Background: ViroLogic has established clinically based phenotypic breakpoints for most of the nucleoside reverse transcriptase inhibitors (NRTIs). While several prevalent mutational patterns and their effect on clinical response to NRTIs are relatively well understood, the increasing frequency of new drugs and different drug combinations may increase the incidence of patterns that are currently rare. In these cases, knowledge of the phenotypic correlates of mutational patterns may provide new, clinically useful information. For example, regimens including ddI, ABC, and/or TDF, may select for 2 mutations that are currently uncommon (K65R and/or L74V), especially in the absence of ZDV (or possibly d4T) which appears to counter-select K65R and L74V.

Methods: The ViroLogic database was searched for paired genotypes (GTs) and phenotypes (PTs). We used 10,478 unique pairs to evaluate the median phenotype for 27 mutational patterns involving NRTI associated mutations.

Results: Shown in the table below are 6/27 queries. The other 21 will be presented.

Genotype	N*	phenotypically “sensitive” NRTIs
184V/I only	977	ABC, ddI, d4T, ZDV, TDF
65R only	22	ABC, d4T, ZDV
65R + 184V/I only	7	d4T, ZDV
74V/I + M184V/I only	68	d4T, ZDV, TDF
67N/70R/219Q/E/N/R + 184V/I	130	ABC, ddI, d4T, TDF
41L/210W/215Y + 184V/I	108	none

 * Number of matched GTs and PTs

 

As expected, multiple thymidine-associated mutations (TAMs) limit NRTI treatment options, with the 41L/210W/215Y pattern giving much broader cross-resistance than the 67N/70R/219Q/E/N/R pattern. However, selection for these TAM patterns is a relatively slow process and their prevalence appears to be decreasing. On the other hand, rare patterns involving K65R and/or L74V lead to broad cross-resistance with fewer mutations than the TAM pathway, suggesting they may be selected more quickly following virologic failure.

Conclusions: Multiple mutational pathways may lead to broad cross-resistance in the NRTI class. Currently uncommon patterns with low genetic barriers to resistance, such as 184V plus either K65R or L74V (only 2 mutations needed) may increase in prevalence if ABC, ddI and/or TDF are used in the absence of thymidine analogs.