Therapie Hepatitis C anno Stefan Bourgeois 29 oktober 2015

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1 Therapie Hepatitis C anno 2015 Stefan Bourgeois 29 oktober 2015

2 Wie had in 2010 gedacht dat

3 RNA-virus Familie van de Flaviviridae nm Ontdekt in 1989 tevoren nona-nonb hepatitis

4 Verschillende genotypes

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6 Epidemiologie

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8 Epidemiological data (2011) Belgium France Germany Italy Spain UK Prevalence* 0.87% 0.84% 0.6% 4% 1.9% 0.7% 73, , ,000 2,000, , ,000 Screening* 50% 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 2001; Rossol, Gesundheitswesen 2007; Zehnter et al. Hepatology 2005; Beutels et al. Eur J Epidemiol 1997; Carsauw et al. Acta Gastroenterol Belg 2003; Dominguez et al. J Med Virol 2001; Meffre et al. J Med Virol 2010; Mariano et al. Dig Liver Dis 2009; Ansaldi et al, J Med Virol 2005; Gungabissoon et al., Epidemiol Infect 2007 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 2005; De Maeght et al, Acta Gastroenterol Belg 2008; Delwaide et al, Eur J Gastroenterol Hepatol 2005; Serra et al, J Viral Hepatitis 2003 ; Mohsen et al, Gut 2001; Mariano et al, Scand J Infect Dis 2009

9 Transmissie

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11 Risicogroepen voor Hepatitis C Bloedtransfusie vòòr 1992 Hemodialyse I.V.-drugsverslaafden (ook intranasaal druggebruik!) Orgaantransplantatie Familieleden van HCV-patiënten Gezondheidswerkers (prikaccident,...) Tatoeage, piercing, acupunctuur Sexuele promiscuïteit Onvoldoende sterilisatie/desinfectie bij tandheelkundige en chirurgische ingrepen, endoscopie Babyboomers ( 45 70) Nog niet geïdentificeerde risicogroepen

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13 Diagnostiek HCV-antistoffen PCR HCV-RNA Indirecte methode Voordelen vrij eenvoudig niet duur Directe methode Voordelen onmiddellijk positief meet viraal RNA genotype bepaling Nadelen niet specifiek later positief soms vals negatief (immuundepressie) Nadelen afhankelijk van staalmanipulatie duurder

14 Natuurlijk verloop HCV Cirrose Cirrotische decompensatie

15 Evolutie naar cirrose Bij HCV patienten zonder risicofactoren: > 20 j Bij HCV en ethylabusus: 4x meer kans Bij HIV/HCV coïnfectie: tot 25 % met cirrose na 10 jaar infectie

16 Het leven zoals het is

17 in Stuivenberg

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19 J. B., man, 57 j Medische voorgeschiedenis 2009: staging Hep C: gt 1a, HVL, afw TA, F3 Transmissie: 15 j verblijf in Turkije met dagelijks barbier

20 Behandeling Tot Gepegyleerd interferon + Ribavirine

21 Interferon Cytokine; lichaamseigen eiwit (WBC) Antiviraal > Stimuleert in de geïnfecteerde cel de produktie van antivirale proteïnen die de synthese van viraal DNA & RNA inhiberen Immunomodulerend & -stimulerend > Versterkt de immuniteit zodat er een betere herkenning en opruiming van de geïnfecteerde cellen is

22 Interferon Pegylated Interferon alfa > Pegasys (PEG INFα-2a) 180 µg/w > PEG-Intron (PEG INFα-2b) 1,5 µg/kg/w Subcutane toediening (peri-umbilicaal)

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24 Nevenwerkingen Interferon Griepaal syndroom (95%) Anemie & adynamie Neutropenie & thrombocytopenie Alopecia Depressie (33%), psychose, suicidaal gedrag Anorexie & vermagering Insomnia Huiduitslag Schildklierlijden

25 Ribavirine (Rebetol/Copegus) Nucleoside-analoog In vitro actief tegen RNA & DNA virussen In vivo onbekend werkingsmechanisme > In monotherapie: niet werkzaam > In combinatie met interferon: additioneel effect op virusklaring Dosis ifv gewicht: 800 tot 1200 mg/d PO Nevenwerkingen > Hemolytische anemie, nausea, jeuk > Teratogeen!!!

26 J. B., man, 57 j Medische voorgeschiedenis 2009: staging Hep C: gt 1a, HVL, afw TA, F3 Transmissie: 15 j verblijf in Turkije met dagelijks barbier 1/2010: start PI/R (100/1000) 6/2010: stop R/ owv partial responder & depressie ++ Raadpleging 9/2011 Patiënt consulteert i.k.v. verdere aanpak chronische Hep. C. Patiënt vermeldt geen specifieke klachten. Hij is van beroep decorateur in het theater. Tabagisme ++, ethyl weinig (vroeger veel) Patiënt is afkomstig uit Frankrijk.

27 J. B., man, 57 j Laboresultaten GPT 81 U/l (nl < 49) Normaal albumine & bilirubine PCR gt 1a; IU/ml IL 28B rs CT genotype Therapievoorstel?

28 Behandeling Vanaf 2012.

29 DAA Telaprevir

30 Behandeling genotype 1 Pegylated interferon SC 1x/week Ribaverine 800 à 1400 mg/d Telaprevir (Incivo) of Boceprevir (Victrelis) Totale behandeling 48 weken > Doch RGT (response guided therapy) Strikte klinische, psychische en biochemische follow-up Controle viral load in eerste 12 weken ikv stoppingrules (futility rules)

31 Response-Guided Therapy? Response-guided therapy is tailoring HCV treatment for patients based on virologic response to treatment 1 > Therapy can be tailored based on viral load, biological markers 1, and dosage 2 Time of First Undetectable Viral Load RVR START Week 4 Week 12 Week a Week 48 a Treatment Duration cevr cevr = complete early virologic response; HCV = hepatitis C virus; RVR = rapid virologic response. a The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for weeks. 1. Shiffman ML. Curr Gastroenterol Rep. 2010;12: Sulkowski M et al. Gastroenterology. 2010;139:

32 Telaprevir regimen in G1 HCVinfected patients: treatment-naïve without cirrhosis Stop at Week if undetectable at Week 4 and 12 Telaprevir + PR Peg-IFN alfa + ribavirin Peg-IFN alfa + ribavirin if detectable at Week 4 or 12* 0 48 Weeks HCV RNA: If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week or 36: discontinue PR *In Phase III studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/mL and a limit of detection of IU/mL was used to determine whether HCV RNA levels were undetectable. Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for undetectable for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates Telaprevir EU SmPC

33 Boceprevir regimen in G1 HCVinfected patients: treatment-naïve without cirrhosis PR lead-in BOC + PR Stop treatment at Week 28 if undetectable at Week 8 and If detectable at Week 8 but undetectable at Week : BOC + PR* PR* Weeks HCV RNA Assess for RGT criterion If 100 IU/mL discontinue all drugs If detectable discontinue all drugs *This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

34 Dosing duration in all patients with compensated cirrhosis TVR + Peg-IFN + RBV Peg-IF + RBV >1000 IU/mL: Stop 3 drugs >1000 IU/mL: Stop 3 drugs Detectable: Stop PR Detectable: Stop PR Peg-IFN + RBV BOC+ Peg-IFN + RBV 100 IU/mL: Stop 3 drugs Detectable: Stop 3 drugs Telaprevir EU SmPC; Boceprevir EU SmPC

35 Side-effect of tripple regimens Side effects remain a problem (Peg-IFN/RBV side effects dominant) Additional side effects with DAAs include > Telaprevir: 1 4 rash, anemia, anorectal itching > Boceprevir: 5,6 anemia, dysgeusia, neutropenia Rash: 1 4,7 > Most rashes (>90%) are mild, responsive to treatment (compatible with treating-through ) > Treat rash early and monitor patient closely > Few cases of severe cutaneous reactions (SJS, DRESS) (resolved with treatment discontinuation) Anemia > Increased with telaprevir and boceprevir (EPO use only allowed in boceprevir trials) > Anemia with telaprevir is limited (12 weeks) > Strategies for treating anemia include RBV dose reduction and blood transfusions 1. Jacobson IM, et al. N Engl J Med 2011;364:05 16; 2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 3. Zeuzem S, et al. N Engl J Med 2011;364:17 28; 4. Telaprevir EU SmPC 5. Poordad F, et al. N Engl J Med 2011;364: ; 6. Bacon BR, et al. N Engl J Med 2011;364:

36 J. B., man, 57 j Raadpleging 16/1/2012 Uitleg +++ rond belang van compliance en ernst van nevenwerkingen Start Pegasys 180, Copegus 1000 mg/d, Incivo 2250 mg/d gewicht 69 kg Advies psy: WellButrin (bupropion) 300 mg/d

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38 J. B., man, 57 j Raadpleging 1/2/2012 (week 2) Vermoeid, rash voorarmen en peri-umbilicaal (gr 1) WBC 2750 (W0 8400) BP (W ) Hb 15.3 (W0 16,6) Raadpleging 13/2/2012 (week 4) Diarree, beter indien Riba & TVR separaat ingenomen Droge mond en irritatie thv de tong Rash OK WBC en BP stabiel Hb 13 g/dl PCR: niet detecteerbaar (RVR)

39 J. B., man, 57 j Raadpleging 12/3/2012 (week 8) Vermoeidheid en adynamie nemen toe Psychisch enorm zwaar (iom psy: opdrijven WellButrin) WBC & BP stabiel Hb 11.3 Raadpleging 29/3/2012 (week 10) Oropharyngeale klachten +++ met belangrijke insomnia Anorectale last +++ Dreigende psychische en fysische decompensatie!

40 J. B., man, 57 j Raadpleging 10/4/2012 (week 12) Globaal weer wat beter, minder insomnia WBC & BP genormaliseerd Hb 10.3 PCR: niet detecteerbaar (ervr) Raadpleging 7/5/2012 (week 16) Vermoeid en spierpijnen met zeer slechte inspanningstolerantie Zeer emotioneel Sterk gemotiveerd om R/ verder te zetten! Hb 11,4

41 J. B., man, 57 j Hoe lang behandelen??? Dus: Partial responder bij eerdere behandeling Metavir F3 ervr

42 Telaprevir regimen in G1 HCV-infected patients Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (ervr) STOP Telaprevir + PR PR PR Weeks Non-cirrhotic naïves and relapsers without ervr Partial and null responders Patients with cirrhosis HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week or 36: discontinue PR Telaprevir EU SmPC

43 J. B., man, 57 j Raadpleging 2/7/2012 (week ) Blijvend matige tolerantie Respiratoire infectie en COPD-opstoot: R/AB & puffers Hb 10.7 PCR: niet detecteerbaar Raadpleging 6/8/2012 (week 29) Vermoeidheid en insomnia Hoesten Hb 12,1

44 J. B., man, 57 j Raadpleging 17/12/2012 (week 48) Blijvend matige tolerantie Vnl vermoeidheid en spierpijnen PCR: niet detecteerbaar Raadpleging maar 2013(FU week 12) Vrij goede recuperatie Genormaliseerde hematologie PCR positief!! Beeld van relapse!

45 1 januari 2015 Nieuwe molecules Nieuwe onderzoekstechnieken

46 Evolution of HCV genotype 1 treatment 59 75% SVR rate (%) % IFN % IFN + RBV % Peg- IFN + RBV 2 4 DAA + Peg- IFN + RBV 5 8 Future? IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response 1. McHutchison JG, et al. N Engl J Med 1998;339: ; 2. Fried M, et al. N Engl J Med 2002;347: Manns MP, et al. Lancet 2001;358:958 65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140: Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

47 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:

48 Direct-acting antiviral (DAA) targets Signal peptidase NS3-NS4A protease NH 2 C E 1 NS3/4A protease inhibitors Telaprevir Boceprevir BI TMC435 Danoprevir (R7227/ITMN- 191) GS 9256 BMS ACH 1625 ABT 450 SPP E 2 p 7 NS 2 NS3 NS4 A NS2-NS3 protease NS5A inhibitors BMS ABT 267 NS4 B Pockros P, et al. Therap Adv Gastroenterol 2010;3: ; Wyles D, et al. Top HIV Med 2010;18:132-6; Kieffer T, et al. J Antimicrob Chemother 2010;65:202-12; Zeuzem S, et al. Hepatology 2010;52(Suppl.):400A; Zeuzem S, et al. Hepatology 2010;52(Suppl.):876A; Lok A, et al. J Hepatol 2011;54(Suppl. 1):S536; NS5 A NS5B polymerase inhibitors Nucleoside Mericitabine (R7128) IDX-184 PSI-7977 Non-nucleoside ABT-333 ANA598 GS 9190 BI Filibuvir (PF ) ABT-072 VX-222 NS5 B COOH

49 Direct Acting Antivirals Against HCV Asunaprevir Danoprevir ABT-450/r MK-5172 Sovaprevir.. Daclatasvir Ledipasvir ABT-267 asvirs NS5A Inhibitors Simeprevir Faldaprevir Boceprevir Telaprevir ABT-333 Deleobuvir BMS VX-222 ABT-072 Setrobuvir Filibuvir. previrs Protease Inhibitors Nucs Non-Nucs Polymerase Inhibitors buvirs Sofosbuvir Mericitabine ALS-2200 Manns, von Hahn, Nat Rev Drug Discov 2013

50 The European HCV treatment landscape is changing rapidly Standard of care: pegifn + RBV Daclatasvir : multigenotypic EMA approval Simeprevir EMA approval Sofosbuvir EMA approval Pre First PIs launched: boceprevir and telaprevir Sofosbuvir + Ledipasvir EMA approval Paritaprevir/Ombitasvir Rritonavir + Dasabuvir EMA approval EMA, European Medicines Agency; pegifn, pegylated interferon; PI, protease inhibitor; RBV, ribavirin; SmPC, Summary of Product Characteristics. Wendt A, et al. Clin Pharmacol 2014;6:1 17. Ribavirin Mylan SmPC PegIntron SmPC Victrelis SmPC Incivo SmPC Solvadi SmPC All available from: Accessed October 2014.

51 Behandeling Vanaf 2015

52 Behandeling Vanaf 2015

53 Behandeling Vanaf 2015

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57 Combination treatment Side effects Drug-drug interactions Resistance

58 Telaprevir: DDIs with HIV antiretrovirals HIV antiretroviral Studies completed Atazanavir/r (Reyetaz ) Darunavir/r (Prezista ) Lopinavir/r (Kaletra ) Fosamprenavir/r (Telzir ) Ritonavir (r) (Norvir ) Efavirenz (Stocrin )/(Atripla *) Etravirine (Intelence ) Rilpivirine (Edurant ) Raltegravir (Isentress ) Tenofovir (Viread ) Studies not completed Zidovudine (Retrovir ) Abacavir (Ziagen )/ Recommendation Clinical and laboratory monitoring for hyperbilirubinemia is recommended Not recommended Used as booster for HIV PIs. No effect on telaprevir. TVR dose increase necessary (1125mg q8h) No dose adjustment required No dose adjustment required.../r: ritonavir-boosted *Atripla: combination efavirenz + emtricitabine + tenofovir UDP-glucuronosyltransferase: uridine 5'-diphospho-glucuronosyltransferase Increased clinical and laboratory monitoring is warranted An effect of telaprevir on UDP-glucuronyltransferases cannot be ruled out and may affect the plasma concentrations of abacavir or zidovudine (not studied)

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62 1. Fibroscan 1 cut-offs of ELASTOGRAFY in chronic hepatitis C (agreed at RIZIV-INAMI ) Valid if 10 correct measurements, success rate > 60%, IQR < 30% F3 9.5 kpa F kpa 2. Shear wave elastografie 2 F3 8.7 kpa F kpa 3. Acoustic radiation forse impulse (ARFI, Siemens technique) 3,4 F3 1,55 m/s F4 1,80 m/s 1 Castera et al. Gasteroenterology Ferraioli et al Hepatology Friedrich-Rust et al J Viral Hepat Ferraioli et al J Ultrasound Med 2014

63 Niet invasieve fibrosemeting Shearwave Elastografie

64 cut-offs of BIOLOGICAL FIBROSIS-SCORES in chronic hepatitis C (agreed at RIZIV-INAMI ) 1. Fibrotest (Biopredictive): Elelements : α2 macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT F3: F3-F4: F4: 0.75 To be executed per excel-sheet (annex) 2. Apri (ast-platelet ratio) In a pure HCV cohort F3: 1 F4: 1.6 Reference: Holmberg, Clin Infect Dis Fib-4 (age, AST,ALT, platelets) F3: 2.1 F3-F4: 3.25 F4: 3.85 References: Vallet-Pichard, Hepatology 2007, Holmberg, Clin Infect Dis 2013, Martinez APT 2011 Useful website:

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66 AI : SVR12 in Patients with F3 Fibrosis DCV + SOF ± RBV, 12 or weeks HCV GT 1, 2, or 3 naive, and GT 1 TVR or BOC Failures Back SVR12 a : Patients With F3 Fibrosis b Patients with SVR, % weeks weeks GT 1 PI failure GT 2 naive GT 3 naive GT 1 naive a HCV RNA < 25 IU/mL documented on or after posttreatment Week 12. b Metavir scores were derived from FibroTest scores per the manufacturer ( patients with a score of F4 were required to have no evidence of cirrhosis on the basis of a liver biopsy. SOF, sofosbuvir; BOC, boceprevir; TVR, telaprevir. BMS data on file DACL-002.

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68 HCV infection is associated with an increased overall mortality Lee et al. JID 2012

69 HCV-associated complications will increase markedly over the next 5 10 years Germany France Spain England HCC, hepatocellular carcinoma. Razavi H, et al. J Viral Hepat 2014;21:(Suppl. 1),34 59.

70 SVR is associated with reduced mortality ALL CAUSE MORTALITY LIVER RELATED MORTALITY Van der Meer AJ, et al. JAMA 2012

71 Patients with SVR have a normal overal survival Van der Meer, AASLD 2013, Abstract 1425

72 Hepatitis C is not only a liver disease! CNS disorders 1,2 Fatigue Endocrine disorders 2 Depression Dermatologic disorders 1,2 Cardiovascular diseases 2 Haematologic disorders 2 Social/legal consequences Renal disorders 2 Rheumatologic disorders 1,2 CNS, central nervous system. 1. Cacoub P, et al. Medicine 2000;79: Mauss S, et al. In: Hepatology A Clinical Textbook, 2014.

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74 Treatment of HCV in 2015: already too many options?

75 When to start treatment? How long to treat? Which drugs to use? Impaired renal function? RBV: yes/no? How to treat GT-3? TOUGH DECISIONS AHEAD Advanced liver disease? DDI profile and HAART? Resistance?

76 Take home message Onbekend maakt onbemind : screening! HCV virus kan geëradiceerd worden met eindige therapie Behandeling heeft weinig nevenwerkingen Zeer, zeer goede resultaten Compliance is cruciaal Complexe terugbetalingscriteria Zeer duur Nieuwe medicatie start vandaag!

77 The End!