Complications
Heightened immune response to hepatitis B virus (HBV) resulting in massive immune-mediated lysis of infected hepatocytes is thought to be the cause of fulminant hepatitis associated with acute infection.[30]
It occurs in <1% (around 0.1% to 0.5%) of cases of acute HBV. Co-infection with hepatitis C or D virus increases the risk of developing fulminant hepatitis.[185][186]
Referral for liver transplantation is essential to prevent morbidity and mortality.
Cirrhosis occurs in about 20% of patients with chronic hepatitis B virus (HBV) and is thought to be due to ongoing immune attack of infected cells in the liver, resulting in development of fibrosis and regenerative nodules.[31]
Risk factors associated with progression to cirrhosis include co-infection (with hepatitis C or D, and/or HIV), older age, high levels of HBV DNA, and habitual alcohol intake.[172]
Treatment can be initiated in most patients with chronic HBV infection and cirrhosis.
The incidence of hepatitis B virus (HBV)-related HCC has increased and accounts for 50% of all HCC worldwide.[173] HBV and hepatitis D virus (HDV) dual infection may increase the risk of HCC compared to HBV monoinfection.[174]
Screening for HCC should be started as suggested by the recommended guidelines.[2]
HCC associated with HBV infection is thought to result from chronic inflammation and cellular regeneration.[30] Cirrhosis seems to be the greatest risk factor for developing HCC, although 30% to 50% of HBV-related HCC occurs without cirrhosis.[175] Male sex, older age, diabetes mellitus, co-infection with HDV, co-infection with hepatitis C virus (HCV), core promoter mutation, family history of HCC, presence of hepatitis B surface antigen (HBsAg), and high levels of HBV DNA are risk factors for the development of HCC.[176][177][178][179][180]
Liver transplantation can be considered in the early stages, with small HCC without any evidence of metastasis. Non-curative therapies, such as transarterial chemo-embolisation (TACE), transarterial radio-embolisation (TARE), and systemic chemotherapy/immunotherapy, aim to slow tumour progression and consequently prolong survival.
Hepatitis B virus (HBV)-related glomerulonephritis is not a common complication of HBV infection, and the cause of glomerulonephritis in HBV infection is controversial.
The optimal therapy is also not well defined.
Reactivation is emerging as an important cause of morbidity and mortality in patients who have current or prior exposure to HBV infection, particularly in those who require immunosuppressive or biological therapies (including chemotherapy or immunotherapies), people with hepatitis C or D infection who are receiving antiviral therapy, and patients living with HIV.[181][182] Patients who are hepatitis B surface antigen (HBsAg)-positive with hepatocellular carcinoma (HCC) are at intermediate or high-risk of HBV reactivation, depending on the type of therapy used to treat HCC.[183]
Defined as a loss of HBV immune control in HBsAg‐positive/antibody to hepatitis B core antigen (anti‐HBc)-positive, or HBsAg‐negative/anti‐HBc-positive patients receiving immunosuppressive therapy for a concomitant medical condition. Diagnostic criteria include: (a) a rise in HBV DNA level compared to baseline (or an absolute level of HBV DNA when a baseline is unavailable); and (b) reverse seroconversion (seroreversion) from HBsAg-negative to HBsAg-positive for HBsAg‐negative/anti‐HBc-positive patients. Following reactivation, a hepatitis flare (indicated by an increase in alanine aminotransferase [ALT] level) can occur.[2]
Onset is variable; it can be up to 2 weeks after starting immunosuppressive therapy, or up to a year after ceasing immunosuppressive therapy. The risk of reactivation depends on multiple factors including host factors (e.g., older age, male sex, cirrhosis), virological factors (e.g., hepatitis B e antigen [HBeAg] status, HBV DNA level), and the type and degree of immunosuppressive therapy.[181]
Screening for HBsAg and anti-HBc (total or IgG) is recommended in patients before starting any immunosuppressive, cytotoxic, or immunomodulatory therapy.[2][184] Testing for HBV DNA is recommended before starting immunosuppressive therapy in HBsAg-negative and anti-HBc-positive individuals.[29]
Risk assessment for HBV reactivation and indication for antiviral prophylaxis is based on HBsAg, anti-HBc, and HBV DNA status, the planned immunosuppressive regimen, and the underlying disease requiring immunosuppressive treatment.[29]
[Figure caption and citation for the preceding image starts]: Hepatitis B virus (HBV) reactivation by immunosuppressive therapy groups. anti-HBc=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; TNF=tumor necrosis factorRajbhandari et al. BMJ 2025; 389: e079579; used with permission [Citation ends].
Antiviral prophylaxis is required in patients who are HBsAg-positive and are at high or moderate risk of reactivation. Patients who are HBsAg-positive and are at low risk of reactivation do not require prophylaxis if HBV DNA monitoring can be performed every 3 months. HBsAg-negative/anti-HBc-positive patients who are HBV DNA-positive can be managed in the same way as patients who are HBsAg-positive. HBsAg-negative/anti-HBc-positive patients who are HBV DNA-negative can receive antiviral prophylaxis if the immunosuppressive regimen is associated with a high risk of HBV reactivation, while those on a regimen with a low to moderate risk of reactivation do not require prophylaxis if they can be monitored closely (HBsAg status and/or HBV DNA level every 3 months).[29]
Antiviral prophylaxis should be started as soon as possible, continued during immunosuppressive therapy, and for at least 6-12 months (18 months in high-risk settings) after cessation of immunosuppressive therapy, depending on the type of therapy. Tenofovir disoproxil, tenofovir alafenamide, or entecavir are the preferred options.[2][29][184]
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