LEVER AANDOENINGEN.

Présentation au sujet: "LEVER AANDOENINGEN."— Transcription de la présentation:

1 LEVER AANDOENINGEN

2 HEPATITES AIGUES CHRONIQUES VIRUS A,B,C,D,E Virus B,C, E? MEDICAMENTS
TOXIQUES ALCOOL AUTOIMMUNE FOIE CARDIAQUE WILSON MIGRATION LITHIASE BUDD CHIARI METASTASES,LYMPHOME CHRONIQUES Virus B,C, E? MEDICAMENTS ALCOOL STEATOHEP.DYSMETB AUTOI GENETIQUES BUDD-CHIARI

3 D E VIRUS HEPATOTROPES

4 Geelzucht

5 TRANSMISSION VHA Although treatment is not a feasible way of controlling hepatitis A or hepatitis B, there are a number of measures that can be adopted to prevent these diseases. Spread of the hepatitis A virus can be reduced by adopting measures that interrupt the faecal-oral route of virus transmission. These include: providing clean water for drinking, cooking and washing disposing of sewage properly providing good living conditions without overcrowding encouraging good personal hygiene including thorough hand-washing after defaecating and before handling food hygienic cleaning procedures, including the use of disposable gloves when cleaning toilets and wash basins, for example, in hotels, hospitals and other institutions effective control of shellfish, fish and other potentially contaminated foods.

6 HAV infection - clinical sequelae
Incubation Symptomatic HA Asymptomatic HA Protracted HA Recovery & immunity Relapsing HA Fulminant HA The slide shows possible clinical courses of a hepatitis A infection. Hepatitis A is usually a self-limiting disease and infection confers lifelong immunity. Serious complications are uncommon but are more likely to develop in subjects with chronic liver disease. They include: protracted hepatitis A - a condition in which the virus is slow to clear and the liver takes longer than usual to regain its normal function relapsing hepatitis A - which affects up to 20% of patients, with symptoms reappearing a few weeks after the initial episode seems to have resolved; the relapse is usually mild but can last for up to 5 weeks [1] fulminant hepatitis A - a rare complication occurring in about 1% of patients characterised by severe jaundice, rapid deterioration in liver function, drowsiness, encephalopathy and coma. Fulminant hepatitis A is associated with a very high mortality rate. In older patients (those >50 years of age), especially those with pre-existing liver damage, about half the cases are fatal .[2] 1. Glikson M et al. Medicine 1992; 71, 14 2. Tabor E. In Gerety RJ. Hepatitis A. Academic Press, Orlando. 1984, 47 Recovery & immunity Death

7 HAV endemicity Serological testing shows that the prevalence of HAV varies widely among geographical areas and population sub-groups. Five main patterns of HAV endemicity can be distinguished but these are constantly shifting and often overlap. In many countries two or more patterns may occur. Hyperendemic and high endemicity areas Hepatitis A is highly endemic in countries where hygiene and sanitation standards are poor. Here, children are exposed to the virus early in life and acquire immunity without major clinical implications [1,2]. HAV infections among native adults are therefore rare [3]. However, visitors to these areas who have no immunity to the virus are at considerable risk of infection. Intermediate endemicity areas In many areas where hepatitis A has been highly endemic, such as Southern and Eastern Europe, some Middle Eastern countries, parts of South East Asia and Latin America, improvements in living standards have brought about a change in the pattern of hepatitis A endemicity [4]. As exposure to the virus falls, the average age of infection moves to older children, adolescents and adults. Outbreaks of hepatitis A are common, because of inadequacies in water supply and sewage systems and increasing numbers of susceptible subjects. Low endemicity and hypoendemic area In the United States, Australia, Japan and many European countries, only relatively small numbers of clinical cases of hepatitis A occur but a large proportion of the population is susceptible to infection. Hepatitis A is often introduced into low endemicity areas by travellers who have been exposed to HAV while visiting high endemicity areas. They then pass on infection to others [5]. Pockets of high HAV endemicity have been found in some populations in low endemicity countries such as American Indians and Inuits in North America, Aborigines in Australia and Maoris in New Zealand. [6,7]. 1. Tsega et al. Am J Epidemiol 1986; 123, 344 2. Bensabath G et al. Bull PAHO 1987; 21, 16 3. El-Raziky E et al. J Egypt Med Assoc 1985; 68, 463 4. Goh KT et al. Asia Pac J Public Health 1987; 1, 9 5. Papaevangelou G. Vaccine 1992; 10 (Suppl 1), S63 6. Shaw FE et al. Am J Publ Health 1990; 80, 1091 7. Shaw F. Viral Hepatitis 1997; 6, 14

8 The three major patterns of age-specific prevalence of anti-HAV Ab
Changing epidemiological patterns The three major patterns of age-specific prevalence of anti-HAV Ab High endemicity (developing countries) 100 HAV (%) - Intermediate endemicity 50 Prevalence of anti Worldwide improvements in hygiene and sanitation are linked to a reduction in the circulation of HAV, and a corresponding rise in the number of people who are not immune to the virus [1,2]. This is seen most clearly in areas such as Latin America and South East Asia where a shift is occurring from high to intermediate or even low endemicity. In thes regions many groups, who in the past would have been immune to hepatitis A, are now at risk [3, 4]. Significant changes in hepatitis A epidemiology have also been observed in Southern Europe over the past years where a dramatic decrease in natural immunity has occurred as a result [5, 6]. Because of these changing patterns, more and more people are reaching adolescence, adulthood, and even old age, without coming into contact with HAV. It is therefore likely that there will be a significant increase in the incidence of more serious clinical hepatitis A infections and related complications. 1. Gust ID, Feinstone SM. Hepatitis A. CRC Press, Boca Raton, Florida 1988, 132 2. Skinhoj P et al. Am J Epidemiol 1977; 105, 140 3. Yap I, Guan R. Trans R Soc Trop Med Hyg 1993; 871, 22 4. Tapia-Conyer R et al. Am. J Trop Med Hyg 1999;61(5): 5. Papaevangelou G. Vaccine 1992; 10 (Suppl 1), S63 6. De Mattia D et al. Riv Ital Pediatr 1991; 17, 21 Low endemicity (industrialised countries) Age (years) : CDC. Hepatitis Surveillance Report No , 18

9 PREVENTION HEPATITE A REGLES D’HYGIENE
PRE-EXPOSITION:vaccin HAVRIX ou TWINRIX rechercher anticorps si âge>30 ans POST-EXPOSITION:vaccin HAVRIX si contact récent(1-2 semaines)avec personne infectée

10 Clinical-Epidemiologic Correlations
HBV Endemicity Location Age of Infection Mode of Transmission Chronicity HCC Risk High 10-15% Asia Sub-Sahara Africa Birth Toddler(bambin) Perinatal Horizontal Likely High Low < 2% N. America W. Europe Scandinavia Early Adulthood Percutaneous(IVDUnosocom,horizontal) Sexual Rare Low The age at time of infection influences the epidemiology of HBV infection worldwide. In areas where HBV is endemic, such as Asia and sub-Saharan Africa, individuals are generally exposed to the virus at the time of birth, perinatally, or early in childhood. The rate of chronicity is therefore high, which perpetuates the burden of chronic HBV infection in the population. In areas of low HBV endemicity, such as North America, individuals are typically exposed to the virus as adults through sexual contact or percutaneous exposure. Because these individuals are likely to clear the virus spontaneously, the risk of chronicity is low and the burden of chronic liver disease related to cirrhosis and liver cancer is also low. Available at: Accessed February 6, 2006. Designed by Jules Dienstag, MD

11 Prevalence of Chronic Hepatitis B
~ 2 million Asians ~ 930, 000 Europeans ~ 400,000 South Americans HBsAg Prevalence ~ 350,000 Africans Immigration patterns play an important role in the demographics of chronic hepatitis B in the United States. Although hepatitis B is not highly prevalent in the United States, individuals from areas where hepatitis B is highly prevalent have been immigrating to the United States, particularly during the past years. This has resulted in a population of HBV-infected individuals in the United States from various backgrounds. > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from Centers for Disease Control. Hepatitis B fact sheet. Available at: Accessed January 31, Mahoney FJ. Clin Microbiol Rev. 1999;12: Hepatitis B Foundation. Hepatitis B statistics. Available at: Accessed January 31, 2006.

12 Hepatitis B Sexuele activiteiten

13 PENSER AU DEPISTAGE +++
Modes de Transmission Transmission sexuelle (MST) Transmission mère-enfant: dépistage femme enceinte 6ème mois sérovaccination du nouveau-né Usage de drogues intraveineuses : Transmission possible par: hospitalisations répétées, chirurgie, examens invasifs, tatouages, piercing, acupuncture, soins dentaires, PENSER AU DEPISTAGE +++

14 Une maladie silencieuse et potentiellement grave
Guérison (90%) Hépatite aiguë Hépatite chronique (10%) Cirrhose (20% à 20 ans) Cancer (20%/5 ans)

15 INITIAL WORK UP Disease activity Infection Replication FTEST FSCAN
Three steps of serological diagnosis 1 2 3 Disease activity Infection Replication Diagnosis of HBV Infection: Using Serum Markers There are three different stages of the serological diagnosis of chronic HBV infection. In step 1, chronic HBV infection is characterised by the persistence of HBsAg in serum for over 6 months. Presence of IgM anti-HBc indicates a recent HBV infection. In step 2, the existence of active viral replication is determined by measuring HBeAg and HBV DNA levels. During step 3, the presence of active hepatic disease is determined by measuring ALT, as levels of this enzyme above the normal range are indicative of active hepatic disease. HBsAg, anti-HBc, Ag HBe/anti-HBe HBV DNA ALT FTEST FSCAN US, BX

16 OBJECTIVES OF TREATMENT
PRIMARY Prolonged and sustained annihilation of HBV replication Normalisation of ALT Improvement of histology including early cirrhosis Prevention of cirrhosis and of complications of cirrhosis and need for LTX Monneja Hepatol 2003,Chen JAMA 2006,Iloeye GE 2006,Liaw NEJM 2004 SECONDARY HBe seroconversion HBs seronversion only criteria to stop θ Prevention of viral transmission

17 Therapeutic options Towards combination therapies ? Immuno-modulators
IFNpeg vaccinothérapy Antivirals Lamivudine Adefovir Entecavir Telbivudine Tenofovir Emtricitabine Clevudine Valtorcitabine Elvucitabine Pradefovir CD8+ HBV Towards combination therapies ?

18 Hepatitis B:Vaccin

19 Hépatite C : quelques données
Très gros problème de Santé Publique non pris en charge par le politique Prévalence 1,1% = Belges 3% dans le monde Par rapport au SIDA 7 fois plus fréquent tue 3 fois plus 10 fois plus contagieux Paucisymptomatique, potentiellement grave

20 HCV Infection: Worldwide Prevalence
<1% 1%–2.4% 2.5%–4.9% 5%–10% >10% No data available WHO. Wkly Epidemiol Rec

21 Progression de la fibrose de la contamination aux complications
Infection VHC Age à l ’infection > 40 Alcool > 50 g/d Homme Durée de l ’infection > 20 ans Obésité Coinfection VHB, VIH Tabagisme 20% guérison 80% porteurs chroniques F0 F1 10-50% en 20 ans F1 F2 F2 F3 cirrhose F3 F4 F4 Décompensation 3% / an Cancer du foie 3-5% / an

22 Hepatitis B disease progression
Disease activity may flare during the natural course of CHB and repeated episodes may lead to progressive fibrosis and cirrhosis, as well as carcinogenesis. Without treatment, the typical progression from cirrhosis is to decompensated cirrhosis. Patients with decompensated cirrhosis are candidates for liver transplantation, without which death can result from end-stage liver disease. References 1. Torresi J, Locarini S. Gastroenterology. 2000;118:S83–S103. 2. Fattovich G, Giustina G, Schalm SW, et al. Hepatology. 1995;21:77–82. 3. Perrillo RP, Wright T, Rakela J, et al. Hepatology. 2001;33:424–432.

23 SHP => > 50% † « ACLD « HTP CIRRHOSE DECOMPENSEE OU
PPHT ASCITE / ICTERE INFECTIONS / PBS SHR type I et II THROMBOSE PORTE HCC HEPATOK HTP => > 50% †

24 Opgepast tot persoonlijke toestel !
RISICOFACTOREN druggebruikers bloed Tatoeering,piercing familie Opgepast tot persoonlijke toestel !

25 tatoeering piercing

26 VHC - Qui dépister ? Usage de drogue(s) par voie intraveineuse/nasale
Avant 1990 : TX de sang, produits du sang situations à risque de TX : chirurgie lourde, hémorragie, réanimation, accouchement compliqué, polytrauma contact avec sang, actes invasifs avec effraction cutanée, hémodialyse Usage de drogue(s) par voie intraveineuse/nasale Risque sexuel : contact avec prostituées, partenaires sexuels multiples  ALT ou asthénie inexpliquée Enfants de mère VHC  Contact, avec objets par du sang provenant d'une personne VHC , piercing, aiguille, tatouage, coupe-ongle familial

27 Différents stades de la fibrose

28 FibroTest: A Continuous Variable (N = 1270)
Expected Fibrosis F4 F3-F4 F3 F2 F1-F2 F1 F0-F1 F0 1.00 0.80 0.60 FibroTest 0.40 0.20 0.00 1 2 3 4 Fibrosis Stage Poynard T, et al. Clin Chem. 2004;50:

29 FibroScan The probe induces an elastic wave through the liver
The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface Explored volume 2.5 cm 1 cm  4 cm LB: 1/50,000 of the liver FibroScan: 1/500 of the liver

30 ACOUSTIC RADIATION FORCE IMPULSE

31 Buts du traitement Eradiquer le virus
Ralentir l’évolution de la maladie Améliorer l’histologie du foie Réduire le risque de décompensation hépatique Réduire le risque de carcinome hépatique Améliorer la qualité de vie EASL International Consensus Conference on Hepatitis C. J Hepatol 1999;31(Suppl 1)

32 Ribavirine

33 IFN PEG-IFN RNA RNA 1ère phase 2ème phase Lu Me Ve Lu Lu

34 Genotype 2 or 3 Treatment algorithm
24 weeks of treatment1 (even for HCV-3 with high viral load2) PEGASYS 180µg qw COPEGUS 800mg regardless of body weight1 48 24 TREATMENT 24 weeks FOLLOW-UP 24 weeks HCV RNA Quantitative HCV RNA Qualitative 1Hadzyannis SJ. Ann Intern Med 2004, 140(5): Rizetto M. Hepatol 2004, 40(4 S1):252A, Abstract #198.

35 Genotype 2 or 3 Chance for a cure
100% 84% 84% 75% 1Rizetto M. Hepatol 2004, 40(4 S1):252A, Abstract #198.

36 Genotype 2 or 3 Reimbursement criteria
Positive HCV RNA AND Genotype 2 or AND ALT elevated on 2 occasions (at least 1 month apart of each other) Liver biopsy no longer required ! Reimbursement for 24 weeks maximum NEW !

37 Genotype 1, 4, 5 or 6 Treatment algorithm
48 weeks of treatment1 PEGASYS 180µg qw COPEGUS 1000mg (<75kg) or 1200mg (≥75kg) 12 48 72 TREATMENT 48 weeks FOLLOW-UP 24 weeks HCV RNA Quantitative HCV RNA Qualitative 1Hadzyannis SJ. Ann Intern Med 2004, 140(5):

38 Evolutions possibles de l'ARN sous traitement
Non-répondeurs Echappement Rechute limite détection RVS PEG-IFN/RIBA Temps (mois) 6

39 PATIENT Sélection Soutien Education Suivi Prise en charge MEDECINS
Adhérence au R/ Médecins généraliste et spécialiste Sélection Soutien Education Suivi Prise en charge - Sélection - Soutien - Education - Suivi - Prise en charge des effets secondaires MEDECINS généraliste spécialiste INFIRMIERE SPECIALISEE Infirmière Pharmacien PHARMACIEN(NE)

40 Potential Targets for Antiviral Intervention in the HCV Life Cycle and Their Location in the HCV Genome Manns MP et al. Nat Rev Drug Discovery. 2007;6:

41 New Oral Small Molecule Antivirals in Development for the Treatment of HCV
Drug name Drug class Preclinical Phase I Phase II Phase III MK-0608 (Merck) Nucleoside polymerase inhibitor X R7128 (Pharmasset & Roche) Nucleoside polymerase inhibitor X X NIM811 (Novartis) Cyclophilin inhibitor X ITMN-191 (InterMune & Roche) Protease inhibitor X MK-7009 (Merck) Protease inhibitor X BI12202 (Boehringer) Protease inhibitor R1626 (Roche) Nucleoside polymerase inhibitor X DEBIO-025 (Debiopharm) Cyclophilin inhibitor X Celgosivir (Migenix) a-glucosidase inhibitor X Telaprevir (Vertex Pharmaceuticals) Protease inhibitor X Boceprevir (Schering-Plough) Protease inhibitor X TMC (Tibotec & Medivir) Protease inhibitor X Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:

42 PROVE 1: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients
Randomized, placebo-controlled, phase II trial Wk 12 Wk 24 Wk 48 Placebo + PegIFN alfa-2a 180 g/wk + RBV 1000/1200 mg QD (n = 75) End of Treatment Treatment-naive patients infected with HCV genotype 1* (N = 250) Telaprevir 750 mg every 8 hrs + PegIFN alfa-2a + RBV (n = 79) PegIFN alfa-2a + RBV End of Treatment 24-Week Follow-up Telaprevir + PegIFN alfa-2a + RBV (n = 79) PegIFN alfa-2a + RBV † SVR 24-Week Follow-up Telaprevir + PegIFN alfa-2a + RBV (n = 17) † SVR *Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. †Patients must achieve undetectable HCV RNA at Wk 4 (< 10 IU/mL) and at last test before stopping therapy at 12 or 24 wks. EASL 2008 – McHutchinson JG, Abstract 4

43 PROVE 1: Response Rates (ITT)
Treatment Week 4 Undetectable*, % Week 12 Undetectable*, % SVR, % Relapse,% (N) PegIFN/RBV 48w (n=75) 11 45 41 23 (35) TPV 12w + PegIFN/RBV 48w (n=79) 81 80 67 6 (51) TPV 12w + PegIFN/RBV 24w (n=79) 68 61 2† (41) TPV 12w + PegIFN/RBV 12w (n=17) 59 71 35 33† (9) * HCV RNA < 10 IU/L †Only subjects who met the RVR criterion and stopped at 12 or 24 total weeks of treatment McHutchison J, et al. EASL Abstract 4. 43

44 SPRINT-1 Final Analysis
4/11/2017 SPRINT-1 Final Analysis RR : relapse rate VB : viral breakthrough DT : discontinuation due to AE Total 28 weeks of therapy Total 48 weeks of therapy 75 % 3% RR 5% VB 9% DT 10 20 30 40 50 60 70 80 67 % 7% RR 12% VB 19% DT 56 % 23% RR 4% VB 15% DT 55 % 30% RR 7% VB 11% DT 38 % 24%RR 0% VB 8% DT % patients HCV negative Control 48 wks (P/R) SVR 24 No lead-in and total 28 wks (P/R/B) SVR 24 Lead-in and total 28 wks (P/R  P/R/B) SVR 24 No lead-in and total 48 wks (P/R/B) SVR 24 Lead-in and total 48 wks (P/R  P/R/B) SVR 24 This information is in response to your unsolicited request; for MSL purposes only; not to be copied or distributed. April 23, 2009 Kwo et al. EASL 2009 44

45 HEPATITE E This information is in response to your unsolicited request; for MSL purposes only; not to be copied or distributed. April 23, 2009

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