Successful introduction of Model for End-stage Liver Disease scoring in deceased donor liver transplantation in Korea: analysis of first 1 year experience at a high-volume transplantation center

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Abstract

Backgrounds/Aims

Model for End-stage Liver Disease (MELD) score was adopted in June 2016 in Korea.

Methods

We analyzed changes in volumes and outcomes of deceased donor liver transplantation (DDLT) for 1 year before and after introduction of MELD scoring at Asan Medical Center.

Results

There were 64 cases of DDLT in 1 year before MELD introduction and 106 in 1 year after MELD introduction, an increase of 65%. The volume of DDLTs abruptly increased during first 3 months, but then returned to its usual level before MELD introduction, which indicated 3-month depletion of accumulated recipient pool with high MELD scores. The number of pediatric DDLT cases increased from 3 before MELD introduction to 11 after it, making up 21.4% and 47.8% of all cases of pediatric liver transplantation, respectively. The number of cases of retransplanted DDLTs increased from 4 to 27, representing 6.3% and 25.5% of all DDLT cases, respectively. The number of status 1 DDLT cases increased from 5 to 12, being 7.8% and 11.3% of all cases. Patient survival outcomes were similar before and after MELD introduction.

Conclusions

The number of DDLTs temporarily increased after adoption of MELD scoring due to accumulated recipient pool with high MELD scores. The numbers of retransplanted and pediatric DDLT cases significantly increased. Patient survival in adult and pediatric DDLT was comparable before and after adoption of MELD scoring. These results imply that Korean MELD score-based allocation system was successfully established within its first year.

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KASL clinical practice guidelines: management of chronic hepatitis B

(2016)

PREAMBLE Aims 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. Target population 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. Intended users 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. Developer and funding 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. Evidence collection 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. Levels of evidence and grades of recommendation 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. List of the clinical questions 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: - acute hepatitis B - liver transplantation - chemotherapy/immunosuppression - chronic kidney disease - coinfection [with hepatitis C virus (HCV), hepatitis D virus (HDV), and/or human immunodeficiency virus (HIV)] 16. How can we reduce vertical transmission in pregnant CHB patients? 17. What is the optimal management of CHB in children? Review of the manuscript 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. Release of the guidelines The revised CHB guidelines of KASL were released on November 26, 2015 (http://www.kasl.org). Plan for updates 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. EPIDEMIOLOGY Hepatitis B virus (HBV) infection, as a causative factor of liver disease of 240 million patients globally and death of 600 thousand patients annually [1], is a major cause of acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It has been recognized as an important public health problem in Korea since the 1970s [2] and was designated a third-class communicable disease by law in 1982 and is now the target of a national vaccination program as a second-class communicable disease [3]. The prevalence of HBV infection in the Korean population as estimated by positivity rates for hepatitis B surface antigen (HBsAg) was 8–9% for males and 5–6% for females before commercialization of an HBV vaccine in the early 1980s [4]; thereafter, the prevalence of HBV infection tended to decline gradually due to the initiation of a vaccination program for newborn infants in 1991 and a national vaccination program in 1995. For example, in 2006 the prevalence of HBV among children aged 4 to 6 years had decreased to 0.2% [5]. Nevertheless, according to the 2005 National Health and Nutrition Examination Survey, the HBsAg positivity rate was 4.0% at 2009 [6]. The Ministry of Health and Welfare reported that the HBsAg positivity rate was 3.4% for males and 2.6% for females, with 3.0% of the total population being infected with HBV in 2012 [7]. Positivity rates for HBsAg among pregnant females, which represents a major infection route for hepatitis B, declined steadily after 2004, as did the positivity rates among females in the childbearing period [7]. Given that HBsAg is detected in approximately 70% of patients with chronic hepatitis or cirrhosis [8], and in 65–75% of HCC patients [9,10], it can be concluded that CHB infection is a matter of importance for public health in Korea. Most Korean CHB patients are infected with HBV genotype C2 [11], and tend to have lower hepatitis B e antigen (HBeAg) seroconversion rates, more rapid progression to cirrhosis and HCC, reduced efficacy of interferon treatment, and are subject to higher rates of relapse after antiviral treatment, compared to those infected with other HBV genotypes [12,13]. Natural history 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). 1. Immune-tolerant phase In cases of perinatal infection, the immune-tolerant phase is characterized by HBeAg positivity, high levels of serum HBV DNA (generally ≥107 IU/mL), normal levels of aspartate aminotransferase/alanine aminotransferase (AST/ALT), and mild or no liver necroinflammation [16-19]. Elevation of ALT level was detected in 16% of patients in the immune-tolerant phase during 5 years of follow up [19]. This phase may continue for more than three decades in patients infected with HBV genotype C, which is common among Korean patients, and the rate of spontaneous HBeAg loss is very low [20]. Therefore, many females infected with this genotype are in the HBeAg-positive immune-tolerant phase when they are of childbearing age. The absence of, or only mild histologic liver damage, despite high levels of HBV DNA, is attributed to immune tolerance to HBV [21]. 2. Immune-active HBeAg-positive CHB Most patients in the immune-tolerant phase will experience immune responses to HBV as they grow older, and finally reach the immune-active phase, which is characterized by HBeAg positivity, lower serum HBV DNA levels, and increased or fluctuating ALT levels [22,23]. Histologic findings in this phase include moderate-to-severe liver inflammation and, in some patients, rapid progression of fibrosis [24]. Such changes are due to enhancement of hepatitis B core antigen (HBcAg) or HBeAg-specific cytotoxic T-lymphocyte activity and the resulting destruction of infected hepatocytes [25]. Sustained HBV DNA suppression occasionally accompanies HBeAg seroconversion. Once HBeAg seroconversion occurs, the natural course of the disease may have one of three clinical features: (1) repeated HBeAg reversion and seroconversion, (2) inactive state, or (3) HBeAg-negative CHB [26,27]. Typically, 10–40% of patients who experience seroconversion revert to HBeAg positivity and then experience recurrence of seroconversion at least once with progression of hepatitis activity [24,28,29]. In particular, reversion frequently occurs in patients with HBV genotype C, and the rate decreases with age [20]. Hepatic decompensation, which occurs in 5% of patients with acute exacerbation, may be fatal [30]. 3. Immune-control inactive CHB Most patients who seroconvert during the immune-active phase progress to the immune-control phase, which is characterized by HBeAg negativity, persistent normal ALT levels, and HBV DNA levels of 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]. PREVENTION Because HBV infection is endemic in Korea, any person at high risk of liver disease or has suspected liver disease is recommended to have their HBsAg and anti-HBs statuses checked [14]. CHB patients can transmit virus to others, and hence they should be counseled regarding how to modify their lifestyle so as to prevent HBV transmission. Epidemiologic studies found that the daily consumption of 40–80 g of alcohol is associated with liver damage and the progression of liver disease [83-88], and a long-term prospective cohort study of patients with chronic HBV infection showed that alcohol consumption increases the risks of liver cirrhosis and HCC development [57,59]. No data are available on the threshold level of alcohol consumption required to significantly increase the risks of liver cirrhosis and HCC in patients with chronic HBV infection. In the general population, a daily alcohol intake of 24 g in males and 12 g in females significantly increases the risk of liver cirrhosis [89]. So, abstinence or a very limited consumption of alcohol is recommended in patients with chronic HBV infection [89]. According to a long-term prospective study of patients with chronic HBV infection, smoking also increases the risks of liver cirrhosis and HCC, and so non-smoking is recommended in patients with chronic HBV infection [57,59,90]. Vertical infection is the most important route of HBV transmission. Following initiation of the HCV vaccination program, the HBsAg positivity rate among pregnant females was 3.32% (308/9281) and the vertical transmission rate was 1.59% (4/252) in 2014. Therefore, the vaccination program is effective for control of vertical transmission [91]. HBV immunoglobulin and vaccination after delivery can prevent 90-95% of vertical transmission to newborns from HBsAg-positive mothers [92-94]. Therefore, such infants should receive 0.5 mL HBIG and scheduled HBV vaccination within 12 hours of birth and after. Adding immunoglobulin is more effective than vaccination only. The introduction of HBV vaccination did not result in the rate of HBV infection among newborns differing between breast- and formula-feeding HBsAg-positive mothers (0% vs. 3%, respectively) [95]. In patients negative for HBsAg and anti-HBs, vaccination is recommended. Isolated anti-HBc positive patients negative for HBsAg and anti-HBs should consider vaccination, especially if liver function results are abnormal. As HBV is endemic in Korea, patients negative for HBsAg and anti-HBs should be vaccinated [92,93], particularly the household members and sexual partners of patients with chronic HBV infection, as such persons are at increased risk of HBV infection [96,97]. Patients with chronic HBV infection are not candidates for vaccination because of its lack of effectiveness. Sexual partners who have not been tested for HBV serologic markers, have not completed the full immunization series, or who are negative for anti-HBs should use barrier protection methods, such as condoms. The three doses constituting the hepatitis B vaccine series administered intramuscularly at 0, 1, and 6 months induce a protective antibody response (anti-HBs >10 mIU/mL) in >90% of recipients. Most non-responders (44–100%) subsequently respond to a further three-dose revaccination [92,93]. Although serologic testing for anti-HBs is not necessary after routine vaccination in immunocompetent adults, post-vaccination testing of anti-HBs status is recommended in some subjects, such as newborns of HBV-infected mothers or 9-18 months old young infants whose family members has CHB. Healthcare workers, dialysis patients, workers in dialysis units and operation rooms, immunocompromised subjects (e.g., HIV infection, hematopoietic stem cell transplants, patients with chemotherapy), and sexual partners of patients with chronic HBV infection should be tested 1-2 months after their completion of the HBV immunization series [92,93]. While anti-HBs levels can decline or disappear over several decades, vaccinated subjects remain protected against HBV infection and there is no need for booster vaccination in immunocompetent individuals. However, an anti-HBs 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 test 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 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. Biochemical test 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]. Liver biopsy 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. Noninvasive fibrosis test 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]. Screening for hepatocellular carcinoma 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. [Recommendations] 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) TREATMENT GOALS The goals of hepatitis B treatment are to decrease the mortality rate and increase the survival rate by alleviating hepatic inflammation and preventing the development of fibrosis, which ultimately reduces the frequency of progression of hepatitis to liver cirrhosis or HCC [141-145]. The optimal treatment result would be the loss or seroconversion of HBsAg, but since intranuclear cccDNA persists despite treatment, complete clearance of HBV is almost impossible to achieve [146]. This is why indices such as ALT level normalization, undetectable HBV DNA, loss or seroconversion of HBeAg, and histologic improvement are used (rather than the loss or seroconversion of HBsAg) to predict the treatment response in the clinical context. Therefore, a realistic virologic goal of anti-HBV therapy is the suppression of viral replication. Most guidelines state that antiviral treatment is required for patients with acute liver failure, decompensated liver cirrhosis or in the acute phase of severe chronic HBV hepatitis regardless of HBV DNA and ALT levels, and the treatment has almost no complications, although few controlled studies have been performed [147]. Antiviral therapy decreases the rate of recurrence of viral infection in patients who require liver transplantation [148]. The HBV DNA and HBeAg levels in CHB are indices of viral replication and active hepatitis, respectively, and patients with HBeAg-positive hepatitis B with high levels of HBV DNA have an increased risk of developing liver cirrhosis or HCC [57,59,74]. Patients with disappearance or conversion of serum HBeAg have a low risk of liver cirrhosis and hepatocellular carcinoma, and so have a good prognosis [26,149]. The loss or seroconversion of HBeAg during the natural course of hepatitis B or after IFN-α treatment indicates a favorable long-term outcome with a decreased probability of liver cirrhosis or HCC development [26,53,149,150]. Therefore, clearance or seroconversion of HBeAg is an important goal of antiviral treatment in patients with HBeAg-positive active hepatitis. A decrease in the HBV DNA level has recently been suggested to be even more important. The decrease in the HBV DNA level after antiviral treatment in active hepatitis with elevated HBV DNA levels results in histologic improvement, seroconversion of HBeAg, and normalization of ALT levels, and thus a slowing of the progression of hepatitis [151,152]. However, even in cases with HBV DNA levels of less than 104 copies/mL, which is considered to be inactive hepatitis, the hepatitis can still progress to liver cirrhosis and HCC. Therefore, a decrease in HBV DNA to an undetectable level is recommended for patients on antiviral treatment [153]. [Recommendations] 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) TREATMENT INDICATIONS AND STRATEGIES Long-term viral suppression by drugs with potent antiviral activity and high genetic barrier to resistance is a current paradigm of antiviral treatment for CHB aimed at the prevention of disease progression and improvement of survival. Since eradication of HBV infection is rarely achieved with currently available drugs, long-term treatment is necessary in most cases. Treatment protocol should be individualized according to various factors: host factors such as mode of infection, disease status, and immunity; viral factors such as genotypes, prior antiviral treatment, mutation, and susceptibility level; and drug factors such local availability, cost, and reimbursement policy [35]. The durations of currently available antiviral trials are insufficient to assess the effects of treatment on long-term survival [35]. Long-term treatment with oral nucleos(t)ide analogs (NAs) ameliorates histologic abnormalities such as necroinflammation and/or fibrosis, both in HBeAg-positive [35,154,155] and HBeAg-negative [155-158] CHB. Therefore, long-term antiviral therapy may prevent disease progression and reduce the risk of liver cirrhosis [145]. Immune tolerance phase 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]. [Recommendations] 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) Chronic hepatitis B 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 0.166 log10 IU/mL/year) were predictive of qHBsAg seroclearance, strengthening the prognostic role of HBsAg measurements during NA therapy [203]. Compliance and antiviral-resistance mutations should be monitored in patients who develop virologic breakthrough while receiving NA, and an appropriate rescue therapy should be initiated if necessary [215-219]. Most NAs are excreted through the kidney, and hence dose adjustment is required in patients with renal insufficiency (Table 4) [35], and regular monitoring of renal function should be performed in patients receiving adefovir or tenofovir. Several reports have associated tenofovir with bone loss in patients with HIV, although there was no consistent report during tenofovir monotherapy [220-222]. Studies of entecavir-related carcinogenicity are in progress. There have been few reports on telbivudine-related myositis; however, monitoring of the serum creatine kinase (CK) level is recommended due to the possibility of CK elevation [223-226]. For clevudine prescription, serum CK level and related symptoms should be monitored due to clevudine-related myositis and CK elevation [227-229]. 2. Peginterferon-α The serum CBC and ALT level of patients receiving peginterferon-α should be tested monthly. Serum HBV DNA should be measured after 3–6 months of treatment to verify the primary response. For response prediction, qHBsAg assay can be used before the treatment and at 12 and 24 weeks of treatment. All patients treated with peginterferon-α should be checked for the known adverse effects of interferon at every visit. HBeAg-positive CHB 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 CHB 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 1 log from baseline at the end of treatment had a 78% positive predictive value and 96% negative predictive value for a 12-month sustained post-treatment response (HBV DNA ≤200 IU/mL) to lamivudine in HBeAg-negative patients [249]. During telbivudine treatment, a decline in serum HBsAg levels (≥ 1 log10 IU/mL) in the first year was related to a greater likelihood of achieving HBsAg clearance at year 3 [202]. Serum HBsAg levels ≤2 log IU/mL at treatment week 104 are highly predictive of sustained virologic response to telbivudine at 2 years off-treatment [250]. 2. Peginterferon-α Pretreatment factors predictive of HBeAg seroconversion in HBeAg-positive patients are a high ALT level, low viral load, a high inflammatory activity score in a liver biopsy, and HBV genotype [183,251]. There is no consensus among previous reports for patients with HBeAg-negative hepatitis, but generally a pretreatment high ALT level, young age, and female gender are reported to be associated with a favorable treatment response [124,252]. A decrease in serum HBV DNA to less than 20,000 IU/mL after 12 weeks of treatment is associated with a 50% probability of HBeAg seroconversion in HBeAg-positive patients and with a 50% probability of a sustained response in HBeAg-negative patients [124,253]. A decrease in HBeAg at week 24 may predict HBeAg seroconversion [118,253]. In HBeAg-positive patients, HBsAg levels 20,000 IU/mL at week 24 [230,231]. In HBeAg-negative patients, at week 12 of peginterferon-α treatment, the combination of a decline in serum HBV DNA 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. Adefovir No randomized trial of adefovir treatment in patients with entecavir resistance has been performed. Adding adefovir to entecavir would be more reasonable for reducing adefovir resistance and improving the antiviral efficacy [330]. Combination therapy of adefovir plus lamivudine could also be considered [331]. However, small retrospective cohort studies demonstrated that the virologic response rate was 24-51% at 1 or 2 years of treatment with the combination of adefovir and entecavir or lamivudine [326-328,332]. 2. Tenofovir Tenofovir does not show cross-resistance to entecavir in vitro and has excellent potency [333]. A Korean multicenter randomized trial was performed in HBV patients with entecavir resistance-associated mutations comparing TDF monotherapy and TDF and entecavir combination therapy for 48 weeks [334]. All patients had at least one entecavir-resistance mutation: rtT184A/C/F/G/I/L/S, rtS202G, and rtM250L/V, in addition to rtM204V/I. At week 48, the proportion of patients with HBV DNA 0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. [Recommendations] 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) Management of tenofovir-resistance 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]. Management of multiple drug resistance 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. [Recommendations] 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) RESPONSE-GUIDED THERAPY DURING ORAL ANTIVIRAL DRUG TREATMENT FOR CHB Once antiviral-resistant HBV mutants have been selected, they are persistently archived (retained in the virus population) in ccc-DNA in the nucleus of infected cells, even if treatment is stopped, which can limit future therapeutic options [341,342]. Preventing the development of resistance is important to ensure long-term therapeutic efficacy. Persistence of viral replication during antiviral treatment is associated with the emergence of drug resistance [225,343,344]. Therefore, evaluation of the treatment response using sensitive PCR assays to measure serum HBV DNA levels every 3-6 months is recommended. The response patterns of oral antivirals during treatment are classified as complete response, partial response and primary non-response. Complete response is defined as undetectable serum HBV DNA by PCR during treatment. Partial virologic response is defined as detectable serum HBV DNA with a more than 2 log10 IU/mL reduction in HBV DNA level from baseline [345]. A primary non-response is defined as a reduction in the serum HBV DNA level of less than 2 log10 IU/mL at week 24 [35]. Virologic breakthrough is defined as an increase in serum HBV DNA level of more than 1 log10 IU/mL from nadir. Although virologic break-through is generally associated with emergence of resistance mutations, up to 30% of the cases of virologic breakthrough in clinical trials are related to medication noncompliance [346]. Therefore, compliance should be checked in all patients with a sub-optimal response. In patients with a complete virologic response, treatment should be continued until the endpoint is achieved, which should be evaluated by measuring the serum HBV DNA level every 3–6 months [117,347]. Primary non-response is very rare in oral antiviral therapy, with the exception of adefovir. Therefore, few studies of primary non-response patients have been performed. In patients with primary non-response with good compliance, switching to a drug with a high genetic barrier is indicated if the patient is taking a drug with a low genetic barrier, due to the possibility of immanent resistance [117,347]. However, a recent study of entecavir for treatment-naïve CHB reported a primary non-response rate of 1.3-1.7%, and all patients achieved a virologic response after continuing entecavir therapy during follow up [348,349]. Therefore, if the patient is taking a drug with a high genetic barrier, such as entecavir or tenofovir, treatment could either be switched to another high-genetic-barrier drug or be continued using the same high genetic barrier drug with monitoring for virologic response at 3-6-month intervals in patients with primary non-response. The rate of emergence of lamivudine or telbivudine-resistant HBV was directly proportional to the HBV DNA level after 24 weeks of treatment [225,343,344]. Yuen and colleagues found that these rates were 8%, 13%, 32%, and 64% for patients with 24-week HBV DNA levels 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]. [Recommendation] 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) Immunosuppression and chemotherapy 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 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. [Recommendation] 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 with chronic kidney disease and under dialysis 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 1 year. (B1) HIV Co-infection 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. [Recommendation] 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) Female patients of childbearing age 1. Treatment before pregnancy When planning treatment for females of child-bearing age, special considerations for the fetus and the duration of treatment are needed in addition to the aforementioned general considerations. For example, IFN preparations are preferred in female patients who are planning pregnancy as the period of treatment is more clearly defined. However, the IFN side effect of fetal malformations makes it contraindicated during pregnancy, and so it must be recommended in combination with contraception during the therapy and until 6 month after cessation of therapy. Females who want to be pregnant should be treated with antiviral agents that belong to pregnancy category B drugs (which, according to the results of animal studies, carry no teratogenic or embryogenic risk and for which there have been no controlled human studies or for which animal studies may indicate a risk, but controlled human studies refute the findings). Tenofovir and telbivudine belong to pregnancy category B, while entecavir, adefovir and lamivudine belong to pregnancy category C drugs (drugs that exert teratogenic or embryocidal effects in animals and for which there are no controlled studies in humans) [15]. 2. Treatment during pregnancy Pregnant females with chronic HBV infection are usually in the immune-tolerance phase [534], and changes in the maternal immune system during pregnancy, such as a shift in the Th1-Th2 balance toward a Th2 response, lead to an increase in the HBV DNA level and a reduction in the ALT level [535]. These immune responses are restored after delivery, thereby causing a reduction in the HBV DNA level and ALT elevation, and so careful monitoring is needed [535-537]. The optimal antiviral treatment strategy during pregnancy is based on the aforementioned general principles for the treatment of CHB. However, all decisions regarding the timing and duration of treatment in pregnancy should include an analysis of the risks and benefits for both the mother and fetus. In addition, pregnant females often experience worsening of liver disease unrelated to HBV infection (e.g., acute fatty liver of pregnancy), which is difficult to discriminate from an HBV flare-up. Thus, antiviral treatment should be considered when liver disease is present (e.g., jaundice or prolongation of PT), and the HBV DNA level meets the general criteria for antiviral treatment. When starting antiviral therapy during pregnancy, category B drugs are recommended. Safety data of antiviral agents during pregnancy can be found at the Antiretroviral Pregnancy Registry (APR; http://www.apregistry.com). The APR is an international, voluntary, prospective registry that reports the rate of birth defects of newborns born to mothers receiving antiretroviral therapy, and it contains a considerable amount of data on lamivudine and tenofovir. According to the APR, the rates of birth defects among females exposed to lamivudine and tenofovir in the first trimester (3.1% and 2.4% of live births, respectively) are similar to that in the general population (2.7%), as reported by the CDC birth defect surveillance system. Few cases related to other drugs such as telbivudine and entecavir have been reported. However, since the APR is designed to report only defects identified at birth, it may not contain accurate data on developmental anomalies (e.g., cardiac or neurologic defects). Oral antiviral agents may cause mitochondrial toxicity by inhibiting mitochondrial DNA replication. It is difficult to estimate their effects on the fetus, especially in the developmental stages [224]. Thus, based on considerations of fetal safety oral antiviral agents should not be administered, especially in the first trimester of pregnancy. However, the decision about whether to discontinue drugs in patients receiving treatment with oral antiviral agents should be individualized. One retrospective study showed that ~14% of pregnant females with active chronic hepatitis B without antiviral therapy can progress to hepatic failure and have a risk of maternal or fetal death, so appropriate antiviral therapy should be considered in pregnant females in the active phase of chronic hepatitis B [538]. In childbearing females who require treatment with an oral antiviral agent against HBV, pregnancy category B drugs such as tenofovir can be considered if the patient wants to become pregnant. In females already receiving antiviral therapy with a category C drug who want to become pregnant, the category C drug should be changed to a category B drug, such as tenofovir. In the first trimester of pregnancy, pregnant females with mild chronic hepatitis B and undetectable HBV DNA ( 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. [Recommendations] 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) Children and adolescents 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 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 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)

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Results of the first year of the new liver allocation plan.

R Merion, , Brian Edwards … (2003)

Liver allocation policy in the U.S. was recently changed to a continuous disease severity scale with minimal weight given to time waiting in an effort to better prioritize deceased donor liver transplant candidates. We compared rates of waiting list registrations, removals, transplants, and deaths during the year prior to implementation of the new liver allocation policy (2/27/01-2/26/02, Era 1) with the first year's experience (2/27/02-2/26/03, Era 2) under this new policy. Rates were adjusted for 1,000 patient years on the waiting list and compared using z-tests. A 1-sided test was used to compare death rates; 2-sided tests were used to compare transplant rates. Overall and subgroup analyses were performed for demographic, geographic, and medical strata. In Era 2, we observed a 12% reduction in new liver transplant waiting list registrations, with the largest reductions seen in new registrants with low MELD/PELD scores. In Era 2, there was a 3.5% reduction in waiting list death rate (P =.076) and a 10.2% increase in cadaveric transplants (P <.001). The reduction in waiting list mortality and increase in transplantation rates were evenly distributed across all demographic and medical strata, with some variation across geographic variables. Early patient and graft survival after deceased donor liver transplantation remains unchanged. In conclusion, by eliminating the categorical waiting list prioritization system that emphasized time waiting, the new system has been associated with reduced registrations and improved transplantation rates without increased mortality rates for individual groups of waiting candidates or changes in early transplant survival rates.

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Pediatric liver transplantation.

Alex Cuenca, Heung Bae Kim, Khashayar Vakili (2017)

Considerable strides have been made over the last several decades toward improving outcomes in pediatric liver transplantation. Refinements in surgical technique has allowed for the use of living donor and deceased donor split-liver grafts, thus expanding the pool of available organs and reducing waitlist mortality. The use of a multidisciplinary team continues to be paramount in the care of the transplant recipient. With improvements in overall graft and survival, indications for liver transplantation have also broadened. Currently, pediatric transplant patients have a 5-year survival of over 85%. Long-term morbidity is mainly associated with complications from immunosuppression and chronic rejection. Here we review indications for liver transplantation in children, surgical considerations, post-operative complications, and long-term outcomes.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Hepatobiliary Pancreat Surg

Journal ID (iso-abbrev): Ann Hepatobiliary Pancreat Surg

Journal ID (publisher-id): AHBPS

Title: Annals of Hepato-Biliary-Pancreatic Surgery

Publisher: Korean Association of Hepato-Biliary-Pancreatic Surgery

ISSN (Print): 2508-5778

ISSN (Electronic): 2508-5859

Publication date (Print): November 2017

Publication date (Electronic): 30 November 2017

Volume: 21

Issue: 4

Pages: 199-204

Affiliations

Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Author notes

Corresponding author: Shin Hwang. Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3930, Fax: +82-2-3010-6701, shwang@ 123456amc.seoul.kr

Article

DOI: 10.14701/ahbps.2017.21.4.199

PMC ID: 5736739

SO-VID: f27a0be7-3419-4752-80a2-9b594bedceb8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 01 November 2017

Date revision received : 10 November 2017

Date accepted : 15 November 2017

Funding

Funded by: Ministry of Science, ICT and Future Planning, CrossRef http://dx.doi.org/10.13039/501100003621;

Successful introduction of Model for End-stage Liver Disease scoring in deceased donor liver transplantation in Korea: analysis of first 1 year experience at a high-volume transplantation center

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KASL clinical practice guidelines: management of chronic hepatitis B

Results of the first year of the new liver allocation plan.

Pediatric liver transplantation.

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