What is the recommended treatment for a patient with Hepatitis B virus (HBV) infection?

Treatment of Chronic Hepatitis B Virus Infection

First-line treatment for chronic HBV infection should be entecavir (0.5 mg daily) or tenofovir (either tenofovir disoproxil fumarate 300 mg daily or tenofovir alafenamide) as monotherapy, due to their superior potency, high genetic barrier to resistance, and proven long-term efficacy in preventing progression to cirrhosis, liver failure, and hepatocellular carcinoma. 1

Treatment Decision Algorithm

HBeAg-Positive Patients

• Initiate treatment when HBV DNA >20,000 IU/mL AND ALT >2× upper limit of normal (ULN) 1
• First-line options: entecavir 0.5 mg daily, tenofovir disoproxil fumarate 300 mg daily, or tenofovir alafenamide 1
• Entecavir achieves virologic suppression (HBV DNA <50 IU/mL) in 83% of patients after 96 weeks, with no genotypic resistance detected after 8 years in treatment-naive patients 1
• Tenofovir disoproxil fumarate demonstrates 93% virologic suppression at 48 weeks and maintains efficacy even in patients with baseline viral loads ≥9 log10 copies/mL, with no resistance detected after 8 years 1
• Continue nucleos(t)ide analogue for at least 1 year after HBeAg seroconversion, then an additional 3-6 months 1
• Peginterferon alfa-2a (180 mg weekly subcutaneously for 48 weeks) can be considered in select patients, particularly those with genotype A or B, high ALT, low HBV DNA, and younger age 1

HBeAg-Negative Patients

• Initiate treatment when HBV DNA >2,000 IU/mL AND ALT >2× ULN 1
• First-line options: entecavir, tenofovir (DF or AF), or peginterferon alfa-2a 1
• Long-term or indefinite treatment typically required, as relapse rates reach 80-90% if stopped within 1-2 years 2, 1

Compensated Cirrhosis

• Treat if HBV DNA ≥2,000 IU/mL, regardless of ALT level 1
• Strongly prefer entecavir or tenofovir over lamivudine due to high resistance rates with lamivudine (up to 70% over 5 years) that could precipitate decompensation 2, 1
• Peginterferon may be considered in select patients if liver function is well preserved, with careful monitoring for deterioration 1

Decompensated Cirrhosis

• Immediately treat all patients with any detectable HBV DNA, regardless of viral load level, HBeAg status, or ALT 1
• Use entecavir 1 mg daily (higher dose than compensated disease) or tenofovir 1, 3
• Peginterferon is absolutely contraindicated due to risk of liver failure and further decompensation 1

Agents to Avoid as First-Line Therapy

Do not use lamivudine, adefovir, telbivudine, or clevudine as first-line treatment due to low potency and/or high resistance rates. 1

• Lamivudine has resistance rates up to 70% over 5 years 2
• Adefovir has inferior efficacy compared to tenofovir and resistance rates of 3%, 9%, 18%, and 28% after 2,3,4, and 5 years respectively 1, 4
• Telbivudine has high resistance rates despite potent antiviral activity 1

Critical Special Populations

Lamivudine-Experienced Patients

• Avoid entecavir entirely - even brief prior lamivudine exposure creates archived resistance mutations in HBV covalently closed circular DNA that serve as foundation for entecavir resistance 1
• Use tenofovir (DF or AF) instead 1

Patients with Renal Dysfunction or Bone Disease Risk

• Switch from tenofovir DF to entecavir or tenofovir AF based on prior treatment history 1
• Monitor renal function closely during therapy, particularly with tenofovir DF 1, 5
• Consider monitoring bone density in patients on tenofovir DF with risk factors 1

HIV/HBV Co-infection

• All HIV-infected persons should be tested for HBsAg 1, 6
• Use triple combination antiretroviral therapy including two agents active against HBV (emtricitabine/tenofovir or lamivudine/tenofovir, preferably as fixed-dose formulations) 1, 6
• Treatment should include agents active against both viruses to prevent development of resistance 6
• If HIV is untreated, entecavir may increase the chance of HIV resistance to HIV medication 3

Cancer Patients Receiving Chemotherapy/Immunosuppression

• Patients with chronic HBV infection (HBsAg-positive) or past exposure (HBsAg-negative and anti-HBc–positive) who are receiving higher-risk chemotherapy require antiviral prophylaxis with tenofovir or entecavir 2
• Preemptive antiviral prophylaxis with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide is recommended when HBsAg or HBV DNA is positive 2
• Treatment should be continued for at least 12 months after discontinuation of chemotherapy or immunosuppressive therapy (18 months for rituximab-based regimens and HSCT) 2
• Patients with isolated anti-HBc positivity should be monitored with HBsAg, ALT, and HBV DNA testing every 3 months during therapy and up to 6 months after 2

Pregnancy

• Prophylactic treatment is indicated in the last trimester of pregnancy in women with high viraemia to prevent vertical transmission 7

Monitoring During Treatment

• Check HBV DNA and ALT every 3-6 months 1
• Monitor HBeAg status regularly in HBeAg-positive patients 1
• Monitor renal function, particularly with tenofovir DF 1
• For patients being monitored without prophylaxis, HBV-DNA levels should be obtained every 1-3 months 2
• Patients should be monitored for up to 12 months after cessation of anti-HBV therapy 2

Managing Inadequate Response

• First, verify medication adherence - this is the most common cause of breakthrough rather than true resistance 1
• For partial virologic response (detectable HBV DNA after 48 weeks on high genetic barrier drugs), switch to tenofovir if on entecavir, or add tenofovir if needed 1
• For confirmed drug resistance, switch to tenofovir (DF or AF) or combine entecavir with tenofovir 1

Treatment Goals and Duration

Primary Goals

• Sustained suppression of HBV DNA to undetectable levels to prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma 1, 7
• Secondary goals include ALT normalization and histologic improvement 1
• Ideal endpoint is HBsAg loss with or without anti-HBs seroconversion 2, 1

Duration Considerations

• Peginterferon alfa-2a: 48 weeks, with consideration to stop if no HBsAg decline at week 12 1
• Nucleos(t)ide analogues: potentially lifelong in cirrhotic patients, continuing until HBsAg loss occurs 1
• For HBeAg-positive patients, treatment should be continued for at least 6 months after loss of HBeAg and appearance of anti-HBe 2
• For HBeAg-negative/anti-HBe-positive patients, relapse rates are 80%--90% if treatment is stopped in 1--2 years 2

Critical Pitfalls to Avoid

• Do not discontinue therapy prematurely in HBeAg-negative patients or those with cirrhosis, as this can lead to severe hepatitis flares 1
• Severe acute exacerbations of hepatitis may occur in patients who discontinue treatment; monitor hepatic function closely for at least several months after discontinuation 2, 5
• Patients should remain under the care of a physician while taking treatment and should not stop medication without discussing with their healthcare provider 3
• Treatment with entecavir or tenofovir has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination 3
• All patients anticipating systemic anticancer therapy should be tested for HBV by 3 tests—HBsAg, anti-HBc total immunoglobulin or IgG, and antibody to hepatitis B surface antigen—but anticancer therapy should not be delayed 2
• Coordination of care with a clinician experienced in HBV management is recommended for patients with chronic HBV to determine HBV monitoring and long-term antiviral therapy after completion of anticancer therapy 2