What are the current European Association for the Study of the Liver (EASL) guidelines for the management of hepatitis B?

EASL 2017 Hepatitis B Guidelines: Key Recommendations

First-Line Treatment Selection

The long-term administration of entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) as monotherapy represents the treatment of choice for chronic hepatitis B, regardless of disease severity. 1 These three nucleos(t)ide analogues (NAs) have high barriers to resistance and provide universally high levels of viral suppression. 1

• Lamivudine (LAM), adefovir (ADV), and telbivudine (TBV) are explicitly not recommended due to high resistance rates and inferior efficacy. 1
• After 8 years of TDF treatment, no resistance has been detected, and ETV resistance remains <1% after 5 years. 1

Treatment Indications

Patients Without Cirrhosis

• Treat when HBV DNA >2,000 IU/ml AND serum ALT above 40 IU/L (traditional ULN) AND at least moderate necroinflammation/fibrosis on biopsy. 1
• Patients with HBV DNA ≥20,000 IU/ml AND ALT ≥2× ULN can start treatment without liver biopsy. 1
• Patients with HBV DNA ≥2,000 IU/ml and at least moderate fibrosis may be treated even with normal ALT levels. 1
• Non-invasive markers (liver stiffness <9 kPa with normal ALT or <12 kPa with elevated ALT) can exclude severe fibrosis/cirrhosis and guide treatment decisions. 1

Patients With Cirrhosis

• All cirrhotic patients with detectable HBV DNA must be treated immediately, regardless of ALT levels or HBV DNA levels. 1, 2

Decompensated Cirrhosis: Critical Management

Patients with decompensated cirrhosis require immediate treatment with ETV or TDF, irrespective of HBV replication level, and must be assessed for liver transplantation. 1

• PegIFNα is absolutely contraindicated in decompensated disease. 1
• The licensed ETV dose for decompensated cirrhosis is 1 mg (double the standard 0.5 mg dose for compensated disease). 1
• Undetectable HBV DNA can be achieved in >80% after 1 year, reducing HCC risk. 1
• Lifelong treatment is mandatory for all decompensated patients. 1
• Close monitoring for lactic acidosis and kidney dysfunction is required. 1

Pegylated Interferon-α Strategy

PegIFNα for 48 weeks can be considered in selected patients with mild to moderate chronic hepatitis B who seek finite-duration therapy. 1

• This approach aims to induce long-term immune control rather than continuous viral suppression. 1
• Response is highly variable and depends on baseline HBV genotype, HBsAg levels, HBeAg status, and ALT elevation. 1
• Early stopping rules should be applied to discontinue therapy in patients with low likelihood of response. 1
• Many contraindications exist, including decompensated disease and significant comorbidities. 1

Treatment Response Definitions

Virological Response

• Undetectable HBV DNA by sensitive PCR assay during NA therapy. 2
• After 48-52 weeks: ETV achieves 67% response in HBeAg-positive and 90% in HBeAg-negative patients; TDF achieves 76% and 93%, respectively; TAF achieves 64% and 94%. 1

Biochemical Response

• ALT normalization to ≤40 IU/L (traditional ULN). 1
• Requires minimum 1-year follow-up post-treatment with ALT checks every 3 months to confirm sustained off-treatment response. 1

Histological Response

• Decrease in necroinflammatory activity by ≥2 points without worsening fibrosis. 1

Special Populations

Liver Transplantation

• All transplant candidates must receive NA therapy to achieve undetectable HBV DNA pre-transplant. 1
• Post-transplant: Combination of HBIG plus potent NA reduces graft infection to <5%. 1
• Selected low-risk patients (HBV DNA negative at transplant) may discontinue HBIG but require lifelong NA monoprophylaxis. 1
• High-risk patients (HBV DNA positive, HBeAg-positive, HCC, HDV/HIV co-infection) require lifelong combination therapy. 1

HIV Co-infection

• All HIV-HBV co-infected patients should start antiretroviral therapy (ART) regardless of CD4 count. 1
• TDF- or TAF-based ART regimens are mandatory as they have dual activity against both viruses. 1
• Stopping TDF/TAF-containing ART risks severe hepatitis flares and decompensation. 1

HDV Co-infection

• PegIFNα for at least 48 weeks is the treatment of choice in HDV-HBV co-infected patients with compensated disease. 1
• If ongoing HBV DNA replication exists, add NA therapy. 1

Surveillance Requirements

HCC surveillance is mandatory for all cirrhotic patients and those with moderate-to-high HCC risk scores, even under effective NA therapy. 1

• The risk of HCC remains elevated despite viral suppression in cirrhotic patients. 1
• Patients not on treatment require ALT checks every 3 months, HBV DNA every 6-12 months, and fibrosis assessment annually. 2

TAF vs. TDF: Safety Considerations

TAF demonstrates less renal tubular dysfunction and bone mineral density loss compared to TDF through 96 weeks. 1

• In patients with deteriorating renal function, low eGFR, osteopenia/osteoporosis, or older age, both ETV and TAF are suitable, with TAF having advantages in LAM-exposed patients. 1
• Long-term clinical outcome data for TAF remain limited, but HIV co-infection studies show improved eGFR and bone density when switching from TDF to TAF. 1

Treatment Duration

Long-term, potentially indefinite NA therapy is required until HBsAg loss (the optimal endpoint), which is rarely achieved. 1

• Stopping NA after achieving HBeAg seroconversion may be considered in selected HBeAg-positive cases with adequate consolidation treatment, but relapse risk is moderate. 1
• For HBeAg-negative disease, relapse risk after stopping is high. 1

Common Pitfalls

• Do not use combination NA therapies—they are not generally recommended. 1
• Do not rely on traditional ALT cutoffs alone—normal ALT does not exclude significant necroinflammation or fibrosis. 2
• Do not delay treatment in cirrhotic patients—all require immediate therapy regardless of viral load or ALT. 1, 2
• Monitor renal function carefully when using calcineurin inhibitors post-transplant with NAs. 1