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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

Obesity and Response to Hepatitis C Therapy

Hossam Kandil

Gastroenterology& Nutrition

University of Pittsburgh

May 2010


Natural history of hepatitis c
Natural History of Hepatitis C

Acute Hepatitis C

10-20 years

Chronic Hepatitis

75%-85 %

Cirrhosis 20 %

Annual rate

Decompensation 3-6 %


Treatment of hepatitis c
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


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.


Weight and response to hepatitis c treatment
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


Risk factors for non response to hepatitis c treatment
Risk Factors for Non-Response to Hepatitis C Treatment

  • Genotype 1 & 4

  • Presence of advanced fibrosis/cirrhosis

  • Age

  • High viral load

  • Ethnicity

  • Steatosis

  • Obesity


How does obesity decrease response to hepatitis c treatment
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.


Metabolic Syndrome

Obesity (Central)

Diabetes, HTN

Dyslipidemia

Fatty liver Disease

Insulin Resistant State


Fat-Derived Factors

Regulate Hepatic Inflammatory Response

Hormones

Leptin

Resistin

Adiponectin

Cytokines

TNF a

IL-6

Fat

Fatty

Acids

Triglycerides

Liver


Metabolic Syndrome

Abnormal production of hormones & cytokines that regulate inflammatory responses

ANTI-

inflammatory

TNFa

IL-1, IL-6

Lepin

PRO-

inflammatory


Steatosis and hepatitis c
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-


Metabolic syndrome
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.


Effect of weight management
Effect of Weight management

If obese subjects do not respond to standard hepatitis C treatment;

Can weight management improve response to Hepatitis C treatment??


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


Rationale objective
Rationale/Objective Treatment-Naïve Hepatitis C is Associated with Improved Virological Response

  • 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.


Methods
Methods Treatment-Naïve Hepatitis C is Associated with Improved Virological Response

  • 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


Methods1
Methods Treatment-Naïve Hepatitis C is Associated with Improved Virological Response

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


Effect of weight loss at 1 month on virological responses
Effect of Weight Loss at Treatment-Naïve Hepatitis C is Associated with Improved Virological Response1 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


Effect of weight loss at 3 months on virological responses
Effect of Weight Loss at Treatment-Naïve Hepatitis C is Associated with Improved Virological Response3 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


Factors associated with virological responses
Factors Associated with Virological Responses Treatment-Naïve Hepatitis C is Associated with Improved Virological Response

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


Conclusion
Conclusion Treatment-Naïve Hepatitis C is Associated with Improved Virological Response

  • 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.


Effects of dietary and behavioral management of obesity and metabolic syndrome on response to Hepatitis C therapy

Randomized, Double Blind, Placebo Controlled Pprospective Study.


Intervention group bmi 30
Intervention Group (BMI metabolic syndrome on response to Hepatitis C therapy≥ 30)

Standard 12 month treatment

Pegylated Interferon + Ribavirin

Monthly follou up cessions

Nutr Education

Orlistat/Placebo


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