Introduction CHB Infection :

Prevalence, Natural history and liver function,

serology and virology marker in CHB Management

Faculty of Medicine
UNISSULA
Prevalence
 Prevalensi Hepatitis B di dunia
620.000 meninggal tiap
tahunnya
akibat penyakit hati yang
berhubungan dengan Hepatitis B3
75% HBK karier di Asia dan
2 milyar sudah Pasifik Barat4
Pada anak yang terinfeksi dan
pernah terinfeksi
2 menjadi kronis saat dewasa,
Hepatitis B 25%nya
meninggal karena kanker hati dan
350 juta HBK2
sirosis2

Populasi dunia 6 milyar1

McMahon BJ. Am J Gastroenterol 2006;101:S7-S11. 2. WHO Fact Sheet 2008.

Weinbaum CM, et al. CDC MMWR 2008;57(RR08);1-20. 4. Hou JL, et al. Int J Med Sci 2005;2:50-57
The HBV Iceberg 2 million individuals in the US
have chronic HBV infection
50,000 receive treatment
Clinical populations are 150,000 are diagnosed in
care and meet treatment

the tip of the iceberg 300,000 are guidelines

diagnosed in care
500,000 are potentially
Individuals in treatment eligible for treatment
600,000 are aware of their chronic HBV infection
are the tip of the tip
Population-based studies
1.4 million are unaware of
allow us to look at the their chronic HBV infection

whole iceberg
Asia has been the place
for these

Cohen C, et al. J Viral Hepatitis. 2011;18:377-383.

 Endemisitas HBsAg

Weinbaum CM, et al. CDC MMWR 2008;57(RR08);1-20

 Prevalensi HBsAg di Indonesia
Prevalensi bervariasi pada tiap
pulau; secara umum, di luar
P.Jawa lebih tinggi (9.2%)
dibandingkan P.Jawa (5%)

4.0 20.3 %

Carriers HBsAg Healthy population

Mulyanto, et al. Arch Virol 2009; 154(7):1047-59

 HBsAg Karier di antara Populasi Sehat di
Berbagai Pulau di Indonesia

Khan M, et al. Journal of Gastroenterology and Hepatology 2004;19:S419-S430

Data Riskesdas 2007
Dari 10 391 sampel darah yg diperiksa :
HbsAg (+) : 9.4 %
Umur : Tertinggi : 45-49 tahun (11.9%)
Terendah : 5-9 tahun (6.92%)
Anti Hbs (+) : 30.6 % dari 16.904 sampel darah
Anti Hbc (+) : 32.8 % dari 18.867 sampel darah

Sumber : Presentasi Sub Dit Diare dan

Hepatitis Kemenkes , WHD Semarang 2012
 Distribusi Genotip Virus Hepatitis B
Genotip Distribusi Geografik
A Eropa Utara, Afrika,
Amerika Serikat
B dan C Asia
D Eropa Selatan, Timur
Tengah
E Afrika
F dan H Amerika Tengah dan
Selatan
G Afrika
A, B, C, D Amerika Serikat
Di Cina dan Jepang, beberapa studi menemukan bahwa penyakit hati lebih berat pada genotip C
dibandingkan pada genotip B, namun studi lain tidak menemukan adanya hubungan

McMahon BJ. Seminars in Liver Disease 2004;24(Suppl1):17-21. Wright TL. Am J Gastroenterol 2006;101:S1-S6.
 Genotipe Hepatitis B di Indonesia

Mulyanto, et al. Arch Virol 2009; 154(7):1047-59

Genetic diversity of hepatitis B virus in Indonesia

The diversity of Hepatitis B in Indonesia could be

divided into 4 zones
(i) predominant zone consisting of Sumatra, Java, the
southern part of Kalimantan, Bali, Lombok, Ternate,
and Morotai;
(ii) zone of the eastern part of Nusa Tenggara and the
Moluccas,
(iii) zone of Irian Jaya; and
(iv) a mixed subtype-zone of Kalimantan, Sulawesi and
Sumbawa. M Khan et al , Journal of Gastroenterology
and Hepatology (2004) 19, S419?S430
Gambaran distribusi geografi HBV berdasar genotipe/subgenotipe dan sub
tipe di Indonesia

Mulyanto, Arch Virol 2009

DOI 10.1007/s00705-009-0406-9
 14 subgenotypes
within genotypes A: two (A1 and A2) in genotype A
(HBV/A)
five (B2, B3, B5, B7, and a novel subgenotype,
tentatively designated B8) in HBV/B
five (C1, C2, C5, C6, and another novel subgenotype, C7)
in HBV/C and
Two (D1 and D3) in HBV/D.
The distribution of HBV genotypes/subgenotypes, including
B8 and C7, seems to be associated with ethnological
origins in Indonesia
 Mengapa tes genotipe virus hepatitis B ?

Differences in natural history and treatment responsiveness

B is associated with less active disease, slower progression, and
lower incidence of HCC than C
C has higher risk of HCC and cirrhosis
A and B respond better to IFN than C and D
F is associated with fulminant liver disease; rare

Current guidelines indicate that additional data are needed

before testing for genotypes in clinical practice is
recommended

Lok AS, et al. Hepatology. 2009;50:661-662. EASL. J Hepatol. 2009;50:227-242.

 Gejala Hepatitis B
Asimtomatik
Mayoritas HBK tetap asimtomatis sampai onset sirosis atau gagal
hati

Manifestasi klinis keadaan akut:

kelelahan,
tidak nafsu makan,
mual, muntah,
nyeri pada abdomen,
demam,
ikterik,
urin berwarna gelap,
feses berwarna putih, dll
Weinbaum CM, et al. CDC MMWR 2008;57(RR08);1-20
 Transmisi Hepatitis B
Virus Hepatitis B virus ditransmisikan antara manusia yaitu
kontak dengan darah atau cairan tubuh (contoh: semen
dan cairan vagina) dari penderita
Transmisi Hepatitis B:
Vertikal :
perinatal (dari ibu ke bayi saat melahirkan)

Horizontal:
Penggunaan jarum suntik

yang tidak steril

Transfusi darah
Hubungan seksual

Hepatitis B dapat dicegah dengan vaksin

WHO Fact Sheet 2008
Konsentrasi virus hepatitis B pada berbagai
cairan tubuh

Low/Not
High Moderate Detectable

blood semen urine

serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
Natural History
Natural history of HBV

Slide 7
 Hepatitis B
Hepatitis B Akut

Perinatal Anak - anak Dewasa

10% 90% 20% - 50% 50% - 80% 95% 5%

Sembuh Infeksi Kronis Sembuh Infeksi Kronis

25% sirosis &HCC 15% sirosis &HCC

1. Elgouhari HM, et al. Cleveland Clinic Journal of Medicine 2008. 2. Weinbaum CM, et al. CDC MMWR 2008;57(RR08);1-20
The phases of chronic hepatitis B

Immune Immune Immune Immune

tolerance clearance control escape

HBeAg+ve HBeAgve
< >< >
HBV-DNA

ALT

HBeAg +ve Inactive (carrier) HBeAg ve active

chronic hepatitis state* chronic hepatitis

*Previously considered to be healthy Slide 8

HBV Control

Inflammatory: normalize serum ALT, biopsy

Virologic: decrease HBV DNA
Immune: seroconversion
o HBeAg to HBeAb
o HBsAg to HBsAb

HBV never cured but controlled

Slide 9
 Risk Factors for Progression to Cirrhosis or HCC
in HBsAg-Positive Individuals

Host Viral
Older age (> 40 yrs) HBeAg positive
Male sex Higher HBV DNA
Asian/African ancestry Genotype B, C
HCC family history Precore mutation
Clinical Basal core promoter
mutation
Cirrhosis
HCV coinfection
Other
Smoking, alcohol
Obesity, diabetes
McClune AC, et al. Clin Liver Dis. 2010;14:461-476.
Liver function ALT

Virologic marker HbV DNA

 Pts With Chronic HBV Infection and Normal ALT May
Have Significant Liver Disease

Retrospective review of pts with chronic HBV infection

Persistently normal ALT
ALT 1.0-1.5 x ULN
ALT > 1.5 x ULN
37% of pts with chronic HBV infection and persistently
normal ALT had evidence of significant fibrosis (stage 2-4)
or inflammation (grade 2-3) by liver biopsy

Lai M, et al. J Hepatol. 2007;47:760-767.

 Normal Serum AST and ALT and Risk
of Death From Liver Disease

Prospective, cohort study RR of Death Men Women

From Liver
Cause of death based on Disease
death certificates AST, IU/L
94,533 males and 47,522 < 20 1.0 1.0
females aged 35-59 yrs with
20-29 2.5 3.3
8-yr follow-up
30-39 8.0 18.2
Results ALT, IU/L
690 deaths from liver disease < 20 1.0 1.0
ALT or AST 20 IU/L 20-29 2.9 3.8
significantly associated with 30-39 9.5 6.6
increased risk for death from
liver disease in men
Kim HC, et al. BMJ. 2004;328:983.
 Adverse Liver Outcomes (Cirrhosis and HCC) in
Chronic HBV Infection

Long-term follow-up (median: 29 mos) of 3233 patients from Hong Kong

with chronic HBV infection
Cirrhosis-assoc complications: ascites, SBP, variceal bleeding, PSE, HCC
*P < .0001 vs ALT < 0.5 x ULN.
40 P < .05 vs ALT < 0.5 x ULN.
Risk of Complications (%)

ALT > 1 to 2 x ULN*
ALT > 2 to 6 x ULN*
ALT 0.5-1.0 x ULN*
30
ALT > 6 x ULN
ALT < 0.5 x ULN
20

10

0
0 30 60 90 120 150 180
Follow-up (Mos)
Reproduced from Yuen MF, et al. Gut. 2005;54:1610-1614 2005 with permission from BMJ Publishing Group Ltd.
 Serum HBV DNA Level and Risk of HCC
(REVEAL Study)

Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis
and HCC among untreated HBsAg+ individuals in Taiwan
Multivariable-Adjusted HR

12
All participants (N = 3653) 10.6
10 HBeAg negative (n = 3088)

8
6.6 6.1
6.1
6

4
2.3 2.6
2 1 1 1.1 1
0
< 300 300-9999 10,000- 100,000- 1 million
99,999 999,999
HBV DNA (copies/mL)
Chen CJ, et al. JAMA. 2006;295:65-73.
 Petanda Biokimia
Serum ALT biasa digunakan untuk menilai penyakit hati
Merupakan kriteria yang penting untuk menentukan
kandidat terapi
ALT sendiri tidak dapat digunakan untuk mengidentifikasi
pasien dengan aktivitas nekroinflamasi atau fibrosis

eefe EB, et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341

 Parameters Used to Determine Candidates for
Treatment of HBV

ALT
New normal or healthy ALT: < 30 U/L for men and
< 19 U/L for women[1]
Presence of 1 normal value does not exclude significant disease or
subsequent complications

HBV DNA
Predicts development of cirrhosis and HCC[2,3]
Interpret in conjunction with ALT and/or histology
Liver biopsy
Useful in situations where ALT or HBV DNA do not provide clear
guidelines for treatment[1]
1. Lok AS et al. Hepatology. 2009;50:661-662. 2. Iloeje UH et al. Gastroenterology. 2006;130:678-686.
3. Chen CJ et al. JAMA. 2006;295:65-73.
Virology and serology
Hepatitis B Virion, Dane particle and HBsAG

From Murray et. al., Medical Microbiology

5th edition, 2005, Chapter 66, published by
Mosby Philadelphia,,
Key Features of Hepatitis B Virus

Virus has a strict tissue tropism to the liver

Virus infected cells produce and release large

amounts of HBsAg particles lacking DNA

Viral DNA can integrate into the host chromosome

The growth cycle
of Hepatitis B
virus

From Murray et. al., Medical Microbiology 5th edition,

2005, Chapter 66, published by Mosby Philadelphia,,
 Petanda untuk Hepatitis B Kronik
Petanda Serologi: HBsAg1,
Anti-HBs1,
Anti-HBc2,
HBeAg1,
Anti-Hbe1
Petanda Virologi: HBV DNA1
Petanda Biokimia: ALT/SGPT1
Petanda Histologi: biopsi1

1. Keefe EM, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962;

2. Keefe EM, et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341
 Petanda Serologi
HBsAg:
Merupakan petanda pertama yang muncul setelah
infeksi1
Menetap > 6 bulan infeksi kronik1,2
Digunakan untuk diagnosis infeksi hepatitis B dan
skrining3
Anti-HBs menunjukkan kekebalan dan/atau sembuh1

1. Keefe EB, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962;

2. Keefe EB, et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341.
3. Available at: www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index3.html. Accessed: April 3rd, 2012
 Petanda Serologi
Anti-HBs1,2:
Timbul 1 4 bulan setelah infeksi menunjukkan kesembuhan dan
imunitas.

Anti-HBc2,3:
Digunakan bersama dengan pemeriksaan HBsAg dan anti-HBs
untuk menentukan infeksi akut, kronik, pernah terinfeksi, atau
pernah vaksinasi.

IgM anti-HBc (+) menunjukkan infeksi akut

IgG anti-HBc (+) tanpa IgM timbul pada keadaan infeksi kronik dan
sembuh
. Keefe EB, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962;
. Available at: www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index3.html. Accessed: April 3rd, 2012
. Keefe EB, et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341.
 Petanda Serologi
HBeAg:
Mengindikasikan adanya replikasi virus

Tidak terdeteksi pada hepatitis B kronik dengan HBeAg-

negatif/precore/core promoter mutant (sudah terjadi mutasi)

Serokonversi (hilangnya HBeAg diikuti dengan timbulnya anti-Hbe)

merupakan end-point therapy pada penderita dengan HBeAg (+)

Anti-Hbe:
Serokonversi atau HBeAg-negatif

eefe EB, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962

Quantitative HBsAg in Patients Receiving PegIFN

Levels of serum HBsAg crudely reflect levels of hepatic cccDNA[1]

Several studies indicate serum HBsAg levels indicative of likelihood of
response to pegIFN therapy[2-5]
In HBeAg-negative patients, early serum HBsAg loss found to predict SVR
(undetectable HBV DNA 24 wks after treatment)
> 0.5 log10 IU/mL decrease at Wk 12 and > 1.0 log10 IU/mL decrease at
Wk 24[4]

In HBeAg-positive patients, nonresponse (defined as failure to achieve

HBeAg loss with HBV DNA < 10,000 copies/mL at Wk 26 posttreatment)
observed in 97% of patients who failed to achieve any decline in HBsAg at
Wk 12[5]
May help clinicians define stopping rules for pegIFN once
commercially available in the near future
1. Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758. 2. Gish RG, et al. Am J
Gastroenterol. 2007;102:2718-2723. 3. Manesis EK, et al. Antivir Ther. 2007;12:73-82. 4. Moucari R, et
al. Hepatology. 2009;49:1151-1157. 5. Sonneveld MJ, et al. Hepatology. 2010;52:1251-1257.
Quantitative HBsAg and HBV DNA Predict SVR in HBeAg-Negative CHB on
PegIFN

102 patients on PegIFN RBV x 48 wks

HBsAg decline No Yes

at Wk 12 (n = 54; 53%) (n = 48; 47%)

HBV DNA decline < 2 logs 2 logs < 2 logs 2 logs

at Wk 12 (n = 20; 20%) (n = 34; 33%) (n = 20; 20%) (n = 28; 27%)

Chance of
sustained response
(HBV DNA < 4 logs 0% 24% 25% 39%
at Wk 72)
Stopping Rule
Rijckborst V, et al. Hepatology. 2010;52:454-461.
 Hasil Interpretasi Petanda Serologi

HBsAg Total IgM Anti-HBs Interpretasi

Anti-HBc Anti-HBc
Negatif Negatif -- Negatif Rentan
Negatif Positif -- Positif Imun karena infeksi alami
Negatif Negatif -- Positif Imun karena vaksinasi
Positif Positif Negatif Negatif Infeksi kronik hepatitis B
Positif Positif Positif Negatif Infeksi akut hepatitis B
Negatif Positif -- Negatif Tidak jelas; dapat berarti:
1. Infeksi yang sudah sembuh (paling
sering)
2. False-positive anti-HBc; rentan
3. Low-level infeksi kronik
4. Infeksi akut yang sembuh

Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm. Accessed March 21st, 2012

 Hubungan Petanda Serologi pada Stage yang
Berbeda pada Infeksi Hepatitis B

Stage HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe

IgG IgM
Hepatitis B akut + - + + + -
atau persisten
karier
HBsAg karier + - +++ +/- - +
Hepatitis B + - +++ +/- + -
kronik, persisten
karier
Masa - ++ ++ +/- - +
konvalesens
Recovery - +/- +/- - - -
Vaksinasi baru - ++ - - - -

Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm. Accessed March 21st, 2012

 Petanda Virologi
Tes HBV DNA dalam serum digunakan sebagai ukuran
replikasi virus
Peningkatan kadar HBV DNA selama terapi antiviral
berhubungan dengan resistensi virus

eefe EB, et al. Clinical Gastroenterology and Hepatology 2004;2:87-106

 Petanda Histologi
Biopsi hati
Indikator penyakit hati yang lebih sensitif dan akurat
dibandingkan dengan ALT1
Keterbatasan:2
Invasif
Sampling error
(kesalahan sampel)
Komplikasi

. Keefe EM, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962;

. Carey E, Carey WD. Cleveland Clinic Journal of Medicine 2010;77:519-527.
 Diagnosis HBK
4 stadium hepatitis B kronik:
Toleransi imun (Immune Tolerance)
Bersihan imun (Immune Clearance)
Stadium inaktif
Reaktivasi

won H, Lok ASF, et al. Nat Rev Gastroenterol Hepatol 2011;8:275-284

 Who should be considered for
treatment?
Immune Immune Immune Immune
tolerance clearance control escape

HBeAg+ve HBeAgve
< >< >
HBV-DNA

ALT

treat treat
HBeAg +ve Inactive (carrier) HBeAg ve/+ve active
chronic hepatitis state chronic hepatitis

Slide 11
Overview of Algorithm Used to Determine
Need for Treatment of HBV

HBeAg Positive HBeAg Negative

HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL

ALT Level

Elevated ALT Normal ALT

Monitor ALT Consider Liver

Q3mos for 1y Biopsy If >40yrs

Significant fibrosis or
Treat
inflammation

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008

Lok AS et al Hepatology,Slide
200912
Therapeutic endpoints over time
Improved Improved
histology Anti-HBs+ survival

Anti-HBe+ Loss of
HBsAg
Loss of
HBeAg
Loss of
HBV DNA

TIME
 Terapi Hepatitis B Kronik
Peginterferon alfa-2a

Entecavir
Lamivudine Tenofovir

1992 1998 2002 2005 2006 2008

Interferon alfa-2b Adefovir Telbivudine

Pilihan terapi di Indonesia:

1. IFN 2. Antiviral NA
1. Peg alfa 2b 1. Lamivudine
2. Peg alfa 2a 2. Adefovir
3. IFN alfa 2b 3. Entecavir
4. Telbivudine

Note: tahun berdasarkan approval oleh fda

. Lin KW, et al. Am Fam Physician 2004;69:75-82. 2. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

. MIMS.com
Take Home Messages
Indonesia termasuk dalam negara dengan endemisitas
tinggi
Gejala yang asimtomatis menyebabkan infeksi hepatitis B
seperti gunung es
Petanda serologi, virologi, biokimia, dan histologi penting
untuk menentukan diagnosis hepatitis B kronik
Tujuan terapi adalah supresi HBV DNA, serokonversi
HBeAg, normalisasi ALT, dan mencegah progresivitas
menjadi sirosis hepatik dan kanker hati
TERIMA KASIH

THANK YOU
STUDI KASUS
 Terapi Hepatitis B Kronik
Peginterferon alfa-2a

Entecavir
Lamivudine Tenofovir

1992 1998 2002 2005 2006 2008

Interferon alfa-2b Adefovir Telbivudine

Pilihan terapi di Indonesia:

1. IFN 2. Antiviral NA
1. Peg alfa 2b 1. Lamivudine
2. Peg alfa 2a 2. Adefovir
3. IFN alfa 2b 3. Entecavir
4. Telbivudine

Note: tahun berdasarkan approval oleh fda

. Lin KW, et al. Am Fam Physician 2004;69:75-82. 2. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

. MIMS.com
 Terapi Hepatitis B Kronik
Tujuan:
Supresi HBV DNA tidak terdeteksi
Serokonversi HBeAg
Normalisasi ALT/SGPT
Mencegah sirosis hepatis dan kanker hati

aw YF, et al. Hepatol Int 2008;2:263-283

Risk of HCC and Cirrhosis According
to Baseline HBV DNA

HBV DNA (copies/mL) HBV DNA (copies/mL)

1.4 3.0
< 300 < 300
1.2 300-9999 300-9999
2.5
10,000-99,999 10,000-99,999

Cirrhosis (% per Yr)[2]

1.0 100,000-999,999 100,000-999,999
HCC (% per Yr)[1]

1 million 2.0 1 million

0.8
1.5
0.6
1.0
0.4

0.2 0.5

0 0

1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.