What can be concluded if the hepatitis B antigen level remains high in the serum

Methodology of guideline development

These APASL clinical practice guidelines represent an update of the last APASL guidelines published in 2012. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation [GRADE] system [Table 1]. The strength of recommendations reflects the quality of the underlying evidence, which has been classified into one of three levels, according to the GRADE system: high [A], moderate [B] or low [C]. The GRADE system offers two grades of recommendation: strong [1] and weak [2] [1, 2] [Table 1]. Thus, the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted. Grades are not provided for definitions.

Table 1 Grading of evidence and recommendations [adapted from the GRADE system] [1, 2]

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1 Introduction

An estimated 240 million persons worldwide are chronically infected with hepatitis B virus [HBV] [3], placing them at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma [HCC]. Although most chronically HBV-infected subjects will not develop hepatic complications, 15–40 % will develop serious sequelae during their lifetime.

Why this update was needed?

New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. These new data and information relate to new terminology, natural history of hepatitis B, diagnosis, assessment of the stage of liver disease using invasive and noninvasive methods, and the indications, timing, choice and duration of treatments in noncirrhotic and cirrhotic patients and in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant. In the current guidelines, policy recommendations for support and directions for HBV prevention and eradication in Asian countries have also been provided. The 2015 guidelines are an update to the 2012 APASL guidelines, and reflect new knowledge and evidence regarding HBV infection.

2 Context of guidelines

2.1 Epidemiology and public health burden of chronic HBV infection in Asia Pacific

HBV infection is a serious global public health problem. It is estimated that at least two billion people, or one-third of the world's population, have been infected with HBV. Approximately 240 million people, or about 6 % of the world's population, are chronically infected with HBV [3]. The prevalence of HBV infection is highly heterogeneous throughout the world, with an intermediate to high prevalence in the Asia-Pacific region, representing three-quarters of chronic HBV-positive subjects worldwide [4]. In addition, the Western Pacific region [defined by the World Health Organization as 37 countries including China, Japan, South Korea, Philippines, and Vietnam] accounts for nearly 50 % of all chronic HBV infection globally, although it has less than one-third of the world's population [5].

Prior to implementation of the HBV vaccination program, the Asian-Pacific region was divided into three categories in terms of HBsAg prevalence [6]. High-prevalence [>8 %] regions included mainland China, the Hong Kong special administrative region [SAR], Taiwan, Korea, Mongolia, Philippines, Thailand, Vietnam, and the South Pacific island nations. Intermediate-prevalence [2–8 %] regions included central Asia, the Indian subcontinent, Indonesia, Malaysia, and Singapore. Low-prevalence [20 per 100,000 individuals [16], and is higher in males than females. For example, in Korea, the age-standardized incidence rate of HCC is 47.1 per 100,000 persons for males and 11.4 per 100,000 persons for females. In Thailand, the annual incidence is 38.6/100,000 persons for males and 17.2/100,000 persons for females, and in China it is 37.9/100,000 and 14.2/100,000 for males and females, respectively [16].

In India, where a large study in 1987 of approximately 8575 pregnant women had shown a 3.7 % incidence of HBV infection [17], a recent study of 20,104 pregnant women revealed a prevalence of around 1.1 %. The precise reasons for the decreased incidence of HBV infection could be the introduction of the HBV vaccination [18] and the wide availability of antiviral drugs to treat the primary infection in infected subjects. A large number of past studies have shown a reduction in the prevalence of HBV infection in the Indian subcontinent.

2.2 Terminology in chronic HBV infection

Various clinical terms relating to HBV infection have been adopted worldwide for diagnosis, staging of the disease, natural history, and treatment strategies. These can be classified into five categories:

1. 1.

   Related to HBV infection

2. 2.

   Related to natural history of chronic HBV infection

3. 3.

   Related to response to antiviral therapy

4. 4.

   Related to resistance to nucleo[s]tide analogues [NAs]

5. 5.

   Occult HBV infection

Terminologies related to HBV infection

1. 1.

   Alanine aminotransferase [ALT] level Determination of serum ALT level is important for starting antiviral treatment as well as for follow-up of patients with chronic HBV infection. Serum ALT level is termed as high normal serum ALT if it is between 0.5 and 1× the upper limit of laboratory reference [ULN]; as low normal serum ALT if the level is ≤0.5× ULN; as minimally raised serum ALT if between ULN and 2× ULN of ALT level; and as raised ALT if >2× ULN [19]. Some authors have suggested lower values be used to define the ULN for an ALT level of 30 U/l for male and 19 U/l for female [20]. While it would be worthwhile to have the lower ALT values for early identification of liver injury and treatment of patients chronically infected with HBV, at present, the majority of countries in Asia are using ALT of 40 IU/ml as the upper limit of normal. Although there is data to suggest that patients with ALT values >0.5 times the upper limit of normal but 2 × 104 IU/ml had significant histology [34]. Also, in an Indian study of 73 HBeAg-positive patients with persistently normal ALT, 40 % had significant fibrosis. Of these patients, 23 had HBV DNA levels of ≥2 × 106 IU/ml and 50 had HBV DNA levels of  horizontal], immune status [suppressed > competent], ethnicity [Asians > non-Asians], HBV genotype C > B, D > A, baseline biochemical and histological activity [higher > lower], and ALT flare during follow-up [present > absent] [30].

   Immune-reactive phase

   During the immune-reactive phase [also known as immune active/immune clearance/HBeAg-positive CHB/HBeAg clearance phase], symptoms of liver disease may appear for the first time, as the host immune response leads to hepatocyte lysis with a flare in aminotransferase levels. Increased immune pressure on the virus during this phase is reflected by suppression of serum HBV DNA levels and accelerated clearance of HBeAg with seroconversion to anti-HBe positivity. This phase is characterized by the presence of HBeAg, high or fluctuating serum HBV DNA levels, persistent or intermittent elevation in serum aminotransferases, and active inflammation on liver biopsy. These flares may precede HBeAg seroconversion, but many flares only result in transient decreases in serum HBV DNA levels without loss of HBeAg, and some flares may lead to hepatic decompensation. More typically, the flare subsides after a variable period of time, although the associated liver injury may not regress and fibrosis can result [38]. The annual rate of spontaneous HBeAg clearance in this phase ranges from 3 to 12 %. Factors associated with higher rates of spontaneous HBeAg seroconversion include older age, higher aminotransferase levels, and HBV genotypes [A, B, D, F, B > C] [39, 40]. Genotype C is also associated with more liver injury at the time of seroconversion [41]. In a study from Alaska, it was found that after losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state as compared to those with other genotypes [A, B, D] [p 7–8 log10 IU/ml] [125, 126]. In a recent analysis comparing the cost-effectiveness of HBV control strategies combining universal vaccination with hepatitis B immunoglobulin [HBIG] treatment for neonates of chronically HBV-infected mothers, it was concluded that HBIG treatment for neonates of HBsAg positive mothers is likely to be a cost-effective addition to universal vaccination, particularly in settings with adequate health care infrastructure. Targeting HBIG to neonates of higher risk, HBeAg-positive mothers may be preferred where willingness to pay is moderate. However, in very resource-limited settings, universal vaccination alone is optimal [127].

   Transmission of HBV from infected health care workers to patients may occur in rare instances [see “3.13.4 Health care workers” section].

   1. 3.2

      Recommendations: counseling and prevention of transmission of hepatitis B from individuals with chronic HBV infection:

      1. 3.2.1

         Chronic HBV-infected persons should be counseled regarding prevention of transmission of HBV [Table 4] [A1].

      2. 3.2.2

         Sexual and household contacts of chronic HBV-infected persons who are negative for HBV seromarkers should receive hepatitis B vaccination [A1].

      3. 3.2.3

         Abstinence of alcohol is recommended in chronic HBV-infected subjects [A1].

      4. 3.2.4

         Chronic HBV-infected subjects should not be discriminated and stigmatized in the society or in their work place [A1].

      5. 3.2.5

         HBV-infected children should not be isolated in the educational and social environment [A1].

   3.3 Assessment of persons with chronic HBV infection

   The initial evaluation of an individual with HBV infection should include a detailed history and physical examination. Alcohol consumption, family history of HBV and HCC, and assessment of risk factors to determine the likely mode of HBV acquisition and possible superinfection with other hepatitis virus[es] should be part of the history taking. Comorbidities such as obesity, diabetes mellitus and metabolic syndrome should be assessed. Hepatic steatosis in individuals with CHB is related to co-existent metabolic factors rather than being virally induced [128, 129]. The physical examination focuses on identifying presence of cirrhosis or decompensated liver disease, as it has an impact on prognosis. A complete blood count, biochemical tests, serological and virological markers of HBV, and hepatic ultrasound should be part of the initial evaluation. The biochemical tests include ALT, AST, GGT, alkaline phosphatase, serum albumin and prothrombin time. The virological assessment consists of HBeAg, anti-HBe antibodies and Hepatitis B DNA measurement, the latter being the best marker of viral replication [130]. A real-time PCR quantification assay should be used to measure serum HBV DNA levels [131, 132].

   Other causes of chronic liver disease should be systematically looked for, including coinfections with HDV, HCV and/or HIV. Comorbidities, including alcoholic, autoimmune, and metabolic liver disease with steatosis or steatohepatitis should be assessed.

   In addition, all first-degree relatives and sexual partners of patients with chronic HBV infection should be advised to get tested for HBV serological markers [HBsAg, anti-HBc, anti-HBs] and to be vaccinated, if they are negative for these markers.

   In subjects with chronic HBV infection, accurate assessment of the extent of hepatic fibrosis and/or the severity of necroinflammatory activity is essential for choosing therapeutic strategies and for monitoring the responses to anti-viral or anti-fibrotic treatment. Knowledge of the underlying histology can help guide therapeutic decisions when patients do not meet the clinical practice guidelines and treatment may be helpful. Aminotransferase levels may fluctuate with time, and single measurements of ALT and AST do not indicate disease stage. Usually, the ALT concentrations are higher than those of AST, but with disease progression to cirrhosis, the AST/ALT ratio may be reversed. A progressive decline in serum albumin concentrations, rise in bilirubin and prolongation of the prothrombin time are characteristically observed as decompensated cirrhosis develops. In chronic HBV infection, a liver biopsy is usually recommended to determine the stage of fibrosis and/or the grade of activity in patients with a high viral load and high-normal or minimally raised ALT levels and in those older than 30 years without clinical evidence of cirrhosis. Liver biopsy is considered the reference standard for the histological evaluation of liver disease. However, it is important to remember that a liver biopsy represents just ~1/50,000 of the entire liver, and that liver injury is typically irregularly distributed in the liver. Thus, liver biopsy is an imperfect reference standard; taking into account a range of accuracies of the biopsy, even in the best possible scenario, an area under the receiver operating characteristic [AUROC] >0.90 cannot be achieved even for a perfect marker of liver disease [133]. The diagnostic accuracy of liver biopsy decreases because it is often subject not only to sampling error, but also to intra- and inter-observer variability in histological interpretation [134]. Moreover, even if it is generally accepted to be a safe procedure, it is invasive and can be associated with rare but potentially serious complications, including hemorrhage, pneumothorax, and procedure-related mortality. Thus, although there is still an important role for liver biopsy among chronic HBV infection, there is an obvious need to develop and use noninvasive, accurate, and reproducible tests for detecting liver injury. For example, noninvasive tests are helpful in assessing the stage of fibrosis in chronic HBV infection with no clear indication for a liver biopsy, or in those who require follow-up assessment of the stage of fibrosis during or after treatment.

   Several noninvasive tests based on serum fibrosis markers or radiographic techniques have been introduced, and they are being increasingly used to assess the severity of liver disease in clinical practice. These include serum biochemical parameters, such as the ratio of aspartate aminotransferase [AST] to ALT, the fibrosis score-4 [FIB-4], the AST to platelet ratio index [APRI], the age-spleen-platelet index, the Forns index, and the Hui index. Specialized tests include Fibrotest, Hepascore, the enhanced liver fibrosis test and, for elasticity imaging, magnetic resonance [MR] elastography and transient elastography [TE] [135, 136].

   The APRI is a simple test that is readily available, is inexpensive, does not require particular expertise in interpretation, and can be performed in an outpatient setting. APRI uses two cutoff points for diagnosing specific fibrosis stages, as the use of a single cutoff would result in suboptimal sensitivity and specificity. A high cutoff with high specificity is used to diagnose persons with a particular stage of fibrosis, and a low cutoff with high sensitivity [i.e., fewer false-negative results] is used to rule out the presence of a particular stage of fibrosis. Some persons will fall in the indeterminate range of test results [i.e., their score will be between the low and the high cutoff] and will need future re-testing and evaluation. Most commonly reported cutoff values for APRI for the detection of significant fibrosis and cirrhosis are as follows: For significant fibrosis [METAVIR ≥F2], low and high cutoffs for APRI are 0.5 and 1.5; and for cirrhosis [METAVIR F4], low and high cutoffs for APRI are 1.0 and 2.0. Sensitivity, specificity, PPV and NPV for diagnosing significant fibrosis [METAVIR ≥F2] were 71–84, 50–69, 52–61 and 76–84 % for APRI low cutoff; and 28–45, 90–95, 68–81 and 65–72 % for APRI high cutoff. Sensitivity, specificity, PPV and NPV for diagnosing cirrhosis [METAVIR F4] were 55–73, 70–80, 18–28 and 93–97 % for APRI low cutoff; and 22–49, 81–94, 19–34 and 91–94 % for APRI high cutoff [137].

   Emerging technologies utilizing ultrasound and MR imaging platforms, such as acoustic radiation force impulse imaging and diffusion-weighted MR imaging have been developed as well. These approaches make up for the weak points in the liver biopsy by improving the histology results, but they also reduce the need for liver biopsy.

   Liver stiffness measurement using TE [Fibroscan®] was first developed in 2003 and is the most extensively evaluated method of this type. Following vigorous validations in many studies, TE was shown to be a reliable and accurate surrogate for liver biopsy in assessing the severity of liver fibrosis [138–140]. In recent years, many patients in Asia-Pacific countries have been evaluated by TE, resulting in extensive accumulated experience. The performances of TE in diagnosing significant fibrosis [≥F2 stage] and cirrhosis [F4 stage] are good, with AUROC of 0.81–0.95 and 0.8–0.98, respectively. Most studies report estimated cutoff ranges of 6.3–7.9 and 9.0–13.8 kPa for the diagnosis of significant fibrosis and cirrhosis, respectively. However, although TE has displayed reliable diagnostic accuracy in this setting, it can be influenced by factors such as necroinflammation, edema, food intake, and cholestasis, resulting in an overestimation of TE values. Because of the complex natural history of chronic HBV infection, which frequently presents as fluctuating patterns associated with necroinflammatory activity, serum levels of ALT and bilirubin must be considered as a potential confounder when interpreting the TE values of chronic HBV-infected patients.

   Liver fibrosis is a dynamic process. Beyond the cross-sectional studies, recent evaluations of noninvasive tests have focused on their ability to predict the risk of disease progression or liver-related death, and on their use in monitoring the treatment response during long-term, follow-up longitudinal assessments [141, 142]. A major advantage of noninvasive tests is that they allow repeated serial measurements of liver fibrosis. Indeed, the role of noninvasive tests is no longer confined to the detection of the severity of liver fibrosis; rather, noninvasive approaches provide a surveillance tool that predicts clinical outcome and long-term prognosis, thus helping to determine treatment strategies. Furthermore, to improve the overall diagnostic performance, the advantages of combining TE and serum markers have been established in several studies [143–145], but further validation is still required.

   Neither noninvasive testing nor liver biopsy alone is sufficient to make a definitive decision in clinical practice, and regardless of specific methodological advances, all of the available clinical and biological data must be taken into account in therapeutic decision-making. The utilization of noninvasive tests for assessing liver histology can significantly reduce, but not completely replace, the need for liver biopsy and should be seen as a complementary tool in the management of chronic HBV-infected patients.

   Use of risk calculators

   Chronic HBV infection remains an important cause of HCC development. HCC causes poor quality of life and shortened survival, and is thus regarded as a major health challenge. The risk of CHB progressing to HCC may be reduced by antiviral therapy [146], and surveillance with abdominal ultrasonography and serum alpha-fetoprotein tests can be used to screen patients for early HCC treatment. Although, the global number of individuals infected with CHB is extensive, especially in endemic areas such as Asian-Pacific and sub-Saharan African regions, only a small number of patients develop end-stage liver diseases. Therefore, the identification and triage of patients who are at high risk of HCC development is important. Several factors, such as gender, age, family history of HCC, presence of hepatic inflammation/fibrosis, alcohol consumption, elevated viral load, hepatitis Be antigen [HBeAg] positivity, and specific HBV genotypes [e.g., genotype C], have been identified to be independently associated with elevated risk of HCC development [13, 67, 147]. These factors, including patient, viral, and environmental factors, interact with one another and lead to HCC development in patients with chronic HBV infection. From the individualized medicine point of view, these factors should be used to reveal the future risk of HCC progression in patients with viral hepatitis so that preventive measures can be applied to those at high risk [148].

   Risk calculators for HCC in chronic HBV-infected patients without antiviral treatment

   Many Asian study groups established prediction models that incorporated several clinical variables to estimate HCC risk for chronic HBV-infected patients. These included IPM from Korea [hospital based using gender, HCV infection, HBV infection, AFP levels, chronic hepatitis, cirrhosis, alcohol use and ALT levels] [149]; GAG-HCC risk score from Hong-Kong [hospital based using gender, age, HBV DNA levels, core promoter mutations and cirrhosis] [150]; CUHK clinical scoring system from Hong-Kong [hospital based using age, albumin, bilirubin, HBV DNA levels and cirrhosis] [151]; and REVEAL nomograms from Taiwan [community based using gender, age, ALT levels, family history of HCC, alcohol consumption, HBV DNA levels, HBeAg and HBV genotype] [152]. The most important issue with these was the lack of external validation. All these groups then collaborated to develop a HCC risk score [REACH-B] incorporating gender, age, serum alanine transaminase [ALT] concentration, HBeAg status, and serum HBV DNA level as the predicting parameters [153]. This study derived a 17-point risk model from 3584 treatment-free and cirrhosis-free CHB patients in a community-based Taiwanese cohort [REVEALHBV], and validated its use in a composite hospital-based cohort [n = 1505] from Hong Kong and Korea. This risk score could predict HCC with a wide range of risks, ranging from 0.0 to 23.6 % at 3 years, 0.0 to 47.4 % at 5 years, and 0.0 to 81.6 % at 10 years for patients with the lowest through the highest scores. Although the derivation and validation cohorts were quite different in their distributions of sex, age, HBeAg serostatus, ALT concentration, HBV DNA level, and cirrhosis, the risk score developed from the derivation cohort accurately and reliably estimated the HCC risk at 3, 5 and 10 years of follow-up in the validation cohort. The area under the receiver operating characteristic curve [AUROC] and the corresponding 95 % CI were 0.811 [0.790–0.831], 0.796 [0.775–0.816], and 0.769 [0.747–0.790], respectively, in predicting 3-, 5- and 10-year HCC risk, indicating a fair discriminatory capability. The performance of the risk score was improved when cirrhotic patients were excluded from the validation cohort [153].

   With recent studies showing utility of quantitative serum HBsAg levels [which are reproducible and low cost] in providing additional predictability of HCC, especially in patients with low levels of HBV DNA [20,000 IU/ml and PNALT should also be followed up every 3 months. A liver biopsy should be considered in viremic patients older than 35–40 years, especially those with high normal or minimally raised ALT levels or family history of HCC or cirrhosis, with intent to identify the group of patients with significant fibrosis requiring treatment [Fig. 2].

   Fig. 2

   Treatment indications for noncirrhotic HBeAg-positive chronic HBV-infected patients

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   Patients with active HBV replication [HBV DNA >2000 IU/ml] and minimally elevated [1–2× ULN] or persistently normal ALT should have liver fibrosis assessed. Liver biopsy may be needed before therapy to assess the necroinflammatory grade, determine the fibrotic stage, and exclude other possible causes of raised ALT levels as a guide for consideration of antiviral treatment. Treatment should be instituted if moderate to severe hepatic necroinflammation or significant fibrosis is found. If liver biopsy is not feasible, noninvasive assessment of liver fibrosis should be considered as an alternative.

   Immunotolerant patients need special attention. HBeAg-positive patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level, without any evidence of liver disease and without a family history of HCC or cirrhosis, generally do not require immediate therapy. In these cases, noninvasive assessment of liver fibrosis should be done. Follow-up should be done at least every 3–6 months. A liver biopsy should be considered if significant fibrosis is suspected or if there is family history of HCC or cirrhosis.

   HBeAg-negative patients with persistently normal ALT levels [ALT determinations every 3 months for at least 1 year] and HBV DNA levels below 2000 IU/ml, without any evidence of liver disease, do not require immediate therapy. Evaluation of the severity of fibrosis by a noninvasive method might be useful as the first screening test in such cases. A suspicion of significant fibrosis should help identify patients for liver biopsy. There is however, limited data using such an algorithmic approach in CHB. Follow-up with ALT and alpha-fetoprotein determinations every 3–6 months and ultrasonography and/or HBV DNA every 6–12 months is needed [Fig. 3].

   Fig. 3

   Treatment indications for noncirrhotic HBeAg-negative chronic HBV-infected patients

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   1. 3.5

      Recommendations: indications of therapy in chronic HBV infection

      1. 3.5.1

         HBsAg positive patients with decompensated cirrhosis and detectable HBV DNA require immediate antiviral treatment with NA[s]. Liver transplantation should be considered if patients do not stabilize with medical management [A1].

      2. 3.5.2

         Patients with compensated cirrhosis and HBV DNA >2000 IU/ml should be considered for treatment even if ALT levels are normal [A1]. Patients with compensated cirrhosis should be treated irrespective of the ALT and HBV DNA levels [C2].

      3. 3.5.3

         Patients with suspected severe reactivation [reactivation with the presence of coagulopathy with prolonged prothrombin time [prolonged by more than 3 s] or INR increased to >1.5] of chronic HBV infection should be started on antiviral therapy immediately after sending tests for quantitative HBV DNA, but without waiting for the results [B1].

      4. 3.5.4

         Treatment may be started in pre-cirrhotic chronic HBV-infected patients if they have persistently elevated ALT levels >2 times upper limit of normal [ULN] [at least 1 month between observations] and HBV DNA >20,000 IU/ml if HBeAg positive and >2000 IU/ml if HBeAg negative [B1].

      5. 3.5.5

         Patients with high HBV DNA levels [>20,000 IU/ml if HBeAg positive and >2000 IU/ml if HBeAg negative] but ALT 35 years or there is family h/o HCC or cirrhosis. They should be considered for treatment if biopsy shows moderate to severe inflammation or significant fibrosis [B1].

      6. 3.5.6

         HBeAg-positive patients with HBV DNA 35 years or there is family h/o HCC or cirrhosis. They should be considered for treatment if biopsy shows moderate to severe inflammation or significant fibrosis [B1].

      7. 3.5.7

         HBeAg-negative patients with HBV DNA 35 years or there is family h/o HCC or cirrhosis. They should be considered for treatment if biopsy shows moderate to severe inflammation or significant fibrosis [C1]. More long-term data using antiviral therapy is needed for these groups of patients.

      8. 3.5.8

         Noninvasive methods for the estimation of the extent of fibrosis are useful in selecting patients for liver biopsy. Patients with the suggestion of significant fibrosis by noninvasive markers [mean liver stiffness ≥8 kPa [by Fibroscan] or APRI ≥1.5] should be considered for liver biopsy followed by treatment, if biopsy shows moderate to severe inflammation or significant fibrosis [C1] [Table 5]. Patients with suspected significant fibrosis but unwilling to undergo liver biopsy may be considered for treatment [C2] or should be kept on regular follow-up [B1].

      9. 3.5.9

         Patients who are not considered for treatment should be followed up regularly by measurement of ALT levels, HBV DNA, AFP, ultrasonography and fibrosis assessment [Table 5] [B1].

   3.6 Results of currently available therapies, predictors of response to therapy, follow-up and stopping rules during therapy in chronic HBV infection

   3.6.1 Results of and predictors of response to nucleos[t]ide analogues

   Lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir disoproxil fumarate have been approved in most Asia Pacific countries. Clevudine has been approved in Korea and the Philippines, while its development has been stopped in others countries due to myopathy.

   l-Nucleoside analogues

   Lamivudine

   In the Asian lamivudine [LAM] trial and a multi-center trial in China, HBeAg seroconversion was achieved in approximately 44–47 % after 4–5 years of therapy [169]. In a long-term follow-up study among 95 CHB patients [43 HBeAg-positive] on lamivudine for at least 10 years with maintained viral suppression [HBV DNA 140,000 copies/ml] rate after 12-month consolidation was 8.7 % in 5 years, in contrast to 61.9 % in those with consolidation therapy