Table 3.
Ex vivo drug susceptibility and molecular markers of drug resistance by light microscopy Day 3 positivity
| All |
DHA/PPQ |
AS + DHA/PPQ |
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 3-negative |
Day 3-positive |
P | Day 3-negative |
Day 3-positive |
P | Day 3-negativea |
Day 3-positive |
P | |||||||
| Ex vivo drug assays | N | N | N | N | N | N | |||||||||
| DHA survival rateb | 5 | 5.4 (0–10.7) | 18 | 48.5 (22.4–88.4) | 0.048 | 4 | 8.1 (2.7–81.8) | 7 | 44.1 (35.2–90.2) | 0.130 | 0 | – | 11 | 52.9 (19.1–88.4) | – |
| AS survival rateb | 5 | 13.7 (5.4–14.3) | 18 | 43.4 (25.2–101.0) | 0.021 | 4 | 14.0 (9.5–49.2) | 7 | 39.5 (30.1–115.0) | 0.089 | 0 | – | 11 | 47.3 (21.4-101.0) | – |
| PPQ IC50 (nM)c | 12 | 35.9 (24.0–53.7) | 17 | 45.4 (34.8–59.2) | 0.352 | 5 | 24.5 (16.6–36.1) | 7 | 44.5 (36.3–54.7) | 0.007 | 7 | 47.1 (25.1–88.7) | 10 | 46.0 (28.6–74.1) | 0.770 |
| CQ IC50 (nM)c | 12 | 48.2 (37.1–62.4) | 17 | 70.0 (53.8–91.2) | 0.037 | 5 | 47.1 (34.2–64.8) | 7 | 85.0 (61.6–117.1) | 0.028 | 7 | 48.9 (30.5–78.5) | 10 | 61.2 (40.4–92.6) | 0.329 |
| Drug resistance markers | n/N | (%) | n/N | (%) | n/N | (%) | n/N | (%) | n/N | (%) | n/N | (%) | |||
| K13 non-synonymous mutations | 14/20 | (70) | 25/25 | (100) | 0.005 | 11/14 | (79) | 10/10 | (100) | 0.180 | 3/6 | (50) | 15/15 | (100) | 0.015 |
| K13-C580Y | 8/20 | (40) | 20/25 | (80) | 0.012 | 7/14 | (50) | 9/10 | (90) | 0.079 | 1/6 | (17) | 11/15 | (73) | 0.046 |
| KEL1 lineaged | 5/18 | (28) | 15/22 | (68) | 0.011 | 5/13 | (38) | 6/9 | (67) | 0.193 | 0/5 | (0) | 9/13 | (69) | 0.009 |
| PGB of artemisinin resistance | |||||||||||||||
| arps10-(V127M+D128H) | 16/22 | (73) | 26/29 | (90) | 0.150 | 12/16 | (75) | 9/10 | (90) | 0.617 | 4/6 | (67) | 17/19 | (89) | 0.234 |
| fd-D193Y | 11/22 | (50) | 24/29 | (83) | 0.017 | 10/16 | (63) | 10/10 | (100) | 0.052 | 1/6 | (17) | 14/19 | (74) | 0.023 |
| crt-(N326S+I356T) | 8/22 | (36) | 20/29 | (69) | 0.026 | 7/16 | (44) | 8/11 | (73) | 0.239 | 1/6 | (17) | 12/18 | (11) | 0.061 |
| mdr2-T484I | 9/22 | (41) | 4/28 | (14) | 0.051 | 5/16 | (31) | 1/10 | (10) | 0.352 | 4/6 | (67) | 3/18 | (17) | 0.038 |
| exonuclease-E415G | 0/23 | (0) | 0/30 | (0) | – | 0/17 | (0) | 0/11 | (0) | – | 0/6 | (0) | 0/19 | (0) | – |
| pm2 multicopy | 2/22 | (9) | 3/26 | (12) | 0.581 | 2/18 | (11) | 1/11 | (9) | 0.684 | 0/4 | (0) | 2/15 | (13) | 0.614 |
| mdr1 multicopy | 2/21 | (10) | 2/26 | (8) | 0.610 | 1/17 | (6) | 0/11 | (0) | 0.607 | 1/4 | (25) | 2/15 | (13) | 0.530 |
| crt-CVI(E/D)T haplotypes | 17/22 | (77) | 26/27 | (96) | 0.077 | 15/17 | (88) | 11/11 | (100) | 0.505 | 2/5 | (40) | 15/16 | (94) | 0.028 |
DHA, dihydroartemisinin; AS, artesunate; PPQ, piperaquine; CQ, chloroquine; PGB, parasite genetic background.
a
No successful RSA in Day 3-negative samples in the AS + DHA/PPQ arm.
b
Median (IQR).
c
Geometric mean (95% CI).
d
Presence of at least three of the following SNPs in Chr13: positions 1700345, 1717359, 1718288, 1739315 and 1862741 (Table S1).