Diagnosis and management of chronic hepatitis B in children, young people, and adults: summary of NICE guidanceBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3893 (Published 26 June 2013) Cite this as: BMJ 2013;346:f3893
- Grammati Sarri, senior research fellow1,
- Maggie Westby, clinical effectiveness lead1,
- Sarah Bermingham, health economist1,
- Grant Hill-Cawthorne, lecturer and clinical adviser2,
- Howard Thomas, emeritus professor and chairman of the Guideline Development Group3
- on behalf of the Guideline Development Group
- 1National Clinical Guideline Centre, Royal College of Physicians of London, London NW1 4LE, UK
- 2Sydney Emerging Infections and Biosecurity Institute and School of Public Health, University of Sydney, Australia
- 3Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College, London
- Correspondence to: G Sarri
Chronic hepatitis B describes a spectrum of disease resulting from chronic hepatitis B virus (HBV) infection. About a third of the world’s population has serological evidence of past or present HBV infection, and 350-400 million people have chronic HBV infection.1 In the UK about 326 000 people are thought to have chronic hepatitis B.2 In some people, chronic hepatitis B may cause liver fibrosis, cirrhosis, and hepatocellular carcinoma; in others it is inactive and does not lead to important health problems.3 Antiviral therapy suppresses HBV replication and decreases the risk of progressive liver disease.4 This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) on the diagnosis and management of chronic hepatitis B in children, young people, and adults.5
NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
Assessment and referral in primary care
Children, young people, and adults who are seropositive for HBV surface antigen (HBsAg)
Refer to a paediatric or adult hepatologist, gastroenterologist, or infectious disease specialist with an interest in hepatology.
Arrange the following tests and include test results with the referral:
- Hepatitis B e antigen (HBeAg, an indirect marker of high levels of viraemia and infectivity) or antibody status (anti-HBe, an indirect marker of lower levels of viraemia and infectivity)
- HBV DNA level (quantitative direct measure of level of viraemia and infectivity)
- IgM antibody to hepatitis B core antigen (IgM anti-HBc, evidence of recent infection with HBV)
- Hepatitis C virus antibody (anti-HCV)
- Hepatitis delta virus antibody (anti-HDV)
- HIV antibody (anti-HIV)
- Hepatitis A virus antibody (anti-HAV)
- Alanine aminotransferase (ALT) or aspartate aminotransferase, γ-glutamyltransferase, serum albumin, total bilirubin, total globulins, full blood count, and prothrombin time
- Tests for hepatocellular carcinoma, including hepatic ultrasound and α fetoprotein testing.
[Based on the experience and opinion of the GDG]
Pregnant women who test positive for HBsAg at antenatal screening
Refer pregnant women as above for assessment within six weeks of receiving the screening test result in order to allow treatment in the third trimester. [Based on the experience and opinion of the GDG]
Assessment of liver disease in secondary specialist care
Throughout the following sections, “abnormal ALT” is defined as ≥30 IU/mL alanine aminotransferase for males and ≥19 IU/mL for females measured by two consecutive tests conducted three months apart.
Adults with chronic hepatitis B
Offer transient elastography as the initial test to assess severity of liver disease and need for treatment:
- For a transient elastography score ≥11 kPa, offer antiviral treatment (as below) without liver biopsy (as such patients are very likely to have cirrhosis and confirmation by liver biopsy is not needed).
- For a transient elastography score between 6 and 10 kPa, consider liver biopsy to confirm the level of fibrosis and offer antiviral treatment (as below).
- For a transient elastography score <6 kPa, offer liver biopsy and antiviral treatment (as below) if younger than 30 years with HBV DNA level >2000 IU/mL and abnormal ALT (adults with such a score are unlikely to have significant fibrosis). If ALT is normal and HBV DNA <2000 IU/mL, do not offer liver biopsy or antiviral treatment.
[Based on moderate to low quality evidence from diagnostic test accuracy studies and the experience and opinion of the GDG]
Offer an annual reassessment of liver disease using transient elastography to adults who are not taking antiviral treatment. [Based on the experience and opinion of the GDG]
Refer to the NICE guideline5 for recommendations regarding monitoring of liver disease or fibrosis of people in the immune tolerant phase of chronic hepatitis B (positive for HBeAg with high levels of HBV replication with normal ALT levels and minimal liver necro-inflammation) and in the immune control phase (negative for HBeAg with very low or undetectable levels of HBV DNA, normal ALT, and minimal fibrosis progression) (see figure for natural course of chronic HBV infection⇓).
Offer a personalised care plan outlining proposed treatment and long term management—for example, a copy of the hospital consultation summary. [Based on the experience and opinion of the Guideline Development Group (GDG)]
Treatment criteria for adults
Offer antiviral treatment to adults after consistent results from two consecutive tests conducted three months apart, as follows:
- Patients aged ≥30 years who have HBV DNA levels >2000 IU/mL and abnormal ALT
- Patients aged <30 years who have HBV DNA levels >2000 IU/mL and abnormal ALT if there is evidence of necro-inflammation or fibrosis on liver biopsy or a transient elastography score >6 kPa
- Patients with HBV DNA levels >20 000 IU/mL and abnormal ALT regardless of age or the extent of liver disease
- Patients with cirrhosis if any detectable HBV DNA is present, regardless of HBeAg status, HBV DNA levels, and ALT levels.
[Based on moderate to low quality evidence from cohort studies and the experience and opinion of the GDG]
Refer to the NICE guideline5 for recommendations regarding monitoring to determine treatment response and adherence for each antiviral therapy in each population.
All adults (except those who are pregnant or breastfeeding or who are receiving immunosuppressive therapy)
Offer a 48 week course of peginterferon alfa-2a as first line treatment. [Based on moderate to low quality evidence from randomised trials, directly applicable cost effectiveness evidence, and the experience and opinion of the GDG]
Adults with HBeAg positive chronic hepatitis B and with compensated liver disease (in which liver fibrosis is present but liver function is preserved and stable)
Consider stopping peginterferon alfa-2a after 24 weeks if the HBV DNA level has decreased by less than 100-fold and/or HBsAg level is >20 000 IU/mL. [Based on low to very low quality evidence from cohort studies and the experience and opinion of the GDG]
Offer nucleoside analogues tenofovir or entecavir, as second and third treatment respectively, to people who do not undergo HBeAg seroconversion or who revert to being HBeAg positive after seroconversion. [Based on high to low quality evidence from randomised trials, directly applicable cost effectiveness evidence, and the experience and opinion of the GDG]
Consider stopping nucleoside or nucleotide analogue treatment 12 months after HBeAg seroconversion in people without cirrhosis; do not stop treatment in people with cirrhosis. [Based on the experience and opinion of the GDG]
Adults with HBeAg negative chronic hepatitis B and compensated liver disease
Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if the HBV DNA level has decreased by less than 100-fold and HBsAg has not decreased. [Based on low to very low quality evidence from cohort studies, and the experience and opinion of the GDG]
Offer tenofovir or entecavir as second line treatment to people with detectable HBV DNA; offer a third line treatment option as described in the NICE guideline.5 [Based on high to low quality evidence from randomised trials, directly applicable cost effectiveness evidence and the experience and opinion of the GDG]
Consider stopping nucleoside or nucleotide analogue treatment 12 months after achieving undetectable HBV DNA and HBsAg seroconversion in people without cirrhosis; do not stop treatment in people with cirrhosis. [Based on the experience and opinion of the GDG]
Children and young people with chronic hepatitis B and compensated liver disease
Offer antiviral treatment if there is evidence of significant fibrosis or abnormal ALT on two consecutive tests conducted three months apart. See the NICE guideline for a full definition of significant fibrosis.5 [Based on the experience and opinion of the GDG]
Consider a 48 week course of peginterferon alfa-2a as first line treatment (see the NICE guideline for UK marketing authorisation for this drug). [Based on low quality indirect evidence from a randomised trial and the experience and opinion of the GDG]
Women who are pregnant or breast feeding
Offer tenofovir to women with HBV DNA >107 IU/mL in the third trimester to reduce the risk of transmission of HBV to the baby (see the NICE guideline for UK marketing authorisation for this drug). [Based on the experience and opinion of the GDG]
People starting immunosuppressive therapy
Offer tests for anti-HBs antibodies, HBV DNA, HBeAg, and ALT in people who are seropositive for HBsAg or anti-HBc antibodies. Offer prophylaxis with entecavir or tenofovir if HBV DNA is >2000 IU/mL and consider the nucleoside analogue lamivudine otherwise. Start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of six months after HBeAg seroconversion and HBV DNA is undetectable. Then monitor and manage according to the NICE guideline.5 [Based on moderate to very low quality evidence from randomised and non-randomised studies, and the experience and opinion of the GDG]
In people who are HBsAg negative and anti-HBc positive and who are starting rituximab or other B cell depleting therapies, offer lamivudine as prevention against reactivation. Otherwise monitor and consider antiviral treatment as described in the NICE guideline.5 [Based on experience and opinion of the GDG]
Surveillance testing for hepatocellular carcinoma
Perform six monthly surveillance for hepatocellular carcinoma by hepatic ultrasound and α fetoprotein testing in people with significant fibrosis or cirrhosis (see the NICE guideline for a definition of significant fibrosis5). [Based on very low quality evidence from randomised and non-randomised studies, and the experience and opinion of the GDG]
In people without significant fibrosis or cirrhosis consider six monthly surveillance for hepatocellular carcinoma if the person is >40 years old, has a family history of hepatocellular carcinoma, or has HBV DNA ≥20 000 IU/mL. [Based on very low quality evidence from randomised and non-randomised studies, and on the experience and opinion of the GDG]
Adults with decompensated liver disease
Refer adults who develop decompensated liver disease immediately to a hepatologist or to a gastroenterologist with an interest in hepatology. [Based on the experience and opinion of the GDG]
Adults co-infected with chronic hepatitis B and hepatitis C
Offer peginterferon alfa and ribavirin. [Based on the experience and opinion of the GDG and on the indirect evidence from randomised studies]
Adults co-infected with chronic hepatitis B and hepatitis delta
For adults co-infected with chronic hepatitis B and hepatitis delta and evidence of significant fibrosis, offer a 48 week course of peginterferon alfa-2a.
Consider stopping treatment if HDV RNA is detectable after 6-12 months of treatment. Otherwise continue treatment and re-evaluate treatment response annually.
Stop treatment after HBsAg seroconversion.
[Based on moderate to very low quality evidence from randomised studies, and on the experience and opinion of the GDG]
Between 250 000 and 500 000 people in the UK are thought to have chronic hepatitis B. However, most cases are undiagnosed. Therefore, it is essential that this guideline is read in association with the NICE public health recommendations on improving case identification of HBV and HCV.6
We recommend that essential serological tests are performed in primary care and that the results accompany the patient to the specialist to ensure more timely and efficient care.
Although costly, antiviral therapy can prevent downstream liver disease, reduce mortality, and improve quality of life. Based on best available evidence, the recommended sequence of therapies is the most effective and cost effective over the patient’s lifetime.
We recommend that the need for treatment is first assessed with transient elastography, minimising the need for invasive liver biopsy in some cases. Access to transient elastography is currently limited; this recommendation may require additional investment.
Further information on the guidance
The guideline was developed according to NICE guideline methodology (www.nice.org.uk/guidelinesmanual). This involved systematic searching, critically appraising, and summarising the clinical and cost effectiveness evidence. The guideline development group consisted of clinical and academic hepatologists, two patient carer members, a virologist, a general practitioner, a paediatric infectious disease specialist, a nurse consultant, and a specialist in infectious diseases. NICE has produced four different versions of the guideline: a full version; a version known as the “NICE guideline” (which summarises the recommendations); a NICE pathway (an interactive tool that brings together all related NICE guidance on a topic in one interface); and a version for patients and the public. All these versions are available from the NICE website (http://guidance.nice.org.uk/CG165). Updates of the guideline will be published according to the NICE guideline development programme.
Research recommendations were made around five main topics:
Which parameters can be used to predict a durable response to antiviral treatment and therefore indicate when it is safe to stop treatment in HBeAg negative disease?
Which ALT values for children and young people can be used to assess disease activity?
What is the long term safety of tenofovir in chronic hepatitis B?
In people receiving immunosuppressive therapy, what are the optimal strategies to identify those at risk of HBV reactivation and what is the most effective prophylactic treatment to prevent reactivation?
Cite this as: BMJ 2013;346:f3893
This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
The members of the Guideline Development Group were Aftab Ala, Elizabeth Boxall, Steven Bradley, Geoffrey Dusheiko, Patrick Kennedy, Emily Lam, Alan Mitchell, Angela Narbey, Howard Thomas, Gareth Tudor-Williams, Francisco Javier Vilar, and Sarah Wise.
Contributors: GS drafted the article. All authors revised it critically for important intellectual content and approved the final version to be published. All authors are guarantors of this article.
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: all authors were members of the Guideline Development Group for the NICE guideline (GS the systematic reviewer, SB the health economist, MW the methodological lead, GH the clinical adviser, and HT the guideline chair).
Provenance and peer review: Commissioned; not externally peer reviewed.