hcv genotypic resistance testing - genafor · treatment costs: sof + dcv 12 weeks = 90k sof mono 24...
TRANSCRIPT
![Page 1: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/1.jpg)
HCV Genotypic Resistance Testing
Jörg Timm AREVIR Meeting Köln 8. Mai 2015
![Page 2: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/2.jpg)
Protease-Inhibitors
NS5A-Inhibitors Polymerase-Inhibitors
Source: Nature Reviews Gastroenterology & Hepatology 6, 403-411 (July 2009)
Targets of directly acting antivirals (DAAs)
![Page 3: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/3.jpg)
list of licensed DAAs (5/2015)
Protease-Inhibitors NS5A-Inhibitors Polymerase-Inhibitors
…previr …asvir …buvir
• Telaprevir (TVR) • Boceprevir (BOC) • Simeprevir (SMV) • Paritaprevir (PTV)
• Daclatasvir (DCV) • Ledipasvir (LDV) • Ombitasvir (OMV)
nucleoside: • Sofosbuvir (SOF)
non-nucleoside: • Dasabuvir (DSV)
![Page 4: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/4.jpg)
Genotype 1 Genotype 2 Genotype 3
Telaprevir (TVR) Boceprevir (BOC)
Daclatasvir (DCV) Ledipasvir (LDV) Ombitasvir (OMV)
Sofosbuvir (SOF)
Genotype 4
Simeprevir (SMV) Paritaprevir (PTV)
Dasabuvir (DSV)
Sofosbuvir (SOF) Sofosbuvir (SOF) Sofosbuvir (SOF)
Simeprevir (SMV) Paritaprevir (PTV)
Daclatasvir (DCV) Daclatasvir (DCV) Daclatasvir (DCV) Ledipasvir (LDV) Ledipasvir (LDV)
Ombitasvir (OMV)
list of licensed DAAs (5/2015)
![Page 5: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/5.jpg)
Genotype 1
Sofosbuvir + Ledipasvir (Harvoni®)
TN TE TN TE
without cirrhosis with cirrhosis
+RBV
12 weeks
ION-1 und ION-2
TN: treatment-naive TE: treatment-experienced
![Page 6: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/6.jpg)
Genotype 1
Paritaprevir/RTV + Ombitasvir (Viekirax®) + Dasabuvir (Exviera®)
TN TE TN TE
without cirrhosis with cirrhosis
+RBV
1a 1b 1a 1b 1a 1b 1a 1b
PEARL-III PEARL-IV SAPPHIRE-II TURQOISE-II
![Page 7: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/7.jpg)
structural proteins non-structural proteins
HCV genome
![Page 8: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/8.jpg)
treatment failure – DCV + SMV after LTX
NS3: D168V NS5A: ΔP32 Start: SOF
NS3: D168V NS5A: Y93H
Herzer et al. Digestion 2015
![Page 9: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/9.jpg)
positions of resistance-associated variants (RAVs)
R155 A156 D168
M28 Q30 L31 P32 Y93
Nucleoside (S282) Non-Nucleoside C316 Y448
Protease-Inhibitors NS5A-Inhibitors Polymerase-Inhibitors
![Page 10: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/10.jpg)
absence of
selection pressure
negative selection neutral selection
destiny of RAVs after treatment
RAVs in NS5A
RAVs in NS3 und NS5B
![Page 11: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/11.jpg)
K155
R155
Kim and Timm JID 2009
RAVs in a treatment-naive patient
Clonal sequences collected over 5 years
![Page 12: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/12.jpg)
50% 58%
84%
pegIFNα RBV
Q80K „wildtype“
nur GT1a
pegIFNα RBV
Simeprevir 24 weeks (12 + 12)
Hepatology. 2013 Dec;58(6):1918-29. Gastroenterology. 2014 Mar 3. pii: S0016-5085(14)00293-5
Simeprevir (Olysio®)
![Page 13: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/13.jpg)
Genotype 3
TN TE
without cirrhosis
with cirrhosis
12 weeks
Sofosbuvir (Sovaldi®) + Daclatasvir (Daklinza®)
ALLY-3 Nelson et al. Hepatology 2015
TN TE Y93 H93
p=0.0007
prevalence of H93 = 8.8%
![Page 14: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/14.jpg)
RBV Sofosbuvir
56%
84%
12 weeks
RBV Sofosbuvir
24 weeks
N Engl J Med. 2013 May 16;368(20):1878-87.
Genotype 3
Sofosbuvir (Sovaldi®)
![Page 15: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/15.jpg)
100 patients infected with genotype 3a
treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k
92 x Y93 8 x H93
SOF mono 24w 2 x 100k = 200 000,- €
100 x 150,- = 15 000,- € genotype
92 x Y93 8 x H93
8 x 90k = 720 000,- € SOF+DCV 12w
92 x 90k = 8 280 000,- € SOF+DCV 12w 92 x 90k = 8 280 000,- € SOF+DCV 12w
SOF mono 24w 8 x 100k = 800 000,- €
9 000 000,- € 9 095 000,- €
4 failures! 1 failures!
![Page 16: HCV Genotypic Resistance Testing - Genafor · treatment costs: SOF + DCV 12 weeks = 90k SOF mono 24 weeks = 100k 92 x Y93 . 8 x H93 SOF mono 24w 2 x 100k = 200 000,- € genotype](https://reader036.vdocuments.mx/reader036/viewer/2022071019/5fd387c3076d2d49842ee425/html5/thumbnails/16.jpg)
Conclusions
• Selection of RAVs in patients who fail to achieve SVR is almost universal
• Some RAVs are associated with low fitness costs and are stable
• Genotypic resistance testing may help to optimize treatment outcome
„Prediction is very difficult, especially about the future“ Niels Bohr