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 Italy Belgium Bulgaria France Turkey USA Saudi Arabia Moldavia Egypt 0.1% 0.5% 0.9% 1.1% 1.1% 1.5% 1.8% 3% 22.5% 9.4% 65.8% 16.3% 31.4% 10% 1998 1999 1998 1998 2000 1998 2003 1.8% 4.9% 57% 75% 2001 1999 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, 3a 1a, 1b, 2b, 3a 1a, 1b 2a, 2b, 2c, 3a 4 4 1b, 3a 3b 2a 1b, 6 1b 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!

< 10% simtomatik > 90% asimtomatik Didiagnosis menderita Hepatitis C Tidak terdiagnosis Diobati

 

170 juta orang telah terinfeksi (di Indonesia 4 juta) 315.000 kasus baru/tahun



4,1% dari seluruh kasus karsinoma



312.000 meninggal/tahun

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(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

2.

1.

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

Normal

Progresi penyakit hati (20−30 tahun) CH/LC*

Advanced LC*

HCC* HCV HEPATITIS C KRONIK SIROSIS LANJUT 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 narkotika transfusi Hubungan seks berisiko suntikan 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

Prediksi “Sustained Response” Penilaian Skrining Konfirmasi Lama Terapi Menilai respon terapi SGPT/SGOT

Anti-HCV by Enzyme immunoassay (EIA) Supplemental assay (RIBA*) for anti-HCV HCV RNA qualitative assay HCV RNA quantitative assay HCV genotype

X

X X X X X X

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* 2. Anti-HCV positif / negatif 3. HCV RNA positif 4. SGPT meningkat * Operasi / transfusi / trauma dll

.

1. Anti-HCV positif > 6 bulan 2. HCV RNA positif 3. SGPT meningkat / normal

    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 ”

o

Virus “lenyap” 1

o

Stop perkembangan penyakit

o

Hilangkan gejala Tujuan Sekunder

o

Cegah fibrosis 1

o

Cegah terjadinya sirosis 2

o

Cegah Gagal Hati

o

Cegah Kanker Hati 2 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 o SVR adalah tujuan utama terapi Hepatitis C 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 80 60 42% 40 25-39% 16% 20 0 6% IFN 24 weeks IFN 48 weeks PEG-IFN 48 weeks IFN + Ribavirin 48 weeks 1991 54-63% PEG-IFN + Ribavirin 48 weeks 2009

100%

Interferon inhibits the virus AND enhances the immune response

Lymphocyte

0% 1st dose Induction phase Maintenance phase 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  Fever, chills  Headache  Fatigue or asthenia  Myalgia, arthralgia  Cough  Nausea  Anorexia  Diarrhoea  Pruritus          Rash Weight loss Psychiatric symptoms  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 Pegylated interferon alfa-2b (12KD) Interferon alfa-2b PEGASYS ® (40KD) Interferon alfa-2a Struktur PEG Isomer posisional Kecil, linier, 12KD PEG 14 Besar, bercabang, 40KD PEG 6 Ikatan protein 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

m

g 180

m

g

Lamb MW, Martin NE.

Ann Pharmacother

. 2002;36:933-935.

180

m

g

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) PEG IFN Metabolised through kidney Absorption PEG IFN Metabolised through liver

PegIFN alfa-2b is metabolised in the kidney, thus

PEG Urine Excretion PEG BLOOD

there could be accumulation of PegIFN alfa-2b, which may cause more side effects

Slower Rapid degradation by peptidases degradation by peptidases Biliary Excretion

Courtesy of Peter Ferenci.

PEGASYS

®

can be safely administered in patients with renal impairment

PEGASYS ® PEGASYS ® 135

m

g/week (n=6) 180

m

g/week (n=6) Single dose 18 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 Time (hours) 120 144 168

Lamb M, et al. Hepatology 2001; 34: 326A

A number of factors influence response to therapy

• • • • • • •

Host factors Race Age Gender Body weight* Insulin resistance* Substance abuse* Comorbidities* Reasons for

• •

Viral factors Genotype Viral load treatment failure

• • •

Disease factors Coinfection* Fibrosis Cirrhosis

• • • • • •

Treatment 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 events 1  High discontinuation rates 1 Interferon-based therapies may require dose adjustment due to alterations in clearance 1   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 80 75 60 52 51 40 40 20 0 ko inf ek si HIV ko -H inf CV ek si HC V-H BV AL T N orm al He mo dia lis is RV R+ LV L G 1 Re lap se r 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

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