Скачать презентацию Hepatology Update Sanjeev Arora M D Distinguished Professor Скачать презентацию Hepatology Update Sanjeev Arora M D Distinguished Professor

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Hepatology Update Sanjeev Arora M. D. Distinguished Professor of Medicine Director Project ECHO Department Hepatology Update Sanjeev Arora M. D. Distinguished Professor of Medicine Director Project ECHO Department of Internal Medicine University of New Mexico Health Sciences Center, Albuquerque NM 87131 -0001 Tel: 505 -272 -2808 E-mail: [email protected] unm. edu

Estimated 170 Million Persons With HCV Infection Worldwide • Europe • Western Pacific • Estimated 170 Million Persons With HCV Infection Worldwide • Europe • Western Pacific • 8. 9 million • Americas • 62. 2 million • (1. 03%) • (3. 9%) • Southeast Asia • 13. 1 million • (1. 7%) • Africa • Eastern Mediterranean • 31. 9 million • 21. 3 million • (5. 3%) • 32. 3 million • (4. 6%) • (2. 15%) • World Health Organization. Wkly Epid Rec. 1999; 74: 425 -427. World Health Organization. Hepatitis C: Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000; 20: 103 -126. Wasley A, et al. Semin Liver Dis. 2000; 20: 1 -16.

Future Burden of Hepatitis C Related Morbidity and Mortality in the US – Markov Future Burden of Hepatitis C Related Morbidity and Mortality in the US – Markov model of health outcomes • Of 2. 7 M HCV infected persons in primary care o 1. 47 M will develop cirrhosis o 350, 000 will develop liver cancer o 897, 000 will die from HCV-related complications Rein D, et al. Dig Liver Dis 2010.

Mortality associated with Hepatitis B, Hepatitis C, and HIV United States, 1999 – 2008 Mortality associated with Hepatitis B, Hepatitis C, and HIV United States, 1999 – 2008 * From: K Ly et al, Ann Intern Med 2012; 156: 271 -8

NEW CDC Recommendation – Adults born during 1945 through 1965 should receive one-time testing NEW CDC Recommendation – Adults born during 1945 through 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk factor – Benefits of therapy • Reduces risk of liver cancer by 70% • Reduces risk of all-cause mortality by 50%

Screening for HCV infection in Adults: USPSTF Recommendations • Released June 24, 2013 • Screening for HCV infection in Adults: USPSTF Recommendations • Released June 24, 2013 • USPSTF Grade B recommendation o Adults at high risk o Adults born 1945 -1965 • Grade B – o Co-pay support (ACA) o Priority for performance measures, and changes in EMR • Consistent with CDC recommendations

HCV Test, Care, and Cure Continuum 50% 38% 23% 11% Holmberg S, et al, HCV Test, Care, and Cure Continuum 50% 38% 23% 11% Holmberg S, et al, NEJM, 2013) 6%

Educate Communities Educate Communities

HCV Testing Algorithm HCV Testing Algorithm

HCV antibody Positive and HCV RNA negative patients • If liver function tests are HCV antibody Positive and HCV RNA negative patients • If liver function tests are normal no further testing or follow up required • Patients who have attained sustained viral response with treatment need not have repeated tests for HCV RNA to confirm a cure • If liver function tests are elevated evaluate for other etiologies of liver disease

Treatment Rates Are Low • Estimated that treatment will prevent only 14. 5% of Treatment Rates Are Low • Estimated that treatment will prevent only 14. 5% of potential liverrelated deaths caused by HCV between 2002 and 2030 if 2009 trends continued Volk ML, et al. J Hepatol. 2009; 50: 1750 -1755.

Treatment Reduces All-Cause Mortality in Patients With Advanced Fibrosis Van der Meer AJ, et Treatment Reduces All-Cause Mortality in Patients With Advanced Fibrosis Van der Meer AJ, et al. JAMA. 2012; 308: 2584 -2593.

Impact of Treatment on HCC Van der Meer AJ, et al. JAMA. 2012; 308: Impact of Treatment on HCC Van der Meer AJ, et al. JAMA. 2012; 308: 2584 -2593.

Impact of Treatment on Liver Failure Van der Meer AJ, et al. JAMA. 2012; Impact of Treatment on Liver Failure Van der Meer AJ, et al. JAMA. 2012; 308: 2584 -2593.

Management of the Patient with Hepatitis C Management of the Patient with Hepatitis C

Approach to the Patient with Newly Diagnosed HCV • Patients need to be educated Approach to the Patient with Newly Diagnosed HCV • Patients need to be educated on – – – the natural history of disease modes of transmission of how to avoid transmission to family members the availability of effective treatment the promise of new highly effective and safe interferon free treatments in the near future • Screen for depression • Reassurance • Patients may benefit from referral to a support group

Additional Measures for Newly Diagnosed Patients with HCV • Vaccinate for hepatitis A and Additional Measures for Newly Diagnosed Patients with HCV • Vaccinate for hepatitis A and hepatitis B • Counsel for weight loss if appropriate. Obesity increases likelihood of liver fibrosis • Recommend avoiding doses of acetaminophen exceeding 1 -2 grams per day • Determine presence or absence of cirrhosis • NSAIDs should be avoided in patients with advanced fibrosis or cirrhosis

Measures to Avoid Transmission of Hepatitis C • • Avoid Sharing Razors or Toothbrushes Measures to Avoid Transmission of Hepatitis C • • Avoid Sharing Razors or Toothbrushes Cover Bleeding Wounds Stop Injection Drug Use Advise Not to Share Needles and Paraphernalia • Advise Not to Donate Blood, Organs, Tissue or Semen

Sexual Transmission of HCV • Risk of Sexual Transmission is Low in Monogamous Heterosexual Sexual Transmission of HCV • Risk of Sexual Transmission is Low in Monogamous Heterosexual Relationships • Many Experts do not Recommend Barrier Protection for Couples that are in a Monogamous Long Term Relationship • Patients with Multiple Sexual Partners, and Patients with HIV Should Use Barrier Protection

Steps to Slow Progress of Liver Disease • Obesity and Smoking Increase Liver Fibrosis Steps to Slow Progress of Liver Disease • Obesity and Smoking Increase Liver Fibrosis • Daily Marijuana Use Increases Fibrosis Progression Rate. Odds Ratio = 3. 4 (1. 5 -7. 4) • Patients Should be Counseled to: – Lose Weight if Necessary – Stop Smoking – Discontinue Marijuana Use • • Hu KQ: J Hepatol. 2004 Jan; 40(1): 147 -54 Hu SX: J Clin Gastroenterol. 2009 Sep; 43(8): 758 -64 Mallat A: J Hepatol. 2008 Apr; 48(4): 657 -65 Hezode C: Hepatology. 2005 Jul; 42(1): 63 -71

Hepatitis C and Alcohol • Hepatitis C Infection Rates in Alcoholics are Significantly Higher Hepatitis C and Alcohol • Hepatitis C Infection Rates in Alcoholics are Significantly Higher Than Controls • Alcohol Use in Patients with HCV Infection Increases Fibrosis Progression Rate, Risk for Liver Cancer and Overall Mortality • Abstinence from Alcohol is Recommended • Educate on Synergistic Damage to liver by Alcohol and HCV • Refer to Alcohol Rehab Programs if appropriate • • Coelho-Little ME: Alcohol Clin Exp Res. 1995; 19(5): 1173 Chen CM: Alcohol Clin Exp Res. 2007; 31(2): 285 Delarocque-Astagneau E: Ann Epidemiol. 2005; 15(8): 551 Hassan MM: Hepatology. 2002; 36(5): 1206

Screening for Depression • Mental health screening prior to initiating HCV therapy is recommended: Screening for Depression • Mental health screening prior to initiating HCV therapy is recommended: – Patients infected with HCV have increased rates of depression – depression and other psychiatric illnesses may worsen during interferon-based treatment – active and untreated mental health issues can interfere with adherence to HCV treatment Weinstein AA. Psycosomatics. 2011; 52: 127 -32. Lee DH. Dig Dis Sci. 1997; 42: 186 -91. Morasco BJ, J Affect Disord. 2007 Nov; 103(1 -3): 83 -90.

Screening for Depression • An evaluation prior to therapy serves as a baseline if Screening for Depression • An evaluation prior to therapy serves as a baseline if psychiatric issues develop during HCV therapy. • Family and social support issues should be explored to improve patient adherence to therapy. • We recommend the use of the Patient Health Questionnaire (PHQ-9), a standardized depression screening tool, before and during HCV treatment. • IFN-induced depression responds rapidly to treatment; Prophylactic antidepressants are required only for patients with a history of depression or anxiety disorders or history of IFNinduced depression. Weinstein AA. Psycosomatics. 2011; 52: 127 -32. Lee DH. Dig Dis Sci. 1997; 42: 186 -91. Morasco BJ, J Affect Disord. 2007 Nov; 103(1 -3): 83 -90.

Baseline Studies in Persons with Chronic HCV Infection • CBC, PT, INR • Comprehensive Baseline Studies in Persons with Chronic HCV Infection • CBC, PT, INR • Comprehensive metabolic panel including LFTs • Serum ferritin level, serum iron and total iron binding capacity • Urine analysis • HCV genotype and subtype • Quantitative HCV RNA • Hepatitis A serology (total or Ig. G) • Hepatitis B serology (Hep. Bs. Ag, Hep. Bs. Ab, Hep. Bc. Ab) • HIV Antibody For Patients not interested or being considered for treatment repeat liver function tests every 3 -6 months. It is not necessary to repeat HCV RNA or genotype

Additional Diagnostic Studies in Selected Patients • Serum Ceruloplasmin (Wilson’s Disease) • Serum ANA Additional Diagnostic Studies in Selected Patients • Serum Ceruloplasmin (Wilson’s Disease) • Serum ANA and Anti Smooth Muscle Antibody (Autoimmune Hepatitis) • Serum Cryoglobulins • IL-28 B testing: CC Genotypes CC at the rs 12979860 polymorphic site have higher rates of Sustained Viral Response (Ge D, Fellay J: Nature. 2009; 461(7262): 399 -401. )

HCV and Diabetes Mellitus • Meta analysis of 34 studies • Pooled estimators indicated HCV and Diabetes Mellitus • Meta analysis of 34 studies • Pooled estimators indicated significant DM risk in HCV-infected cases in comparison to non-infected controls. – Retrospective studies(OR(adjusted)=1. 68, 95% CI 1. 15 -2. 20) – Prospective studies (HR(adjusted)=1. 67, 95% CI 1. 28 -2. 06) – Excess DM risk was also observed in comparison to HBV-infected controls (OR(adjusted)=1. 80, 95% CI 1. 20 -1. 40) – Suggestive excess risk of DM observed in HCV+/HIV+ cases in comparison to HIV+ controls (OR(unadjusted)=1. 82, 95% CI 1. 272. 38). • Data suggests a potential direct viral role in promoting DM risk • White DL: J Hepatol. 2008; 49(5): 831

Patients with Extrahepatic Manifestations should be prioritized for treatment • • • Essential Mixed Patients with Extrahepatic Manifestations should be prioritized for treatment • • • Essential Mixed Cryoglobulinema Leukocytoclastic vasculitis B Cell Non Hodgkin’s Lymphoma Porphyria Cutanea Tarda Necrolytic acral erythema Renal Disease – Membranoproliferative glomerulonephritis – Membranous nephropathy – Nephrotic syndrome

Classical Cryoglobulinemia-related small vessel vasculitis with erythematosus palpable maculopapular rash in a HCV positive Classical Cryoglobulinemia-related small vessel vasculitis with erythematosus palpable maculopapular rash in a HCV positive patient composed of monoclonal and polyclonal gamma globulins. Room Temperature 4 degrees http: //openi. nlm. nih. gov/

Membranoproliferative Glomerulonephritis There is increased lobulation, intracapillary hypercellularity (including neutrophil infiltration), and thickening of Membranoproliferative Glomerulonephritis There is increased lobulation, intracapillary hypercellularity (including neutrophil infiltration), and thickening of the capillary walls Need to get permission to use:

Does the Patient Have Advanced Fibrosis or Cirrhosis? F 0 F 1 F 2 Does the Patient Have Advanced Fibrosis or Cirrhosis? F 0 F 1 F 2 F 3 F 4 • Metavir Staging • Stage F 0 – No Fibrosis • Stage F 1 – Portal fibrosis • Stage F 2 – Bridging fibrosis with few septa • Stage F 3 – Bridging. Bedossawith many septa • fibrosis P, Poynard T Hepatology. 1996; 24(2): 289 • Stage F 4 – Cirrhosis

Diagnosis of Cirrhosis Changes Approach to Patients with HCV • • Screen for HCC Diagnosis of Cirrhosis Changes Approach to Patients with HCV • • Screen for HCC every 6 months Evaluate for esophageal varices with endoscopy Avoid all hepatotoxic drugs Refrain from use of NSAIDs including aspirin, ibuprofen, naproxen, and others due to an increased risk of gastrointestinal bleed, potential for renal toxicity, and impaired response to diuretic therapy. • Prioritize for treatment • Recommend weight loss for obese patients • Avoid use of aminoglycosides for treatment of infections

Findings Suggestive of Cirrhosis • Clinical exam – Spider nevi, palmar erythema, gynecomastia, firm Findings Suggestive of Cirrhosis • Clinical exam – Spider nevi, palmar erythema, gynecomastia, firm liver on palpation, splenomegaly • Noninvasive diagnostic tests suggesting cirrhosis – – – – Low platelet count (150 thousand) Low serum albumin, AST/ALT ratio >1 Prolonged prothrombin time High APRI score or Fibrosure test score Ultrasound transient elastography Platelets < 150 thousand Neutropenia • Liver biopsy

Commonly Used Biochemical Tests to Assess Severity of Liver Disease • AST to Platelet Commonly Used Biochemical Tests to Assess Severity of Liver Disease • AST to Platelet Ratio Index (APRI score) • Fibro. Test (Europe) and Fibro. Sure (United States • MELD (Serum Bilirubin, Serum Creatinine and international normalized ratio for prothrombin time -INR)

AST to Platelet Ratio Index (APRI score) • APRI = (AST elevation/platelet count) x AST to Platelet Ratio Index (APRI score) • APRI = (AST elevation/platelet count) x 100 • A patient has an AST level of 80 IU/L in a lab with an ULN = 40 IU/L. AST Elevation is 80/40=2. Platelet count is 130, 000/mm 3. APRI score is: (2/130) x 100 = 1. 54 • APRI score > 1. 0 has a sensitivity of 76% and specificity of 72% for cirrhosis • Area Under ROC curve is 0. 80 • Lin ZH et al: Hepatology. 2011; 53(3): 726, Castera L. Gastroenterology. 2012; 142: 1293–

Ultrasound based Transient Elastography (Fibro. Scan) • The more stiff/fibrotic the liver the faster Ultrasound based Transient Elastography (Fibro. Scan) • The more stiff/fibrotic the liver the faster the wave propagates. • Liver Biopsy 1/50, 000 of liver, Fibroscan 1/500 of liver • Is quick, painless and reproducible • Friedrich-Rust M, et al. Gastroenterology 2008; 134: 960.

All HCV Patients Should be Considered for Treatment Decision for an Individual Based On All HCV Patients Should be Considered for Treatment Decision for an Individual Based On Risk/Benefit – Fibrosis stage – type of assessment/accuracy – Likelihood of SVR • IL 28 B, IFN-response characteristics – Likelihood to tolerate – IFN + additional AEs – Stage of life • Age, family planning, job, finances – Other factors • Transmission risk, extra hepatic manifestations – Patient Preference

SVR Rates with Peg. IFN/RBV According to Genotype • 76%-82% • 42%-46% • Genotype SVR Rates with Peg. IFN/RBV According to Genotype • 76%-82% • 42%-46% • Genotype 1 • Genotype Non-1 • Adapted from Strader DB et al. Hepatology. 2004; 39: 1147 -1171.

DAAs Uniquely Target Hepatitis C Virus Potential targets for antiviral intervention in the HCV DAAs Uniquely Target Hepatitis C Virus Potential targets for antiviral intervention in the HCV lifecycle and their location in the HCV genome Receptor binding and endocytosis Fusion and uncoating Transport and release α- glucosidase Inhibitors N 3/4 protease inhibitors (telaprevir, boceprevir) Viral assembly RNA replication Translation and polyprotein processing NS 5 B polymerase inhibitors Cyclophilin inhibitors Adapted from Manns MP, et al. Nature reviews. Drug discovery. 2007; 6(12): 991 -1000.

Treatment Naïve: Protease Inhibitors IM Jacobson et al. N Eng J Med 2011; 364: Treatment Naïve: Protease Inhibitors IM Jacobson et al. N Eng J Med 2011; 364: 2405 -2416. F Poordad et al. N Engl J Med 2011; 364: 1195 -1206

Sample of Investigational HCV Regimens with one DAA + PEG-IFN alfa/RBV ABT-072, -333 (NNIs) Sample of Investigational HCV Regimens with one DAA + PEG-IFN alfa/RBV ABT-072, -333 (NNIs) ABT-450 (PI) BI 201335 (PI) Daclatasvir (NS 5 A) Asunaprevir(PI) Danoprevir (PI) Mericitabine (NI) GS-7977 (NI) Tegobuvir (NNI) TMC-435 (PI) Alisporivir (Cyp) Regimens with two DAAs (± PEG-IFN alfa and/or RBV) GS-9526 (PI) + tegobuvir Daclatasvir + Asunaprevir VX-222 (NNI) + telaprevir NNI = non-nucleoside NS 5 B inhibitor, NI = nucleoside NS 5 B inhibitor, PI = protease inhibitor, RBV = ribavirin, NS 5 A = replication complex inhibitor Cyp= cyclophilin inhibitor, r= ritonavir IFN-free regimens GS-7977 + RBV Daclatasvir + GS-7977 Daclatasvir + Asunaprevir ± RBV ABT-450/r + ABT-072 + RBV ABT-450/r + ABT-333 + RBV BI-201335 + BI-207127 ± RBV Mericitabine + Danoprevir/r + RBV GS-5885 + GS-9451 + Tegobuvir + RBV Alisporivir ± RBV Go to Home EASL 2012 program http: //www 2. kenes. com/liver-congress/Pages/Home. aspx

Simeprevir and Faldaprevir: New Protease Inhibitors: Naïve Patients M Manns : European Association for Simeprevir and Faldaprevir: New Protease Inhibitors: Naïve Patients M Manns : European Association for the Study of Liver Disease 2013. P Ferenci: European Association for the Study of Liver Disease 2013. Go to Home

Nucleoside/tide Analog Polymerase Inhibitors Are Chain-Terminators NI Chain-terminator Primer strand 5’ G C C Nucleoside/tide Analog Polymerase Inhibitors Are Chain-Terminators NI Chain-terminator Primer strand 5’ G C C 3’ C G G A U U NI G RNA chain cannot be elongated A C G 5’ Template strand Go to Home

Sofosbuvir - Neutrino Trial (Genotype 1, 4, 5, 6) Treatment Naïve • Sofosbuvir + Sofosbuvir - Neutrino Trial (Genotype 1, 4, 5, 6) Treatment Naïve • Sofosbuvir + Pegylated Interferon + Ribavirin for 12 weeks (n=327) SVR Rate: 90% (genotype 1: 89%, cirrhosis 80%) E Lawitz : N Engl J Med 2013; 368: 1878 -1887 Go to Home

Fission Trial (Genotype 2 and 3 naïve patients) N Engl J Med 2013; 368: Fission Trial (Genotype 2 and 3 naïve patients) N Engl J Med 2013; 368: 1878 -1887 May 16, 2013 SVR 12, % Sofosbuvir/Riba Peginterferon/Riba (n = 256) (n = 243) Genotype 2 97 78 • No cirrhosis 98 82 • Cirrhosis Genotype 3 91 56 62 63 • No cirrhosis 61 71 • Cirrhosis 34 30 Go to Home

Preliminary Results of New Interferon Free Regimens in Phase 2 Trials Regimen Sufosbuvir + Preliminary Results of New Interferon Free Regimens in Phase 2 Trials Regimen Sufosbuvir + Ledipasvir + RBV ABT 450/r + ABT 267 + ABT 333 + RBV Faldaprevir + 207127 + RBV (GT 1 B) DCV + ASV +BMS-791325 SVR Rate Duration in Weeks >95% 8 -12 12 ~90% 12 -24 88 -94% 12 -24 Presentations at European Association of Study of Liver Disease and Press releases Go to Home

Characteristics of New Generation DAA Regimens • Antiviral activity seen in all genotypes • Characteristics of New Generation DAA Regimens • Antiviral activity seen in all genotypes • High Barrier to Resistance • Higher SVR rates and shorter treatment duration • Oral, IFN-free, combination regimens have less side effects and higher SVR rates • Patients with cirrhosis and decompensated cirrhosis will benefit from less toxic regimens Go to Home

Two New Protease Inhibitors in Development • Greatly improved Hb profile with simeprevir and Two New Protease Inhibitors in Development • Greatly improved Hb profile with simeprevir and faldaprevir vs boceprevir/telaprevir with no significant increase over peg. IFN/RBV • Simeprevir: Once a day with Peg + Ribavirin: SVR-80% – Generally well tolerated; no added safety signals with triple therapy • Faldaprevir: Once a day with Peg + Ribavirin: SVR-80% – Generally well tolerated (clinically benign and transient bilirubin increases with 240 mg dose; higher incidence of gastrointestinal events and rash) 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. to Home Go Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.

HCV Treatment Based on Individualized Risk-Benefit Analysis Treat now Defer § Triple therapy substantially HCV Treatment Based on Individualized Risk-Benefit Analysis Treat now Defer § Triple therapy substantially increases SVR rates § Current PIs are imperfect § Successful treatment may arrest progression of liver disease § Earlier treatment has higher success rates § Uncertainty about timelines for approval and reimbursement – Complex regimens (TID, lead-in) – Challenging adverse events – Unsuccessful treatment may reduce subsequent treatment success § Next-wave DAAs may achieve – Higher cure rates – Shorter treatment duration – Improved safety and tolerability – IFN-free treatment – Better resistance profile – Activity in non-GT 1 Go to Home

Summary • Educate the patient on preventing transmission of virus and ways to slow Summary • Educate the patient on preventing transmission of virus and ways to slow progress of liver disease • Vaccinate for Hepatitis A and Hepatitis B • Determine if the patient has advanced fibrosis or cirrhosis • Non invasive tests such as APRI score and Transient Elastography are useful to assess extent of liver fibrosis • Successful treatment of patients with advanced fibrosis is life saving. • New Treatments in the next 12 -18 months will have increased efficacy and reduced toxicity Go to Home