Rapid and Slow Fibrosers in Chronic HCV Infection

1. Rapid and Slow Fibrosers in Chronic HCV Infection DrSaeed Hamid Professor & Chair Department Of Medicine The Aga Khan University Karachi, Pakistan

2. Natural History of Fibrosis progression in chronic HCV • The natural history of patients with chronic hepatitis C is characterized by a slow progression of liver fibrosis. • Cirrhosis may develop after an average of 20 to 30 years. • In some patients, the rate of fibrosis progression is much faster and cirrhosis develops after 10 to 15 years. • The pathogenesis of HCV-induced liver fibrosis is now better understood. • HCV infects hepatocytes, causing oxidative stress and inducing the recruitment of inflammatory cells, which leads to HSC activation and collagen deposition. • The HCV core protein stimulates secretion of pro-fibrogeniccytokines by hepatocytes. Rockey, SeminGastrointestDis 2000; Bataller, Hepatology2002; 2003

3. Challenges in the study of fibrosis progression in CHC • Time of infection is often not clear. • Not many prospective studies available. • Assumptions that fibrosis progression is linear

4. Rate of Progression of Hepatic Fibrosis: The HALT-C Study • “fast” progression:1 Ishakstage ≤5 years • “slow” progression: 1 stage in ≥ 5 years. Hoefs, Gastro 2011

5. Clinical correlates between rapid and slow progressors • Rapid progressorshad more advanced CLD at baseline (P≤.0001) • More frequent evidence of hepaticinjury (↑AST, ALT, AFP), with no correlation to histologic inflammation. • Fast progressorswere almost 5 times more likely to experience a clinical outcome. Hoefs, Gastro 2011

6. Liver fibrosis progression in patients with chronic HCV • rapid ‘‘fibrosers’’ (median • time to cirrhosis <20 yrs) • slow ‘‘fibrosers’’ (median time to cirrhosis >50 yrs Poynard, Lancet 1997

7. Linear regression model to analysepredictors for rate of fibrosis Wright, et al, Gut 2003

8. Regulation of gene expression in hepatic stellate cells during fibrosis Hernandez-Gea, Annu. Rev. Pathol. Mech. Dis. 2011

9. Pathogenesis of liver fibrosis and sites of action of studied candidate genes Bataller, Hepatology 2003

10. Main Cytokine pathways regulating liver fibrosis Hernandez-Gea, Annu. Rev. Pathol. Mech. Dis. 2011

11. Gene Polymorphisms That Influence Progression of Liver Fibrosis in Humans Bataller, Hepatology 2003

12. Fibrosis Progression rate (units/year) related to TGFb1 genotypes of the four polymorphisms • 48 patients of whom the exact time point • of HCV-infection could be assessed • Progression calculated as the ratio between fibrosis stageat time of biopsy and the • estimated duration of infection The heterozygous ArgProof codon 25 predicts significantly faster fibrotic progression than the homozygous 25ArgArg genotype Location of presently known polymorphisms in the TGF-b1 gene Gewaltig , ClinicaChimicaActa2002

13. Distributionof IL-10 genotypes among fast vs slow fibrosis progressors • Fibrosis rate= fibrosis score/years of infection • Male gender and age at infection (<40) were associated with rapid fibrosis IL-10 (1082) AA genotype (low IL-10 producing genotype) and the ATA/ATA and ACC/ACC homozygous haplotypes were more frequent among patients with rapid fibrosis. Knapp, Immunogenetics (2003)

14. Progression According to Initial Fibrosis Stage and Cirrhosis Risk Score • 271 untreated patients with chronic hepatitis C, METAVIR stage F0 (n=104), • F1 (n=101), or F2 (n=59), followed up for at least 5 years. • 7 SNPs contributed to the CRS, (low risk, CRS 0.5; moderate risk, CRS 0.5-0.7; high risk, CRS 0.7). The association of CRS score with fibrosis progression was highly significant in male patients Marcolongo, Hepatology2009

15. Mannose-Binding Lectin Polymorphisms in Patients with HCV Infection • Variations in mannose-binding lectin and specific HLA-II alleles (DRB1*0405-DQB1*0401), which are involved in host defense against viral infections, also influence cirrhosis development. Sasaki,Scand J Gastroenterol 2000

16. TAP2*0201 Allele and risk of early cirrhosis • Transporter Associated With Antigen Processing 2 plays an important role in the antigen processing system where it translocates antigenic peptides from the cytosol into the endoplasmic reticulum. Akuta, J Med Virol 2001

17. Fast Fibrosis Progression in HIV/HCV Co-infected patients • Over a 3 year period, 44%of patients progressed one or more stages of fibrosis. • Progression of fibrosis was predicted by - the degree of necrosis and inflammation in the first biopsy. - ETR with anti-HCV therapy and - suppression of HIV replication • gp120 or inactivated HIV enhanced TGF-beta 1 expression in both uninfected and HCV-infected hepatocytes Macı´as, HEPATOLOGY 2009

18. Conclusions • Major advances in characterizing the geneticdeterminants of fibrosis progression. • To use them clinically as effective prognostic parameters has been a challenge. Some potential uses would be: - Tailor follow up - Timing of specific therapy - Design of clinical trials Friedman, Nature Reviews 2010

19. Consensus Recommendation • Clinical and Demographic factors for fibrosis progression are well defined and have worked well over time (A) • Although many genetic markers are now defined for prediction of fibrosis progression, more prospective randomized data is required before these markers can be recommended for general clinical use. (B, 2) • Genetic markers can be very helpful in the conduct of therapeutic trials of fibrosis therapy, and should be routinely included in clinical trials of anti-fibrotic therapy (B, 1).