Hepatitis virus C : overview

Hirlan

Hery Djagat Purnomo

Bag Penyakit Dalam RS Dr Kariadi/ FK UNDIP Semarang

Genome virus hepatitis C (VHC)

C E1 E2 NS2 NS3 NS4A.B NS5 A.B 5’NC 3’NC

Daerah paling conserved : C = gen capsidDaerah paling heterogen : Bagian 5’ E2 Hypervariable region 1 (HVR1)

Internal ribosomal enttry site pada 5’ NC

HVR1

Genome HVC

• The HCV Genome and Expressed Polyprotein. • HCV, a single-stranded RNA virus of 9.5 kb, consists of a single open

reading frame and two untranslated regions (UTRs). It encodes a polyprotein of approximately 3000 amino acids, which is cleaved into single proteins by a host signal peptidase in the structural region and the HCV-encoded proteases in the nonstructural (NS) region. The structural region contains the core protein and two envelope proteins (E1 and E2). Two regions in E2, called hypervariable regions 1 and 2 (HVR 1 and HVR 2), show extreme sequence variability, which is thought to be the result of selective pressure by virus-specific antibodies. E2 also contains the binding site for CD81, the putative HCV receptor or coreceptor. The nonstructural proteins have been assigned functions as proteases (in the case of NS2, NS3, and NS4A), helicase (in the case of NS3), and RNA-dependent RNA polymerase (NS5B). Although the crystal structure of NS3 and NS5 is known,31 the function and properties of the other proteins (such as p7) are less well characterized. A region in NS5A has been linked to the response to interferon alfa therapy and is therefore called the interferon-sensitivity–determining region (ISDR). However, the relevance and importance of this region are still unclear.

•

Heterogenitas genetik

Heterogenitas sequence merupakan ciri khas genome VHC

- Heterogenitas sequence VHC terdapat 6 major genotype yakni genotype 1 - 6 - Setiap genotype mempunyai subtype ditulis dengan huruf a, b, dst Sehingga genotype VHC : 1a, 1b, 2a.2b dst

- Genotype dapat menentukan gambaran klinik dan respons terapi

Heterogenitas genetik

Quasispesies - Adalah bentuk heterogenitas pada satu individu yang terinfeksi VHC - Terjadi pada HVR1 . - Pada genotype 1b disamping HVR1 juga terjadi pada HVR2 - Menyebabkan sulit dikenal sistem immun VHC cenderung kronik

Spektrum klinik

Di negara Barat :

20% kasus hepatitis akut 70% kasus hepatitis kronik 30% kasus end state liver disease

Di Indonesis

40-50% kasus end state liver disease 2,5-3,8% diantara donor darah

Nat history HCV

Nat history HCV

• The Natural History of HCV Infection and Its Variability from Person to Person.

• The course of infection varies widely among persons. Factors that decrease the risk of progression include female sex and a younger age at infection; factors that increase the risk include alcohol intake, an older age at infection, male sex, and coinfection with other viruses. Persons with a favorable risk profile often do not have progressive liver disease until 30 or more years after infection. In contrast, 20 percent of persons with chronic hepatitis C will eventually have cirrhosis, and this can occur 20 years or less after infection, especially in those with alcohol abuse or coinfection with human immunodeficiency virus type 1 or hepatitis B virus. Once cirrhosis is established, the risk of hepatocellular carcinoma is 1 to 4 percent per year.

•

Faktor risiko

Cara penularan utama :

• Direct percutaneous exposures : transfusi darah/transplantasi organ jarum / instrumen tajam terkontaminasi • Membrana mukosa• Inapparent parenteral exposure • Sexual / perinatal transmision

Faktor risiko

44% sosial ekonomi rendah

38% injeksi / penyalahguna obat

10% sexual / household contact

4% transfusi darah2% berhubungan dengan pekerjaan1% dialisis

Diagnosis

Simptom HKVC : Nonspesifik Ringan Intermitten .Keluhan yang sering ditemui

• Fatique • Gatal-gatal • Nyeri perut • Urine berwarna gelap • Nausea• Tanpa keluhan sama sekali

Diagnosis

Transaminase serum

• Peningkatan Alt berkorelasi positif kuat terhadap skor histopatologik• Alt selalu normal tidak terdapat pada HKVC lanjut• Alt tinggi menjadi indikasi dasar terapi anti-virus• Sering menjadi salah satu tanda keberhasilan terapi• Memerlukan pemeriksaan serial yang ketat karena fluktuatif

Tes serologik

Anti-HCV:- Mendeteksi antigen virus - Tidak mempunyai nilai protektif - VHC memproduksi antigen << - Awal penyakit, tidak terdeteksi

Non-struktur Core

Antigen protein C 100 5-1-1 C33 C22

Elisa 1 + RIBA 2 + + Elisa 2/RIBA 4 + + + +

Tes serologi

HCV-RNA

cDNA-PCR , kwalitatif sensitif untuk positif / negatif

Branch DNA signal amplification, kwantitatif kurang sensitif mahal berkorelasi dengan hasil terapi

Perjalanan alamiah

• Masa inkubasi 3 - 20 minggu rata-rata 7 minggu• Hanya 30% kasus diikuti simptom• Self limited case hanya pada sebagian kecil kasus (15%)• Serokonversi pada hepatitis kronik C hampir tidak pernah ada

Spektrum klinik : HVC akut, self limited

1000 -

800 -

600 -

400 -

200 -

0 . . . . . . , . . . . 2 4 6 8 10 12 24 1 2 3 4

*

*

*

+ + + + + - - - - - HCV-RNA

Anti-HCV

Symptoms

ALT

Minggu tahun

Batas normal

Hepatitis kronik virus C

1000 -

800 -

600 -

400 -

200 -

0 - . . . . . . . . . . . . . 2 4 6 8 10 12 24 1 2 3 4 5 6

Minggu Tahun

ALT

- + + + + + + - + + + + + HCV-RNA

* *

*

*

Anti-HCV

Symptom

Batas normal

Histologi hepatitis C

• Figure 3. Histologic Stages of HCV Infection. • In Panel A, a core-biopsy specimen from a patient with

chronic HCV infection shows dense portal lymphocytic infiltrates (arrow) and architectural changes (arrowhead) (hematoxylin and eosin, x10). The lymphocytes are not limited to the portal tract but also extend into the lobules (arrowheads in Panel B) (hematoxylin and eosin, x100). Panel C shows normal liver architecture with scant fibrous tissue (arrows) limited to the portal tracts (trichrome stain, x20). During the progressive course of infection, the fibrotic areas expand and bridging fibrosis develops (arrows in Panel D) (trichrome stain, x20). The final stage of cirrhosis (Panel E) is characterized by marked fibrosis and regenerative nodules (RN) (trichrome stain, x20). Once cirrhosis has become established, hepatocellular carcinoma (Panel F) is a feared complication (hematoxylin and eosin, x40).

•

Perjalanan klinik

Hepatitis C akut

Hepatitis C kronik

Sirosis Hep Hep. Kronik ringan-sedang

Ca. hepar

Sembuh meninggal

>80% 15% <1%

=

Perjalanan penyakit HVC

tahun

Hepatitis kronik, mild-mod

Fibrosis berat (bridging )

Sirosis hepatis

HCC

18

14

27

53

Pengelolaan

Anti HCV pos

HCV-RNA pos, Alt HCV-RNA neg HCV-RNA pos, Alt N

HCV-RNA, Alt

Terapi, anti virusAlt NAlt,

Cari kausa lain, biopsi

Evaluasi

Pengelolaan

Faktor prediksi keberhasilan terapi

• Genotype. 1b disebut paling buruk• Titer HCV-RNA. Rendah > baik• Usia , muda lebih baik• Lamanya sakit, baru lebih baik• Tanpa HIV

PengelolaanHCV-RNA posAlt meningkat

Sirosis hepatis berat (-)

Interferon +Ribavirin

PCR, pd 24 mg

Neg, faktorPrediksi baik

Neg, faktorPrediksi << Pos

Stop terapi24 minggu

Teruskan terapi38 minggu

Stop terapi anti virus

Faktor prediksi HKVC End State Liver Disease

faktor virus : Titer HCV-RNA Genotype Quasispecies

Faktor Host : Usia Ras Sex

Faktor lain : NASH/Alkoholik Infeksi virus lain Smoking

Pencegahan

• Belum ditemukan vaksin yang efektif• Screening thd donor organ/darah thd pasien dialisa thd pasien bedah elektif ?• Pencegahan infeksi pada peristiwa-peristiwa yang berisiko tinggi