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K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine.

Abstract：

:Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.

journal_name

Antivir Ther

journal_title

Antiviral therapy

authors

Røge BT,Katzenstein TL,Obel N,Nielsen H,Kirk O,Pedersen C,Mathiesen L,Lundgren J,Gerstoft J

subject

Has Abstract

pub_date

2003-04-01 00:00:00

pages

173-82

issue

eissn

1359-6535

issn

2040-2058

journal_volume

pub_type

临床试验,杂志文章,多中心研究,随机对照试验

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K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine.