What are the indications and preferred medications for the treatment of hepatitis B?

Treatment of Hepatitis B: Indications and Preferred Medications

Entecavir and tenofovir are the preferred first-line agents for chronic hepatitis B due to their high potency and superior resistance profiles, with treatment indicated when HBV DNA ≥2,000 IU/mL combined with elevated ALT or evidence of significant liver disease. 1, 2

Treatment Indications

HBeAg-Positive Patients

• Treat when HBV DNA is elevated with ALT >2 times upper limit of normal (ULN) or moderate/severe hepatitis on biopsy, after observing for 3-6 months for possible spontaneous HBeAg seroconversion 1
• Patients over 30 years old with HBV DNA >20,000 IU/mL can begin treatment regardless of histology 3
• Treatment should not be initiated if ALT is persistently normal or minimally elevated (<2 times ULN) unless liver biopsy demonstrates moderate/severe inflammation 1

HBeAg-Negative Patients

• Treat when HBV DNA ≥2,000 IU/mL and ALT ≥2 times ULN, or when moderate/severe hepatitis is present on biopsy 1, 2
• Patients with HBV DNA >2,000 IU/mL and liver stiffness >9 kPa (or >12 kPa if ALT ≤5xULN) should begin treatment 3

Cirrhotic Patients

• All patients with cirrhosis and detectable HBV DNA should be treated regardless of ALT levels 4, 1, 2
• This represents an absolute indication due to high risk of decompensation and hepatocellular carcinoma 5

Additional Indications Requiring Prophylactic Treatment

• Pregnant women in the third trimester with high viremia to prevent mother-to-child transmission 4, 1
• Patients requiring immunosuppression or chemotherapy to prevent HBV reactivation 4, 1
• HBV-related liver transplantation patients to prevent recurrence 4, 3

First-Line Medications

Preferred Agents (High Potency, High Barrier to Resistance)

Entecavir:

• Indicated for chronic hepatitis B with evidence of active viral replication and either persistent aminotransferase elevations or histologically active disease 6
• Resistance rate of only 1.2% after 5 years in treatment-naïve patients 2
• Preferred for compensated cirrhosis 1

Tenofovir (Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide):

• No documented resistance in treatment-naïve patients in initial studies 2
• Preferred for compensated cirrhosis 1
• For decompensated cirrhosis, tenofovir is recommended with close monitoring of renal function 1
• Tenofovir alafenamide has improved renal and bone safety profile 2

Agents to Avoid as Monotherapy

• Lamivudine, emtricitabine, and telbivudine should be avoided as monotherapy due to high resistance rates (lamivudine resistance up to 70% in first 5 years) 1
• When entecavir and tenofovir are unavailable, combination therapy with adefovir/lamivudine or adefovir/telbivudine is recommended 1

Adefovir Dipivoxil:

• Indicated for chronic hepatitis B in patients ≥12 years with evidence of active viral replication and persistent aminotransferase elevations or histologically active disease 7
• Effective for lamivudine-resistant hepatitis B 7
• Resistance rate of 30% at 5 years 1

Interferon-Based Therapy

• Pegylated interferon-alfa can be considered in mild to moderate chronic hepatitis B patients 4
• Contraindicated in decompensated cirrhosis due to risk of serious complications 4, 1
• Conventional or pegylated interferon-alfa is the only effective treatment for HDV co-infection 4

Treatment Duration

HBeAg-Positive Patients

• Minimum 1 year of nucleos(t)ide analogue treatment, continuing for 3-6 months after HBeAg seroconversion 1, 2
• Without HBeAg seroconversion, long-term treatment is required due to high relapse risk 2

HBeAg-Negative Patients

• Long-term or indefinite treatment is typically required, as optimal duration is not established 2
• Longer treatment duration compared to HBeAg-positive patients 1

Cirrhotic Patients

• Indefinite treatment is generally recommended 1

Treatment Discontinuation

• After HBsAg seroclearance (functional cure), treatment can be discontinued 8
• Requires confirmation with repeat HBsAg testing on at least two occasions, 3-6 months apart 8

Special Populations

HBV/HIV Co-infection

• Co-infected patients should receive triple combination antiretroviral therapy including two agents active against HBV: either emtricitabine/tenofovir or lamivudine/tenofovir 4, 1
• Lamivudine, entecavir, and tenofovir are contraindicated as single agents in co-infected patients due to risk of HIV resistance 4

Decompensated Cirrhosis

• Lamivudine or tenofovir recommended with close monitoring of renal function 1
• Patients should be referred for liver transplantation and treated with first-line antivirals as early as possible 5
• Interferon-alfa is absolutely contraindicated 4, 1

Pregnancy

• Telbivudine or tenofovir preferred during pregnancy (pregnancy category B) 2
• Treatment in third trimester for women with high viremia prevents vertical transmission 1

Pediatric Patients (≥12 years)

• Children with ALT >2 times normal for >6 months should be considered for treatment 1
• Adefovir approved for patients ≥12 years 7

HCV Co-infection

• Treat with pegylated interferon-alfa plus ribavirin as for HCV monoinfection 4
• Monitor for HBV reactivation during or after HCV clearance, which must be treated with nucleos(t)ide analogues 4

Monitoring During Treatment

Virological and Biochemical Monitoring

• Regular assessment of HBV DNA levels every 3-6 months to evaluate virological response 1, 2
• Monitor ALT every 6 months for patients on entecavir 1

Renal Monitoring (for Tenofovir)

• Measure baseline serum creatinine and spot urine protein-creatinine ratio if possible 1
• Monitor serum creatinine every 6 months 1

Hepatocellular Carcinoma Surveillance

• Baseline alpha-fetoprotein and ultrasound in patients at risk 1
• Continue surveillance every 6 months, even after HBsAg seroclearance in cirrhotic patients 8

Management of Treatment Failure

Lamivudine Resistance

• Switch to adefovir, especially with worsening liver disease, decompensated cirrhosis, or need for immunosuppressive therapy 1
• Adefovir and entecavir are effective against lamivudine-resistant strains 4, 9

Primary or Secondary Treatment Failure

• Switch to alternative high-potency agents (tenofovir or entecavir if not already used) 2
• Monitor for resistance with regular HBV DNA assessment 2

Treatment Endpoints

Optimal Endpoint

• HBsAg loss with or without anti-HBs seroconversion represents functional cure 2, 8
• Associated with improved survival, reduced liver-related mortality, and decreased risk of hepatocellular carcinoma 8

Realistic Endpoints

• For HBeAg-positive patients: HBeAg seroconversion with undetectable HBV DNA 2
• For HBeAg-negative patients: sustained ALT normalization and undetectable HBV DNA 2
• Long-term suppression of HBV replication to prevent disease progression 4

Critical Pitfalls to Avoid

• Never use lamivudine, emtricitabine, or telbivudine as monotherapy in treatment-naïve patients due to high resistance rates 1
• Never use lamivudine, entecavir, or tenofovir as single agents in HBV/HIV co-infected patients due to risk of HIV resistance 4
• Never use interferon in decompensated cirrhosis due to risk of fatal complications 4, 1
• Never discontinue treatment in HBeAg-positive patients without HBeAg seroconversion due to very high relapse risk 2
• Do not stop monitoring after HBsAg seroclearance in cirrhotic patients—continue hepatocellular carcinoma surveillance indefinitely 8