Article Figures & Data
Figures
- Fig 1
Correlations between the viral reduction in JTK-853-treated HCV-infected patients and the JTK-853 susceptibility in their NS5B-harboring replicon at the BL (A) and EOT (B). The x axis represents the EC50, and the y axis represents the change in HCV RNA load from the BL to the EOT in a 3-day monotherapy. The correlation coefficient (R) is indicated in each panel. The symbols are as follows: circles, 800 mg BID; triangles, 1,200 mg BID; squares, 1,600 mg BID; diamonds, 1,200 mg TID.
Tables
- Table 1
Baseline characteristics of the patientsa
Treatment Patient no. HCV genotype Time point HCV RNA load (IU/ml) Change in HCV RNA load from BL (log10) 800 mg BID 0402 1a BL (day 1) 10,300,000 EOT (day 4) 595,000 −1.24 FU (wk 4) 306 −4.53 FU (wk 12) <15 <−5.84 FU (wk 24) <15 <−5.84 FU (wk 48) <15 <−5.84 0403 1a BL (day 1) 2,080,000 EOT (day 4) 325,000 −0.81 FU (wk 4) 15,700 −2.12 FU (wk 12) <15 <−5.14 FU (wk 24) <15 <−5.14 FU (wk 48) <15 <−5.14 0404 1a BL (day 1) 1,390,000 EOT (day 4) 1,370,000 −0.01 FU (wk 4) 51,500 −1.43 FU (wk 12) <15 <−4.97 FU (wk 24) 31,800 −1.64 FU (wk 48) 1,200,000 0.06 0405 1a BL (day 1) 6,610,000 EOT (day 4) 90,200 −1.86 FU (wk 4) 534 −4.09 FU (wk 12) <15 <−5.64 FU (wk 24) <15 <−5.64 0406 1a BL (day 1) 7,600,000 EOT (day 4) 537,000 −1.15 0407 1a BL (day 1) 580,000 EOT (day 4) 232,000 −0.40 1,200 mg BID 0101 1a BL (day 1) 20,000,000 EOT (day 4) 25,100,000 0.10 0102 1b BL (day 1) 562,000 EOT (day 4) 16,700 −1.53 0103 1b BL (day 1) 4,860,000 EOT (day 4) 162,000 −1.48 FU (wk 4) 4,920 −2.99 FU (wk 12) <15 <−5.51 FU (wk 24) <15 <−5.51 FU (wk 48) <15 <−5.51 0104 1a BL (day 1) 30,400,000 EOT (day 4) 149,000 −2.31 0105 1a BL (day 1) 1,560,000 EOT (day 4) 654,000 −0.38 0106 1a BL (day 1) 5,630,000 EOT (day 4) 95,900 −1.77 FU (wk 4) 202,000 −1.45 FU (wk 12) <15 <−5.57 FU (wk 24) <15 <−5.57 FU (wk 48) <15 <−5.57 1,600 mg BID 0201 1a BL (day 1) 4,830,000 EOT (day 4) 389,000 −1.09 FU (wk 4) 95 −4.71 FU (wk 24) <15 <−5.51 FU (wk 48) 3,110,000 0.19 0203 1a BL (day 1) 9,340,000 EOT (day 4) 1,090,000 −0.93 FU (wk 4) 10,800 −2.94 FU (wk 12) <15 <−5.79 FU (wk 24) <15 <−5.79 FU (wk 48) <15 <−5.79 0204 1a BL (day 1) 4,590,000 EOT (day 4) 248,000 −1.27 FU (wk 4) 780,000 −0.77 FU (wk 12) 1,820,000 −0.40 0206 1a BL (day 1) 9,800,000 EOT (day 4) 1,820,000 −0.73 FU (wk 4) 539,000 −1.26 FU (wk 12) 414 −4.37 FU (wk 24) <15 <−5.82 FU (wk 48) <15 <−5.82 0207 1b BL (day 1) 5,620,000 EOT (day 4) 11,700 −2.68 FU (wk 4) 78,100 −1.86 1205 1a BL (day 1) 116,000 EOT (day 4) 471 −2.39 FU (wk 4) <15 <−3.89 FU (wk 12) <15 <−3.89 FU (wk 24) <15 <−3.89 FU (wk 48) <15 <−3.89 1,200 mg TID 0301 1a BL (day 1) 20,000,000 EOT (day 4) 1,800,000 −1.05 FU (wk 4) 172,000 −2.07 FU (wk 12) <15 <−6.12 FU (wk 24) <15 <−6.12 FU (wk 48) <15 <−6.12 0302 1a BL (day 1) 405,000 EOT (day 4) 193,000 −0.32 FU (wk 4) 34,100 −1.07 FU (wk 12) <15 <−4.43 FU (wk 24) <15 <−4.43 FU (wk 48) <15 <−4.43 0303 1a BL (day 1) 82,500 EOT (day 4) 2,390 −1.54 FU (wk 4) <15 <−3.74 FU (wk 12) <15 <−3.74 0305 1a BL (day 1) 4,420,000 EOT (day 4) 1,260,000 −0.55 FU (wk 4) 270,000 −1.21 FU (wk 12) 1,170 −3.58 FU (wk 24) <15 <−5.47 FU (wk 48) <15 <−5.47 0306 1a BL (day 1) 1,060,000 EOT (day 4) 12,400 −1.93 FU (wk 4) 13,100 −1.91 FU (wk 12) <15 <−4.85 FU (wk 24) <15 <−4.85 FU (wk 48) <15 <−4.85 0307 1a BL (day 1) 1,450,000 EOT (day 4) 934,000 −0.19 FU (wk 4) 29,600 −1.69 FU (wk 12) <15 <−4.99 FU (wk 24) 407,000 −0.55 FU (wk 48) 2,620,000 −0.26 Placebo 0107 1a BL (day 1) 18,100,000 EOT (day 4) 16,100,000 −0.05 0202 1a BL (day 1) 2,350,000 EOT (day 4) 1,450,000 −0.21 0304 1b BL (day 1) 2,040,000 EOT (day 4) 2,970,000 0.16 0401 1b BL (day 1) 39,500 EOT (day 4) 67,400 0.23 ↵a BL, baseline; EOT, end of treatment; FU, follow-up period; BID, twice daily; TID, three times daily.
- Table 3
Population sequencing and phenotypic susceptibility in JTK-853-treated patientsa
Treatment Patient no. GT Change in HCV RNA from BL to EOT (log10) BL (day 1) EOT (day 4) Fold change in EC50 from BL Substitution EC50 (nM) RC (%) Substitution EC50 (nM) RC (%) 800 mg BID 0402 1a −1.24 — 172 7.4 — 61 9.3 0.35 0403 1a −0.81 — 137 18 — ND 0.01 ND 0404 1a −0.01 — 396 11 — ND 0.02 ND 0405 1a −1.86 — 56 10 M414T 1,320 6.9 24 0406 1a −1.15 — 119 0.54 — ND 0.01 ND 0407 1a −0.40 — 294 0.15 — ND 0.01 ND 1,200 mg BID 0101 1a 0.10 — 537 2.2 — 310 13 0.58 0102 1b −1.53 — 33 99 — 37 88 1.1 0103 1b −1.48 — 62 8.3 — 33 80 0.53 0104 1a −2.31 — 61 0.62 — 273 8.9 4.5 0105 1a −0.38 — 234 5.3 — 243 1.6 1.0 0106 1a −1.77 — 222 8.2 — 333 0.10 1.5 1,600 mg BID 0201 1a −1.09 — 213 0.36 — 360 4.7 1.7 0203 1a −0.93 — 380 12 — ND 0.02 ND 0204 1a −1.27 — ND 0.01 — 186 29 ND 0206 1a −0.73 — 189 20 — 318 26 1.7 0207 1b −2.68 — 32 79 — 23 83 0.72 1205 1a −2.39 — ND 0.02 — 388 0.03 ND 1,200 mg TID 0301 1a −1.05 — 199 1.3 — 639 0.08 3.2 0302 1a −0.32 — ND 0.02 — 416 0.28 ND 0303 1a −1.54 — 292 45 — 147 0.03 0.50 0305 1a −0.55 — 359 4.6 — 424 40 1.2 0306 1a −1.93 — ND 0.04 — ND 0.01 ND 0307 1a −0.19 — 189 24 — 264 13 1.4 Placebo 0107 1a −0.05 — 171 2.0 0202 1a −0.21 — ND 0.02 0304 1b 0.16 — 16 11 0401 1b 0.23 — 20 3.1 ↵a —, no amino acid substitution at residue 316, 414, 445, 448, 452, or 466. ND, not determined owing to a low replication capacity (<0.03%); GT, genotype; BL, baseline; EOT, end of treatment; BID, twice daily; TID, three times daily; RC, replication capacity. For the reference strain of Con1 (GenBank accession number AJ238799), the EC50 was 23 to 56 nM. Data for the EC50s represent the results from one experiment. Replication efficiency = (luciferase activity at 96 h/luciferase activity at 4 h) × 100; replication capacity = (replication efficiency of a patient's NS5B-harboring replicon/replication efficiency of the reference strain) × 100.
- Table 4
Clonal sequencing in JTK-853-treated patientsa
Patient no. Treatment GT Time point Change in HCV RNA from BL (log10) Residue (% of patients) in: C316 M414 C445 Y448 Y452 L466 0402 800 mg BID 1a BL (day 1) — — — — H (9) — EOT (day 4) −1.24 — — — — — — FU (wk 4) −4.53 — — — — — — FU (wk 12) <−5.84 NT NT NT NT NT NT FU (wk 24) <−5.84 NT NT NT NT NT NT FU (wk 48) <−5.84 NT NT NT NT NT NT 0403 800 mg BID 1a BL (day 1) — — — — — — EOT (day 4) −0.81 — T (18) — — — — FU (wk 4) −2.12 — — — — — — FU (wk 12) <−5.14 NT NT NT NT NT NT FU (wk 24) <−5.14 NT NT NT NT NT NT FU (wk 48) <−5.14 NT NT NT NT NT NT 0405 800 mg BID 1a BL (day 1) — — — — — — EOT (day 4) −1.86 — T (100) — — — — FU (wk 4) −4.09 — T (8) — — H (8) — FU (wk 12) <−5.64 NT NT NT NT NT NT FU (wk 24) <−5.64 NT NT NT NT NT NT FU (wk 48) NS 0406 800 mg BID 1a BL (day 1) — — — — — — EOT (day 4) −1.15 — — — H (10) — — FU (wk 4) NS FU (wk 12) NS FU (wk 24) NS FU (wk 48) NS 0407 800 mg BID 1a BL (day 1) — — — — — — EOT (day 4) −0.40 — — R (7) — — — FU (wk 4) NS FU (wk 12) NS FU (wk 24) NS FU (wk 48) NS 0101 1,200 mg BID 1a BL (day 1) — — — — — — EOT (day 4) 0.10 — — — — — F (10) FU (wk 4) NS FU (wk 12) NS FU (wk 24) NS FU (wk 48) NS 0102 1,200 mg BID 1b BL (day 1) — — — — — — EOT (day 4) −1.53 — — — C (9) — — FU (wk 4) NS FU (wk 12) NS FU (wk 24) NS FU (wk 48) NS 0302 1,200 mg TID 1a BL (day 1) — — R (20) — — — EOT (day 4) −0.32 — — — — — — FU (wk 4) −1.07 — — — — — — FU (wk 12) <−4.43 NT NT NT NT NT NT FU (wk 24) <−4.43 NT NT NT NT NT NT FU (wk 48) <−4.43 NT NT NT NT NT NT 0305 1,200 mg TID 1a BL (day 1) — — — — H (18) — EOT (day 4) −0.55 — — — — — — FU (wk 4) −1.21 — — — — — — FU (wk 12) −3.58 — — — — — — FU (wk 24) <−5.47 NT NT NT NT NT NT FU (wk 48) <−5.47 NT NT NT NT NT NT 0307 1,200 mg TID 1a BL (day 1) — — R (7) — — — EOT (day 4) −0.19 — — — — — — FU (wk 4) −1.69 — — — — — — FU (wk 12) <−4.99 NT NT NT NT NT NT FU (wk 24) −0.55 — — — — — — FU (wk 48) −0.26 — — — — — — ↵a More than 10 clones of the NS5B gene were examined for each patient and time point. —, no amino acid substitution at residue 316, 414, 445, 448, 452, or 466; NS, no sample; NT, not tested, as genotypic analysis was not performed because the serum HCV RNA was lower than the limit of detection (<15 IU/ml); GT, genotype, BL, baseline, EOT, end of treatment; FU, follow-up period; BID, twice daily; TID, three times daily.
Supplemental material
Files in this Data Supplement:
- Supplemental file 1 -
Table S1, sequences of primers for cDNA synthesis and gene amplification.
PDF, 14K
- Supplemental file 2 -
Table S2, amino acid substitutions arising during the treatment phase outside of the reported mutations associated with viral resistance in the patients' NS5B at the EOT by population sequencing analysis.
PDF, 7.7K
- Supplemental file 1 -
