For patients with CHB, the Practice Guidelines Committee of the AASLD recommends antiviral treatment of adults with immune-active CHB (hepatitis B e antigen HBeAg negative or HBeAg positive) to decrease the risk of liver-related complications.¹ They also suggest antiviral treatment in immune-tolerant adults aged older than 40 years with normal alanine aminotransferase (ALT), elevated HBV DNA (1,000,000 IU/mL), and a liver biopsy specimen showing significant necroinflammation or fibrosis.

Additional factors that may influence the choice to recommend treatment include age, family history of hepatocellular carcinoma (HCC) or cirrhosis, previous treatment history, presence of extrahepatic manifestations, and presence of cirrhosis. Certain comorbidities may also influence treatment candidacy or selection of treatment.

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.

The AASLD guidance defines immune-active and immune-tolerant CHB as follows¹:

Immune-active patients are HBsAg positive for at least 6 months. In HBeAg-positive patients, serum HBV DNA is >20,000 IU/mL; in HBeAg-negative patients, serum HBV DNA is >2000 IU/mL. These patients have persistently elevated serum aminotransferase levels. Liver biopsy or noninvasive test results show chronic hepatitis with moderate or severe necroinflammation with or without fibrosis.

Immune-tolerant patients have also been HBsAg positive for at least 6 months and are HBeAg positive. They have very high HBV DNA levels with normal or only minimally elevated serum aminotransferase levels. Liver biopsy or noninvasive test results show chronic hepatitis with minimal necroinflammation and no fibrosis. As previously noted, only a select subgroup of these patients is recommended for antiviral therapy, whereas the remainder should undergo active monitoring.

Several tests are essential to guide initiation of treatment and to evaluate patient response during antiviral therapy in patients with CHB.¹ The decision to treat now vs monitor is based primarily on serum ALT level, quantitative HBV DNA testing, and measurement of liver histology and inflammation—either by liver biopsy or noninvasive measures—because these parameters predict long-term outcomes. The presence of HBeAg may also affect the decision to treat now vs monitor.

According to AASLD guidance, the upper limit of normal (ULN) for ALT in healthy adults is 29-33 U/L for men and 19-25 U/L for women. However, to guide treatment, the AASLD uses a ULN of 35 U/L for men and 25 U/L for women.

HBV DNA is typically measured quantitatively via real-time polymerase chain reaction methodology.

The presence of cirrhosis is an indication for treatment. As we will see later, in patients without cirrhosis, tests that can accurately measure the level of fibrosis may be needed to determine treatment candidacy. Noninvasive evaluation of the liver can include transient elastography or risk calculators based on serum markers.

HBsAg quantitation is not recommended for routine testing or follow‐up of patients with CHB, but it can be used to identify true inactive carriers ( <1000 IU/mL and HBV DNA <2000 IU/mL). HBsAg quantitation may also be useful in managing patients receiving peginterferon alfa () therapy because it can help predict response to treatment and provide a stopping rule.

Viral resistance testing in treatment‐naive patients is not recommended, but it can be useful in patients with past treatment experience, those with persistent viremia on nucleos(t)ide analogue therapy, or those who experience virologic breakthrough during treatment.

HBV genotyping can be useful in patients being considered for pegIFN-α therapy. With pegIFN-α therapy, genotypes A and B are associated with higher rates of HBeAg and/or HBsAg loss than genotypes C and D. HBV genotyping is not otherwise recommended for routine testing or follow‐up of patients with CHB.

In noncirrhotic HBeAg-positive patients¹:

• If ALT is within normal limits, treatment is not currently recommended, regardless of HBV DNA
  • ALT and HBV DNA should be monitored every 3-6 months and HBeAg every 6-12 months

• If ALT is greater than the ULN but not yet 2 x ULN (regardless of HBV DNA) or if ALT is ≥2 times the ULN and HBV DNA is 2000-20,000 IU/mL:
  • Causes other than HBV should be investigated for ALT elevation. If ALT elevation persists in the absence of other causes, treatment should ensue, particularly if the patient is older than 40 years of age
  • Using results from noninvasive tests and/or liver biopsy, treatment should start if fibrosis is stage METAVIR F2 or greater and/or inflammation is stage A3 or greater
  • In addition, if HBV DNA is 2000-20,000 IU/mL, this may represent seroconversion. In these patients, HBV DNA should be monitored every 1-3 months; if persistently elevated for >6 months, treatment should be initiated
• If ALT is ≥2 x ULN and HBV DNA is >20,000 IU/mL, treatment is recommended

To learn about choosing treatments for HBV, see the section in this module entitled “2018 AASLD Guidance: What to Start as Initial HBV Therapy.”

In noncirrhotic HBeAg-negative patients, treatment decisions are guided by the following criteria¹:

• In patients with ALT within normal limits, treatment is not recommended, regardless of HBV DNA
  • In patients with higher HBV DNA (≥2000 IU/mL), ALT and HBV DNA should be monitored every 3 months for the first year and then every 6 months
  • In patients with lower HBV DNA (<2000 IU/mL), ALT and HBV DNA should be monitored every 3 months for 1 year and then every 6-12 months. HBsAg should be monitored annually
• If ALT is > ULN and HBV DNA <2000 IU/mL, or when ALT is between 1 and 2 x ULN and HBV DNA is ≥2000 IU/mL:
  • Causes other than HBV should be investigated for ALT elevation. If ALT elevation persists, treatment should ensue, particularly if the patient is older than 40 years of age
  • Using results from noninvasive tests and/or liver biopsy, treatment should start if fibrosis is METAVIR stage F2 or greater and/or inflammation is stage A3 or greater
• If ALT is ≥2 x ULN and HBV DNA is ≥2000 IU/mL, treatment is recommended

Selection of optimal HBV therapy will be addressed later in this module.

AASLD guidance recommends that patients with CHB who are not currently receiving antiviral therapy should be under surveillance.¹

• In immune-tolerant patients, ALT and HBV DNA should be monitored every 3-6 months and HBeAg every 6-12 months. These patients should be treated if HBV DNA increases to >20,000 IU/mL for 3-6 months and ALT increases to >2 x ULN. Liver biopsy should be considered in patients with persistent borderline normal or slightly elevated ALT levels, particularly in patients older than 40 years or age who have been infected with HBV from a young age. Patients with moderate to severe inflammation (A3 or higher) and/or fibrosis (F2 or higher) can be considered for antiviral therapy. Noninvasive methods may be used instead of liver biopsy; transient elastography is more accurate than serum fibrosis panels in patients with inflammation.
• Patients with inactive CHB should be followed to ensure that they remain in the inactive phase. ALT should be measured every 3 months for the first year and then every 6-12 months. If ALT becomes elevated, other causes (including HBV DNA) should be investigated. HBsAg with HBV DNA should be assayed annually.

Patients who spontaneously clear HBsAg during monitoring should still be followed for HCC indefinitely if they are at high risk (have cirrhosis, a first-degree relative with HCC, or a long duration of HBV infection).

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

The preferred first-line antiviral therapies for patients with CHB are pegIFN-α or the oral nucleos(t)ide analogues entecavir (ETV), tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF).

The decision among these treatment options may be informed in part by the patient’s desire for finite therapy because pegIFN-α has a defined treatment duration of 48 weeks, but it is delivered by subcutaneous injection and is associated with many potential adverse events.

The preferred nucleos(t)ide analogues are oral agents with favorable safety and resistance profiles. The duration of nucleos(t)ide analogue therapy in CHB may be prolonged and is indefinite for most patients.

PegIFN-α 2a 180 µg/week administered as a subcutaneous injection is a preferred treatment option for first-line therapy of CHB.¹ The duration of therapy is generally 48 weeks. Combinations of pegIFN-α and nucleos(t)ide analogue treatments have been studied but are not currently recommended.

While receiving pegIFN-α therapy, patients should be monitored with complete blood count every 1-3 months, for thyroid-stimulating hormone every 3 months, and clinically for autoimmune, ischemic, neuropsychiatric, and infectious adverse events of treatment. Potential adverse events include influenza-like symptoms, fatigue, mood disturbances, cytopenia, and autoimmune disorders in adults.

Preferred oral first-line nucleos(t)ide analogue options are ETV 0.5 mg/day, TAF 25 mg/day, or TDF 300 mg/day. Although other nucleos(t)ide analogues are approved for the treatment of CHB, ETV, TAF, and TDF are recommended owing to high levels of efficacy and a high barrier to resistance at the time of virologic failure.

While receiving therapy, patients should be evaluated for therapy-specific adverse events. Before use of nucleos(t)ide analogue monotherapy, patients should be tested for HIV to avoid potential for HIV resistance to these agents, because HBV nucleos(t)ide analogues such as TAF and TDF are also active against HIV. Patients with advanced HIV disease should be monitored for lactic acidosis, an uncommon adverse event of nucleos(t)ide analogue therapy.

Patients receiving TDF should be monitored for decline in renal function and bone mineral density, which have been documented in studies of patients with HIV receiving this agent.² Nephropathy, Fanconi syndrome, and osteomalacia are uncommon adverse events that have been seen with TDF.

Patients treated with TAF should be monitored for serum creatinine and phosphorus as well as urine glucose and protein.

The dose of ETV and TDF should be modified in patients with decreased renal function, and TAF should not be used in patients with an estimated creatinine clearance <15 mL/min, per the AASLD guidance.

(By contrast, the EASL guidelines specifically recommend the use of either TAF or ETV in patients receiving hemodialysis.¹⁷)

The dose of ETV should also be modified in lamivudine-experienced patients.

Treatment duration with nucleos(t)ide analogues is generally indefinite. The exception to this is the HBeAg-positive patient without cirrhosis who seroconverts to anti‐HBe on therapy. This patient can discontinue nucleos(t)ide analogue therapy after a period of consolidation.

In this AASLD compilation of separate, non–head-to-head studies, the efficacy of first-line therapies for CHB is outlined.^3-13 In general, HBV DNA suppression and ALT normalization are greater with nucleos(t)ide analogues than with pegIFN-α.

According to AASLD guidance, several patient and disease characteristics may guide the choice of ETV, TAF, or TDF.¹

For patients with lamivudine resistance, the ETV dose must be doubled to 1 mg/day. TAF and TDF are not affected by lamivudine resistance.

Pregnancy categories in drug prescribing information no longer use the alphabetical designation. However, at the time of writing, the AASLD guidance used letter categories to denote pregnancy safety of the nucleos(t)ide analogues. TDF is pregnancy category B (no adverse events in animal studies), and data are available in >3000 patients in the HIV Antiretroviral Pregnancy Registry.¹⁴ TAF currently has insufficient human data to inform its safety in pregnancy. ETV is pregnancy category C (adverse events in animal studies, insufficient data in humans).

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.^2,15 TAF is associated with lower rates of bone and renal abnormalities than TDF.¹⁶ AASLD suggests no preference between ETV or TDF regarding potential long‐term risks of renal and bone complications but notes that TAF is associated with lower rates of bone and renal abnormalities than TDF. In patients already at risk for renal dysfunction or bone disease, AASLD recommends consideration of ETV or TAF.

The AASLD guidance currently advises against the use of TAF in patients with estimated creatinine clearance (CrCl) <15 mL/min and those receiving hemodialysis. However, the EASL guidelines specifically recommend the use of either TAF or ETV in patients receiving hemodialysis.

Whereas ETV and TDF dose may need to be adjusted in patients with declining renal function, no dose adjustment of TAF is required in adults and adolescents 12 years of age or older and ≥35 kg body weight (with estimated CrCl ≥15 mL/min or with estimated CrCl 15 mL/min who are receiving hemodialysis).²³

In persons who are receiving TDF, renal safety monitoring with serum creatinine, phosphorus, urine glucose, and urine protein should be assessed before treatment initiation and periodically thereafter. In the absence of other risk factors for osteoporosis or osteomalacia, there is insufficient evidence for or against monitoring of bone mineral density in HBV.

TAF or TDF would be preferable over ETV in patients coinfected with HIV because TAF and TDF are each coformulated in a complete HIV antiretroviral therapy regimen that is also active against HBV. ETV must be added to a complete HIV antiretroviral therapy regimen.

ETV and TDF may be preferred over TAF in patients for whom cost is an issue because generic formulations of these drugs are available.

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 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.

Treatment is recommended for patients with compensated cirrhosis to avoid progression to decompensation regardless of HBV DNA level.¹ Nucleos(t)ide analogues are preferred owing to safety, but pegIFN-α is not contraindicated. If treatment is not offered in those with HBV DNA <2000 IU/mL, then HBV DNA should be monitored every 3-6 months and treatment initiated with any rise in HBV DNA and/or clinical .

Patients with decompensated cirrhosis and CHB should be referred to a specialist and should undergo immediate antiviral treatment, regardless of HBV DNA or ALT level.¹ ETV and TDF are the recommended first-line drugs for this population. However, TAF may be considered when these options are suboptimal, for instance, in patients with renal dysfunction and/or bone disease. PegIFN is contraindicated for these patients because of safety concerns.

PegIFN or bulevirtide (if available) can be used to treat patients with compensated cirrhosis and HBV/HDV dual infection. 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 insufficiency. Referral for concurrent consideration of liver transplantation is also indicated in appropriate candidates.

All individuals with CHB and liver disease requiring transplantation should be referred to a specialist and should receive antiviral treatment with ETV, TAF, or TDF before transplantation to reduce HBV DNA and risk of reinfection.¹

After liver transplantation, all patients should receive lifelong prophylactic therapy with a nucleos(t)ide analogue. In patients at low risk of recurrence (ie, undetectable HBV DNA at time of transplantation), coadministration of hepatitis B immunoglobulin (HBIg) is not required but may be used short term for 5-7 days. Those at high risk (eg, detectable HBV DNA at time of transplantation, with drug-resistant HBV, coinfected with HIV or HDV, or at risk for noncompliance) should be treated long term with HBIg and a nucleos(t)ide analogue. HBsAg-negative patients receiving HBsAg-negative/anti-HBc–positive grafts should be managed with lifelong nucleos(t)ide analogue therapy without HBIg.

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

All patients with HBV infection should be screened for HIV before commencing HBV therapy to avoid the occurrence of HIV resistance with antiviral monotherapy that would not fully suppress HIV.¹ Patients who are HIV/HBV coinfected should be treated immediately with a complete 3-drug antiretroviral regimen containing TAF or TDF plus (emtricitabine or lamivudine 300 mg/day) plus a third agent active against HIV. ETV should only be used in combination with a complete suppressive antiretroviral therapy regimen.

Stopping TAF, TDF, emtricitabine, or lamivudine should be avoided, if possible, due to 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 2018 AASLD guidance does not provide treatment recommendations on HBV/HDV/HIV triple coinfection.

In patients coinfected with hepatitis C virus (HCV) and HBV, a treatment strategy is selected by measuring HCV RNA and HBV DNA before treating. HCV treatment with HCV direct-acting antivirals (DAAs) is recommended for all patients with HCV viremia.¹ HBV treatment is determined by HBV DNA and ALT levels by the same criteria as for monoinfected patients.

Patients who are ineligible for HBV treatment should be monitored accordingly before, during, and after HCV DAA therapy.¹

• HBsAg‐positive patients are at higher risk of HBV DNA and ALT flares with HCV DAA therapy
  • They should be monitored for HBV DNA levels every 4‐8 weeks during HCV treatment and for 3 months after HCV treatment concludes
• HBsAg-negative, anti–HBc-positive patients are at very low risk of reactivation with HCV DAA therapy

• ALT levels should be monitored when first starting HCV treatment, at the end of HCV treatment, and during follow‐up
• Among this group of patients, HBV DNA and HBsAg testing should be reserved for those whose ALT levels increase or fail to normalize during treatment or posttreatment

The 2018 AASLD guidance does not provide treatment recommendations on HBV/HCV/HDV triple coinfection.

The 2018 AASLD guidance recommends that HBsAg‐positive persons at risk for HDV, including those with HIV infection, persons who inject drugs, men who have sex with men, and immigrants from areas of high HDV endemicity, should be tested for HDV coinfection. However, risk-based screening may not capture all patients who need to be screened and experts recommend screening all patients with CHB for HDV.

HDV screening is a 2-step process to first screen for HDV antibodies and if antibody positive, screen for HDV RNA.

HDV/HBV-dually infected patients should be treated for both viruses with 12 months of pegIFN-α therapy.¹ The primary endpoint of treatment is the suppression of HDV replication 24 weeks after the end of treatment. This is usually accompanied by normalization of ALT levels and a decrease in necroinflammatory activity on liver biopsy. Due to high rates of relapse, HDV RNA should be assessed if ALT elevation occurs after treatment. If HBV DNA levels are elevated at baseline, ETV, TAF, or TDF should be offered concurrent with pegIFN-α treatment.

Bulevirtide is an entry inhibitor for the treatment of HDV that has conditional authorization in the European Union and is being evaluated by the FDA.

Given the limited efficacy of current therapies, it is reasonable to refer patients to specialized centers that offer access to experimental therapies for HDV.

Pregnant people with immune-active CHB should be treated regarding their own health according to the criteria for nonpregnant people.

In cases where pregnant people do not meet standard indications for treatment but have HBV DNA >200,000 IU/mL, antiviral therapy is recommended to prevent perinatal transmission.

• TDF, a pregnancy category B drug with extensive usage in HIV-positive people,¹⁴ is preferred in this population for its potency and high barrier to resistance
  • Other antivirals with data during pregnancy include lamivudine and telbivudine
• Most studies initiated HBV treatment at 28-32 weeks of pregnancy and discontinued treatment between birth and 3 months later

Antiviral therapy is not recommended to reduce the risk of perinatal transmission in HBsAg-positive people with HBV DNA ≤200,000 IU/mL.¹

Infants born to HBsAg-positive people should receive immunoprophylaxis (ie, HBV vaccination with or without HBIg per WHO and CDC recommendations).

Breastfeeding is not contraindicated in people treated with nucleos(t)ide analogue therapy.¹ HBV antivirals are only minimally excreted in breast milk and are unlikely to cause significant toxicity. The parent should be educated about the potential risk of low‐level exposure to the infant.

There are no recommended treatments for HDV during pregnancy.

HBV reactivation may occur in patients who are immunosuppressed. For those preparing to undergo immunosuppressive therapy or chemotherapy (including immunomodulation), screening for HBsAg and anti-HBc should be performed before therapy starts.

If patients are HBsAg positive and anti-HBc positive, prophylactic therapy for HBV should be administered before immunosuppressive regimens are initiated.¹

HBsAg-negative, anti‐HBc–positive patients demonstrate lower risk of HBV reactivation compared with their HBsAg-positive counterparts. Accordingly, they may be initiated on HBV prophylaxis or carefully monitored for ALT, HBV DNA, and HBsAg with the intent of on‐demand anti-HBV therapy at the first sign of reactivation (elevation in HBV DNA level or HBsAg seroreversion).¹

• If monitoring is chosen, measure HBV DNA every 1-3 months; treat with ETV, TAF, or TDF upon reactivation

Individuals being treated with an anti-CD20 antibody (eg, rituximab) or undergoing stem cell transplantation should receive prophylactic therapy, regardless of HBsAg status.

When indicated, anti‐HBV prophylaxis with ETV, TAF, or TDF should be initiated as soon as possible after screening. Nucleos(t)ide analogue treatment should start before or, at the latest, simultaneously with the onset of immunosuppressive therapy. It should continue during immunosuppressive therapy and for 6 months or longer (or 12 months or longer for patients receiving anti‐CD20 therapies) after completion of immunosuppressive therapy.

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