AREVIR MEETING 2013 11-12 April 2013 Odysseum, Cologne EuResist - PowerPoint PPT Presentation

AREVIR MEETING 2013 11-12 April 2013 Odysseum, Cologne

 EuResist was launched in 2006 to apply advanced statistics and modeling to HIV treatment  At that time only NRTI, NNRTI and PI (plus T20) were in clinical use  Later, IN Inhibitors and Coreceptor Antagonists have been incorporated into the system  Now, HCV treatment is a reality  EuResist database redesigned to host HCV (and HBV) treatment data  What is the balance between efforts/challenges and rewards/opportunities?

Virus factors   Viral load  Genetic variability Host factors   Ethnicity and race (i. e. host genetic background such as IL28b SNPs)  Gender & age  Fibrosis/cirrhosis stage  Obesity and insulin resistance  Vitamin D levels  … Treatment factors   Adherence  Side effects  Patient’s beliefs & social support  Provider experience  …

HOST OUTPUT (e.g. SVR or VIRUS others) THERAPY Interaction layers Potential benefits  Patient tailored treatment  Increased SVR  Minimal toxicity  Optimal use of available resources

Ge, Nature 2009

Whites (n = 871) Blacks (n = 191) Hispanics (n = 75) Factor Associated With SVR Odds Ratio (95% CI) 7.3 6.1 IL28B rs12979860 genotype (CC vs TT) 5.6 4.2 Baseline HCV RNA 5.1 (< vs ≥ 600,000 IU/mL) 2.4 3.0 1.1 Baseline fibrosis (METAVIR F0-F2 vs F3-F4) 4.1 0.1 1.0 10.0 Ge, Nature 2009

Gene(s) in Model Time of the Sensitivity % Specificity % PPV NPV P- AUC observation Predictive (95% CI) (95% CI) % % value Model 0.881 EP300, 85.7 83.3 (0.651 Pre-treatment .001 75.0 90.9 SOCS6 (42.2– 97.6) (51.6 –97.4) – 0.980) 24 hours after 0.74 71.4 81.8 initiation of IL1B, 71.4 81.8 (0.484 .009 (29.3–95.5) (48.2–97.2) treatment ADAM9 – 0.913) 7 days after 0.786 100.0 66.7 initiation of 63.6 100.0 (0.540 PRKRIR .009 (58.9–100.0) (34.9–89.9) treatment – 0.936) PPV = positive predictive value; NPV = negative predictive value; AUC = area under the curve; Younossi ZM, et al. J Hepatol. 2008;48:S285.

IL28b [Thomas, Nature 2009; Suppiah, Nat Genet 2009; Tanaka, Nat Genet  2009]  r s12979860  rs8099917  ss469415590 Low Density Lipoprotein Receptor (LDLR) [Pineda, AIDS 2011]   rs14158 Low molecular polypeptide 7 (LMP -7) [Omran, World J Hepatol 2013]   Codon 49 Concentrative nucleoside transporter 3 (CNT-3) [Rau, J Hepatol 2012]   rs11854484 Other genes related to specific treatment toxicity   e.g Inosine triphosphatase (ITPA) and anemia with RBV [Fellay, Nature 2010]

SVR = Sustained Virological Response, i.e. undetectable HCV RNA after 12 or 24 weeks following treatment completion (a consistent proxy for HCV eradication)

IFN-free DAA IFN/RBV plus DAA IFN/RBV

Dabbouseh, Nature Rev Gastroenterol Hepatol 2013

31%– 33% nucleotide difference among the 6 HCV genotypes  20%–25% among HCV subtypes 

 Standard of care: pegIFN plus RBV  Neither IFN nor RBV target any virus specific function  Selection of resistance to pegIFN/RBV in vivo has been not documented…  …however natural susceptibility to pegIFN/RBV is different in the different HCV genotypes

The most these aa and regions diverge from genotype 1 consensus, the higher the probability to achieve a cure (SVR) Core aa 70 IFN/RBV Resistance Arg → Gln, His Determining Region NS5A aa 261 - 306 Core aa 91 Met → Leu IFN Sensitivity Determining Region NS5A aa 236 -275

5’ UTR 3’ UTR 9.6 kb RNA region region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Polyprotein Processing C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Envelope RNA-dependent Protease Serine Helicase Serine Glycoproteins RNA polymerase Protease Protease Replication Cofactor complex RNA and Zn binding NS3-4A NS5B Protease Polymerase inhibitors NS5A inhibitors inhibitors Nucleoside Non-nucleoside analogs analogs Adapted from Terrault N, 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0104.

10 12 virions per day 10 4 to 10 7 virions per ml 10 -4 to 10 -5 nt changes per cycle

Population Cloning sequencing Next generation sequencing

Chevaliez, EASL 2011

5’ UTR 3’ UTR 9.6 kb RNA region region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Polyprotein Processing C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Envelope RNA-dependent Protease Serine Helicase Serine Glycoproteins RNA polymerase Protease Protease Replication Cofactor complex RNA and Zn binding NS3-4A NS5B Protease Polymerase inhibitors NS5A inhibitors inhibitors Nucleoside Non-nucleoside analogs analogs Adapted from Terrault N, 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0104.

Sarrazin, J Hepatol 2012

TELAPREVIR BOCEPREVIR NS3P/NS4A recombinants of genotypes 2a, 3a, 5a, and 6a prototype isolates or with resistance mutations showed differential sensitivity to protease inhibitors but not to interferon- alfa2. Cultures were infected with culture adapted NS3P/NS4A recombinants of the SIMEPREVIR DANOPREVIR indicated genotype(isolate) or 2a(JFH1) with putative resistance mutations, 2a(JFH1)RES. Values are means of 3 replicates with standard error of mean. VANIPREVIR IFN-alfa Gottwein, Gastroenterol 2011

TELAPREVIR BOCEPREVIR Compared with genotype 2a , SIMEPREVIR DANOPREVIR genotype 3a isolates were less sensitive to protease inhibitors. Cultures were infected with culture adapted NS3P/NS4A recombinants of the indicated 2a and 3a isolates Values are means of 3 replicates with standard error of mean. VANIPREVIR IFN-alfa Gottwein, Gastroenterol 2011

 How often NS3 inhibitor resistance mutations do occur as dominant species in nature?

 507 patients from US, Germany and Switzerland  Collectively, 5.5% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant NS3 PI resistance mutation  No impact of NS3 PI resistance mutations on viral load  Suggests possible fitness changes are adjusted by the genetic background (compensatory mutations) Kunzen, Hepatology 2008

Study N RAVs with >1% prevalence in RAVs with >1% prevalencein GT1a GT1b Gaudieri 2009 259 54S 4.4%, 170A 5.8% 170A 7.8% Trevino 2011 55 55A 5.2%, 80K 21.1% None Suzuki 2012 307 Not included 54S 3.3% Paolucci 2012 70 54S 6.4%, 55A 3.2%, 80K 9.7% None Vicenti 2012 109 54S 3.0%, 55A 1.5%, 80K 16.4% 54S 2.4% Bartels 2012 3447 54S 3.1%, 55A 2.7%, 80K 37.6% 54S 1.9%  Caveats:  Different reference mutation lists used  Different geographic regions

5 All the main linear NS3i RAV are below 5% 4,5 4 3,5 gt1a (2266) gt1b (2056) 3 gt2 (165) 2,5 % gt3 (470) 2 gt4 (142) gt5 (26) 1,5 gt6 (74) 1 0,5 0 36A 36M 36G 54A 54S 54G 54C 55A 55I 155K 155T 155G 156S 156T 156V Source: 5,199 NS3 sequences from LANL HCV db accessed 16 March 2013

Higher prevalence of macrocyclic 100 NS3i RAV (including cases with RAV as consensus) 90 80 70 gt1a (2266) 60 gt1b (2056) gt2 (165) 50 % gt3 (470) 40 gt4 (142) No RAV for next- 30 generation macrocyclic gt5 (26) NS3i (e.g. MK-5172) gt6 (74) 20 10 0 36A 36M 36G 43S 54S 55I 80K 80R 80L 122A 122R 138T 155K 156T 156V 168A 168V 168H 168Y 168N 168P 168Q 168I 168K Source: 5,199 NS3 sequences from LANL HCV db accessed 16 March 2013

 Does natural variability impact on response to NS3 inhibitors?

Data from SPRINT-1 trial Vierling, AASLD 2010

 Putative RAVs identified from in vitro and in vivo data  V36, Q41, F43, T54, V55, R155, A156, V158, V170, M175  Population sequencing (~20% sensitivity on minor species)

90 79 78 76 80 70 60 50 IFN responders % SVR 40 34 IFN nonresponders 30 23 20 10 0 0 No RAVs Other RAVs Major RAVs IFN responders: >1 log VL decrease at treatment week 4 (lead - in with pegIFN/RBV only) IFN non responders: <1 log VL decrease at treatment week 4 (lead - in with pegIFN/RBV only) Major RAVs: V36M, T54AS, V55A, R155K MSD, data on file

P = 0.042 P = 0.786 80 75 70 65 60 50 42 SVR % 36 40 RAVs (N = 112) 30 no RAVs (N = 1864) 20 10 0 Naive & relapsers (N = Prior nonresponders 1594) (N = 382) Pooled phase II and III TVR data analysis Bartels, J Virol 2013

N = 10 N = 6 N = 50 Pooled phase II and III TVR data analysis Bartels, J Virol 2013

 Phase II triple-therapy study on treatment-naive  Prevalence of previously identified variants conferring reduced susceptibility to simeprevir at baseline  Q80K , n = 40, 10.4% (38 in GT1a, 2 in GT1b)  R155K, n = 3, 0.8%  D168E, n = 1, 0.3% Simeprevir 75 mg (n = 153) Simeprevir 150 mg (n = 156) 80K no 80K 80K no 80K 100 100 80 80 60 60 40 40 20 20 0 0 Lack of SVR24 Virological Relapse Lack of SVR24 Virological Relapse breakthrough breakthrough Lenz, AASLD 2011

Lenz, EASL 2012