Therapie Hepatitis C anno 2015

Stefan Bourgeois 29 oktober 2015

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Wie had in 2010 gedacht dat…

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RNA-virus Familie van de Flaviviridae 55 – 65 nm Ontdekt in 1989 tevoren nonA-nonB hepatitis

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Verschillende genotypes

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Epidemiologie

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Belgium France Germany Italy Spain UK

Prevalence* 0.87% 0.84% 0.6% 4% 1.9% 0.7%

73,000 360,000 460,000 2,000,000 690,000 340,000

Screening* 50% 64% 48% 46% 35% 34%

Genotype†

%G1 61% 56% 56% 62% 65% 44%

%G2-3 26% 32% 32% 37% 23% 53%

%G4-5-6 13% 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

Epidemiological data (2011)

Transmissie

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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 tandheelkun-

dige en chirurgische ingrepen, endoscopie… Babyboomers (‘45 – ‘70) Nog niet geïdentificeerde risicogroepen

Risicogroepen voor Hepatitis C

PresenterPresentation Notesref. 3: Trepo C., 27-28 October 1995, Vienna, Public Health Threat and Emerging Concensus, an educational Symposium.

ref. 8: Alter M., Epidemiology of Hepatitis C Virus infection , Supplemental Monograph;

ref. 9: Esteban R., Epidemiology of hepatitis C virus infection, Journal of Hepatology, 1993; 17 (Suppl.3): S67-S71

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Indirecte methode Voordelen vrij eenvoudig niet duur Nadelen niet specifiek later positief soms vals negatief (immuundepressie)

Directe methode Voordelen onmiddellijk positief meet viraal RNA genotype bepaling Nadelen afhankelijk van staalmanipulatie duurder

HCV-antistoffen PCR HCV-RNA

Diagnostiek

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Natuurlijk verloop HCV

Cirrotische decompensatie

Cirrose

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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

Evolutie naar cirrose

http://bioquest.stmichaelcollege.nl/images/code/lever_yorick_001.jpg

Het leven zoals het is…

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… in Stuivenberg

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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

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Gepegyleerd interferon +

Ribavirine

Behandeling

Tot 2011….

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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

Interferon

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Interferon

> Pegasys ® (PEG INFα-2a) 180 µg/w

> PEG-Intron ® (PEG INFα-2b) 1,5 µg/kg/w

Pegylated Interferon alfa

Subcutane toediening (peri-umbilicaal)

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Nevenwerkingen Interferon

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

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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!!!

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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.

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J. B., man, 57 j

Laboresultaten GPT 81 U/l (nl < 49) Normaal albumine & bilirubine PCR gt 1a; 1.130.000 IU/ml IL 28B rs12979860 CT genotype

Therapievoorstel?

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Behandeling

Vanaf 2012….

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DAA

Telaprevir

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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)

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Response-Guided Therapy?

Response-guided therapy is tailoring HCV treatment for patients based on virologic response to treatment1

> Therapy can be tailored based on viral load, biological markers1, and dosage2

cEVR = complete early virologic response; HCV = hepatitis C virus; RVR = rapid virologic response. aThe treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks. 1. Shiffman ML. Curr Gastroenterol Rep. 2010;12:70–75. 2. Sulkowski M et al. Gastroenterology. 2010;139:1602–1611.

STA

RT

Treatment Duration

Week 4 Week 12 Week 24a Week 48a

RVR

cEVR

Time of First Undetectable Viral Load

PresenterPresentation NotesOptimal results require individualized treatment based on the potential success of each patient. While some patients may require less than 6 months of therapy to achieve SVR, others can benefit from extending therapy to 72 weeks.1Response-guided therapy is the use of viral kinetics, specifically when HCV RNA is undetectable during treatment to predict the patients that may be able to shorten therapy versus the patients that require longer therapy to boost potential for success.1 This slide shows a response-guided treatment regimen, whereby patients with RVR continue treatment only to 24 weeks, and patients with cEVR continue to 48 weeks.2 �Notably, consider one European study designed to examine shortening therapy for HCV-1 chronic infection in adult patients naïve to previous treatment and with HCV RNA ≤600,000 IU/mL.3 Although SVR was exceptionally high after only 24 weeks of treatment for HCV (89%) genotype 1 patients with a rapid virologic response, relapse was unacceptably high (75%–80%) in patients who did not experience rapid virologic response.3 Therefore, when altering the course of treatment, it is very important to base these decisions on virologic response.1

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Telaprevir regimen in G1 HCV-infected patients: treatment-naïve without cirrhosis

*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 10–15 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

Peg-IFN alfa + ribavirin if detectable at Week 4 or 12*

Peg-IFN alfa + ribavirin

Stop at Week 24 if undetectable at Week 4 and 12

Telaprevir + PR

If >1000 IU/mL at Week 4 or 12: discontinue all drugs

If detectable at Week 24 or 36: discontinue PR

HCV RNA:

0 48 Weeks 4 24 36 12

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Boceprevir regimen in G1 HCV-infected patients: treatment-naïve without cirrhosis

PR lead-in

BOC + PR*

0 48 Weeks 28 4 8 24

BOC + PR

36

PR*

If detectable at Week 8 but undetectable at Week 24:

12

HCV RNA

*This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

Assess for RGT

criterion

If ≥100 IU/mL discontinue all

drugs

If detectable discontinue all

drugs

Stop treatment at Week 28 if undetectable at Week 8 and 24

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48 4 0 12 36 24

Dosing duration in all patients with compensated cirrhosis

BOC+ Peg-IFN + RBV Peg-IFN + RBV

≥100 IU/mL: Stop 3 drugs

Detectable: Stop 3 drugs

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

Telaprevir EU SmPC; Boceprevir EU SmPC

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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;364:2405–16; 2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 3. Zeuzem S, et al. N Engl J Med 2011;364:2417–28; 4. Telaprevir EU SmPC

5. Poordad F, et al. N Engl J Med 2011;364:1195–206; 6. Bacon BR, et al. N Engl J Med 2011;364:1207–17 7. http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

PresenterPresentation NotesKey PointTelaprevir- and boceprevir-based therapy have the potential to significantly improve SVR rates among HCV genotype 1-infected treatment-naïve patients. However, with these increased response rates there are also additional patient management considerations. Particularly, telaprevir may lead to increases in anemia, rash and anorectal events, which are generally manageable and do not lead to discontinuation. In addition, boceprevir can increase the occurrence of anemia and dysgeusia.

NotesTreatment with DAAs may result in additional patient management considerations. With telaprevir treatment, increased rash, anemia and anorectal events have been recorded.1–4 With boceprevir treatment, increased anemia and dysgeusia events may occur.5,6Rash events with telaprevir are generally mild or moderate and can be managed using the rash management plan implemented for Phase III trials. Drug interruption is generally not needed for mild or moderate rash. For severe rash, telaprevir should be discontinued immediately, and for SCAR all treatment should be permanently and immediately discontinued. Rash adverse events resulted in 6% discontinuation of telaprevir, were manageable and reversible upon cessation of treatment.Anemia was observed at higher frequency in patients treated with boceprevir and telaprevir.Anemia occurred in around 30% of patients treated with telaprevir and half of patients treated with boceprevir.Patients treated in the SPRINT-1 boceprevir trial frequently received erythropoietin. However, erythropoietin was not allowed during telaprevir dosing in the PROVE trials.

References1. Jacobson IM, et al. N Engl J Med 2011;364:2405–16.2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A.3. Zeuzem S, et al. N Engl J Med 2011;364:2417–28. 4. INCIVO (telaprevir) EU SmPC. 5. Poordad F, et al. N Engl J Med 2011;364:1195–206.6. Bacon BR, et al. N Engl J Med 2011;364:1207–17.

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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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J. B., man, 57 j

Raadpleging 1/2/2012 (week 2) Vermoeid, rash voorarmen en peri-umbilicaal (gr 1) WBC 2750 (W0 8400) BP 99.000 (W0 224.000) 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)

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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!

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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

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J. B., man, 57 j

Hoe lang behandelen???

Dus: Partial responder bij eerdere behandeling Metavir F3 eRVR

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Telaprevir regimen in G1 HCV-infected patients

24 0 48 12 36 4 Weeks

STOP

PR

Telaprevir EU SmPC

Telaprevir + PR PR

Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (eRVR)

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 24 or 36: discontinue PR

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J. B., man, 57 j

Raadpleging 2/7/2012 (week 24) 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

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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!

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1 januari 2015

Nieuwe molecules Nieuwe onderzoekstechnieken

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Evolution of HCV genotype 1 treatment

1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82 3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55

5. 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

IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response

100

80

60

40

20

0

SVR

rate

(%)

1990 2000 2010 2020

2–7%

IFN1

16–28%

IFN +

RBV1

42–54%

Peg-IFN + RBV2–4

59–75%

DAA +

Peg-IFN + RBV5–8

Future?

PresenterPresentation NotesThe HCV treatment paradigm has evolved over the last two decadesAs new treatments have become available, old regimens have generally become obsolete, with Peg-IFN replacing IFN and Peg-IFN/RBV combinations replacing monotherapy Changes in clinical practice have provided improved chances of successHigher SVR rates in all HCV-infected patients Shorter duration of therapyOpportunities for therapy individualizationThe introduction of DAAs provides further opportunities for improving treatment outcome and moving the treatment paradigm forward

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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;6:991-1000.

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Direct-acting antiviral (DAA) targets

NS3/4A protease inhibitors Telaprevir Boceprevir BI 201335 TMC435 Danoprevir (R7227/ITMN-191) GS 9256 BMS 650032 ACH 1625 ABT 450

NS5A inhibitors BMS-790052 ABT 267

NS5B polymerase inhibitors Nucleoside Mericitabine (R7128) IDX-184 PSI-7977 Non-nucleoside ABT-333 ANA598 GS 9190 BI 207127 Filibuvir (PF-868554) ABT-072 VX-222

NH2 C E1

E2

p7

NS2

NS3 NS4A

NS4B

NS5A

NS5B

COOH

Signal peptidase

NS2-NS3 protease

NS3-NS4A protease

SPP

Pockros P, et al. Therap Adv Gastroenterol 2010;3:191-202; 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; www.abbott.com; www.achillion.com

Direct Acting Antivirals Against HCV

Manns, von Hahn, Nat Rev Drug Discov 2013

NS5A Inhibitors

Protease Inhibitors Polymerase Inhibitors Nucs Non-Nucs “…previrs“

“…asvirs“

“…buvirs“

Sovaprevir

MK-5172 ABT-450/r

Danoprevir Asunaprevir

Faldaprevir

Simeprevir

Telaprevir Boceprevir

Ledipasvir Daclatasvir

ABT-267

…..

BMS-731225 Deleobuvir

VX-222

ABT-333

Filibuvir Setrobuvir

….

ABT-072

Mericitabine Sofosbuvir ALS-2200

2012 2014 2013 2011 Pre-2011 2015

The European HCV treatment landscape is changing rapidly

Standard of care: pegIFN + RBV

First PIs launched: boceprevir and

telaprevir

Sofosbuvir EMA approval

Sofosbuvir + Ledipasvir EMA approval

Simeprevir EMA approval

Daclatasvir : multigenotypic 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 2010. PegIntron SmPC 2010. Victrelis SmPC 2014. Incivo SmPC 2011. Solvadi SmPC 2014.

All available from: http://www.ema.europa.eu/ema/. Accessed October 2014.

…… Paritaprevir/Ombitasvir Rritonavir + Dasabuvir

EMA approval

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Behandeling Vanaf 2015

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Behandeling Vanaf 2015

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Behandeling Vanaf 2015

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Combination treatment

Side effects Drug-drug interactions Resistance

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Telaprevir: DDIs with HIV antiretrovirals

HIV antiretroviral Recommendation

Studies completed

Atazanavir/r (Reyetaz®) Clinical and laboratory monitoring for hyperbilirubinemia is recommended

Darunavir/r (Prezista®) Lopinavir/r (Kaletra®) Fosamprenavir/r (Telzir®)

Not recommended

Ritonavir (r) (Norvir®) Used as booster for HIV PIs. No effect on telaprevir.

Efavirenz (Stocrin®)/(Atripla® *) TVR dose increase necessary (1125mg q8h)

Etravirine (Intelence®) Rilpivirine (Edurant®) No dose adjustment required

Raltegravir (Isentress®) No dose adjustment required

Tenofovir (Viread®) Increased clinical and laboratory monitoring is warranted

Studies not completed

Zidovudine (Retrovir®) Abacavir (Ziagen®)/

An effect of telaprevir on UDP-glucuronyltransferases cannot be ruled out and may affect the plasma concentrations of abacavir or zidovudine (not studied)

.../r: ritonavir-boosted *Atripla: combination efavirenz + emtricitabine + tenofovir UDP-glucuronosyltransferase: uridine 5'-diphospho-glucuronosyltransferase

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cut-offs of ELASTOGRAFY in chronic hepatitis C (agreed at RIZIV-INAMI 23.12.2014)

1. Fibroscan1 Valid if 10 correct measurements, success rate > 60%, IQR < 30% F3 ≥ 9.5 kPA F4 ≥ 12.5 kPA

2. Shear wave elastografie2

F3 ≥ 8.7 kPA F4 ≥ 10.4 kPA

3. Acoustic radiation forse impulse (ARFI, Siemens technique)3,4 F3 ≥ 1,55 m/s F4 ≥ 1,80 m/s

1Castera et al. Gasteroenterology 2005 2Ferraioli et al Hepatology 2012

3Friedrich-Rust et al J Viral Hepat 2012 4Ferraioli et al J Ultrasound Med 2014

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Niet invasieve fibrosemeting

Shearwave Elastografie

cut-offs of BIOLOGICAL FIBROSIS-SCORES in chronic hepatitis C (agreed at RIZIV-INAMI 23.12.2014)

1. Fibrotest (Biopredictive): Elelements : α2 macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT F3: 0.59-0.72 F3-F4: 0.73-0.74 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 2013 3. 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: www.hepatitisc.uw.edu/page/clinical-calculators

http://www.hepatitisc.uw.edu/page/clinical-calculatorshttp://www.hepatitisc.uw.edu/page/clinical-calculatorshttp://www.hepatitisc.uw.edu/page/clinical-calculators

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HCV GT 1, 2, or 3 naive, and GT 1 TVR or BOC Failures DCV + SOF ± RBV, 12 or 24 weeks AI444-040: SVR12 in Patients with ≥F3 Fibrosis

Back

aHCV RNA < 25 IU/mL documented on or after posttreatment Week 12. bMetavir scores were derived from FibroTest scores per the manufacturer (www.biopredictive.com); 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.

Patie

nts w

ith S

VR

, %

SVR12a: Patients With ≥ F3 Fibrosisb

12 weeks GT 2 naive GT 1 naive

GT 1 PI failure 24 weeks GT 3 naive

27 27

14 14

20 20

8 8

5 5

PresenterPresentation NotesStandard abbreviations:

DCV, daclatasvirASV, asunaprevir325, BMS-791325P/R or pegIFN, peginterferon alfaLambda, peginterferon lambdaRBV, ribavirinSOF, sofosbuvirTVR, telaprevirBOC, boceprevirPI, HCV NS3 protease inhibitorAE, adverse eventGT, HCV genotypeALT, alanine aminotransferaseAST, aspartate aminotransferase�SVR, sustained virologic responseSVR12, SVR at posttreatment Week 12SVR24, SVR at posttreatment Week 24mITT, modified intention-to-treat includes all patients who received ≥ 1 dose of study medication.ULN, upper limit of normal.LLOQ, lower limit of assay quantitationRAV, resistance-associated variant

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HCV infection is associated with an increased overall mortality

Lee et al. JID 2012

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.

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24 Van der Meer AJ, et al. JAMA 2012

ALL CAUSE MORTALITY LIVER RELATED MORTALITY

SVR is associated with reduced mortality

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24 Van der Meer, AASLD 2013, Abstract 1425

Patients with SVR have a normal overal survival

Endocrine disorders2

Rheumatologic disorders1,2

Cardiovascular diseases2

CNS disorders1,2

Haematologic disorders2

Dermatologic disorders1,2

Hepatitis C is not only a liver disease!

Renal disorders2

Fatigue

Depression

Social/legal consequences

CNS, central nervous system. 1. Cacoub P, et al. Medicine 2000;79:47–56. 2. Mauss S, et al. In: Hepatology – A Clinical Textbook, 2014.

http://www.google.de/imgres?hl=de&biw=1140&bih=434&tbm=isch&tbnid=0hJZ6hguYszwGM:&imgrefurl=http://www.apotheken-umschau.de/Schlaf/Muedigkeit--Ursachen-Lebensgewohnheiten-Umwelt-119585_3.html&docid=ztGxchAYh3bpzM&imgurl=http://www.apotheken-umschau.de/multimedia/191/286/293/5155307537.jpg&w=462&h=249&ei=tmiQUtynK5GR7AaV9oCgCQ&zoom=1

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Treatment of HCV in 2015: already too many options?

TOUGH DECISIONS

AHEAD

When to start treatment?

Impaired renal function?

Which drugs to use?

How long to treat?

RBV: yes/no?

How to treat GT-3? Advanced liver

disease?

DDI profile and HAART?

Resistance?

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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!

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The End!

Therapie Hepatitis C�anno 2015Wie had in 2010 gedacht dat…Slide Number 3Slide Number 4Slide Number 5EpidemiologieSlide Number 7Epidemiological data (2011)TransmissieSlide Number 10Slide Number 12Slide Number 13 HCV-antistoffen PCR HCV-RNANatuurlijk verloop HCVSlide Number 16Het leven zoals het is…Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22InterferonSlide Number 24Nevenwerkingen InterferonRibavirine� (Rebetol/Copegus)Slide Number 27Slide Number 28Slide Number 29DAABehandeling �genotype 1Response-Guided Therapy?Telaprevir regimen in G1 HCV-infected patients: �treatment-naïve without cirrhosisBoceprevir regimen in G1 HCV-infected patients:�treatment-naïve without cirrhosis Slide Number 35Side-effect of tripple regimensSlide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Telaprevir regimen in G1 HCV-infected patients Slide Number 44Slide Number 451 januari 2015Evolution of HCV genotype 1 treatment Potential Targets for Antiviral Intervention in the HCV Life Cycle and Their Location in the HCV GenomeDirect-acting antiviral (DAA) targetsSlide Number 50The European HCV treatment landscape is changing rapidlySlide Number 52Slide Number 53Slide Number 54Slide Number 55Slide Number 56Slide Number 57Combination treatmentTelaprevir: DDIs with HIV antiretroviralsSlide Number 60Slide Number 61Slide Number 62Slide Number 63Niet invasieve fibrosemetingSlide Number 65Slide Number 66Slide Number 67Slide Number 68Slide Number 69HCV-associated complications will increase markedly over the next 5–10 yearsSlide Number 71Slide Number 72Hepatitis C is not only a liver disease!Slide Number 74Treatment of HCV in 2015: already �too many options?Slide Number 76Take home messageSlide Number 78