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Predictors of selection of K65R: tenofovir use and lack of TAMs
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ABSTRACT 40
Antiviral Therapy 2004; 9:S46.
L Valer, L Martín-Carbonero, A Corral, C de Mendoza and V Soriano
Hospital Carlos III, Madrid, Spain
BACKGROUND: Mutation K65R at the HIV-1 RT gene reduces the susceptibility to tenofovir (TDF) and in less extent affect the activity of other nucleosideanalogues. Data about the rate of K65R and its association with other nucleoside analogue resistance mutations are scarce.
METHODS: The presence of K65R was examined in a large database of genotypic drug resistance reports collected over the last 5 years from drug-naive (n=216) and treatment-experienced (n=1630) HIV+ patients inSpain.
RESULTS: A total of 53 specimens showed K65R after testing plasma samples from 1846 different individuals (overall rate, 2.9%). None of drug-naive individuals showed K65R. The prevalence of K65R increased overtime in pre-treated patients: 1/156 (0.6%) in 1999, 3/464 (0.6%) in 2000, 0/167 (0%) in 2001, 11/366 (3%) in 2002, 29/399 (7.3%) in 2003 and 9/78(11.5%) during the first trimester of 2004. While K65R was identified mainly in subjects failing TDF-based combinations, in 10 individuals it appearedwithout exposure to TDF. These subjects were receiving d4T+ddI (4), ABC+3TC (2), d4T+3TC (2), d4T+ABC (1) and ddC (1). The remaining 43 specimens carrying K65R were collected from subjects failing different TDF-based combinations: TDF+ddI (32), TDF+ABC (6), TDF+3TC (4) and TDF alone (1).
The presence of TAMs was significantly lower in patients with K65R with respect to the rest. Accordingly, the rate of zero, one and two TAMs was4.6%, 5.6% and 2.3%, respectively. Moreover, only K70R and/or K219E were seen along with K65R. No patients with >=3 TAMs had K65R. In the multivariateanalysis, the presence of K65R was inversely associated with the number of TAMs (OR=0.54; 95% CI=0.24--0.54) and the presence of T215Y/F (OR=0.09; 95% CI=0.01--0.9), while it was positively associated with the presence of Q151M (OR=4.82; 95% CI=1.76--13.22) and the total number of nucleoside analogue resistance mutations excluding TAMs (OR=1.59; 95% CI=1.25--2.02). M184V accompanied K65R in 24 cases (45%).
CONCLUSION: The selection of K65R is significantly associated with the use of TDF. However, other nucleoside combinations including d4T, ddI and/or ABC,may favour its selection as well, although more rarely. Reciprocal exclusion of K65R and TAMs may reflect that they represent divergent and antagonistic pathways driving to nucleoside analogue resistance. The frequent selection of M184V along with K65R result in a novel multi-nucleoside resistance genotype.
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