This guideline partially replaces TA96.
This guideline is the basis of QS65 and QS152.
Overview
This guideline provides a detailed approach to the assessment and management of chronic hepatitis B in individuals of all ages, including children, young people, and adults. Its primary objective is to enhance the quality of care for those affected by hepatitis B by clearly defining the appropriate diagnostic tests and treatment strategies based on age and disease severity.
Who is it for?
This guideline is specifically designed for:
- Healthcare professionals involved in the diagnosis and management of hepatitis B.
- Commissioners and providers of healthcare services.
- Individuals living with chronic hepatitis B, as well as their families and caregivers.
Introduction
This guideline represents an updated version, replacing recommendations previously outlined in NICE technology appraisal 96. It integrates recommendations from several NICE technology appraisals, including 96, 153, 154, and 173. For detailed update information, please refer to Update information.
Chronic hepatitis B encompasses a spectrum of disease conditions, typically identified by the persistent presence of hepatitis B surface antigen (HBsAg) in the blood or serum for a period exceeding 6 months. While some individuals with chronic hepatitis B may experience an inactive phase without significant health implications, others may progress towards more severe liver conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of liver disease is closely linked to the levels of hepatitis B virus (HBV) DNA in the bloodstream. Without antiviral intervention, the cumulative incidence of cirrhosis over 5 years ranges from 8% to 20%. Individuals with cirrhosis face a substantial risk of decompensated liver disease if left untreated, with 5-year survival rates among untreated individuals with decompensated cirrhosis potentially as low as 15%. Chronic hepatitis B is further classified into e antigen- (HBeAg) positive or HBeAg-negative forms, based on the presence or absence of e antigen. The presence of HBeAg usually indicates higher viral replication rates, thus increasing infectivity.
The primary objective of hepatitis B treatment is to prevent the development of cirrhosis, HCC, and liver failure. Clinical practice utilizes surrogate markers to monitor disease progression and treatment response. These markers include the normalization of serum alanine aminotransferase (ALT) levels, reduction in inflammation scores, stabilization or improvement in liver fibrosis (assessed via biopsies), suppression of serum HBV DNA to undetectable levels, loss of HBeAg and seroconversion to HBe antibody (anti-HBe), and loss of HBsAg and seroconversion to HBs antibody (anti-HBs).
Antiviral therapies are crucial in suppressing HBV replication and mitigating hepatic inflammation and fibrosis, thereby reducing the risk of severe liver disease. Since the introduction of interferon alfa, several nucleoside and nucleotide analogs, along with pegylated interferon alfa, have been approved for treating chronic hepatitis B in adults. With a range of effective and safe treatment options available, key considerations include determining which patients require immediate treatment, the optimal sequence and combination of drug regimens, and identifying patients who can be monitored with delayed treatment initiation.
This guideline addresses critical aspects of chronic hepatitis B management, including:
- The information needs of individuals with chronic hepatitis B and their caregivers.
- Appropriate settings for assessing children, young people, and adults with chronic hepatitis B.
- Methods for assessing liver disease severity, including non-invasive tests and genotype testing.
- Criteria for initiating antiviral treatment.
- The effectiveness, safety, and cost-effectiveness of current treatment options.
- Selection of first-line therapies.
- Management strategies for treatment failure or drug resistance.
- The potential role of combination therapy.
- Determining when treatment can be safely discontinued.
- Care management for pregnant and breastfeeding women and prevention of vertical transmission.
- Prophylactic treatment during immunosuppressive therapy.
- Monitoring protocols for treatment response, fibrosis progression, and HCC development.
The HBV DNA exhibits a high spontaneous mutation rate. Exposure to nucleoside or nucleotide analogs can lead to mutations in the polymerase gene, resulting in drug resistance or reduced drug susceptibility. The risk of drug resistance is a significant factor when considering treatment with these analogs, including the potential for cross-resistance between different agents.
Figure 1 illustrates the natural progression of chronic HBV infection. The immune-tolerance phase, typically observed in HBeAg-positive disease, is characterized by high HBV replication levels, normal ALT levels, and limited liver necroinflammation. Due to a minimal immune response to the virus, spontaneous HBeAg loss is uncommon during this phase, which is frequently seen in children. This phase is succeeded by the immune-clearance or immune-reactive phase, where the immune system begins to recognize and clear the virus. ALT levels in this phase are often elevated or fluctuating, and there is an increased risk of liver fibrosis. This is often the initial phase in adults infected with HBV, lasting from weeks to years and culminating in HBeAg seroconversion.
Figure 1
Alt text: Diagram illustrating the natural history of chronic Hepatitis B Virus (HBV) infection, detailing the phases from immune tolerance to immune control, crucial for hepatitis B diagnosis and understanding disease progression.
Natural history of chronic HBV infection.
Following HBeAg loss, individuals may enter an immune-control phase characterized by very low or undetectable HBV DNA levels, normal ALT, and minimal fibrosis progression. However, some individuals may experience increasing HBV DNA levels despite HBeAg negativity. This is attributed to virions that do not express HBeAg due to genetic mutations. This immune-escape phase can lead to renewed necroinflammation and fibrosis progression.
While significant advancements have been made in chronic hepatitis B treatment over the past decade, the optimal timing for treatment initiation remains a subject of ongoing debate. Although current treatments effectively suppress HBV replication, they typically do not eradicate the virus, often requiring long-term or lifelong therapy.
This guideline assumes that prescribers will utilize a drug’s summary of product characteristics to guide treatment decisions in individual patients.
This guideline includes recommendations for drug use that may be outside of their UK marketing authorization at the time of publication, provided there is robust evidence supporting such use. In these cases, prescribers must adhere to relevant professional guidelines and take full responsibility for their decisions. Informed consent from the patient (or their legal representatives) is essential and must be documented. Refer to the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information. Recommendations involving ‘off-label’ drug use are marked with a footnote.
Patient-centred care
This guideline offers best practice advice on the care of children, young people and adults with chronic hepatitis B.
Patients and healthcare professionals have rights and responsibilities as set out in the NHS Constitution for England – all NICE guidance is written to reflect these. Treatment and care should take into account individual needs and preferences. Patients should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. If the patient is under 16, their family or carers should also be given information and support to help the child or young person to make decisions about their treatment. Healthcare professionals should follow the Department of Health’s advice on consent. If someone does not have capacity to make decisions, healthcare professionals should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards. In Wales, healthcare professionals should follow advice on consent from the Welsh Government.
NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in Patient experience in adult NHS services.
If a young person is moving between paediatric and adult services, care should be planned and managed according to the best practice guidance described in the Department of Health’s Transition: getting it right for young people.
Adult and paediatric healthcare teams should work jointly to provide assessment and services to young people with chronic hepatitis B. Diagnosis and management should be reviewed throughout the transition process, and there should be clarity about who is the lead clinician to ensure continuity of care.
Terms used in this guidance
Chronic hepatitis B
Chronic hepatitis B is defined as persistence of hepatitis B surface antigen (HBsAg) for 6 months or more after acute infection with hepatitis B virus (HBV).
HBV DNA
HBV DNA level, or ‘viral load’, is an indicator of viral replication. Higher HBV DNA levels are usually associated with an increased risk of liver disease and hepatocellular carcinoma. HBV DNA level typically falls in response to effective antiviral treatment.
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antigen (HBsAg) is a viral protein detectable in the blood in acute and chronic hepatitis B infection, crucial for hepatitis B diagnosis.
HBsAg seroconversion
The development of antibodies against HBsAg is known as HBsAg seroconversion. It signifies clearance of HBsAg and resolution of the chronic infection, a key outcome in hepatitis B diagnosis and treatment monitoring.
Hepatitis B e antigen (HBeAg)
Hepatitis B e antigen (HBeAg) is an indicator of viral replication, although some variant forms of the virus do not express HBeAg (see ‘HBeAg-negative chronic hepatitis B’ below). Active infection can be described as HBeAg-positive or HBeAg-negative according to whether HBeAg is secreted.
HBeAg-negative chronic hepatitis B
HBeAg-negative hepatitis B is a form of the virus that does not cause infected cells to secrete HBeAg. People can be infected with the HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge later in the course of infection in people initially infected with the HBeAg-positive form of the virus.
HBeAg seroconversion
HBeAg seroconversion occurs when people infected with the HBeAg-positive form of the virus develop antibodies against the ‘e’ antigen. The seroconverted disease state is referred to as the ‘inactive HBV carrier state’ when HBeAg has been cleared, anti-HBe is present and HBV DNA is undetectable or less than 2000 IU/ml. Once seroconversion has taken place, most people remain in the inactive HBV carrier state (the immune-control phase; see figure 1). However, increasing HBV DNA and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus (the immune-escape phase; see figure 1).
Key priorities for implementation
The following recommendations have been identified as priorities for implementation.
Assessment and referral
Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease
- Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-positive chronic hepatitis B and compensated liver disease[1].
- Offer tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a.
- Offer entecavir as an alternative second-line treatment to people who cannot tolerate tenofovir disoproxil or if it is contraindicated.
Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease
- Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-negative chronic hepatitis B and compensated liver disease[1].
- Offer entecavir or tenofovir disoproxil as second-line treatment to people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.
Women who are pregnant or breastfeeding
Prophylactic treatment during immunosuppressive therapy
1. Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
The wording used in the recommendations in this guideline (for example, words such as ‘offer’ and ‘consider’) denotes the certainty with which the recommendation is made (the strength of the recommendation). See About this guideline for details.
In this guideline, children and young people are defined as aged up to 18 years. Please follow the recommendations for women who are pregnant for young people with chronic hepatitis B who are pregnant.
1.1. Patient information
1.1.1.Provide information on the following topics to people with chronic hepatitis B and to family members or carers (if appropriate) before assessment for antiviral treatment:
- the natural history of chronic hepatitis B, including stages of disease and long-term prognosis
- lifestyle issues such as alcohol, diet and weight
- family planning
- monitoring
- routes of hepatitis B virus (HBV) transmission
- the benefits of antiviral treatment, including reduced risk of serious liver disease and death and reduced risk of transmission of HBV to others
- treatment options and contraindications based on the patient’s circumstances, including peginterferon alfa-2a and nucleoside or nucleotide analogues
- short- and long-term treatment goals
- causes of treatment failure, including non-adherence to prescribed medicines, and options for re-treatment
- risks of treatment, including adverse effects and drug resistance.
1.1.2.Offer a copy of the personalised care plan to people with chronic hepatitis B and to family members or carers (if appropriate) outlining proposed treatment and long-term management, for example, a copy of the hospital consultation summary.
1.1.3.Provide information on self-injection techniques to people beginning peginterferon alfa-2a or to family members or carers.
1.1.4.NICE has produced public health guidance on ways to promote and offer testing to people at increased risk of infection with hepatitis B. All healthcare professionals should follow the recommendations in Hepatitis B and C: ways to promote and offer testing to people at increased risk of infection (NICE public health guidance 43).
1.1.5.NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in Patient experience in adult NHS services (NICE clinical guidance 138).
1.2. Assessment and referral in primary care
Adults who are HBsAg positive
1.2.1.Arrange the following tests in primary care for adults who are hepatitis B surface antigen (HBsAg) positive:
- hepatitis B e antigen (HBeAg)/antibody (anti-HBe) status
- HBV DNA level
- IgM antibody to hepatitis B core antigen (anti-HBc lgM)
- hepatitis C virus antibody (anti-HCV)
- hepatitis delta virus antibody (anti-HDV)
- HIV antibody (anti-HIV)
- lgG antibody to hepatitis A virus (anti-HAV)
- additional laboratory tests including alanine aminotransferase (ALT) or aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum albumin, total bilirubin, total globulins, full blood count and prothrombin time
- tests for hepatocellular carcinoma (HCC), including hepatic ultrasound and alpha-fetoprotein testing.
1.2.2.Refer all adults who are HBsAg positive to a hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.
1.2.3.Include the results of the initial tests with the referral (see recommendation 1.2.1).
Pregnant women who test HBsAg positive at antenatal screening
1.2.4.Refer pregnant women who are HBsAg positive to a hepatologist, or to a gastroenterologist or infectious disease specialist with an interest in hepatology, for assessment within 6 weeks of receiving the screening test result and to allow treatment in the third trimester (see recommendation 1.5.39).
Adults with decompensated liver disease
1.2.5.Refer adults who develop decompensated liver disease immediately to a hepatologist or to a gastroenterologist with an interest in hepatology. Symptoms of decompensated liver disease include (but are not limited to) ascites, encephalopathy and gastrointestinal haemorrhage.
Children and young people who are HBsAg positive
1.2.6.Arrange the following tests for children and young people who are HBsAg positive as part of hepatitis B diagnosis:
- HBeAg/anti-HBe status
- HBV DNA level
- anti-HBc lgM
- anti-HCV
- anti-HDV
- anti-HIV
- anti-HAV
- additional laboratory tests, including ALT or AST, GGT, serum albumin, total bilirubin, total globulins, full blood count and prothrombin time
- tests for HCC, including hepatic ultrasound and alpha-fetoprotein testing.
1.2.7.Refer all children and young people who are HBsAg positive to a paediatric hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.
1.2.8.Include the results of the initial tests with the referral (see recommendation 1.2.6).
1.3. Assessment of liver disease in secondary specialist care
Adults with chronic hepatitis B
Please refer to recommendations 1.5.3 to 1.5.7 for detailed guidance on offering antiviral treatment.
1.3.1.Ensure all healthcare professionals who refer adults for non-invasive tests for liver disease are trained to interpret the results and aware of co-factors that influence liver elasticity (for example, fatty liver caused by obesity or alcohol misuse).
1.3.2.Discuss the accuracy, limitations and risks of the different tests for liver disease with the patient.
1.3.3.Offer transient elastography as the initial test for liver disease in adults newly referred for assessment in hepatitis B diagnosis.
1.3.4.Offer antiviral treatment without a liver biopsy to adults with a transient elastography score greater than or equal to 11 kPa[4], in line with recommendation 1.5.6.
1.3.5.Consider liver biopsy to confirm the level of fibrosis in adults with a transient elastography score between 6 and 10 kPa[5]. Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7.
1.3.6.Offer liver biopsy to adults with a transient elastography score less than 6 kPa if they are younger than 30 years and have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart[6]. Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7.
1.3.7.Do not offer liver biopsy to adults with a transient elastography score less than 6 kPa who have normal ALT (less than 30 IU/L in males and less than 19 IU/L for females) and HBV DNA less than 2000 IU/ml as they are unlikely to have advanced liver disease or need antiviral treatment (see recommendations 1.5.3 to 1.5.7)[7].
1.3.8.Offer an annual reassessment of liver disease using transient elastography to adults who are not taking antiviral treatment.
Children and young people with chronic hepatitis B
1.3.9.Discuss the accuracy, limitations and risks of liver biopsy in determining the need for antiviral treatment with the child or young person and with parents or carers (if appropriate).
1.3.10.Consider liver biopsy to assess liver disease and the need for antiviral treatment in children and young people with HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart. Offer biopsy under a general anaesthetic to children who are too young to tolerate the procedure under a local anaesthetic.
1.4. Genotype testing
1.4.1.Do not offer genotype testing to determine initial treatment in people with chronic hepatitis B.
1.5. Antiviral treatment
Adults with chronic hepatitis B
Recommendations 1.5.8 to 1.5.12 are reproduced from existing NICE technology appraisals on options for the treatment of chronic hepatitis B, and 1.5.13 to 1.5.15 update guidance in NICE technology appraisal 96[7]. The GDG has reviewed the evidence and has made recommendations on treatment sequences and combination drug regimens (see recommendations 1.5.16 to 1.5.28).
Recommendations 1.5.8 to 1.5.43 do not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or HIV.
1.5.1.Discuss treatment options, adverse effects and long-term prognosis with the patient before starting treatment.
1.5.2.Re-assess the person’s risk of exposure to HIV before starting treatment and offer repeat testing if needed.
1.5.3.Offer antiviral treatment to adults aged 30 years and older who have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart.
1.5.4.Offer antiviral treatment to adults younger than 30 years who have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart if there is evidence of necroinflammation or fibrosis on liver biopsy or a transient elastography score greater than 6 kPa.
1.5.5.Offer antiviral treatment to adults who have HBV DNA greater than 20,000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart regardless of age or the extent of liver disease.
1.5.6.Offer antiviral treatment to adults with cirrhosis and detectable HBV DNA, regardless of HBeAg status, HBV DNA and ALT levels.
1.5.7.Consider antiviral treatment in adults with HBV DNA greater than 2000 IU/ml and evidence of necroinflammation or fibrosis on liver biopsy.
1.5.8.Peginterferon alfa-2a is recommended as an option for the initial treatment of adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative), within its licensed indications. [This recommendation is from Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B (NICE technology appraisal guidance 96).]
1.5.9.Entecavir, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. [This recommendation is from Entecavir for the treatment of chronic hepatitis B (NICE technology appraisal guidance 153).]
1.5.10.Tenofovir disoproxil, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. [This recommendation is from Tenofovir disoproxil fumarate for the treatment of hepatitis B (NICE technology appraisal guidance 173).]
1.5.11.Telbivudine is not recommended for the treatment of chronic hepatitis B. [This recommendation is from Telbivudine for the treatment of chronic hepatitis B (NICE technology appraisal guidance 154).]
1.5.12.People currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop. [This recommendation is from Telbivudine for the treatment of chronic hepatitis B (NICE technology appraisal guidance 154).]
1.5.13.Do not offer adefovir dipivoxil for treatment of chronic hepatitis B.
1.5.14.People currently receiving adefovir dipivoxil should be offered the option to switch to a different treatment. Offer tenofovir disoproxil or entecavir, depending on previous antiviral exposure:
- offer tenofovir disoproxil to people with a history of lamivudine resistance.
1.5.15.Antiviral treatment should be initiated only by an appropriately qualified healthcare professional with expertise in the management of viral hepatitis. Continuation of therapy under shared-care arrangements with a GP is appropriate.
Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease
1.5.16.Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-positive chronic hepatitis B and compensated liver disease[8].
1.5.17.Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and/or if HBsAg is greater than 20,000 IU/ml, and offer second-line treatment in line with recommendations 1.5.18 and 1.5.19.
1.5.18.Offer tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a.
1.5.19.Offer entecavir as an alternative second-line treatment to people who cannot tolerate tenofovir disoproxil or if it is contraindicated.
1.5.20.Review adherence in people taking tenofovir disoproxil who have detectable HBV DNA at 48 weeks of treatment and, if appropriate, provide support in line with Medicines adherence (NICE clinical guidance 76).
- If HBV DNA remains detectable at 96 weeks, and there is no history of lamivudine resistance, consider adding lamivudine to tenofovir disoproxil.
- In people with a history of lamivudine resistance, consider adding entecavir to tenofovir disoproxil.
1.5.21.Consider stopping nucleoside or nucleotide analogue treatment 12 months after HBeAg seroconversion in people without cirrhosis.
1.5.22.Do not stop nucleoside or nucleotide analogue treatment 12 months after HBeAg seroconversion in people with cirrhosis.
Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease
1.5.23.Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-negative chronic hepatitis B and compensated liver disease[8].
1.5.24.Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and HBsAg has not decreased, and consider second-line treatment in line with recommendation 1.5.25.
1.5.25.Offer entecavir or tenofovir disoproxil as second-line treatment to people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.
1.5.26.Consider switching from tenofovir disoproxil to entecavir, or from entecavir to tenofovir disoproxil, as third-line treatment in people who have detectable HBV DNA at 48 weeks of treatment.
1.5.27.Consider stopping nucleoside or nucleotide analogue treatment 12 months after achieving undetectable HBV DNA and HBsAg seroconversion in people without cirrhosis.
1.5.28.Do not stop nucleoside or nucleotide analogue treatment after achieving undetectable HBV DNA and HBsAg seroconversion in patients with cirrhosis.
Children and young people with chronic hepatitis B and compensated liver disease
1.5.29.Discuss treatment options, adverse effects and long-term prognosis with the child or young person and with parents or carers (if appropriate) before starting treatment.
1.5.30.Re-assess the child or young person’s risk of exposure to HIV before starting treatment and offer repeat testing if necessary.
1.5.31.Offer antiviral treatment if there is evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart.
1.5.32.Consider a 48-week course of peginterferon alfa-2a as first-line treatment in children and young people with chronic hepatitis B and compensated liver disease[8],[9].
1.5.33.Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and/or if HBsAg is greater than 20,000 IU/ml.
1.5.34.Consider a nucleoside or nucleotide analogue as second-line treatment in children and young people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a[10].
Adults with decompensated liver disease
1.5.35.Manage decompensated liver disease in adults in conjunction with a liver transplant centre.
1.5.36.Do not offer peginterferon alfa-2a to people with chronic hepatitis B and decompensated liver disease.
1.5.37.Offer entecavir as first-line treatment in people with decompensated liver disease if there is no history of lamivudine resistance.
- Offer tenofovir disoproxil to people with a history of lamivudine resistance.
- Reduce the dose of tenofovir disoproxil in people with renal impairment, in line with guidance in the summary of product characteristics.
Women who are pregnant or breastfeeding
1.5.38.Discuss with pregnant women the benefits and risks of antiviral treatment for them and their baby.
1.5.39.Offer tenofovir disoproxil to women with HBV DNA greater than 107 IU/ml in the third trimester to reduce the risk of transmission of HBV to the baby[11].
1.5.40.Monitor quantitative HBV DNA 2 months after starting tenofovir disoproxil and ALT monthly after the birth to detect postnatal HBV flares in the woman.
1.5.41.Stop tenofovir disoproxil 4 to 12 weeks after the birth unless the mother meets criteria for long-term treatment (see recommendations 1.5.4 to 1.5.8).
1.5.42.Offer active and passive hepatitis B immunisation in infants and follow up in line with the guidance below:
1.5.43.Advise women that there is no risk of transmitting HBV to their babies through breastfeeding if guidance on hepatitis B immunisation has been followed, and that they may continue antiviral treatment while they are breastfeeding.
Adults who are co-infected with hepatitis C
1.5.44.Offer peginterferon alfa and ribavirin in adults co-infected with chronic hepatitis B and C[8].
Adults who are co-infected with hepatitis D
1.5.45.Offer a 48-week course of peginterferon alfa-2a in people co-infected with chronic hepatitis B and hepatitis delta infection who have evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3)[8].
1.5.46.Consider stopping peginterferon alfa-2a if there is no decrease in HDV RNA after 6 months to 1 year of treatment. Otherwise, continue treatment and re-evaluate treatment response annually.
1.5.47.Stop treatment after HBsAg seroconversion.
Prophylactic treatment during immunosuppressive therapy
1.5.48.Perform the following tests in people who are HBsAg and/or anti-HBc positive before starting immunosuppressive therapy for autoimmune or atopic diseases, chemotherapy, bone marrow or solid organ transplantation:
- antibody to hepatitis B surface antigen (anti-HBs)
- plasma or serum HBV DNA level
- ALT.
1.5.49.In people who are HBsAg positive and have HBV DNA greater than 2000 IU/ml, offer prophylaxis with entecavir or tenofovir disoproxil[12].
- Start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after HBeAg seroconversion and HBV DNA is undetectable.
1.5.50.In people who are HBsAg positive and have HBV DNA less than 2000 IU/ml, offer prophylaxis.
- Consider lamivudine[12] if immunosuppressive therapy is expected to last less than 6 months. -Monitor HBV DNA monthly in people treated with lamivudine and change to tenofovir disoproxil if HBV DNA remains detectable after 3 months.
- Consider entecavir or tenofovir disoproxil[12] if immunosuppressive therapy is expected to last longer than 6 months.
- Start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.
1.5.51.In people who are HBsAg negative and anti-HBc positive (regardless of anti-HBs status) and are starting rituximab or other B cell-depleting therapies:
- offer prophylaxis with lamivudine[12]
- start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.
1.5.52.In people who are HBsAg negative, anti-HBc positive and anti-HBs negative and are not taking rituximab or other B cell-depleting therapies:
1.5.53.Do not offer prophylaxis to people who are HBsAg negative and anti-HBc and anti-HBs positive who are not taking rituximab or other B cell-depleting therapies.
1.6. Monitoring
Monitoring in people who do not meet criteria for antiviral treatment
Further information on the progression of chronic hepatitis B can be found in the Introduction (see Figure 1).
Adults with HBeAg-positive disease in the immune-tolerant and immune clearance phases
1.6.1.Monitor ALT levels every 24 weeks in adults with HBeAg-positive disease who are in the immune-tolerant phase (defined by active viral replication and normal ALT levels [less than 30 IU/L in males and less than 19 IU/L in females]).
1.6.2.Monitor ALT every 12 weeks on at least 3 consecutive occasions if there is an increase in ALT levels.
Adults with inactive chronic hepatitis B (immune-control phase)
1.6.3.Monitor ALT and HBV DNA levels every 48 weeks in adults with inactive chronic hepatitis B infection (defined as HBeAg negative on 2 consecutive tests with normal ALT [less than 30 IU/L in males and less than 19 IU/L for females] and HBV DNA less than 2000 IU/ml).
- Consider monitoring more frequently (for example, every 12–24 weeks) in people with cirrhosis who have undetectable HBV DNA.
Children and young people
1.6.4.Monitor ALT levels every 24 weeks in children and young people with HBeAg-positive disease who have normal ALT levels (less than 30 IU/L for males and less than 19 IU/L for females) and no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3).
1.6.5.Review annually children and young people with HBeAg-negative disease who have normal ALT (less than 30 IU/L for males and less than 19 IU/L for females), no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3) and HBV DNA less than 2000 IU/ml.
1.6.6.Review every 12 weeks children and young people with HBeAg-negative disease who have abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) and HBV DNA greater than 2000 IU/ml.
Children, young people and adults with HBeAg or HBsAg seroconversion after antiviral treatment
1.6.7.In people with HBeAg seroconversion after antiviral treatment, monitor HBeAg, anti-HBe, HBV DNA level and liver function at 4, 12 and 24 weeks after HBeAg seroconversion and then every 6 months.
1.6.8.Monitor HBsAg and anti-HBs annually in people with HBsAg seroconversion after antiviral treatment and discharge people who are anti-HBs positive on 2 consecutive tests.
Monitoring in people taking antiviral treatment
Children, young people and adults taking peginterferon alfa-2a
1.6.9.Review injection technique and adverse effects weekly during the first month of treatment in people taking peginterferon alfa-2a[10].
1.6.10.Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels) and thyroid function (and in children, weight and height) before starting peginterferon alfa-2a and 2, 4, 12, 24, 36 and 48 weeks after starting treatment to detect adverse effects[10].
1.6.11.Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting peginterferon alfa-2a at 12, 24 and 48 weeks after starting treatment to determine treatment response[10].
Children, young people and adults with compensated liver disease taking entecavir or lamivudine
1.6.12.Monitor full blood count, liver function (including bilirubin, albumin and ALT) and renal function (including urea and electrolyte levels) in people with compensated liver disease before starting entecavir or lamivudine, 4 weeks after starting treatment and then every 3 months to detect adverse effects[10].
1.6.13.Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting entecavir or lamivudine, 12, 24 and 48 weeks after starting treatment and then every 6 months to determine treatment response and medicines adherence[10].
1.6.14.Monitor HBV DNA levels every 12 weeks in people with HBeAg-negative disease who have been taking lamivudine for 5 years or longer[10].
Children, young people and adults with compensated liver disease taking tenofovir disoproxil
1.6.15.Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), and phosphate levels in people with compensated liver disease before starting tenofovir disoproxil, 4 weeks after starting treatment and then every 3 months to detect adverse effects[10].
1.6.16.Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting tenofovir disoproxil, 12, 24 and 48 weeks after starting treatment and then every 6 months to determine treatment response and medicines adherence[10].
Children, young people and adults with decompensated liver disease who are taking entecavir or lamivudine
1.6.17.Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting entecavir or lamivudine and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in ‘Children, young people and adults with compensated liver disease taking entecavir or lamivudine’[10].
Children, young people and adults with decompensated liver disease who are taking tenofovir disoproxil
1.6.18.Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio) and phosphate, blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting tenofovir disoproxil and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in ‘Children, young people and adults with compensated liver disease taking tenofovir disoproxil’[10].
1.7. Surveillance testing for hepatocellular carcinoma in adults with chronic hepatitis B
1.7.1.Perform 6-monthly surveillance for HCC by hepatic ultrasound and alpha-fetoprotein testing in people with significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or cirrhosis.
1.7.2.In people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3), consider 6-monthly surveillance for HCC if the person is older than 40 years and has a family history of HCC and HBV DNA greater than or equal to 20,000 IU/ml.
1.7.3.Do not offer surveillance for HCC in people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3) who have HBV DNA less than 20,000 IU/ml and are younger than 40 years.
More information
You can also see this guideline in the NICE pathway on hepatitis B (chronic).
To find out what NICE has said on topics related to this guideline, see our web page on hepatitis.
See also the guideline committee’s discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee.
2. Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
2.1. Stopping antiviral treatment in HBeAg-negative disease
Further research should be undertaken to evaluate the clinical and cost effectiveness of hepatitis B surface antigen (HBsAg) quantitative assays in determining treatment duration in hepatitis B e antigen- (HBeAg) negative disease.
Why this is important
In HBeAg-positive disease, HBeAg seroconversion is a predictor of durable response to antiviral treatment and can be used as a milestone after which treatment can be stopped. At present, similar parameters have not been defined in HBeAg-negative disease. Quantitative HBsAg may have a role in determining treatment duration in this setting. Establishing threshold levels for HBsAg titre associated with durable off-treatment control in HBeAg-negative disease would transform current treatment strategies. People on long-term nucleoside or nucleotide analogues could safely stop treatment once they achieved a threshold level of HBsAg. Further research is needed to define these levels of HBsAg and to determine when treatment in HBeAg-negative disease can be safely stopped.
2.2. ALT values for children and young people
Further research should be undertaken to examine whether the upper limit of normal ALT values for adults (below 30 IU/L for males and below 19 IU/L for females) are appropriate for use in children and young people with chronic hepatitis B when making decisions on when to initiate treatment.
Why this is important
Recent studies have highlighted the imprecision of using biochemical activity as a measure of immune activity in children and young people with chronic hepatitis B. Researchers have found T-cell exhaustion and even HBV-specific immune responses in children and young people considered to have immune-tolerant disease. These findings need to be validated in larger studies to see if upper limit of normal ALT values derived from adults accurately reflect disease activity in children and young people. Further research is needed to investigate whether there is a genuine state of immune tolerance in children and young people reflected in lower levels of biochemical activity and a lower upper limit of normal ALT value.
2.3. Long-term safety of tenofovir disoproxil in chronic hepatitis B
Further research should be undertaken to determine the long-term safety of tenofovir disoproxil, including the risk of clinically significant hypophosphataemia and related bone toxicity, in people with chronic hepatitis B. The cost effectiveness of routine monitoring for phosphate loss and bone disease in people with chronic hepatitis B who are receiving tenofovir disoproxil treatment needs further evaluation.
Why this is important
Tenofovir disoproxil is recommended as an option for treatment of people with chronic hepatitis B, and is typically prescribed for long-term use. Kidney dysfunction has been reported in people treated with tenofovir disoproxil, including rare cases of proximal renal tubular dysfunction that appear related to long-term exposure but are not well understood. Adverse renal effects such as hypophosphataemia may have an impact on bone architecture which could result in clinical problems such as fragility fractures. Monitoring for phosphate loss and bone disease could have a role in preventing clinically significant bone problems in people with chronic hepatitis B receiving long-term tenofovir disoproxil. However, the cost effectiveness and clinical utility of routine monitoring needs to be established before recommendations can be made about its use.
2.4. Prophylactic treatment in people receiving immunosuppressive therapy
Further research should be undertaken to determine whether long-term use of mild immunosuppressive agents for autoimmune and allergic problems presents a risk for reactivation of HBV infection in people with previous or current chronic hepatitis B, including occult HBV infection. The cost effectiveness of routine tests for HBV in this population, including HBV DNA for occult HBV infection, and the need for prophylactic treatment with nucleoside or nucleotide analogues needs further evaluation.
Why this is important
Reactivation of HBV may occur spontaneously or arise during immunosuppression. Solid organ transplantation, chemotherapy and immunosuppressive drugs used to treat autoimmune diseases are key causes of HBV reactivation. Antiviral agents can be used as prophylaxis to prevent reactivation of HBV infection in people receiving immunosuppressive therapy but the optimal treatment and duration of therapy are unknown. Decision-making and cost-effectiveness studies are needed to determine optimal screening strategies to identify people at risk of HBV reactivation. People with occult HBV (including people coming from high endemicity regions) might carry a low, but not negligible, risk of viral reactivation. Prospective studies are needed to assess the risk of HBV reactivation in people receiving mild immunosuppressants or biological treatment for autoimmune diseases, to identify risk factors that predict HBV reactivation in this population, and evaluate treatment or pre-emptive strategies using existing nucleoside and nucleotide analogues.
Update information
October 2017: A footnote was changed to update the information on UK marketing authorisations for entecavir.
January 2014: A correction has been made to the units used for abnormal alanine aminotransferase (ALT) in men and women. The abnormal ALT levels should read greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females, not IU/ml. This has been changed in recommendations 1.3.6, 1.3.7, 1.3.10, 1.5.3–5, 1.5.31, 1.6.1, 1.6.3–6, and 2.2.
June 2013: Recommendations 1.5.13 to 1.5.15 in this guideline update and replace recommendations 1.2 to 1.4 on the use of adefovir dipivoxil for treating chronic hepatitis B in Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B (NICE technology appraisal guidance 96). NICE technology appraisal guidance 153, 154, 173 and recommendation 1.1 of NICE technology appraisal guidance 96 have been incorporated into this guideline and remain extant.
Footnotes
[1]Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
[2]At the time of publication (June 2013), tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
[3]At the time of publication (June 2013), entecavir, lamivudine and tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
[4]Adults with a transient elastography score greater than or equal to 11 kPa are very likely to have cirrhosis and confirmation by liver biopsy is not needed.
[5]The degree of fibrosis cannot be accurately predicted in adults with a transient elastography score between 6 to 10 kPa. Some people may choose to have a liver biopsy in these circumstances to confirm the extent of liver disease.
[6]Adults with a transient elastography score less than 6 kPa are unlikely to have significant fibrosis.
[7]Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B (NICE technology appraisal guidance 96), Entecavir for the treatment of chronic hepatitis B (NICE technology appraisal guidance 153), Telbivudine for the treatment of chronic hepatitis B (NICE technology appraisal guidance 154) and Tenofovir disoproxil fumarate for the treatment of hepatitis B (NICE technology appraisal guidance 173).
[8]Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
[9]At the time of publication (June 2013), peginterferon alfa-2a did not have a UK marketing authorisation for use in children for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
[10]At the time of last review (October 2017), peginterferon alfa-2a did not have a UK marketing authorisation for use in children for this indication, tenofovir disoproxil did not have a UK marketing authorisation for use in children younger than 12 years for this indication and entecavir did not have a UK marketing authorisation for use in children younger than 2 years for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
[11]At the time of publication (June 2013), tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
[12]At the time of publication (June 2013), entecavir, lamivudine and tenofovir disoproxil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
Your responsibility: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.
Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.
Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.
Created: June 26, 2013; Last Update: October 2017.
