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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: ± 4 juta orang
Di Indonesia: ± 4 juta orang
WHO Wkly Epidemiol Rec 2000;75:18-19.
PREVALENCE OF HCV INFECTION
Country
Prevalence in general population
Prevalence in dialysis population*
referenc 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, 3a
1a, 1b 2a, 2b, 3a
4
4
2a 1b, 3a
1b
1b, 6
3b
1a, 1b, 2b, 3a 5a
Indonesia: 1a+1b: 60 – 65% 2a: 17 – 26%
1b, 3a
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% simtomatik
Diobati
170 juta orang telah terinfeksi (di > 90% asimtomatik
Tidak terdiagnosis
Indonesia 4 juta)
315.000 kasus baru/tahun 4,1% dari seluruh kasus karsinoma 312.000 meninggal/tahun (Sulaiman A, Selayang pandang Hepatitis C, 2004)
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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. 2.
Hepatitis C National Surveillance data 2009)
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
HCV
CH/LC*
HEPATITIS C KRONIK
Advanced LC*
SIROSIS LANJUT
HCC*
KANKER HATI
*: 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
Hubungan seks berisiko
narkotika
suntikan
transfusi
tattoo
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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
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Kegunaan Uji Diagnostik Penilaian
Skrining Konfirmasi
SGPT/SGOT
X
Anti-HCV by Enzyme immunoassay (EIA)
X
Supplemental assay (RIBA*) for anti-HCV
X
HCV RNA qualitative assay
Lama Terapi
X
*Tidak lazim dipakai lagi
Prediksi “Sustained Response”
X
HCV RNA quantitative assay HCV genotype
Menilai respon terapi
X
X
X NIDDK. Chronic hepatitis C: current disease management.
Kriteria Diagnostik Infeksi HCV: Hepatitis C Akut
Hepatitis C Kronik
1. Diketahui paparan < 6 bulan* 2. Anti-HCV positif / negatif 3. HCV RNA positif 4. SGPT meningkat
1. Anti-HCV positif > 6 bulan 2. HCV RNA positif 3. SGPT meningkat / normal
* 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 Stop perkembangan penyakit o Hilangkan gejala
o Cegah terjadinya sirosis2 o Cegah Gagal Hati 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 o
(50 IU/mL) hingga 6 bulan setelah terapi selesai 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
% Sustained vriologic response
Selama >10 tahun 100 80 54-63%
60
42%
40 16% 20 0
25-39%
6% IFN 24 weeks
1991
IFN 48 weeks
PEG-IFN 48 weeks
IFN + Ribavirin 48 weeks
PEG-IFN + Ribavirin 48 weeks
2009
Interferon inhibits the virus AND enhances the immune response
HCV RNA
100%
Lymphocyte
Induction phase Maintenance phase
0% 1st dose
Detection limit
14–28 Days
? 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
Myalgia, arthralgia
Cough Nausea Anorexia Diarrhoea Pruritus
Rash Weight loss Psychiatric symptoms
Fatigue or asthenia
Fever, chills Headache
Depression Insomnia
Alopecia Injection-site reaction Leukopenia Thyroiditis Autoimmunity 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
Interferon Struktur PEG Isomer posisional Ikatan protein
Pegylated interferon alfa-2b (12KD)
PEGASYS® (40KD)
Interferon alfa-2b
Interferon alfa-2a
Kecil, linier, 12KD PEG
Besar, bercabang, 40KD PEG
14
6
Ikatan uretan tidak stabil
Ikatan amida 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
Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935.
180 mg
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 PEGASYS® (40KD) (Stable Bond)
Small linear PEG-IFN PEG
Metabolised through kidney IFN
Metabolised through liver
PEG
IFN
Absorption Urine PegIFN alfa-2b is metabolised in the kidney, thus
PEG
Excretion
PEGto be it is NOT IFN used in hemodialysis patients as
BLOOD
IFN alfa-2b, there could be accumulation of PegIFN
which may cause more side effects Rapid degradation by peptidases
Slower degradation 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
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Mean PEGASYS® concentration (ng/mL)
16 14 12
10 8 6 4 2 0 0
24
48
* Shaded area denotes concentration of PEGASYS® in subjects with normal renal function for both doses
72 96 120 Time (hours)
144
168
Lamb M, et al. Hepatology 2001; 34: 326A
A number of factors influence response to therapy Host factors
Viral factors
• • • • • • •
• Genotype • Viral load
Race Age Gender Body weight* Insulin resistance* Substance abuse* Comorbidities*
Reasons for treatment failure
Disease factors
Treatment
• Coinfection* • Fibrosis • Cirrhosis
• Adherence* • Side effects* • Type of regimen* • Dose* • Duration* • Experience of MD*
* Factors which can be influenced
HCV treatment in end-stage renal disease
ESRD patients have impaired drug absorption, distribution, metabolism and clearance leading to: Increase in adverse events1 High discontinuation rates1 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 dialysis2–4 RBV should not be administered to patients with creatinine clearance
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