What is chronic hepatitis B?

Chronic Hepatitis B: Comprehensive Overview

Definition and Disease Spectrum

Chronic hepatitis B (CHB) is a persistent infection with hepatitis B virus (HBV) lasting more than 6 months, characterized by the presence of hepatitis B surface antigen (HBsAg) in serum, representing a dynamic disease process that can progress through multiple phases and lead to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). 1

CHB encompasses a spectrum from minimal liver inflammation to active necroinflammatory disease, with approximately 350 million people infected worldwide and 500,000-1 million deaths annually from HBV-related complications. 1

Natural History and Disease Phases

The natural course of chronic HBV infection is divided into five distinct phases that are not necessarily sequential: 1

Phase 1: Immune Tolerant Phase (HBeAg-Positive Chronic Infection)

• HBeAg positive with very high HBV DNA levels (often >10^7 IU/mL) 1
• Normal or minimally elevated ALT levels 1
• Minimal liver necroinflammation and slow/no fibrosis progression 1
• More common and prolonged in patients infected perinatally or in early childhood 1
• Very low rate of spontaneous HBeAg loss 1
• Highly contagious due to high viremia 1

Phase 2: Immune Reactive HBeAg-Positive Phase (HBeAg-Positive Chronic Hepatitis)

• HBeAg positive with lower HBV DNA levels compared to immune tolerant phase 1
• Elevated or fluctuating ALT levels (>1.3 times upper limit of normal) 1
• Moderate to severe liver necroinflammation with more rapid fibrosis progression 1
• Enhanced rate of spontaneous HBeAg loss 1
• May last weeks to years before HBeAg seroconversion 1

Phase 3: Inactive HBV Carrier State (HBeAg-Negative Chronic Infection)

• HBeAg negative, anti-HBe positive 1
• Very low or undetectable HBV DNA (<2,000 IU/mL) 1
• Persistently normal ALT levels 1
• Favorable long-term prognosis with very low risk of cirrhosis or HCC in most patients 1
• Spontaneous HBsAg loss occurs in 1-3% per year after several years of undetectable HBV DNA 1

Phase 4: HBeAg-Negative Chronic Hepatitis

• HBeAg negative, anti-HBe positive with HBV variants (precore/core promoter mutations) 1
• Detectable HBV DNA (typically >2,000 IU/mL, often fluctuating between 2,000-20 million IU/mL) 1
• Elevated or fluctuating ALT levels 1
• Active hepatitis with periodic reactivation 1
• Represents a later phase in natural history, more common in older patients 1
• Increasing prevalence, now representing the majority of CHB cases in Europe 1

Phase 5: HBsAg-Negative Phase (Resolved Hepatitis B)

• HBsAg negative with previous history of acute or chronic hepatitis B 1
• Presence of anti-HBc ± anti-HBs 1
• Undetectable serum HBV DNA (very low levels may be detectable with sensitive PCR) 1
• Normal ALT levels 1

Disease Progression and Prognosis

Cirrhosis Development

• 5-year cumulative incidence of cirrhosis: 8-20% after CHB diagnosis 1
• Annual progression rate to cirrhosis approximately 2-5% in untreated patients 2

Decompensated Cirrhosis

• 5-year cumulative incidence of hepatic decompensation: ~20% in patients with compensated cirrhosis 1
• 5-year survival probability: 14-35% in patients with decompensated cirrhosis 1
• 5-year survival: 80-86% in patients with compensated cirrhosis 1

Hepatocellular Carcinoma (HCC)

• Annual incidence: 2-5% when cirrhosis is established 1
• HCC can develop even without cirrhosis, though less commonly 1
• Geographic variation in incidence correlates with underlying liver disease stage and environmental carcinogens (e.g., aflatoxin) 1
• HBV-related HCC represents the fifth most common cancer globally (~5% of all cancers) 1

Transmission and Epidemiology

Routes of Transmission

• Perinatal transmission (mother to infant at birth) - most common in endemic areas 1
• Horizontal transmission in childhood (person-to-person) 1
• Sexual transmission 1
• Percutaneous exposure (injection drug use, needlestick injuries) 1
• Environmental contamination from blood spills (HBV survives on surfaces for at least 1 week) 1

Risk of Chronicity

• 90% of infants infected perinatally develop chronic infection 1
• <5% of children under 5 years develop chronic infection 1
• <10% of adults develop chronic infection after acute HBV 1
• Higher rates in immunosuppressed persons 1

High-Risk Populations Requiring Screening

• Persons born in endemic areas (HBsAg prevalence >2%): 13% HBsAg positive, 70-85% with any HBV marker 1
• Men who have sex with men: 6% HBsAg positive, 35-80% with any marker 1
• Injection drug users: 7% HBsAg positive, 60-80% with any marker 1
• Dialysis patients: 3-10% HBsAg positive, 20-80% with any marker 1
• HIV-infected individuals: 8-11% HBsAg positive, 89-90% with any marker 1
• Pregnant women 1
• Household contacts, sexual partners, and family members of HBV-infected persons: 3-6% HBsAg positive, 30-60% with any marker 1

Diagnostic Evaluation

Initial Serologic Testing

• HBsAg - primary marker for chronic infection 1
• HBeAg and anti-HBe - determines disease phase and infectivity 1
• Anti-HBc - indicates current or past infection 1
• Anti-HBs - indicates immunity from vaccination or resolved infection 1

Virologic Assessment

• Serum HBV DNA quantification (PCR-based assays preferred, linearity 10^2 to 10^9-10^10 copies/mL) 1
• Quantitative HBsAg (qHBsAg) - helpful in differentiating disease phases 1

Biochemical Monitoring

• ALT/AST levels - markers of hepatic necroinflammation 1
• Persistently elevated ALT ≥1.3 times ULN indicates active disease 1

Assessment of Liver Disease Severity

• Liver biopsy - gold standard for assessing necroinflammation (Knodell score) and fibrosis (Ishak score) 1, 3
• Non-invasive fibrosis markers (transient elastography, serum markers) 1
• Imaging studies (ultrasound, CT, MRI) 1
• Clinical findings (signs of portal hypertension, hepatic decompensation) 1

Additional Testing

• Screen for co-infections: HCV, HDV, HIV in at-risk patients 1
• Assess for HCC: AFP, liver imaging (ultrasound every 6 months in cirrhotic patients) 1
• Family history of HBV infection and liver cancer 1
• Alcohol use assessment (>40 g/day associated with accelerated progression) 1

Monitoring Strategies

Patients NOT Indicated for Treatment

• Monitor ALT and HBV DNA every 3-6 months 1
• Monitor HBeAg/anti-HBe every 6-12 months 1
• Inactive carriers require long-term monitoring as disease can reactivate after years of quiescence 1

Patients in "Grey Area" (Uncertain Treatment Indication)

• More frequent monitoring: ALT and HBV DNA every 1-3 months 1
• HBeAg/anti-HBe every 2-6 months 1
• Consider non-invasive fibrosis assessment or liver biopsy if uncertainty persists 1

Treatment Indications

General Treatment Criteria (Based on EASL 2017 Guidelines)

Treatment is indicated when: 1

• HBV DNA ≥2,000 IU/mL AND
• Elevated ALT AND/OR
• At least moderate histological lesions (necroinflammation or fibrosis)

Specific Populations Requiring Treatment

Compensated or Decompensated Cirrhosis

• ALL cirrhotic patients with detectable HBV DNA should be treated, regardless of ALT level or HBeAg status 1

Decompensated Cirrhosis

• Initiate nucleos(t)ide analogues (NAs) immediately if serum HBV DNA is detected, regardless of level or ALT 1
• Liver transplantation should be considered concurrently 1
• Interferon is absolutely contraindicated (may cause liver failure) 1

HBeAg-Positive Chronic Hepatitis

• HBV DNA ≥2,000 IU/mL (often much higher, typically >20,000 IU/mL) 1
• Elevated ALT 1
• Active necroinflammation on biopsy 1

HBeAg-Negative Chronic Hepatitis

• HBV DNA ≥2,000 IU/mL 1
• Elevated ALT 1
• Active necroinflammation on biopsy 1

Special Indications

• Prevention of mother-to-child transmission in pregnant women with high viremia 1
• Prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy 1

Treatment Options and Strategies

First-Line Antiviral Agents

Nucleos(t)ide Analogues (NAs) with High Genetic Barrier

These are the preferred oral agents: 1, 2

• Entecavir 0.5 mg once daily (1 mg daily in lamivudine-resistant patients) 3, 2

  • High potency with high barrier to resistance 2
  • Superior histologic improvement compared to lamivudine 3
  • Excellent safety profile 2

• Tenofovir disoproxil fumarate (TDF) 1, 2

  • High potency with high barrier to resistance 2
  • Effective in lamivudine-resistant patients 2

• Tenofovir alafenamide (TAF) 1

  • Newer formulation with improved renal and bone safety profile 1

Pegylated Interferon-alfa

• Peginterferon alfa-2a can be considered in mild to moderate chronic hepatitis B 1
• Finite duration therapy (advantage over NAs) 1
• Higher rate of HBsAg loss compared to NAs 1
• Contraindicated in decompensated cirrhosis 1
• Associated with significant side effects 4
• Duration: 48 weeks for HBeAg-positive, 48 weeks for HBeAg-negative 4

Treatment Duration

With Nucleos(t)ide Analogues

• Indefinite therapy is typically required for most patients 1, 2
• Minimum 1 year, but optimal duration not established 4
• Longer duration needed in most patients 4
• May consider stopping in select patients who achieve sustained virologic suppression and HBsAg loss 1

With Peginterferon

• HBeAg-positive: 4-6 months (some guidelines recommend 48 weeks) 4
• HBeAg-negative: 12 months 4

Combination Therapy

• NOT generally recommended as initial treatment 1
• Combination peginterferon plus NA offered no significant advantage over monotherapy 1
• Particularly not recommended in Korea/Asia where genotype C is prevalent 1

Treatment Goals and Endpoints

Primary Goal

Improve survival and quality of life by preventing disease progression to cirrhosis and HCC 1

Main Treatment Endpoint

Long-term suppression of HBV replication (undetectable HBV DNA) 1, 2

Optimal Endpoint

HBsAg loss with or without anti-HBs seroconversion (functional cure) 1, 2

• Achievable in only a small minority of treated patients with current therapies 2
• Spontaneous HBsAg loss: 1-3% per year in inactive carriers 1

Secondary Endpoints

• ALT normalization 3, 4
• Histologic improvement (≥2-point reduction in Knodell Necroinflammatory Score without worsening fibrosis) 3
• HBeAg seroconversion (in HBeAg-positive patients) 4
• Prevention of hepatic decompensation 1
• Reduced need for liver transplantation 1

Treatment Outcomes and Efficacy

With Entecavir (Nucleoside-Naïve Patients at 48 Weeks)

• Histologic improvement superior to lamivudine 3
• Significant reduction in viral load 3
• ALT normalization achieved in majority 3
• Mean baseline HBV DNA: 9.66 log₁₀ copies/mL (HBeAg-positive), 7.58 log₁₀ copies/mL (HBeAg-negative) 3

With Adefovir

• Effective in lamivudine-resistant patients 5, 4
• Low rate of drug resistance 4
• Small risk of reversible nephrotoxicity requires monitoring 5, 4

Decompensated Cirrhosis Outcomes

• Antiviral therapy improves liver function, decreases need for transplantation, and improves survival 1
• Virological response and clinical recovery take time 1
• Some patients with severely impaired function may not recover despite therapy 1

Monitoring During Treatment

Virologic Monitoring

• HBV DNA levels to assess treatment response 1
• Monitor for viral breakthrough (indicates resistance) 1

Biochemical Monitoring

• ALT/AST levels 1
• Renal function (especially with tenofovir and adefovir) 5

Serologic Monitoring

• HBeAg/anti-HBe (in HBeAg-positive patients) 1
• HBsAg levels (qHBsAg) 1

HCC Surveillance

• All treated patients require ongoing HCC surveillance 1
• Ultrasound every 6 months in cirrhotic patients 1
• AFP measurement 1
• HCC remains the major concern even in successfully treated patients 1

Treatment Adherence

• Close monitoring essential as non-adherence leads to viral breakthrough and resistance 1

Co-infections and Special Populations

HBV/HCV Co-infection

• 10-15% of CHB patients have HCV co-infection 1
• Higher rate of cirrhosis and HCC compared to mono-infection 1
• More common in injection drug users 1

HBV/HDV Co-infection

• HDV is dependent on HBV for replication 1
• Coinfection: more severe acute hepatitis, higher mortality, but rarely chronic 1
• Superinfection: almost always results in chronic HDV infection 1
• Higher rates of cirrhosis, decompensation, and HCC compared to HBV alone 1

HBV/HIV Co-infection

• 6-13% of HIV-infected persons have HBV co-infection 1
• Higher HBV DNA levels, lower HBeAg seroconversion rates 1
• More severe liver disease and increased liver-related mortality 1
• Severe hepatitis flares can occur with immune reconstitution after HAART initiation 1
• Test all HIV patients for HBsAg AND anti-HBc 1
• "Occult HBV" (HBV DNA positive, HBsAg negative) can occur 1
• Vaccinate HIV patients when CD4 >200/μL 1

Prevention and Counseling

Vaccination of Contacts

• All household and sexual contacts should be tested (HBsAg and anti-HBs) 1
• Vaccinate all seronegative contacts 1
• Vaccination of sexual partners is 95% effective in preventing transmission 1

Prevention of Perinatal Transmission

• All pregnant women should be screened for HBsAg 1
• Newborns of HBsAg-positive mothers must receive HBIG and hepatitis B vaccine immediately after delivery 1
• 95% efficacy in preventing perinatal transmission with HBIG plus vaccine 1
• Infants need to complete vaccination series and have follow-up testing at 1 year 1
• High maternal viremia may require antiviral therapy during pregnancy 1

Lifestyle Modifications

• Avoid heavy alcohol use (>40 g/day accelerates progression to cirrhosis and HCC) 1
• Cover open cuts/scratches 1
• Clean blood spills with bleach (HBV survives on surfaces ≥1 week) 1
• Use barrier protection with casual sexual partners or partners not fully vaccinated 1

Healthcare Workers

• HBeAg-positive healthcare workers should not perform invasive procedures without expert review and patient notification 1

Adverse Events and Safety Considerations

Severe Acute Exacerbations After Treatment Discontinuation

• Severe hepatitis flares reported after stopping anti-HBV therapy 5
• Monitor hepatic function closely (clinical and laboratory) for several months after discontinuation 5
• Resumption of therapy may be warranted 5

Nephrotoxicity

• Chronic adefovir administration may cause nephrotoxicity in patients with underlying renal dysfunction 5
• Monitor renal function closely 5
• Dose adjustment required based on creatinine clearance 5
• Tenofovir also requires renal monitoring 1

HIV Resistance

• HIV resistance may emerge in patients with unrecognized/untreated HIV treated with anti-HBV therapies that have anti-HIV activity 5
• Screen for HIV before initiating HBV treatment 5

Lactic Acidosis and Hepatic Steatosis

• Rare but potentially fatal with nucleoside analogues 5

Carcinogenicity (Entecavir)

• Lung, liver, vascular, and brain tumors observed in rodent studies at exposures 3-42 times human exposure 3
• Clinical relevance uncertain 3

Testicular Effects (Entecavir)

• Seminiferous tubular degeneration in rodents and dogs at ≥35 times human exposure 3
• No fertility impairment in rats at >90 times human exposure 3

Emerging Concepts and Future Directions

Early Treatment Considerations

• Traditional exclusion of "immune tolerant" patients from treatment is being challenged 6
• Evidence suggests this phase is not truly immunologically tolerant 6
• Events associated with tumorigenesis present even in early disease 6
• EASL 2017 lowered treatment threshold to potentially include HBeAg-positive chronic infection patients 6
• Goal: prevent disease progression and potentially achieve functional cure 6

Novel Therapeutic Targets

• Current treatments suppress but do not cure HBV 2, 7
• HBsAg loss achievable in only a few patients with current therapies 2
• Eradication of HBV appears unrealistic with current agents 2
• Research focusing on multiple targets in HBV replicative cycle 2, 7
• Therapeutic vaccines, vector-based treatments under investigation 7
• Targeting host integration of virus for potential total cure 7

HBV-Related Acute-on-Chronic Liver Failure (ACLF)

• Catastrophic syndrome requiring specific prognostic tools and treatment timing 7
• Newer clinical prognostic scores improving management 7
• Reactivation of HBV is a major trigger 7

Key Clinical Pitfalls to Avoid

• Never use interferon in decompensated cirrhosis - can cause fatal liver failure 1
• Do not delay treatment in cirrhotic patients with any detectable HBV DNA 1
• Do not assume "inactive carriers" are permanently inactive - requires lifelong monitoring 1
• Do not use lamivudine or adefovir as first-line due to resistance concerns - use entecavir or tenofovir 1, 2
• Do not stop monitoring after treatment - HCC risk persists even with viral suppression 1
• Do not forget to screen and vaccinate household/sexual contacts 1
• Do not overlook renal function monitoring with tenofovir or adefovir 5
• Do not miss screening for HIV before starting HBV treatment 5
• Do not discontinue treatment without close monitoring - risk of severe flares 5