Coffin CS, Fung SK, Alvarez F, et al. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada. Can Liv J. 2018:1(4):156-217. doi: 10.3138/canlivj.2018-0008. Published December 1, 2018.
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. PMID: 29405329; PMCID: PMC5975958.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18. PMID: 28427875.
Terrault NA, Bzowej NH, Chang K-M, et al; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan;63(1):261-83. doi: 10.1002/hep.28156. Epub 2015 Nov 13. PMID: 26566064; PMCID: PMC5987259.
Definition, Etiology, PathogenesisTop
Chronic hepatitis B is a chronic (>6 months) liver disease that is characterized by necroinflammatory lesions caused by persistent hepatitis B virus (HBV) infection (see Acute Hepatitis B). HBV DNA can integrate into the host’s genome of hepatocytes and other cells and may also be present in the form of HBV covalently closed circular DNA (cccDNA) that is capable of HBV replication. Chronic HBV infection can cause hepatocellular carcinoma (HCC) with or without cirrhosis.
Clinical Features and Natural HistoryTop
1. Signs and symptoms: Early disease is usually asymptomatic, and most patients have no symptoms for a long time. If symptoms occur early, they may include fatigue (most common) and depressed mood (relatively frequent). Developing manifestations may include:
1) Potentially mild hepatomegaly and in more severe cases moderate jaundice (constant or intermittent).
2) Presentations in some patients are due to:
a) Cirrhosis and portal hypertension (causing splenomegaly and other symptoms).
b) Extrahepatic complications caused by immune complexes: Polyarteritis nodosa, leukocytoclastic vasculitis, glomerulonephritis, and polymyalgia rheumatica.
2. Natural history can be separated into distinct phases during which hepatitis B surface antigen (HBsAg) is positive and anti-HBs antibody is negative until phase 5 (this employs the new nomenclature for describing chronic states as used in the 2017 European Association for the Study of the Liver [EASL] guidelines):
1) Phase 1 (previously labeled “immune tolerant”): Chronic HBV infection, positive HBeAg. HBV DNA is present in high concentrations, alanine aminotransferase (ALT) is normal, and there is minimal fibrosis and inflammation.
2) Phase 2 (previously “immune active”): Chronic HBV infection, positive HBeAg. HBV DNA levels are declining, ALT is elevated, and inflammation, necrosis, and fibrosis of varying severity occur. The clinical evolution may include seroconversion with clearance of HBeAg and production of anti-HBe antibodies (although in some patients HBeAg reversion may occur). If seroconversion does not occur, inflammation, necrosis, and fibrosis continue to progress.
3) Phase 3 (previously “inactive HBV carrier”): Chronic HBV infection, negative HBeAg. Anti-HBe antibodies are present, HBV DNA levels are low, and ALT decreases. Improved immune control signifies a better prognosis in patients without cirrhosis.
4) Phase 4 (previously “HBeAg-negative chronic hepatitis B”): Chronic HBV infection, negative HBeAg. The levels of HBV DNA and ALT fluctuate and liver damage progresses. This is usually related to the development of a mutation allowing the virus to escape anti-HBe control.
5) Phase 5: Negative HBsAg. This phase is also referred to as “occult hepatitis.” It occurs if HBsAg is cleared (occurring spontaneously in <1% of phase 4 patients per year) and anti-HBs antibody may appear. Phase 5 signifies functional cure (persistent HBV cccDNA remains in the liver).
Treatment is indicated in phases 2 and 4 (as opposed to all infection phases).
1. Laboratory and serologic tests include hepatitis B surface antigen (HBsAg, positive in phases 1-4), hepatitis B surface antibody (HBsAb) (may be positive in phase 5), hepatitis B e antigen (HBeAg, positive in phases 1-2), anti-HBe antibody, and serum aminotransferase levels. In patients with more advanced disease, intermittent or constant mixed hyperbilirubinemia may be observed.
2. Virologic tests: Measurements of serum HBV DNA levels (polymerase chain reaction [PCR]) and quantitative assessment of HBsAg (in Canada available for research purposes only) allow for the evaluation of viral replication (viral load).
3. Fibrosis assessment: Liver biopsy with histologic examination of specimens may be indicated in patients meeting the criteria of chronic hepatitis. This includes evaluation of liver injury (characterized by periportal mononuclear cell infiltrates, hepatocyte necrosis, and fibrosis) and allows for the exclusion of other causes of the disease. Noninvasive testing, such as FibroScan and FibroTest, may be used instead if only fibrosis assessment is required.
Differential diagnosis for elevated liver enzymes includes:
1) Acute hepatitis, chronic hepatitis C, coinfection with hepatitis D virus.
2) Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis.
3) Drug-induced liver injury, alcoholic liver disease, nonalcoholic fatty liver disease.
4) Wilson disease, hemochromatosis, alpha1-antitrypsin deficiency.
Abstinence or minimal consumption of alcohol (alcohol increases liver injury and accelerates progression to cirrhosis). Hepatitis A vaccination in patients susceptible to hepatitis A virus infection. There are no contraindications to work or regular daily activities including sports, unless the presence of blood-borne infection precludes specific activities (eg, some medical exposure-prone procedures).
1. The objective of antiviral treatment is sustained suppression of HBV replication, with the ultimate ideal goal of HBsAg clearance to prevent the development of cirrhosis and HCC. Specific treatment objectives depend on the phase and severity of the disease:
1) In chronic hepatitis without cirrhosis, the objective is regression of fibrosis and reduction of inflammation and necrosis.
2) In compensated cirrhosis, delaying the progression to decompensated cirrhosis and possible reduction of fibrosis to a noncirrhotic stage after prolonged antiviral therapy.
3) In patients with decompensated cirrhosis and contraindications to liver transplant, the objective is to prolong survival and revert to compensated cirrhosis.
2. Intermediate treatment objectives:
1) Normalization of levels of biochemical markers of hepatitis.
2) In HBeAg-positive patients, seroconversion to anti-HBe.
3. Qualification for treatment of both HBeAg-positive and HBeAg-negative patients in general requires documented positive HBsAg for ≥6 months, detectable HBV DNA, and fulfilment of ≥2 out of the 3 following criteria, according to guidelines from the EASL and the Canadian Association for the Study of the Liver (CASL):
1) HBV DNA >2000 IU/mL (~10,000 copies/mL).
2) Serum ALT levels > upper limit of normal (ULN).
3) Histologic features of at least moderate liver necroinflammation or fibrosis in a liver biopsy specimen or significant fibrosis detected with noninvasive fibrosis testing. Patients with decompensated cirrhosis and detectable HBV DNA should initiate treatment promptly, regardless of the HBV DNA level, HBeAg status, or ALT level. Treatment decisions are usually made in specialized settings and may differ in specific jurisdictions.
Another group of patients who should be evaluated for treatment are those who are planned for cancer chemotherapy or immunosuppressive treatment and who are HBsAg-positive only or anti-HBc–positive only regardless of HBV DNA presence. Antiviral treatment should be given prior to initiating chemotherapy or immunosuppressive treatment in HBsAg-positive patients, especially those with positive HBV DNA titer.
Pregnant HBsAg-positive mothers should be evaluated before the third trimester. If HBV DNA is >200,000 IU/mL, antiviral therapy should be started, ideally by 28 weeks’ gestation. In addition, hepatitis B immunoglobulin (passive immunization) and neonatal hepatitis B vaccination (active immunization) should be given to the newborn within 12 hours of life. Physicians should also ensure the remainder of neonatal vaccinations are completed at 1 and 6 months of life to minimize the risk of vertical transmission from mother to child.
4. Treatment endpoint:
1) The ideal endpoint in both HBeAg-positive and HBeAg-negative individuals is functional cure, that is, sustained off-therapy HBsAg loss, with or without seroconversion to anti-HBs.
2) Induction of sustained off-therapy virologic suppression in both HBeAg-positive patients with sustained anti-HBe seroconversion and in HBeAg-negative patients is a satisfactory endpoint.
3) If sustained off-therapy response is not achievable, the next most desirable endpoint is maintained virologic remission, that is, undetectability of HBV DNA by a sensitive PCR assay under long-term antiviral therapy in HBeAg-positive patients who do not achieve anti-HBe seroconversion and in HBeAg-negative individuals.
1) This field is evolving. Current treatments usually focus on viral suppression. Oral nucleoside or nucleotide analogues (NAs) are typically used indefinitely (see below) and include adefovir (ADF) (now rarely used), entecavir (ETV), lamivudine (LAM), telbivudine (used predominantly in Asia), tenofovir (TDF), and tenofovir alafenamide (TAF). These drugs are generally well tolerated; nephrotoxicity may rarely occur with ADF and TDF. ETV, TDF, and TAF are used preferentially if resources permit. The use of LAM is limited by the emergence of resistant strains (up to over 50% within 5 years).
2) Subcutaneous pegylated interferon (PEG-IFN) alpha (this does not induce HBV resistance) for 48 weeks: Now used very rarely and reserved for patients who value the important advantage of receiving therapy of finite duration.
Contraindications: Autoimmune diseases (including untreated hyperthyroidism), major depression (resistant to treatment), severe heart failure, decompensated cirrhosis, prior organ transplant, thrombocytopenia (<100×109/L), and pregnancy. Not recommended in patients with extrahepatic manifestations of hepatitis B.
Adverse effects: Most commonly influenza-like symptoms, fatigue, loss of appetite, weight loss, and transient severe alopecia. Less common symptoms include myelosuppression (neutropenia, thrombocytopenia), anxiety, nervousness, and depression (including suicidal ideations).
6. Other treatment considerations: Ideally treatment with TDF, ETV, or TAF should be used, although access to therapy may dictate initial options. In Canada, certain provinces have mandated the use of LAM as first-line therapy despite the known high rate for genetic barrier of resistance. ETV should not be used in patients who had an inadequate response to LAM because of the considerably increased risk of developing resistance to ETV.
The duration of therapy in the majority of patients is indefinite, given the low incidence of achieving HBsAg clearance with currently available treatments. However, in HBeAg-positive patients who developed HBeAg loss and anti-HBe antibody positivity, after a minimum of 12 months of ongoing therapy a trial of discontinuation may be considered as long as careful serial monitoring is arranged and therapy is resumed in the setting of relapse or HBeAg reversion.
Current guidelines recommend that HBV carriers receiving or planned for cancer chemotherapy or immunosuppressive treatment should be given NA therapy continued for ≥12 months after completion of cancer treatment. The risk of HBV reactivation depends on the chemotherapy or immunosuppression regimen and treatment duration should be tailored accordingly.
1. Monitoring for HCC is usually done every 6 months (see Complications, below).
2. In patients not currently meeting the criteria for therapy, monitoring of liver function tests and liver enzymes (ALT) should be performed every 3 to 6 months and HBV DNA every 6 months. Ideally, evaluation of liver fibrosis should be updated every 1 to 3 years, depending on the HBeAg status and HBV DNA.
3. Monitoring of antiviral treatment:
1) Patients treated with PEG-IFN: After 1 week of treatment and then every 4 weeks monitor white blood cell, neutrophil, and platelet counts; if any of these falls below normal, reduce the dose of PEG-IFN or skip a dose. Severe leukopenia, neutropenia, or thrombocytopenia (<2% of patients) requires discontinuation of treatment. Measure ALT levels every 4 weeks as well as thyroid-stimulating hormone (TSH) and HBV DNA levels every 12 weeks. Assess the efficacy of treatment at 24 weeks and after the end of therapy.
2) Patients treated with NAs: Liver enzymes and liver function testing should be performed every 3 to 6 months and HBV DNA every 6 to 12 months. Renal function should also be checked every 6 to 12 months, and patients with worsening renal function (higher risk associated with ADF and TDF) should change agents to those with fewer renal adverse effects (TAF, ETV) or have dose adjustments based on their glomerular filtration rate if other treatment is not available.
1. Cirrhosis develops within 5 years in 8% to 20% of patients with chronic hepatitis B. Risk factors include intensive HBV replication; HCV, HDV, or HIV coinfection; middle-aged or elderly patients; male sex; frequent exacerbations; low ALT levels; and alcohol use.
2. HCC: The risk is highest among HBsAg-positive patients with cirrhosis (with the cumulative 5-year incidence up to 20%). In patients without cirrhosis, those of Asian or African descent traditionally are at higher risk compared with White populations. Other known factors include age, male sex, immunosuppression, close family members with HCC, high serum HBV DNA and high ALT, prolonged time to HBeAg seroconversion, concurrent viral infections, excessive alcohol use or smoking, and nonalcoholic steatohepatitis.
3. Diseases caused by immune complexes are rare and most frequently include glomerulonephritis, polyarteritis nodosa, or mixed cryoglobulinemia.
In patients with cirrhosis screening begins when the diagnosis of chronic hepatitis B is made. In Asian male patients, those with a family history of HCC, and those with HIV coinfection, screening should be started at the age of 40 years. In Asian female patients, the threshold for starting screening is 50 years. In patients of African descent, screening was previously recommended to start at the age of 20 years, but recently this has become a controversial recommendation.
Screening modality: Abdominal ultrasonography every 6 months remains the standard. Alpha-fetoprotein (AFP) is not advised as a stand-alone screening tool due to the lack of accuracy.
Serious complications (cirrhosis, liver failure, or HCC) develop in 15% to 40% of patients with chronic HBV infection. The 5-year mortality rate is 14% to 20% in patients with compensated cirrhosis and may be >80% in patients with decompensated cirrhosis.
As in acute hepatitis B.