What are the indications and treatment options for a patient with chronic hepatitis B (HBV) infection, including recommended medications and monitoring parameters?

Hepatitis B: Treatment Indications and Drug Therapy

Treatment Indications

Treatment should be initiated in patients with chronic hepatitis B who have HBV DNA ≥20,000 IU/mL (HBeAg-positive) or ≥2,000 IU/mL (HBeAg-negative) combined with ALT ≥2× upper limit of normal, or in any patient with cirrhosis and detectable HBV DNA regardless of ALT levels. 1, 2

Specific Treatment Criteria by Disease Phase:

HBeAg-Positive Chronic Hepatitis B:

• Treat if HBV DNA ≥20,000 IU/mL AND ALT ≥2× ULN 3, 1
• Consider 3-6 month observation period for possible spontaneous HBeAg seroconversion before initiating therapy 3, 1
• Treat immediately if moderate-to-severe necroinflammation or significant fibrosis (≥F2) on biopsy, even with lower ALT levels 3, 1

HBeAg-Negative Chronic Hepatitis B:

• Treat if HBV DNA ≥2,000 IU/mL AND ALT ≥2× ULN 3, 1, 2
• European guidelines recommend treatment with ALT >ULN (not just 2× ULN) if HBV DNA >2,000 IU/mL and moderate necroinflammation or fibrosis present 3, 4

Cirrhosis (Compensated or Decompensated):

• Treat all patients with any detectable HBV DNA, regardless of ALT levels 1, 2, 5
• This is critical to prevent hepatic decompensation and hepatocellular carcinoma 5, 6

Immune Tolerant Phase:

• Generally monitor without treatment if age <30 years, HBV DNA ≥10^7 IU/mL, and normal ALT 3
• Consider liver biopsy and treatment if age ≥30-40 years, family history of HCC or cirrhosis, or noninvasive tests suggest significant fibrosis 3

First-Line Treatment Options

Entecavir and tenofovir (disoproxil fumarate or alafenamide) are the preferred first-line agents due to high potency and high genetic barrier to resistance. 1, 4, 2

Specific Drug Regimens:

Entecavir:

• Dose: 0.5 mg once daily for treatment-naïve patients 1, 7
• Dose: 1 mg once daily for lamivudine-refractory patients or those with known resistance mutations 1, 7
• Administer on an empty stomach 7
• Resistance rate: <1% at 4 years in treatment-naïve patients 3, 1

Tenofovir Disoproxil Fumarate (TDF):

• Dose: 245 mg once daily 1, 2
• Preferred in pregnancy (start at 24-32 weeks if HBV DNA >200,000 IU/mL) 2
• Requires monitoring of renal function and bone density with long-term use 1

Tenofovir Alafenamide (TAF):

• Dose: 25 mg once daily 1, 2
• Improved renal and bone safety profile compared to TDF 1

Peginterferon alfa-2a:

• May be considered in non-cirrhotic patients with mild-to-moderate disease 2
• Contraindicated in decompensated cirrhosis and pregnancy 1, 2
• Finite treatment duration (typically 48 weeks) unlike nucleos(t)ide analogues 8

Drugs to Avoid as Monotherapy:

Lamivudine, emtricitabine, and telbivudine should not be used as monotherapy due to high resistance rates (lamivudine: up to 70% at 5 years; telbivudine: 2.3-5% at 1 year). 3, 1

Special Populations

HBV/HIV Co-infection:

• Use triple antiretroviral therapy including two agents active against HBV (emtricitabine/tenofovir or lamivudine/tenofovir as fixed-dose combinations) 1
• Never use entecavir without concurrent HAART due to risk of HIV resistance 7
• If already on lamivudine without tenofovir, switch to include tenofovir 1

Decompensated Cirrhosis:

• Use tenofovir or lamivudine (not entecavir as first choice) with close renal monitoring 1
• Interferon-α is absolutely contraindicated 1

Pregnancy:

• Tenofovir DF at 24-32 weeks gestation if HBV DNA >200,000 IU/mL to prevent vertical transmission 2

Children (≥12 years):

• Consider treatment if ALT >2× ULN for >6 months 1
• Interferon-α: 6 MU/m² three times weekly (maximum 10 MU) 1
• Lamivudine: 3 mg/kg/day (maximum 100 mg/day) 1

Treatment Duration

HBeAg-Positive Patients:

• Minimum 1 year, continuing for 3-6 months after HBeAg seroconversion 1, 2
• May require indefinite treatment if HBeAg seroconversion not achieved 2

HBeAg-Negative Patients:

• Long-term or indefinite treatment typically required 1, 4, 2
• HBsAg loss (functional cure) occurs in only 1-12% even after years of therapy 4

Cirrhosis:

• Indefinite treatment generally recommended 1

Monitoring During Treatment

Virological and Biochemical Monitoring:

• HBV DNA and ALT every 3-6 months to assess response and detect resistance 1, 2, 9
• Goal: Undetectable HBV DNA by sensitive PCR (<10-15 IU/mL) 2

Renal Monitoring (for tenofovir):

• Baseline serum creatinine and spot urine protein-creatinine ratio 1
• Monitor serum creatinine every 6 months 1

Hepatocellular Carcinoma Surveillance:

• Baseline alpha-fetoprotein and liver ultrasound 3, 2
• Ultrasound every 6 months for cirrhotic patients, Asian men >40 years, Asian women >50 years, Africans >20 years, and those with family history of HCC 3, 2

Management of Treatment Failure

Lamivudine Resistance:

• Switch to adefovir, especially with worsening liver disease or decompensated cirrhosis 1
• Alternatively, add tenofovir (preferred over adefovir due to higher potency) 1

Suboptimal Response:

• Assess medication adherence first 8
• Consider switching to or adding a more potent agent with no cross-resistance 8

Critical Warnings

Severe Acute Exacerbations After Discontinuation:

• Monitor hepatic function closely for at least several months after stopping therapy 7
• Reinitiation of treatment may be warranted 7

Lactic Acidosis Risk:

• Rare but potentially fatal complication with nucleoside analogues 7
• Suspend treatment if suspected 1

Patients Not Requiring Immediate Treatment:

• Inactive HBsAg carriers (HBV DNA <2,000 IU/mL, normal ALT) should be monitored periodically as disease may reactivate after years of quiescence 3
• Monitor every 3-6 months with ALT and HBV DNA 3