The clinical practice guidelines for the management of chronic hepatitis B (CHB) were first presented in 2004 by the Korean Association for the Study of the Liver (KASL), and were revised in 2007 and 2011. The American Association for the Study of Liver Diseases (AASLD) published their guidelines in 2015, the European Association for the Study of the Liver (EASL) in 2012, the Asian Pacific Association for the Study of the Liver (APASL) in 2015 and the World Health Organization (WHO) in 2015. These guidelines carry some variations due to ethnic differences and different medical environments. Therefore, there is a demand for Korean practice guidelines which reflect medical practice in Korea. Problems with emergence of drug resistant mutation are eminent in Korea and the KASL updated their guidelines regarding the management of antiviral resistant mutation in 2014.

In 2015, the objective of this manuscript was to update the recommendations for management of CHB, including epidemiology, prevention, natural history, diagnosis, treatment, monitoring, drug resistance mutations and treatment of special populations discussed herein based on current evidences or if, evidences lack, on expert opinions after deliberation.

The main targets of this guideline are patients both newly diagnosed with CHB and those being followed up or treated for CHB. This guideline is also intended to facilitate management of patients under the following special circumstances: malignancy, transplantation, kidney dysfunctions, co-infection with other viruses, pregnancy, and children.

This revised CHB guideline is designed as a resource for all Korean clinicians caring for patients with CHB. It also provides physicians undertaking training courses with practical information on the management of CHB.

The CHB Clinical Practice Guideline Revision Committee (CPGRC) comprising 17 hepatologists and 1 pediatrician was formed with support from the KASL. All of the required funding was provided by the KASL. Each member of the CHB-CPGRC collected and evaluated evidence, and contributed to writing the manuscript.

Conflicts of interest of the CHB-CPGRC members are summarized in Conflicts of interest.

Relevant evidences obtained from a comprehensive literature search using MEDLINE (up to 2015) were systematically reviewed and selected. The languages were limited to English and Korean. In addition to published articles, abstracts of important meetings published before 2015 were also evaluated. The following search terms were used: “hepatitis B”, “hepatitis B virus”, “HBV”, “chronic hepatitis”, and other key words related to clinical questions (see below). These clinical questions covered a variety of pertinent topics ranging from epidemiology, natural course, prevention, diagnosis, treatment, antiviral resistance, and special situations.

The evidence and recommendations were graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system with minor modifications (Table 1). The levels of evidence were determined as the possibility of change in the estimate of clinical effect by further research, and were described as high (A), moderate (B) or low (C). The grades of recommendation were either strong (1) or weak (2), as determined by the quality of evidence as well as patient-important outcomes and socioeconomic aspects.

The committee considered the following questions as key components to be covered in this guideline.

1. How does this guideline differ from previous guidelines?

2. What is the updated knowledge on the epidemiology?

3. What is the updated knowledge on the natural course of CHB?

4. How should the infection be prevented?

5. How are patients evaluated prior to treatment?

6. When should treatment be considered?

7. What are the goals and endpoints of treatment?

8. What are the optimal first-line treatments for different disease status?

9. How should the treatment be monitored?

10. When can we consider stopping treatment?

11. What are the predictors of a treatment response?

12. What are the definitions of treatment failure?

13. How should we manage drug-resistant CHB patients?

14. What are the definitions of recurrence after treatment completion and how should these be managed?

15. How should we manage the following special groups:

16. How can we reduce vertical transmission in pregnant CHB patients?

17. What is the optimal management of CHB in children?

Drafts of the revised guideline were thoroughly reviewed at separate meetings of the committee. A revised manuscript was reviewed at a meeting of an external review board, and at a symposium open to all KASL members, and was modified further prior to publication. The external review board comprised of 18 specialists in CHB who are members of the KASL. The final manuscript was endorsed by the board of executives of the KASL.

The revised CHB guidelines of KASL were released on November 26, 2015 (http://www.kasl.org).

Updates or full revision will be planned when major new evidence regarding the diagnosis and/or treatment of CHB becomes available. Detailed plans for updates will be posted on the KASL website at a later date.

The progression of CHB may be divided into the following five clinical phases: the immune-tolerant phase, immune-active phase, immune-control phase, immune-escape phase, and HBsAg-clearance phase. Individual patients do not necessarily experience these clinical phases in a continuous manner, and clinical phases are not always correlated with criteria or indications of antiviral therapy [14,15]. HBV DNA positivity indicates an acute or chronic HBV infection, and negativity indicates resolution of infection. For this reason, the WHO decided to delete the term ‘hepatitis B carrier.’ The natural history of CHB is outlined below (Table 2).

The accumulated incidence of cirrhosis developing from CHB is generally reported to be 8–20% [54,55]. In Korea, the reported annual and 5-year accumulated incidences of cirrhosis are 5.1% and 23%, respectively, while those for HCC are 0.8% and 3% [54]. The risk factors for hepatitis B progressing to cirrhosis or HCC can be divided into demographic, environmental, social, and viral factors (Table 3) [56].

Regarding demographic factors, the risk of developing HCC is three- to fourfold higher for males than for females, and the risk of HCC and cirrhosis is low among those younger than 40 years, then increases exponentially with increasing age after the fourth decade of life [33,57-59]. Those with a family history of HCC also have a higher risk of contracting HCC [60,61]. Environmental and social risk factors for progression to cirrhosis or HCC are alcohol consumption, exposure to aflatoxin [62], and smoking [63]. It is suggested that obesity, metabolic syndrome, and fatty changes in histologic tests increase the risk of CHB patients progressing to hepatic fibrosis or HCC [64-67]. Many epidemiological research studies have found that coffee exerts protective effects against the development of hepatic fibrosis and HCC [68-72].

Viral factors that may influence the progression of CHB patients to cirrhosis or HCC include high levels of serum HBV DNA (≥20,000 IU/mL), genotype C, BCP variants, and coinfection with other viruses [57,59,73-75]. According to the Taiwanese Risk Evaluation of Viral Load Elevation and Association Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study, the risk of developing HCC during the study period among subjects aged at least 40 years was significantly higher in those with an HBV DNA level of ≥10⁴ copies/mL (cpm) at the start of observation and 10⁵ cpm 11 years later than among those with an entry HBV DNA level of <10⁴ cpm. Likewise, the incidence of cirrhosis was significantly associated with HBV DNA levels higher than 10⁴ cpm at study entry [58,59]. If the HBV DNA level decreased during the follow-up period, the risk of developing HCC or cirrhosis decreased. Subsequent research highlighted the clinical importance of careful evaluation of patients with an HBV DNA level >2,000 IU/mL who are older than 40 years (especially those HBeAg positive) for the development of fibrosis [57] and HCC [74,75]. Therefore, intervention with antiviral therapy should be performed when appropriate, as recommended by established practice guidelines [56].

Unlike HCV infection, the HBV genotype exerts a profound effect on the clinical outcome but—with the exception of interferon—little effect on the treatment outcome [76]. Eight HBV genotypes have been identified, and that with the worst prognosis is genotype C, which is the most common in Korean CHB patients [77]. Genotype C is associated with delayed natural seroconversion and rapid progression to liver cirrhosis and HCC. Therefore, it is an independent risk factor for HCC development. According to a cohort study in Alaska, patients infected with A-, B-, and D-genotype hepatitis B typically experience seroconversion from HBeAg to anti-HBe before the age of 20 years, whereas in those infected with the C genotype this occurs at a mean age of 47 years [20]. This implies that those infected with genotype C would on average experience a much longer period of infection with high HBV viral loads, and may in part explain why the risks of HCC and cirrhosis are so high in patients infected with genotype C.

Two important genetic mutations of HBV that affect the natural history of CHB infection are the BCP and PC mutations [42,45,75,77-79]. BCP mutations are A1762T and G1764A mutations in the HBV BCP regions, and multiple cross-sectional and prospective studies have indicated that they increase the risks of cirrhosis and HCC [42,45,77,78]. According to the results of the REVEAL-HBV study, 359 and 1,149 individuals without and with BCP mutations, respectively, developed HCC among a population of 100,000 [80]. PC mutation typically appears near the time of HBeAg seroconversion. The mutation results in an amino-acid change that creates a stop codon at site 1896 on the HBV genome, which results in the virus being able to transcribe hepatitis B core protein but not HBeAg [45]. Patients infected with PC mutants are characterized by HBeAg negativity and HBeAg positivity, but high levels of HBV DNA [81,82]. However, the observed effects of PC mutants on the natural history of CHB have been inconsistent; a recent analysis of the role of PC in the prospective population-based REVEAL-HBV study revealed the opposite to the findings of cross-sectional clinic-based studies—that the presence and absence of the PC mutation decreased and increased, respectively, the subsequent annual incidence of HCC (269 and 996 per 100,000, respectively) [80].

1. HBV vaccination is recommended for persons negative for HBsAg and anti-HBs. (A1)

2. Abstinence from alcohol and smoking is recommended for patients with chronic HBV infection. (A1)

3. Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. (A1)

4. Hepatitis A vaccine should be given to patients with chronic HBV infection negative for anti-HAV. (A1)

HBsAg immunoassay is a necessary and accurate test for diagnosis of CHB. By definition, patients who remain positive for HBsAg for longer than 6 months have progressed to chronic infection. Quantitative measurement of HBsAg is now possible and the combination of HBsAg quantification and HBV DNA level is an integral component of monitoring the response to antiviral therapy. Serologic tests, including anti-HBs and anti-HBc, can assist in screening of populations for HBV infection and differentiating among acute, chronic, and past infections. In acute HBV infection, HBsAg appears 1-10 weeks after exposure to HBsAg and disappears 4-6 months after recovering from HBV infection [101]. Acute HBV infection is diagnosed by being HBsAg positive and anti-HBc IgM positive. Anti-HBc IgM is the only marker present during the window period, the interval between disappearance of HBsAg and appearance of anti-HBs.

Anti-HBc typically persists for life, but IgM anti-HBc is detectable for 6 months, and anti-HBc is detectable thereafter in patients with resolved acute HBV infection. IgM anti-HBc can be detected at low levels during chronic HBV infection [93]. Persistently positive anti-HBc is shown when anti-HBs titer from the past HBV infection becomes undetectable over time or in cases with occult hepatitis B infection [102-105]. Measurement of the serum HBV DNA level might be helpful in these settings. Patients with these serologic patterns should be followed with repeated testing of HBsAg, anti-HBs, and anti-HBc for 3–6 months. Patients who recover from HBV infection will test negative for HBsAg and positive for anti-HBs and anti-HBc. Patients who respond adequately to hepatitis B vaccines will test negative for anti-HBc and positive for antiHBs, since anti-HBc emerges only after HBV infection and persists for life.

Laboratory tests for patients with CHB should include HBeAg and anti-HBe. HBeAg positivity generally indicates a high level of viral replication, and anti-HBe positivity a low level. Serum HBV DNA and AST/ALT levels are important parameters in HBeAg-negative patients. HBeAg-negative, anti-HBe-positive patients with a normal ALT level and an HBV DNA level of <2,000 IU/mL (<10,000 cpm) may be in the inactive phase. These patients usually have mild or no liver necroinflammation and no or slow progression of fibrosis, but some patients with severe liver damage during the immune-active phase may present with a cirrhotic liver. HBeAg-negative CHB patients have an elevated ALT and an HBV DNA level of >2,000 IU/mL. HBe-negative CHB is associated with viral mutants in the PC and/or BCP regions that are unable to produce or produce only low levels of HBeAg [40]. They have severe liver necroinflammation with a low rate of prolonged spontaneous disease remission and a high risk of subsequent complications, such as decompensated cirrhosis and HCC [106].

Acute hepatitis A co-infection in chronic hepatitis B patients can result in increased icteric manifestation, longer recovery time, and increased risk of fulminant hepatic failure. Underlying chronic liver disease is an important risk factor for fulminant hepatic failure and death in patients with acute HAV infection [106-108]. Therefore, CHB patients younger than 50 years should undergo testing for IgG anti-HAV, and all patients with a negative immune status for hepatitis A should receive HAV vaccine. Laboratory tests should include tests for coinfection with HCV and/or HIV in those at risk.

Serum HBV DNA testing provides a direct measure of the level of viral replication. This quantification is essential for characterizing the status of infection, diagnosing the disease, making the decision to treat, and subsequent monitoring of patients. It is also important for predicting the risks of cirrhosis and HCC. Therefore, it should be applied to all patients diagnosed with CHB. The introduction of the international unit (IU) (1 IU is equivalent to 5.6 HBV DNA copies) as a recommended reporting unit for HBV DNA has facilitated standardized reporting and comparison of serum HBV DNA levels [109]. The methods used to quantify HBV DNA levels have evolved rapidly. Real-time PCR-based assays have been introduced and demonstrate both high sensitivity and a broad linear range (10–10⁸ IU/mL) of quantification [110]. The same test should be specified each time when monitoring HBV DNA levels for a given patient in clinical practice to ensure consistency.

HBV genotypes appear to influence the progression of disease, risk of HCC, and response to therapy (including interferon therapy) [75,111,112]. Some studies in Asia have suggested that genotype C is associated more frequently with HBV reactivation, severe liver disease, and HCC than is genotype B [111,113-115]. The specific genotype has also been shown to affect the response to interferon therapy, with the rate of an antiviral response to pegylated interferon (peginterferon) therapy being higher for genotypes A and B than for genotypes C and D [116]. In CHB, examination of genotyping is recommended selectively to help identify patients who might be at greater risk of disease progression, and routinely to determine the most appropriate candidates for peginterferon therapy [117]. However, genotyping is recommended as being unnecessary in Korea because Korean patients are almost exclusively infected with genotype C.

Assessments of the severity of liver disease should include biochemical markers such as AST, ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), prothrombin time (PT), and serum albumin. A progressive decline in the serum albumin level and prolongation of the PT, often accompanied by a decrease in the platelet count, are characteristically observed after cirrhosis develops. The serum ALT level has been commonly used in assessments of liver disease and as an important criterion for defining which patients are candidates for therapy [118]. The ALT level is usually higher than that of AST, but the ratio may be reversed when the disease progresses to cirrhosis. HBV-infected patients with normal or mildly elevated ALT levels have been thought to have mild-to-no or significant necroinflammation on liver biopsy, respectively. However, there is no correlation between the degrees of liver cell necrosis and ALT level [119]. ALT activity might also be affected by other factors such as body mass index, gender, abnormal lipid and carbohydrate metabolism, and uremia [119,120]. Therefore, relying solely on the finding of elevated ALT as a prerequisite for treatment candidacy has limitations. Data from clinical studies have shown that the true normal level of ALT is significantly lower than the previously established limits: 40 IU/mL for males and 30 IU/mL for females. Moreover, data from cohort studies indicate that the upper limit of normal (ULN) ALT and AST levels should be decreased to 30 IU/mL for males and 19 IU/mL for females [119,120]. Clinical studies have shown that patients with ALT levels of 40–45 IU/mL have a high risk of significant liver disease and mortality from complications [121]. According to the treatment algorithm for CHB suggested by Keefee et al., serum ALT levels of 30 and 19 IU/mL for males and females, respectively, should be used as the ULN levels when deciding to commence treatment [117]. Further prospective studies are needed to clarify this issue.

A recent prospective study in Korea involving 2,000 liver donors suggested that healthy serum ALT values should be 33 IU/L for males and 25 IU/L for females [122]. Ninety thousand males and 40,000 females aged 35 to 59 years in the prospective NHS cohort exhibited upper limits of AST and ALT values for prediction of liver diseases of 31 IU/L and 30 IU/L, respectively [121].

A liver biopsy is recommended for determining the degree of necroinflammation and fibrosis in patients with elevated ALT, an HBV DNA positive or both, because liver histology is useful when deciding whether or not to commence treatment. A liver biopsy is invasive but the rate of serious complications is very low (1/4,000-10,000) [123]. Several recent clinical studies found that 12–43% of patients with persistent normal ALT levels had histologic evidence of significant fibrosis or inflammation in a biopsy, particularly those older than 35-40 years [116-121,124]. A retrospective study of the relationship between ALT level and fibrosis in CHB patients reported similar results: of the 59 patients with persistent normal ALT levels, 18% had stage 2 fibrosis and 34% had grade 2 or 3 inflammation, with 37% of all patients with persistent normal ALT levels having significant fibrosis and inflammation [125]. Subgroup analysis also demonstrated that most of the patients with fibrosis had high normal ALT levels. These results indicate that the ALT level in CHB patients with high normal ALT levels should be interpreted in conjunction with the serum HBV DNA level, age, and liver histology results when deciding to commence treatment. Therefore, in HBsAg-positive patients with HBV DNA levels of ≥20,000 IU/mL and normal ALT levels, a liver biopsy should be considered in those older than 35 years since they are less likely to be in the immune-tolerance phase of infection. Treatment should be considered if a liver biopsy reveals fibrosis at stage 2 or greater and/or necroinflammation. When deciding whether to commence treatment in this patient population, it must be recognized that long-term therapy is likely to be needed due to the low probability of HBeAg seroconversion occurring within 1 year. A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or when treatment is indicated irrespective of the grade of activity or the stage of fibrosis. This is because only a small portion of the liver is sampled, and the low intra/interobserver reliabilities. Therefore, the efficacy of noninvasive methods such as the Fibroscan device or serum markers in assessing fibrosis in CHB has increased.

The severity of liver fibrosis and determination of ALT and HBV DNA levels have essential roles in treatment decisions. Noninvasive methods to estimate liver fibrosis have been developed and used. These methods include the aspartate aminotransferase-platelet ratio index (APRI), AST/ALT ratio (AAR), Forns’ fibrosis index (age, platelets, GGT, cholesterol), FIB-4 (platelets, ALT, AST, Age). Also, the FibroTest that uses indirect markers (α-2 macroglobulin, haptoglobin, r-globulin, apolipoprotein A1, and GGT), the FibroSpect II Enhanced Liver Fibrosis test that uses direct markers (Hepascore, FibroMeter, hyaluronic acid and tissue inhibitor of matrix metalloproteinase-1, 2) are available [126]. The age-spleen-platelet ratio index (ASPRI) is the most accurate in predicting liver fibrosis in chronic HBV infection [127]. APRI is useful for diagnosis of not only for liver fibrosis but also liver cirrhosis, while FIB4 is useful for mild fibrosis. However FIB4 has limitations in terms of predicting fibrosis of stage F2 and above as it has low sensitivity and specificity [126].

Transient elastography using Fibroscan^® has a high degree of accuracy for assessment of advanced liver fibrosis. It is the most commonly used method for chronic liver diseases because of its noninvasiveness and high reproducibility [128].

Fibroscan^® can be perform rapidly (5 min) in the outpatient clinics of hospitals and produce a result immediately after the test [129,130]. However, only procedures involving ≥10 successful measurements are considered reliable. Moreover, a success rate (SR) of at least 60% and an interquartile range (IQR) of less than 30% of the median value are required (Interquartile range/median value (IQR/M) [131], Fibroscan^® has limitations in subjects with ascites, obesity, or narrow intercostal spaces. Moreover, the system may yield false-positive results in subjects with acute hepatitis and extrahepatic biliary tract obstruction [132-134].

Fibroscan^® has greater diagnostic accuracy than APRI or FIB-4 for liver cirrhosis in a study that compared liver biopsy, AAR, APRI, Fibroscan^®, and FIB-4 in patients with chronic hepatitis [135,136]. Also, Fibroscan^® was more predictive of liver fibrosis and liver cirrhosis in a study that compared Fibroscan^® and APRI in 567 subjects with chronic hepatitis (Area under Receiver Operating Characteristic: F3 0.849 vs. 0.812, F4 0.902 vs. 0.707) [137].

The initial evaluation of patients with CHB should include tests for HCC. Periodic surveillance is also needed in these patients to ensure early detection of HCC during follow-up. The issue of HCC is treated in detail in the “Practical Guidelines for Management of Hepatocellular Carcinoma 2014 [138].” Standard tools for HCC screening include measuring the α-fetoprotein level and ultrasound. Magnetic resonance imaging and computed tomography might be preferred for some patients with severe cirrhosis or obesity, since ultrasound has poor sensitivity in those conditions. Patients at a high risk of HCC include those older than 40 years [139], patients with cirrhosis, those with a family history of HCC, and any carriers older than 40 years exhibiting persistent or intermittent ALT elevation, a high HBV DNA level (>2,000 IU/mL), or both [14]. Keeffe et al. recently recommend earlier screening (at 30–35 years of age or even younger) in Asian patients with presumed infection at the time of birth or in early childhood due to the higher risk of HCC in this patient population.

The use of antiviral therapies improves liver function and increases survival rates of patients with liver failure (liver decompensation).

Consistent inhibition of HBV replication with antiviral therapies delays progression of liver fibrosis, induces reversal of advanced liver fibrosis, reduces the incidence of liver cirrhosis, and prevents diseases including hepatocellular carcinoma in patients with advanced liver fibrosis or liver cirrhosis [140].

Recently developed treatments can decrease the incidence of liver diseases or delay their progression but cannot prevent all possible complications. Therefore, surveillance and screening for hepatocellular carcinoma are required at regular intervals for early diagnosis and a complete recovery.

1. The initial evaluation of patients with CHB should include a thorough history-taking and physical examination, with emphasis on risk factors such as coinfection, alcohol consumption, and the family history of HBV infection and liver cancer. (A1)

2. Laboratory tests to assess liver disease should include the complete blood count (CBC), AST/ALT, ALP, GGT, bilirubin, albumin, creatinine, and PT. (A1)

3. Tests for HBV replication include HBeAg/anti-HBe and quantitative serum HBV DNA levels. A real-time PCR quantification assay is strongly recommended for quantifying the HBV DNA level. (A1)

4. An anti-HCV test is necessary to rule out coinfection with HCV. (B1)

5. An anti-HAV test is necessary in CHB patients younger than 50 years. (A1)

6. Liver biopsy is useful for determining the degree of liver inflammation and fibrosis. (A1)

7. Noninvasive tests such as serum markers and liver elasticity are used for diagnosis of the degree of liver fibrosis. (B1)

8. Standard tools for HCC screening include ultrasound and serum α-fetoprotein measurement. (A1)

1. The treatment goals in hepatitis B are to decrease the mortality rate and increase the survival rate by alleviating hepatic inflammation and preventing the development of fibrosis, which would ultimately reduce the frequency of progression of hepatitis to liver cirrhosis or HCC. (A1)

2. To achieve HBsAg clearance, which is the ideal treatment goal, long-term maintenance of an undetectable HBV DNA level is recommended. (B1)

3. The ultimate treatment goals in patients with HBeAg-positive hepatitis are normalization of the ALT level, undetectable HBV DNA level, and the clearance or seroconversion of HBsAg and HBeAg. In patients with HBeAg-negative hepatitis the treatment goals are normalization of the ALT level, an undetectable HBV DNA level, and the clearance or seroconversion of HBsAg. (B1)

Antiviral therapy is not indicated for patients in the immune-tolerant phase despite HBeAg positivity and a high level of HBV DNA, because of the benign natural course of the disease and such treatment results in minimal histologic changes [159].

Patients in the immune-tolerant phase (HBeAg positive and persistently normal ALT level as recommended by this guideline rather than local laboratory ULNs) are not indicated for antiviral therapy. (B1)

CHB patients with active viral replication and significant inflammation and/or fibrosis are appropriate targets for antiviral treatment. Early guidelines generally agreed that antiviral treatment could be recommended for CHB patients (especially those without liver cirrhosis) with serum HBV DNA level > 20,000 IU/mL and serum ALT level> 2 ULN [160,161]. However, recent guidelines suggest that the indications of antiviral treatment should be expanded to those with lower serum HBV DNA levels and/or lower serum ALT levels [35,162,163].

Serum HBV DNA level is a marker of viral replication and an indicator of the efficacy of antiviral treatment in individuals with CHB. Progression to cirrhosis in HBV-infected patients is reported to be strongly correlated with the level of circulating virus [57,59]. However, an HBV DNA level of 10⁵ cpm or 20,000 IU/mL was arbitrarily chosen by early guidelines as the cut-off level for indication of antiviral treatment. Some patients with lower serum HBV DNA levels (300–10⁵ cpm), especially those with HBeAg negative hepatitis and/or cirrhosis, frequently show progression of liver disease and hence may need treatment [35,161,164]. A serum HBV DNA level of ≥20,000 IU/mL has been suggested as the cut-off for HBeAg-positive CHB [164]. However, the distinction between HBeAg-negative CHB and inactive carriers is not clear due to the fluctuating course of HBeAg-negative CHB [164]. A population-based cohort study revealed increased risks of liver cirrhosis and HCC when the serum HBV DNA level exceeds 2,000 IU/mL [57,59,165], therefore this level is widely accepted as the cut-off for indicating antiviral therapy.

Serum ALT has been used as a convenient surrogate marker for liver injury, and elevated serum ALT is indicated as a risk factor for disease progression in CHB [57]. A serum ALT level > 2 ULN was suggested as a suitable indication of antiviral treatment for CHB by early guidelines, especially in CHB patients without cirrhosis [160,161,166]. However, an increased risk of developing liver cirrhosis and HCC has been documented in patients with mildly elevated serum ALT and even in those with serum ALT levels in the upper normal range [119,121,167]. About two-thirds of CHB patients with mildly elevated ALT (1–2 ULN) show significant hepatic fibrosis (F2 or higher) [168], and CHB patients with persistently normal ALT levels and HBV DNA levels of >20,000 IU/mL may actually have significant fibrosis or inflammation [125,168,169], which are indications for antiviral therapy. A cohort study in Hong Kong demonstrated that the risk of liver-related complications in CHB patients was higher for ALT levels of 0.5–1 ULN and 1–2 ULN than for those <0.5 ULN. Thus, previous ALT criteria might exclude some patients with existing or potentially significant disease [170,171].

Liver biopsy has three major roles: diagnosis, assessment of prognosis (disease staging), and assistance in making therapeutic decisions [172]. In CHB, liver biopsy is especially useful for patients who do not meet definite criteria for treatment but still have a possible risk of significant disease [35]. Age of the patient, serum HBV DNA level, serum ALT level, and family history of HCC should be considered before deciding whether to perform a biopsy. ALT and HBV DNA levels may miss cases of histologically significant disease [169], and so histologic confirmation should be considered, especially in patients of advanced age with serum AST/ALT levels in the upper normal range or higher.

Peginterferon-α and NAs including lamivudine, adefovir, clevudine, telbivudine, entecavir, and tenofovir, have been used for antiviral treatment of CHB. Drug of choice can differ according to various factors, including effectiveness, safety, risk of resistance, and cost of drugs, preference of patients and physicians, and any plans for pregnancy [35].

Lamivudine and telbivudine are not preferred due to their weak antiviral potency and high frequency of drug resistance, unless a good response is predicted or the anticipated duration of treatment is short. Adefovir is not an ideal option due to its weak anti-viral activity and high frequency of drug resistance after 48 weeks. There are insufficient long-term follow-up data on the efficacy and safety of clevudine. Entecavir and tenofovir are safe agents with potent antiviral effects and low frequency of drug resistance. Due to convenience of usage, peginterferon-α is preferred over interferon-α. To date, there has been no report confirming the superiority of combination therapies over monotherapy in treatment-naïve patients.

Currently, monotherapy with entecavir, tenofovir, or peginterferon-α is the preferred initial therapy for CHB. Other NAs might be used in patients with good predictors of response, and can be continued or modified according to on-treatment response.

In patients treated with lamivudine, the predictive factors for a good response to therapy are increased initial serum ALT level and high histologic activity index score [118]. During telbivudine treatment, a combination of pretreatment characteristics (low HBV DNA level; HBV DNA < 10⁹ copies/mL (HBeAg positive CHB) or HBV DNA < 10⁷ copies/mL (HBeAg negative CHB) and ALT level ≥ 2 ULN) plus non-detectable serum HBV DNA at treatment week 24 is suggested to be the strongest predictor of optimal outcomes at 2 years [173]. Of CHB patients receiving lamivudine or telbivudine treatment, those with a virologic response at week 24 (< 300 copies/mL) achieved a high rate of HBeAg seroconversion at week 52 [125]. Less resistance was reported in patients with low serum HBV DNA levels (< 1,000 copies/mL) at week 48 during long-term therapy with adefovir [157].

Liver biopsy has been considered the gold standard for diagnosis of liver cirrhosis. Whereas use of liver biopsy is limited in real clinical practice; imaging studies such as CT, abdominal ultrasound, and MRI are helpful for the diagnosis of liver cirrhosis. Typical image findings of liver cirrhosis include nodular liver surface, splenomegaly, and the presence of intra-abdominal collateral vessels, which indicate increased portal venous pressure. If esophageal or gastric varices is observed in upper gastrointestinal endoscopy, liver cirrhosis can be diagnosed [174]. With imaging studies, laboratory findings such as albumin, bilirubin, or prothrombin time and platelet values are helpful for the diagnosis of liver cirrhosis.

Patients with compensated cirrhosis and elevated serum HBV DNA (HBV DNA ≥ 2,000 IU/mL) can benefit from treatment with long-term oral NAs, because such treatment may prevent disease progression [141] and the development of HCC [144,145,175-178]. Compensated cirrhosis patients with a low viral load, although HBV DNA < 2,000 IU/mL, are at considerable risk for HCC, and antiviral treatment in these patients was suggested to reduce the risk of HCC [179]. Antiviral therapy is recommended in CH-B patients with significant hepatic fibrosis regardless of AST/ALT levels [35,162,163,180]. The levels of AST/ALT should not be used as criteria for starting antiviral therapy in patients with liver cirrhosis, because they already have significant hepatic fibrosis and frequently have nearly normal AST/ALT levels.

In a cohort of HBeAg-positive liver cirrhosis patients, long-term follow-up data after interferon-α therapy showed that the HBeAg seroconversion rate was similar (67% vs. 60%, respectively) but the ALT normalization rate (62% vs. 47%) and HBsAg loss rate (23% vs. 3%) were better in the interferon-α treated group than in the control group [181]. Interferon-α treatment in cirrhotic patients requires careful monitoring because it may cause acute exacerbation of hepatitis, which leads to hepatic failure [182]. After treating CHB patients with peginterferon-α-2b alone or in combination with lamivudine for 52 weeks, the virologic response rate (as indicated by HBeAg seroconversion and an HBV DNA level of <10,000 copies/mL) was superior in those with cirrhosis than in those without cirrhosis (35% vs. 14%, respectively) [183]. However, acute exacerbation of hepatitis (33% vs. 12%, respectively) and requirement for dose reduction (63% vs. 30%) were more common in cirrhotic patients than in noncirrhotic patients [183]. Therefore, interferon-α can be used with caution in cirrhotic patients with preserved liver function.

In patients with decompensated liver cirrhosis, long-term lamivudine treatment significantly reduced the complications and hepatocellular carcinoma compared to placebo. However, the benefit was less in patients with lamivudine resistance [141]. Entecavir treatment of patients with advanced hepatic fibrosis or cirrhosis for 48 weeks showed improvements in the liver histology in 57%, 59%, and 43% of patients with HBeAg-positive, HBeAg-negative, and lamivudine-resistant CHB, respectively [184]. A study including a small number (n=40) of patients showed that telbivudine effectively decreased HBV DNA levels in patients with compensated liver cirrhosis, and HBV DNA was undetectable after 48 weeks of telbivudine treatment in 92.5% [185]. A study comparing the effects of clevudine treatment for 48 weeks found that the virologic response rate (HBV DNA <1,000) (87.1% vs. 71.4%, respectively) and biochemical response rate (83.9% vs. 80.9%) did not differ significantly between patients with CHB (n=21) and those with liver cirrhosis (n=31) [186]. A phase III clinical trial of tenofovir adopting paired liver biopsy at baseline and at week 240 revealed that, of the 96 (28%) patients with liver cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had liver cirrhosis (≥1 unit decrease in score) at follow-up biopsy [187].

Since long-term antiviral therapy is generally required in patients with liver cirrhosis, the AASLD and EASL guidelines recommend the use of entecavir or tenofovir due to their potent antiviral efficacy and high genetic barrier to drug resistance.

Decompensated liver cirrhosis is defined as liver cirrhosis complicated with ascites, variceal bleeding, hepatic encephalopathy, or jaundice [174]. Patients with decompensated liver cirrhosis should be treated at an institution that can provide appropriate management for complications of liver cirrhosis. Liver transplantation should be considered in patients with decompensated liver cirrhosis. Oral NAs may improve hepatic function [142] and decrease the need for liver transplantation in Child-Turcotte-Pugh (CTP) class C cirrhosis [188]. The use of interferon-α in patients with decompensated liver cirrhosis is contraindicated due to the risk of serious complications, such as infection or hepatic failure [189]. Lamivudine treatment for longer than 6 months was shown to improve or stabilize liver function and prolong the time to liver transplantation in patients with decompensated liver cirrhosis [190-192]. A study comparing the effects of telbivudine and lamivudine in patients with decompensated liver cirrhosis found a higher rate of HBV DNA undetectability (47% vs. 36%, respectively) and a lower viral breakthrough rate (29% vs. 39%, respectively) in the telbivudine group than in the lamivudine group [193]. A study of the effect of adefovir in lamivudine-resistant cirrhotic patients (n=101) found that the virologic response rate was lower in decompensated cirrhotic patients (n=53) than in compensated cirrhotic patients (n=48) (50.9% vs. 83.3%, respectively), whereas ALT normalization and HBeAg loss did not differ between the two groups [194].

A randomized study comparing the effects of entecavir (1 mg/day) and adefovir (10 mg/day) in patients with decompensated liver cirrhosis found that the rates of HBV DNA undetectability at weeks 24 and 48 were higher in the entecavir group than in the adefovir group (week 24, 49% vs. 16%, respectively; week 48, 57% vs. 20%), while HBeAg seroconversion at week 48 did not differ significantly between the two groups (6% vs. 10%) [195]. Entecavir therapy showed improvement of the CTP score (to ≥2) in almost half (27/55) of treatment-naïve patients with decompensated liver cirrhosis (n=55) and a 1-year transplantation-free survival rate of 87.1% [142].

A randomized trial comparing the effects of tenofovir (n=45), tenofovir plus emtricitabine (n=45), and entecavir (n=22) in patients with decompensated liver cirrhosis showed that the requirement for early withdrawal of drug (6.7%, 4.4%, and 9.1%, respectively) and elevation of serum creatinine (8.9%, 6.7%, and 4.5%) did not differ among the three groups. The rates of HBV DNA undetectability at week 48 were 70.5%, 87.8%, and 72.7%, respectively, and those of HBeAg loss/seroconversion were 21%/21%, 27%/13%, and 0%/0% [143].

Because prompt treatment is required in patients with decompensated liver cirrhosis, oral antiviral therapy is the treatment of choice if HBV DNA is detectable by PCR tests [35,162,180]. An antiviral drug with a potent antiviral efficacy and high genetic barrier to drug resistance should be used. Since clinical improvement often requires 3–6 months of antiviral therapy, progression to hepatic failure is possible even during antiviral therapy in some patients. Hence, liver transplantation should be considered together with antiviral treatment [192]. Pre- and post-transplantation antiviral therapy has been reported to reduce the risk of reactivation of hepatitis after liver transplantation.

After diagnosis and initial evaluation of patients with CHB, their serum HBV DNA, ALT, HBeAg, and anti-HBe levels should be regularly monitored until they are considered for treatment [35,168,196,197]. The HBV genotype test is not recommended in Korea because most Korean patients are known to have HBV genotype C [198,199].

Applying a quantitative HBsAg (qHBsAg) assay before or during antiviral treatment may assist prediction of the treatment response [200-203]. HBsAg is generated by transcription and translation of cccDNA or HBV DNA integrated into the genome, and can be detected on the surface of infective virions and on circular and linear non-infective particles. The quantity of HBsAg (qHBsAg) showed a positive correlation with the amount of cccDNA in hepatocytes, which enabled a standardized qHBsAg assay [204,205]. HBsAg quantity is highest during the immune-tolerant phase (4.5–5.0 log₁₀ IU/mL), starts to decrease during the immune-active phase (3.0–4.5 log₁₀ IU/mL), and decreases gradually after HBeAg seroconversion. The HBsAg quantity is lowest in the immune-control phase (1.5–3.0 log₁₀ IU/mL), and starts to increase in HBeAg-negative CHB (2.5–4.0 log₁₀ IU/mL) [206-208]. During long-term lamivudine treatment, a low level before treatment and large decrement during treatment of qHBsAg were predictors of HBsAg seroconversion. Several studies reported that the decrement of qHBsAg correlated with the decrement of HBV DNA level [203,209,210].

1. Chronic hepatitis (HBeAg positive or negative)

1) In patients with persistently normal AST/ALT levels, liver function should be tested and serum HBV DNA should be measured by real-time PCR at 2–6-month intervals, plus HBeAg status (HBeAg and anti-HBe) should be checked every 6–12 months. (C1)

2) If AST/ALT levels increase above the normal limit, liver function should be tested every 1–3 months, and serum HBV DNA should be measured by real-time PCR plus HBeAg status should be checked every 2–6 months. (C1)

2. Compensated liver cirrhosis Liver function should be tested every 2–6 months, and serum HBV DNA should be measured by real-time PCR plus HBeAg status should be checked every 2–6 months. (C1)

3. Decompensated liver cirrhosis Liver function should be tested every 1–3 months, and serum HBV DNA should be measured by real-time PCR plus HBeAg status should be checked every 2–6 months. (C1)

Patients should be tested for HBeAg and anti-HBe at 6 and 12 months during the treatment, and at 6 months post treatment. After cessation of treatment, patients should be monitored for 6–12 months to check if additional treatment is required. There is a high probability of HBsAg loss if serum HBV DNA becomes undetectable during treatment. HBeAg-positive patients who achieve HBeAg seroconversion with peginterferon-α require a long follow-up due to the possibility of HBeAg reversion or development of HBeAg-negative CHB. HBsAg loss should be checked at 6-month intervals after HBeAg seroconversion if serum HBV DNA is undetectable. The qHBsAg assay assists in predicting the treatment response [230,231]. In case of a primary non-response (failure to achieve a 1 log₁₀ reduction in serum HBV DNA from baseline after 3 months of peginterferon-α treatment), peginterferon-α treatment should be stopped and replaced by a NA. Several studies recommend that peginterferon-α treatment should be stopped if qHBsAg does not decrease below 20,000 IU/mL after 24 weeks of treatment, which is predictive of non-response [230,231].

HBeAg-negative patients should be monitored similarly to HBeAg-positive patients during 48 weeks of treatment. A virologic response with a serum HBV DNA level of <2,000 IU/mL is generally associated with remission of the liver disease [231]. Undetectable serum HBV DNA by real-time PCR is the ideal off-treatment sustained response, with a high probability of HBsAg loss in the longer term. HBsAg should be checked at 6-month intervals if HBV DNA is not detectable. qHBsAg levels after 12 and 24 weeks of treatment as well as serum HBV DNA levels can be major predictive factors of a treatment response [210,232,233]. Several studies recommend treatment interruption when qHBsAg after 12 weeks of treatment does not decrease, together with a < 2 log₁₀ serum HBV DNA level [234,235].

1. During treatment with NAs, liver function should be tested and serum HBV DNA should be measured by real-time PCR every 1–3 months, plus HBeAg status (HBeAg and anti-HBeAg) should be checked every 3–6 months. (C1) qHBsAg assay may assist prediction of the treatment response and identification of cases in which discontinuation of antiviral therapy may be attempted. (C1)

2. During treatment with peginterferon-α, CBC and ALT level should be measured monthly. Serum HBV DNA should be measured by real-time PCR at 1- to 3-month intervals, plus HBeAg and anti-HBe should be checked at 6 and 12 months during the treatment and at 6 months post-treatment. (C1) qHBsAg assay should be performed before, at 12 and 24 weeks during the treatment and at the end of treatment. (B1)

3. After identification of a complete virologic response, serum HBV DNA should be measured by real-time PCR after 3–6 months and then retesting should be performed at 2–3 months after HBeAg seroclearance is achieved. (C1)

4. Patients who develop virologic breakthrough while receiving a NA should be monitored for compliance and antiviral-resistance mutations. (A1)

5. During antiviral therapy, close monitoring for side effects of each drug is mandatory. (A1)

The response to antiviral treatment persists in some patients, while others relapse. Non-responders should prepare for the deterioration of liver function. Therefore, regular monitoring is needed to check for the durability of the treatment response, relapse, and liver function.

1. During the first year after the cessation of antiviral treatment, liver function should be monitored and serum HBV DNA should be measured by real-time PCR every 1–3 months, plus HBeAg and anti-HBe should be checked at 3- to 6-month intervals. Beyond 1 year after the cessation of antiviral treatment, liver function and serum HBV DNA by real-time PCR should be tested every 3–6 months to detect viral relapse. (C1)

2. For early detection of HCC, ultrasound and serum α-fetoprotein measurement should be performed regularly. (A1)

Although the ideal goal of treatment is to achieve HBsAg loss, the primary endpoint when treating patients with HBeAg-positive hepatitis is to achieve HBeAg seroconversion. Undetectable serum HBV DNA by real-time PCR and HBeAg seroconversion are strongly correlated with favorable biochemical and histologic responses. NA can be stopped when HBeAg seroconversion is achieved and antiviral treatment has been maintained at least for 12 months [236]. However, cessation should be decided carefully since 40–90% of patients developed reactivation of HBeAg-positive or -negative hepatitis after HBeAg seroconversion induced by NA treatment [237-240]. HBsAg should be tested at 6-month intervals after HBeAg seroconversion. HBsAg loss is rarely observed after NA therapy; however, low baseline qHBsAg levels and greater rate of HBsAg reduction were highly predictive of HBsAg seroclearance [203]. Peginterferon-α is generally administered for 48 weeks, and its efficacy was confirmed in a recent double-blind, randomized controlled study [241,242].

The recommended duration of peginterferon-α treatment in patients with HBeAg-negative hepatitis is 48 weeks, but the optimal treatment duration for NA is unknown, and cessation of treatment should be individually decided according to the clinical treatment response and the baseline severity of the liver disease. Treatment with NA should be continued until the loss of HBsAg. Treatment discontinuation can be considered if undetectable serum HBV DNA has been documented on three separate occasions 6 months apart [163]. However, close follow up is required due to the high probability of reactivation (29.7–91.0%) after treatment discontinuation [239,243-245]. Peginterferon-α administration for 48 weeks is recommended.

Long-term treatment is required in patients with cirrhosis. In HBeAg-positive patients with compensated cirrhosis, treatment discontinuation can be considered when NA is administered for at least a further 12 months after HBeAg seroconversion. Treatment discontinuation can be considered after achievement of HBsAg loss in HBeAg-negative patients. Monitoring for viral relapse and acute exacerbation of disease is mandatory after discontinuation. Long-term treatment should be planned in patients with decompensated cirrhosis, including the possibility of liver transplantation.

The definitions of responses to antiviral therapy vary according to the type of therapy.

Certain baseline and on-treatment predictors of the subsequent treatment response have been identified. The predictors of the responses to existing antiviral therapies at various time points vary according to the agent.

It is estimated that more than 10 [11] new virions are produced daily in a human body with active HBV replication [259]. Some of the HBV mutants that emerge naturally during active replication are selected by the selection pressure exerted by the human immune system or antiviral therapy. Those mutants with maximal replication become predominant during antiviral therapy. Primary antiviral-resistant mutants usually have a low replication capacity, but recover to the level of the wild-type virus when compensatory mutations appear [260]. In addition, a higher fold resistance to antiviral therapy allows increased replication of the mutant virus. A genetic barrier is defined as the number of genetic mutations needed to develop antiviral resistance, with a higher genetic barrier indicating a lower risk of resistance [261]. The antiviral potency of drugs also influences the development of resistance. Drugs with a lower antiviral potency or potent antiviral activity have lower risks of antiviral resistance, because the former is associated with a lower selection pressure and the latter with complete suppression of the virus. However, drugs with intermediate potency have an increased risk of resistance because residual viremia during treatment may result in selection of mutants with good replication fitness [262]. Clinically, the HBV DNA level, history of prior antiviral treatment, duration of treatment, serum drug concentration (peak and trough), and patient compliance are the most important factors influencing the development of resistance. Definitions of terms associated with antiviral resistance are provided in Table 5.

Antiviral agents for the treatment of HBV infection are classified into two groups: NAs and nucleotide analogues. Cyclopentenes (entecavir) and L-nucleoside analogues (lamivudine, telbivudine, and clevudine) are NAs, while acyclic phosphonates (adefovir and tenofovir) are nucleotide analogues [263]. The incidences of resistance to individual antiviral drugs are shown in Table 6.

Prior antiviral resistance predisposes individuals to subsequent viral mutations and limits the choice of rescue therapies due to the presence of cross-resistance [263,279]. Although antiviral agents without cross-resistance may be selected, the resistance to the rescue therapy is greater than that of treatment-naïve subjects [279-281].

It is therefore critical to initially choose the antiviral agent with the lowest resistance rate.

Appropriate monitoring during treatment is needed to detect virologic and biochemical breakthroughs as early as possible. Anti-viral resistance testing is required when a virologic or biochemical breakthrough is detected in subjects with good compliance. If genotypic resistance is confirmed, rescue therapy should be initiated before the clinical situation deteriorates [282].

General principles of antiviral resistance management:

1. An antiviral resistance test should be performed when virologic breakthrough occurs, especially in cases with good compliance. (A1)

2. Rescue antiviral therapy should be started as soon as possible upon emergence of resistant variants, especially when viral breakthrough is detected and genotypic resistance is confirmed. (A1)

1. Switch to tenofovir or combine tenofovir with a nucleoside analogue. (A1)

2. Consider combination of adefovir and a nucleoside analogue if use of tenofovir is contraindicated. (B1)

3. Stop lamivudine and consider treatment with peginterferon-α if the patient has compensated liver function. (B2)

Few data related to telbivudine resistance are available. In a study in which telbivudine- resistant patients or viral breakthrough patients without resistance (n=68) were treated with adefovir, over 70% of patients had an HBV level of ≤300 copies/mL after 12 months [305]. Treatment based on tenofovir could be a therapeutic option, but comparative data for telbivudine and lamivudine are insufficient. The general principles of management of telbivudine resistance are similar to those for the management of lamivudine resistance.

1. Follow the recommendations for the management of lamivudine-resistant CHB. (B2)

The HBV mutations rtN236T and rtA181V/T result in primary resistance to adefovir [157,275]. rtA181T can also be detected in subjects receiving lamivudine monotherapy or combination therapy of adefovir plus lamivudine [272,275-277,306]. rtN236T and rtA181T result in 7- to 10-fold and 2.5- to 5-fold, respectively, greater resistance to adefovir relative to the wild-type virus [263,272]. The double mutation (rtA181T/V and rtN236T) results in a 5.2- to 18-fold reduction in sensitivity to adefovir [272]. Patients with persistent drug-resistant HBV viremia are more likely to suffer hepatitis flares, disease progression, and death than those without drug-resistant HBV [307].

The rate of adefovir-resistance is 20% and 29% after 5 years of adefovir treatment in HBeAg-positive and HBeAg-negative treatment naïve patients, respectively [157,308]. The risk of genotypic resistance to adefovir increases in patients resistant to lamivudine compared to treatment-naïve patients. After 48 weeks of adefovir treatment, the rate of resistance was 18% and 0% in lamivudine-resistant and treatment-naïve patients, respectively [280]. Moreover, the rate of adefovir resistance can reach 22-25% after 2 years of treatment in lamivudine-resistant patients [281,309].

1. Switch to tenofovir or combine tenofovir with entecavir. (B1)

2. Combination therapy with tenofovir and a nucleoside analogue other than entecavir. (B2)

3. Consider combination of adefovir and a nucleoside analogue if use of tenofovir is contraindicated. (B2)

In patients with lamivudine-resistant HBV, the rate of entecavir resistance increases to 51% after 5 years of entecavir treatment, in contrast to a 1.2% resistance rate in NA-naïve patients [273,274]. The difference is because the entecavir resistance barrier is lowered by the initial selection of the lamivudine-resistance HBV mutation, rtM204V/I [323]. In vitro studies have shown that susceptibility to entecavir is decreased by 10-250-fold when one of the entecavir resistance-associated substitutions at rtT184, rtS202, or rtM250 is present in combination with rtM204V/I, and by >500-fold when two or more of these mutations are present [273,323].

In vitro studies suggest that entecavir-resistant HBV mutants are susceptible to adefovir and TDF [324,325]. A few cohort studies have reported the efficacy of adefovir or TDF in patients with entecavir-resistant HBV [326-329].

1. Switch to tenofovir or combine tenofovir with entecavir. (B1)

2. Consider combination of adefovir and a nucleoside analogue if use of tenofovir is contraindicated. (B2)

No tenofovir-resistant patients have been reported to date. A prospective study found no HBV strain resistant to TDF after up to 8 years of treatment [335]. An in vitro study reported that A194T in combination with lamivudine resistance mutations, rtL180M and rtM204V, might account for TDF resistance in HBV [278]. However, other in vitro studies have reported inconsistent results [336,337].

Multidrug resistance is defined as resistance to two or more groups of antiviral drugs; i.e., L-nucleoside (lamivudine, telbivudine, clevudine), cyclopentane (entecavir), or nucleotide analogue (adefovir and tenofovir) [279,318].

Interferon has not been used for the management of patients with multidrug-resistant HBV. However, there is also no suggestion that such patients have decreased susceptibility to interferon.

In vitro clonal analyses showed that multidrug-resistance mutations usually reside in the same viral genome [279,318], and replicating clones with lamivudine- and adefovir- associated mutations had >50-fold reduced susceptibility to combination of lamivudine and adefovir [338,339]. In fact, a cohort study demonstrated that in patients with HBV resistant to lamivudine and adefovir, combination therapy with these two drugs was not effective and indeed was inferior to entecavir monotherapy in terms of suppressing HBV DNA [311]. However, the response to entecavir monotherapy was not optimal. Entecavir was markedly less effective in patients refractory to both lamivudine and adefovir than in those with lamivudine monoresistance [313], or treatment-naïve patients [273].

In patients with multidrug-resistant HBV, a combination of the two most potent drugs, TDF and entecavir, would likely prevent the emergence of resistance to TDF [340]. However, two randomized trials in patients with resistance to entecavir and/or adefovir in addition to lamivudine resistance showed no difference in virologic response between TDF monotherapy and TDF and entecavir combination therapy, and no emergence of additional resistance mutations [322,334]. Based on their comparable antiviral efficacy, extremely low risk of TDF resistance, lower cost, and potentially better safety profile, TDF monotherapy would be a reasonable option for the treatment of entecavir-resistant patients.

1. Switch to tenofovir or combine tenofovir with entecavir. (B1)

2. Consider combining adefovir with a nucleoside analogue if use of tenofovir is contraindicated. (B2)

1. In patients with a complete virologic response, treatment should be continued until the treatment endpoint is achieved, and monitored by measuring the serum HBV DNA level every 3–6 months. (B1)

2. Drug compliance should be checked thoroughly in patients with a partial virologic response or primary non-response. For patients treated with a drug with a low genetic barrier, treatment should be switched to a drug with a higher genetic barrier. (B1) For patients treated with a drug with a high genetic barrier, treatment could either be switched to another drug with a high genetic barrier or be continued with monitoring for a virologic response at 3-6-months intervals. (C1)

3. In the event of viral breakthrough, rescue therapy should be implemented according to the genotypic resistance profile. (A1)

4. The treatment strategy should follow the recommendations for treating drug-resistant HBV when genotypic resistant mutations are identified. (A1)

Acute hepatitis B resolves spontaneously and does not progress to the chronic stage in more than 95% of patients, so antiviral therapy is generally not recommended [363,364]. Early initiation of antiviral therapy has been reported to interfere with the normal protective immune response and suppresses production of neutralizing antibodies against hepatitis virus, increasing the risk of chronic hepatitis [365]. However, acute hepatitis B infection seldom progresses to serious hepatitis and may lead to hepatic failure [364]. According to a randomized controlled trial in 71 patients with severe acute hepatitis B, HBV DNA levels were significantly lower in the lamivudine-treated group (n=31, 3.7 log₁₀ copies/mL) compared with the control group (n=40, 4.2 log₁₀ copies/mL) after 4 weeks. However, the rate of HBsAg loss after 12 months was similar in the two groups (93.5% in the lamivudine group and 96.7% in the placebo group) [366]. In this study, the rate of development of protective anti-HBs after 1 year was 67.7% in the lamivudine group and 85% in the placebo group; the difference was not significant. A recent, small, prospective, controlled study also reported no significant benefit of lamivudine in severe acute hepatitis B [367]. In contrast, Tillman et al. reported that lamivudine is safe in patients with severe acute or fulminant hepatitis B, leading to rapid recovery with the potential to prevent liver failure and liver transplantation when administered sufficiently early [368]. However, only a few case reports of antiviral agents as treatment for acute hepatitis B other than lamivudine have been published to date [369-371].

1. For patients with acute hepatitis B, oral antiviral therapy might be considered in cases of persistent serious hepatitis or acute liver failure. (C1)

In the past, severe liver damage and a low survival rate due to HBV recurrence after liver transplantation in HBV-related liver disorder patients were major problems [372-379]. However, in an extensive cohort study of 372 patients who received liver transplants in the early 1990s and were positive for HBsAg, the study group treated with HBIG therapy for more than 6 months showed a significantly lower rate of hepatitis B recurrence than the group treated with HBIG therapy for less than 6 months or those who were not treated. The study group also had a higher long-term survival rate than the other groups [380]. Since then, several studies have reported hepatitis B recurrence rates ranging from 16% to 35% after liver transplantation in groups receiving high-dose HBIG (10,000 IU) therapy [381-383].

Lamivudine and HBIG combination therapy reduces the rate of HBV recurrence to less than 10% after 1–2 years and is superior to high-dose HBIG therapy with respect to cost and effectiveness [384-387]. In a meta-analysis of six independent studies, lamivudine and HBIG combination therapy was found to reduce the rates of HBV recurrence and death 12-fold compared with HBIG therapy alone [388,389]. A meta-analysis of 46 studies in which 2,161 HBV-infected patients received liver transplants found that adefovir and HBIG combination therapy significantly reduced the rate of hepatitis B recurrence to 2% compared to 6% with lamivudine and HBIG combination therapy [390].

In patients who received lamivudine monotherapy without HBIG, the hepatitis B recurrence rate after 4 years of liver transplantation was ~40% [391,392]. In contrast, a study of lamivudine and adefovir combination therapy reported no recurrence in CHB patients during the 22-month observation period [393]. In patients who received entecavir monotherapy without HBIG [394,395], the rate of HBsAg loss was 88-91% and negative viremia was maintained in more than 98% during a 26-53-month follow up; moreover, the rate of HBV recurrence was lower than that with lamivudine monotherapy [395].

In a meta-analysis of 19 studies, lamivudine or adefovir with HBIG significantly reduced HBV recurrence compared to monotherapy with either lamivudine or adefovir [396]. However, in a meta-analysis of 17 studies with 519 patients, those treated with lamivudine and HBIG (6.1%) combination therapy showed a rate of HBV recurrence comparable to that of those treated with either entecavir or tenofovir monotherapy (3.9%, P=0.52), and significantly higher than that of those treated with the combination of HBIG and either entecavir or tenofovir therapy (1%, P<0.001) [397]. To date, few studies regarding entecavir or tenofovir monotherapy for the prevention of HBV recurrence after liver transplantation have been reported. Therefore, the combination of an antiviral and HBIG is recommended to prevent HBV recurrence after liver transplantation.

To reduce the cost of HBIG, studies of low-dose HBIG in combination with an antiviral or conversion to antiviral monotherapy after short-term HBIG combination therapy have been performed. In a study of 147 patients who received liver transplants, Gane et al. showed that lamivudine and low-dose HBIG (400–800 IU) combination therapy effectively suppressed the recurrence of hepatitis B at a moderate cost, as the 5-year recurrence rate of hepatitis B was 4% [398]. Furthermore, patients with HBV DNA levels of less than 2.5 pg/mL before liver transplant and treated with lamivudine and HBIG (2,000 IU) combination therapy for 1 month after liver transplant were randomly assigned to either a combination therapy maintaining group or lamivudine monotherapy group. The rates of HBV recurrence and patient survival did not differ between the two groups [399]. Two other retrospective studies reported no recurrence of HBV when lamivudine and HBIG combination therapy or HBIG therapy alone for 2 years after liver transplantation was replaced with lamivudine monotherapy [400,401]. In a recent study by Angus et al., lamivudine and low-dose HBIG (800 IU) combination therapy was continued for at least 12 months after liver transplantation. The group in which HBIG was replaced by adefovir and the group in which HBIG was continuously administered showed similar rates of hepatitis B recurrence [402]. Lamivudine and adefovir combination therapy with initial short-term low-dose HBIG (400-800 IU) did not show HBV recurrence during the 57-month follow-up period [393].

Few studies with a small number of patients have evaluated entecavir- or tenofovir-based therapy to reduce HBIG usage. The HBV recurrence rate was reported to be 10% (1/10) [403] and 0% (0/11) [404] when combination entecavir and HBIG therapy was converted to entecavir monotherapy; there was no HBV recurrence after converting to tenofovir monotherapy in 9 patients [403] and 17 patients [404]. The rates of recurrence were 5.9% (1/17) [405] and 4.8% (1/21) [406] in a study of conversion to tenofovir and emtricitabine (Truvada^®); however, HBIG withdrawal had an economic benefit. Although these studies suggested the possibility of reducing the dose and duration of HBIG treatment, further work is needed to determine the optimal duration, amount and type of antiviral treatment.

If hepatitis B recurs after preventive HBIG therapy following liver transplantation, lamivudine therapy could effectively inhibit the virus. However, it has been reported that long-term lamivudine therapy is associated with a resistance rate of >50% after 3 years [407-409]. Such lamivudine resistance causes inflammatory changes and hepatic fibrosis in the transplanted liver; indeed, death following hepatic failure is possible in severe cases [408,410,411].

A few studies have reported the effects of tenofovir and entecavir on hepatitis B recurrence after liver transplantation; however, further research is required [412]. Several studies have reported relatively good efficacy of lamivudine and adefovir in patients with recurrent hepatitis B who exhibit lamivudine resistance after liver transplantation. The most extensive study administered the combination therapy to 241 patients with recurrent hepatitis B. The rate of reduction in HBV DNA was 65%, whereas the rate of lamivudine resistance at 96 weeks after the initiation of therapy was 2% [413]. Although these studies were conducted for a short period in small groups, it was recently reported that tenofovir is effective against mutants with lamivudine resistance [411,414]. However, a high rate of emergence of entecavir resistance has been reported when entecavir is administered as a rescue therapy to patients with lamivudine resistance [274]. Therefore, entecavir is not recommended in patients with lamivudine resistance after liver transplantation.

If HBsAg seronegative patients receive liver transplants from positive anti-HBc donors, ~50% will develop new hepatitis B [415]. When HBIG therapy was administered to these patients after liver transplantation, hepatitis B occurred in >20%. However, when lamivudine therapy was applied, hepatitis B developed only in 2–3% of patients. Nevertheless, lamivudine and HBIG combination therapy had no additional preventive effects compared to lamivudine therapy alone [415-417]. The protective effect against HBV recurrence was similar between lamivudine and entecavir or tenofovir [418]. Lamivudine was more cost-effective than entecavir or tenofovir according to a Markov model [419].

1. Pre-transplant therapy with a NA is recommended for all HBsAg-positive patients undergoing liver transplantation to achieve the lowest possible level of HBV DNA before transplantation. (A1)

2. Antiviral therapy before liver transplantation should comply with the guidelines for chronic hepatitis B therapy. (B1)

3. Therapy with a NA and HBIG should be administered for the lifetime of the patient to prevent recurrence of hepatitis B after liver transplantation, until more evidence regarding alternative treatment regimens is accumulated. (B1) If serum HBV DNA becomes negative before the liver transplant, withdrawal of HBIG may be considered in certain patients after long-term monitoring. (B1)

4. In case of HBV recurrence after liver transplantation, a potent NA with a high barrier to resistance is recommended. (B1) Upon emergence of drug-resistant variants, the CHB treatment guidelines should be followed. (B1)

5. When an HBsAg-negative recipient receives an HBsAg-negative but anti-HBc-positive graft, the recipient should take oral antivirals indefinitely. (B1)

The clinical course of individual patients with chronic hepatitis B is affected by the interaction between the virus and the host immune system. Impaired host immunity due to chemotherapy or immunosuppressive treatment increases the risk of HBV reactivation [420]. Previously, HBV reactivation referred to the reappearance of necroinflammatory disorders in patients with either inactive CHB or with resolved hepatitis [421], and was commonly defined as an increase in the serum HBV DNA of >10-fold the baseline level or an absolute level of >10⁸ IU/mL together with elevated serum ALT (higher than 3× ULN or an absolute increase of >100 IU/L) [422,423]. However, most studies of HBV reactivation used their own definition of HBV reactivation, and so the exact incidence of HBV reactivation during immunosuppressive therapy or chemotherapy was unclear. In addition, several terms such as “preventive”, “prophylactic” and “preemptive” were used but not clearly defined, which resulted in confusion in scientific communications. In this guideline, “prophylactic” therapy means starting antiviral therapy simultaneously with initiation of immunosuppressive therapy or chemotherapy. Meanwhile, “preemptive” therapy means deferring antiviral therapy until the HBV DNA level increases. We prefer the term “preventive” therapy, which means not only starting antiviral therapy upon initiation of immunosuppressive therapy or chemotherapy but also deferring antiviral therapy until the HBV DNA level increases.

Two definitions of HBV reactivation are in use [424]. One is exacerbation of chronic HBV infection, and the other is relapse of past HBV infection. Exacerbation of chronic HBV infection is defined ≥2log₁₀ increase of HBV DNA level from the baseline level or a new appearance of HBV DNA to a level of ≥100 IU/mL. Relapse of past HBV infection is defined among HBsAg negative, IgG anti-HBc positive and HBV DNA negative patients as reappearance of HBsAg or detectable HBV DNA. The diagnosis of HBV reactivation requires the exclusion of other conditions such as chemotherapy-related hepatic injury, hepatic metastases, and other types of viral hepatitis. The reactivation rate has been reported to be 20-50%, although the ranges varied among studies. Many patients with HBV reactivation are asymptomatic, but the clinical course varies widely from jaundice to decompensation or even death [422,425-427]. In typical cases, HBV DNA appears in the serum during immunosuppressive treatment, followed by elevation of ALT after treatment cessation. If HBV reactivation occurs during chemotherapy, treatment disruption or premature termination may adversely affect the outcome of chemotherapy [428-430]. Predictive factors for HBV reactivation include the pretreatment HBV DNA level, HBeAg positivity, cccDNA in hepatocytes and PC/BCP mutation as viral factors, type of malignancy, male and young age as host factors, and type or intensity of immunosuppression or chemotherapy and hematopoietic stem cell or organ transplantation as environmental therapeutic factors [431].

The reported reactivation rate in lymphoma patients ranges from 24% to 67%, possibly due to intense chemotherapeutic regimens against lymphoma and higher HBsAg positivity rates in these patients [426,432-434]. Rituximab, which is commonly administered with corticosteroid for lymphoma, further increases the risk of HBV reactivation [435,436]. One retrospective study reported a 27.8% (45/162) HBV reactivation rate among HBsAg-positive lymphoma patients, with a lower rate of HBV reactivation in the preventive antiviral therapy group compared to the non-preventive antiviral therapy group (22.9% [32/140] vs. 59.1% [13/22]; P<0.001) [437]. In this study, entecavir reduced the rate of HBV reactivation to a greater degree than lamivudine (6.3% vs. 39.3%; P<0.05). In HBsAg negative/anti-HBc positive patients, the rate of HBV reactivation was 2.4% in this retrospective study. Another prospective study of HBsAg negative/anti-HBc-positive lymphoma patients reported a higher rate of HBV reactivation and hepatitis aggravation (10.4 and 6.4 per 100 person-years, respectively) during rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy [438]. In this study, close monitoring of HBsAg and HBV DNA with immediate antiviral therapy usually overcame the complications of HBV reactivation; however, some cases showed marked aggravation and progression of severe hepatitis, which was associated with reappearance of HBsAg compared to reappearance of HBV DNA without HBsAg (100% vs. 28%). A rituximab-containing regimen increased the risk of HBV reactivation among HBsAg-positive and HBsAg-negative/anti-HBc-positive lymphoma patients (relative risk 2.14, 95% CI 1.42–3.22, P=0.0003), especially in HBsAg-negative/anti-HBc-positive lymphoma patients (relative risk 5.52) [439]. Preventive anti-viral therapy in lymphoma reduced the rate of HBV reactivation significantly compared to a non-preventive group (13.3% vs. 60%) [440]. Pretreatment screening for HBsAg and anti-HBc before R-CHOP chemotherapy in lymphoma and preventive antiviral therapy enhanced survival and cost-effectiveness by reducing the rate of HBV reactivation [441].

The risk of reactivation is also elevated when high-intensity chemotherapy is applied prior to hematopoietic stem-cell transplantation in hematologic malignancies [442,443]. Similarly, preventive anti-viral therapy with lamivudine or entecavir reduced the rate of HBV reactivation [444]. Although the reactivation rate was 14-21% in solid tumors, higher rates of 41-70% were reported in breast cancer, possibly related to the use of high-dose chemotherapy with anthracycline agents and steroids [430,445,446]. The rate of HBV reactivation during transcatheter arterial chemoembolization (TACE) as a therapeutic option for HCC was 4-40% [447-450]. Preventive lamivudine therapy compared to non-preventive group reduced the rates of HBV reactivation (2.8% vs. 40.5%), hepatitis aggravation (2.8% vs. 29.7%) and hepatic failure (0% vs. 8.1%) significantly [448]. Preventive antiviral therapy can be considered in cases undergoing TACE for HCC treatment to reduce HBV reactivation; however, the rates of HBV reactivation during TACE differed according to procedure method, interval, frequency and the TACE agents [447,448,451]. Therefore, further studies are required to elucidate the criteria for preventive antiviral therapy in TACE. Sorafenib, which was approved for advanced HCC, seems not to cause HBV reactivation [452] but this should be confirmed in further investigations. Steroids can suppress the host immune system but also induce HBV replication directly, which increases the risk of HBV reactivation. Other risk factors for reactivation include the use of anti-TNF agents for inflammatory bowel diseases or rheumatologic diseases (e.g., infliximab, etanercept, and adalimumab), the HBV genotype or specific mutations in the HBV genome, and recovery from neutropenia [453-462]. The rate of HBV reactivation was 12.3% among HBsAg-positive patients receiving an anti-TNFα antibody or disease-modifying antirheumatic drug (DMARD), which are used in rheumatologic diseases [463]. Other study reported a rate of HBV reactivation of 39% among HBsAg-positive patients and 5% among isolated anti-HBc-positive patients receiving anti-TNFα antibody therapy. Preventive antiviral therapy decreased the rate of HBV reactivation significantly (23% vs. 62%, P=0.003) [464].

Because HBV reactivation is associated with the risk of hepatic failure and death, prevention is of utmost importance. This necessitates screening for HBsAg and IgG anti-HBc . Vaccination should be considered if there is no evidence of (past) HBV infection (i.e., negative for both HBsAg and IgG anti-HBc). Preventive antiviral therapy is recommended in HBsAg-positive patients regardless of the serum HBV DNA level [455]. Preventive lamivudine therapy has significantly reduced the rates of HBV reactivation, hepatic failure, and mortality in randomized controlled studies of lymphoma patients in Hong Kong and Taiwan [433,443,465,466]. Therefore, it is recommended that preventive antiviral therapy be started simultaneously with the initiation of chemotherapy rather than deferring until the HBV DNA level increases, and should be maintained for certain period after the termination of chemotherapy (e.g., at least 6 months) [466,467]. However, evidence that can be used to determine the duration of preventive antiviral therapy remains limited. Elevated risk of reactivation was reported with cessation of preventive lamivudine therapy at 3 months following the termination of chemotherapy, especially in cases with a high HBV DNA level before chemotherapy (≥2,000 IU/mL) [468]. Therefore, the duration of preventive antiviral therapy could be determined based upon treatment guidelines for CHB if the pre-treatment HBV DNA level is high. In contrast, attention should be paid to reports of reactivation after more than 6 months irrespective of the pre-treatment HBV DNA level. Although there is limited information about the efficacy of preventive treatment with other antiviral agents—such as adefovir, telbivudine, clevudine, entecavir, and tenofovir—these agents could be administered for preventive purpose considering their mechanisms of action and therapeutic results. Since resistance was reported in preventive lamivudine therapy, other antiviral agents with lower resistance rates should be considered in cases with prolonged treatment (e.g., >1 year) [433]. A retrospective study reported that the risks of hepatitis and chemotherapy disruption due to HBV reactivation in lymphoma patients were lower for entecavir than for lamivudine [469]. However, data on the relative efficacy and cost-effectiveness of antiviral agents are scarce. Prospective studies to determine the appropriate antiviral agents and optimal treatment duration in various types of malignancy are needed, as most previous studies involved only lymphoma patients. If cost is ignored, entecavir and tenofovir are appropriate choices based on their potency and resistance rate. Interferon-α is contraindicated for preventive use due to its bone marrow suppression and exacerbation of underlying hepatitis.

In some cases, HBV reactivation occurs not only in HBsAg-positive patients but also in IgG anti-HBc-positive patients without HBsAg [470]. The latter cases correspond to either occult HBV infection in which HBV DNA is detected in the hepatocytes or even in the serum, or reverse seroconversion (seroreversion) of HBsAg in which HBV replication resumes after immunosuppression with reappearance of HBsAg [422,471,472]. The rate of HBV reactivation is higher in patients with isolated anti-HBc than in patients with both anti-HBc and anti-HBs [473]. IgG anti-HBc-positive patients (HBsAg-negative) have a risk of HBV reactivation irrespective of anti-HBs, but a uniform treatment recommendation cannot be provided because the effects of the type of malignancy or immunosuppressive/chemotherapeutic agents used on the reactivation risk are unclear. However, preventive therapy should be started if serum HBV DNA is positive in high-risk groups such as patients with lymphoma under a rituximab-containing regimen or those with leukemia who undergo hematopoietic stem cell transplantation; preventive treatment may be started together with immunosuppressive/chemotherapy or determined with periodic monitoring (e.g., every 1-2 months) of the HBV DNA level in patients with no detectable serum HBV DNA at baseline.

1. It is recommended to screen for HBsAg and IgG anti-HBc prior to initiation of immunosuppressive treatment or chemotherapy. If either is positive, serum HBV DNA should be tested. (A1)

2. Patients without evidence of HBV infection should be vaccinated. (B1)

3. Consider preventive antiviral therapy simultaneously with the initiation of immunosuppressive treatment/chemotherapy if HBsAg or HBV DNA is positive. (A1) Although selection of a NA requires consideration of the serum HBV DNA level, the intensity and duration of immunosuppressive treatment/chemotherapy and the cost, entecavir or tenofovir can be preferentially considered if the baseline HBV DNA level is high or long-term treatment is anticipated. (C1)

4. If IgG anti-HBc is positive without HBsAg or HBV DNA, irrespective of anti-HBs, serum HBV and HBsAg should be tested regularly and preventive antiviral therapy should be considered if either reappears during immunosuppressive treatment/chemotherapy. (A1) Preventive antiviral therapy in patients with isolated anti-HBc can be initiated in high-risk groups such as patients with lymphoma under a rituximab-containing regimen or those with leukemia who undergo hematopoietic stem cell transplantation. (B2)

5. Serum HBV DNA should be monitored periodically during and after preventive antiviral therapy. (A1)

6. Preventive antiviral therapy should be maintained for at least 6 months after the termination of immunosuppressive treatment/chemotherapy. (C1)

Patients under dialysis are relatively prone to being exposed to HBV infection, which might exert a negative influence on their long-term prognosis. Exacerbation of hepatitis B is of particular importance for immunosuppression after renal transplantation [474]. Fortunately, the incidence of HBV infection in dialysis patients has decreased due to surveillance of blood products, enhanced infection control, and widespread use of erythropoietin. The prevalence of HBV infection based on HBsAg positivity in this population is 0-6.6% in Western countries, and ~5% in Korea in recent reports [475-477]. The prevalence of occult HBV infection was higher than the HBsAg-positivity rate in one report [478], but this was not the case in Korea [479]. The standard precautions to avoid nosocomial transmission are of the highest priority for preventing new HBV infections in dialysis patients [480]. Vaccination against HBV is widely recommended in these patients; the efficacy is higher with earlier vaccination because the antibody production rate is 50-60% compared with ~90% in the general population, and decreases as residual renal function declines [481-483]. Data on antiviral treatment in dialysis patients are insufficient. Although a randomized controlled study of interferon-α in HBV-infected patients with glomerulonephritis has been performed [484], it is difficult to recommend its use due to the increased adverse events in this population due to pharmacodynamic changes [485,486]. Several small studies have reported the effectiveness of lamivudine [487-489]. Resistance to lamivudine was 39% at 16.5 months of treatment, which was similar to the rate in patients with normal renal function [490]. Entecavir or tenofovir may be preferentially used, given their potency and resistance profile in patients with normal renal function [35]. Careful dose adjustment is required for adefovir and tenofovir due to their potential nephrotoxicity in patients with residual renal function [491-494]. Tenofovir is less nephrotoxic than adefovir. Two of 426 patients with chronic hepatitis B who underwent tenofovir therapy for 144 weeks showed elevation of serum creatinine to >0.5 mg/dL compared to baseline with no reduction in glomerular filtration rate to <50 mL/min [495].

1. Vaccination is recommended for patients under dialysis negative for HBsAg and anti-HBs. (A1)

2. Oral NAs such as entecavir and tenofovir are preferable to interferon therapy in patients under dialysis. (B1) NAs should be dose-adjusted according to residual renal function. (A1)

In patients with CHB the anti-HCV antibody positivity rate varies from 0.1% to 22%, depending on the region [496-499] with it being very low in Korea (0.1%) [497]. Patients with HBV/HCV co-infection have an increased risk of severe or fulminant infection, and high incidences of cirrhosis and HCC [500-503]. The scarcity of data makes it impossible to recommend a treatment for HBV/HCV co-infection [504-506]. However, it is necessary to determine which virus is dominant by means of serologic or virology tests. If HCV RNA is positive with a low or undetectable serum HBV DNA level, HCV infection should be considered dominant and the patient treated as for HCV monoinfection. Combination therapy of pegIFN-α-2a plus ribavirin is equally effective in patients with HCV monoinfection and HBV/HCV co-infection [507,508]. HBV treatment should be added when HBV reactivates, which can reportedly occur during or after combination therapy of pegIFN-α plus ribavirin for HCV [509].

The role of direct-acting agents (DAAs) in HBV/HCV co-infection needs to be elucidated.

1. After confirming the dominant cause of liver disease in HBV/HCV coinfection, treatment following the same strategy as that for the dominant virus is recommended. (B1)

2. HBV treatment should be initiated when HBV proliferation is identified during or after treatment for HCV. (B1)

It is estimated that ~20 million people are infected with HDV worldwide [510]. HDV infection is prevalent in Mediterranean countries, the Middle East, central Africa, and South America [511]. The HDV co-infection rate in CHB patients has been reported to be 0-3.6% in Korea [512-514]. The incidences of cirrhosis and HCC are higher in patients with HBV/HDV coinfection than in those with HBV monoinfection [515,516].

HDV infection can be diagnosed by detecting anti-HDV antibody or HDV RNA in the serum or by detecting HDV antigen in liver tissue by immunohistochemistry. The treatment goals are to inhibit HDV replication, normalize ALT, and improve histology findings. IFN-α (conventional or pegylated) is the only drug that can inhibit HDV replication [517-521]. The biochemical, virologic, and histologic responses to high-dose IFN-α therapy (9 MU, three times per week) were better than those to the conventional dose of IFN-α (3 MU, three times per week), with the high-dose therapy producing an HDV RNA negativity rate of 43% at 6 months after the end of 48 weeks of treatment [520]. PegIFN-α showed HDV RNA negativity rates of 17-43% at 6 months after the end of 48 or 72 weeks of treatment [517,521,522]. No head-to-head comparison trial between high-dose IFN-α and pegIFN-α therapies has been performed and hence either pegIFN-α or high-dose IFN-α therapy for longer than 1 year is recommended for patients with HBV/HDV co-infection [523]. The treatment response can be evaluated by measuring the serum HDV RNA level at week 24. Both lamivudine and adefovir were found to be ineffective in terms of inhibiting HDV replication [524,525]. Combination therapy of lamivudine plus IFN-α was not superior to IFN-α monotherapy [526], and adefovir plus pegIFN-α therapy did not improve the response rate compared to pegIFN-α monotherapy [525]. In addition, the rates of HDV DNA negativity at 24 weeks after therapy with the combination of adefovir plus pegIFN-α or pegIFN-α monotherapy for 48 weeks were superior to those following adefovir monotherapy for 48 weeks (26%, 31% and 0%, respectively) [527].

1. CHB patients with HDV co-infection should be treated with peginterferon-α or high dose interferon-α (9 MU, three times per week) for >1 year. (B1)

The incidences of cirrhosis and HCC are reportedly higher in patients with HBV/HIV coinfection than in those with HBV monoinfection [528,529]. HBV should be treated in HBV/HIV-coinfected patients who exhibit ALT elevation due to HBV. Before such treatment it is necessary to determine whether treatment for HIV is also required [530]. Patients who are not indicated for HAART should receive the standard treatment for CHB. In such cases anti-viral agents (e.g., IFN, adefovir, or telbivudine) that do not affect HIV proliferation should be selected, to prevent the future development of HIV cross-resistance. Entecavir or tenofovir monotherapy should not be used in patients with HBV/HIV co-infection due to the development of resistant HIV. Patients who need treatment for both HIV and HBV should be treated with antiviral agents that are effective against both viruses, such as tenofovir/emtricitabine, tenofovir or lamivudine, as highly active anti-retroviral therapy (HAART) [531-533]. When HAART regimens are altered, antiviral agents that are effective against HBV should be included to avoid HBV reactivation, except in patients who meet the criteria for discontinuation of anti-HBV treatment.

1. HBV/HIV-coinfected patients who exhibit ALT elevation due to HBV should be considered for HBV treatment. (B1)

2. Patients who are not indicated for HAART at present or in the near future should receive the standard treatment for CHB. In such cases, NAs that do not affect HIV proliferation should be used to prevent the future development of HIV cross-resistance. (B1)

3. Patients who need treatment for both HIV and HBV should be treated with HAART agents effective against both viruses; e.g., tenofovir/emtricitabine or tenofovir plus lamivudine. (B1)

A high maternal HBV DNA level is associated with a high rate of failure of neonatal passive-active immunoprophylaxis [540-543]. In a double-blind, randomized controlled trial, pregnant females with high serum HBV DNA levels (>103 Meq/mL [~10⁹ cpm]) were given lamivudine from week 32 of gestation to week 4 postpartum in addition to neonatal passive-active immunoprophylaxis. HBsAg positivity was present in 18% and 39% of 1-year-old infants from lamivudine- and placebo-treated mothers, respectively (P=0.014) [544] No safety concerns were noted in the lamivudine-treated mothers and their newborns. However, these data should be interpreted with caution due to the high dropout rates, especially in the placebo group (13% in the lamivudine group and 31% in the placebo group). A prospective study included pregnant females with HBeAg-positive and high serum HBV DNA levels (>10⁷ copies/mL) who were treated with lamivudine from week 24 to week 32 in addition to neonatal passive-active immunoprophylaxis as the treatment group. The HBsAg-positivity rates of infants at 1 year after birth were significantly different: 0% (0/94) in the treatment group and 7.7% (7/91) in the placebo group [545] Another prospective study included pregnant females with high serum HBV DNA levels (>10⁶ copies/mL) treated with telbivudine from week 12–30 to birth in addition to neonatal passive-active immunoprophylaxis as the treatment group. The HBsAg-positivity rates of infants at 6 months after birth were significantly different: 0% (0/54) in the treatment group and 8.6% (3/35) in the placebo group [546]. Another prospective controlled study included pregnant females with high serum HBV DNA levels (>10⁷ copies/mL) treated with telbivudine from weeks 20 to 32 of gestation to week 4 postpartum in addition to neonatal passive-active immunoprophylaxis. HBsAg positivity was present in none (0/132) of the 6-month-old infants from telbivudine-treated mothers, whereas it was present in 8% (7/88) of those from placebo-treated mothers [547]. Another prospective study included pregnant females with high serum HBV DNA levels (>10⁷ copies/mL) treated with tenofovir or lamivudine from week 32 to week 4–12 postpartum in addition to neonatal passive-active immunoprophylaxis as the treatment group. The HBsAg-positivity rates of infants at 9 months after birth were significantly different: 1% (1/87) in the treatment group and 20% (2/10) in the placebo group [548]. The prevalence of safety issues did not differ significantly between the two groups. These studies imply that antiviral medication in the late stage of pregnancy is likely to reduce the rate of vertical transmission. However, the decision about whether or not to treat should be individualized in patients not indicated for the treatment of HBV, based on the treatment duration, stopping point, possible appearance of drug-resistant strains, and the patient’s preferences.

1. Peginterferon-α has an advantage in female patients who are planning pregnancy due to its finite treatment duration. (C1) However, the side effects pertaining to fetal malformations make peginterferon-α treatment contraindicated during pregnancy, and it should be recommended in combination with contraception. (A1)

2. When antiviral treatment is needed during pregnancy, pregnancy category B NAs are recommended. (B1)

3. The antiviral treatment strategy during pregnancy is based on the general principles of CHB treatment; however, decisions should be based on analysis of the risks and benefits for both the mother and fetus. (C1)

4. Breastfeeding is not recommended in females receiving treatment with NAs. (C1)

Providing HBIG and HBV vaccine to newborns of HBsAg-positive mothers within 12 h of birth can prevent 90–95% of cases of perinatal infection. Ninety percent of infants infected as a neonates progress to chronic infection. Most children remain in the immune-tolerant phase until late childhood or adolescence. However, some children progress to the immune-reactive phase. The spontaneous HBeAg seroconversion rate in immune-tolerant Korean children was 4.6%, 7.1%, and 28.0% for patients aged <6, 6-12, >12 years, respectively [549]. A Taiwanese study reported annual spontaneous HBeAg seroconversion rates of 2% and 4–5% in children younger than 3 years and older than 3 years, respectively [550]. Children who are in the immune-reactive phase—with increased ALT levels and histologic findings of liver inflammation and fibrosis—are usually asymptomatic. Long-term treatment in children with CHB is expected, and a prudent decision should be made based on the adverse effects of the drugs and the potential for viral resistance to affect future therapies. The treatment window should not be missed because cirrhosis can occur in their 20s and HCC later in life. The goals of therapy are to suppress viral replication, reduce liver inflammation, reverse liver fibrosis, and prevent cirrhosis and HCC.

Treating children in the immune-tolerant phase is not beneficial, and there is a high risk of development of drug resistance, which would limit treatment options in later life. Children with a persistent elevated serum ALT level should be evaluated for viral active replication, including measurement of HBV DNA levels. HBeAg-positive children should be considered for treatment when their serum ALT levels are above 2 ULN for at least 6 months and their HBV DNA levels are above 20,000 IU/mL [551]. Acute elevation of liver enzymes with an ALT level of >5 ULN may be followed by spontaneous HBeAg seroconversion. It is therefore reasonable to delay treatment for an observation period of at least 3 months if there is no concern regarding hepatic decompensation. Children with moderate-to-severe necroinflammation or periportal fibrosis in a liver biopsy are recommended for treatment. The decision to treat is based on factors such as age, liver biopsy findings, and family history of HBV-associated cirrhosis or HCC. In obese children it is important to remember that ALT elevations may be due to fatty liver disease [552]. The responses to interferon-α and lamivudine are better in children with higher activity scores in a liver biopsy [553,554].

A randomized controlled trial of interferon-α therapy involving children aged 1 to 17 years found that 36% of those with a baseline ALT level of at least 2 ULN became negative for HBeAg at the end of treatment. HBsAg seroconversion occurred in 10% of the treated children [553]. Factors predictive of a positive response among children are being younger than 5 years [555], having a low serum HBV DNA level, and having active inflammation in a liver biopsy [553]. After 5 years of observation, the rate of HBeAg seroconversion did not differ between the treatment and control groups. However, loss of HBsAg occurred in 25% of children who responded to treatment, but in none of the children in the nonresponse and control groups [556]. The recommended treatment regimen for interferon-α is 6 MU/m² three times per week by subcutaneous injection for 6 months. Interferon-α is approved in children older than 12 months, and its advantages include the finite duration of treatment and no development of viral resistance. The adverse effects include fever, flu-like symptoms, bone marrow suppression, depression, and transient growth suppression. Interferon-α is contraindicated in children with decompensated cirrhosis and autoimmune disease. Clinical trials of peginterferon in children with CHB are ongoing. The efficacy and safety of peginterferon were demonstrated in children with chronic hepatitis C, and an update of the Swedish national recommendations for the treatment of CHB recommends the use of peginterferon (100 μg/m² weekly) in children [557].

A randomized controlled study of lamivudine involving children aged 2–17 years found that loss of HBeAg at 52 weeks of treatment occurred in 34% of those with a baseline ALT level of at least 2 ULN, and that the resistance rate was 18% [558]. The HBeAg seroconversion rate after 2 years of therapy was 54% in children without lamivudine-resistant virus. The resistance rate was 64% in children who received lamivudine for 3 years. Lamivudine treatment for >3 years did not significantly increase seroconversion rates and increased the incidence of viral resistance [559]. Studies of Korean children found that the HBeAg seroconversion rates after 2 and 3 years of treatment were 65% and 70%, respectively [560,561]. Loss of HBsAg was observed in 20% of children after 2 years of lamivudine treatment, and the resistance rates at 1 and 2 years of treatment were 10% and 23%, respectively. Factors associated with a response were elevated baseline ALT, high baseline histology-activity-index score [554], and being younger than 7 years [560]. Long-term durability of HBeAg seroconversion was observed in more than 90% of the subjects after they had taken lamivudine for at least 2 years [562]. Lamivudine is orally administered at a dose of 3 mg/kg/day, with a maximum of 100 mg/day [552]. Lamivudine treatment should be continued for at least 1 year, and it is desirable to continue treatment for 1 year after HBeAg seroconversion. If lamivudine resistance develops, it should be treated in accordance with the guidelines for antiviral resistance management in adults.

A randomized controlled study of 173 HBeAg-positive children aged 2–17 years showed undetectable HBV DNA and a normal ALT level after 48 weeks of adefovir treatment in 23% of 12- to 17-year-old subjects, but there was no significant difference between adefovir and placebo in those aged 2–11 years. The HBeAg seroconversion rate in the adefovir group and placebo group was 16% and 5%, respectively (P=0.051). No subject developed adefovir resistance [563]. Continuation of adefovir treatment for a further 4 years was safe. Resistance to adefovir was observed in one child [564].

Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance. Entecavir is considered the first-line therapy in children older than 2 years and tenofovir in those older than 12 years. A randomized controlled trial of tenofovir in adolescents aged 12 to 17 years reported that the rate of a virologic response (HBV DNA <400 copies/mL) at week 72 was significantly higher in patients (n=52) who received tenofovir than those (n=54) who received placebo (89% vs. 0%) [565]. No resistance to tenofovir developed through week 72. The rate of grade 3/4 adverse events was higher among patients treated with placebo (24%) than those treated with tenofovir (10%). In a randomized controlled study involving 180 children aged 2 to 17 years with HBeAg-positive CHB, the HBeAg seroconversion and HBV DNA <50 IU/mL rates at week 48 were significantly higher with entecavir than placebo (24.2% versus 3.3%). The cumulative probability of entecavir resistance at 1 and 2 years was 0.6% and 2.6%, respectively. Entecavir showed no difference in safety compared with placebo [566].

1. HBeAg-positive CHB children with an HBV DNA level >20,000 IU/mL and HBeAg-negative CHB children with an HBV DNA level >2,000 IU/mL should be considered for treatment when the AST or ALT level is > 2 ULN for at least 6 months, or moderate-to-severe necroinflammation or periportal fibrosis is evident in a liver biopsy. (A1)

2. Tenofovir, entecavir or interferon-α is the first-line therapy in children with CHB. (B1) Data on peginterferon are currently scarce, but its use in children can be based on the results of studies involving adults. (C1)

3. If antiviral resistance develops, it should be treated in accordance with the guidelines for antiviral resistance management in adults. (B1)