Presentation is loading. Please wait.

Presentation is loading. Please wait.

JEAN-MARC FIX VICE PRESIDENT - RESEARCH AND DEVELOPMENT HEPATITIS C GAME CHANGER.

Similar presentations


Presentation on theme: "JEAN-MARC FIX VICE PRESIDENT - RESEARCH AND DEVELOPMENT HEPATITIS C GAME CHANGER."— Presentation transcript:

1 JEAN-MARC FIX VICE PRESIDENT - RESEARCH AND DEVELOPMENT HEPATITIS C GAME CHANGER

2 AGENDA Epidemiology Portrait of a virus and etiology Transmission Evaluation Natural history Treatment

3 THE SILENT EPIDEMIC A round 4-5 million infected people including 3+ million with active infection Around 16,000 new cases a year No big presence in the news Leads to complication that will significantly tax health care systems if untreated or treated too late E Chak Liver International 2011

4 EPIDEMIOLOGY

5

6

7 Source: National Notifiable Diseases Surveillance System (NNDSS)

8

9

10

11 Availability of information on risk exposures/behaviors associated with acute hepatitis C — United States, 2012 Source: National Notifiable Diseases Surveillance System (NNDSS) *Includes case reports indicating the presence of at least one of the following risks 6 weeks to 6 months prior to onset of acute, symptomatic hepatitis C: 1) using injection drugs; 2) having sexual contact with suspected/confirmed hepatitis C patient; 3) being a man who has sex with men; 4) having multiple sex partners concurrently; 5) having household contact with suspected/confirmed hepatitis C patient; 6) having had occupational exposure to blood; 7) being a hemodialysis patient; 8) having received a blood transfusion; 9) having sustained a percutaneous injury; and 10) having undergone surgery.

12 Acute hepatitis C reports, by risk behavior † — United States, 2012 *A total of 1,778 case reports of hepatitis C were received in † More than one risk behavior may be indicated on each case report. § Risk data not reported. ¶ A total of 955 hepatitis C cases were reported among males in Source: National Notifiable Diseases Surveillance System (NNDSS) Number of cases

13 Acute hepatitis C reports, by risk exposure † — United States, 2012 Source: National Notifiable Diseases Surveillance System (NNDSS) Number of cases *A total of 1,778 case reports of hepatitis C were received in † More than one risk exposure may be indicated on each case report. § Risk data not reported.

14 GLOBAL PREVALENCE D Lavanchy Clin Micro and Infect :

15 COUNTRIES WITH VERY HIGH PREVALENCE Egypt Pakistan Taiwan Southern Italy Most of Africa Russia and former USSR

16 EVOLUTION OF PREVALENCE BY AGE Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

17 MORTALITY RATES COMPARISON Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

18 FORECASTED DEATH Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

19 AGENDA Epidemiology Portrait of a virus and etiology Transmission Evaluation Natural history Treatment

20 PORTRAIT OF A VIRUS AND ETIOLOGY Born Dead circa 2030

21 VIRUS CHARACTERISTICS A flavivirus (same family as yellow fever) Single stranded RNA 9600 nucleotide bases long Finds its way to the liver Each infected cell will produce around 50 virus

22 HEPATITIS C GENETIC MATERIAL hypervariable region capsidenvelope protein protease/helicase RNA- dependent RNA polymerase c22 5’ coreE1E2NS2 NS3 33c NS4 c-100 NS5 3’ Circa 1999

23 HEPATITIS C GENETIC MATERIAL TKH Scheel & CM Rice Nature Medicine :837-49

24 GENOTYPES There can be more than 25-30% variation in genome between Hep c viruses 11 “genotypes” identified so far (or is it 6?- 10 folds in 3, 7,8,9,11 in 6) Adapted from P Simmonds Hepatology :

25 GENOTYPES P Simmonds fig 1 Hepatology :

26 GENOTYPES DISTRIBUTION J Messina Hepatology :

27 GENOTYPE DISTRIBUTION J Messina Hepatology :

28 GENOTYPE TIMELINE IN THE US N Zein Clin Microbiol Rev (2):

29 WHY DO GENOTYPE MATTER Impact on treatment Impact on disease progression (1b harder to treat than 1a but is it true?)

30 FUNCTIONAL PORTRAIT

31 VIRAL PENETRATION OF CELL

32 VIRAL REPLICATION

33 ACUTE INFECTION Mostly through blood 70-80% have no or very mild symptoms- hence the “silent” part in “silent epidemic” Symptoms appear 6-7 weeks after exposure Fever, fatigue, loss of appetite, nausea, vomiting, abdominal pains, joint pain Dark urine, clay colored stools, jaundice Can be spread even if symptom less

34 AGENDA Epidemiology Portrait of a virus and etiology Transmission Evaluation Natural history Treatment

35 TRANSMISSION Cause IdentifiedNumber Intravenous Drug Use513 Multiple Sex Partners187 Surgery86 Needle Stick52 Sex18 Occupation14 Household Contact8 Dialysis4 Total1,778 Men having Sex with Men (out of 955 Men) 17 Source: National Notifiable Diseases Surveillance System (NNDSS) Multiple responses were possible

36 Hemodialysis: very low since 1997 although outbreaks have occurred, not uncommon before Hemophilia: virtually nil since 1987, 6-10 thousand before Household contact: very rare (don’t share your razor) Immune Globulin-IV: outbreaks in 1993 and 1994 Non-injection drug use (pipes, tubes) Organ/tissue transplants: very rare Perinatal: 5-10% of babies of infected mothers Tattoos (in unregulated environments) TRANSMISSION Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

37 Injection Drug Use Sex, especially if multiple sex partners or men having sex with men Receiving blood transfusion long ago(in the 1960s: 33%, since mid 90 very low 0.3%) MAIN TRANSMISSION Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

38 DETECTION Serology Enzyme Immuno Assay (EIA or ELISA) currently 3 rd generation -97+% sensitive, 94%+ specific (1) Detect antibodies to HCV (anti-HCV) (from 4 different areas) Confirmatory test may be Recombinant ImmunBlot Assay (RIBA) Past not too recent infection (7-8 weeks before positive) Virology Identify and now measures HCV-RNA By polymerase chain reaction- amplification of the viral genetic material Virus active in cell (1) Ahrq.gov 2011 Screening for Hepatitis C Infection p32

39 DETECTION N Zein Clin Microbiol Rev (2):

40 INTERPRETATION OF TEST RESULTS EIA/ ELISA HCV-RNASupplemental (RIBA) Interpretation - n/a Not infected [JM: or too early] + Not done ? Need confirmation +++/ nd Active infection +- Not done ? Need repeat RNA or RIBA +-+ Infected, need repeat RNA + Not done + Infected, need RNA + nd /-- False positive R Kesli Arch Clin Microbio (4):1 doi /233

41 LIVER FUNCTIONS

42

43 EVALUATION Genotype: 1-6 (through PCR) Interleukin 28: (gene mediating viral immune response)-has an impact on treatment “CC” mutation best, “TT” worst, “CT” in between Profile: who is the applicant Biopsy: how is the liver Other non invasive LFT: ALT and AST/ALT J Vergniol Gastroenterology : TJS Cross Journ Viral Hep 2009

44 INVASIVE TEST Gold (plated) standard: liver biopsy Highly dependent on evaluator Complications – 1. pain/anxiety/discomfort – 15-20% 2. hemorrhage – 0.5% (operator dependent?) 3. mortality – 0.01% Small sample of the liver analyzed J West Gastroenterology : JF Cadranel Hepatology : L Seeff Clin Gastroenterol Hepatol (10):

45 NON INVASIVE TESTS Fibroscan (transient elastography or liver stiffness measurement) King’s score: [age x AST (in IU/L) x INR]/platelet counts (in x10 9 /L) PPV/NPVFibroscanKing’s score Fibrosis (F3+)78/4953/75 Cirrhosis (F5+) 68/ 98 70/91 TJS Cross J of Viral Hep 2009 (consecutive patients London, UK) values Fx is Ishak fibrosis score INR= international normalized ratio prothrombin time in test/ normal PT PPV positive predictive value true positive/all positive NPV true negative/ all negative

46 NON INVASIVE TESTS APRI score: AST and platelet count FIB-4: as above + age and ALT Fibro-test-Acti test: Keeping in mind that from a univariate perspective AGE is the key driver L de Lucca Schiavon World J of Gastroenterology (11): J Vergniol Gastroenterolgy : For cirhosis AUROCSensitivitySpecificity APRI0.7777%94% FIB %92% Fibro test93%70% PPV= (sen x prev)/ [sen x prev+ (1-spec)x(1- prev)] NPV= [spec x(1-prev)] / [(1-sen) x prev+ spec x (1-prev)]

47 NON INVASIVE VS. INVASIVE TESTS T Poynard J Hepatol (3): C Lackner Hepatology : For advanced fibrosis SensitivitySpecificity Fibro Test93%70% Fibroscan96%45% Biopsy67%63% ALT79%78% For cirrhosisSensitivitySpecificity Fibro Test87%41% Fibroscan93%39% Biopsy95%51% ALT78%8% AST/ALT>=1.0*78%97%

48 NATURAL HISTORY health-fts.blogspot.com retrieved 10/14

49 NATURAL HISTORY THE REAL STORY N Zein Clin Microbiol Rev (2):

50 NATURAL HISTORY MODELING HH Thein 2011 Estimating the Prognosis of Canadians Infected With the Hepatitis C Virus Through the Blood Supply, th revision

51 FACTORS AFFECTING PROGRESSION VirusPatientExternal Concentration??Age at infectionAlcohol Genotype/species?Current age?Smoking? Age at diagnosis Gender (M)Environmental??? Race Coinfection: HIV, HBV Comorbidity: hemochromatosis, NASH, porphyria ct, iron overload?, liver steatosis, Diabetes M Genetic: HLA II antigens Adapted from Table 3, LB Seef Hepatology :S35-S46, S Bruno Hep Med Evidence and Research :21-28

52 PREDICTED HISTOLOGY BY AGE J Wong Am J of Pub Health : Age gropMild HepMod HepCirrhosis %0% %1%0% %11%0% %22%7% %32%18% %43%28% %54%39% %50% 80 & up0%40%60%

53 PAST TREATMENT

54 WAS CURRENT TREATMENT Combination Protease inhibitor (Incivek-telaprevir or Victrelis-boceprevir) Interferon (Pegintron or Pegasys) Ribavirin (Ribasphere)(nucleoside analog)

55 CURRENT TREATMENT December 2013: FDA Approved Sovaldi (sofosbuvir) for Genotype 1-6 Combination of sofosbuvir (Sovaldi) (for gen 1 to 6) Ribavirin (Ribasphere) (for gen 1 to 6) Pegylated interferon (for gen 1, 4, 5, 6) For those who can’t receive interferon Sovaldi+Olysio (simeprevir-protease inhibitor)+ribavirin (for gen 1) Hot off the press: sofosbuvir+lepisdavir=Harvoni No interferon! (gen type 1)

56 SOON TO BE CURRENT topics/news/whats-pipeline % cure rate for gen 1b

57 FUTURE TREATMENT EASL 44 th Annual Meeting

58 FUTURE TREATMENT TARGETS

59 DOWN THE PIKE faldaprevir simeprevir (Olysio) danoprevir vaniprevir paritaprevir sovaprevir asunaprevir (Sunvepra) mericitabine sofosbuvir (Sovaldi) BI filbuvir VX-222 setrobuvir dasabuvir ABT-072 tegobuvir telaprevir (Incivek) boceprevir (Victrelis) MK-5172 miravirsen BMS GS-9669 TMC VX-135 GS-9451 ombitasvir ACH-3102 daclatasvir (Dazlinka) GS-5816 ledipasvir GSK IDX-719 MK-8742 Nucleoside inhibitor Protease inhibitor Non nucleoside inhibitor NS5 Inhibitor APPROVED SUBMITTED FOR APPROVAL PHASE III PHASE II

60 ONLY HALF THE PICTURE Treatment is great but… From a health care impact, key missing link is timely detection (and prevention) Right now 50% diagnosed, 35% referred to care, 10% start treatment, 5% cured. Treatment is extremely expensive the $1,000 pill Adapted from L Highleyman 2013 news from AASLD 2013

61 NATURAL HISTORY health-fts.blogspot.com retrieved 10/14

62 TRANSITION RATES Stage TransitionAnnual Rate RNA + to Fibrosis 15.7% Fibrosis 1 to 214.5% Fibrosis 2 to 315.0% Fibrosis 3 to 412.0% Fibrosis 4 to decompensation6.5% Fibrosis 4 to HCC3.3% HH Thein 2011 Estimating the Prognosis of Canadians Infected With the Hepatitis C Virus Through the Blood Supply, th revision

63 TRANSITION RATES R Allison J Infect Dis : After 25 years of infection on 185 patients (initially asymptomatic blood donors) 33% no fibrosis 52% stage 1 or 2 fibrosis 12% stage 3-4 bridging fibrosis 2% Cirrhosis Seems lower than Thein

64 TRANSITION RATES Stage TransitionAnnual Rate Modifier RNA + to Fibrosis 14.3%75% Fibrosis 1 to 25.8%40% Fibrosis 2 to 36.0%40% Fibrosis 3 to 4 (cirrhosis)4.8%40% Fibrosis 4 to decompensation6.5%100% Fibrosis 4 to HCC3.3%100% Fix model based on Thein to give Allison’s numbers

65 FIBROSIS PROGRESSION R Allison J Infect Dis : % stable 14% fibrosis decreased 33% fibrosis increased fibrosis score at first biopsy fibrosis score at second biopsy

66 SCORING WARNING METAVIR stage 4 and ISHAK (or ISHAK-KNODELL or HAI) stage 6= cirrhosis

67 HOW DOES HEP C KILL YOU? All rates are annual rates Moderate chronic: 7.3% cirrhosis 0.1% HCC Cirrhosis 2.5% ascites: 6.7% refractory ascites, 11% death 1.1% variceal hemorrhage:40% death Y1, 13% thereafter 0.4% hepatic encephalopathy: 68% death Y1, 40% thereafter 0.5% HCC: 86% death Liver transplant: 21% y1 5.7% thereafter J Wong AM J of Pub Health :

68 MORTALITY Insurance industry ALT>45 U/L => reflex to Hep C 9% ALT>45, 4-5% Hep C antibody positive (mostly from reflex testing) 0.6% positive (vs. 1-2% in adult US population) Some are missed due to reflex scheme. VF Dolan On the Risk (3):68-71

69 MORTALITY VF Dolan On the Risk (3):68-71 Age groupFemalesMales Caveats: Antibody positive HCV viral status unknown Median of 7 years o follow-up

70 MORTALITY AND ALT LEVEL D Winsemius eEnvoy July 2009 (Heritage Labs)

71 VIRAL LOAD AND HCC All stages of fibrosis For sustained virologic responders HCC risk is 24% of risk for non responders US Subset (US vets) 31% Advanced Fibrosis For sustained virologic responders HCC risk is 23% of risk for non responders US Subset (not same group as above) 18% Observational meta-analysis… RL Morgan Annals of Internal Med 158(5):

72 QUESTIONING You know: you have EIA + HCV RNA + Probably does not know status If knows, what is treatment? You suspect: EIA + or missing no other tests Highly endemic area Old IDU or blood transfusion

73 QUESTIONING What does the liver “look” like? LFT pattern - but don’t overestimate ALT level importance (unless very very high: x10 normal) Best case:

74 TAKE HOME NUGGETS Transmission & risk factor Diagnosis Progression Evaluation Treatment revolution Public health challenge


Download ppt "JEAN-MARC FIX VICE PRESIDENT - RESEARCH AND DEVELOPMENT HEPATITIS C GAME CHANGER."

Similar presentations


Ads by Google