Hepatitis C Virusreplicatie en...
Transcript of Hepatitis C Virusreplicatie en...
![Page 1: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/1.jpg)
Hepatitis C
Virusreplicatie en DAA-resistentieSophie WillemseMaag-Darm-Leverarts Amsterdam UMC locatie AMC
Hepatitis Masterclass – Module 525 juni 2019
![Page 2: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/2.jpg)
Disclosures
Research support
AbbVie, Enyo Pharma, Gilead, Roche
Speaker’s fees, consultancy or advisory board
AbbVie, Bristol-Myers-Squibb, Gilead
Hepatitis C | 25-06-2019 2
![Page 3: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/3.jpg)
Hepatitis C replicatie en DAA-resistentie
Hepatitis C | 25-06-2019 3
![Page 4: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/4.jpg)
Hepatitis C Virus
Positive single-stranded RNA virus
Flaviviridae
Genotype 1-6 (7)
Hepatitis
- Chronisch 80%
- Mogelijk leidend tot levercirrose/HCC
Geen vaccin
Hepatitis C | 25-06-2019 4
![Page 5: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/5.jpg)
Hepatitis C Virus 115 → 70 miljoen
Hepatitis C | 25-06-2019 5Gower et al. J Hepatol 2014
![Page 6: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/6.jpg)
Phylogenetische classificatie
6Hepatitis C | 25-06-2019 Bukh. J Hepatol 2016
![Page 7: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/7.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 7
![Page 8: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/8.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 8Bartenschlager et al. J Hepatol 2010
![Page 9: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/9.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 9
![Page 10: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/10.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 10
![Page 11: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/11.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 11
![Page 12: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/12.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 12
![Page 13: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/13.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 13
![Page 14: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/14.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 14
![Page 15: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/15.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 15
1. Attachment
& uncoating
2. Translation &
processing
Fusion &
uncoating
Nucleocapsid
Envelope
RNA
4. Assembly
& release
Viral assembly
Transport
through
Golgi
apparatus
Viral RNA
targeted to ER
Viral replication
complexes form in a
membranous web
structure
3. Replication
NS
2
NS4A
Cyp
B
Cytoplasm
ER
lumen
Viral RNA
NS3 NS5A NS5B
Receptor binding
Viral proteins
translated
Viral
RNA
Polyprotein
Ribosome
Endocytosis
NS4B
Protease inhibitors
Assembly inhibitors
Cyclophyllin inhibitors
NS5A inhibitors
Polymerase inhibitors
Asselah and Marcellin. Liver Int 2011
![Page 16: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/16.jpg)
Hepatitis C replicatiecyclus
Hepatitis C | 25-06-2019 16
![Page 17: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/17.jpg)
HCV Genome
• p7
– Appears to function as an ion channel
– Essential for virus particle assembly
and release of infectious virions
• NS2
– Transmembrane metalloproteinase
• NS3
– Serine protease and NTPase/helicase
activity
• NS4A
– Acts as a cofactor for NS3
– Involved in targeting NS3 to the ER
membrane
• NS4B
– Recruits viral proteins to the
replication complex
• NS5A
– Key roles in the viral replication
complex, modulation of cell signalling
pathways, and viral assembly and
release
• NS5B
– RNA-dependent RNA polymerase
UTR = untranslated region; IRES = internal ribosome entry site.
Moradpour and Penin. Curr Top Microbiol Immunol. 2013;369:113.
Parfieniuk et al. World J Gastroenterol. 2007;13:5673.
NS4B3' UTR
p7
5' UTR NS5B4ACore E1 E2 NS2 NS3 NS5A
Structural proteins Nonstructural proteins
IRES
![Page 18: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/18.jpg)
Targets for DAAs
Hepatitis C | 25-06-2019 18Adapted from McGovern et al. Hepatology 2008
![Page 19: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/19.jpg)
Protease
Glecaprevir (alle genotypes)
Voxilaprevir (alle genotypes)
Grazoprevir (genotype 1,4)
NS5B
Sofosbuvir (alle genotypes)
NS5A
Velpatasvir (alle genoypes)
Pibrentasvir (alle genotypes)
Ledipasvir (genotype 1,4-6)
Elbasvir (genotype 1,4)
DAAs beschikbaar in Nederland
Hepatitis C | 25-06-2019
![Page 20: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/20.jpg)
Maviret
Glecaprevir
Pibrentasvir
Zepatier
Elbasvir
Grazoprevir
Epclusa
Velpatasvir
Sofosbuvir
DAAs beschikbaar in Nederland
Hepatitis C | 25-06-2019
Sovaldi
Sofosbuvir
Vosevi
Velpatasvir
Voxilaprevir
Sofosbuvir
![Page 21: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/21.jpg)
2017
Hepatitis C | 25-06-2019
Historisch overzicht hepatitis C behandeling
![Page 22: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/22.jpg)
Resistance-associated substitutions
Resistance-associated substitutions (RAS)
- Nucleotide substitutie “willekeurig” tijdens replicatiecyclus
- Kunnen geassocieerd zijn met resistentie
- Meestal minder “fitte” virussen
Resistente varianten
- Virussen die beter groeien dan wild-type virus in de aanwezigheid van een DAA
- Voorkeursterm in geval van in vitro studies
Hepatitis C | 25-06-2019 22
![Page 23: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/23.jpg)
Viral fitness
DAAs maken geen RAS maar selecteren ze uit
- Substituties zorgen meestal voor verminderde fitness van het virus
- RAS-varianten zijn “fitter” dan de rest in aanwezigheid van DAAs
- Bij wegvallen van DAAs overschaduwd door wild-type variant
Fitness van bepaalde RAS varianten bepaalt persisteren na therapie
- Sofosbuvir-associated RAS S282T slechte fitness/replicatie en verdwijnt snel
- High-level protease inhibitor RAS lage “fitness”
- Zelden op baseline aanwezig
- Verdwijnen doorgaans na verloop van tijd na gefaalde therapie
- NS5A RAS vrijwel even fit als wild-type en competitief
- Blijven vaak bestaan na gefaalde therapie
- Kunnen reeds op baseline aanwezig zijn
Hepatitis C | 25-06-2019 23
Wyles et al. J Hepatol 2016
Krishnan et al. J Hepatol 2015
Krishnan et al. Antimicrob Agents Chemother 2015
Liu et al. Antimicrob Agents Chemother 2015
![Page 24: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/24.jpg)
RAS – verschillende klassen
Hepatitis C | 25-06-2019 24Krishnan et al. J Hepatol 2015
![Page 25: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/25.jpg)
Relevante RAS
Hepatitis C | 25-06-2019 25Sorbo et al. Drug Resist Update 2018
![Page 26: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/26.jpg)
![Page 27: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/27.jpg)
RAS - effect
Hepatitis C | 25-06-2019 27Liu et al. Antimicrob Agents Chemother 2015
![Page 28: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/28.jpg)
Baseline RAS testing
Hepatitis C | 25-06-2019 28Pawlotsky. Gastroenterology 2016
![Page 29: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/29.jpg)
Resistance associated substitutions
Pre-existent
– Q80K polymorphisme (genotype 1a) • “low level” resistentie tegen proteaseremmers
– Wisselend effect afhankelijk van verschillende factoren
Na gefaalde therapie
– Cross-reactiviteit per klasse
– NS3, verdwijnt na een tijd
– NS5A, kan jaren blijven bestaan
– NS5B, hangt af van generatie, meestal “unfit” virus
– Overall hangt effect af van fitness mutant
Hepatitis C | 25-06-2019 29
![Page 30: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/30.jpg)
Wanneer baseline RAS testen?
Alleen als het je beleid beïnvloedt!
– Keuze middel
– Duur behandeling
– Toevoegen ribavirine
Na gefaalde therapie
– Welk type RAS aanwezig voor keuze middel
Bij genotype 3 en cirrose
Hepatitis C | 25-06-2019 30
![Page 31: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/31.jpg)
RAS
Hepatitis C | 25-06-2019 31Liu et al. Antimicrob Agents Chemother 2015
![Page 32: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/32.jpg)
Hepatitis C | 25-06-2019 32
Casuïstiek
![Page 33: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/33.jpg)
Dhr N, 60 jaar
Chronische HCV-infectie genotype 3a
- Fibroscan 6.5 kPa
- HCV RNA 1.56x10E7 IU/mL
Verwezen vanuit ander centrum vanwege eerder gefaalde therapie
- Sofosbuvir en daclatasvir gedurende 12 weken
Overige voorgeschiedenis
- DM2
- Maagklachten waarvoor PPI
Hepatitis C | 25-06-2019 33
![Page 34: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/34.jpg)
Dhr N, 60 jaar
Vragen achteraf:
- RAS testing vooraf aan behandeling?
- Was SOF/DAC juiste keuze
En nu?
- Opnieuw dezelfde behandeling maar dan zonder PPI?
- Ribavirine toevoegen?
- Andere behandeling?
Hepatitis C | 25-06-2019 34
![Page 35: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/35.jpg)
Dhr N, 60 jaar
RAS testing
- RAS Y93H - high-level of resistance voor NS5A remmers
En nu?
- Opnieuw dezelfde behandeling maar dan zonder PPI?
- Andere behandeling?
- Duur?
- Met/zonder ribavirine?
Hepatitis C | 25-06-2019 35
![Page 36: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/36.jpg)
Dhr N, 60 jaar
Pibrentasvir/glecaprevir (Maviret)
- Gedurende 16 weken
- Met ribavirine 1200 mg per dag
PPI gestaakt tijdens behandeling
Sustained virological response
- Sofosbuvir en daclatasvir gedurende 12 weken
Hepatitis C | 25-06-2019 36
![Page 37: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/37.jpg)
Dhr S, 68 jaar
Chronische hepatitis C genotype 6F
- Fibroscan varierend tussen 10 en 16 kPa
- Geen tekenen portale hypertensie
Reeds geruime tijd op poli Hepatologie, met eerdere behandelingen
- Peginterferon-ribavirine gedurende 24 weken, gestaakt vanwege non-response
- Proteaseremmer en NS5A remmer in studieverband gedurende 12 weken (Elbasvir/grazoprevir) waarna relapse
Hepatitis C | 25-06-2019 37
![Page 38: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/38.jpg)
Dhr S, 68 jaar
RAS-testing NS5A
- Q24A, L28M, r30A, T58P, 93T (“wild-type” voor genotype 6F)
- L31M (beschreven als RAS voor genotype 6F)
RAS-testing NS3
- Niet mogelijk vanwege “bijzondere” genotype
Genotype 6 minder gevoelig voor NS5A remmers dan andere genotypes
- Waarschijnlijk door deze “wild-type” mutaties op belangrijke NS5A polymorfe sites
Hepatitis C | 25-06-2019 38
![Page 39: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/39.jpg)
Dhr S, 68 jaar
Behandeling met Velpatasvir/Sofosbuvir/Voxilaprevir
- Duur?
- Ribavirine?
Hepatitis C | 25-06-2019 39
![Page 40: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/40.jpg)
Dhr S, 68 jaar
Behandeling met Velpatasvir/Sofosbuvir/Voxilaprevir
- Gedurende 12 weken
- Met ribavirine 1000 mg per dag
SVR
Hepatitis C | 25-06-2019 40
![Page 41: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/41.jpg)
Mw K, 60 jaar
Chronische hepatitis C virus infectie genotype 1a
- Fibroscan 13.6 kPa
- Morbide obesitas
- Leverbiopt: inflammatie periportaal passend bij hepatitis C infectie, steatose en matige fibrose
Reeds geruime tijd op poli Hepatologie, met eerdere behandelingen
- Peginterferon-ribavirine gedurende 24 weken, gestaakt vanwege non-response
- Proteaseremmer en NS5A remmer in studieverband gedurende 12 weken (Daclatasvir/asunaprevir) waarna relapse
- Wachten op nieuwe medicatie
Hepatitis C | 25-06-2019 41
![Page 42: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/42.jpg)
Mw K, 60 jaar
Komt na enige tijd terug op de polikliniek
- Status na gastric bypass chirurgie
- BMI genormaliseerd, evenals fibroscan
Virologie
- HCV RNA 5.64 x 10E6 IU/mL
- NS3 RAS niet meer aantoonbaar > 1 jaar na einde eerdere behandeling
- NS5A RAS geassocieerd met high-level resistance: L31M/I en Y93H
Wat nu?
Hepatitis C | 25-06-2019 42
![Page 43: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/43.jpg)
Mw K, 60 jaar
Sofosbuvir en simeprevir
- Start met normaal gebruikelijke dosis, echter simeprevir op geleide van spiegels opgehoogd
Ribavirine
– Week 3 dalspiegel 2.5 mg/L
– Week 14 dalspiegel 3.5 mg/L
– Hb 5.8 mmol/L (was 7.7 mmol/L)
– Dosis ribavirine verlaagd naar 800 mg per dag
HCV RNA niet detecteerbaar vanaf week 4
SVR week 12 en 48
Hepatitis C | 25-06-2019 43
![Page 44: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/44.jpg)
Mw K, 60 jaar
Hepatitis C | 25-06-2019 44
![Page 45: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/45.jpg)
Mw K, 60 jaar
Hepatitis C | 25-06-2019 45
![Page 46: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/46.jpg)
Wat te doen bij RAS?
NS3
– Kies ander regime (zonder proteaseremmer)
– Wacht tot NS3 RAS verdwenen is
NS5A
– Afhankelijk van genotype, type RAS en cirrose
– Verlenging duur
– Toevoeging ribavirine
– Combinatie alle componenten: • Vosevi (Velpatasvir, Sofosbuvir, Voxilaprevir)
• Maviret + Sofosbuvir (Pibrentasvir, Glecaprevir, Sofosbuvir)
Hepatitis C | 25-06-2019 46
![Page 47: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/47.jpg)
Take home messages
RAS beïnvloedt viral fitness
– Na wegvallen DAA langzame terugkeer wild-type
– Afhankelijk van viral fitness mogelijk blijvende mutant (pre-existent)
Wisselend effect op behandelsucces
– Of kunnen door kleine aanpassingen overkomen worden
Doe alleen RAS-testing als het je behandeling beinvloedt
– Keuze middel
– Verlenging duur
– Toevoeging ribavirine
– Hoe dan ook bij DAA failure
Hepatitis C | 25-06-2019 47
![Page 48: Hepatitis C Virusreplicatie en DAA-resistentieregist2.virology-education.com/presentations/2019/...Titel presentatie Author: Kerssens, Inge Created Date: 11/1/2019 3:28:34 PM ...](https://reader031.fdocument.pub/reader031/viewer/2022011920/601eb5117a3fcb54d13dcd2a/html5/thumbnails/48.jpg)
Vragen?
Hepatitis C | 25-06-2019 48