Background:  The K65R mutation in HIV1-RT is a relatively infrequent mutation associated with abacavir (ABC), didanosine (ddI), and tenofovir (TDF) therapy. In vitro when the K65R is isolated, susceptibility to all nucleosidics RT inhibitors (NRTI) except AZT and d4T is reduced. Mutation M184V partially restore susceptibility to NRTI. As TDF is largely used in patients escaping to a first line of treatment, we looked for its presence in TDF-naïve patients.

Methods:  Genotypic data issued from the 4 last years were analyzed for the presence of K65R mutation. The other associated mutations and the antiviral drugs were also collected.

Results:  During  the study period, 3.025 genotypes were performed. The K65R mutation was present in 24 patients representing 0.8% of the samples. A total of 18 K65R concerned TDF-naïve patients (none of the 6 TDF-experienced patients had the Q151M mutation); 6 of these patients (33%) were ddI- and ABC-naïve (12 were ABC-naïve and 8 were ddI-naïve). M184V mutation was associated to K65R in 8 cases (44%). Surprisingly, Q151M was associated to K65R in 9 patients (50%) (in the same study period Q151M was present only in 33 patients; thus 9/33 Q151M⁺ patients had the double mutations). The K65R + Q151M mutations were mostly associated with V75I, F77L, Y115F, and F116Y, the cluster of mutations associated with multi-nucleoside resistance (6 patients).

Conclusions:  In TDF-naïve patients, K65R is rare; this mutation can be selected without ABC or ddI therapy (39%) and is frequently associated with the Q151M mutation (50%). As virus carrying these 2 mutations show high-level resistance to all NRTI and the strongest resistance to TDF, genotypic resistance tests should be systemically performed in therapy failure especially when TDF treatment is proposed. We have now to define if the emergence of the K65R mutation could be a way towards the Q151M mutation emergence

Keywords: K65R; Q151M; TENOFOVIR