Hepatitis C

Unggul Budihusodo
Departemen Ilmu Penyakit Dalam
FKUI – RSCM
WORLD HEPATITIS DAY
28 JULY
 Hepatitis C
 Radang (inflamasi) hati akibat
infeksi virus hepatitis C (HCV)

 Ditularkan melalui darah dan/atau

cairan tubuh yang terinfeksi
(transfusi darah, hubungan seks,
tato, tindik dan injeksi)

 80-90% kasus menunjukkan gejala

dan tanda yang minimal, kecuali bila
komplikasi telah terjadi (pada tahap
lanjut)  “silent killer”
Infeksi HCV: Masalah Global !
( Di Dunia: 170 juta orang terinfeksi HCV )

Di AS: Di Indonesia:
± 4 juta orang ± 4 juta orang

WHO Wkly Epidemiol Rec 2000;75:18-19.

 PREVALENCE OF HCV INFECTION
Prevalence in Prevalence in
general dialysis referenc
Country population population* e (year)

Netherlands 0.1% 3% 1998

Italy 0.5% 22.5% 1999
Belgium 0.9% 9.4% 1998
Bulgaria 1.1% 65.8% 1998
France 1.1% 16.3% 2000
Turkey 1.5% 31.4% 1998
USA 1.8% 10% 2003
Saudi
Arabia 1.8% 57% 2001
Moldavia 4.9% 75% 1999
Egypt 18.1% 80% 2000
Fabrizi F et al. Hepatology 2002
*Infection of dialysis patients via nosocomial transmission
 Infeksi HCV: Masalah Global

Distribusi Geografis Genotipe HCV:

1a, 1b
2a, 2b, 2c,
1a, 1b 3a 2a 1b
2a, 2b, 4 1b,
3a 1b,
6
4 3a
3b
1a, 1b,
2b, 3a
5a 1b,
Indonesia: 3a
1a+1b: 60 – 65%
2a: 17 – 26%

Fang JWS et al. Clin Liver Dis. 1997;1:493-514.

Penyakit sistemik bukan hanya hati yang menanggung!
 INFEKSI HCV GLOBAL:
Fenomena Gunung Es!

Didiagnosis menderita
Hepatitis C

< 10% Diobati

simtomatik

 170 juta orang telah terinfeksi

> 90% (di Indonesia 4 juta)
asimtomatik  315.000 kasus baru/tahun
 4,1% dari seluruh kasus
Tidak karsinoma
terdiagnosis  312.000 meninggal/tahun
8
(Sulaiman A, Selayang pandang Hepatitis C, 2004)
 Hepatitis C Kronik:
Besaran Masalah di Indonesia
 1-2%1,2 (sekitar 3,4 juta) populasi Indonesia
terinfeksi kronis oleh virus hep C (HCV)
 60-65% (sekitar 2 juta) terinfeksi virus genotipe 1
(sulit diterapi)
 20-25% (sekitar 474,000) akan mengalami sirosis
dalam 15-20 tahun
 1-4% (sekitar 14,000) tiap tahun dari pasien
sirosis akan menderita kanker hati dan 20%nya
akan meninggal akjbat kanker hati dan gagal hati

1. Hepatitis C National Surveillance data 2009)

2. Study of chronic hepatitis C prevalence in health care professionals, 2008
 Infeksi Virus Hepatitis C (HCV)
“Rumus 20”

Pada infeksi HCV hanya 20% yang tidak

berlanjut menjadi infeksi kronis
Dalam waktu 20 tahun, 20% dari pasien
hepatitis C berlanjut menjadi sirosis hati
Sekitar 20% pasien sirosis akibat HCV akan
meninggal karena kanker hati atau gagal hati
 Hepatitis C Kronik: Komplikasi
Progresi penyakit hati
(20−30 tahun)
Normal CH/LC* Advanced LC* HCC*

HCV HEPATITIS C SIROSIS

KRONIK KANKER HATI
LANJUT

*: CH = Chronic Hepatitis; LC = Liver Cirrosis; HCC = Hepatocellular Carcinoma

Risk factors for HCV infection
• Injecting drug users
• Blood transfusions before screening was
introduced (in most countries before 1992)
• Needle stick injuries (healthcare workers)
• Haemodialysis and organ transplant patients
• Medical or dental interventions where
equipment is not adequately sterilised
• Tattooing, body piercing, and shaving using
unsterilised equipment
• Unprotected sex involving injury (even minor)
 tindik narkotika transfusi

Hubungan seks berisiko suntikan tattoo 14

 Diagnosis Hepatitis C
Bila termasuk Kelompok Risiko Tinggi atau pernah
terpapar darah yang diduga terkontaminasi HCV:

 Pemeriksaan darah awal: SKRINING anti-HCV

 Pemeriksaan lanjutan bila anti-HCV positif:
HCV RNA kuantitatif & genotipe HCV
17
 Kegunaan Uji Diagnostik
Menilai Prediksi
Lama respon “Sustained
Penilaian Skrining Konfirmasi Terapi terapi Response”

SGPT/SGOT X

Anti-HCV by Enzyme X
immunoassay (EIA)

Supplemental assay X
(RIBA*) for anti-HCV

HCV RNA qualitative X X

assay

HCV RNA quantitative X X

assay

HCV genotype X

*Tidak lazim dipakai lagi

NIDDK. Chronic hepatitis C: current disease management.
 Kriteria Diagnostik Infeksi HCV:
Hepatitis C Akut Hepatitis C Kronik

1. Diketahui paparan < 6 bulan* 1. Anti-HCV positif > 6 bulan

2. Anti-HCV positif / negatif 2. HCV RNA positif
3. HCV RNA positif 3. SGPT meningkat / normal
4. SGPT meningkat

* Operasi / transfusi / trauma dll.

 Gejala & tanda biasanya ringan, tidak khas atau asimtomatik

 Singkirkan penyebab lain (virus, obat, autoimunitas)
 Pikirkan kemungkinan infeksi ganda (dgn HAV/HBV/HIV)
 Periksa genotipe HCV  lama pemberian terapi IFN
 Tests of liver condition
 Noninvasive tests of fibrosis and activity
 Panel of biochemical markers, e.g. FibroTest
 Ultrasonography, FibroScan

 Liver biopsy
 Gold standard for grading inflammation and
disease stage
 Tujuan Terapi Hepatitis C
Tujuan primer = “sembuh” Tujuan Sekunder

o Virus “lenyap”1 o Cegah fibrosis1

o Cegah terjadinya sirosis2

o Stop perkembangan
penyakit o Cegah Gagal Hati

o Hilangkan gejala o Cegah Kanker Hati2

Kriteria kesembuhan dalam praktek  bila tercapai SVR

(Sustained Virological Response)

1. Worman HJ. Hepatitis C: current treatment.

2. Peters MG et al. Medscape HIV/AIDS eJournal. 2002;8(1).
 Sustained Virological Response (SVR)
o SVR adalah tujuan utama terapi Hepatitis C
o SVR = Jumlah virus dibawah batas deteksi
(50 IU/mL) hingga 6 bulan setelah terapi selesai
o Indikator terbaik untuk :
 Menilai perbaikan klinis (parameter kesembuhan)
 Perbaikan histologis (regresi fibrosis)
 Mencegah KHS
 Faktor-faktor yang Memengaruhi
Keberhasilan Terapi
 Genotipe virus
 Jumlah virus dalam tubuh
 Usia & Gender pasien
 BMI (IMT) pasien
 Kondisi penyakit hati
 Kapan terapi dimulai
 Ketaatan menjalani program terapi
Rekomendasi Terapi Hepatitis C kronik
Perhimpunan Peneliti Hati Indonesia (PPHI)

 Baku emas terapi saat ini:

 Kombinasi pegylated interferon alfa dan ribavirin
 Pegylated interferon alfa: keunggulan farmakokinetik
dan farmakodinamik vs. interferon alfa konvensional:
- 1 x seminggu
- efek supresi virus yang optimal
- efikasi lebih tinggi
 Pegylated interferon ditoleransi lebih baik
 Durasi terapi tergantung pada genotipe HCV:
- Genotipe 1 / 4 : 48 minggu
- Genotipe 2 / 3 : 24 minggu
 Terapi Hepatitis C Kronik :
Perkembangan Selama >10 tahun

100
% Sustained vriologic response

80
54-63%
60
42%
40 25-39%
16%
20 6%

0 IFN IFN PEG-IFN IFN +

PEG-IFN
24 weeks 48 weeks 48 weeks + Ribavirin
Ribavirin
48 weeks
48 weeks

1991 2009
 Interferon inhibits the virus AND
enhances the immune response
100%
HCV RNA

Lymphocyte

Induction phase
Maintenance phase
Detection limit
0%
14–28 Days ?
1st dose
Ferenci P, et al. Viral Hep Rev 1999; 5: 229
 Side effects of treatment
 Experience of side effects varies between individuals
 Side effects are reversible and appear to be dose
dependent
 Side effects can be managed
 Dose reduction is a common management strategy

 Referral to the multidisciplinary team as necessary

 Psychiatrist or psychologist or counsellor

 Dietician

 Social worker
 Most common side effects of
interferon treatment
 Flu-like symptoms  Rash
 Fever, chills  Weight loss
 Headache  Psychiatric symptoms
 Fatigue or asthenia  Depression
 Myalgia, arthralgia  Insomnia

 Cough  Alopecia
 Injection-site reaction
 Nausea
 Leukopenia
 Anorexia
 Thyroiditis
 Diarrhoea  Autoimmunity
 Pruritus  Thrombocytopenia
 Most common side effects of
ribavirin treatment
 Haemolytic anaemia
 Teratogenicity
 Cough and dyspnoea
 Rash and pruritus
 Insomnia
 Anorexia
1. REBETOL®. PDR®
2. Chutaputti A. J Gastroenterol Hepatol 2000; 15(suppl): E156
 Beda antara PEGASYS dengan PEG-IFN α-2b
Pegylated PEGASYS® (40KD)
interferon alfa-2b
(12KD)
Interferon Interferon alfa-2b Interferon alfa-2a

Struktur PEG Kecil, linier, Besar, bercabang,

12KD PEG 40KD PEG
Isomer posisional 14 6

Ikatan protein Ikatan uretan Ikatan amida

tidak stabil stabil
1. Bailon P, et al. Bioconjugate Chem 2001; 12: 195
2. Kozlowski A, et al. BioDrugs 2001; 15: 419
3. Wang Y-S, et al. Biochemistry 2000; 39: 10634
4. Youngster S, et al. Curr Pharm Des 2002; 8: 2139
5. Grace M, et al. J Interferon Cytokine Res 2001; 21: 1103
 PEGASYS® (Peginterferon Alfa-2a [40KD]) tidak
perlu disesuaikan dengan berat badan
Volume distribusi PEG-IFN a-2a (40KD) kecil

180 mg 180 mg 180 mg

Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935.
Original Article:
HEPAT ITIS C VIRUS INFECTION IN PATIENTS ON
LONG TERM HEMODIALYSIS

Abdul Karim Zarkoon*, Khalid Shah**, Habib ur

Rehman***, Aamir Daud****, Jamil Ahmed*****

 January 2006 to June 2007

 23/97 (23.7%) were anti-HCV positive
 history of dialysis for more than two years is a
significant risk factor for getting HCV infection

 HDU in others: Lahore 68%; India 83%; Tunisia 33%; Saudi

Arabia 46%; Swiss 5%; USA 10%; Egypt 80%
(Gomal Journal of Medical Sciences 2008, Vol. 6, No. 1)
Prevention and Control of Viral Hepatitis in Spain: Strict
adherence to the universal infection control precautions.
Pachon I, Shouval D. Viral Hepatitis 2007; 15 (1)
 PEG Attachment Versus Detachment
Small linear PEG-IFN PEGASYS® (40KD) (Stable Bond)
Metabolised PEG Metabolised
PEG through through liver
IFN kidney IFN
Absorption
PegIFN alfa-2b is metabolised in the kidney, thus
Urine
PEG Excretion
it is NOT
PEGto be
IFN used in hemodialysis patients as
BLOOD
there could be accumulation of PegIFN
IFN alfa-2b,

which may cause more side effects

Slower
degradation
Rapid degradation by peptidases
by peptidases
Biliary
Excretion

Courtesy of Peter Ferenci.

 PEGASYS® can be safely administered in
patients with renal impairment
PEGASYS® 135 mg/week (n=6) Single
PEGASYS® 180 mg/week (n=6) dose
18
16
concentration (ng/mL)

14
Mean PEGASYS®

12
10
8
6
4
2
0
0 24 48 72 96 120 144 168
Time (hours)
* Shaded area denotes concentration of PEGASYS® in Lamb M, et al. Hepatology 2001; 34: 326A
subjects with normal renal function for both doses
 A number of factors influence
response to therapy
Host factors Viral factors
• Race • Genotype
• Age • Viral load
• Gender
• Body weight*
• Insulin resistance*
• Substance abuse*
• Comorbidities* Reasons for
treatment failure
Disease factors Treatment
• Coinfection* • Adherence*
• Fibrosis • Side effects*
• Cirrhosis • Type of regimen*
• Dose*
• Duration*
* Factors which can be influenced • Experience of MD*
 HCV treatment
in end-stage renal disease
 ESRD patients have impaired drug absorption, distribution,
metabolism and clearance leading to:
 Increase in adverse events 1

 High discontinuation rates 1

 Interferon-based therapies may require dose adjustment due

to alterations in clearance1
 Reducing doses of peginterferon and/or RBV may allow
safe treatment of ESRD patients on dialysis 2–4
 RBV should not be administered to patients with
creatinine clearance <50 mL/min 5
1. Fabrizi F, et al. Hepatology 2002; 36: 3
2. Rendina M, et al. J Hepatol 2007, 46: 768
3. Bruchfeld A, et al. J Viral Hepat 2006; 13: 316
4. Sikole A et al. Renal Failure 2007; 29: 961
5. COPEGUS® SPC
 Pencapaian SVR pada berbagai
kelompok pasien dengan PEGASYS
100
100
84
75
80
60 52 51
40
40
20

0
C V B V m al lis is G1 ser
H r p
H I V- C V- H No odi a +L VL
R el a
si iH T
e k k s A L
H em R VR
inf inf
e
ko k o

1. Torriani. NEJM 2004;351:438-50. 2. Liu et al. AASLD 2007.poster

3. Zeuzem et al.Gastroenterology 2004; 127:1724-32
4. Kokoglu et al. J Gastroenterol Hepatol. 2006;21:575-80 5. Yu et al. AASLD 2007 poster
6. Kaiser et al, AASLD 2008, poster
 Simpulan
Hepatitis C merupakan salah satu penyebab sirosis
hati dan kanker hati
Pegylated interferon (Peg-IFN) dan ribavirin
merupakan baku emas terapi hepatitis C kronik
Tujuan utama terapi hepatitis C ialah tercapainya
SVR (Sustained Virological Response)
Capaian SVR untuk hepatitis C pada populasi pasien
CKD dengan HD cukup tinggi meskipun tidak setinggi
pada populasi pasien tanpa CKD
Peg-IFN α-2A adalah obat terpilih untuk Hep C pada
pasien HD karena diekskresikan terutama di hati
SAATNYA LAWAN HEPATITIS
28 JULY
 28 JULI

SAATNYA LAWAN HEPATITIS

43