What is the treatment for chronic hepatitis B infection?

Treatment of Chronic Hepatitis B Infection

Entecavir or tenofovir are the preferred first-line agents for treating chronic hepatitis B due to their high potency and high genetic barrier to resistance. 1, 2, 3

Treatment Indications

The decision to initiate treatment depends on HBeAg status, HBV DNA levels, ALT elevation, and presence of cirrhosis:

HBeAg-Positive Patients

• Treat if ALT >2 times upper limit of normal (ULN) AND HBV DNA >20,000 IU/mL after observing for 3-6 months for possible spontaneous HBeAg seroconversion 4, 1
• Patients with obviously active disease (ALT >2× ULN and HBV DNA >20,000 IU/mL) may start treatment without liver biopsy 4

HBeAg-Negative Patients

• Treat if ALT ≥2 times ULN AND HBV DNA ≥2,000 IU/mL 1, 2
• Patients with persistently normal ALT and HBV DNA between 2,000-20,000 IU/mL do not require immediate therapy but need close monitoring every 3 months 4

Cirrhotic Patients

• All patients with compensated or decompensated cirrhosis and detectable HBV DNA must be treated regardless of ALT levels 4, 1, 2
• This is critical as these patients are at highest risk for hepatic decompensation and hepatocellular carcinoma 2

Patients Who Should NOT Be Treated

• Those with persistently normal ALT (<2× ULN) unless liver biopsy shows moderate/severe inflammation 1, 3
• Inactive HBsAg carriers with normal ALT and low HBV DNA 4

First-Line Treatment Selection

Preferred Agents

Entecavir 0.5 mg daily or tenofovir 300 mg daily are the only recommended first-line monotherapies due to superior resistance profiles 1, 2, 3:

• Entecavir: <1% resistance at 4 years in treatment-naïve patients 1, 5
• Tenofovir: 30% resistance at 5 years, but still superior to older agents 1
• Both achieve HBV DNA suppression in 90-93% of patients at 1 year 4

Agents to AVOID as Monotherapy

Lamivudine, emtricitabine, and telbivudine should be avoided as monotherapy due to unacceptably high resistance rates 1:

• Lamivudine: 10-27% resistance at year 1, escalating to 60-70% by year 5 1, 6
• Telbivudine: 2.3-5% resistance at year 1,9-22% by year 2 1, 6

Alternative Regimens When First-Line Unavailable

• Combination of adefovir/lamivudine or adefovir/telbivudine if entecavir and tenofovir are not available 4, 1
• Pegylated interferon-α can be used for specific subgroups with appropriate monitoring, but only achieves sustained response in a minority of patients 4, 1, 6

Special Populations

HBV/HIV Co-infection

All co-infected patients requiring treatment should receive triple antiretroviral therapy including two agents active against HBV 4, 1, 2:

• Preferred: emtricitabine/tenofovir or lamivudine/tenofovir as fixed-dose combinations 4, 2
• If already on lamivudine without tenofovir, switch to include tenofovir to prevent resistance 4, 2
• Entecavir monotherapy is contraindicated in HIV/HBV co-infection not receiving HAART due to risk of HIV resistance 7

Decompensated Cirrhosis

• Urgent treatment with nucleos(t)ide analogues is required 4
• Tenofovir or entecavir 1 mg daily preferred 3
• Interferon-α is absolutely contraindicated due to risk of serious complications and hepatic decompensation 4, 3
• Consider liver transplantation evaluation simultaneously, as antiviral therapy may not rescue patients with very advanced disease 4

Compensated Cirrhosis

• Entecavir or tenofovir recommended 1, 3
• Treatment should be indefinite given high risk of complications 1

Pregnancy

• Tenofovir is preferred due to pregnancy category B classification and established safety profile 2

Renal Impairment

• Dose adjustment required for entecavir when creatinine clearance <50 mL/min 7
• For tenofovir, monitor baseline and every 6 months: serum creatinine and spot urine protein/creatinine ratio 4, 1, 2
• Entecavir, tenofovir alafenamide (TAF), or besifovir preferred for patients with significant renal dysfunction 2

Pediatric Patients

• Children rarely require treatment unless they have advanced fibrosis or cirrhosis 4, 2
• For those requiring treatment: entecavir or tenofovir can be used in adolescents ≥16 years 7
• Tenofovir approved for children ≥12 years and ≥35 kg at 300 mg daily 8

Treatment Duration

HBeAg-Positive Patients

• Minimum 1 year, continuing for 3-6 months after confirmed HBeAg seroconversion 4, 1, 3
• This endpoint provides the best chance for sustained off-therapy response 9

HBeAg-Negative Patients

• Long-term or indefinite treatment typically required 1, 2
• Relapse rates reach 80-90% if treatment stopped within 1-2 years 2
• Optimal duration not established; many patients require lifelong therapy 3, 9

Cirrhotic Patients

• Indefinite treatment is generally recommended regardless of HBeAg status 1

Monitoring During Treatment

For All Patients on Nucleos(t)ide Analogues

• Monitor compliance at every visit 4
• HBV DNA levels regularly to assess virological response 1, 3
• ALT every 6 months 4, 1, 2

Specific to Entecavir

• ALT monitoring every 6 months is sufficient 4, 1
• No routine renal monitoring required unless baseline renal disease 7

Specific to Tenofovir

• Baseline: serum creatinine and spot urine protein/creatinine ratio 4, 1, 2
• Every 6 months: ALT and serum creatinine 4, 1, 2
• More frequent monitoring if renal dysfunction develops 8

For Patients at Risk of HCC

• Baseline and periodic alpha-fetoprotein and liver ultrasound 1
• Continue surveillance even with viral suppression, especially in cirrhotic patients 1

Management of Treatment Failure and Resistance

Lamivudine Resistance

• Switch to adefovir or add adefovir to lamivudine 4, 3
• Switching is especially important with worsening liver disease or decompensated cirrhosis 4, 3

Multidrug Resistance

• For resistance to both lamivudine and adefovir: combine tenofovir plus entecavir 1 mg 2
• Sequential monotherapy must be avoided as it strongly promotes multidrug resistance 2

Prior Interferon Failure

• May be retreated with entecavir or tenofovir if treatment criteria are met 4, 3

Critical Pitfalls to Avoid

Discontinuation of Therapy

• Severe acute exacerbations of hepatitis B can occur after stopping treatment 7, 8
• Monitor hepatic function closely with clinical and laboratory follow-up for at least several months after discontinuation 7, 8
• Resumption of therapy may be warranted if flare occurs 8

HIV Co-infection

• Never use entecavir alone in HIV/HBV co-infected patients not on HAART due to risk of HIV resistance development 7
• Always ensure two HBV-active agents are included in the antiretroviral regimen 4, 2

Drug Interactions and Combinations

• Do not combine tenofovir with other tenofovir-containing products (TRUVADA, ATRIPLA, COMPLERA, STRIBILD, etc.) 8

Monitoring Gaps

• Failure to monitor renal function with tenofovir can lead to nephrotoxicity 8
• Inadequate monitoring after treatment discontinuation risks missing severe hepatitis flares 7, 8