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HEPATITIS C IN 2014 Lisa M. Chirch, M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England.

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Presentation on theme: "HEPATITIS C IN 2014 Lisa M. Chirch, M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England."— Presentation transcript:

1 HEPATITIS C IN 2014 Lisa M. Chirch, M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England AETC

2 Disclosures None

3 Objectives Describe epidemiology, transmission, and clinical presentation of Hepatitis C infection Understand and implement new testing and screening recommendations Apply relevant data from recent publications regarding treatment of chronic hepatitis C infection

4 Hepatitis C - Chapter 3 - 2012 Yellow Book | Travelers' Health | CDC wwwnc.cdc.gov

5 Magnitude of the Problem Nearly 4 million persons in United States infected Approximately 35,000 new cases yearly Acute infections on the rise since 2010 <10% chronically infected patients are treated Leading cause of  Chronic liver disease  Cirrhosis  Liver cancer  Liver transplantation http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm.

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7 “Silent Epidemic”  NHANES survey: estimated unidentified HCV infections – 43%  May 2011: U.S. Viral Hepatitis Action Plan  Federal platform  Educate providers and communities  Increase awareness, testing and linkage to care  USPSTF has aligned with CDC on testing recommendations – Grade B Ronald Valdiserri – DHHS Deputy Assistant Secretary; The Liver Meeting 2013

8 Hepatitis C, a Silent Killer, Meets Its Match November 4, 2013

9 Sources of Infection with HCV

10 Indications for HCV screening? HIV IDU History of chronic HD, transfusion, blood product or organ transplant prior to 1992 Unexplained persistent elevation in ALT (?RNA) and….

11 Hepatitis C: Screening guidelines CDC 2012: Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965 Recommendations and Reports, August 17, 2012 …one-time testing without prior ascertainment of HCV risk for persons born during 1945 -1965, a population with a disproportionately high prevalence of HCV infection and related disease.

12 2013: Update of Guidance for Clinicians and Laboratories MMWR May 2013 Availability of rapid test for HCV antibody (OraQuick) –Fingerstick or venipuncture –CLIA waiver by FDA in 2011 Discontinuation of the RIBA HCV Recommended testing sequence:

13 MMWR May10, 2013

14 Question  A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her?  A) 0%  B) 15%  C) 50%  D) 75%  E) 99%

15 Answer  A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her?  A) 0%  B) 15%  C) 50%  D) 75%  E) 99%

16 Hepatitis C Virus Infection Natural History Stable 80% (68%) HCC Liver failure 25% (4%) Slowly progressive 75% (13%) Resolved 15% (15%) Acute HCV Cirrhosis 20% (17%) Chronic HCV 85% (85%) HCC, hepatocellular carcinoma

17 Hepatitis C Virus Genotypes in the USA All others 1% Type 3 10% Type 2 17% Type 1 72% McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

18 Management of Chronic HCV Disease SeverityResponse to Therapy AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology Transient Elastography ALT HCV RNA HCV genotype Liver histology

19 IL28B IL28B:gene coding for IFN-λ3, associated with IFN sensitivity –C/C genotype (vs C/T or T/T) associated with favorable response to HCV treatment in pts treated with PEG/ribavirin Clark PJ, Am J Gastroenterol Oct 2010

20 HCV RNA and Liver Histology Fibrosis Genotype No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis  Serum HCV RNA does not correlate with level of fibrosis 0 2 4 6 8 Log HCV RNA (copies/mL) 1 2 3 4 Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

21 How to Stage

22 Hepatitis C Virus Infection Liver Biopsy Only test that can accurately assess – Severity of inflammation – Degree of fibrosis Determines – Risk for developing cirrhosis in future – Need for therapy – Need for ongoing therapy when initial treatment has failed

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24 Sampling error of liver biopsy

25 Serum Markers of Liver Fibrosis

26 Fibroscan

27 Validity of Fibroscan Versus Biopsy

28 Poynard T, et al. Lancet. 1997;349:825-832. HCV Fibrosis Progression Effect of Alcohol Alcohol intake > 50 g/day* < 50 g/day *50 g is equal to approximately 3.5 drinks < 10 11-2021-3031-40 > 40 Duration of Infection (Years) 4.0 3.0 2.0 1.0 0 Fibrosis Score

29 Fibrosis Progression in HCV Effect of Steatosis 2% 4% 7% 18% 6% 18% 30% 33% 0 20 40 60 80 100 < 5%5%-10%11%-30%> 30% Percentage of Steatosis at Initial Biopsy Cumulative Probability of Fibrosis Progression (%) Year 4 Year 6 Fartoux L, et al. Hepatology. 2005;41:82-87. Cumulative Probability of Fibrosis According to Level of Steatosis

30 Chronic Hepatitis C Virus Extrahepatic Manifestations Nonspecific antibodies Essential mixed cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Mooren’s corneal ulcer Non-Hodgkin’s lymphoma Autoimmune thyroiditis Diabetes mellitus Sjögren’s syndrome

31 HCV Treatment Goals  Goals of treatment for chronic HCV  Viral eradication (undetectable viral load)  Delay progression of fibrosis  Prevent decompensation, HCC, and death  Best indicator of successful treatment is sustained virologic response (SVR)

32 Sustained virologic response  SVR: serum HCV RNA is undetectable based on a quantitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after treatment ends  SVR 12: …12 weeks after treatment ends  RVR  EVR

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34 Treatment of Chronic HCV Peginterferon and Ribavirin 0 20 40 60 80 100 12-3 Genotype Sustained Virologic Response (%) PegIFN-2a/RBV PegIFN-2b/RBV Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

35 Interferon Flu-like symptoms: fatigue, headache, myalgias Dose-related myelosuppression –Reversible with dose reduction (cost?) –Use of G-CSF and erythropoietin Depression: risk assessment prior to therapy initiation –35-40% –Management with SSRIs and TCAs

36 Months Incidence/Severity Depression Fatigue Influenza-like symptoms Time Course of Treatment- Associated Psychiatric Adverse Effects 12340 0 20 40 60 80 100 Dan A, et al. J Hepatol. 2006;44:491-498. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.

37 Ribavirin  Nucleoside analog  Inhibits inosine monophosphate dehydrogenase  Potentiates purine analogs, ie didanosine  Immune modulator, shift from Th2 to Th1 response  Teratogenic  both men and women must use contraception during and for 6 months after treatment  Dose-dependent hemolytic anemia  Increased risk for lactic acidosis

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39 HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Block replication complex formation, assembly NS5A* inhibitors

40 Simple Regimen Short duration, simple, straightforward stopping rules What Are the Key Elements of an Ideal HCV Regimen? Pan-Genotypic Regimen can be used across all genotypes Highly Effective High efficacy in traditionally challenging populations (ie, poor IFN sensitivity, cirrhosis) Safe and Tolerable Few or easily manageable adverse effects All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance Easy Dosing Once daily, low pill burden

41 HCV Therapy: Past, Present and Future Interferon Ribavirin Pegylated interferons Proof of concept for DAA (PI) Suppression of HCV with DAA combination (PI + NI) Telaprevir and boceprevir Curability of HCV without interferon Frequent curability of diverse populations without IFN  Approval of simeprevir and sofosbuvir with IFN  First approved IFN-free therapy: SOF + RBV for GT2/3 IFN-free DAA combinations (GT1) Potential approval of other DAAs with IFN 1990 2000 2005 2010 2011 2012 2013 2014 2015-

42 Telaprevir - PROVE McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 0 20 40 60 80 100 Wk 4 Patients (%) 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 59* Wk 12Wk 24Wk 48 12-wk TVR + pegIFN/RBV (n = 17) Control (n = 75) 81* 11 81* 71 68 45 80 N/A 57 71 SVRRelapse N/A 47 65 N/A 35 61 † 41 67 ‡ 33 2 23 6 Undetectable HCV RNA N/A, not applicable. *P <.001 vs control. † P =.02 vs control. ‡ P =.002 vs control.

43 Summary of Key Conclusions 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV increased SVR rates in treatment- naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV TVR increased rate of treatment discontinuation due to adverse effects, predominantly anemia, rash, rectal symptoms (FIARRHEA) Small subset experienced virologic breakthrough with protease resistance mutations McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

44 No Free Lunch Treatment is more effective but much more difficult Jordan Feld, MD, MPH. Toronto Western Hospital Liver Centre

45 Other Issues With PI-Based Therapy Pill burden Food requirement CYP3A4 PI metabolites Drug-drug interactions Resistance BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day

46 20 grams of fat… Breakfast Ideas –2-egg omelet with 1 ounce shredded cheese; oatmeal with 1 ounce nuts and ½ tablespoon butter; toast with 2 tablespoons unsalted peanut butter and glass of 2% milk; bagel with 2 tablespoons cream cheese and glass of whole milk 1 egg and 1-3 sausage links (check sausage label, need 15 g fat) Lunch / Dinner –6 ounces salmon; ½ box prepared macaroni and cheese; 3 tablespoons of 2 cups of canned chili with meat; sandwich with 3 slices bologna; 1½ beef hot dogs; 1 chicken leg and thigh with skin; burrito with beans, cheese, and guacamole; 2 pork chops; french fries, medium order; quarter-pound hamburger or double cheeseburger

47 Drug–Drug Interactions a Clinical Challenge With Current Therapy Several drugs contraindicated; many more require dose adjustment or caution Drug ClassContraindicated With BOC [1] Contraindicated With TVR [2] Alpha 1-adrenoreceptor antagonist Alfuzosin AnticonvulsantsCarbamazepine, phenobarbital, phenytoin N/A AntimycobacterialsRifampin Ergot derivativesDihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agentsCisapride Herbal productsHypericum perforatum (St John’s wort)Hypericum perforatum HMG CoA reductase inhibitorsLovastatin, simvastatin Oral contraceptivesDrospirenoneN/A NeurolepticPimozide PDE5 inhibitorSildenafil or tadalafil when used for tx of pulmonary arterial hypertension Sedatives/hypnoticsTriazolam; orally administered midazolam Orally administered midazolam, triazolam 1Boceprevir [package insert]. November 2012. 2. Telaprevir [package insert]. October 2012.

48 Limited Efficacy With Telaprevir and Boceprevir in Some Patient Groups 1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bronowicki J, et al. EASL 2012. Abstract 11. 6. Zeuzem S, et al. EASL 2011. Abstract 5. 0 20 40 60 80 100 SVR (%) RelapserNaive White/ Nonblack Null Responder Naive BlackPartial Responder Cirrhotic Null Responder 68-75 [3,4] 53-62 [3,4] *Pooled TVR arms of REALIZE trial. 75-83 [1,2] 40-59 [1,2] 29-40 [1,5] 14 [6] * 42-62 [3,4] Naive Cirrhotic

49 Question  A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed?  A) get a liver biopsy – this will help me decide  B) He cannot receive therapy due to comorbidities  C) Treat with just IFN/ribavirin, he will not likely tolerate a PI  D) Treat with just telaprevir, he will not likely tolerate IFN  E) wait for something better

50 Answer  A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed?  A) get a liver biopsy – this will help me decide  B) He cannot receive therapy due to comorbidities  C) Treat with just IFN/ribavirin, he will not likely tolerate a PI  D) Treat with just telaprevir, he will not likely tolerate IFN  E) wait for something better

51 Standard of Care of Chronic HCV Infection- October 2014 www.hcvguidelines.org GenotypeRegimenDurationConsiderations 1Sofosbuvir + Ledipasvir (FDC) 12 weeks (24 for experienced cirrhotics) FDA approved, not yet in guidance 1Sofosbuvir + IFN/RBV 12 weeksMinimal drug interactions 1Sofosbuvir + Simeprevir +/- RBV 12 weeksOff label to date For IFN ineligible 2Sofosbuvir + RBV12 weeks 3Sofosbuvir + RBV24 weeks

52 NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level Lawitz E, et al. EASL 2013. Abstract 1411. N Engl J Med 2013; 368:1878-1887 SVR12 (%) 92 80 100 80 60 40 20 0 No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) 89 96 100 80 60 40 20 0 GT 1GT 4GT 5,6 261/29227/28 7/7 SVR12 According to Genotype n/N =

53 COSMOS: SVR12 in Cohorts 1 and 2 by HCV Subgenotype and Baseline Q80K Cohort 1 (F0-F2 Nulls)* [1] Cohort 2 (F3-F4 Naives/Nulls)* [2] 1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165. SMV/SOF ± RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 Wks 12 Wks Overall 4/ 4 7/ 7 8/ 9 3/ 3 7/ 7 3/ 3 6/ 6 12/ 12 8/ 9 4/ 4 5/ 6 *Excluding patients who discontinued for nonvirologic reasons. 100 93 88 95 100 88 100 96 SMV/SOF ± RBV SMV/SOF + RBV SMV/SOF 24 Wks12 WksOverall 6/ 6 11/ 11 4/ 4 7/ 7 4/ 4 5/ 5 13/ 14 7/ 8 3/ 3 7/ 8 3/ 3 18/ 18 38/ 40 25/ 26 100 80 60 40 20 0 100 89 100 89 100 83 100 89 GT1b GT1a without Q80KGT1a with Q80K 30/ 30 7/ 17 24/ 27

54 TURQUOISE II: SVR12 With 3 DAAs + RBV in Cirrhotic Pts by HCV Subtype 12 wks 24 wks 100 NaiveRelapse 100 85.7100 Partial Response Null Response GT1b Poordad F, et al. EASL 2014. Abstract O163 SVR12 (%) NaiveRelapse Partial Response Null Response GT1a 59/ 64 14/ 15 52/ 56 13/ 13 11/ 11 40/ 50 10/ 10 39/ 42  Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders 100 80 60 40 20 0 92.2 92.9 93.3 100 80.0 92.9 100 80 60 40 20 0 22/ 22 25/ 25 18/ 18 20/ 20 6/7 14/ 14 3/3 10/ 10

55 Summary of Investigational HCV Agents ClassDrugDosing NS3/4A protease inhibitorABT-450/RTV150/100 mg NS3 protease inhibitorAsunaprevir200 mg BID NS3/4A protease inhibitorFaldaprevir120 mg or 240 mg QD NS3 protease inhibitorGS-9451200 mg QD NS3/4A protease inhibitorMK-5172100 mg QD NS3/4A protease inhibitorSimeprevir*150 mg QD NS5B nonnucleoside polymerase inhibitorABT-333400 mg BID NS5B nonnucleoside polymerase inhibitorBMS-79132575 mg or 150 mg BID NS5B nonnucleoside polymerase inhibitorDeleobuvir600 mg BID NS5B nonnucleoside polymerase inhibitorGS-9669500 mg QD NS5B nucleotide polymerase inhibitorSofosbuvir*400 mg QD NS5A inhibitorABT-26725 mg QD NS5A inhibitorDaclatasvir30 mg BID or 60 mg QD NS5A inhibitorLedipasvir**90 mg QD NS5A inhibitorMK-874220 or 50 mg QD NS5A inhibitorPI-688200 mg QD *FDA approved December 2013; **October 2014

56 RegimenGenotypeMechanism of ActionApproximate SVR in naïve/relapsers Daclatasvir + Sofosbuvir +/- RBV 1,2,3NS5A/NS5B polymerase98/92/89% ION-1,2,3: Sofosbuvir + Ledipasvir (FDC) +/- RBV N Engl J Med. 2014 Apr 11. 1, naïve and previously treated Polymerase / NS5A97-99% Sof/LDV + RBV or GS 9669 1Polymerase / NS5A inhibitor + non-nuc. 100/100% SAPPHIRE-I and –II: ABT-450/RTV + ombitasvir + Dasabuvir + RBV N Engl J Med 2014;370:17. 1Protease/NS5A/NS5B polymerase/ritonavir >95% TURQUOISE-II: ABT-450/RTV + ombitasvir + Dasabuvir + RBV N Engl J Med. 2014 Apr 11. [Epub ahead of print] 1, cirrhosisProtease/NS5A/NS5B polymerase/ritonavir 92-96% C-WORTHY: MK-5172/MK-8742 +/- RBV 12 nd gen protease, NS5A90-100 HALLMARK-DUAL: Daclatasvir + asuneprevir 1bNS5A / 2 nd gen protease73-91% The Liver Meeting 2013, Washington, D.C.; EASL 2014, London, U.K.

57 Enter the Nonspecialist: –Will Evolving Hepatitis C Therapies Reduce the Need for Specialized Care? –Graham R. Foster, FRCP, PhD - 10/8/2013 “A rapid expansion of patients and providers will mirror improving efficacies and gentler adverse event profiles…the introduction of a single-tablet regimen for HCV therapy—a development that will propel hepatitis C care to its future in nonspecialist providers offices. Information will be the key to overcoming preconceptions about adverse events and regimen complexities, finally allowing nonspecialists to take a central role in caring for HCV-infected patients”.

58 Parting thoughts  The last word…  “Back to the Future”…? The future is here.  Liang and Ghany  “The Costs of Success”  Hoofnagle and Sherker

59 Connecticut Infectious Diseases Society Annual Meeting, New Haven, CT. May 15, 2014


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