Presentation is loading. Please wait.

Presentation is loading. Please wait.

Nezam AFDHAL. Initial Presentation  47-year-old white male  Ex-IVDU 20 years ago  Alcohol >20 g/day for 8 years, none for 18 years  Asymptomatic apart.

Similar presentations


Presentation on theme: "Nezam AFDHAL. Initial Presentation  47-year-old white male  Ex-IVDU 20 years ago  Alcohol >20 g/day for 8 years, none for 18 years  Asymptomatic apart."— Presentation transcript:

1 Nezam AFDHAL

2 Initial Presentation  47-year-old white male  Ex-IVDU 20 years ago  Alcohol >20 g/day for 8 years, none for 18 years  Asymptomatic apart from fatigue

3 History  Hypertension for 8 years, on HCTZ  History of high blood sugar but no treatment  Gout  Meds:  HCTZ  Allopurinol

4 Physical Examination  Weight: 290 lbs (132 kg)  Height: 5′10″ (175 cm)  BMI: 41.6  Hepatomegaly

5 HCV genotype 1 Viral load 1.45 million IU ( 6.1 log 10 ) Liver function ALT ALT96 AST AST110 Blood count Platelets Platelets87,000 Hgb Hgb14.8 WBC WBC4.3 Patient Data

6 Which of the following is the major risk factor for advanced liver disease in this patient Which of the following is the major risk factor for advanced liver disease in this patient  A. History of alcohol use  B. Male sex  C. Age  D. Diabetes  E. Hepatic steatosis Question 1

7  Age  Male sex  Co-infections - HBV/HIV  Alcohol  Steatosis / Obesity / DM / Insulin Resistance Clinical Risk Factors for Fibrosis in HCV

8 Distribution of Fibrosis Stage by Body Weight Patients in primary safety analysis (n = 4913) for whom data were available (n = 4871). F0F1F2F3F4 <65 kg n = 690 ≥65 – 85 kg n = 2005 >105 kg n = – 105 kg n = 1654

9 Mechanisms for Hepatic Fibrosis Development Hepatic Fibrosis Obesity Steatosis Insulin Resistance Inflammation Genotype 3

10 Which of the following is an appropriate next test Which of the following is an appropriate next test  A. CT Scan or Ultrasound  B. Liver biopsy  C. Biomarkers such as FibroTest / FibroScan  D. Fasting Insulin / Glucose  E. All of the above Question 2

11

12 Viral Factors: Genotype 3 HCV-RNA level Increased fibrosis progression Resistance to antiviral therapy Patel et al. Clin Liver Dis 2005;9: HCV + Steatosis Host Factors: Visceral obesity Altered lipid metabolism Age Insulin resistance

13 Increased body mass index (≥30 kg/m 2 ) Central adiposity Hypertension Dyslipidemia Insulin resistance Metabolic Syndrome

14 Association of Hepatic Steatosis and Fibrosis Hourigan HF et al. Hepatology 1999;29: Steatosis Grade

15 Association of Hepatic Steatosis and Fibrosis P-value <0.001 Adinolfi LE et al. Hepatology 2001; 33:

16 Which of the following is true about treatment Which of the following is true about treatment  A. SVR should be 55%  B. Cirrhosis has little impact on SVR  C. RBV dose should be fixed at 1200mg for optimal response  D. Viral eradication will improve steatohepatitis  E. Weight loss and weight based dosing of both IFN and RBV may improve SVR Question 3

17 Current HCV Treatment Patient Population HCV Eradication Rate Genotype 2 or 3 75%–90% Genotype 1 45%–52% African Americans (genotype 1) 19%–25% HIV Coinfection (genotype 1) 18%–29% Contraindications to IFN (Mental illness, drug use) 0% PEG-IFN SC Injection Weekly + RBV PO b.i.d. for 24–48 wk HCV, hepatitis C virus; PEG-IFN, peginterferon; SC, subcutaneous; RBV, ribavirin; PO, by mouth; b.i.d., twice daily; HIV, human immunodeficiency virus; IFN, interferon

18 SVR Rate in Patients with F0-2 or F3-4 Fibrosis Manns et al. SVR, % (n/N) Minimal/ No Fibrosis (F0-2) Bridging Fibrosis/ Cirrhosis (F3-4) 3MIU IFN alfa-2b 3  weekly + RBV ‡ (n = 468*) 1.5  g/kg/wk PEG-IFN alfa-2b + RBV † (n = 469*)  g/kg/wk PEG-IFN alfa-2b + RBV ‡ (n = 491*) 49 (164/336) 57 (189/333) 51 (175/345) 41 (54/132) 44 (60/136) 43 (63/146) Fried et al. No Cirrhosis Cirrhosis 3MIU IFN alfa-2b 3  weekly + RBV ‡ (n = 54*) 180  g/wk PEG-IFN alfa-2a + RBV ‡ (n = 56*) 180  g/wk PEG-IFN alfa-2a + placebo (n = 54*) NDNDND 33 (18/54) 43 (24/56) 21 (7/34) Manns Lancet 2001;358: Fried NEJM 2002;347: * Patients with fibrosis data available. † 800 mg/day. ‡ 1000 mg/day if  75 kg and 1200 mg/day if >75 kg. ND = not done.

19 SVR Rates Across Individual Fibrosis Stages Patients in primary safety analysis (n = 4913). * In logistic regression, patients with F0-3 had more responders than patients with F4. Patients With SVR, % P =.0005 vs F4* P <.0001 vs F4* n = 654n = 1460n = 1324n = 975n = 500

20

21 Jacobson IM et al. AASLD WIN-R Trial: SVR And Body Weight RBV: FD (800 mg) vs WBD ( mg) + PEG IFN 2b 1.5 ug/kg 49% 52% 45% 44% 42% 39% 47% 34% FDWBD SVR (%) <65 kg65–85>85–105>105

22 PEG-IFN  -2a 180 vs 270 μg + RBV 1200 vs 1600 mg G1 HVL, Body Weight >85 kg Fried M et al. AASLD % 32% 36% 47% SVR (%) PEG 2a RBV 1200 PEG 2a RBV 1600 PEG 2a RBV 1200 PEG 2a RBV 1600 n=46n=

23 HCV and Obesity  Tolerating treatment well with no dose reductions  Platelet count: 42,000  WBC: 3.6; neutrophils: 67%  Physician deems him a nonresponder; wants to stop therapy  Patient declines and wishes a 2nd opinion; comes to see a Master 9,00012,40079,000 HCV RNA (IU) Week 24 Week 12 Week HCV RNA (log 10 ) STARTS PEG-IFN alfa-2a 180 μg and RBV 1200 mg

24  How does my body size effect response?  Was I treated with enough interferon?  Was my dose of RBV appropriate? Patient Asks the Physician

25 Which of the following statements is true about this patient Which of the following statements is true about this patient  A. Insulin resistance has little impact on SVR  B. Patient should be given daily IFN therapy  C. Maintenance therapy will reduce risk of HCC and liver failure  D. Screening for HCC should commence Question 4

26 n=43n=45n=25 Insulin Resistance and HCV: Effects on Response to Therapy % SVR in Genotype 1 HOMA: HOmeostasis Model of Assessment: an index of insulin resistance calculated as fasting insulin (mIU/L) × fasting glucose (mmol/L) ÷ HOMA <2HOMA 2–4HOMA >4 PEG-IFN alfa-2b or alfa-2a + RBV 1000–1200 mg Romero-Gomez et al. Gastroenterology 2005;128:

27 Possible Interventions to Overcome Insulin Resistance Lifestyle modifications – Weight loss and exercise programs Higher, weight-based IFN dosing Insulin sensitizers Optimal management of hyperlipidemia and diabetes Weight-based IFN Weight-based RBV

28 Previous therapy DIRECT Trial: Study Design

29 DIRECT Study: Interim Results 26% 32% 22% 25% 14%20% 16% 19% N=171N=172N=171 N=172 Bacon BR et al, AASLD 2006 % PCR neg 24 weeks 48 weeks

30 DIRECT Study: Results at 48 Weeks %PCR neg 19% 28% 16% 19% 8% 6% N=72 N=68 N=61 N=54 N=37 N=49 Bacon BR et al, AASLD 2006 EOT Response by Fibrosis Score

31 Maintenance Therapy: Any Role At Present? Mechanistic basis Histologic improvement in some nonresponders Improved outcome in treated nonresponders Published randomized trial Easier to tolerate than full dose comb therapy PROS CONS Large randomized trials still in progress Precludes participation in trials with novel agents Potential toxicity

32 COPILOT: Study Design Colchicine 0.6 mg BID LB, US, endoscopy PEG-IFN-a2b 0.5 µg/kg/wk Clinical evaluation q 12 weeks US q 24 weeks Endoscopy, LB Endoscopy, LB Interferon / Rebetron / PEG + RBV Nonresponders Interferon / Rebetron / PEG + RBV Nonresponders 5 Jahre Baseline 12 weeks 24 weeks 2 years4 years 600 patients; 557 currently enrolled Ishak fibrosis stage >3 LB = liver biopsy; US = ultrasound

33 COPILOT: Endpoints  Primary endpoints  Death  Liver transplant  Hepatocellular carcinoma  Variceal or portal hypertensive bleeding  Increase in CPT >2 points with jaundice, encephalopathy, or ascites CPT = Child-Turcotte-Pugh Score

34 COPILOT: All Patients Event-Free Survival PEG-IFN  -2b Colchicine P=0.007; 95% Cl 1.18–3.08 Days Afdhal N et al. Hepatology. 2004;40:239A. Abstract 171.

35 COPILOT: Stratification by Portal Hypertension Days Event-Free Survival Log rank; P<0.01 PEG-IFN  -2b Colchicine

36 HAI, histological activity index What Is the Status of Maintenance Therapy?  Several suggestive lines of evidence favor potential benefit  Benefits thus far from controlled trials are reduced HAI and reduced risk of bleeding from portal hypertension  Not HCC, OLT, survival  Criteria for patient selection, monitoring for efficacy unclear (interim reduction of HAI, reduced ALT, reduced HCV RNA) - potential major role for fibrosis markers  Still investigational


Download ppt "Nezam AFDHAL. Initial Presentation  47-year-old white male  Ex-IVDU 20 years ago  Alcohol >20 g/day for 8 years, none for 18 years  Asymptomatic apart."

Similar presentations


Ads by Google