Editor: Sang Hoon Ahn, Yonsei University College of Medicine, Korea
Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.
Chronic hepatitis B virus (HBV) infection is a global health problem [
CHB is a life-long disease that can start at the beginning of life by perinatal transmission, especially in Asian countries [
The first phase is the CHB immune tolerant phase (immune tolerant CHB). It is characterized by very high levels of HBV replication, persistently normal alanine aminotransferase (ALT) levels, and minimal or no necroinflammatory activity. During this phase, patients are typically positive and show high titers of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Inflammatory activity is assumed to be absent, which prompted the EASL to revise the name of the first phase to HBeAg-positive chronic HBV infection [
The second phase is the HBeAg-positive immune active phase. This is also termed the immune reactive or immune clearance phase [
The third phase is the immune inactive phase, previously known as the immune controlled phase [
The fourth phase is the HBeAg-negative CHB immune active phase, which was previously known as the immune escape phase or reactivation phase [
The last phase is the HBsAg loss phase, in which HBsAg is spontaneously cleared [
The treatment goals and aims were updated in the KASL guidelines [
High level HBV replication is associated with an increased risk of liver damage and liver-related complications [
Previously, most practice guidelines did not recommend antiviral therapy for CHB patients in the immune tolerant phase (
The KASL guidelines suggest liver biopsy if the patient is ≥30–40 years of age, the serum HBV DNA levels are <107 IU/mL, a noninvasive fibrosis test shows a range of significant hepatic fibrosis, or ALT is at the borderline of the ULN [
Antiviral treatment during the immune active phase decreases the risk of liver cirrhosis, hepatic decompensation, and HCC [
On the contrary, for HBeAg-negative patients with elevated HBV DNA levels (≥2,000 IU/mL) and normal ALT levels, treatment may be delayed or considered after liver biopsy, because these patients are considered to be in a gray area or transitional zone [
The KASL suggested that the immune inactive phase, which features low HBV DNA levels (<2,000 IU/mL) and normal ALT, is not an indicator for antiviral therapy [
Most guidelines recommend treating compensated liver cirrhosis if the HBV DNA level is ≥2,000 IU/mL, regardless of the ALT level [
Antiviral therapy should be initiated regardless of the ALT level if serum HBV DNA is detected in patients with decompensated liver cirrhosis [
Interferons and oral NAs represent the currently available antiviral agents [
Contrary to interferons, NAs are directly acting antiviral agents that inhibit HBV replication and have no fixed treatment duration [
Lamivudine and adefovir have been used for extended periods but are no longer recommended given their low potency and high incidence of resistance [
Entecavir and tenofovir DF have been the preferred antiviral agents for more than a decade since their approval for CHB treatment. Recently, these drugs were compared in terms of long-term treatment outcomes, especially for the prevention of HCC [
Currently, generic and less expensive forms of entecavir and tenofovir (tenofovir disoproxil or tenofovir fumarate aspartate) are available in Korea and other countries, which can improve the cost-effectiveness of antiviral treatment [
Tenofovir AF is a nucleotide reverse transcriptase inhibitor and a novel prodrug of tenofovir. It has greater plasma stability than tenofovir DF and efficiently delivers the active form of tenofovir to hepatocytes at a lower dose [
Besifovir is an acyclic nucleotide phosphonate developed in Korea that was approved by the Ministry of Food and Drug Safety in 2017 [
Currently, there is limited data regarding the use of besifovir or tenofovir AF in patients with decompensated liver cirrhosis or HCC. However, there seems to be no reason not to use these drugs. In the future, more data regarding besifovir and tenofovir AF will be available for CHB patients in various situations. The AASLD and EASL recommend entecavir, tenofovir DF, and tenofovir AF monotherapy as the preferred regimens for the treatment of CHB and liver cirrhosis patients. The APASL only recommends entecavir and tenofovir DF, likely owing to the limited data available at the time of its publication in 2016 [
No guidelines recommend a combination of peg-interferon and NA or a combination of NAs as initial therapy due to their limited benefits [
Although the antiviral efficacy of drugs has remarkably improved, patients with very high HBV DNA levels may show PVR featuring a decreased but still detectable level of HBV DNA after at least 48 weeks of continued treatment with high genetic barrier drugs. Other causes of PVR include decreased susceptibility owing to previous drug exposure, decreased medication compliance, and altered drug metabolism. The clinical significance of low level viremia due to PVR is unclear although an increased risk of liver-related complications was found in patients with advanced liver diseases [
There are slightly different definitions of PVR. They are summarized in
Modification of therapy may be considered for PVR, especially when using low genetic barrier drugs (
Although antiviral resistance is uncommon in previously treatment-naïve patients receiving high genetic barrier drugs, entecavir resistance was found in 1–3% of patients, and variants resistant to tenofovir DF have been identified [
After antiviral resistance is confirmed, it is assumed that one of two strategies can be applied: switching to another class of antiviral monotherapy with a high genetic barrier to resistance or adding a second antiviral drug that lacks cross-resistance (
There are insufficient data regarding tenofovir resistance, although guidelines recommend adding or switching to entecavir. In these cases, it is likely that new antiviral agents other than NAs, such as capsid assembly inhibitors, may be needed [
NAs are relatively safe drugs, even with long-term use. However, all drugs may have side effects. Clinically significant adverse effects associated with NA therapy include lactic acidosis (entecavir, tenofovir DF, adefovir, lamivudine, and telbivudine), nephropathy, osteomalacia, Fanconi syndrome (tenofovir DF and adefovir), increasing low-density lipoprotein cholesterol (tenofovir AF), carnitine depletion (besifovir), pancreatitis (lamivudine), peripheral neuropathy, creatinine kinase elevation, and myopathy (telbivudine and clevudine) [
Among the high genetic barrier drugs preferred as first-line agents for CHB treatment, tenofovir DF has an increased risk of renal and bone toxicity [
The standard duration of peg-interferon therapy is 48 weeks for HBeAg-positive or -negative CHB [
There is no predefined duration for NA therapy. As such, stopping NAs before achieving the ultimate goal of antiviral therapy, which is the improvement of survival by the prevention of liver disease progression and HCC development [
Previously, HBeAg loss or seroconversion was considered an indication to stop therapy in HBeAg-positive CHB [
Relapse is common after stopping antiviral therapy in HBeAg-negative CHB patients owing to the presence of immune escape mutants [
For patients with compensated or decompensated cirrhosis, indefinite therapy is recommended by most guidelines (
CHB patients may face situations requiring special consideration. HCC may develop, accompanying renal or bone abnormalities may be detected, and anticancer chemotherapy or immunosuppressive therapy may be needed.
Patients who develop renal dysfunction or decreased bone density during tenofovir DF or adefovir treatment may need to change medication, as described above concerning adverse effects [
Only the KASL and APASL have recommendations for patients with HBV-related HCC (
Patients with chronic HBV infection are at an increased risk of hematological and solid malignancies [
Immunological changes occur during pregnancy, and HBV may replicate more actively [
The KASL, AASLD, and EASL agree that breastfeeding is generally not contraindicated, even if tenofovir DF is being administered to the mother, based on previous studies [
Although acute hepatitis B is generally a self-limiting disease, severe cases resulting in hepatic failure, liver transplantation, or even death have been reported, albeit uncommonly [
The AASLD recommends using entecavir or tenofovir DF/AF, whereas the EASL refrains from recommending tenofovir AF owing to a lack of data [
The KASL clinical practice guidelines for the management of CHB were recently revised, given the emergence of new NAs and continuously updated data regarding treatment initiation, modification, and cessation. Considering the 4- to 5-year interval of guideline revisions, other international guidelines are expected to be updated soon. Through a thorough and systematic approach for the management of CHB based on clinical practice guidelines, the cure of chronic HBV infection is expected to be a real treatment endpoint in the near future.
YHJ conceptualized and designed the study. YHJ, KJH, PJY, YEL, PH, KJH, SDH, LSH, LJ-H, and LHW performed a review of literature, revised the current KASL guidelines, and incorporated those revisions into the manuscript through interactive discussion. YHJ wrote the manuscript. YHJ, KJH, PJY, YEL, PH, KJH, SDH, LSH, LJH, and LHW reviewed and approved the final submission of the manuscript.
This work was funded in part by the Korean Association for the Study of the Liver and Korea University Research Grants.
Nomogram of treatment indicators for chronic hepatitis B without liver cirrhosis for (A) HBeAg-positive patients and (B) HBeAg-negative patients. Gradation toward dark gray suggests immediate treatment, and gradation toward white suggests observation and monitoring. Intermediate gradation suggests the need for fibrosis assessment before determining treatment according to the international guidelines and the Korean Association for the Study of Liver Guidelines. The initiation of antiviral therapy is indicated by a noninvasive fibrosis test suggesting evidence of significant fibrosis or a liver biopsy showing significant necroinflammation or fibrosis (≥A2 or ≥F2). HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ALT, alanine aminotransferase; ULN, upper limit of normal; NA, nucleos(t)ide analog.
Comparison of current clinical practice guidelines for chronic hepatitis B management
KASL | AASLD | EASL | APASL | |
---|---|---|---|---|
Published year | Jun-19 | Apr-18 | Aug-17 | Jan-16 |
Journal | Clinical Molecular Hepatology | Hepatology | Journal of Hepatology | Hepatology International |
Type | Clinical practice guidelines | Guidance incorporated with guidelines | Clinical practice guidelines | Clinical practice guidelines |
Listed author(s) | KASL | An expert panel of the AASLD | EASL | A panel of Asian experts chosen by the APASL |
Recommendation | GRADE | Guidance developed by the consensus of an expert panel, GRADE (2016) | GRADE | GRADE |
Interval since the previous update | 3 years | 2 years | 5 years | 4 years |
Target population | Korean | American | European | Asian |
Suggested normal ALT (IU/L) | ||||
Male | <34 | <35 | <40 | <40 |
Female | <30 | <25 | <40 | <40 |
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; GRADE, Grading of Recommendations Assessment, Development and Evaluation system; ALT, alanine aminotransferase.
Comparison of terminology and characteristics associated with the natural history of chronic hepatitis B
Phase 1 | Phase 2 | Phase 3 | Phase 4 | Phase 5 | ||
---|---|---|---|---|---|---|
Terminology | ||||||
KASL | Immune tolerant CHB (CHB, immune tolerant phase) | Immune active HBeAg-positive CHB (HBeAg-positive CHB, immune active phase) | Immune inactive CHB (CHB, Immune inactive phase) | Immune active HBeAg-negative CHB (HBeAg-negative CHB, immune active phase) | Resolved CHB, (HBsAg loss phase) | |
AASLD | Immune tolerant CHB | Immune active HBeAg-positive CHB | Inactive CHB | Immune active HBeAg-negative CHB | Resolved CHB (functional cure state) | |
EASL | HBeAg-positive chronic HBV infection | HBeAg-positive CHB | HBeAg-negative chronic HBV infection | HBeAg-negative CHB | Resolved HBV infection | |
APASL | Immune tolerant chronic HBV infection (immune tolerant phase) | HBeAg-positive CHB (immune reactive phase) | Low replicative chronic HBV infection (low replicative phase) | HBeAg-negative CHB (reactivation phase) | Resolved hepatitis B infection | |
Characteristics | ||||||
HBsAg HBeAg | High Positive | High/intermediate Positive | Low Negative | Intermediate Negative | Negative Negative | |
HBV DNA level | >106–107 |
>2×104 IU/mL (104–107 IU/mL) |
<2,000 IU/mL | >2,000 IU/mL | Undetectable | |
ALT level | Persistently normal | Elevated | Persistently normal | Elevated | Normal | |
Histological activity |
None/minimal | Moderate/severe | Minimal | Moderate/severe | None |
KASL, Korean Association for the Study of the Liver; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; HBV, hepatitis B virus; ALT, alanine aminotransferase.
HBV DNA >106 IU/mL by the AASLD, HBV DNA >107 IU/mL by the KASL and EASL, and no clear cut-off by the APASL although ranges from >2×106–107 IU/mL are favored.
Activity depends on necroinflammation, and fibrosis stage can vary according to the degree of liver injury accumulation.
EASL criteria for HBeAg-positive chronic hepatitis B.
Comparison of treatment indicators for chronic hepatitis B
KASL | AASLD | EASL | APASL | |
---|---|---|---|---|
Immune tolerant CHB | 1) Monitor patients with very high HBV DNA (≥107 IU/mL) and normal ALT (male <34 IU/mL, female <30 IU/mL) | 1) Monitor patients with high HBV DNA (≥106 IU/mL) and normal ALT (male <35 IU/mL, female <25 IU/mL) | 1) Monitor patients with high HBV DNA (≥107 IU/mL) and normal ALT (<40 IU/L) if there are no signs of chronic hepatitis | 1) Monitor patients with high HBV DNA (e.g., >2×106–107 IU/mL) and normal ALT (<40 IU/L) if age <30 years |
1) Monitor | 2) Liver biopsy to determine treatment if there are risk factors (age ≥30–40 years, HBV DNA levels <107 IU/mL, noninvasive fibrosis tests suggesting significant hepatic fibrosis, or ALT is approaching the ULN) | 2) Antiviral therapy is suggested in selected patients (age >40 years with normal ALT and elevated HBV DNA [1,000,000 IU/mL], liver biopsy showing significant necroinflammation or fibrosis) | 2) Antiviral therapy may be indicated for patients >30 years of age, regardless of the severity of liver histological lesions | 2) Liver biopsy if indicated (age is >35 years or there is a family history of HCC or cirrhosis, noninvasive tests suggest evidence of significant fibrosis, persistently elevated ALT) Treat if ≥A2 or ≥F2 |
2) Consider | Patients with a family history of HCC or cirrhosis and extrahepatic manifestations can be treated | |||
Immune active CHB | 1) Treat if HBV DNA ≥20,000 (for HBeAg-positive CHB) or ≥2,000 (for HBeAg-negative CHB) IU/mL and serum ALT level ≥2× ULN | 1) Treat if elevated HBV DNA (≥20,000 IU/mL for HBeAg-positive or ≥2,000 IU/mL for HBeAg-negative CHB) and ALT ≥2× ULN or there is evidence of significant histological disease | 1) Treat if HBV DNA >20,000 IU/mL and ALT >2× ULN, regardless of the degree of fibrosis | 1) Treat if HBV DNA >20,000 IU/mL for HBeAg-positive or >2,000 IU/mL for HBeAg-negative CHB and ALT levels are elevated >2× ULN |
1) Treat | 2) Consider liver biopsy if ALT is 1–2× ULN and treat if there is moderate to severe necroinflammation (≥A2) or significant fibrosis (≥F2) | 2) Consider the severity of liver disease to determine treatment for patients with ALT >1–2× ULN | 2) Treat all patients with HBeAg-positive or -negative CHB, defined by HBV DNA >2,000 IU/mL, ALT>ULN (40 IU/L), and/or at least moderate liver necroinflammation or fibrosis by biopsy | 2) Patients with high HBV DNA levels (>20,000 IU/mL for HBeAg-positive and >2,000 IU/mL for HBeAg-negative CHB) but ALT <2× ULN should depict a noninvasive fibrosis assessment |
2), 3) Consider | 3) In HBeAg-negative patients with HBV DNA ≥2,000 IU/mL and normal ALT levels, follow-up or liver biopsy/noninvasive fibrosis tests can be considered | Biopsy should be considered if indicated |
||
Antiviral therapy is recommended if ≥A2 or ≥F2 | ||||
Immune inactive CHB | 1) Monitor | 1) Monitor | 1) Monitor | 1) Monitor |
1) Monitor | 2) Patients with HBeAg-negative chronic HBV infection, family history of HCC or cirrhosis, and extrahepatic manifestations can be treated even if typical treatment indications are not present | 2) HBeAg-negative patients with HBV DNA <2,000 IU/mL, should be evaluated for other causes if ALT is elevated and obtain a noninvasive fibrosis assessment | ||
2) Consider | Biopsy should be considered if indicated |
|||
Antiviral therapy is recommended if ≥A2 or ≥F2 | ||||
First-line agents | Entecavir, tenofovir DF, tenofovir AF, besifovir, peg-interferon | Entecavir, tenofovir DF, tenofovir AF, peg-interferon | Entecavir, tenofovir DF, tenofovir AF, peg-interferon | Entecavir, tenofovir DF, peg-interferon |
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; CHB, chronic hepatitis B; HBV, hepatitis B virus; ALT, alanine aminotransferase; ULN, upper limit of normal; HCC, hepatocellular carcinoma; ≥A2, moderate to severe inflammation; ≥F2, significant fibrosis or more; HBeAg, hepatitis B e antigen; tenofovir DF, tenofovir disoproxil fumarate; tenofovir AF, tenofovir alafenamide fumarate; peg-interferon, pegylated interferon.
APASL recommends the consideration of liver biopsy if noninvasive tests suggest evidence of significant fibrosis, ALT becomes persistently elevated, age is >35 years, or there is a family history of HCC or cirrhosis.
Comparison of treatment indicators for patients with liver cirrhosis
KASL | AASLD | EASL | APASL | |
---|---|---|---|---|
Compensated cirrhosis | 1) Treat if HBV DNA level is ≥2,000 IU/mL, regardless of the ALT level | 1) Treat if HBV DNA is >2,000 IU/mL, regardless of the ALT level | 1) Treat for any detectable HBV DNA, regardless of the ALT levels, in patients with compensated or decompensated cirrhosis | 1) Treat if HBV DNA is >2,000 IU/mL, even if the ALT levels are normal |
1) Treat | ||||
2) Consider | 2) Treatment can be considered if HBV DNA is detectable but low (<2,000 IU/mL), regardless of the ALT level | 2) Treat patients with low level viremia (HBV DNA <2,000 IU/mL), regardless of the ALT level | 2) Treatment can be considered irrespective of HBV DNA and ALT levels | |
Decompensated cirrhosis | 1) Treat with a NA if serum HBV DNA is detected, regardless of the ALT level | 1) Treat with antiviral therapy indefinitely, regardless of the HBV DNA level, HBeAg, or ALT level | 1) Immediately treat with a NA with high barrier to resistance, irrespective of the HBV replication level | 1) Immediately treat with a NA for patients with detectable HBV DNA |
1) Treat | 2) Consider liver transplantation | 2) Consider liver transplantation | 2) Assess for the possibility of liver transplantation | 2) Consider treatment for all patients with hepatic decompensation, irrespective of HBV DNA levels |
2), 3) Consider | 3) Consider liver transplantation | |||
First-line agents |
Entecavir, tenofovir DF, tenofovir AF, |
Entecavir, tenofovir DF, tenofovir AF |
Entecavir, tenofovir DF, tenofovir AF |
Entecavir, tenofovir DF |
KASL, Korean Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; HBV, hepatitis B virus; ALT, alanine aminotransferase; NA, nucleos(t)ide analog; HBeAg, hepatitis B e antigen; tenofovir DF, tenofovir disoproxil fumarate; tenofovir AF, tenofovir alafenamide fumarate.
Peg-interferon can only be used, with caution, for compensated cirrhosis, but may not be preferred owing to safety concerns.
Insufficient data for decompensated cirrhosis.
Comparison of partial virological response management during chronic hepatitis B treatment
KASL | AASLD | EASL | APASL | |
---|---|---|---|---|
Definition | A decreased but detectable level of HBV DNA after at least 48 weeks of therapy using high genetic barrier drugs (24 weeks for low genetic barrier drugs) | Persistent viremia is defined as a plateau in the decline of HBV DNA and/or failure to achieve an undetectable HBV DNA level after 96 weeks of therapy | A decrease in HBV DNA level of more than 1 log10 IU/mL but HBV DNA remains detectable after at least 12 months of therapy | Reduction of serum HBV DNA level >1 log IU/mL but still detectable at 24 weeks of therapy |
PVR to low genetic barrier (e.g., lamivudine or telbivudine) | 1) Switch: switching to NAs with high genetic barriers and no cross-resistance is recommended | – | – | 1) Switch: treatment can be modified |
1) Switch | ||||
PVR to high genetic barrier (e.g., entecavir or tenofovir) | 1) Continue: treatment can be continued | 1) Continue: patients with persistent low level viremia (HBV DNA <2,000 IU/mL) on entecavir or tenofovir may continue treatment | 1) Continue: patients with declining serum HBV DNA levels may continue treatment with the same agent | 1) Continue: for patients with detectable HBV DNA after 24 weeks, continuation of the same treatment is recommended |
1) Continue | 2) Switch: switching to tenofovir is recommended in the case of partial virological response to entecavir | 2) Switch or add: in cases where HBV DNA levels plateau, a switch to another drug or a combination of entecavir/tenofovir can be considered | ||
2) Switch/add |
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; HBV, hepatitis B virus; PVR, partial virological responses; NA, nucleos(t)ide analog.
Comparison of antiviral resistance management during chronic hepatitis B treatment
KASL |
AASLD |
EASL | APASL | |
---|---|---|---|---|
Lamivudine/telbivudine resistance | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to TDF |
1) Switch | ||||
Entecavir resistance | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to TDF |
1) Switch | 2) Combine with tenofovir (TDF or TAF) | |||
2) Combine | ||||
Adefovir resistance | 1) Switch to tenofovir (TDF or TAF) | 1) Switch to ETV or tenofovir (TDF or TAF) | 1) Switch to ETV or tenofovir (TDF or TAF) (LAM-naïve) | 1) Switch to either ETV or TDF (no LAM-resistance) |
1) Switch | 2) Combine ETV plus tenofovir (TDF or TAF) | 2) Switch to tenofovir (TDF or TAF) (LAM-resistance) | 2) Switch to TDF monotherapy (LAM-resistance) | |
2) Switch/combine | If HBV DNA plateaus: combine ETV or switch to ETV | |||
Tenofovir resistance | 1) Combine with ETV | 1) Switch to ETV | 1) Switch to ETV (LAM-naïve) | – |
1) Combine/switch | 2) Combine with ETV (LAM-resistance) | |||
2) Combine | ||||
Multidrug resistance | 1) Combine ETV and tenofovir (TDF or TAF) | 1) Combine ETV and tenofovir (TDF or TAF) | 1) Combine ETV and tenofovir (TDF or TAF) | 1) Combine ETV and TDF |
1) Combine | 2) Switch to tenofovir (TDF or TAF) | |||
2) Switch |
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide fumarate; LAM, lamivudine; HBV, hepatitis B virus; ETV, entecavir.
Preferred treatment was suggested.
Comparison of cessation criteria for chronic hepatitis B treatment
KASL | AASLD | EASL | APASL | ||
---|---|---|---|---|---|
NAs | |||||
HBeAg-postive CHB | 1) HBsAg loss | 1) HBeAg seroconversion with 12 months consolidation plus undetectable HBV DNA | 1) HBsAg loss with/without anti-HB seroconversion | 1) HBeAg seroconversion with 12 months consolidation (preferably 3 years) | |
2) HBeAg loss/seroconversion with 12 months consolidation plus undetectable HBV DNA | 2) Alternatively, treat until HBsAg is lost | 2) HBeAg seroconversion with 12 months consolidation plus undetectable HBV DNA | 2) HBsAg loss or seroconversion | ||
HBeAg-negative CHB | 1) HBsAg loss | 1) Indefinite | 1) HBsAg loss with/without seroconversion | 1) HBsAg loss or seroconversion | |
2) May be considered after HBsAg loss | 2) May be considered after long-term (≥3 years) virological suppression after NA therapy | 2) Undetectable HBV DNA for at least 2 years on 3 separate occasions each 6 months apart | |||
Liver cirrhosis | 1) Long-term treatment for compensated cirrhosis | 1) Indefinite (may be considered after HBsAg loss) | 1) Indefinite | 1) NA therapy should be continued for life in compensated and decompensated cirrhotic patients | |
2) Indefinite for decompensated cirrhosis | |||||
Peg-Interferon | |||||
HBeAg (+) | 48 weeks | 48 weeks | 48 weeks | 48 weeks | |
HBeAg (-) | 48 weeks | 48 weeks | 1) 48 weeks | 48 weeks | |
2) Extending treatment beyond 48 weeks may be beneficial |
1) Preferred, 2) alternative.
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; NA, nucleos(t)ide analog; HBeAg, hepatitis B e antigen; CHB, chronic hepatitis B; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; peg-interferon, pegylated interferon.
Comparison of chronic hepatitis B management for special populations
KASL | AASLD | EASL | APASL | |
---|---|---|---|---|
Renal or bone disease | 1) Entecavir, TAF, and besifovir are preferred | 1) No preference between entecavir or TDF regarding the potential long-term risk of renal and bone complications TAF is associated with fewer bone and renal abnormalities than TDF | 1) Entecavir or TAF are preferred over TDF for patients with increasing age (>60 years), bone diseases, or renal alterations | 1) Entecavir or telbivudine are the first-line treatment options for chronic HBV-infected patients with any level of renal dysfunction and renal replacement therapy |
1) Selection | ||||
2) Switch | ||||
2) Treatment can be switched to TAF, besifovir, or entecavir in high risk patients | 2) TDF should be substituted with TAF or entecavir for TDF-associated renal dysfunction and/or bone disease | 2) Switching to entecavir or TAF should be considered for patients on TDF at risk of development and/or with underlying renal or bone disease | 2) Renal function and bone profiles should be monitored at least every 3 months if TDF or ADV is used | |
HCC | 1) Antiviral therapy should be initiated in patients with HBV-related HCC if serum HBV DNA is detected | – | – | 1) NA treatment should be given to patients with HBV-related HCC (at least 1–2 weeks before, during, and after chemotherapy, locoregional therapies, resection, or liver transplantation), if there is detectable serum HBV DNA |
1) Treat | ||||
2) Prophylaxis | ||||
2) Prophylactic antiviral therapy should be considered in patients undergoing anticancer treatment, regardless of serum HBV DNA levels | ||||
Immunosuppression or chemotherapy | 1) If either HBsAg is positive or HBV DNA is detected, prophylactic antiviral therapy should be initiated before immune-suppression or chemotherapy | 1) Anti-HBV prophylaxis should be initiated in HBsAg-positive anti-HBc-positive patients before starting immunosuppressive or cytotoxic therapy | 1) All HBsAg-positive patients should receive ETV, TDF, or TAF as treatment or prophylaxis | 1) Prophylactic antiviral therapy should be administered in anti-HBc-positive patients with either HBsAg-positive or detectable serum HBV DNA |
1) Prophylaxis (HBsAg-positive) | ||||
2) Monitor/treat/prophylaxis (HBsAg-negative) | ||||
2) HBsAg-negative anti-HBc-positive patients with undetectable HBV DNA should be monitored for serum HBsAg and HBV DNA during immunosuppression/chemotherapy and NAs should be initiated if HBV reactivation occurs | 2) HBsAg-negative anti-HBc-positive patients should be carefully monitored for ALT, HBV DNA, and HBsAg to provide therapy as needed | 2) HBsAg-negative anti-HBc-positive patients should receive anti-HBV prophylaxis if they are at high risk of HBV reactivation | 2) HBsAg-negative anti-HBc-positive patients with undetectable serum HBV DNA levels who receive chemotherapy and/or immunosuppression should be carefully monitored and be treated with NAs upon HBV reactivation | |
If rituximab is included, initiate antiviral therapy at the start of immunosuppression or chemotherapy | For patients receiving anti-CD20 antibody therapy (e.g., rituximab) or undergoing stem cell transplantation, anti-HBV prophylaxis is recommended | |||
Pregnant women | 1) Initiate or switch to TDF if treatment is needed | 1) TDF is preferred | 1) TDF should be continued, whereas ETV or other NAs should be switched to TDF | 1) TDF is the drug of choice for mothers requiring antiviral treatment |
1) Treat/switch | ||||
2) Prevention | ||||
3) Lactation | 2) For pregnant women with serum HBV DNA levels >200,000 IU/mL, TDF administration is recommended to prevent MTCT, beginning at 24–32 weeks of gestation and stopping 2–12 weeks after delivery | 2) If HBV DNA >200,000 IU/mL at 28–32 weeks of gestation, antiviral therapy is recommended to reduce the risk of perinatal transmission | 2) In all pregnant women with high HBV DNA levels (>200,000 IU/mL) or HBsAg levels >4 log10 IU/mL, antiviral prophylaxis with TDF should begin at 24–28 weeks of gestation and continue for up to 12 weeks after delivery | 2) For pregnant women with HBV DNA >6–7 log10 IU/mL, short-term maternal NA therapy with tenofovir or telbivudine is recommended beginning at 28–32 weeks of gestation |
3) TDF, which is relatively safe for the fetus and pregnant women, is not contraindicated during breastfeeding | 3) Breastfeeding is not contraindicated, but there are insufficient long-term safety data in infants born to mothers who received antiviral agents during pregnancy and while breastfeeding | 3) Breast feeding is not contraindicated in HBsAgpositive untreated women or on TDF-based treatment or prophylaxis | 3) Breast feeding is discouraged during maternal NA treatment | |
Acute hepatitis B | 1) In patients with severe acute hepatitis B (e.g., coagulopathy, severe jaundice, liver failure), NA therapy can be initiated | 1) Indicators for antiviral therapy are total bilirubin >3 mg/dL, international normalized ratio >1.5, encephalopathy, or ascites | 1) Patients with severe acute hepatitis B, characterized by coagulopathy or protracted course, should be treated with NAs and considered for liver transplantation | 1) Treatment is only indicated for patients with fulminant hepatitis B or for those with severe or protracted acute hepatitis B |
1) Treat |
KASL, Korean Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian-Pacific Association for the Study of the Liver; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; HBV, hepatitis B virus; ADV, adefovir; HCC, hepatocellular carcinoma; NA, nucleos(t)ide analog; HBeAg, hepatitis B e antigen; anti-HBc, antibody to hepatitis B core antigen; ALT, alanine aminotransferase; ETV, entecavir; MTCT, mother-to-child transmission.