The hepatitis B surface antigen (HBsAg) burden may contribute to T-cell and B-cell exhaustion.
Insertion of hepatitis B hepatocellular DNA may contribute to the pathogenesis of hepatocellular carcinoma by driving downstream cellular transcription, or through expression of viral proteins, particularly HBV.
HBV generally causes a self-limiting illness in adults, and viral control is mediated primarily by the adaptive immune response.
In contrast, more than 90% of cases of perinatal infection develop into chronic infection.
The causal pathways to chronicity and immunopathogenesis reflects persistent viral replication that cannot be contained by the depleted and defective HBV-specific CD4 and CD8 T-cell response that is a result of high antigen-dose exhaustion and liver-tolerizing pathways, including inhibitory checkpoints regulatory cells, and metabolic dysfunction.
Antibodies against HBsAg are inadequately produced by dysfunctional HBsAg-specific B cells.
HBeAg-positive infection occurs predominantly in young persons.
Near-normal aminotransferase levels despite high levels of viremia (>7 log10 IU per milliliter) reflect the noncytopathic nature of HBV.
The absence of inflammation in this phase has been considered indicative of immunologic tolerance.
HBeAg-positive disease is characterized by elevated HBV DNA levels (typically 5 to 7 log10 IU per milliliter) and abnormal aminotransferase levels, with exacerbations leading to necroinflammation and hepatic fibrosis.
Spontaneous HBeAg seroconversion occurs in approximately 15% of cases per annum.
The transition to HBeAg-negative, inactive infection reduces the risk of progression, but the disease necessitates longitudinal monitoring.
HBeAg seroconversion, conversely, can augur a change to HBeAg-negative disease, with mutations in the precore or basal core promoter down-regulating HBeAg, despite continued HBV replication.
Spontaneous seroclearance of HBsAg has been associated with improved clinical outcomes but is infrequent, accounting for an estimated 1 to 2% of cases per year.
The annual incidence of hepatocellular carcinoma is low among patients without cirrhosis.
The annual incidence of hepatocellular carcinoma is increased, up to 10%, among those with cirrhosis.
There is a linear relationship between HBV DNA levels and the risks of cirrhosis and hepatocellular carcinoma among HBeAg-negative patients,
Among HBeAg-positive patients, the risk of cirrhosis and hepatocellular carcinoma is lower for those with HBV DNA levels exceeding 8 log10 IU per milliliter than for those with HBV DNA levels of 5 to 7 log10 IU per milliliter.
In HBeAg-positive patients with active disease, the infection is likely to be transitioning from a low inflammatory–high replicative state to a different immunologic phenotype and phase.
The transition is characterized by a decrease in HBV DNA levels and an increase in necroinflammatory damage, which lead to an increase in hepatocyte turnover (and to the gradual selection of HBeAg-negative variants).
HBsAg, HBeAg, anti-HBc (antibodies against hepatitis B core antigen [HBcAg]), and hepatitis B DNA are established markers of chronic hepatitis B.
Serologic assays for HBsAg detect virion and subviral particles in blood.
HBV has 10 listed genotypes and at least 24 subtypes.
HBV genotypes and subtypes influence clinical outcomes, including HBeAg and HBsAg seroconversion rates, mutational patterns in the precore and core promoter regions, the risks of cirrhosis and hepatocellular carcinoma, and the treatment response.
Improved outcomes associated with low HBV DNA levels (<2000 IU per milliliter), plus low HBsAg levels (<1000 IU per milliliter) and normal serum aminotransferase levels.
HBV DNA becomes the predominant source of HBsAg in HBeAg-negative infection.
Higher HBsAg levels increase the risk of hepatocellular carcinoma.
Increased levels of HBV RNA are present in HBeAg-positive infection.
The major guidelines base treatment on serum aminotransferase and HBV DNA levels and on the severity of liver disease.
A HBV DNA level of more than 2000 IU per milliliter is a strong predictor of cirrhosis and hepatocellular carcinoma.
Treatment for all patients with HBV DNA levels exceeding 2000 IU per milliliter confer circumvents the transition to active disease, reducing transcriptionally active integrations, and inducing a slow decline in the cccDNA pool and hepatic clone size to prevent hepatocellular carcinoma.
Treatment of young adults would also decrease sexual transmission, as well as vertical transmission from a mother to her infant.
The benefit may be smaller for those at lower risk, but any negative effect of prolonged antiviral therapy could in the future be mitigated by finite, curative treatment regimens.
The treatment options for chronic hepatitis B (CHB) include both immunomodulatory and antiviral therapies.
The primary goals of treatment are to prevent cirrhosis, liver decompensation, and hepatocellular carcinoma by suppressing HBV replication and achieving sustained virological response.
Immunomodulatory Therapy
1Interferon-alpha (IFN-α) and Pegylated Interferon-alpha (Peg-IFN-α):
Therapcan achieve hepatitis B e antigen (HBeAg) seroconversion in 20-30% of patients.
Nucleos(t)ide Analogues:
Lamivudine: Effective in suppressing HBV DNA but associated with high rates of resistance with up to 65% after 4 years.
Adefovir Dipivoxil: Effective against lamivudine-resistant strains but has a lower resistance rate compared to lamivudine.
Entecavir: Highly potent with a low resistance rate in treatment naive patients -<1% after 4 years.
Telbivudine: Effective but associated with resistance.
Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF): Highly effective with no reported resistance.
TDF and TAF are preferred due to their high genetic barrier to resistance.
Treatment of hepatitis B is generally recommended for patients with elevated aminotransferase levels (>2x ULN) and high serum HBV DNA levels (>20,000 IU/mL).
Combination therapy has not shown significant benefits over monotherapy in most cases.
Tenofovir, tenofovir alafenamide, and entecavir compete with the endogenous nucleotide substrate to bind the active site of the HBV polymerase, disrupting the 5′ to 3′ phosphodiester linkage and terminating DNA chain elongation.
Tenofovir alafenamide is a phosphoramidite prodrug of tenofovir.
Nucleoside analogues are safe and effective.
Decreases in renal function and bone mineral density may occur with tenofovir, which are lessened in trials of tenofovir alafenamide.
Current guidelines suggest a change to entecavir or tenofovir alafenamide for patients who are older than 60 years of age or have renal dysfunction.
Cholesterol and low-density lipoprotein levels increase with tenofovir alafenamide.
Weight gain has been reported with tenofovir.
The goals of treatment is to reduce HBV DNA to undetectable levels, normalize serum aminotransferase levels, and reduce inflammation and fibrosis.
Tenofovir reduces viremia in pregnant women in order to limit mother-to-child transmission of HBV.
Nucleoside analogues are used to treat fulminant hepatitis B and decompensated cirrhosis.
Other indications include prevention of HBV reactivation during immunosuppressive treatment.
Prevention of a recurrence after liver transplantation by means of preemptive nucleoside analogue treatment is now the rule.
Treatment complements HBV vaccination and safe sexual practices to reduce the risk of sexually transmitted HBV infection.
Nucleoside analogues target a late stage in the viral life cycle.
They act on the reverse-transcription step of formation of progeny virus but exert no direct effect on pgRNA transcription and do not directly affect HBsAg expression from integrated genomes.
HBeAg loss is uncommon (occurring in 20 to 30% of patients after 1 to 2 years), and HBsAg loss is rare.
The reported average incidence of HBsAg seroclearance is 0.22% per year, with a 10-year cumulative incidence of 2.11%.
HBsAg loss, if it occurs, improves outcomes.
Nucleoside analogues do not eliminate the risk of hepatocellular carcinoma.
Rports have suggested that reduction in the risk of new or recurrent hepatocellular carcinoma is greater with tenofovir than with entecavir.
Resistance to entecavir develops after 5 years in only 1% of previously untreated patients.
The management of chronic hepatitis B (CHB) involves antiviral therapy aimed at reducing morbidity and mortality by suppressing HBV replication, improving liver histology, and preventing complications such as cirrhosis and hepatocellular carcinoma (HCC).
Recommendation is for first-line treatment with nucleos(t)ide analogues (NAs) such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and entecavir due to their high efficacy and excellent safety profiles.
Pegylated interferon (Peg-IFN) is also an option, particularly for patients who prefer a finite duration of therapy.
NAs are generally preferred due to their better tolerability and lower risk of resistance. TDF and TAF are particularly favored for their potent antiviral activity and favorable safety profiles, especially in patients with renal impairment or bone disease.
Entecavir is another effective option, particularly in patients with decompensated cirrhosis.
Peg-IFN may be considered in younger patients with mild to moderate liver disease and those without contraindications to interferon therapy.
Peg-IFN offers the advantage of a finite treatment duration but is associated with more frequent side effects.
Monitoring of treatment response involves regular assessment of HBV DNA levels, liver function tests, and hepatitis B surface antigen (HBsAg) levels.
The treatment goal is to achieve sustained virological suppression, HBeAg seroconversion in HBeAg-positive patients, and ideally, HBsAg loss.
The management of CHB primarily involves the use of NAs such as TDF, TAF, and entecavir, with Peg-IFN as an alternative in selected patients.
Nucleoside analogues may be discontinued in HBeAg-negative patients to maintain a low replicative state off treatment and to trigger HBsAg loss.
HBsAg loss is the only acceptable end point for stopping nucleoside analogue treatment.
Cirrhosis contraindicates discontinuation of treatment.
Withdrawal of nucleoside analogues results in relapse in most patients; the relapse occurs earlier with tenofovir withdrawal than with entecavir withdrawal.
At cessation of treatment, HBsAg levels associated with HBsAg seroclearance are less than 100 IU per milliliter in Asian patients and less than 1000 IU per milliliter in White patients.
Off-treatment HBsAg seroclearance occurs in 4 to 19% of HBeAg-negative patients.
Discontinuation carries the risk of hepatic decompensation, the benefits and the disadvantages should be carefully weighed.
Treatment should be reinstated before any rise in serum aminotransferase levels if a rapid increase in the HBV DNA level (to 3 to 4 log10 IU per milliliter) is detected.
An array of treatments may induce HBV reactivation, including cancer chemotherapy, checkpoint inhibitor therapy, immunosuppressive therapy, bone marrow and stem-cell treatment, anti–tumor necrosis factor therapy, treatment with newer classes of immunobiologic agents. including tyrosine kinase inhibitors. chimeric antigen receptor T-cell treatment, and treatment of coexisting hepatitis C.
Rituximab treatment is particularly dangerous.
A controlled trial of tenofovir plus pegylated interferon alfa-2a resulted in loss of HBsAg in 9% of patients — a higher percentage than with monotherapy.
Cure of HBV infection requires eradication, degradation, or silencing of cccDNA; silencing of integrated viral genomes; and correction of antigen-specific immune dysfunction.
RNA-interfering agents, including siRNA and antisense oligonucleotides (ASOs) exploit a complementary sequence of the target RNA to trigger specific RNA degradation and perturb translation
ASOs are synthetic, single-stranded oligonucleotides with various biochemical characteristics.
ASOs bind to complementary HBV RNA transcripts to form a hybrid ASO-RNA complex, resulting in cleavage by ribonuclease.
The dose-dependent decline in HBsAg during treatment and the prolonged effect with siRNA and ASOs are encouraging findings, and even though the end points for a functional cure have not been met to date, these data indicate that an HBsAg reduction to less than 100 IU per milliliter can be achieved in the majority of patients.
The inclusion of HBV vaccine in the expanded program of immunization has decreased the prevalence of hepatitis B in children under the age of 5 years and has reduced incident cases of chronic hepatitis B and hepatocellular carcinoma.
Th global birth-dose vaccination (i.e., vaccination within 24 hours after birth) coverage is unsatisfactory.
Also, vaccine protection may fail in more than 10% of infants born to mothers with a high viremic load.
To decrease incident acute hepatitis B, it recommended universal hepatitis B vaccination for adults between the ages of 19 and 59 years and has liberalized the recommendation for vaccination of adults who are 60 years of age or older.
It is proposed universal one-time hepatitis B screening be done for all adults (≥18 years).
The WHO recommends focused testing for most affected populations (people who inject drugs, men who have sex with men, sex workers, people living with human immunodeficiency virus [HIV], health care workers, migrants from regions where hepatitis B is endemic, and children of HBV-positive mothers), for persons in whom there is a clinical suspicion of chronic viral hepatitis, and for family members or sexual partners of affected persons.
General population testing is recommended in areas where the prevalence of HBsAg exceeds 2%.