Managing Hepatitis B and D
Insights on the Management of Patients With Chronic Hepatitis B and Hepatitis Delta

Released: December 01, 2022

Expiration: March 01, 2026

Maria Buti
Maria Buti, MD
Paul Y. Kwo
Paul Y. Kwo, MD
Grace LH Wong
Grace LH Wong, MD

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2015 APASL Guidelines: Criteria for Treatment of CHB

The goal of therapy for CHB is to improve the quality of life and survival of the infected person by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC, and death; and prevent the transmission of HBV to others.21

The indication for treatment of CHB is primarily based on serum HBV DNA level, serum ALT level, and severity of liver disease as assessed by clinical evaluation, liver biopsy, or noninvasive methodology (eg, transient elastography or serum risk calculators).21

Other considerations include the patient’s HBeAg status, age, family history of HCC or cirrhosis, and extrahepatic manifestations of CHB.21

For individuals with CHB for whom treatment is not currently indicated, active monitoring is recommended. For many of these individuals, treatment candidacy may change in the future as their disease progresses. For this reason, patients must be followed at regular intervals as outlined within the guidelines.

2015 APASL Guidelines: Extrahepatic Manifestations

Some extrahepatic manifestations of CHB that may cause concern and may be an indication for treatment include glomerulonephritis, polyarteritis, mixed cryoglobulinemia, and dermatologic manifestations (eg, papular acrodermatitis).21

If the patient is HBsAg positive with active HBV replication, these extrahepatic manifestations may respond to anti-HBV therapy. However, hepatic manifestations that are immune mediated may be worsened by treatment with pegIFN-α.

In severe cases, plasmapheresis, corticosteroids, and intravenous immunoglobulin combined with oral nucleos(t)ide analogue therapy may be useful.21

2015 APASL Guidelines: Monitor vs Treat in HBeAg-Positive Patients

The decision to monitor vs treat differs based on the patient’s HBeAg status. This figure depicts the decision tree for HBeAg-positive patients.

Noncirrhotic patients with lower levels of HBV DNA (<20,000 IU/mL) may be monitored every 3 months regardless of ALT level. If ALT is elevated, other causes of this elevation should be excluded. Using results from noninvasive tests and/or liver biopsy, fibrosis should be assessed noninvasively, with liver biopsy pursued only if noninvasive assessment indicates significant fibrosis, ALT remains persistently elevated, the patient is older than 35 years of age, or there is a family history of HCC or cirrhosis. Treatment is indicated for these patients when either of the following is demonstrated21:

  • Moderate to severe inflammation defined as METAVIR activity score A2/3 or Ishak activity score >3/18 by biopsy
  • Significant fibrosis defined as METAVIR fibrosis score ≥ F2 or Ishak fibrosis stage ≥3 by liver biopsy, liver stiffness ≥8 kPa by FibroScan, or APRI ≥1.5

In HBeAg-positive patients with HBV DNA >20,000 IU/mL, ALT level is the criterion that indicates the need for treatment.

  • If ALT is normal or within 1-2 times the ULN, the patient may be monitored every 3 months. The same assessment of fibrosis and inflammation should be undertaken and used to dictate indication for treatment, as in HBeAg-positive patients with lower HBV DNA levels.

If ALT is persistently elevated (>2 x ULN with >1 month between observations), treatment should be considered and fibrosis assessed. Noninvasive methods are especially helpful if the patient starts therapy without a liver biopsy. If there is no concern of hepatic decompensation, the patient may be observed for 3 months before starting therapy.21

Hep B Consult: Young Man With HBeAg-Positive CHB, Elevated HBV DNA, and Normal ALT

Using the associated Interactive Decision Support Tool, “Hep B Consult: US, European, and Asian-Pacific Guideline Recommendations on Whether and How to Treat HBV and HDV,” you can see guideline recommendations for CHB management for any patient characteristics entered.

This figure shows the recommendations for a 27-year-old man with HBeAg-positive CHB and the following characteristics:

  • ALT 1.2 x ULN
  • HBV DNA 1.5 million IU/mL
  • No liver necroinflammation or fibrosis
  • No other comorbidities
  • No hepatitis delta infection

2015 APASL Guidelines: Monitor vs Treat in HBeAg-Negative Patients

This figure depicts the decision tree for HBeAg-negative patients. For these patients, the HBV DNA level indicated for therapy is much lower than for their HBeAg-positive counterparts: 2000 IU/mL.

Noncirrhotic patients with HBV DNA levels <2000 IU/mL should be monitored regardless of ALT level.

  • If ALT is elevated, monitoring should be undertaken every 3 months, and other causes of this elevation should be excluded.
  • If ALT is normal, monitoring can be every 3-6 months for ALT and every 6-12 months for HBV DNA.
  • Fibrosis should be assessed noninvasively with liver biopsy pursued only if noninvasive assessment indicates significant fibrosis, ALT remains persistently elevated, the patient is older than 35 years of age, or there is a family history of HCC or cirrhosis. Treatment is indicated for these patients only when moderate to severe inflammation or significant fibrosis is found, the diagnostic cutoffs of which are described above.21

In patients with HBV DNA >2000 IU/mL, treatment should be considered.

  • If ALT is normal or within 1-2 x ULN, the same assessment of fibrosis and inflammation should be undertaken, as in the HBeAg-negative patient with a lower HBV DNA level. Treatment should commence if moderate to severe inflammation or significant fibrosis is present, the diagnostic cutoffs of which are described above.
  • If ALT is persistently elevated (>2 x ULN with >1 month between observations) and the patient does not seroconvert, treatment should be considered.
  • Fibrosis should be assessed either by liver biopsy or noninvasively. Noninvasive methods are especially helpful if the patient starts therapy without cirrhosis assessment. If there is no concern of hepatic decompensation, the patient may be observed for 3 months before starting therapy.21

2015 APASL Guidelines: Monitoring

Patients not considered eligible for treatment should be followed regularly by assessing changes in HBV DNA, ALT level, and alpha fetoprotein. Liver histology should be followed by ultrasound and regular fibrosis assessment, either by liver biopsy or by noninvasive methods.21

2015 APASL Guidelines: Criteria for Selecting PegIFN-α vs Nucleos(t)ide Analogues

The 2 therapeutic approaches currently used for the suppression of HBV replication are nucleos(t)ide analogues and immune-based therapies (ie, pegIFN-α).22

The main advantages of pegIFN-α are the absence of resistance and the potential for immune-mediated control of HBV infection. The latter may result in sustained virologic response off treatment and a chance for HBsAg loss in patients who achieve and maintain undetectable HBV DNA.

Because of different modes of action, the goals of treatment differ. In those receiving pegIFN-α, the goal of therapy is sustained HBV suppression (ie, HBV DNA <2000 IU/mL) and normalization of ALT; for nucleos(t)ide analogue therapy, the goal is undetectable HBV DNA and normalization of ALT.

PegIFN-α is administered by subcutaneous weekly injections; its duration of therapy is finite, generally 48 weeks. Treatment with nucleos(t)ide analogues is administered orally; treatment duration is indefinite and may be prolonged.

PegIFN-α is contraindicated in patients with hepatic decompensation, immunosuppression, pregnancy, and psychiatric or medical contraindications. Potential adverse events including influenza-like symptoms, loss of appetite, insomnia, diarrhea, dryskin, temporary hair loss, injection-site reactions, and depression are frequent. This therapy may be more appropriate for younger patients who are more likely to tolerate therapy and have the best chance for seroconversion.

PegIFN-α–induced HBeAg seroconversion may be more durable than nucleos(t)ide analogue–induced HBeAg seroconversion. With nucleos(t)ide analogue therapy, there is a high rate of viral relapse on therapy cessation.

2015 APASL Guidelines: Peginterferon

The preferred first-line interferon-based options are pegIFN-α 2a and pegIFN-α 2b.21 Pegylation involves the attachment of polyethylene glycol to interferon. This process has been shown to significantly extend half-life, reduce immunogenicity, and enhance biologic activity when compared with the native protein.22

PegIFN-α regimens have several potential adverse events that must be monitored carefully. On-therapy monitoring includes a full blood count and serum ALT every month, thyroid-stimulating hormone and HBsAg every 3 months, and adverse events through the entire 12 months of treatment. HBeAg and anti-HBe (if HBeAg positive) and HBV DNA should be assessed every 6 months. In patients with compensated cirrhosis, extra caution and monitoring are recommended. As an example, HBV DNA should be monitored every 3 months during the first year of treatment.

2015 APASL Guidelines: Nucleos(t)ide Analogues

TDF 300 mg/day and ETV 0.5 mg/day are the APASL preferred nucleos(t)ide analogues. One of these should be chosen for first-line therapy.21 These nucleos(t)ide analogues are preferred over adefovir, lamivudine, and telbivudine because both are potent with high barriers to resistance on treatment failure.21 

Note that tenofovir alafenamide was not yet available at the time these guidelines were published and, therefore, has not been incorporated into the guidance.

Recommended monitoring on nucleos(t)ide analogue therapy is less frequent than for pegIFN-α treatment. On-therapy monitoring for patients receiving nucleos(t)ide analogue therapy includes HBeAg and anti-HBe (if HBeAg positive) and serum ALT every 3 months and HBV DNA at Months 3 and 6 of treatment and then every 3-6 months thereafter. In patients receiving adefovir or TDF, renal function and a bone profile should be done every 3 months.21

Hep B Consult: Middle-Aged Woman With HBeAg-Negative CHB, Elevated HBV DNA and ALT

Using the associated Interactive Decision Support Tool, “Hep B Consult: US, European, and Asian-Pacific Guideline Recommendations on Whether and How to Treat HBV and HDV,” you can see guideline recommendations for CHB management for any patient characteristics entered.

This figure shows the recommendations for a 45-year-old woman with HBeAg-negative CHB and the following characteristics:

  • ALT 2.7 x ULN
  • HBV DNA 455,000 IU/mL
  • No liver necroinflammation or fibrosis
  • No other comorbidities
  • No hepatitis delta virus

The guidelines recommend treatment with any of the recommended agents in this scenario.

2015 APASL Guidelines: Managing CHB in Patients With Cirrhosis

Patients with cirrhosis should be treated regardless or HBV DNA or ALT levels.21 Evidence for treating is strongest if HBV DNA >2000 IU/mL.

Those with compensated cirrhosis by liver biopsy or noninvasive methods should be treated with pegIFN-α, TDF, or ETV.

Urgent treatment with TDF or ETV should be pursued for those with decompensated cirrhosis. Further histologic assessment is not needed. Liver transplantation should be considered if the patient does not stabilize on treatment.

There is no treatment authorized for patients dually infected with HBV and HDV who have decompensated cirrhosis.

2015 APASL Guidelines: Managing CHB in Patients Undergoing Liver Transplantation

Patients with CHB preparing for liver transplantation should be referred to a specialist and treated with TDF or ETV with the goal of achieving undetectable HBV DNA and, therefore, reducing risk of HBV recurrence. Lifelong prophylactic therapy is recommended after transplantation.

The addition of HBIg to TDF or ETV therapy is stratified:

  • Patients at “high risk” of HBV recurrence (ie, those with detectable HBV DNA at liver transplantation, drug-resistant HBV, coinfection with HIV or HDV, HCC, or poor adherence to treatment) should receive concomitant HBIg for up to 1 year
  • Patients at “low risk” of HBV recurrence (ie, those with undetectable HBV DNA at the time of liver transplantation and no other risk factors) can receive TDF or ETV without HBIg

Bulevirtide is not expected to be indicated in patients with liver transplant and HBV/HDV dual infection.

2015 APASL Guidelines: Managing CHB in Patients With HIV Coinfection

Patients with HBV/HIV coinfection should consider early therapy with agents that are active against both viruses. HIV coinfection has been shown to hasten the progression of liver fibrosis in HBV.23

The 2015 APASL guidelines do not provide treatment recommendations on HBV/HDV/HIV triple coinfection.

The recommended antiviral therapy is TDF plus (emtricitabine or lamivudine administered at the anti-HIV dose, 300 mg once daily) plus a third agent active against HIV.

TDF, lamivudine, or ETV should not be used as single agents to avoid the potential of HIV resistance to these drugs.

2015 APASL Guidelines: Managing CHB in Patients With HCV Coinfection

The primary goal for treatment of HCV and HBV coinfection is to eliminate or permanently suppress both viruses with the long-term goal of reducing or preventing hepatic necroinflammation, preventing progression to cirrhosis and the development of HCC, and ultimately prolonging survival.21

The 2015 APASL guidelines do not provide treatment recommendations on HBV/HCV/HDV triple coinfection.

The therapeutic strategy is to identify the dominant virus before starting therapy. This is accomplished by measuring HBV DNA and HCV RNA and determining if the patient meets criteria for treatment of either or both viruses.21

Note that the APASL guidelines were published before HCV DAA therapy became more commonly used in the region. When deciding on therapy for HCV, consider referring to the most recent HCV guidelines from APASL and speaking with an HBV expert about the impact of this selection on HBV management.

  • In those with active HCV and inactive HBV, therapy for HCV should commence; guidelines currently recommend pegIFN-α plus ribavirin. The patient should be observed for HBV reactivation.
  • If both infections are active, guidelines currently recommend that HCV be treated with pegIFN-α plus ribavirin and the patient be observed for HBV response or reactivation. Conversely, the patient could be treated for both viruses with pegIFN-α plus ribavirin plus an HBV nucleos(t)ide analogue.
  • If HBV is active and HCV inactive, the patient should be treated for HBV with pegIFN-α or a nucleos(t)ide analogue.
  • If both viruses are inactive, the patient can be observed.

2015 APASL Guidelines: Managing CHB in Patients With HDV Dual Infection

In patients dually infected with HBV and HDV, HDV is generally the dominant virus because it suppresses HBV through replication.

These patients should be treated with pegIFN-α for 12-18 months with continued monitoring for at least 6 months following treatment end.

Bulevirtide is an entry inhibitor for the treatment of HDV that has conditional authorization in the European Union and is not yet available for use in countries in the Asia-Pacific region.

In patients with persistent or fluctuating serum HBV DNA >2000 IU/mL, follow-up treatment with nucleos(t)ide analogues can be considered.21

2015 APASL Guidelines: Managing CHB in Pregnant and Breastfeeding People

Special considerations apply for people chronically infected with HBV who are pregnant or considering pregnancy.

People considering pregnancy should be treated with pegIFN-α because of the finite duration of treatment.20 These people should be advised not to become pregnant while receiving pegIFN-α therapy.

Those already pregnant when HBV is diagnosed should be monitored for HBeAg, HBV DNA status, and ALT level.21

  • If the pregnant person meets the criteria for HBV therapy, she may be treated with TDF, a pregnancy category B drug
  • If the pregnant person has stable liver disease, short-term TDF or telbivudine therapy may be recommended if HBV DNA is >6-7 log10 IU/mL. This is primarily a strategy to prevent perinatal transmission and can be stopped at birth if there is no indication for treatment at that time.20 This strategy could also be used in pregnant people with lower HBV DNA levels

The guidelines do not endorse breastfeeding during nucleos(t)ide analogue treatment.

There are no recommended treatments for HDV during pregnancy.

2015 APASL Guidelines: Managing CHB in Patients With Chronic Kidney Disease, Those Undergoing Dialysis or Renal Transplantation

Patients with renal disease should be screened for HBV infection, and although vaccine responsiveness is impaired, HBV-seronegative patients should be vaccinated.21

Renal patients undergoing anti-HBV therapy should be followed not only for treatment efficacy, but also for stage of liver disease and renal disease status.21

In CHB patients with renal dysfunction who require treatment for HBV, pegIFN-α or nucleos(t)ide analogues may be used. Preferred first-line options are ETV and telbivudine. If ETV or TDF are used, the dose should be adjusted if CrCl <50 mL/min.

HBV treatment for those undergoing renal transplantation should be restricted to nucleos(t)ide analogue therapy. Nucleos(t)ide analogues should be administered prophylactically to HBsAg-positive patients undergoing renal transplantation. PegIFN-α is contraindicated because of the risk of organ rejection associated with this drug.21

Bulevirtide is not expected to be indicated in patients with renal transplant and HBV/HDV dual infection.

2015 APASL Guidelines: Managing CHB in Patients Receiving Immunosuppressive Therapy or Chemotherapy

Patients being prepared for immunosuppressive therapy or cytotoxic chemotherapy should be screened for HBsAg and anti-HBc before these therapies are started.21

If the patient is positive for HBsAg, prophylactic antivirals should be given during immunosuppressive therapy and for 12 months after, regardless of HBV DNA level.21

If the patient is negative for HBsAg but positive for anti-HBc, he or she should be tested for HBV DNA. If HBV DNA is detectable, treatment should ensue as outlined above for HBsAg-positive patients; if undetectable, HBV DNA and ALT should be monitored. Treatment with nucleos(t)ide analogues should commence upon reactivation before ALT becomes elevated.21

Treatment of HBV/HDV dual infection in a patient receiving immunosuppressive therapy or chemotherapy must be considered on a case-by-case basis.