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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)

8

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

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 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

18

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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