Clinically Relevant Genotype Interpretation of Resistance to Didanosine

Abstract

We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as ؉1), while secondarily, mutations associated to a better response (scored as ؊1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L ؉ T69D ؉ L74V؉ T215Y/F ؉ K219Q/E ؊ K70R ؊ M184V/I; P ‫؍‬ 4.5 ؋ 10 ؊9 ) and by comparing that to only mutations added (set I, M41L ؉ T69D ؉ L74V ؉ L210W ؉ T215Y/F ؉ K219Q/E; P ‫؍‬ 1.2 ؋ 10 ؊7 ). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log 10 copies/ml when they were ranked as having a genotypic score II of ؊2, ؊1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.

Fitness Comparison of Thymidine Analog Resistance Pathways in Human Immunodeficiency Virus Type 1

“…Subsequent studies have shown that the L210W mutation commonly occurs together with M41L and T215Y and contributes significantly to ZDV resistance (14,37). Moreover, didanosine and tenofovir are significantly less active against viruses that carry the 41L/210W/215Y combination (27,30). Our results provide additional insights that help explain the ordered appearance of ZDV resistance mutations.…”

“…Mutations that occur together with T215Y (including M41L, L210W, and sometimes D67N) constitute the TAM-1 cluster; mutations that occur together with K70R (including D67N, T215F, and K219Q) constitute the TAM-2 cluster (10,26,36). The division of TAMs into two distinct clusters has important clinical significance: ZDV-resistant viruses carrying TAM-1 mutations usually are cross-resistant to didanosine and tenofovir, whereas viruses carrying TAM-2 mutations usually remain susceptible to those drugs (27,30). The T215Y mutation may be found by itself or in combination with M41L and L210W, but T215F rarely occurs alone or with the M41L and L210W mutations.…”

HIV-1 Protease Codon 36 Polymorphisms and Differential Development of Resistance to Nelfinavir, Lopinavir, and Atazanavir in Different HIV-1 Subtypes

“…The V82A mutation is known to emerge in subtype B HIV-1 following LPV therapy and to modestly decrease the level of binding between PIs and PR because of changes to the enzyme active-site cavity (17,22,23). Our results show that V82A results in a modest increase in the LPV fold resistance (Table 1) at great expense to viral replication capacity (Fig.…”

Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

“…This provides objective information for the guidance of drug selection based on genotypes, in particular for treatment-experienced patients (11,14,23). Here, we have identified a list of protease mutations that impair the virological response to boosted FPV in PI-experienced patients using stepwise methodologies as previously proposed (6,14,15,23). We described the mutations associated with FPV/r virological response at week 12 based on virological data from a pooled analysis of FPV/r 700/100 mg b.i.d.…”

“…The removing procedure began with all k mutations retained from the univariate analysis. The nonparametric Jonckheere-Terpstra (JT) test for ordered alternatives that allows testing of a specific a priori sequence was used (6,10,15). From the initial set of k mutations, the first step was to remove one mutation.…”