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:
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
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
Age Male sex Co-infections - HBV/HIV Alcohol Steatosis / Obesity / DM / Insulin Resistance Clinical Risk Factors for Fibrosis in HCV
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 = 522 85 – 105 kg n = 1654
Mechanisms for Hepatic Fibrosis Development Hepatic Fibrosis Obesity Steatosis Insulin Resistance Inflammation Genotype 3
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
Increased body mass index (≥30 kg/m 2 ) Central adiposity Hypertension Dyslipidemia Insulin resistance Metabolic Syndrome
Association of Hepatic Steatosis and Fibrosis Hourigan HF et al. Hepatology 1999;29:1215-19. Steatosis Grade
Association of Hepatic Steatosis and Fibrosis P-value <0.001 Adinolfi LE et al. Hepatology 2001; 33:1358-64.
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
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
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*) 0.5-1.5 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;358:958-65 Fried NEJM 2002;347:975-82 * Patients with fibrosis data available. † 800 mg/day. ‡ 1000 mg/day if 75 kg and 1200 mg/day if >75 kg. ND = not done.
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
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 4 4.9 4.1 3.9 HCV RNA (log 10 ) STARTS PEG-IFN alfa-2a 180 μg and RBV 1200 mg
How does my body size effect response? Was I treated with enough interferon? Was my dose of RBV appropriate? Patient Asks the Physician
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
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) ÷ 22.5. 60.5 40 20 0 40 60 80 100 HOMA <2HOMA 2–4HOMA >4 PEG-IFN alfa-2b or alfa-2a + RBV 1000–1200 mg Romero-Gomez et al. Gastroenterology 2005;128:636-41.
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
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
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
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