14th International HIV Drug Resistance Workshop 7-11 June 2005, Québec City, Canada

RARE SELECTION OF K65R MUTATION IN NAÏVE PATIENTS FAILING A FIRST-LINE ABACAVIR/LAMIVUDINE HAART CONTAINING REGIMEN.

Antivir Ther. 10, Suppl 1:S17 (abstract no. 15)

D Descamps¹, S Delarue¹, M Ait-Khaled², C Craig³, G Collin¹, F Brun-Vézinet^1
1Laboratoire de Virologie, Hopital Bichat-Claude Bernard, Paris, France ²Clinical Department, GlaxoSmithKline, UK ³Virology Department, GlaxoSmithKline, UK

BACKGROUND: Previous studies described the presence of L74V in highly experienced subjects as a risk factor for reduced response to tenofovir and K65R selection. These observations may not be extrapolated to antiretroviral (ART)-naïve patients experiencing a first confirmed virological failure (VF) with L74V. The current study therefore examines whether K65R might occur as minority variants where L74V was the major variant selected upon virological failure of a first line abacavir(ABC)/lamivudine (3TC) HAART.

METHODS: Four ART-naïve subjects, receiving ABC/3TC and protease inhibitors (n=3) or efavirenz (n=1) with VF virus having L74V and M184V (n=3) or M184V alone (n=1) in RT, were selected. Clonal analyses were performed at baseline and time of VF. Clones were screened for the presence of K65R mutation by real time K65R selective PCR (K65R-sPCR). RT genes from clones detected with K65R in this screen were sequenced.

RESULTS: At baseline, bulk population sequencing showed wild-type RT sequences for all four samples. All the clones generated (376, 450, 675 and 720 in the four samples respectively) were wild-type at codon 65 by K65R-sPCR, except in one patient where 1/720 clones had K65R by K65R-sPCR and sequencing. At failure, two patients, with L74V and M184V mutations by bulk population sequencing had 1/466 and 1/855 K65R mutant clones respectively, the latter being the patient harbouring the K65R clone at baseline. Clonal sequencing showed that K65R was associated with M184V in one patient and with L74V+M184V in the other patient. All the 524 and 270 clones from the two remaining patients’ plasma were wild-type at codon 65.

CONCLUSION: Minority species harbouring K65R are uncommon and at very low frequency in patients experiencing virological failure, while receiving a first line ABC/3TC HAART containing regimen. These results show that the co-selection of L74V with K65R and of M184V with K65R mutations in these patients was rare. Indeed, the selection of L74V in a patient with baseline K65R suggests that M184V/L74V is the preferred ABC/3TC resistance pathway. The clinical significance of mutations present at ≤1% on first failure, of the same order as found in a patient at baseline, remains undetermined.

PRESENTING AUTHOR: D Descamps

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2005-06-07
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