ASSESSMENT PRIOR TO TREATMENT DO WE NEED IL28B TESTING?

Transcription

1 ASSESSMENT PRIOR TO TREATMENT DO WE NEED IL28B TESTING? DO WE NEED LIVER BIOPSY? Mitchell L Shiffman, MD Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA POTENTIAL CONFLICTS OF INTEREST Abott: DSMB, G Anadys: DSMB, G Bayer: S Bristol-Myers-Squibb: A,G,S Conatus: A,G Exalenz: A Genentech/Roche: A,C,G,S Gilead: A,G,S Globeimmune: A,G Idenix: G Inhibitex: A,G Intercept: A,G Merck/Schering-Plough: A,G,S Novartis: A,G Pfizer: A Romark:C Salix: A,S Vertex: A,S Human Genome Sciences: C Zymogenetics: A,G A=Advisor, C=Consultant, G=Grants, S=Speaker 1

2 INTERFERON MECHANISMS OF ACTION INF ISG 2,5 OAS PKR MX Anti-viral effect: Entry, uncoating mrna & protein synthesis Immunologic Effects: Cell surface antigen NK cells Cytotoxic T cells Macrophage Immunoglobulins Interleukins TNF Samuel CE. Clin Microbiol Rev. 21; 14: TREATMENT OF CHRONIC HCV PHASES OF VIROLOGIC RESPONSE l) HCV RNA (IU/ml Log Phase1: Direct anti-viral effect of INF Phase 2: Immune effects of INF DAYS E Herman et al. Antivir Ther 2; 5:

3 VIROLOGIC RESPONSE PATTERNS ) HCV RNA (IU/ml Log Peginterferon/Ribavirin 2-log decline Limit it of detection ti A Sethi and ML Shifman Clin Liver Dis 25; 9: WEEKS SVR SUSTAINED VIROLOGIC RESPONSE BASIS FOR HOST GENETIC EFFECT SVR rates are highly variable among various racial groups: Asians highest African Americans lowest Variable response patterns during treatment even with the same viral genotype Not explained by host phenotypic factors alone: Cirrhosis Body weight Insulin resistance Liver transaminases 3

4 GENOME WIDE ASSOCIATION STUDY MECHANISM DNA from patients with SVR DNA from patients with No SVR RELATIONSHIP BETWEEN IL28B AND SVR IDENTIFICATION Author Ge et al Tanaka et al Suppiah et al Genotype N Location North America Japan N Europe Australia Grouping SVR VR SVR # SNPs JG McHutchison Liver Intl 211; 31(suppl 1):

5 IL28B POLYMORPHISM THE INTERFERON SWITCH Host gene Modulates the interferon response Chromosome 19 SNP at loci rs CC haplotype (cure): Highly interferon sensitive High rates of spontaneous resolution High rates of RVR High rates of virologic response High rates of SVR CC-ON D Ge et al. Nature 29; 461: IL28B POLYMORPHISM THE INTERFERON SWITCH Host gene Modulates the interferon response Chromosome 19 SNP at loci rs TT haplotype (terrible): Minimally interferon sensitive No spontaneous resolution Low rates of RVR Low rates of virologic response Low rates of SVR TT-OFF D Ge et al. Nature 29; 461:

6 IL28B POLYMORPHISM THE INTERFERON SWITCH Host gene Modulates the interferon response Chromosome 19 SNP at loci rs CT halotype: Lower interferon sensitivity Low rates of spontaneous resolution Low rates of RVR Low rates of virologic response Low rates of SVR CT MIDDLE D Ge et al. Nature 29; 461: IL28 B POLYMORPHISM AND SVR IMPACT OF RACE AND ETHNICITY 1 SVR (%) Caucasians Hispanics Asians 2 African Americans Frequency of ILB-28 CC Haplotype D Ge et al. Nature 29; 461:

7 IL28 B POLYMORPHISM IMPACT OF RESPONSE AND RACE Caucasian African American CC Non-CC CC Non-CC RVR 28% 5% 15% 2% cevr 87% 33% 5% 22% ETR 92% 54% 7% 26% SVR 69% 3% 48% 14% Relapse 14% 34% 23% 36% A Thompson et al. Gastroenterology 21; 139: PHASES OF VIROLOGIC RESPONSE IMPACT OF IL28B HCV RNA (IU/ml) Log ) IL28B-CC IL28B-CT or TT ML Shiffman Clin Liver Dis 211; 15: DAYS 7

8 TREATMENT OF HCV INTERFERON RESPONSIVENESS Even with a protease inhibitor achieving i SVR is still dependent upon the ability to respond to interferon Can be assessed by a lead-in response Can be assessed by prior treatment response Null response poorly responsive Relapse highly responsive Interferon responsiveness is genetically mediated IL28B genotype CC highly responsive IL28B genotype TT poorly responsive INTERFERON RESPONSIVENESS IL28B GENOTYPE 1 8 SVR (%) TPV BOC PEGINF/R CC CT TT IL28B GENOTYPE IM Jacobson et al. EASL 211 F Poordad et al. EASL 211 8

9 TELAPREVIR IL28B AND RAPID RESPONSE 1 % of Patients CC CT TT IM Jacobson et al. EASL 211 ervr SVR SVR SVR with All without ervr Patients ervr BOCEPREVIR IL28B AND RAPID RESPONSE 1 % of Patients Lead-In: >1 log decline Week 8: HCV RNA - UD SVR F Poordad et al. EASL 211 CC CT TT IL28B GENOTYPE 9

10 VIROLOGIC RESPONSE IMPACT OF IL28B GENOTYPE IL28B Genotype CC CT TT Lead-In RVR Delayed Response Resistance TREATMENT OF CHRONIC HCV WHY IS LIVER HISTOLOGY USEFULL SVR is lower in patients with advanced fibrosis and cirrhosis If advanced fibrosis or cirrhosis is present: Should treat for 48 weeks More complications during treatment If cirrhosis is present: must screen for HCC even after achieve SVR If mild disease the patient might prefer not to treat Histology can be utilized to predict the rate of fibrosis progression 1

11 TREATMENT OF HCV IMPACT OF LIVER HISTOLOGY SVR (%) 1 1 TPV 8 Placebo SVR (%) 6 4 BOC Placebo 2 2 Mild BF/Cx Mild BF/Cx IM Jacobson et al. N Eng J Med 211; 364: F Poordad et al. N Engl J Med 211; 364: RE-TREATMENT WITH TELAPREVIR IMPACT OF LIVER HISTOLOGY SVR (%) No Cx Cirrhosis 2 Relapse Partial Null PRIOR RESPONSE S Zeuzem et al. N Eng J Med 211; 364:

12 RE-TREATMENT WITH BOCEPREVIR IMPACT OF LIVER HISTOLOGY SVR (%) 1 1 No Cx 8 Cirrhosis SVR (%) In pts with RVR I Relapse Partial PRIOR RESPONSE B Bacon et al. N Engl J Med 211; 364: RVR RGT 48 wks DURATION OF TREATMENT CHRONIC HCV INFECTION PROGRESSION TO CIRRHOSIS CIRROSIS (%) Initial fibrosis: Bridging Portal None YEARS M Yano et al. Hepatology 1996; 23:

13 PREDICTING FIBROSIS PROGRESSION EFFECT OF INFLAMMATION r Change in brosis Score/Yea Fi. MG Ghany et al. Gastroenterol 23; 124: >4 Piecemeal Necrosis Score at Baseline CHRONIC HCV FIBROSIS PROGRESSION Mild Moderate 15-25% Severe Cirrhosis A Cirrhosis C HCC 25-33% ML Shiffman Viral Hepatitis Rev 1999; 5: YEARS 13

14 TREATMENT OF CHRONIC HCV LIVER HISTOLOGY IS NOT USEFULL Liver biopsy is invasive Complications can occur Most patients with cirrhosis can be identified without a liver biopsy Non-invasive assessment of liver histology is good enough Since treatment is more effective we should treat all patients regardless of histology BIOCHEMICAL MARKER OF CIRRHOSIS AST/ALT RATIO 2 2. AST/ALT F F1 F2 F3 Cx-A Cx-B Cx-C Biopsy Stage and Cirrhosis Class ML Shiffman et al. Hepatology 1994; 19:

15 MARKERS OF ADVANCED FIBROSIS AST AND PLATELET COUNT Platelet Count AST/(ULN) x 1 Platelet Ct Biopsy Stage Biopsy Stage CT Wai et al. Hepatology 23; 38: NON-INVASIVE MARKERS OF FIBROSIS FIBROTEST Utilizes 5 serum biochemical markers to predict fibrosis Alpha-2 macroglobulin Haptoglobin Gamma glutamyl transpeptidase Total bilirubin Apolipoprotein A1 Markers of inflammation NOT fibrosis 15

16 NON-INVASIVE MARKERS OF FIBROSIS FIBROTEST Fibrosis score ranges from -1 Fibrotest is reliable at identifying patients with: No fibrosis score under.1 Cirrhosis score of over.75 It is not reliable in predicting between stages 1-3 Patients with bridging fibrosis may not be recognized T Poynard et al. Clin Chem 27; 53: F4 Cirrhosis F3 F2 F1 No fibrosis ASSESSMENT OF LIVER HISTOLOGY SERUM TESTS FIBROTEST ACTITEST FIBROSIS STAGE ACTIVITY GRADE T Poynard et al Hepatology 23; 38:

17 NON-INVASSIVE MARKERS OF FIBROSIS FIBROSCAN Transient elastrography: Ultrasound waves enter liver Bounce off fibrosis Return to transducer The greater the degree of fibrosis the faster the sound waves return to the transducer NON-INVASSIVE MARKERS OF FIBROSIS FIBROSCAN The impact of obesity? 17

18 NON-INVASIVE MARKERS OF FIBROSIS COMPARISON OF TESTS Sensitivity Fibroscan Fibrotest APRI Specificity L Castera et al. Gastroenterology 25; 128: All noninvasive markers of fibrosis provide similar information All separate mild disease from advanced fibrosis None of these tests can differentiate between mild and advanced fibrosis None of these tests can predict which patients will develop progressive fibrosis TREATMENT OF CHRONIC HCV ASSESSMENT OF SVR Likelihood of SVR >95% Increase chance for SVR: IL28B genotype CC Mild fibrosis Prior relapse Low viral load (< 2, IU) 75% Start point Decrease chance for SVR: ~15% IL28B genotype TT Bridging fibrosis or cirrhosis Prior non-response 18

19 IL28B GENOTYPE AND LIVER BIOPSY SUMMARY Both IL28B genotype and knowledge of liver histology are useful for: Assessing the need for treatment Assessing the likelihood that treatment will be successful Non-invasive tests of liver fibrosis can accurately predict patients with cirrhosis but cannot reliably differentiate mild from advnaced fibrosis AST/ALT ratio Platelet count 19