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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 <50 mL/min5
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
40
52
51
40
20
0
1
V
V
al
is
er
G
s
C
s
B
i
m
l
r
p
H
VL
V- H
di a
No
I Vel a
L
o
C
+
H
R
T
L
iH
si
em
VR
A
s
k
H
R
k
e
e
inf
inf
o
ko
k
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