Phenotypic resistance to ddI is less frequent than resistance to ZDV, 3TC and abacavir

The refinement of resistance testing is in progress and several studies presented at the 41st ICAAC meeting addressed issues surrounding the interpretation of genotypes. It is now well known that resistance to didanosine (ddI, Videx) is complex and related to several mutations.

In a study by Larder and colleagues, the frequency or ddI resistance in a resistance database containing 7196 recent North American isolates with genotypes and phenotypes was evaluated in an effort to identify the common genetic determinants of ddI resistance.

Newly defined biological cut-off values were used to define drug susceptibility, with the cut off used for ddI being a fold resistance (FR) of 3.5 fold.

In this study, 12.4% of the 7196 isolates examined were ddI resistant. Resistance to zidovudine (ZDV, AZT, Retrovir), lamivudine (3TC, Epivir), abacavir (ABC, Ziagen) and stavudine (d4T, Zerit) was found in 32.9%, 50%, 27.6% and 11.8% of the samples, respectively.

The median ddI FR in all samples with a 184V mutation was 1.7. The following mutation frequencies were observed in the 885 samples with ddI resistance: 23% 74V, 2.6% 65R, 61% 184V, 61% 215Y/F, 46% 44D and/or 118I, 3.4% 69 inserts, 15% 69D, 11.4% 151M. Of these, samples with 151M or 65R (combined with other mutations) had a median FR of >10, while all others had a median FR of about 5.

Cross-resistance to 3TC or ABC increased from 57% to 100% and 58% to 79% respectively, if the 184V mutation was present. The 74V mutation had a similar effect on suppressing ZDV resistance as the 184V but the greatest effect was seen when 74V and 184V were present together with ZDV mutations.

Isolates with ZDV mutations with or without 184V, 44D, 118I, 69D were ddI susceptible (FR: 0.9 – 2.1), but those with ZDV mutations plus 118I and 69D, or 69 inserts showed modest resistance (4 – 4.8-fold).

Conclusions: Phenotypic ddI resistance was less frequent than ZDV, 3TC or ABC. Modest ddI resistance can be explained by a combination of ZDV mutations, plus other NAMS (particularly 118I & 69D), or the 74V mutation, but not 184V. High-level resistance is due to the 151M complex.

BA Larder and others. Analysis of Clinical Isolates and Site-Directed Mutants Reveals the Genetic Determinants of ddI Resistance. Abstract I-1324.