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Obesity and Response to Hepatitis C Therapy

Obesity and Response to Hepatitis C Therapy. Hossam Kandil Gastroenterology& Nutrition University of Pittsburgh May 2010. Natural History of Hepatitis C. Acute Hepatitis C. 10-20 years. Chronic Hepatitis 75%-85 %. Cirrhosis 20 %. Annual rate. Decompensation 3-6 %.

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Obesity and Response to Hepatitis C Therapy

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  1. Obesity and Response to Hepatitis C Therapy Hossam Kandil Gastroenterology& Nutrition University of Pittsburgh May 2010

  2. Natural History of Hepatitis C Acute Hepatitis C 10-20 years Chronic Hepatitis 75%-85 % Cirrhosis 20 % Annual rate Decompensation 3-6 %

  3. Treatment of Hepatitis C • Currently approved standard treatment is combination of PEG-Interferon-a + Ribavirin • Treatment is for 6 or 12 months (based on genotype) • Overall Response (SVR) 50% • Genotype-1 & 4 40% • Genotype-2 80% • Genotype-3 70% • SVR = Sustained Virological Response

  4. Independent factors associated with an SVR Multiple Logistic Regression Analysis 2    Odds Ratio (95% CI) No effect on SVR Greater effect on SVR Randomizes control Study of Peg-INFa2a versus IFNa2a 3X/week (BMI (> vs ≤ 28) and weight > vs ≤85 kg were NOT risk factors) Zeuzem S. NEJM 2000;343:1666-72.

  5. Weight and Response to Hepatitis C treatment Prospective study of 145 patients with CHC • 95% Caucasian, 5% Asian • IFN, PEG-IFN, or IFN + Ribavirin. • Only those who completed 80% of therapy • Obese = >30 for Caucasians or > 25 for Asians Factors Associated with Non-Response OR (95% CI) Genotypes 1 & 4 4.1 (1.9 – 8.9)* Cirrhosis 3.2 (1.2 – 9.0)* Obesity 3.9 (1.4 – 11.2)* Walsh MJ. Gut 2006;55:529-35

  6. Risk Factors for Non-Response to Hepatitis C Treatment • Genotype 1 & 4 • Presence of advanced fibrosis/cirrhosis • Age • High viral load • Ethnicity • Steatosis • Obesity

  7. How does Obesity decrease Response to Hepatitis C Treatment? • Lower dose/body weight • Larger volume of Distribution • Poor lymphatic drainage from subcutaneous tissue. • Associated Metabolic Syndrome with steatosis and increased fibrosis • Impaired biological response to interferon.

  8. Metabolic Syndrome Obesity (Central) Diabetes, HTN Dyslipidemia Fatty liver Disease Insulin Resistant State

  9. Fat-Derived Factors Regulate Hepatic Inflammatory Response Hormones Leptin Resistin Adiponectin Cytokines TNF a IL-6 Fat Fatty Acids Triglycerides Liver

  10. Metabolic Syndrome Abnormal production of hormones & cytokines that regulate inflammatory responses ANTI- inflammatory TNFa IL-1, IL-6 Lepin PRO- inflammatory

  11. Steatosis and Hepatitis C • In studies of liver biopsies of HCV patients with known date of infection • Obesity (BMI) is associated with steatosis • Central adiposity is associated with steatosis and higher fibrosis progression • Hepatitis C patients with steatosis have: Increased inflammation and fibrosis Higher annular rate of fibrosis progression • Adinolfi LE, Hepatol 2001;33:1358- • Hourigan LF, Hepatology 1999, 29:1215-

  12. Metabolic Syndrome • Inflammation in obesity modulates inflammatory response to IFN suppressors of IFNa activity (e.g. SOCS). TH-1 to TH-2 • Increased TNFa and Leptin resistance associated with non-response to treatment.

  13. Effect of Weight management If obese subjects do not respond to standard hepatitis C treatment; Can weight management improve response to Hepatitis C treatment??

  14. Early Weight Loss During Pegylated Interferon Therapy of Treatment-Naïve Hepatitis C is Associated with Improved Virological Response Hany Alwakeel MD, Hassan Zaghla MD PhD, Nabeel Omar MD PhD, Hassan Alshinnawy MD PhD, Eman Rewisha MD PhD, Azza Taha MD, Stephen O’Keefe MD MSc, Toby Graham MD, Hossam Kandil MD, PhD National Liver Institute, Shibin Alkom, Menofeya, Egypt University of Pittsburgh Medical Center, Pittsburgh, PA JPEN 2010, H44-6

  15. Rationale/Objective • Spontaneous weight loss is commonly experienced during PEG-IFN + Ribavirin combination therapy. • We examined whether treatment-associated weight loss during PEG-IFN + Ribavirin therapy is associated with improved response rate.

  16. Methods • Patients were categorized into 2 groups: • Weight loss group (WL) • No-weight loss group (NWL) - Weight loss = BMI decreased by 0.5 kg/m2 or more versus pre-treatment BMI

  17. Methods Viral response rates compared among WL and NWL • Rapid Virological Response (RVR) Viral clearance at 4 weeks • Early Virological Response (EVR) 2 log drop in viral load at 12 weeks • End of Treatment Response (ETR) Viral clearance at 48 weeks • Sustained Virological Response (SVR) Viral clearance at 72 wks RVR and EVR significantly associated with SVR

  18. Effect of Weight Loss at 1 month onVirological Responses WLNWLp • RVR 50% 43.5% 0.1 • EVR 83.8%* 76.2% 0.01 • ETR 71%* 63.6% 0.02 • SVR 55.3% 48.4% 0.1

  19. Effect of Weight Loss at 3 months on Virological Responses WLNWLp • EVR 89.4%* 76.2% 0.02 • ETR 73.2% 69% 0.6 • SVR 59.3% 47.9% 0.2

  20. Factors Associated with Virological Responses RVREVRSVR Age Wt loss @ 1 m* Genotype* Race Wt loss @ 3 m *Age* Viral load Age Longer Treat* Genotype* Longer Treat *Viral load* Steatosis Fibrosis Genotype * Independently associated with +ve response by multivariate regression analysis

  21. Conclusion • Spontaneous weight loss during the first 3 months of PEG-IFN + Ribavirin therapy is associated with improved early virological response. • Weight management programs at the beginning of PEG-IFN + Ribavirin therapy may improve virological response.

  22. Effects of dietary and behavioral management of obesity and metabolic syndrome on response to Hepatitis C therapy Randomized, Double Blind, Placebo Controlled Pprospective Study.

  23. Intervention Group (BMI ≥ 30) Standard 12 month treatment Pegylated Interferon + Ribavirin Monthly follou up cessions Nutr Education Orlistat/Placebo

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