8/12/14 HEPATITIS B. Chronische hepatitis B en C. Epidemiologie Besmetting Natuurlijke evolutie Symptomen Diagnose Behandeling. Overzicht.

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1 Chronische hepatitis B en C. 1 dec 214 Prof. Dr. Hendrik Reynaert MD, PhD Dienst gastroenterologie-hepatologie UZBrussel Fysiologie VUB Overzicht Epidemiologie Besmetting Natuurlijke evolutie Symptomen Diagnose Behandeling HEPATITIS B 1

2 HBV: A Significant Cause of Worldwide Morbidity and Mortality > 2 billion have been infected [1] 4 million acute cases per year [1] 1 million deaths per year [1] 35-4 million chronic carriers [1] Ø 25% of carriers die from chronic hepatitis, cirrhosis, or liver cancer [1] Ø Nearly 75% of chronic carriers are Asian [2] Second most important carcinogen behind tobacco [3] Causes 6% to 8% of all primary liver cancer [1] HBV is 1 times more contagious than HIV [4] 1. WHO. Hepatitis B Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. 4. CDC. MMWR. 21;5:RR-11. Prevalence of HBV: Global Estimates HBsAg Prevalence High ( 8%) Intermediate (2% to 8%) Low (< 2%) Mast EE, et al. MMWR Recomm Rep. 26;55:1-33. Custer B, et al. J Clin Gastroenterol. 24;38(1 suppl):s158-s168. HBsAg Positive, % Taiwan Vietnam China Africa Philippines Thailand Japan Indonesia 4. South Korea India Russia US.2-.5 Risk Factors Associated With Acute HBV Infection: US (26) MMWR: Surveillance Summary March 21, 28 / Vol. 57 / No. SS 2. 2

3 Preventie! Vermijden van gevaarlijk contact. Ø Bloed, faeces, speeksel, Ø Naalden, puncties, Hygiene Ø Handschoenen, Handen wassen, etc Prikongevallen Ø 25% bij opruimen Ø 5% bij infuus, IM/IV injecties (recappnig) Vaccinatie. Ø Hepatitis A, B 7 Preventie. Vaccinatie Post-exposure immunoglobulines Sexuele transmissie Moeder-kind transmissie Natural History after acute HBV Infection Early Childhood > 95% Immune Tolerance Adulthood < 5% < 5% Cure HBeAg- Chronic Hepatitis B Cirrhosis HBeAg+ Chronic Hepatitis B 95% Cure Inactive Carrier Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hep. 1993;8: Seeff L, et al. N Engl J Med. 1987;316:

4 Diagnose: 4 Phases of Chronic HBV Infection Immune-tolerance phase Ø HBeAg positive; high HBV DNA (2 x IU/mL); normal ALT HBeAg-positive chronic hepatitis (immune clearance) Ø Intermediate to high HBV DNA (2, - 2 x 1 9 IU/mL); high or fluctuating ALT; active inflammation on liver biopsy Inactive HBsAg carrier (low replication phase) Ø Ø HBeAg negative; low HBV DNA (< 2 IU/mL); normal ALT HBsAg may become undetectable HBeAg-negative chronic hepatitis (reactivation phase) Ø Intermediate to high HBV DNA (2, - 2 x 1 9 IU/mL); high or fluctuating ALT; active inflammation on liver biopsy Hepatology. 27;45: Mayo Clin Proc. 27;82: Natural History of Chronic Hepatitis B No further progression Not all patients have progressive disease Normal liver Chronic hepatitis B HCC Cirrhosis HBV-related ESLD or HCC are responsible for >.5-1 million deaths per yr and currently represent 5% to 1% of cases of liver transplantation ESLD 1. EASL. J Hepatol. 212;57: Annual Risk of HBV Progression HBeAg+ chronic hepatitis B 5.% HBeAg-Neg chronic hepatitis B 1.%-2.% All HBsAg + individuals Cirrhosis 3.% 2.%.4% Decompensation HCC Factors linked with progression Duration of active disease Heavy alcohol use Immune suppression (HIV) Juszczyk J. Vaccine. 2;18(suppl 1):S23-S25. 4

5 Higher HBV DNA Associated With Higher Risk of Cirrhosis Over Time Adjusted Relative Risk of Cirrhosis* (95% CI) All Participants (N = 3582 Taiwanese Patients) < ,-99,999 1,-999,999 1 million HBV DNA (copies/ml) *Adjusted for age, sex, cigarette smoking, and alcohol consumption. 5. Iloeje UH, et al. Gastroenterol. 26;13: Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry N = 3653 Taiwanese patients Cumulative Incidence of HCC (%) Baseline HBV DNA Level, copies/ml 1 million 1,-999,999 1,-99, < Yr of Follow-up Chen CJ, et al. JAMA. 26;295: HBV Treatment Landscape in 211 Peginterferon alfa-2a Lamivudine Entecavir Tenofovir Interferon alfa-2b Adefovir Telbivudine 5

6 J Hepatol. 29;5: HBV DNA J Hepatol. 29;5: HBe seroconversie na 1j J Hepatol. 29;5:

7 96% of Pts Treated With Tenofovir Had Stable or Improved Fibrosis at Yr 5 Pts with Ishak score 4: 38% at baseline, 12% at Yr 5 Pts with cirrhosis (Ishak score P 5): <.1 28% at baseline, 8% at Yr 5 (n=96) Patients (%) P <.1 38% 39% 12% 63% Ishak Fibrosis Scores Baseline Yr 1 Yr 5 N = 348 matched biopsies 17. Marcellin P, et al. Lancet. 213;381: Yr Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Cumulative Resistance Rate (%) Lamivudine [1] Adefovir [1] Telbivudine* [1] Entecavir [1] Tenofovir [2] *Telbivudine rate determined at Yr EASL. J Hepatol. 29;5: Marcellin P, et al. AASLD 211. Abstract Kostprijs Pegasys 18 µg/wk subcutaan Ø 83 /maand Ø 5 à 1. /behandeling Lamivudine Ø 3 /maand Ø 18 / 5j Baraclude Ø 41 of 51 /maand Ø 3. / 5j Viread Ø 35 /maand Ø 21. /5j 7

8 Cost-effectiveness ClinicoEconomics and Outcomes Research 211: Cost-effectiveness ClinicoEconomics and Outcomes Research 211: Besluit HBV HBV is heel frequent Evolutie naar cirrose, HCC en transplantatie Preventie! Therapie is Ø Efficient Ø Cost-efficient 8

9 HEPATITIS C Recommendations for Testing, Managing, and Treating Hepatitis C Downloaded from Visit the HCV Guidance website to access the most up-to-date version Revised Date: August 11, 214 9

10 Key discoveries in HCV Nature Reviews Drug Discovery: 12 : : 213 1

11 Epidemiological data (211) Belgium France Germany Italy Spain UK Prevalence*.87%.84%.6% 4% 1.9%.7% 73, 36, 46, 2,, 69, 34, Screening* 5% 64% 48% 46% 35% 34% Genotype %G1 61% 56% 56% 62% 65% 44% %G2-3 26% 32% 32% 37% 23% 53% %G % 12% 12% 1% 12% 3% * Thierfelder et al. Eur J Epidemiol 21; Rossol, Gesundheitswesen 27; Zehnter et al. Hepatology 25; Beutels et al. Eur J Epidemiol 1997; Carsauw et al. Acta Gastroenterol Belg 23; Dominguez et al. J Med Virol 21; Meffre et al. J Med Virol 21; Mariano et al. Dig Liver Dis 29; Ansaldi et al, J Med Virol 25; Gungabissoon et al., Epidemiol Infect 27 Poynard et al, Lancet 1997; Roudot-Thoraval et al, Hepatology 1997; Martinot-Peignoux et al, J Viral Hepatitis 1999; Gerard et al, J Med Virol 25; De Maeght et al, Acta Gastroenterol Belg 28; Delwaide et al, Eur J Gastroenterol Hepatol 25; Serra et al, J Viral Hepatitis 23 ; Mohsen et al, Gut 21; Mariano et al, Scand J Infect Dis

12 Natuurlijke evolutie van chronische HCV Hepatitis C Virus Diagnostic Testing Diagnostic Test Type Specifications Serologic Virologic Mode of detection Antibodies Virus Sensitivity > 95% > 98% Specificity Variable > 98% Detection postexposure 2-6 months 2-6 weeks Use Screening Confirmation Diagnostische work-up Screening: HCV anti-lichamen Bevestiging: PCR-HCV? Gestoorde ALT? Genotype + virale lading Ø Type therapie Graad van fibrose Ø Leverbiopt Ø Niet-invasieve testen Uitsluiten HCC: echo - alfafp 12

13 8/12/14 Leverbiopt Fibrosis Score: 65% Fibrosis Score: 15% 37 Fibrotest: een continue variabele. FibroTest Expected Fibrosis F F3-F F F F1-F F F-F F 38 Fibroscan

14 Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis Approximate Percentage of Patients With Cirrhosis Time (Years) Bridging Portal None HCV in Patients With Cirrhosis Survival and Rate of Decompensation Survival (%) Year Cumulative Survival Decompensation Stable Percentage of Patients Cumulative Probability Decompensation HCC Years HEPATOLOGY 1998;27:

15 SF36 scores for energy and fatigue correlated with serum ALT. HEPATOLOGY 1998;27: Adjusted direct annual cost of healthcare per employee by point of service (HCV versus control) HEPATOLOGY 21;52: Health outcomes among HCV patients and controls Vietri et al. BMC Gastroenterology 213, 13:16 15

16 Costs among HCV patients and controls Vietri et al. BMC Gastroenterology 213, 13:16 HCV: behandeling tot 214 Nieuwe behandelingen 16

17 buvirs previrs asvirs Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1 NIH SPARE Trial: Part 2 Results NIH SPARE Part 2: SVR24 by Fibrosis Stage Patients (%) with SVR / /19 SOF +RBV (Low Dose) Early Stage (-1*) Advanced (3-4*) Fibrosis Stage (Knodell Histology Activity Index Scoring System) SOF = Sofosbuvir; RBV = Ribavirin 29 2/7 SOF +RBV (Wt-Based) 5 3/6 Osinusi A, et al. JAMA. 213;31: Patients with SVR 12 (%) Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results COSMOS (Cohort 2 with F3-F4 Fibrosis): SVR12 by Regimen /3 16/16 25/27 13/14 SOF + SMV + RBV SOF + SMV + RBV SOF + SMV + RBV SOF + SMV 24-Week Treatment 12-Week Treatment SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin Lawitz E, et al. Lancet

18 TURQUOISE-II ABT-45/ritonavir + Ombitasvir + Dasabuvir + RBV Sustained Virologic Response at Post-Treatment Week 12 in Each Treatment Group, Overall and According to Subgroups. Poordad F et al. N Engl J Med 214;37: IFN free regimens in genotype 1 treatment-naïve patients 12 1 ~ 7% cirrhotics 1% cirrhotics 94 15% cirrhotics 1 3% cirrhotics 85 No ~ 2% cirrhotics 1% cirrhotics cirrhotics SVR (%) / 159 SOF/RBV 16/ 17 SOF/SMV* ±RBV 12 wks 41/ 41 SOF + DCV 12 wks 43/53 422/ 427/ SIM + DCV SOF + LDV SOF + LDV ±RBV ±RBV ±RBV 12/24 wks 12 wks 24 wks 455/ 473 3D + RBV 12 wks 81/ 86 3D + RBV 12 wks 7/ 74 3D + RBV 24 wks QUANTUM & NIAID Study COSMOS 2 11-I A LEAGUE 4 ION-1 5 SAPPHIRE-1 6 TURQUOISE-II 7 Cross comparison of studies cannot be carried out 1. Sofosbuvir EU SmPC 2. Lawitz E, et al. EASL 214. O165; 3. Sulkowski M, et al. NEJM 214;37:211 21; 4. Zeuzem S et al. CROI 214. Oral presentation 28LB 5. Afdhal N, et al. N Engl J Med. 214; 37: Feld JJ, et al. N Engl J Med 214; 37: Poordad F, et al. N Engl J Med 214; 37: Terugbetalingscriteria Chronische HCV met F3-F4 Ø Biopt of fibroscan + biologische test Of Op lijst voor levertransplantatie GE verbonden aan UZ E-Health aanvraag Sovaldi Ø GT 1-6 Ø 12 of 24 weken Ø In ascociatie met RBV, PEGINF, Olysio Olysio Ø GT 1 en 4 Ø 12 weken Ø In ascociatie met RBV, PEGINF, Sovaldi 18

19 Kostprijs Ribavirine Ø 35 /maand Peginterferon Ø 83 /maand Incivo Ø 91 /maand Victrelis Ø 325 /maand Olysio Ø 91 /maand Sovaldi Ø 175 /maand HEPATOLOGY 214;6:37-45) Conclusies HCV = belangrijke oorzaak van cirrose, HCC, werkonbekwaamheid, Op 25 j tijd van ontdekking tot +/- 1% genezing. Kostprijs van behandeling is limiterende factor Nature Reviews Drug Discovery: 12 : :