What is the recommended management for acute and chronic hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV), including treatment options, monitoring, and vaccination?

Hepatitis Management

Hepatitis A (HAV)

Acute hepatitis A is self-limiting in >95% of cases and does not require antiviral therapy. 1

Management Approach

• Supportive care only for uncomplicated acute HAV infection—no antiviral agents are indicated 1
• Monitor liver function tests (ALT, AST, bilirubin, INR) weekly until normalization 1
• Hospitalization is required if INR >1.5, encephalopathy develops, or inability to maintain oral hydration occurs 1

Vaccination Strategy

• Vaccinate all chronic hepatitis B and C patients who are anti-HAV IgG negative, as HAV superinfection increases mortality 5.6- to 29-fold 1
• Standard two-dose series at 0 and 6-12 months provides lifelong immunity 1

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Hepatitis B (HBV)

All patients with cirrhosis and any detectable HBV DNA must be treated immediately with entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), regardless of ALT levels. 2, 1

Treatment Indications

Immediate Treatment Required

• Cirrhosis (compensated or decompensated) + any detectable HBV DNA: Start entecavir or tenofovir immediately 2, 1
• Decompensated cirrhosis: Immediate treatment with entecavir or tenofovir AND urgent liver transplant evaluation; peginterferon is absolutely contraindicated 2, 1
• HBV DNA ≥20,000 IU/mL + ALT >2× ULN: Treat immediately without liver biopsy 2, 1
• Life-threatening acute hepatitis B (coagulopathy, severe jaundice, liver failure): Start entecavir or tenofovir immediately 1

Treatment After Assessment

• HBV DNA ≥2,000 IU/mL + ALT >40 IU/L (>1× ULN) + moderate-to-severe necroinflammation or fibrosis on biopsy: Initiate treatment 2, 1
• HBV DNA ≥2,000 IU/mL + normal ALT + liver stiffness ≥9 kPa or moderate fibrosis: Consider treatment 1
• HBeAg-positive patients >30-40 years with persistently high HBV DNA: Treat due to increased HCC risk even with normal ALT 1

First-Line Treatment Options

Entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) are the only recommended first-line agents due to high potency and high barrier to resistance. 2, 1

• Entecavir: 0.5 mg daily; resistance <1% after 5 years 2, 1
• Tenofovir DF: 300 mg daily; no resistance detected after 8 years 2, 1
• Tenofovir AF: 25 mg daily; less renal and bone toxicity than TDF through 96 weeks 1
• Avoid lamivudine: Resistance up to 70% at 5 years 1

Peginterferon alfa-2a can be considered for finite 48-week therapy in mild-to-moderate disease without cirrhosis, but response is variable (23-28%) and side effects limit use 2

Special Populations

Pregnancy

• Tenofovir DF is the preferred agent during pregnancy 1
• Start prophylactic tenofovir DF at 24-32 weeks gestation if HBV DNA >200,000 IU/mL to prevent mother-to-child transmission 1
• Continue therapy up to 4 weeks postpartum with close monitoring for hepatic flares 1
• All infants of HBsAg-positive mothers must receive hepatitis B vaccine AND HBIG within 12 hours of birth 1
• Peginterferon is contraindicated during pregnancy and requires contraception during therapy and for 6 months after cessation 2

Immunosuppression/Chemotherapy

• All HBsAg-positive patients receiving rituximab, anthracyclines, high-dose steroids, or anti-TNF agents require prophylactic antiviral therapy starting 2-4 weeks before immunosuppression 1
• Continue prophylaxis through treatment and for 12 months after completion (24 months for rituximab) 1
• Reactivation risk is 12-50% without prophylaxis 3

HIV Coinfection

• All HIV-HBV coinfected patients should start antiretroviral therapy (ART) immediately, regardless of CD4 count 2, 1
• TDF- or TAF-based ART regimens are mandatory to treat both viruses 2, 1

Monitoring Protocol

During Treatment

• HBV DNA every 3 months until undetectable, then every 6 months 1
• ALT/AST every 3-6 months 1
• Annual quantitative HBsAg to assess for functional cure (HBsAg loss) 1
• Renal function monitoring if on tenofovir DF 1

Not on Treatment

• ALT every 3 months during first year, then every 6-12 months 1
• HBV DNA every 6-12 months 1
• Fibrosis assessment every 12 months by transient elastography or non-invasive markers 1

Hepatocellular Carcinoma Surveillance

Ultrasound every 6 months is mandatory for: 1

• All patients with cirrhosis
• Asian men >40 years
• Asian women >50 years
• Any patient >40 years with persistent ALT elevation or HBV DNA >2,000 IU/mL
• Family history of HCC
• First-generation African-Americans >20 years

Continue HCC surveillance even after achieving HBsAg loss if patient is >40-50 years old 1

Treatment Duration

• Long-term, potentially indefinite treatment is required with nucleos(t)ide analogues 2, 1
• HBsAg loss (functional cure) is the optimal endpoint but is rarely achieved 2, 1
• Stopping therapy may be considered in HBeAg-positive patients who achieve HBeAg seroconversion with undetectable HBV DNA and have completed ≥12 months of consolidation therapy 1

Common Pitfalls

• Do not assume immune-tolerant patients >40 years with high HBV DNA are safe—they have increased HCC risk and should be evaluated for treatment 1
• Do not rely on traditional ALT cutoffs to exclude liver disease—normal ALT does not exclude significant necroinflammation or fibrosis 1
• Do not delay treatment in cirrhotic patients with any detectable HBV DNA 1

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Hepatitis C (HCV)

All patients with chronic HCV should be offered direct-acting antiviral (DAA) therapy immediately, as cure rates exceed 95-97% and prevent cirrhosis, hepatocellular carcinoma, and death. 2, 4

Definition of Cure

• Sustained virological response (SVR12): Undetectable HCV RNA 12 weeks after treatment completion represents permanent viral eradication in >99% of cases 2, 4

Treatment Recommendations

First-Line Regimen

• Sofosbuvir/velpatasvir for 12 weeks achieves 98% SVR for genotype 1a and is pan-genotypic 4
• Treatment duration and regimen selection depend on genotype, presence of cirrhosis, and prior treatment history 2

Priority Populations for Immediate Treatment

• Significant fibrosis or any degree of cirrhosis (F2-F4) 4
• Individuals at risk of transmission: people who inject drugs, men who have sex with men with high-risk practices, women of childbearing age wishing to conceive, hemodialysis patients 4

Historical Context (Pre-2014)

The older peginterferon-alfa and ribavirin regimens are now obsolete due to poor efficacy (40-50% SVR for genotype 1) and significant side effects 2. First-generation protease inhibitors (telaprevir, boceprevir) should no longer be used 2.

Acute Hepatitis C

• Consider delaying treatment for 8-12 weeks to allow spontaneous recovery, which occurs in 15-45% of cases 2
• If treatment is initiated, peginterferon-alfa monotherapy for 24 weeks achieves 80-90% SVR 2
• Testing for HCV RNA is essential when acute hepatitis C is suspected but anti-HCV is negative 2

Post-Treatment Surveillance

Patients with established cirrhosis (F4) or advanced fibrosis (F3) remain at reduced but ongoing risk for HCC even after achieving SVR and require ultrasound every 6 months indefinitely. 4

Contraindications to Treatment (Historical—No Longer Applicable with DAAs)

The following were contraindications to peginterferon-based therapy but are NOT contraindications to modern DAA therapy 2:

• Active alcohol or drug use
• Major depression
• Cytopenias
• Autoimmune disease
• Decompensated cirrhosis

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Hepatitis D (HDV)

All HDV RNA-positive patients are eligible for treatment regardless of liver disease stage. 2

Diagnosis

• Detect anti-HDV or HDV RNA in serum, or HDV antigens in liver tissue by immunohistochemistry 2
• HDV coinfection occurs in ~0.3-3.6% of CHB patients in Korea; higher rates in Mediterranean countries, Middle East, central Africa, South America 2

Treatment

Peginterferon alfa for at least 12 months is the only treatment that inhibits HDV replication. 2

• Response rate: 23-28% at 24 weeks, but relapse is frequent (sustained response only 12% at 4.3 years) 2
• Extended therapy for 24 months may improve sustained response to 47%, but further studies are needed 2
• Nucleos(t)ide analogues (entecavir, tenofovir) do NOT inhibit HDV replication but should be initiated if HBV treatment indications are met or cirrhosis is present to prevent HBV-related liver disease progression 2

Monitoring

• Measure serum HDV RNA levels at 24 weeks to predict sustained virological response 2
• Assess degree of hepatic fibrosis by liver biopsy or non-invasive methods 2

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Hepatitis B/C Coinfection

If HCV RNA is detectable in HBV/HCV coinfection, start DAA therapy for HCV first. 2

Management Algorithm

1. Test HBV DNA and HCV RNA before treatment 2
2. If HCV RNA detectable: Start DAA therapy for HCV 2
3. If HBV DNA detectable and meets HBV treatment criteria: Start nucleos(t)ide analogue (entecavir, tenofovir DF, or tenofovir AF) according to HBV guidelines 2
4. If cirrhosis or HCC history present: Consider simultaneous NA therapy for HBV along with DAA therapy for HCV to reduce risk of HBV reactivation and liver failure 2

HBV Reactivation Risk

• HBV DNA newly detected or increased in 14.1% of patients during DAA therapy; active hepatitis with ALT elevation in 12.2% 2
• Monitor ALT and HBV DNA during and after DAA therapy 2
• In HBsAg-negative, anti-HBc-positive patients, HBV reactivation rate is very low (0-0.1%), but test HBsAg and HBV DNA if ALT elevation occurs 2

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Hepatitis E (HEV)

Acute hepatitis E is usually self-limiting and does not require treatment in immunocompetent patients. 5

Chronic Hepatitis E (Immunocompromised Patients)

• Reduce immunosuppression to allow HEV clearance 5
• Ribavirin shows antiviral efficacy as an off-label treatment option for chronic HEV in transplant recipients 5