Hepatitis Virus

Beban Penyakit, Tantangan, dan Kesempatan

David H. Muljono

Komli Hepatitis Virus

Kemenkes RI
 Viral hepatitis as a global problem
 Epidemiology
 Actions and achievements
 Challenges
 Opportunities
 Viral Hepatitis

The group of viruses (hepatitis A, B, C, D and

E) that gives a major public health problem
globally

Hepatitis B and C viruses are

major causes of severe
Hepatitis D virus illnesses, with 1.4 million deaths
each year:
• 800 000 are due to hepatitis B
• 500 000 due to hepatitis C

WHO Fact Sheet 2015

Hepatitis E virus

Hepatitis E virus
 Liver Cancer:
 is the 2nd leading cause of
cancer death worldwide
(after lung cancer)
 80% are attributable to
chronic hepatitis B or C virus
infections.
Global Burden of Disease 2015.
Lancet 386 (9995) p743–800, 22 August 2015
Estimated annual deaths from selected causes by region, 2010

Lozano et al. Lancet. Vol 380. 2012

Courtesy of IHME – Global Burden of Disease Study
WHO 2012 program budgets per disease specific deaths

Lozano et al. Lancet. Vol 380. 2012

Courtesy of WHO (Dr. Stefan Wiktor) and IHME – Global Burden of Disease Study
 Dimension of Disease Burden

Social effect Economic effect

Loss of work and

Death, Premature loss of life

productivity
HCC,
Transplant

Decompensated Repeated hospitalization,

Cirrhosis high treatment cost
Reduced quality of life

Compensated Frequent out-patient

Cirrhosis visits, treatment cost

Chronic Hepatitis Out-patient visits,

treatment cost

Out-patient visits,
Acute hepatitis
treatment cost
 Average Annual Cost of HBV-related Liver Disease
in the Asia-Pacific Countries (US dollars)

.0 Chronic Compensated Decompensated HCC Liver

HBV Cirrhosis Cirrhosis Transplant
China* 142.24 185.11 1701.58 4740.53 NA
Hong Kong* 810 1321 7490 15 618.00 65 961.00
Singapore* 410.37 671 8794.19 7036.59 49 353.87
Taiwan* 1040.9 1606.18 1559.84 1689.37 2779.47
South Korea* 247.82 679.3 1419.37 3044.34 67 155.84
Vietnam** 450.35 1883.05
*In 2000-2002; **In 2008.

Adapted from: Lesmana et al (2006); Liver International 26: 3-10;

Tu et al (2012)., Value in health regional issues (2012) 1: 23-28
 Viral hepatitis as a global problem
 Epidemiology
 Actions and achievements
 Challenges
 Opportunities
 Hepatitis B

2 billion (~33% of world population)

have been infected

• One of the most neglected global pandemics

• >240 million are chronically infected, with a 15-
25% risk of premature mortality from cirrhosis and
liver cancer
• 75% live in the Asia-Pacific region,

* CHB: chronic hepatitis B

World Health Organization. Fact Sheet #204. 2015
HBV: hepatitis B virus
 Compensated
Resolution Stabilisation cirrhosis

Acute Chronic
infection hepatitis Cirrhosis Liver cancer Death

Chronic Carrier Progression Decompensated

Cirrhosis
(Death)
30–50 years
 Hepatitis B in Indonesia (before 2000):
Island Area N HBsAg (%) Year

Sumatra Padang 200 19.5 1981

HBsAg carrier rate among apparently healthy populations

Java Jakarta 1430 4,8 1990
Jakarta 243 5.8 1991
Jakarta 985 4 1997

from several islands in Indonesia#

Bali Singaraja 1886 5 1993

Lombok Sokong 822 13.7 1985

Mataram 827 7.3 1987
Mataram 435 8.5 1983
Gili Air 479 10.9 1983
Bayan 138 20.3 1987
Gili Gede 859 13.4 1990

Sumbawa Sumbawa Besar 525 11.7 1983

Bima 468 11.3 1989

Flores Bajawa 751 9.7 1997

Waingapu 554 9.2 1991

Sulawesi Makassar 196 7.1 1991

West Timor Kupang 407 4 1996

Papua Jayapura 1467 4 1990

Highlanders 925 10,5 1997 # J Gastroenterol hepatol
19:S419-S430, 2004
 Hepatitis B in Indonesia
(Basic Health Survey 2007 - west and middle region)

HBsAg Distribution of HBsAg (+) According to Age Group #

16
%
14

12

10

0
5–9

10 – 14

25 – 29

30 – 34

35 – 39

50 – 54

55 – 59

> 60
1–4

15 – 19

20 – 24

40 – 44

45 – 49
Age group HBsAg (+)

 HBsAg (+): 9.4% (N = 10,391); Male: Female = 9,68 : 9,28

 HBsAg in 1-4 years group: 7,32%
# Provisional data
 Prevalence of HBsAg in Indonesia: 3-9.4% ##

BANGKA
RIAU JAMBI BELITUNG E. KALIMANTAN GORONTALO N. SULAWESI
2.4% 8.3% 4.4% 6.4% 13.0% C. SULAWESI
NAD
12.8%

N. SUMATRA MOLUCCAS
11.7%

W. IRIAN JAYA
W. SUMATRA
15.1%

BENGKULU PAPUA
19.3%

S. SUMATRA S.E. SULAWESI

9.7%

LAMPUNG
17.0%

JAKARTA W. JAVA C. JAVA JOGJA E. JAVA BALI W. NUSA S KALIMANTAN S. SULAWESI

5.9% 5.6% TENGGARA
8.2% 6.7% 2.5% 10.1% 6.6% 13.4%
5.5%
# Provisional data
 Hepatitis B in Indonesia
(Basic Health Survey 2007)

Anti-HBc Distribution of Anti-HBc (+) According to Age Group #

% 80

70

60

50

40

30

20

10

0
1–4

5–9

30 – 34
10 – 14

15 – 19

20 – 24

25 – 29

35 – 39

40 – 44

45 – 49

50 – 54

55 – 59

> 60
Age group Anti-HBc (+)

• Anti-HBc (+): 32,8 % (N = 18.867)

• Increasing frequency by age group  Role of horizontal transmission

# Provisional data
 Hepatitis B in Indonesia
(Basic Health Survey 2007)

Anti-HBs
Distribution of Anti-HBs (+) according to Age Group

% 60

50

40

30

20

10

0
10 – 14

15 – 19

20 – 24

25 – 29

30 – 34

35 – 39

40 – 44

45 – 49

50 – 54

55 – 59
1 – 4

5 – 9

Age Group Anti-HBs (+)

 Anti-HBs (+): 30,6 % (N = 16.904)

# Provisional data
 Course of HBV is Determined by the Acquisition Time

80% Inapparent disease

90-99% Recovery
Childhood and Adult
20% Acute Hepatitis
1-12% become chronic
1% Fulminant Hepatitis
1-12% Per year Very low risk

HBV Infection Cirrhosis HCC

1-12% Per year 0.5% Per Year

Neonatal Inapparent Disease 95% become Chronic

 Single-shelled RNA Virus of Flaviviridae family
 RNA-dependent RNA polymerase, lacks proofreading
function  prone to mutation
 Situation in Indonesia

General population Anti-HCV (+) : 2.08% National Basic Health Survey 2007 (N =
27,536)

Blood donors Anti-HCV (+) : 0.40% Indonesia Red Cross (2012 ) (N = 9029)

Patients in public Anti-HCV (+) : 4.63% Study on patients in 128 public hospitals
hospitals** /health centers (2007-2012) (N = 6282)**

**Sample Collection Units: 128 Public

hospitals & health centers (N = 128)
 Situation in Indonesia

The genotype distribution (G1: 68%, G2: 9%, G3: 9%, G4: 4%, G other: 10%)
Strategies to manage hepatitis C virus infection disease burden – volume 3
Journal of Viral Hepatitis, 2015, 22 (Suppl. 4), 42–65
 Viral hepatitis as a global problem
 Epidemiology
 Actions and achievements
 Challenges
 Opportunities
Global:

 1975: WHA28.72 - Urged all countries to fully implement

organized, nationally coordinated blood programmes with
appropriate regulatory systems

 1992: WHA45.17 - Urged Member States to include hepatitis B

vaccines in national immunization programmes

 2005: WHA58.22 - Cancer control and prevention including

hepatitis B vaccination
Integration of
Hepatitis and
HIV Programme
 Already in Inplace
Indonesia
In Indonesia
Since 1992: Since 1997:
Screening of Inclusion of
Blood Donors to Hepatitis B
prevent HBV and Immunization to
HCV Infections by all babies < 1
the Indonesian year as a
Red Cross (PMI) National Program

Development of Guidelines for Public 2012: Official designation of Hepatitis

Health Service Control Program in CDC (Within the
Ministry of Health)

2014: Annual (small) budget for Hepatitis

Control Program

2015: Ministerial Regulation (Permenkes)

53/2015
 HB Vaccination in Indonesia

WHO Pilot Project in Lombok Island. Indonesia was selected as the first
model of HB vaccination integrated to EPI

Expanded to 4 Provinces: NTB, Bali,

Jogja & East Java

Added: 3 provinces (Papua, NTT & East Timor)

Added: 6 Provinces (Central Java, West

Java, DKI, Lampung, West Sumatra &
West Borneo)

National Program

1987 1991-1992 1992-1993 1996-1997 1997 2000

Birth dose vaccination started

Hepatitis B immunization in Indonesia (2000-2012)
(HB3 completed)
110
100

100,9
90

94,9

94,9
94,6

93,5
91,6
91,1
90,8
90,6

90,6

90,6
89,6
WHO Target
80

83,1
70
60
50
40
30
20
10
0
2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012
DPT/HB3 combination

Hepatitis immunization program in Indonesia:

• In 1996 vaccination was targeted to all babies < 1 year, and in 1999
to all newly born babies within 24 hours of life
100 Coverage of Birth-dose Hepatitis B immunization in Indonesia (2000-2012*)

90

85,6
WHO Target
80

80,5
75,6
70

68,4
60

60,3
54,2
50

42,8
40 41,2
40

30
31,4

20

10
11,5
1,8

0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
 Viral hepatitis as a global problem
 Dimension of Disease Burden
 Actions and achievement
 Challenges
 Opportunities
 1)
WHO Target

many provinces
Low coverage in
0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
80,0
90,0
100,0
ACEH 77,5
SUMATERA UTARA 76,7
SUMATERA BARAT 72,7
RIAU 67,1
JAMBI 102,4
SUMATERA SELATAN 88,6
BENGKULU 65,7
LAMPUNG 79,4
DKI JAKARTA 74,9
JAWA BARAT 99,9
JAWA TENGAH 97,4
DI YOGYAKARTA 101,2
JAWA TIMUR 98,2
KALIMANTAN BARAT 58,8
KALIMANTAN TENGAH 60,3
WHY?

KALIMANTAN SELATAN 62,6

KALIMANTAN TIMUR 64,6
SULAWESI UTARA 76,6
SULAWESI TENGAH 57,0
SULAWESI SELATAN 87,7
SULAWESI TENGGARA 46,1
BALI 95,0
under-five children

NUSA TENGGARA BARAT 98,2

NUSA TENGGARA TIMUR 60,9
MALUKU 56,1
PAPUA 43,3
BANTEN 89,9
MALUKU UTARA 66,1
New cases continue to occur in

GORONTALO 76,8
BANGKA BELITUNG 92,7
Coverage of Birth-dose Hepatitis B immunization in Indonesia 2012 (By Province)

PAPUA BARAT 38,1

KEPULAUAN RIAU 79,9
SULAWESI BARAT 64,3
INDONESIA 85,6
 New cases continue to occur in
under-five children

WHY?

Prevalence of HBsAg (+) in several cities in Indonesia

Jakarta 1985 4%
Possibility:
2) Mother-to-baby Surabaya 1989 4,6%
transmission? Denpasar 1981 2,46%
Mataram 1993 3,4%
Bali 1996 5%
Jakarta 2009 2,2%
Makassar 2013 5.3%
Jakarta 2013 3.5%
 Hepatitis B in Pregnant Women (Jakarta, 2013)
(N = 5000)

HBsAg : 140 (3.18 %)

Anti-HBc : 842 (19.47 %)
Anti-HBs : 857 (19.47 %)

HBV DNA (+) = 98 Infectious

<4 log IU/mL 56 (57.1%)
4-7 log IU/mL 16 (16.3%)
>7 log IU/mL* 26 (26.5%)

*Viral load that passes to newborns

Courtesy of Directorate of Direct Communicable Disease Control (P2ML), Ministry of Health

 June - August 2014:
• Screening of 943 pregnant women (2014) in
Makassar revealed: 64 (6,8%) were HBsAg
positive

HBV DNA Detection

Sample HBV DNA Positive (n%)
Mother’s sera 18/64 (29,68%)
Cord blood 7/64 (10,93%)
Placenta 13/60(21,67%)
Amnion Fluid 4/40 (10%)

Courtesy of DR. Masita Fujiko,SPOG

 Viral hepatitis as a global problem
 Epidemiology
 Actions and achievements
 Challenges
 Opportunities
 Viral Hepatitis Global Challenges

Lack of
awareness Lack of data

inexplicable Problems in
global response diagnosis and
treatment

Lack of Costly and

Capacity at Complex
Country Treatment
 Viral hepatitis as a global problem
 Epidemiology
 Actions and achievements
 Challenges
 Opportunities
Hepatitis is now a target of the world

 MDG = Millennium  Hepatitis was not mentioned

Development Goal
(2001-2015)

 SDG - Sustainable
 Target 3.3:
Development Goal
(2016-2030)
By 2030, end the epidemics of
AIDS, tuberculosis, malaria
and neglected tropical
diseases and combat hepatitis,
waterborne diseases and other
communicable diseases
Hepatitis B vaccination coverage is one of the 25 indicators
in the WHO Global Action Plan for the prevention and
control of non-communicable diseases 2013–2020
Political commitment:

 Indonesia:
 2010: Official designation of Hepatitis Control Program in
Directorate General of Disease Control and Environmental
Health, Ministry of Health
 Public Health Guidelines on Viral Hepatitis

 Ministerial Regulation (Permenkes) 53/2015

 Installment of Subdit Hepatitis & ISP

 Carry out surveillance and serological surveys of
hepatitis virus
 Coordinate and work together in formal and non-
formal activities:
 Government and non-government
 Involve: Professional association, Media, and civil society
 Join and celebrate activities to increase and
maintain awareness: World Hepatitis Day - 28 July
 Do research and publish
Treatment progress for hepatitis B

Immunomodulatory agent Antiviral agent

Peg-IFN -2a Lamivudin

Peg-IFN -2b Adevovir
Entecavir
Telbivudine
Tenovofir
 Evolution of Hepatitis C Therapies:
SVR rates for HCV infections (genotypes 1–3)
DAAs
according to the treatment regimen and duration
2011

PegIFN
SVR (%)

2001 67-75%
80 RBV
70 54-56%
Standard IFN 1998
60
42% 39%
50 1991 34%
40
30 16%
20 6%
10
0

Treatment regimen and duration

IFN Monotherapy

Strader &Seeff, Clinical Liver Disease 2012; 1:6-11

 Evolution of Hepatitis C Therapies:
SVR rates for HCV infections (genotypes 1–3) DAAs
according to the treatment regimen and duration 2011

PegIFN
SVR (%)

2001 67-75%
RBV
80
70 Standard IFN 1998 54-56%
60
1991 42% 39%
50 34%
40
30 16%
20 6%
10
0

Treatment regimen and duration

IFN Monotherapy

Strader &Seeff, Clinical Liver Disease 2012; 1:6-11

 HCV Therapy
Recent Near future

x
IFN
HEPATITIS C MEDICINES:
Direct Acting Antivirals
All steps can be the targets of antiviral

• Nucleoside/nucleotide
• Non-nucleoside
• Nucleoside/nucleotide
• Non-nucleoside
 … asvir

… buvir

…
previr
• Nucleoside/nucleotide
• Non-nucleoside
HCV DRUGS IN DEVELOPMENT
MiR-122 antagonist
Miravirsen (Micro-RNA
antagonist) Inhibiting Virus
entry binds to 2 sites in the
5’-UTR (potent activity –
injectable)
Entry inhibitor
Inhibiting Virus entry:
Interaction with receptors
via immunoglobulins or
specific HCV antibodies
NS3 Protease
Targets the catalytic cite of the enzyme
and block post-transcriptional processing
of viral protein
Have low barrier resistance
Target host’s protein that
regulates binding of NS5A and
Cyclophilin RdRp
Have ‘pan-genomic’ coverage,
and ‘high barrier to resistance
NS5B Non-Nucleosides
Alter the three-dimensional
structure of RdRp of Genotype 1
Block the functions of NS5A and
disturb virus replication
Have ‘low barrier to resistance
… asvir
NS5A Nucleosides
Block the functions of NS5A and
disturb new replication complex
Have ‘pan-genomic’ coverage,
but ‘low barrier to resistance
… previr
NS5B Nucleosides … buvir
Act as false substrates for RdRp 
chain termination of new RNA
Have high barrier to resistance
 NS5B Inhibitor WHO Registration: 25 Mei 2015
Cyclophilin
Inhibitor

NS3/NS4
Non- Inhibitor
Nucleoside
NS5B
inhibitor

NS5A Inhibitor

Nucleoside
NS5B
inhibitor
• Sophisticated molecular laboratory tests (viral
load measurement, genotyping.etc)
• Complicated treatment procedure
• High cost

Costly and
Complex
Treatment
Pengobatan hepatitis dengan DAA:

• dilakukan oleh dokter Ahli Penyakit Hati/Penyakit Dalam di

Pusat Pusat

• dilakukan oleh dokter Ahli Penyakit Hati/Penyakit Dalam di

Provinsi Daerah

• Dilakukan oleh dokter Ahli Penyakit Hati/Penyakit Dalam di

Kabupaten Daerah
Terima kasih