history of chronic hepatitis B infection

Figure 1 (see below)5 depicts the natural history of chronic HBV infection. The ‘immune tolerance phase’ is seen in HBeAg-positive disease and is characterised by high levels of HBV replication with normal alanine aminotransferase (ALT) levels and limited liver necroinflammation. This phase is commonly seen in children. It is followed by an ‘immune clearance or immune reactive phase’ in which the immune system recognises and starts to clear the virus. Alanine aminotransferase levels are typically elevated or fluctuating, and there is a higher risk of liver fibrosis. This tends to be the initial phase in people infected with HBV as adults. It lasts from weeks to years and ends with HBeAg seroconversion.
 
With the loss of HBeAg, the person may enter an ‘immune control phase’ with very low or undetectable HBV DNA levels, normal ALT and minimal fibrosis progression; however, some people may experience rising HBV DNA levels despite HBeAg negativity. This is caused by virions that do not express HBeAg because of genetic mutations. This ‘immune escape phase’ can lead to active necroinflammation and progression of fibrosis.
 
Figure 1: Natural history of chronic hepatitis B infection
Natural history of chronic hepatitis B infection

HbeAg=hepatitis B e antigen; Anti-HBe=hepatitis B e antigen antibody; HBV=hepatitis B virus; DNA=deoxyribonucleic acid; ALT=alanine aminotransferase; ULN=upper limit of normal of ALT.

Adapted from: Chu C, Karayiannis P, Fowler M et al. Hepatology 1985; 5: 431-434

Case identification in primary care

People with hepatitis B may be asymptomatic in the early stages of infection, and case finding is dependent on identification and testing of high-risk groups. NICE Public Health Guideline 43 (PH43) on ways to promote and offer testing to people at increased risk of hepatitis B (and C) infection recommends that GPs and practice nurses should:6
  • offer testing for hepatitis B surface antigen to:
    • adults and children at increased risk of infection, particularly migrants from medium- or high-prevalence countries and people who inject or have injected drugs
    • people who are newly registered with the practice and belong to a group at increased risk of infection
  • ask newly registered adults if they have ever injected drugs, including image and performance enhancement substances, at their first consultation
  • offer HBsAg testing and HBV vaccination to men who have sex with men who are offered a test for HIV and have not previously tested positive for hepatitis B antibodies
  • offer hepatitis B vaccination to people who test negative for hepatitis B but remain at increased risk of infection
  • ensure people diagnosed with hepatitis B are referred to specialist care.
The importance of offering testing and vaccination to people at increased risk of hepatitis B infection is also included in NICE Quality Standard 65 on hepatitis B. Further details can be found in Dr Hasan Chowhan’s and Valerie Pentney’s Guidelines in Practice article on this topic.7  
 
Dr Chowhan’s article also covers the referral and assessment of pregnant women who are HBsAg positive, plus the importance of neonatal hepatitis B vaccination.

Treatment overview 

The goal of treatment for chronic hepatitis B is to suppress viral replication, reducing viraemia, preventing cirrhosis, HCC, and liver failure. Since the introduction of effective antiviral treatment in the form of interferon alfa, several nucleoside and nucleotide analogues are now approved for use in adults with chronic hepatitis B, together with a pegylated form of interferon alfa. 
 
It is important to note that the spontaneous mutation rate of HBV DNA is high and exposure of HBV to nucleoside or nucleotide analogues selects for mutations in the polymerase gene that confer resistance or decreased susceptibility to drugs. Therefore, the relative risk of drug resistance must be taken into account when considering treatment with nucleoside or nucleotide analogues, including the level of cross-resistance between different agents.1 
 
Antiviral treatment in adults with chronic hepatitis B—including treatment sequences for those with HBeAg-positive and -negative disease—can be found on NICE Pathways at: pathways.nice.org.uk/pathways/hepatitis-b-chronic.
 

Monitoring treatment response

In clinical practice, surrogate markers are used to monitor progression of disease and treatment response, including:1
  • normalisation of ALT levels
  • decrease in inflammation scores
  • no worsening (or improvement in) fibrosis on liver biopsies
  • suppression of viraemia—serum HBV DNA dropping below detection level
  • loss of HBeAg and seroconversion to HBe antibody (anti-HBe); loss of HBsAg and seroconversion to HBs antibody (anti-HBs). 

Discussion

Mortality from liver disease is increasing and is now the fifth most common cause of death in the UK.8 Although alcohol consumption is still the most common aetiological factor, the presence of viral hepatitis is also a significant cause of liver disease. As chronic hepatitis B can be treated, and vaccination offered to babies of mothers who have the disease and those at high risk of HBV exposure, it is essential that affected people are identified and managed appropriately. Many people still believe erroneously that chronic hepatitis B cannot be treated and therefore referral to secondary care does not occur. It is essential that this barrier is overcome in primary health care so that the substantial progress that has been made in the treatment of chronic hepatitis B in the past decade brings the reduced mortality that is possible. Although current therapies are highly effective in suppressing replication of HBV, they do not eradicate the virus, necessitating prolonged, and possibly even lifelong, treatment.1
  1. NICE. Hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. Clinical Guideline 165. NICE, 2013. Available at: www.nice.org.uk/guidance/CG165
  2. NICE website. NICE quality standard on hepatitis B. QS65. www.nice.org.uk/guidance/qs65
  3. Liu T, Fang Y, Xiong H et al. A case-control study of the relationship between hepatitis B virus DNA level and risk of hepatocellular carcinoma in Qidong, China. World J Gastroenterol 2008; 14 (19): 3059–3063.
  4. Liaw Y, Sung J, Chow W et al. Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351 (15): 1521–1531.
  5. Chu C, Karayiannis P, Fowler M et al. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 1985; 5 (3): 431–434.
  6. NICE. Hepatitis B and C: ways to promote and offer testing to people at increased risk of infection. Public Health Guidance 43. NICE, 2012. Available at: www.nice.org.uk/guidance/PH43
  7. Chowhan H and Pentney V. People with hepatitis B need support to access and receive treatment. Guidelines in Practice, October 2014. Available at: GinP.co.uk/oct_14_Chowan_Pentney_HepB
  8. British Society of Gastroenterology website. Chronic management: management of patients with chronic liver diseases. www.bsg.org.uk/clinical/commissioning-report/management-of-patients-with-chronic-liver-diseases.html (accessed 22 October 2014).