Important note: Information in this article was accurate in July 2005. The state of the art may have changed since the publication date.
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HIV Treatment Bulletin - Vol. 6, No. 7, July 2005
Simon Collins, HIV i-Base
A study presented at the meeting by Douglas Barnas and colleagues, provided an explanation for the 91% virological failure rate before week 24 in patients using a triple nucleoside combination of ddI/tenofovir/3TC in the Jemsek Study.
The mechanism of failure for this and several other triple nucleoside combinations has still not been convincingly demonstrated.
M184V was found in 100% and K65R in only 50% of failures, with standard phenotype test (Phenosense) showing no resistance to tenofovir and moderate resistance to ddI (mean change of 0.6-fold and 1.8-fold respectively.
Barnas used single genome sequencing (SGS) of samples from 9/10 patients in the study who failed with both K65R and M184V by standard genotype. Susceptibility to 3TC, ddI, tenfovoir and abacavir and the impact double mutants (where both mutants are on the same genome; n=3), was compared to mixtures (where both mutations were found, but not on the same genome; n=6).
Total number of genomes was 204 with a mean of 22 samples per patient (range 12-46). Most common genotypes were the K65R/M184V double mutant (50%) and M184V single mutant (38%). M184I occurred in 11% samples and only one genome contained K65R single mutant.
| ddI | ABC | TDF | |
| Mean fold-Rx of double mutant | 2.45 | 5.41 | 0.86 |
| Mean fold-Rx of mixture | 1.49 | 2.83 | 0.52 |
| Overal average fold-Rx | 1.81 | 3.69 | 0.63 |
| P value | 0.02 | 0.02 | 0.02 |
| ddI | ABC | TDF | |
| Mean fold-Rx of 184V only | 1.4 | 2.4 | 0.6 |
| Mean fold-Rx of double mutant | 3.5 * | 7.5 * | 1.8 * |
| * P<0.01 | |||
The study concluded that when 65R occurs with 184V in the same genome, hypersensitivity to tenofovir is reversed and ddI resistance is increased, giving the double mutants selective advantage, and that prior section of 184V contributed to this (shown in Table 1 and 2).
Previous phenotypic testing had failed to show resistance to tenofovir, because samples had included single 184V mutations, to which TDF is hypersensitive and this cancelled out the increased resistance from 65R and 184V dual mutations.
Assessment of phenotypic resistance to other nucleosides should also be considered with and without M184V mutations (see report on ddI resistance below).
Ref: Barnas D, Bazmi H, Mellors J et al. Genotypic and phenotypic explanation for failure of triple NRTI therapy with lamivudine, didanosine and tenofovir. Antivir Ther. 10, Suppl 1:S167 (abstract no. 152).
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