This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/JVH.13244 This article is protected by copyright. All rights reserved

Article type : Non-Commissioned Review

Title: Asian Consensus Recommendations on Optimizing the Diagnosis and Initiation of

Treatment of Hepatitis B Virus Infection in Resource-Limited Settings

Short running title: Asian Consensus on Optimizing HBV diagnosis

Authors:

1Edward John Gane, 2Michael R Charlton, 3Rosmawati Mohamed, 4Jose Decena Sollano, 5Kyaw

Soe Tun, 6Thuy Thi Thu Pham, 7Diana Alcantara Payawal, 8Rino Alvani Gani, 9David Handojo

Muljono, 10Subrat Kumar Acharya, 11Hui Zhuang, 12Akash Shukla, 13Kaushal Madan, 14Neeraj

Saraf, 15Satyendra Tyagi, 16Karam Romeo Singh, 17Ian Homer Yee Cua, 18Ganbolor Jargalsaikhan, 19Davadoorj Duger, 20Wattana Sukeepaisarnjaroen, 21Hery Djagat Purnomo, 22Irsan Hasan, 23

Laurentius Adrianto Lesmana, 24Cosmas Rinaldi Adithya Lesmana, 25Khin Pyone Kyi, 26Win

Naing, 27Ravishankar AC, 28Sanjay Hadigal

Affiliations:

1Professor, Liver Unit University of Auckland2Professor of Medicine, Director Transplant Institute; Center for Liver Diseases, University of

Chicago Biological Sciences3Consultant Hepatologist, Department of Medicine, University Malaya Medical Centre4Professor, Medicine, University of Santo Tomas Hospital5Honorary Professor, Department of Gastroenterology and Hepatobiliary Medicine, Defense

Services Medical Academy, Myanmar

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6Assoc. Professor, Hepatology, Medic Medical Center, 254 Hoa Hao St-Dist 10-HCM City,

Vietnam7Clinical Associate Professor, Department of Medicine, Cardinal Santos Medical Center,

Mandaluyong, Metro Manila, Philippines8Vice Chairman, Liver Transplantation team, Ciptomangunkusumo Hospital, Jakarta Indonesia9Deputy Director and Head of Hepatitis Department, Eijkman Institute for Molecular Biology;

Professor of Medicine Hepatitis Department, Eijkman Institute for Molecular Biology, Jakarta,

Indonesia; Universitas Hasanuddin, Makassar, Indonesia; Faculty of Medicine and Health,

University of Sydney, NSW, Australia10Pro-Chancellor, KIIT University, Bhubaneswar, Odisha Department of Gastroenterology

Kalinga Institute of Medical Sciences, KIIT University, Chandrasekharpur, Bhubaneswar, Odisha11Professor Infectious Disease Center, Peking University Health Science Center, Beijing 100191,

China12Professor & Head Department of Gastroenterology, LTM Medical College & Sion Hospital,

Mumbai13Director & Head- Gastroenterology & Hepatology, Max Smart Super Specialty Hospital, Saket14Director Clinical / Transplant Hepatology Institute of Digestive & Hepatobiliary Sciences

Medanta - The Medicity. 15Satyendra Tyagi, Consultant, Meerut Medical Centre16Consultant Gastroenterologist, Associate Prof Liver Clinic Regional Institute of Sciences,

Imphal17Head, Section of Hepatology Institute of Digestive and Liver Diseases, St. Luke's Medical

Center, Philippines18Research doctor; Ph.D. student Department Liver Center; Department International graduate

program in Medicine (IGPM) Institution Ulaanbaatar, Mongolia; College of medicine, Taipei

medical university, Taipei, Taiwan19Consultant, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia20Gastroenterology Unit, Department of Medicine Srinagarind Hospital, Faculty of Medicine,

Khon Kaen University, Khon Kaen, Thailand21Head of Division Gastroentero Hepatology Internal Medicine, Dr Kariadi Hospital, Medical

Faculty Diponegoro University; Jl Dr Sutomo 16 Semarang Indonesia

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22Hepatobiliary Division, Department of Internal Medicine Cipto Mangunkusumo National

General Hospital Jalan Diponegoro, Jakarta, Indonesia23Professor, Department of Hepatobiliary, University of Indonesia24Teaching Staff and senior consultant Department of Internal Medicine, Hepatobiliary Division;

Dr. Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta.25President Myanmar Liver Foundation; Liver Foundation, Yangon, Myanmar26Prof/Head, Department of Hepatology, Yangon General Hospital, University of Medicine,

Yangon, Myanmar27General Manager, Medical Affairs, Mylan Pharmaceuticals Private Limited28Manager, Medical Affairs, Mylan Pharmaceuticals Private Limited.

Corresponding author:

Prof. Edward John Gane

Professor, Liver Unit

University of Auckland

1010, New Zealand

Email: edgane@adhb.govt.nz

Phone: +6421548371

Conflict of interest:

Edward John Gane: Member of Clinical Advisory Board for Gilead Sciences, AbbVie, Janssen,

Arrowhead, Merck, VIR Biotechnology, Assembly Bio. Member of Speakers’ Bureau for Gilead

Sciences, AbbVie, Mylan Pharmaceuticals

Michael Charlton: Gilead Sciences: Consulting and research support, Merck: Consulting and

research support, AbbVie: Consulting and research support, Mylan: Consulting, Novartis:

Consulting and research support

Ravishankar AC: Employee of Mylan Pharmaceuticals Private Limited

Sanjay Hadigal: Employee of Mylan Pharmaceuticals Private Limited

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Acknowledgements: We would like to thank Mylan Pharmaceuticals ltd for financial support in

execution of this project. We would also like thank BioQuest Solutions Ltd for providing writing

assistance.

Abstract:

Asia has an intermediate-to-high prevalence of and high morbidity and mortality from hepatitis B

virus (HBV) infection. Optimization of diagnosis and initiation of treatment is one of the crucial

strategies for lowering disease burden in this region. Therefore, a panel of 24 experts from 10

Asian countries convened, and reviewed the literature, to develop consensus guidance on

diagnosis and initiation of treatment of HBV infection in resource-limited Asian settings. The

panel proposed 11 recommendations related to diagnosis, pre-treatment assessment, and

indications of therapy of HBV infection, and management of HBV-infected patients with co-

infections. In resource-limited Asian settings, testing for hepatitis B surface antigen may be

considered as the primary test for diagnosis of HBV infection. Pre-treatment assessments should

include tests for complete blood count, liver and renal function, hepatitis B e-antigen (HBeAg),

anti-HBe, HBV DNA, co-infection markers, and assessment of severity of liver disease. Non-

invasive tests such as AST-to-platelet ratio index, fibrosis score 4, or transient elastography may

be used as alternatives to liver biopsy for assessing disease severity. Considering the high burden

of HBV infection in Asia, the panel adopted an aggressive approach, and recommended initiation

of antiviral therapy in all HBV-infected, compensated or decompensated cirrhotic individuals with

detectable HBV DNA levels, regardless of HBeAg status or alanine transaminase levels. The

panel also developed a simple algorithm for guiding the initiation of treatment in non-cirrhotic,

HBV-infected individuals. The recommendations proposed herein, may help guide clinicians, to

optimize the diagnosis and improvise the treatment rates for HBV infection in Asia.

Keywords: Hepatitis B Virus; Diagnosis; Consensus; Asia; Algorithm

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Abbreviations:

HBV, hepatitis B virus; WHO, World Health Organization; HBsAg, hepatitis B surface antigen;

SEA, Southeast Asia; HCC, hepatocellular carcinoma; APASL, Asian Pacific Association for the

Study of the Liver; EASL, European Association for the Study of the Liver; AASLD, American

Association for the Study of Liver Diseases; HIV, human immunodeficiency virus; HCV, hepatitis

C virus; HAV, hepatitis A virus; HDV, hepatitis D virus; HBeAg, hepatitis B e-antigen; anti-HBs,

hepatitis B surface antibodies; anti-HBc, hepatitis B core antibody; AST, aspartate transaminase;

ALT, alanine transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase;

PT, prothrombin time; ULN, upper limit of normal; anti-HBe, antibodies to HBeAg; APRI, AST-

to-platelet ratio index; FIB-4, fibrosis score 4; TE, transient elastography; AFP, alpha-fetoprotein;

MELD, model for end-stage liver disease; CTP, Child-Turcotte-Pugh; ART, antiretroviral therapy;

TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; DAA, direct-acting antiviral;

PegIFN-α, pegylated interferon alpha.

Introduction

Epidemiology and Burden of Hepatitis B Virus Infection in Asia

Chronic hepatitis B virus (HBV) infection continues to be a serious global health concern.

According to the 2017 global hepatitis report from the World Health Organization (WHO), the

worldwide prevalence of HBV infection was 3.5% in 2015 (257 million).1 In a systematic review

of the data published from 1965–2013 covering 161 countries conducted to estimate the global,

national, and regional prevalence of HBV infection, the worldwide seroprevalence of hepatitis B

surface antigen (HBsAg) was found to be 3.6%, with figures closely related to WHO estimates.2

The burden of HBV infection varies substantially between geographic regions. In the 2017 WHO

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global hepatitis report, the estimated overall prevalence of HBV infection in the general

population in Southeast Asia (SEA) was noted to be about 2% in 2015 (39 million). The

corresponding prevalence rates in the Western Pacific and Eastern Mediterranean regions, which

include some of the Asian regions, were 6.2% (115 million individuals) and 3.3% (21 million

individuals), respectively.1 The endemicity of HBV within Asia is also heterogeneous, with most

Asian regions having an intermediate-to-high prevalence of HBV infection, and others having low

prevalence.2-9

Despite the development and increasing utilization of effective and safe vaccines, chronic HBV

infection continues to be associated with high morbidity and mortality. Worldwide, an estimated

887,000 deaths occurred in 2015 due to HBV-related complications such as cirrhosis and

hepatocellular carcinoma (HCC).10 In a recent systematic review, covering about 260 studies in 50

countries, more than half of liver cancer cases that occurred worldwide were attributed to HBV

infection.11 Another systematic review of all published studies before 2014, on HCC in Asia,

revealed that over 70% of all global new liver cancer cases were diagnosed in Asia, and that

chronic HBV was the main cause of HCC in this region.12 The majority of global liver cancer

cases attributable to HBV infection occur in Asia,13 where HBV infection is the leading cause of

cirrhosis.14,15

The high prevalence, morbidity, and mortality from HBV infection in Asia may be lowered by the

optimization of diagnosis and initiation of treatment of HBV infection.1,3 However, several unmet

needs have been identified in Asia that may hinder the effective implementation of this strategy.

Unmet Needs in the Diagnosis and Initiation of Treatment of HBV Infection in Asia

Globally, only 9% of individuals infected with HBV have undergone testing and are aware of their

HBV status, and only 8% of those who have been diagnosed with HBV infection have received

treatment with the WHO-recommended antiviral treatments in 2015, with the gap between

diagnosis and treatment being particularly large in Asia.1 The factors contributing to the low

diagnosis and treatment rates of HBV infection in Asia are shown in Table 1.16-25 One of these

factors is the lack of nation-wide HBV testing and management guidelines and referral pathways

to guide clinicians.25 Several regional studies have highlighted the contribution of the lack of

region-specific guidelines that reflect local circumstances, and the relative lack of resources to

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poor implementation of existing guidelines.17,18,20,21,24,25 These reports highlight the need for more

practical guidelines on the diagnosis and initiation of HBV treatment, and also the need for

simplified diagnostic algorithms for scaling up the diagnosis and initiation of treatment in

resource-limited settings such as Asia.

Methodology of Consensus Development

An aggressive and a simplified approach may be required for scaling up the diagnosis and

initiation of treatment in resource-limited settings such as Asia to help achieve the WHO 2030

targets for the elimination of hepatitis. Therefore, a panel of 24 experts, including national and

international society leaders, from 10 Asian countries convened to review the updated literature,

discuss and develop a consensus guidance on the optimization of diagnosis and initiation of

treatment of HBV infection in Asia. The latest recommendations from the Asian Pacific

Association for the Study of the Liver (APASL), the European Association for the Study of the

Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) were

reviewed by the panel, and a set of recommendations were proposed for the diagnosis, pre-

treatment assessment, and indications of therapy for HBV infection in Asia. In addition, the panel

also proposed recommendations for the management of HBV-infected patients with: (1) cirrhosis,

and (2) human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis A virus (HAV),

or hepatitis D virus (HDV) co-infections. Finally, the panel developed a simplified algorithm for

the management of hepatitis B e-antigen (HBeAg)-positive and HBeAg-negative treatment-naïve

patients. The recommendations and the algorithm in this consensus document have been

developed based on a review of current chronic HBV management guidelines and relevant

published literature, coupled with the experience of the expert panel in the management of HBV

infection. The recommendations reflect consensus guidance for simple and practical evaluation

and management of HBV infection in the relatively high prevalence, limited resource settings of

Asia, rather than a synthesis of optimal management where resources are less constrained. The

recommendations are focused on aspects of existing guidelines that were identified as relatively

difficult to adhere to.

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Diagnostic Criteria for Chronic HBV Infection

The Asian, American, and European guidelines recommend testing for HBsAg and hepatitis B

surface antibodies (anti-HBs) for the diagnosis of chronic HBV infection. Testing for total

hepatitis B core antibody (total anti-HBc) may also help diagnose HBV infection. However, in

individuals who test positive for total anti-HBc, additional testing for HBsAg and anti-HBs may

have to be conducted to differentiate between immunity and infection.26-28 The American

guidelines recommend testing for total anti-HBc only in donated blood (or organs) and in patients

who have HIV infection and are about to initiate immunosuppressive therapy or treatment for

HCV infection, cancer, or renal dialysis.27 In contrast to the AASLD, EASL and APASL

guidelines, after considering the intermediate-to-high HBV endemicity and resource-limited

settings in Asia, the expert panel recommended the use of a single test to detect HBsAg, for the

diagnosis of chronic HBV infection.29 Rapid diagnostic tests and point-of-care tests have been

reported to have good sensitivity and specificity compared to conventional laboratory

immunoassays for detecting HBsAg, and may be rapid, cost-effective options for the diagnosis of

HBV infection, especially in resource-limited settings.30,31

After the diagnosis of HBV infection, a detailed history of the patient, including details of

comorbid conditions and alcohol consumption, should be taken. The family history of cirrhosis or

liver cancer should also be evaluated. A thorough physical examination should be conducted for

assessing clinical symptoms and detecting the presence of cirrhosis.

Pre-treatment Assessments in Individuals With Chronic HBV Infection

Recommendation 1: The primary test for the diagnosis of chronic HBV infection is a serological assay to detect HBsAg.

Recommendation 2: Detailed history-taking, evaluation of family history for cirrhosis or liver cancer, and a thorough physical examination to detect cirrhosis should be conducted in all HBsAg-positive individuals.

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The pre-treatment assessments recommended by the expert panel included the following:

1. Complete blood count 26-29

2. Liver enzyme and biochemical profile: Biochemical tests, as a part of pre-treatment

assessments, include tests for aspartate transaminase (AST), alanine transaminase (ALT),

alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin, albumin, and

prothrombin time (PT).26-29 The recommended upper limit of normal (ULN) for ALT for

guiding the management of chronic HBV infection is >ULN, where ULN is defined by local

laboratory.28,32 Elevated liver enzymes have been reported in HBV-infected individuals in

several Asian studies.33-36 Elevated ALT levels have been positively correlated with HBV

DNA positivity, liver stiffness, and an increased risk of fibrosis, cirrhosis, and HCC in Asian

patients with chronic HBV infection.36-38 However, ALT alone may not be a reliable marker

for assessing the severity of liver disease; hepatic fibrosis cannot be ruled out in individuals

with normal ALT levels. A combination of ALT and HBV DNA load should be considered

while evaluating the risk of fibrosis in an HBV-infected individual.38

3. Renal function test: Renal function should be evaluated by testing for serum creatinine.26

4. Virological tests: Tests for HBeAg, antibodies to HBeAg (anti-HBe), and HBV DNA should

be conducted as a part of virological assessment.26-29 Chronic HBV-infected patients with

HBeAg-positive test results have been noted in several Asian studies.34-36,39 Positivity for

HBeAg has been found to be high in individuals with age <20 years and decrease with

increasing age.35 On the contrary, anti-HBe positivity has been noted to be high in advanced

age groups.34 In a recent community-based study conducted in China, a significant correlation

was noted between higher levels of HBeAg and high levels of HBV DNA.39 In another study

conducted in Bangladesh, HBeAg positivity and elevated ALT levels were found to be

independent predictors of HBV DNA positivity in HBV-infected individuals. The study

suggested that HBeAg-positive and anti-HBe negative HBV-infected individuals with raised

ALT and AST may be more likely positive for HBV-DNA.36 However, there may be

discordance of HBV DNA with serological and biochemical markers, with: (1) HBeAg-

positive and anti-HBe negative individuals having no detectable HBV DNA; (2) HBeAg-

negative and anti-HBe-positive individuals having detectable HBV DNA; (3) elevated liver

enzymes regardless of the HBeAg-status; and (4) normal liver enzymes in HBV DNA-

positive cases. Therefore, in resource-limited settings, although serology and biochemical

tests may be an alternative to HBV DNA for assessing the state of chronic HBV infection,

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HBV DNA results play an important role and provide additional information in cases with

discordance between the results of serology and biochemical tests.36 It should be noted that

HBV DNA is an important marker for viral replication, and may help guide decision-making

on the initiation and monitoring of antiviral treatment in HBV-infected individuals.26-28

5. Tests for markers of co-infection: Detection of antibodies to HCV, HDV, and HIV should

be done to guide initiation of appropriate treatment or to exclude co-infection.26,28

6. Testing for anti-HAV: Testing for antibodies against HAV should be performed, and

patients with negative anti-HAV should be advised to be vaccinated against HAV.28

7. Ultrasonography: Ultrasonography may be used to detect signs of cirrhosis or HCC and to

screen patients for early initiation of treatment for HCC.26,27

8. Non-invasive tests for assessment of severity of liver disease: Non-invasive tests that may

be used as alternatives to liver biopsy for the assessment of severity of liver disease in HBV-

infected individuals include AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), or

transient elastography (TE).26-29 The APRI test is inexpensive and simple to use. The cut-off

APRI scores for identifying patients with relatively high probability of cirrhosis and

significant fibrosis are ≥2.0 and ≥1.5, respectively.26,29 The use of these cut-off scores for

predicting fibrosis and cirrhosis has been reported in the regional literature, validating their

use in Asia.40-42 Furthermore, APRI has also been used as an additional predictor of short-term

mortality in HBV-infected patients with decompensated cirrhosis undergoing

hospitalization.41 Another non-invasive test for assessing the severity of fibrosis is the FIB-4

score. The cut-off FIB-4 scores for predicting advanced fibrosis and no or less fibrosis are

>3.25 and <1.45, respectively.42,43 The successful use of the FIB-4 score for detecting

significant fibrosis and cirrhosis and predicting the risk of HCC in individuals infected with

HBV has been reported in Asian studies and meta-analyses.43-45

Assessment of fibrosis using APRI or FIB-4 may not be optimal in HBV-infected patients

with persistently normal ALT levels,46 or for the assessment of improvement in fibrosis

during or after antiviral therapy.47 The use of TE for assessing liver stiffness is more justified

in these patients.46,47 The recommended cut-off scores for TE for predicting significant

fibrosis and cirrhosis are ≥9 kPa and ≥12 kPa, respectively.28 Transient elastography has been

used in several Asian studies to accurately predict fibrosis, cirrhosis, and the risk of HCC in

HBV-infected patients.48-51 Liver stiffness assessment using TE has also been found to be a

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useful predictor of the development of liver-related events in chronic HBV patients with

advanced liver fibrosis.52 In both resourceful and resource-limited settings in Asia, based on

the availability and affordability, TE may a reasonable alternative and may be preferred to

liver biopsy for the assessment of fibrosis in both low- and high-risk HBV-infected patients.49

However, in patients with severe obesity (class II or III), the use of TE may lead to

overestimation of fibrosis.53,54 A high risk of discordance between liver fibrosis estimated by

TE and biopsy has been reported in these patients.51 Therefore, in such patients, and in

settings where TE is not available or accessible, APRI or FIB-4 may be used for the

assessment of the severity of liver disease.29, 51, 53,55

In addition to these pre-treatment assessment tests, the AASLD guidelines recommend testing for

alpha-fetoprotein (AFP) and HBV genotype in select patients, and the EASL guidelines

recommend quantification of HBsAg in HBeAg-negative patients with chronic HBV infection and

in patients in whom treatment with interferon-alfa is planned.27,28 The expert panel opined that

AFP test may be conducted in select patients – (1) with liver cirrhosis or history of HCC in

siblings; or (2) with suspected HCC.56 Considering the resource-limited settings in Asia, other

additional tests were not recommended by the expert panel.

Recommendation 3: The initial pre-treatment assessment should include evaluation of complete blood count, and biochemical tests to assess liver and renal function.

Recommendation 4: Pre-treatment assessment should include: (1) tests for HBeAg, anti-HBe, and HBV DNA to evaluate the stage of infection and the extent of viral replication; (2) evaluation of markers of co-infection to rule out HCV, HDV, and HIV; and (3) testing for anti-HAV, to guide individuals with negative anti-HAV to be vaccinated against HAV.

Recommendation 5: Non-invasive markers for the assessment of severity of liver disease include APRI (cut-off for predicting significant fibrosis: ≥1.5; cirrhosis: ≥2.0), FIB-4 (cut-off for predicting advanced fibrosis: >3.25; no or less fibrosis: <1.45), and TE (cut-off for predicting significant fibrosis: ≥9 kPa; cirrhosis: ≥12 kPa). In resource-limited settings, TE may be preferred over liver biopsy, due to the high cost of, and the requirement of trained physicians for conducting liver biopsy. In HBV-infected patients with persistently normal ALT levels, TE is preferred over APRI for assessing liver stiffness. In chronic HBV patients with severe obesity, and in settings where TE is not available, APRI or FIB-4 may be used.

Recommendation 6: AFP test may be conducted in select patients – (1) with liver cirrhosis or history of HCC in siblings; or (2) with suspected HCC.

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Indications for Initiation of Therapy in Patients With HBV Infection

Antiviral therapy may be initiated in individuals with chronic HBV infection, after careful

consideration of the following criteria: (1) serum ALT levels >ULN, where ULN is defined by

local laboratory;28,32 (2) HBV viral load, assessed by HBV DNA levels; and (3) extent of fibrosis

or cirrhosis, assessed clinically, or by using non-invasive methods or liver biopsy.26,28

Additionally, age, presence of extrahepatic manifestations (glomerulonephritis, polyarteritis

nodosa, mixed cryoglobulinemia [triad of purpura, arthralgias and debilitating weakness], and skin

manifestations)26,28,29,57 and the presence of a first-degree family member with cirrhosis or HCC,

should also be considered.26-28

The expert panel reviewed the Asian, American, and European guideline recommendations on the

initiation of treatment in compensated and decompensated cirrhotic individuals, and in non-

cirrhotic HBeAg-positive and -negative individuals. The panel recommended that all HBV-

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Recommendation 7: All HBV-infected compensated or decompensated cirrhotic individuals with detectable serum HBV DNA levels should be initiated on antiviral therapy, irrespective of ALT levels, or HBeAg status.

infected compensated or decompensated cirrhotic individuals with detectable HBV DNA levels

should be treated with antiviral therapy, regardless of ALT levels, HBeAg status. In studies

conducted across various regions in Asia, treatment of HBV-infected patients with cirrhosis or

advanced fibrosis with antiviral therapy has been found to result in better sustained viral

suppression, delayed clinical progression, and lower frequency of occurrence of death, hepatic

decompensation, and HCC as compared to HBV-infected cirrhotic or advanced fibrotic patients

not treated with any antiviral therapy.58,59 In a multicenter study that included more than 50%

Asian chronic HBV-infected patients with hepatic decompensation, treatment with appropriate

antiviral therapy was found to be well tolerated and resulted in a significant decrease in HBV

DNA levels, normalization of serum ALT levels, loss of HBeAg with seroconversion, and

improvement in the model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP)

scores.60

Given the intermediate-to-high endemicity of HBV infection,61 high risk of HBV transmission,62

high incidence of progression to liver cirrhosis, and HCC in HBV-infected patients,61-65 and

challenges in follow-up monitoring of these patients in Asia,66 the expert panel opined that

countries in this region may benefit from an aggressive approach involving the use of better

diagnostics and effective antiviral treatments, even in resource-limited settings. Timely

management of chronic HBV infection may be of prime importance in this region to prevent

disease progression and the development of adverse disease sequelae.66

The expert panel also developed a simple algorithm for easy guidance on the initiation of antiviral

therapy in non-cirrhotic HBeAg-positive and HBeAg-negative treatment-naïve individuals (Figure

1). The usage of this algorithm has been described in detail under recommendation 8.27,28

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Recommendation 8: Guidance on treatment initiation in HBeAg-positive or HBeAg-negative treatment-naïve, HBV-infected patients (Figure 1) The initial assessment should be based on HBV DNA levels.

If the HBV DNA is >2000 IU/mL, further assessment should be based on ALT levels. If the ALT level is >ULN, where ULN is defined by local laboratory,appropriate antiviral treatment should be initiated.28,32 In individuals with ALT <ULN, antiviral treatment should be initiated in the presence of any one of the following criteria:27,28

o Age >30 yearso Moderate fibrosis o First-degree family member with cirrhosis or HCCo Extrahepatic manifestations*

If the HBV DNA level is <2000 IU/mL, antiviral therapy may be initiated in the presence of any one of the following criteria, regardless of ALT levels: 27,28

o First-degree family member with cirrhosis or HCCo Extrahepatic manifestations*

It is important to exclude other causes of ALT elevation prior to initiating antiviral therapy.

*Glomerulonephritis, polyarteritis nodosa, mixed cryoglobulinemia [triad of purpura, arthralgias and debilitating weakness], and skin manifestations26,28,29,57

Monitoring of

HBV-Infected Patients, Currently Not Being Treated

The expert panel recommended periodic monitoring of HBV-infected patients, who do not fulfill

any of the treatment criteria, by assessment of – (1) serum ALT, (2) HBV DNA, and (3) severity

of liver fibrosis using non-invasive tests. In HBeAg-positive HBV-infected patients who remain

untreated, ALT, HBV DNA and fibrosis assessments should be conducted at least every 3 months,

every 6 –12 months, and every 12 months, respectively. In HBeAg-negative HBV-infected

patients with HBV DNA <2000 IU/mL, the frequency of these assessments should be every 6–12

months for ALT, and every 2–3 years for HBV DNA and liver fibrosis. In HBeAg-negative HBV-

infected patients with HBV DNA ≥2000 IU/mL, assessment of ALT should be done every 3

months for the first one year and every 6 months thereafter; HBV DNA and liver fibrosis

assessment, indirectly by non-invasive means or by liver biopsy, should be conducted at least

every 3 years.28

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Guidance for Stopping of Antiviral Therapy in HBV-Infected Patients

Most patients with chronic HBV infection may require long-term antiviral therapy.

Discontinuation of antiviral therapy may be done in HBV-infected patients with confirmed loss of

HBsAg, with or without seroconversion to anti-HBs. Stopping of antiviral therapy in HBV-

infected, HBeAg-positive, non-cirrhotic patients may be considered, if they have completed at

least 12 months (or preferably 3 years) of consolidation therapy, and if stable HBeAg

seroconversion, undetectable HBV DNA and persistently normal ALT levels have been noted.26,28

Close post-antiviral therapy monitoring is recommended in these individuals.28 Discontinuation of

antiviral therapy may be considered in HBV-infected, HBeAg-negative, non-cirrhotic patients,

after: (1) anti-HBs seroconversion; (2) at least 12 months of a post-HBsAg clearance consolidation

period; or (3) treatment for at least 2 years with undetectable HBV DNA documented on three

separate occasions, 6 months apart.26 In HBV-infected, HBeAg-negative patients, discontinuation

of antiviral treatment may result in greater virologic remission, if there has been an on-treatment

virologic suppression for more than 24 months .67

In addition to measurement of HBV DNA during treatment, quantification of serum HBsAg may

provide useful complementary information for the assessment of on-treatment efficacy and

guidance on stopping antiviral therapy.68 However, considering the resource-constrained settings

in Asia, monitoring of HBsAg was not recommended by the expert panel.

After stopping antiviral therapy, patients should be monitored monthly for HBV DNA and ALT

for the first 3 months, followed by every 3–6 months, thereafter till relapse.26 Retreatment may be

considered in patients with increase in ALT levels, or detectable HBV DNA.27

Indications for Therapy in HBV-Infected Individuals With Co-infections

HIV Co-infection

Antiretroviral therapy (ART) with tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide

(TAF)-containing regimens should be initiated in all HIV-positive patients with HBV co-infection,

regardless of the CD4 cell count. Clinical studies and meta-analyses have proven the effectiveness

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Recommendation 9: All HBV-HIV co-infected patients should be administered ART, irrespective of the CD4 cell count.

Recommendation 10: All HBV-infected patients with positive HCV RNA should be considered for HCV DAA therapy. All patients with HBV-HCV co-infection who fulfil the standard treatment criteria for HBV should receive HBV antiviral therapy.

Recommendation 11: Pegylated interferon alpha for at least 48 weeks is the current treatment of choice in HDV-HBV co-infected patients with compensated liver disease.

of both TDF- and TAF- containing regimens in causing virologic suppression to undetectable

levels.69-71

HCV Co-infection

Hepatitis B virus-infected patients co-infected with HCV have been noted to have accelerated

progression of liver disease and an increased risk of HCC.72,73 The expert panel recommended that

this patient cohort should be initiated on HCV direct-acting antiviral (DAA) therapy. However,

HBV reactivation may occur during treatment of HCV infection with DAAs.74,75 Therefore, all

HBV-HCV co-infected patients who fulfill the standard treatment criteria for HBV should be

initiated on HBV antiviral treatment during and for three months following HCV DAA therapy.

Other patients should be monitored by regular assessment of HBV DNA and ALT during HCV

DAA therapy. Antiviral therapy for HBV infection should be initiated if patients develop HBV

reactivation (increase in HBV DNA by at least 1 log plus elevation in ALT >ULN).

HDV Co-infection

Pegylated interferon alpha (PegIFN-α) for at least 48 weeks is the current treatment of choice in

HDV-HBV co-infected patients with compensated liver disease.28 An improvement in biochemical

and virological parameters has been noted with PegIFN-α therapy in chronic HDV infection.76 In

patients with HBV-HDV co-infection with active HBV replication, suitable antiviral therapy

should be initiated for treating HBV infection.28 Furthermore, long-term follow-up HDV RNA

monitoring is recommended in all HBsAg-positive patients being treated with PegIFN-α.28

Additionally, monitoring of thyroid function is also recommended in patients treated with PegIFN-

α therapy.26,27

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Summary

The intermediate-to-high HBV endemicity, limited resources, lack of adherence to current

guidelines, and other unmet needs in the diagnosis and initiation of treatment of HBV infection in

Asia call for the optimization of the diagnosis of HBV infection and appropriate and timely

linkage to HBV treatment and care. Most regional studies highlight the need for national or

regional diagnostic guidelines with simpler diagnostic algorithms to facilitate easy decision-

making on the diagnosis and initiation of treatment of HBV infection in Asia. The current Asian

consensus guideline considers the resource-limited settings in Asia, incorporates recommendations

from regional experts, and provides optimal guidance on the diagnosis and initiation of HBV

treatment, along with the management of HBV-infected patients with HIV, HCV, and HDV co-

infections. A simple algorithm for guiding the initiation of antiviral therapy in HBV-infected

individuals has also been proposed in this document. Currently, many new therapies are being

developed to treat chronic HBV infection. It is hoped that these new combinations can achieve

functional cure or sustained loss of HBsAg and HBV DNA after a finite course of treatment.77

Until these are available, long-term suppression with oral antiviral therapy should be the goal in all

patients with chronic hepatitis B. The current guideline may help guide clinical practice decisions

and improve the diagnosis and treatment rates for HBV infection in Asia.

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Table 1: Factors contributing to low diagnosis and treatment rates of HBV infection in Asia

S. No. Factors contributing to low diagnosis and treatment of HBV infection

1. Limited availability of reliable national and subnational epidemiological data16-18

2. Low level of awareness among healthcare workers, patients, and the general

population regarding the disease, its routes of transmission, risk factors, and

complications—resulting in under-diagnosis16-20

3. High level of stigma and discrimination against individuals at high risk of HBV

infection16-18,21,22

4. Inadequate screening of transfused blood and blood products in some regions

due to limited knowledge/access to preventive and testing services for the

detection of chronic HBV infection16-20

5. Minimal use of WHO-qualified diagnostic methods18-20

6. Financial barriers and limited resources, leading to limited access to treatment

and care16,17,19,22

7. Lack of appropriate linkage to care16,17,22

8. Provider uncertainty or unawareness of current HBV screening guidelines23

9. Insufficient political commitment in most Asian countries, leading to a lack of a

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dedicated budget and comprehensive national plans with broader coverage for

prevention, diagnosis, and care16-18,24

10. Inadequate surveillance systems for the screening of HBV infection and lack of

formal nation-wide HBV testing and management recommendations/guidelines

and strategic frameworks to guide physicians18-20,21,24

11. Lack of referral pathways from diagnosis to care in most Asian countries25

12. Poor adherence to current screening, testing, and treatment guidelines25

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ULN: Upper limit of normal; HBeAg: Hepatitis B e-antigen; HBV: Hepatitis B virus; DNA:

Deoxyribonucleic acid; HCC: Hepatocellular carcinoma; ALT: Alanine aminotransferase.

*Exclude other causes of ALT elevation; **Glomerulonephritis, polyarteritis nodosa, mixed

cryoglobulinemia [triad of purpura, arthralgias and debilitating weakness], and skin

manifestations26,28,29,57

HBeAgPositive or negative

HBV DNA

<2,000 IU/ml

Presence of any of the following

First-degree family member with cirrhosis or HCC

Extrahepatic manifestations**

Antiviral treatment required irrespective of ALT levels*

HBV DNA

>2,000 IU/ml

ALT levels

< ULN

ALT levels

> ULN

Where ULN is defined by local laboratory28,32Presence of any of the following

Age >30 years Atleast moderate fibrosis First-degree family member

with cirrhosis or HCC Extrahepatic manifestations**

Antiviral treatment required Antiviral treatment required

Figure 1 legend: Algorithm to guide initiation of antiviral therapy in HBeAg-positive and

HBeAg-negative treatment-naïve, HBV-infected individuals.

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