What is the WHO recommended treatment for hepatitis B?

WHO Recommendations for Hepatitis B Treatment

For resource-constrained settings, the WHO recommends tenofovir (either tenofovir disoproxil fumarate or as part of emtricitabine/tenofovir combination) or entecavir as first-line treatment for chronic hepatitis B, with treatment decisions based on HBV DNA levels, ALT elevation, and presence of cirrhosis. 1

First-Line Treatment Selection

Preferred Agents in Resource-Constrained Settings

• Tenofovir-based regimens are the primary WHO recommendation, particularly for HBV/HIV co-infected patients, using either emtricitabine/tenofovir or lamivudine/tenofovir as fixed-dose combinations. 1

• Entecavir is an alternative first-line option for HBV mono-infected patients in resource-limited settings, offering high potency with minimal resistance (<1% at 4 years in treatment-naïve patients). 1, 2

• These agents are prioritized because they have high genetic barriers to resistance and excellent viral suppression rates, critical factors when monitoring resources are limited. 3, 4

Rationale for WHO Recommendations

The WHO specifically selected these agents for resource-constrained settings because:

• Tenofovir shows no documented resistance in initial studies of treatment-naïve patients, making it ideal when HBV DNA monitoring is unavailable. 1, 5

• Fixed-dose combinations simplify treatment adherence and reduce pill burden, particularly important in co-infected patients. 1

• Both drugs can be monitored primarily through ALT and creatinine measurements when HBV DNA testing is unavailable, rather than requiring expensive viral load monitoring. 1

Treatment Indications

HBV Mono-Infection

• Treat patients with HBV DNA ≥2,000 IU/mL (for HBeAg-negative) or ≥20,000 IU/mL (for HBeAg-positive) AND ALT >2× upper limit of normal. 3, 5

• All patients with cirrhosis and detectable HBV DNA require treatment regardless of ALT levels, as they are at highest risk for hepatic decompensation and hepatocellular carcinoma. 3

• Patients with moderate to severe inflammation or significant fibrosis on biopsy should receive treatment even if ALT is only minimally elevated. 2, 5

HBV/HIV Co-Infection

• All co-infected patients requiring treatment for either HBV or HIV should receive triple antiretroviral therapy including two agents active against HBV (emtricitabine/tenofovir or lamivudine/tenofovir). 1

• If patients are already on lamivudine without tenofovir and found to be HBsAg-positive, switch to include tenofovir to prevent resistance development. 1

• This approach prevents the emergence of lamivudine resistance, which occurs in up to 70% of patients during the first 5 years of monotherapy. 1

Monitoring in Resource-Limited Settings

When HBV DNA Testing is Unavailable

For entecavir treatment:

• Monitor medication compliance in all patients. 1
• Measure ALT every 6 months. 1

For tenofovir treatment:

• Measure baseline serum creatinine and spot urine protein/creatinine ratio if possible. 1
• Monitor ALT and creatinine every 6 months. 1
• If renal tests are abnormal, use tenofovir with caution and reduced dosing. 1
• Manage comorbidities, particularly diabetes and hypertension, to reduce nephrotoxicity risk. 1

When HBV DNA Testing is Available

• Measure HBV DNA levels every 3-6 months to assess virologic response and detect early resistance. 5
• The HBV DNA level at week 24 is particularly critical—patients failing to achieve adequate suppression require treatment modification. 1
• Primary treatment failure (HBV DNA reduction <2 log10 IU/mL at week 24 with good compliance) warrants genotypic resistance testing and potential treatment switch. 1

Treatment Duration and Endpoints

HBeAg-Positive Patients

• Minimum 1 year of treatment, continuing for 3-6 months after confirmed HBeAg seroconversion. 2, 5
• The goal is HBeAg loss with anti-HBe development and undetectable HBV DNA. 1

HBeAg-Negative Patients

• Long-term or indefinite treatment is typically required, as relapse rates reach 80-90% if treatment is stopped within 1-2 years. 1, 5
• The optimal endpoint is sustained ALT normalization with undetectable HBV DNA. 5

Ultimate Treatment Goal

• HBsAg loss with or without anti-HBs seroconversion represents the ideal endpoint for all patients, though this is achieved in only a minority with current therapies. 1, 5

Management of Drug Resistance

Multidrug Resistance

• For resistance to both lamivudine and adefovir, combine tenofovir plus entecavir 1 mg. 1
• If mutations to lamivudine, entecavir, and adefovir are detected simultaneously, tenofovir plus entecavir combination is the best option. 1
• Combining adefovir and entecavir 1 mg is an alternative approach. 1

Preventing Resistance

• Sequential monotherapy must be avoided as it is strongly associated with multidrug resistance development. 1
• Starting with high genetic barrier agents (entecavir or tenofovir) prevents the resistance cascade that occurs with lamivudine or adefovir monotherapy. 1, 6, 7

Special Populations

Pregnant Women

• Tenofovir is preferred during pregnancy due to its pregnancy category B classification and safety profile. 5
• Antiviral therapy in the third trimester is recommended for mothers with high viral load to prevent mother-to-child transmission. 3

Children

• Children with chronic HBV rarely require treatment unless they have advanced fibrosis or cirrhosis. 1
• For children meeting treatment criteria with ALT >2× normal for >6 months, consider therapy with appropriate pediatric dosing. 2

Patients with Renal Dysfunction

• Entecavir, tenofovir alafenamide (TAF), or besifovir are preferred for patients with renal dysfunction or bone disease. 3
• Adefovir requires dose adjustment and close renal monitoring (BUN and creatinine every 1-3 months). 2

Critical Pitfalls to Avoid

• Never use interferon-based therapy in decompensated cirrhosis—it is contraindicated due to risk of serious complications and hepatic decompensation. 2
• Do not stop treatment in HBeAg-negative patients after short courses—the extremely high relapse rate necessitates long-term therapy. 1
• Avoid adding lamivudine to adefovir-resistant patients or vice versa—this promotes multidrug resistance rather than controlling it. 1
• Monitor compliance rigorously—inadequate adherence is a primary driver of resistance development and treatment failure. 1, 4