TABLE 3.
Novel substitutions emerging during HBV therapy
| Substitution | Backgrounda | Frequencyb | ETV EC50 (nM [SD])c |
|---|---|---|---|
| A200V | WT | 1 | 7.6 (3.4) |
| A200V | M204I | 1 | 33.0 (27.4) |
| A200V | L180M, M204I | 1 | 10.2 (2.8) |
| L80V | L180M, M204V | 2 | 11.0 (7.1) |
| V27A | L180M, M204V | 1 | NRd |
| I53F | V173F, L180M, M204V | 1 | 22.3 (11.8) |
| S78T | WT | 1 | 2.4 (1.2) |
| L80I | L180M, M204I | 1 | 45.3 (20.5) |
| K168E | M204I | 1 | NR |
| A181T | V173L, L180M, M204V | 1 | 14.2 (7.5) |
| C188S | L80I, L180T, M204V | 1 | 31.2 (20.8) |
| V191Ae | 1 | ||
| V224A | V173L, L180M, M204V | 1 | NR |
| L228P | M204I | 1 | NR |
| L229W | L180M, M204V | 1 | 32.9 (4.7) |
| D263G | WT | 1 | 5.8 (1.7) |
| Q267Stop | L180M, M204V | 1 | NR |
| G295S | L80I, M204I | 1 | NR |
| M309L | WT | 1 | 4.0 (0.4) |
Background resistance-encoding substitutions in the isolates tested.
Frequency indicates the number of patients in whose isolates the substitution emerged.
EC50s (standard deviation) are the averages of three or more tests (only two tests for S78T; A200V, M204I, and L180M; and M309L). Substitutions were tested in the background (WT or LVDr) in which they arose. Parallel assays with either WT or LVDr (with the M204V and L180M or M204I substitution) reference clones yielded ETV EC50s of 5.5 nM and 45 nM, respectively.
NR, no replication (HBV replication was <10% of that for the WT) and unable to measure the phenotype.
V191A was not found in 24 cloned isolates from the patient, and therefore, the isolates were not tested.