The following patients should be considered for treatment, based on strong recommendations from EASL¹⁷:

• All patients with HBeAg-positive or HBeAg-negative CHB with HBV DNA >2000 IU/mL; ALT > ULN and moderate liver necroinflammation or fibrosis (evidence from randomized, controlled trials)
• Patients with compensated or decompensated cirrhosis who have detectable HBV DNA, regardless of ALT levels (evidence from randomized, controlled trials)
• Patients with HBV DNA >20,000 IU/mL and ALT >2 x ULN, regardless of level of fibrosis (evidence from cohort or case-control analytic studies)
  
  According to EASL guidelines, the ULN for ALT is approximately 40 IU/L.
  
  The following patients may also be considered for treatment, based on weaker recommendations from EASL, with evidence from opinions of respected authorities and descriptive epidemiology¹⁷:
• Patients with HBeAg-positive CHB—defined by persistently normal ALT and high HBV DNA levels—who are older than 30 years of age, regardless of the severity of liver histological lesions
• Patients with HBeAg-positive or HBeAg-negative CHB and family history of HCC or cirrhosis and extrahepatic manifestations, even if typical treatment indications are not fulfilled

To learn about choosing treatments for HBV, see the section in this module titled, “2017 EASL Guidelines: What to Start as Initial HBV Therapy.”

EASL guidelines recommend that patients with CHB not eligible for antiviral therapy should be monitored on the following schedule¹⁷:

• Those with HBeAg-positive CHB who are younger than 30 years of age should have:
  • ALT measurements every 3 months
  • HBV DNA determinations every 6-12 months
  • Assessment of liver fibrosis by biopsy or noninvasive measures every 12 months
• Those with HBeAg-negative CHB and serum HBV DNA <2000 IU/mL should have:
  • ALT measurements every 6-12 months
  • Periodic HBV DNA and liver fibrosis assessments, perhaps every 2-3 years

  Monitoring can be less frequent depending on HBsAg levels.

• For those with HBsAg <1000 IU/mL, ALT levels can be measured every 12 months and HBV DNA and liver fibrosis can be assessed every 3 years.
• If HBsAg ≥1000 IU/mL, ALT should be assessed every 6 months and HBV DNA and liver fibrosis assessment at least every 2 years.
• Patients with HBeAg-negative CHB and serum HBV DNA ≥2000 IU/mL should be followed with ALT determinations every 3 months for the first year and every 6 months thereafter for at least 3 years. HBV DNA and liver fibrosis (by noninvasive methods) should be assessed each year.

If indications for treatment are not met, lifetime follow-up is recommended to monitor for changes that could indicate treatment.

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 to minimal liver necroinflammation or fibrosis
• No other comorbidities
• No hepatitis delta infection

There are several therapeutic choices for patients with CHB. These choices can be tailored to each patient, depending on demographic and disease characteristics.¹⁷

The preferred first-line antiviral therapies for patients with CHB are pegIFN-α or nucleos(t)ide analogues.¹⁷

Several nucleos(t)ide analogues have been approved for first-line therapy in Europe: ETV, TAF, TDF, adefovir, lamivudine, and telbivudine. The first 3 in this list are the currently preferred nucleos(t)ide analogues owing to their high level of potency in suppressing HBV DNA replication and high barrier to resistance at treatment failure.

On-treatment monitoring of all patients treated with nucleos(t)ide analogue should include the following:

• Liver function tests every 3-4 months during the first year and every 6 months thereafter
• Serum HBV DNA determined every 3-4 months in the first year and then every 6-12 months
• HBsAg every 12 months if HBV DNA remains undetectable
• Testing for anti-HBs in patients who clear HBsAg

  The duration of nucleos(t)ide analogue therapy in CHB may be prolonged. The stopping rules defined by EASL include the following¹⁷:

• Confirmed HBsAg loss, with or without anti-HBs seroconversion
• After 12 or more months of consolidation therapy in noncirrhotic HBeAg-positive CHB patients who achieve stable HBeAg seroconversion; additional monitoring of these patients is recommended
• After 3 years or longer of virologic suppression with nucleos(t)ide analogue therapy in noncirrhotic HBeAg-negative patients if posttherapeutic monitoring can be accomplished

PegIFN-α should only be considered for patients with mild or moderate CHB or for selected patients with compensated cirrhosis and no portal hypertension. PegIFN-α has a defined treatment duration of 48 weeks, although this can be extended in some HBeAg-negative CHB patients.

PegIFN-α is delivered by subcutaneous injection and is associated with many potential adverse events.

Monitoring of patients receiving pegIFN-α should include the following:

• ALT measurement monthly and thyroid-stimulating hormone measurement every 3 months
• Serum HBV DNA and HBsAg levels in all CHB patients and HBeAg and anti-HBe in HBeAg-positive CHB patients should be checked at 3, 6, and 12 months of pegIFN-α treatment and at 6 and 12 months following treatment

Sustained HBV DNA <2000 IU/mL or HBsAg loss, together with ALT normalization in all CHB patients as well as with HBeAg seroconversion in HBeAg-positive CHB patients are the desired treatment endpoints for pegIFN-α. Early discontinuation (before 48 weeks) of pegIFN-α is generally due to indications of nonresponse.

According to EASL guidelines, several patient and disease characteristics may guide the choice of ETV, TAF, or TDF.¹⁷

TDF has been shown in many clinical trials of patients with HIV to be associated with decreases in bone density and renal function during the first 2 years of use, particularly when used in a regimen with a boosted protease inhibitor.^18,19 Therefore, EASL guidelines suggest that it may be judicious to choose ETV or TAF for older patients or for patients with bone disease or decreased renal function.

Note that ETV dose may need to be adjusted in patients with an estimated glomerular filtration rate <50 mL/min, whereas no dose adjustment of TAF is required in adults and adolescents 12 years of age or older and ≥35 kg body weight with an estimated creatinine clearance >15 mL/min or in adults with creatinine clearance <15 mL/min who are receiving dialysis, per European Medicines Agency labeling.

TAF may be chosen over ETV in patients coinfected with HIV because TAF may be incorporated into a complete suppressive HIV antiretroviral therapy regimen and in patients with lower renal function, as noted above. TAF would also be preferable in patients with previous lamivudine experience, even if adefovir resistance is not present.

ETV may be preferred over TAF in patients for whom cost is an issue, because generic ETV is available. With dose adjustment, ETV may also be preferable for patients with an estimated creatinine clearance <15 mL/min and not on dialysis, where there is no dose recommendation for TAF.

According to EASL guidelines, TDF is the nucleos(t)ide analogue of choice in people who are pregnant and require therapy (eg, advanced fibrosis or cirrhosis).

In pregnant people already receiving nucleos(t)ide analogue therapy, TDF should be continued while ETV or other nucleos(t)ide analogue should be switched.

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 infection

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

What if she were older or had a risk of renal or bone disease?

In this case, the guidelines recommend treatment with ETV or TAF because TDF is associated with decreases in bone density and renal function.

Patients with decompensated cirrhosis and CHB should be referred to a specialist and should undergo immediate antiviral treatment regardless of HBV DNA level.¹⁷ The treatment of choice in this setting is a nucleos(t)ide analogue with a high barrier to resistance, particularly ETV or TDF. TAF may be an option given its favorable safety profile, but studies in decompensated cirrhosis are currently lacking. PegIFN-α is contraindicated for these patients. If ETV is chosen, the dose should be doubled to 1 mg/day.

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

Patients with decompensated cirrhosis should be closely monitored for drug tolerability and other adverse events, including lactic acidosis and renal dysfunction. Liver transplantation may be considered.

All individuals with CHB and liver disease requiring transplantation should be referred to a specialist and should receive antiviral treatment with a nucleos(t)ide analogue, preferably before transplantation.¹⁷ After liver transplantation, patients should receive combination therapy with a nucleos(t)ide analogue plus HBIg to prevent HBV recurrence. If the patient is HBV DNA negative at the time of transplantation (ie, at low risk of recurrence), then HBIg can be discontinued, but nucleos(t)ide analogue therapy should continue.

HBsAg-negative patients receiving livers from anti-HBc–positive donors should receive lifelong prophylaxis with a nucleos(t)ide analogue. The usual choice is lamivudine owing to tolerability and low cost of the generic medication.

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

All patients who are HBsAg positive should be screened for HDV using a 2-step process to first screen for HDV antibodies and, if positive, then screen for HDV RNA. This screening should occur at least once for each person with CHB and should be repeated as clinically indicated.²⁰

All patients with chronic hepatitis delta should be considered for antiviral treatment.²⁰ Those with chronic hepatitis delta and compensated liver disease should be considered for treatment with pegIFN-α or bulevirtide.^17,20

If using pegIFN-α, treatment should last for 48 weeks. Long-term follow-up HDV RNA monitoring is recommended for all treated patients as long as HBsAg is present in . However, pegIFN-α therapy for >48 weeks is not recommended.

If using bulevirtide, an entry inhibitor that has conditional authorization by the European Medicines Agency and is indicated for those with HBV/HDV dual infection and compensated liver disease, treatment should be long term until more data are available to further define treatment duration.²⁰

Dual therapy with pegIFN-α and bulevirtide may be considered if experiencing only a partial response to monotherapy.²⁰

If ongoing HBV DNA replication is documented or in those with advanced liver disease, nucleos(t)ide analogue therapy should be considered.

HIV
All patients with HBV should be screened for HIV infection before therapy to avoid the occurrence of HIV resistance with antiviral monotherapy active against both viruses.¹⁷

Patients who are HIV/HBV coinfected should be treated immediately with a complete 3-drug antiretroviral regimen containing TAF or TDF (with emtricitabine or lamivudine 300 mg/day) and a third active agent. Stopping TAF, TDF, emtricitabine, or lamivudine should be avoided, if possible, due to the potential for hepatitis flares and decompensation with HBV reactivation. Patients with liver cirrhosis and low CD4+ cell counts should receive careful surveillance in the first months after starting antiretroviral therapy to monitor for immune reconstitution syndrome and subsequent liver decompensation due to flares of liver enzymes.

The 2017 EASL guidelines do not provide treatment recommendations on HBV/HDV/HIV triple coinfection.

HCV
Standard treatment for chronic HCV infection in the modern era is combination DAA therapy. In HCV/HBV-coinfected patients, there is a risk of HBV reactivation during or after HCV DAA therapy. Coinfected patients who are candidates for HBV therapy should receive HBV nucleos(t)ide analogue therapy concomitant with HCV DAA therapy.¹⁷ HBsAg-positive CHB patients who do not qualify for HBV treatment should receive nucleos(t)ide analogue prophylaxis through 12 weeks after DAA therapy ends. HBsAg-negative, anti-HBc–positive patients receiving HCV DAA therapy should be monitored and tested for HBV reactivation if ALT elevation is demonstrated.

The 2017 EASL guidelines do not provide treatment recommendations for HBV/HCV/HDV triple coinfection.

HBV infection should not disqualify healthcare workers from their practice, including surgery, dentistry, medicine, or other allied fields. However, precautions for percutaneous injuries should be employed to lessen transmission risk. In healthcare workers who perform exposure-prone procedures and in whom HBV DNA is >200 IU/mL, treatment with nucleos(t)ide analogues may be considered to reduce transmission risk, even if indications for treatment for personal health are not met.¹⁷

Surgeons should be monitored for compliance with HBV therapy.

In people of childbearing age who become infected with HBV, family planning should always be discussed.¹⁷ The person should be fully informed about the safety of HBV drugs during pregnancy but also about concerns of perinatal transmission of virus.

Among patients without advanced fibrosis who plan a pregnancy in the near future, antiviral therapy may be delayed until after birth. For patients with more advanced disease or cirrhosis, pegIFN-α therapy may be administered before pregnancy because of its finite duration. The patient should be cautioned to be on effective contraception during pegIFN-α treatment; pegIFN-α therapy is contraindicated during pregnancy.

If a person becomes pregnant while receiving HBV therapy, indications for HBV treatment should be re-evaluated; these indications are the same as for patients who receive an HBV diagnosis during pregnancy.

Among nucleos(t)ide analogue options during pregnancy, EASL guidelines recommend TDF,¹⁷ which is classified as pregnancy category B and has extensive data during pregnancy in HIV-positive women.²⁰ If the person is already receiving TDF, it should be continued during pregnancy. If the person is receiving ETV or another nucleos(t)ide analogue, EASL guidelines recommend that therapy should be switched to TDF.

There are no recommended treatments for HDV during pregnancy.

Prevention of perinatal transmission is accomplished by a combination of HBIg and perinatal vaccination given within 12 hours of birth. Addition of a nucleos(t)ide analogue (TDF is preferred) to the prophylactic may be considered in those with HBV DNA levels >200,000 IU/mL but normal ALT to decrease viremia. The duration of nucleos(t)ide analogue therapy is undefined but may stop at birth so as to not interfere with breastfeeding. Breastfeeding is not contraindicated in HBsAg-positive untreated people or those receiving TDF-based treatment or prophylaxis.

In patients with CHB, risk of HBV reactivation can be high in the setting of immunosuppressive therapy or chemotherapy, including with newer biological response–modifying agents. All candidates for immunosuppressive therapy or chemotherapy should be tested for HBsAg, anti-HBs, and anti-HBc before starting immunosuppressive therapy.

If HBV seronegative, vaccination is recommended.¹

In those who are HBsAg positive, referral to a hepatitis specialist is recommended and nucleos(t)ide analogue therapy should be commenced as prophylaxis or treatment, depending on the phase of infection.¹⁷ Those with CHB should be treated with ETV, TAF, or TDF, similar to the immunocompetent patient.

HBsAg-negative, anti-HBc–positive individuals should receive anti-HBV prophylaxis with ETV, TAF, or TDF for at least 12 months (or 18 months if rituximab is used) after cessation of the immunosuppressive treatment and discontinued only if the underlying HBV disease is under remission.¹⁷ Liver function and HBV DNA should be tested every 3-6 months during prophylaxis and for 12 months or longer after nucleos(t)ide analogue withdrawal.

If HBsAg-negative, anti-HBc–positive patients are viremic, they should be treated similarly to HBsAg-positive patients.¹⁷ Aviremic patients receiving highly immunosuppressive regimens or rituximab (ie, at high risk of reactivation) should receive anti-HBV prophylaxis with lamivudine, ETV, TAF, or TDF for 18 months after cessation of the immunosuppressive treatment and discontinued only if the underlying disease is under remission. Liver function and HBV DNA should be tested every 3-6 months during prophylaxis and for 12 months or longer after nucleos(t)ide analogue withdrawal.

Prophylaxis is not recommended for patients with moderate or low risk of reactivation.¹⁷ These patients should be monitored for HBsAg and/or HBV DNA every 1-3 months during and after immunosuppression, and nucleos(t)ide analogue therapy with ETV, TAF, or TDF should be started immediately—independent of ALT levels—in case of detectable HBV DNA or HBsAg seroreversion to avoid severe or possibly fatal hepatitis.

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

All candidates for dialysis and renal transplantation should be tested for HBsAg, anti-HBs, and anti-HBc before starting therapy. If HBV seronegative, vaccination is recommended.

Dialysis patients who meet HBV treatment indications should be treated with a nucleos(t)ide analogue.¹⁷ ETV is the preferred agent for nucleos(t)ide analogue–naive patients, and TAF may be considered in nucleos(t)ide analogue–naive or nucleos(t)ide analogue–experienced patients. Doses should be adjusted based on estimated glomerular filtration rate and prescribing information, if relevant. ALT may be reduced by dialysis, so care must be taken in using ALT as a marker for HBV treatment success.

All HBsAg-positive patients with renal transplantation should receive prophylaxis or treatment with a nucleos(t)ide analogue.¹⁷ As in dialysis, ETV is the preferred agent for nucleos(t)ide analogue–naive patients, and TAF may be considered in nucleos(t)ide analogue–naive or nucleos(t)ide analogue–experienced patients. In renal transplantation, renal function should be carefully monitored during treatment with nucleos(t)ide analogues. Decline of renal function during nucleos(t)ide analogue therapy may necessitate a change of treatment or dose modification.

HBsAg-negative, anti-HBc–positive renal transplantation recipients do not require prophylaxis or treatment, but they should be monitored for HBsAg; if seroconversion occurs, nucleos(t)ide analogue therapy with ETV or TAF should be immediately commenced, regardless of ALT.¹⁷

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

Extrahepatic manifestations of HBV infection include vasculitis, purpura, polyarteritis nodosa, arthralgias, peripheral neuropathy, and glomerulonephritis.

Viremic HBsAg-positive patients with extrahepatic manifestations may respond to antiviral therapy with nucleos(t)ide analogues.¹⁷ PegIFN-α should not be used because it may worsen some immune-mediated extrahepatic manifestations.