Curing Hepatitis C: Individualized Approach and New Therapies
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Curing Hepatitis C: Individualized Approach and New Therapies

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  • Histology Fibrosis may exist in an early stage, being confined to the portal tracts, an intermediate stage consisting of expansion of the portal tracts and bridging between portal areas or to the central area, or a late stage of frank cirrhosis characterized by architectural disruption of the liver with fibrosis and regeneration Fibrosis can be graded on a scale from 0 to 4 Stage 0: No fibrosis Stage 1: Enlargement of the portal areas by fibrosis Stage 2: Fibrosis extending out from the portal areas with rare bridges between portal areas Stage 3: Many bridges of fibrosis that link up portal and central areas of the liver Stage 4: cirrhosis
  • SVR and Long-Term Outcomes in HCV-Related Cirrhosis Key point: In patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFN alpha therapy was associated with a reduction of liver-related mortality, lowering both the risk of complications and HCC development Background: Retrospective analysis of all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFN alpha monotherapy between January 1992 and December 1997 at the Liver Unit of the AO Fatebenefratelli e Oftalmico, Milan, Italy Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI, 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI, 1.71-28.42) compared with SVR Reference Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology . 2007;45:579-587.

Curing Hepatitis C: Individualized Approach and New Therapies Curing Hepatitis C: Individualized Approach and New Therapies Presentation Transcript

  • Curing Hepatitis C: Individualized Approach and New Therapies Lorenzo Rossaro, MD Gastroenterology and Hepatology University of California Davis Medical Center
  • c/o  Liver Cancer (HCC)
  • HCV History: Outcome Factors Male, Age, 3.6% POSITIVE ETOH HBV HIV Interferon + Ribavirin Transplant NEGATIVE
  • HCV Screening: Who is at risk (%)
    • Blood product for clotting problems produced  1987 (i.e.hemophilia) ~90
    • Injected illegal drugs (IVDU) 80
    • Long-term kidney dialysis 10
    • Blood transfusion or solid organ transplant  July, 1992 6
    • Born from HCV+ mother 5
    • Tattoos, cocaine, body piercing ?
  • HCV: diagnosis and staging
    • Proposed Algorithm
    • 1 Screening: (ALT) and HCV Antibody
    • 2 Confirmation: HCV-RNA ( not RIBA)
    • 3 Predict success: HCV-Genotype
    • 4 Refer to Liver Clinic and/or Request
    • Liver Biopsy (if appropriate)
  • Hepatitis C Genotype in U.S.: Predict Response to Treatment BEST RESPONSE Type 2 INTERMEDIATE RESPONSE Type 3 and 4 LOWEST RESPONSE Type 1
  • HCV: Severity of Liver Disease
    • Symptoms and Liver “Function” Tests: usually in late stages
    • ALT levels: often normal
    • Ultrasound Examination: not sensitive for fibrosis/staging
    • Liver Biopsy: gold standard
    • Consider fibrosis markers or elastography
  • Fibrospect 
    • Low values (<20) indicative of mild disease
    • High values (>80) indicative of advanced disease
    • Between 20 and 80: can be anything
  • Assessing the Severity of Liver Disease
    • LIVER BIOPSY
    • The most accurate method of determining disease severity and activity
    • Disease severity = Fibrosis ( stage: 1-4 )
    • Indicator of prognosis
    • Helpful in guiding treatment options
  • Liver Biopsy by Stage Cirrhosis Mild Fibrosis
  • Treatment Response by Genotype and Duration of Therapy 1987-1997 2002-2011 1998-2001
  • Hepatitis C The Goals of Treatment
    • Virus eradication = negative HCV-RNA six months after the end of treatment = CURE
    • Decrease progression of disease:
      • from hepatitis to cirrhosis (or reverse ?)
      • risk of cancer (Hepato Cellular Carcinoma)
      • need for liver transplant or retransplant
  • HCV: Who should be treated ?
    • Whoever is affected in some way by the chronic disease
    • AND
    • fully understands the risks and benefits of therapy
  • Side effects of Interferons
    • FLU-like symptoms (®Tylenol)
    • Behavioral changes:
      • Depression, Irritability
    • Myelosuppression:
      • Neutropenia
      • Thrombocytopenia
    • Skin, GI, Thyroid, Hair loss
  • Ribavirin: Risk of Treatment
    • Hemolytic anemia
      • Reversible
      • May require dose reduction or erythropoietin in selected patients
    • Pregnancy Risks
      • Contrtraception required
  • C P C = Complete EVR; P = Partial EVR
  • SVR with 48 wks PEG+RIBA and Patterns of Virological Response (R=Rapid 4w, E=Early 12w, N=none, c=complete, p=partial) RVR cEVR pEVR NVR Marcellin P. AASLD 2007
  •  
  • Factors Associated with Cure
    • Viral
      • Non-1 Genotype (2,3)
      • Lower Viral Load
      • Rapid /Early response
    • Disease related
      • No fibrosis/cirrhosis
      • Higher ALT
      • Lack of steatosis
    • Ribavirin dosage (~15 mg/kg)
    • Adherence
      • More than 80% of intended treatment for > 80% of intended duration
    • Host Factors
      • Lower body weight
      • Younger age
      • Female gender
      • Race (non-AA, non-Latino)
  • January 15, 2009
  • We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). January 15, 2009
  • New Studies for Hepatitis C at UC-Davis Fully enrolled* Roche/ Intermune 2b Naïve geno 1 Protease PEG+RBV Roche/ Pharmassett 2b Naïve geno 1 Polymerase PEG+RBV Sciclone 2b Relapsers New IM+RBV No PEG Novartis 1 Non Responders Cyclophillin + * PEG Schering 3 Naïve genotype 1 And Non Respond. Protease * PEG+RBV Drug Patient Population Phase Sponsor Protease * PEG+RBV Naïve geno 1 3 Vertex
  • NEW drugs for Hepatitis C
    • Will not be approved until 2011-2012 ?
    • Improved efficacy with TRIPLE Rx (~70%)
    • Ribavirin and IFN still platform 3-5 yrs
    • Added side effects: neutropenia, lymphopenia, skin toxicities
    • Breakthrough and resistance concerns
    • How many will pass phase 2 and 3 ?
  •  
  • Education for Health Choices
    • Moving Mountains
      • Train Providers for “Hands on” management of liver disease
    • Leslie Benson (916) 717-5722
    HCV University
    • http://www.hcvu.org
    • HCV University is a project of OASIS, a not-for-profit community-based clinic located in Oakland, CA (Diana Sylvestre)
  •  
  • Summary
    • Hepatitis C is a serious disease
    • Ask about risk factors and  HCV Ab
    • Confirm HCV-RNA and Genotype
    • Consider treatment to cure and to halt progression to cirrhosis and cancer
    • Standard therapy: Pegylated Interferons and Ribavirin
    • Refer for Clinical Trials with New Rx
  • GI and Hepatology Clinical Research Group Thank you
    • Thomas Amankonah
    • Chris Bowlus
    • Juan Carlos Garcia
    • Valentina Medici
    • Thomas Prindiville
    • Lorenzo Rossaro
    • Natalie Torok
    • Shiro Urayama
    • Mark Zern
    • Laura Lester (Supervisor)
    • Annika Bryant
    • Sandeep Dhaliwal
    • Nicole Ekedahl
    • Mia Minoletti
    • Emanuel Obanor
    • Nina Parks
    • Elizabeth Pickett
    • Monica Ruiz
    • Ann Sanchez
    • Yihey Yuk
  • How to refer for GI and Hep studies
    • Laura Lester, NP
    • Phone (916) 734-8696
    • Fax (916) 734-8666
    • E-mail: laura.lester@ucdmc.ucdavis.edu
    • Nina Willis, MA
    • Phone (916) 734-8942
    • Fax (916) 734-8850
    • E-mail: nina.willis@ucdmc.ucdavis.edu