- Email: [email protected]
Hepatitis C Virus Screening Project of Patients on Current Anti-HCV Therapy
POSTER PRESENTATIONS direct acting antivirals has demonstrated a high barrier to resistance with rare emergence of RAVs in these short 6 and 8 week durations. THU-221 HEPATITIS C VIRUS SCREENING PROJECT OF PATIENTS ON CURRENT ANTI-HCV THERAPY E. Knops1, P. Kalaghatgi2, M. Neumann-Fraune1, E. Heger1, E. Schuelter1, T. Lengauer2, V. Keitel3, T. Goeser1, N. Schuebel4, T. von Hahn5, I. Peuser6, N. Qurishi7, K. Römer7, S. Scholten8, M. Daeumer9, J.S. zur Wiesch10, A. Baumgarten11, M. Obermeier12, H. Walter12, R. Kaiser13, S. Sierra13. 1University of Cologne, Cologne; 2Max-PlanckInstitute for Informatics, Saarbrücken; 3University of Duesseldorf, Duesseldorf; 4Klinikum Osnabrueck, Osnabrueck; 5MHH Hannover, Hannover; 6MRV GmbH, Luedenscheid; 7Private Practice Gotenring; 8 Private Practice Hohenstauffenring, Cologne; 9Institut für Immunologie und Genetik, Kaiserslautern; 10University of Hamburg, Hamburg; 11 Private Practice Driesener Strasse; 12MIB Berlin, Berlin; 13University of Cologne, Koeln, Germany E-mail: [email protected] Background and Aims: Clinical outcome of HCV therapy with direct acting antivirals (DAAs) depends on host and viral factors. This observational, retrospective and non-interventional study (PEPSI) collects data of resistance-associated-mutations (RAMs) within the viral NS3/protease, NS5A and NS5B genes, frequency of viral variants and host factors, to predict clinical outcome using the geno2pheno[HCV] tool. Methods: NS3/protease, NS5A and NS5B sequences from baseline samples were obtained. Subtyping and resistance against Asunaprevir (ASV), Boceprevir (BOC), Grazoprevir (GZV), Paritaprevir (PTV), Simeprevir (SMV), Telaprevir (TVR), Daclatasvir (DCV), Elbasvir (ELV), Ledipasvir (LDV), Ombitasvir (OBV), Dasabuvir (DSV) and Sofosbuvir (SOF) was determined by sequencing (Sanger or ultra-deep) and subsequent interpretation of the corresponding viral gene with geno2pheno[HCV]. Results: 1295 HCV-infected patients have been enrolled until Nov 17th 2015. We could obtain 992 NS5B sequences, which were used for genotyping: GT1a = 40.8%; GT1b = 36.6%; GT1d = 0.2%; GT2 = 2.8%; GT3 = 14.2; GT4 = 5.3%.
Baseline NS3/protease-inhibitor susceptibility was determined from 446 baseline sequences and used for baseline resistance prediction (Fig. 1). Baseline resistance was found for ASV = 3.0%; BOC = 8.8%; GZV = 0.6%; PTV = 2.8%; SMV = 23.2%; TVR = 3.0%. For TVR, 20.9% of the samples were predicted as possibly resistant. Baseline NS5A-inhibitor susceptibility was analysed for 251 sequences. The percentage of resistant samples was similar for all four NS5A-inhibitors, 4.4% > 6.0%. Baseline NS5B-inhibitors susceptibility: The sequence sets used for the analysis of each of the NS5B inhibitors varied, since the described RAM-patterns for each drug comprise different amino acid residues. While 10.8% of the
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278 sequences used for DSV screening were reported as resistant, none of the 742 samples screened for SOF were predicted as resistant. Baseline RAM analysis: The mutation NS3 80K was found in 20.0% of the samples. It led to the high proportion of samples resistant to SMV. Substitutions on additional four amino acid positions were found in ≥0.9% of the samples. In the NS5A, the most frequent amino acids exchanges were at positions 30 and 93. In the NS5B, the mutations 556GNR were found in 12.0% of the cases. Conclusions: We found a remarkable number of RAMs in baseline sequences. Baseline sequencing prior to the HCV therapy with DAAs could support personalized therapy decisions. THU-222 IN A 5-DAY MONOTHERAPY TRIAL, MK-8408 DEMONSTRATES POTENT ANTIVIRAL ACTIVITY AND IMPROVED RESISTANCE PROFILE IN HCV PATIENTS WITH GENOTYPES 1, 2, AND 3 INFECTIONS E. Asante-Appiah1, W. Marshall1, E. Gane2, S. Popa3, P. McMonagle1, S. Curry1, L. Maganti1, W. Gao1, G. Garrett1, C. Cilissen1, I. De Lepeleire1, T. Black1, D. Hazuda1, J. Butterton1. 1MERCK, Kenilworth, United States; 2 Auckland Clinical Studies, Auckland, New Zealand; 3Republican Clinical Hospital of Moldova, Chisinau, Republic of Moldova E-mail: [email protected] Background and Aims: MK-8408 is a potent NS5A inhibitor with activity across all major HCV genotypes (GTs, 1–6) in vitro. MK-8408 retains activity against resistance-associated polymorphisms in NS5A and clinically-relevant resistance-associated variants (RAVs) selected by approved NS5A inhibitors. Preclinical and clinical pharmacokinetics supported a once-daily oral administration of MK-8408. MK-8408 was evaluated in a 5-day monotherapy doseranging study in patients chronically infected with HCV GTs 1, 2 or 3. Given the potential for RAVs to impact the activity of NS5A inhibitors, we investigated the presence and impact of baseline NS5A RAVs in these patients. Methods: MK-8408 was administered for 5 days at a dose of 60 mg once-daily in patients (N = 3/arm) infected with GT1, GT2 or GT3; doses of 10, 30 and 120 mg were also evaluated in GT3 patients. Prior to the first dose, patient plasma samples were genotyped and aliquots retained to investigate presence of baseline NS5A RAVs. . Plasma samples were obtained at pre-defined time-points post-dose for evaluation of viral load and presence of RAVs by population sequencing. Clonal sequencing was conducted on a subset of samples to investigate RAV linkage. Results: MK-8408 demonstrated potent antiviral activity in patients infected with HCV GT1, GT2 or GT3. At the 60 mg dose a mean maximal HCV viral load reduction (log10) of 3.86 ± 0.21, 3.62 ± 0.41 and 3.35 ± 0.9 was observed in GT1, GT2 and GT3 patients, respectively. No baseline NS5A RAVs were detected in GT1 patients. There was no difference in antiviral activity in GT2 patients with viruses bearing the common resistance-associated M31 polymorphism as compared to those with L31. GT3 patients who were infected with viruses bearing NS5A RAVs (A30K, S62F/L, and Y93H) at baseline showed no reduction of antiviral activity. However, in 3 GT3 patients, a combination of 2 or more linked NS5A RAVs that included Y93H at baseline reduced MK-8408 clinical activity consistent with >1000-fold potency reduction in replicons bearing these combinations of NS5A amino acid substitutions. Conclusions: A 60 mg dose of MK-8408, a potent next-generation NS5A inhibitor, administered orally once-daily for 5 days, reduced HCV RNA by >3 log10 in HCV GT1, GT2 or GT3 patients. The presence of single baseline NS5A polymorphisms did not impact MK-8408 clinical activity in HCV GT1, GT2 or GT3 patients demonstrating an improved resistance profile compared to approved inhibitors in this class.
Journal of Hepatology 2016 vol. 64 | S213–S424
Baseline NS3/protease-inhibitor susceptibility was determined from 446 baseline sequences and used for baseline resistance prediction (Fig. 1). Baseline resistance was found for ASV = 3.0%; BOC = 8.8%; GZV = 0.6%; PTV = 2.8%; SMV = 23.2%; TVR = 3.0%. For TVR, 20.9% of the samples were predicted as possibly resistant. Baseline NS5A-inhibitor susceptibility was analysed for 251 sequences. The percentage of resistant samples was similar for all four NS5A-inhibitors, 4.4% > 6.0%. Baseline NS5B-inhibitors susceptibility: The sequence sets used for the analysis of each of the NS5B inhibitors varied, since the described RAM-patterns for each drug comprise different amino acid residues. While 10.8% of the
S402
278 sequences used for DSV screening were reported as resistant, none of the 742 samples screened for SOF were predicted as resistant. Baseline RAM analysis: The mutation NS3 80K was found in 20.0% of the samples. It led to the high proportion of samples resistant to SMV. Substitutions on additional four amino acid positions were found in ≥0.9% of the samples. In the NS5A, the most frequent amino acids exchanges were at positions 30 and 93. In the NS5B, the mutations 556GNR were found in 12.0% of the cases. Conclusions: We found a remarkable number of RAMs in baseline sequences. Baseline sequencing prior to the HCV therapy with DAAs could support personalized therapy decisions. THU-222 IN A 5-DAY MONOTHERAPY TRIAL, MK-8408 DEMONSTRATES POTENT ANTIVIRAL ACTIVITY AND IMPROVED RESISTANCE PROFILE IN HCV PATIENTS WITH GENOTYPES 1, 2, AND 3 INFECTIONS E. Asante-Appiah1, W. Marshall1, E. Gane2, S. Popa3, P. McMonagle1, S. Curry1, L. Maganti1, W. Gao1, G. Garrett1, C. Cilissen1, I. De Lepeleire1, T. Black1, D. Hazuda1, J. Butterton1. 1MERCK, Kenilworth, United States; 2 Auckland Clinical Studies, Auckland, New Zealand; 3Republican Clinical Hospital of Moldova, Chisinau, Republic of Moldova E-mail: [email protected] Background and Aims: MK-8408 is a potent NS5A inhibitor with activity across all major HCV genotypes (GTs, 1–6) in vitro. MK-8408 retains activity against resistance-associated polymorphisms in NS5A and clinically-relevant resistance-associated variants (RAVs) selected by approved NS5A inhibitors. Preclinical and clinical pharmacokinetics supported a once-daily oral administration of MK-8408. MK-8408 was evaluated in a 5-day monotherapy doseranging study in patients chronically infected with HCV GTs 1, 2 or 3. Given the potential for RAVs to impact the activity of NS5A inhibitors, we investigated the presence and impact of baseline NS5A RAVs in these patients. Methods: MK-8408 was administered for 5 days at a dose of 60 mg once-daily in patients (N = 3/arm) infected with GT1, GT2 or GT3; doses of 10, 30 and 120 mg were also evaluated in GT3 patients. Prior to the first dose, patient plasma samples were genotyped and aliquots retained to investigate presence of baseline NS5A RAVs. . Plasma samples were obtained at pre-defined time-points post-dose for evaluation of viral load and presence of RAVs by population sequencing. Clonal sequencing was conducted on a subset of samples to investigate RAV linkage. Results: MK-8408 demonstrated potent antiviral activity in patients infected with HCV GT1, GT2 or GT3. At the 60 mg dose a mean maximal HCV viral load reduction (log10) of 3.86 ± 0.21, 3.62 ± 0.41 and 3.35 ± 0.9 was observed in GT1, GT2 and GT3 patients, respectively. No baseline NS5A RAVs were detected in GT1 patients. There was no difference in antiviral activity in GT2 patients with viruses bearing the common resistance-associated M31 polymorphism as compared to those with L31. GT3 patients who were infected with viruses bearing NS5A RAVs (A30K, S62F/L, and Y93H) at baseline showed no reduction of antiviral activity. However, in 3 GT3 patients, a combination of 2 or more linked NS5A RAVs that included Y93H at baseline reduced MK-8408 clinical activity consistent with >1000-fold potency reduction in replicons bearing these combinations of NS5A amino acid substitutions. Conclusions: A 60 mg dose of MK-8408, a potent next-generation NS5A inhibitor, administered orally once-daily for 5 days, reduced HCV RNA by >3 log10 in HCV GT1, GT2 or GT3 patients. The presence of single baseline NS5A polymorphisms did not impact MK-8408 clinical activity in HCV GT1, GT2 or GT3 patients demonstrating an improved resistance profile compared to approved inhibitors in this class.
Journal of Hepatology 2016 vol. 64 | S213–S424