HCV Genotypic Resistance Testing

Jörg Timm AREVIR Meeting Köln 8. Mai 2015

Protease-Inhibitors

NS5A-Inhibitors Polymerase-Inhibitors

Source: Nature Reviews Gastroenterology & Hepatology 6, 403-411 (July 2009)

Targets of directly acting antivirals (DAAs)

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)

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)

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

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

structural proteins non-structural proteins

HCV genome

treatment failure – DCV + SMV after LTX

NS3: D168V NS5A: ΔP32 Start: SOF

NS3: D168V NS5A: Y93H

Herzer et al. Digestion 2015

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

absence of

selection pressure

negative selection neutral selection

destiny of RAVs after treatment

RAVs in NS5A

RAVs in NS3 und NS5B

K155

R155

Kim and Timm JID 2009

RAVs in a treatment-naive patient

Clonal sequences collected over 5 years

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®)

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%

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®)

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!

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