NASKAH LENGKAP

The 11th Liver Update and

The Scientific Meeting of INA ASL/PPHI

In Conjunction with

The 7th China-Indonesia Joint Symposium on

Hepatobiliary Medicine and Surgery (CISHMS)

2018

Theme:

Future Treatment in Hepatopancreatobiliary Diseases

EDITORRino Alvani Gani

Irsan HasanC. Rinaldi A. Lesmana

Perhimpunan Peneliti Hati Indonesia

Hotel Raffles Jakarta, July 5th-7th 2018

Proceeding Book

The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI

In Conjunction with

The 7th China-Indonesia Joint Symposium on Hepatobiliary Medicine and Surgery

(CISHMS) 2018

Theme: Future Treatment in Hepatopancreatobiliary Diseases

Susunan Panitia:Ketua Liver Update & CISHMS: Rino Alvani GaniBendahara: Andri SanityosoPublikasi: Indra Marki

Reviewer: Rino Alvani Gani

Tim Editor:Rino Alvani GaniIrsan HasanC. Rinaldi A. Lesmana

150 x 230 mm

ISBN 978-602-18991-9-9

Hak Cipta Dilindungi Undang-undang:Dilarang memperbanyak, mencetak dan menerbitkan sebagian atau seluruh isi buku ini dengan cara dan bentuk apapun tanpa seizin penulis dan penerbit

Diterbitkan oleh:Perhimpunan Peneliti Hati IndonesiaGedung Wisma Bhakti Mulya Lt. 6 Ruang 602Jl. Kramat Raya No. 160Jakarta 10430

vThe 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Aida LydiaDivisi Ginjal Hipertensi Departemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

David Handojo MuljonoLembaga Biologi Molekuler EijkmanJakarta

Alex ThompsonDirector, Department of GastroenterologySt Vincent’s HospitalThe University of MelbourneSVHM, Victoria, Australia

Fauzi YusufDivisi Gastroentero-hepatologi Bag/SMF Ilmu Penyakit DalamFK UNSYIAH/RSU Dr. Zainoel AbidinAceh

Anthony TeohDeputy Director of EndoscopyDepartment of Surgery The Chinese University of Hong KongHong Kong

Henry LY ChanThe Chinese University of Hong Kong, Hong Kong

Andri SanityosoDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

Hery Djagat PurnomoSubbag. Gastroentero-hepatologiBagian Ilmu Penyakit DalamFK UNDIP / RSUP Dr. KariadiSemarang

Chyntia Olivia Maurine JasirwanDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

Hui Ying RaoPeking University Hepatology InstitutePeking University People’s HospitalBeijing, China

Cleopas Martin RumendeDivisi Respirologi & Penyakit KritisDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

Irsan HasanDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

C. Rinaldi A. LesmanaDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

I Dewa Nyoman WibawaDivisi Gastroentero-Hepatologi Bag/SMF Ilmu Penyakit DalamFK UNUD/RSUP SanglahDenpasar, Bali

KONTRIBUTOR

vi The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Ji Dong JiaDirector, Liver Research CenterBeijing Friendship HospitalCapital Medical UniversityBeijing, China

Li Ying SunVice Director, Department of Critical Care MedicineBeijing Friendship HospitalCapital Medical University, Beijing, China

Juferdy KurniawanDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

Lim Seng GeeDivision of Gastroenterology and HepatologyUniversity Medicine ClusterNational University HospitalSingapore

Jun Qi NiuDirector, Department of HepatologyThe First Hospital of Jilin UniversityChangcun, China

Manoj Kumar SharmaInstitute of Liver and Biliary ScienceNew Delhi, India

Kemal Fariz KalistaDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

Masashi MizokamiDirector, Genome Medical Sciences ProjectNational Center for Global Health and MedicineJapan

Lai WeiDirector of Peking University Hepatology InstituteChief Department of HepatologyPeking University People’s HospitalBeijing, China

Meta Dewi ThedjaLembaga Biologi Molekuler EijkmanJakarta

Laurentius A. LesmanaDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

M. Begawan BestariDivisi Gastroentero-hepatologi Departemen Ilmu Penyakit DalamFKU UNPAD/RSUP Dr. Hasan SadikinBandung

Lawrence Ho Khek YuDivision of Gastroenterology and HepatologyNational University Hospital Singapore

Poernomo Boedi SetiawanSubbag. Gastroentero-hepatologiBagian Ilmu Penyakit DalamFK UNAIR / RSUP Dr. SoetomoSurabaya

Lianda SiregarSMF Gastroentero-HepatologiRS Kanker DharmaisJakarta

Rino Alvani GaniDivisi HepatobilierDepartemen Ilmu Penyakit DalamFKUI/RSCM Dr. Cipto MangunkusumoJakarta

viiThe 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Sang Hoon AhnInstitute of GastroenterologyDepartment of Internal MedicineYonsei University College of MedicineSeoul, Korea

Stephen KY ChangMedical Director, GLAD ClinicMount Elizabeth HospitalSingapore

Shuichiro ShiinaDepartment of Gastroenterological Imaging and Interventional OncologyJuntendo UniversityJapan

Toar JM LalisangDepartemen Bedah Digestif FKUI/RSCM Dr. Cipto MangunkusumoJakarta

xii The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Intensive Care Management in Acute Liver FailureManoj Kumar Sharma ..................................................................................................................... 114

Symposium 9

Complementary Treatment Options for Chronic Liver DiseasesAndri Sanityoso Sulaiman, M. Yusuf Hanif ............................................................................. 116

Hepatic Encephalopathy and Liver Transplantation DecisionRino Alvani Gani, Steven Zulkifly ............................................................................................... 122

Management of Variceal Bleeding in Daily PracticeJuferdy Kurniawan, Steven Zulkifly .......................................................................................... 128

Symposium 10

Current Challenges in Management of Viral HepatitisAndri Sanityoso Sulaiman, M. Yusuf Hanif ............................................................................. 134

Do Newly Developed M2BPGi Predict Liver Fibrosis Stage and HCC in Serum?Masashi Mizokami ............................................................................................................................ 138

Symposium 11

Management of Hepatitis B in Indonesia: From Guideline to Clinical PracticeIrsan Hasan, Steven Zulkifly ......................................................................................................... 140

Management of Hepatitis B NA- Experienced PatientsPoernomo Boedi Setiawan ............................................................................................................ 147

Outcomes Management of Chronic Hepatitis B in Cirrhotic PatientsHery Djagat Purnomo ..................................................................................................................... 148

Symposium 12

Impact and Prevalence of Hepatitis C in Special Population: Focus on Kidney DiseaseAida Lydia ............................................................................................................................................ 156

Are DAAs Safe to Treat Hepatitis C in Chronic Kidney Disease Patients?Andri Sanityoso, Grasella Angelika Putri ................................................................................ 158

140 The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Management of Hepatitis B

in Indonesia: From Guideline

to Clinical Practice

Irsan Hasan1, Steven Zulkifly2

1 Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia/ Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia2 Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

SYMPOSIUM 11

Introduction

Hepatitis B Virus (HBV) infection is a major global health problem, affecting 257 million people (3.5% world population) based on World Health Organization database in 2017. The African and West Pacific regions are the two most prevalence of HBV infection, accounted for 68%. Since the widespread use of hepatitis B vaccine in infants, the incidence of new chronic hepatitis B (CHB) in children less than 5 years has been declined, from 4.7% (in the early 1980s – early 2000s) to 1.3% (in 2015)1

Indonesia Basic Health Research in 2013 reported the chronic HBV infection based on HBsAg positive was 7.1%.2 Based on the genotype, the most HBV infection in Indonesia was genotype B (66%), following by genotype C (26%), D (7%) and A (0.8%).3 Chronic HBV infection can lead to cirrhosis and hepatocellular carcinoma (HCC) if not treated properly. Around 8-20% of untreated CHB patients had cirrhosis in 5 years, and 20% of them would progress to decompensated cirrhosis in next five years. HCC cumulative incidence of chronic HBV infection, who had cirrhosis, reaches 21% in 6-years follow up study.4

Management of Chronic HBV Infection

Comprehensive assessment (viremia level, the degree of inflammation and stage of liver disease, etc) and counseling are recommended before planning the treatment for CHB therapy. The goal of CHB therapy is to improve quality of life and survival by preventing the development of disease, progression to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death; and also by prevention of HBV transmission to others.4,5

Management of Hepatitis B in Indonesia: From Guideline to Clinical Practice

141The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

The ideal endpoint is sustained-off therapy HBsAg loss, with or without seroconversion to anti-HBs. The satisfactory endpoint is no clinical relapse after sustained-off therapy in patient with HBeAg-positive (with sustained seroconversion to antiHBe) and HBeAg-negative. The desirable endpoint is maintenance of virological remission (undetectable HBV DNA) under long-term antiviral therapy in HBeAg positive patients who do not achieve anti-HBe seroconversion and in HBeAg negative patients.4,5

The indications of therapy are based mainly on the combination of (1) serum HBV DNA levels, (2) HBeAg status; (3) serum ALT levels, and (4) severity of liver disease. Age, health status, family history of HCC or cirrhosis and extrahepatic manifestations are also considered by physician. CHB patients with decompensated cirrhosis require urgent antiviral treatment, regardless of the level of HBV-DNA, ALT and HBeAg status. Significant clinical improvement is associated with control of viral replication. Patient with severe chronic reactivation (reactivation with coagulopathy/prolonged prothrombin time > 3 s or INR increased to > 1.5) should be treated to prevent deterioration of hepatic decompensation. Antiviral treatment can be started in the patient with compensated cirrhosis and HBV DNA > 2000 IU/mL even if normal ALT level. 4,5

Figure 1. Treatment Indication for CHB with cirrhosis or reactivation of CHB.4

In pre-cirrhotic patients, treatment is indicated in patient with persistently elevated ALT levels > 2 times the upper limit of normal (ULN) and HBV DNA> 20,000 IU/mL (HBeAg positive) and HBV DNA>2,000 IU/

Irsan Hasan, Steven Zulkifly

142 The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

mL (in HBeAg negative).Liver biopsy is considered in a patient with (1) non-significant fibrosis by using non-invasive method, (2) persistent elevated ALT levels, (3) older than 30 years old years old or (4) less than 30 years old with high-risk factors (family history of cirrhosis or HCC). Treatment could be started in patient with moderate-severe liver inflammation or significant fibrosis. Patients with normal ALT or persistent minimally elevated ALT levels without proof of significant fibrosis or cirrhosis are not indicated to receive antiviral therapy.4

Figure 2. Treatment Indication for Non Cirrhotic HBeAg-positive chronic HBV patients.4

Figure 3. Treatment Indication for Non Cirrhotic HBeAg-negative chronic HBV patients.4

Management of Hepatitis B in Indonesia: From Guideline to Clinical Practice

143The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Observation every three months for HBeAg-positive and every six months for HBeAg-negative patients who are not indicated for CHB antiviral treatment.4

Nowadays, interferon and nucleos(t)ide analogue are only two antiviral for CHB infection that widely accepted. Nucleos(t)ide analogue (NA) includes lamivudine 100 mg, adefovir 10 mg, entecavir 0.5 mg, telbivudine 600 mg and tenofovir 300 mg. The half-time of interferon is relatively short (3-8 hours). The addition of polyethylene glycol molecule (pegylation) slows the absorption and clearance, also maintains serum interferon level for a longer duration.; therefore pegylated interferon is given once weekly.4

Table 1. Characteristics Comparison Interferon versus NA.4

Interferon Nucleos(t)ide Analogue

Duration of Therapy Limited (max. 48 weeks) Long-term treatment (lifetime)

Administration Subcutaneous Oral once daily

Decompensated Cirrhosis No Yes

Side Effects Many Minimal

HBV DNA suppression in 1 year Slightly lower Slightly higher, duration > 1 year increase the rate

HBeAg seroconversion in 1 year (HBeAg positive)

Slightly lower Slightly higher, duration >1 year increase the seroconversion rate

HBsAg seroconversion in 1 year Slightly higher Lower. HBsAg seroconversion will match the interferon regimen, if duration > 1 year

Biochemical response Same Same

Histopathological response Same Same

Resistance No Yes

Long-term response Tend to improve if achieve target therapy

Relapse, if therapy is discontinued

Nucleos(t)ide Analogue

Tenofovir 300 mg or entecavir 0.5 mg daily is the first-line treatment for NA. Second-line therapy, including lamivudine, adefovir or telbivudine, is recommendedin accordance with the drug availability or urgency in naïve patient or patient with unknown resistance profile. During NA therapy, the

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144 The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

level of HBV DNA, HBeAg, anti HBe and ALT should be monitored every 3-6 months.4

Entecavir and tenofovir is recommended for naïve CHB or chronic HBV infection with cirrhosis. Entecavir is contraindicated in patient with known entecavir resistance. Tenofovir is not recommended for CHB patients with renal dysfunction. Lamivudine is considered in naïve CHB patients with HBV DNA < 2 X108 IU/mL and ALT level > 2x ULN. Lamivudine can be continued if HBV DNA < 2 X103 IU/mL (in week 4) and HBV DNA < 2 X102 IU/mL (in week 24). This drug is contraindicated in patient with lamivudine, telbivudine or entecavir resistance.4

Adefovir is recommended in CHB with (1) low viral load and high serum ALT; (2) history of treatment failure with NA. However, adefovir is not recommended in patients with renal dysfunction and adefovir resistance. Telbivudine is recommended in naïve CHB patients with HBV DNA < 2 X108 IU/mL, HBeAg positive, ALT> 2 x ULN and continued if HBV DNA is undetectable in week-24. Patient who resistance of lamivudine, telbivudine or entecavir, is contraindicated to telbivudine.4

The optimal duration of NA therapy for patients with HBeAg-positive patients without liver cirrhosis is at least 1 year after HBeAg seroconversion with undetectable HBV DNA. For patients with HBeAg-negative patients without liver cirrhosis, treatment can be stopped after HBsAg loss. In cirrhotic HBeAg-positive patients, who achieved HBeAg seroconversion, and HBeAg negative, lifelong treatment is recommended.4

HBeAg, ALT and HBV DNA should be monitored every months in first three months after therapy stopped, following by every 3 months in a year. If relapse is not found, monitoring was performed every 3 months in cirrhosis and every 6 months in non-cirrhosis patients.4

Patients with primary treatment failure or partial virological response should be evaluated about compliance. For the compliant patient, drug resistance test should be performed. In patients who developed lamivudine or telbivudine resistance, switching to tenofovir or adding tenofovir is indicated. For patients who developed resistance while on adefovir (without prior lamivudine exposure), switching to tenofovir or entecavir is indicated.4

Management of Hepatitis B in Indonesia: From Guideline to Clinical Practice

145The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Switching to tenofovir monotherapy is recommended for patients who developed resistance while on adefovir with history of lamivudine resistance.For patients who developed entecavir resistance, adding tenofovir or switching to tenofovir is recommended. In cases with multidrug resistance, combination of entecavir and tenofovir is indicated.4

Pegylated Interferon

HBeAg positive and HBeAg negative is 48 weeks. Decompensated cirrhosis, psychiatric disorders, pregnancy and active autoimmune diseases are contraindicated. Baseline Guided Therapy (BGT) can help the physician to predict the outcome. If BGT score> 4 points, the patient is recommended for interferon-based therapy.4

Table 2. Baseline-Guided Therapy PegIFN in HBeAg positive.4

Parameter Score

Genotype Non-AA

02

Gender Laki-lakiPerempuan

01

ALT Ratio (x ULN) < 1,5 x ULN1,5 – 4,0 x ULN> 4,0 x ULN

012

HBsAg (IU/mL) > 20.000 IU/mL< 20.000 IU/mL

01

HBV DNA (log 10 IU/mL) > 10> 8-10< 8

012

Table 3. Baseline-Guided Therapy PegIFN in HBeAg negative.4

Parameter Score

Genotype Non-CC

02

Age > 45 tahun30 - 45 tahun< 30 tahun

012

ALT Ratio (x ULN) < 5 x ULN> 5 x ULN

01

HBsAg (IU/mL) > 3.500 IU/mL1.000 – 3.500 IU/mL< 1.000 IU/mL

012

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146 The 11th Liver Update and The Scientific Meeting of INA ASL/PPHI in Conjunction with The 7th CISHMS 2018

Response-Guided Therapy (RGT) in an effective strategy to predict the response of therapy, for both HBeAg positive and HBeAg negative. In HBeAg-positive, therapy is stopped if failure to achieve HBsAg< 20,000 IU/mL or HBV DNA reduction > 2 log (week 12), or HBsAg> 20,000 IU/mL (week 24). For HBeAg-negative, therapy is stopped if no decline in HBsAg or< 2 log decline in HBV DNA (week 12) or no decline in HBsAg (week 24).4

HCC surveillance should be performed by ultrasonography and AFP every six months in high-risk populations with chronic HBV infection. High-risk population include Asian male > 40 years old, Asian female > 50 years old, cirrhosis or had family history of advanced liver disease).4

References

1. World Health Organization. Global hepatitis report, 2017. France: World Health Organization. 2017.

2. Badan Penelitian dan Pengembangan Kesehatan Kementerian Kesehatan RI. Riset Kesehatan Dasar 2013. Jakarta: Kementerian Kesehatan RI; 2013.

3. Mulyanto, Depamede SN, Surayah K, Tsuda F, Ichiyama K, Takahashi M, et al. A nationwide molecular epidemiological study on hepatitis B virus in Indonesia: identification of two novel subgenotypes. Arch Virol. 2009;154:1047-59.

4. Perhimpunan Peneliti Hati Indonesia. Konsensus Nasional Penatalaksanaan Hepatitis B. Jakarta. 2017.

5. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98.