Predictors of Selection of K65R Mutation: Tenofovir Use and Lack of Thymidine Analogue Mutations

The rate of K65R increased from 0.6% in 1999 to 11.5% in 2004. The recognition of K65R correlated negatively with the presence of thymidine analogue mutations (TAMs) but positively with Q151M.

High rates of early virological failure associated with the emergence of the K65R mutation at the HIV-1 reverse transcriptase gene have recently been reported among HIV-infected patients on tenofovir-containing triple nucleos(t)ide regimens.

Data from large genotypic databases have shown that K65R is quite uncommon, although its rate might be increasing. K65R is selected in vitro by tenofovir, zalcitabine (Hivid), didanosine (Videx), stavudine (Zerit) and abacavir (Ziagen).

In vivo, tenofovir, abacavir and didanosine have been shown to select the K65R mutation. Although K65R reduces the susceptibility to tenofovir and to a lesser extent affects the activity of other nucleoside analogues such as abacavir, didanosine and lamivudine (Epivir), it retains the activity of zidovudine (Retrovir).

Therefore, viruses carrying K65R show broad cross-resistance to nucleos(t)ide reverse transcriptase inhibitors.

Data about the rate of K65R and its association with other nucleoside analogue resistance mutations are scarce. In the present study, researchers describe the rate of K65R in a large database of genotypic drug resistance reports in a reference hospital in Madrid, Spain. Its association with other reverse transcriptase resistance mutations is further described.

Results

A total of 53 specimens showed K65R, providing an overall rate of 2.9%. None of drug-naive individuals showed K65R. The rate of K65R significantly increased over time among treatment-experienced patients, from 0.6% in 1999 to 11.5% in the first trimester of 2004.

As other groups have shown, the selection of K65R is significantly associated with the use of tenofovir. The incidence of this mutation has increased in recent times, presumably as a result of the increasing use of tenofovir in clinical practice.

However, as was shown in our study, other nucleoside combinations may also favour the selection of K65R, although it appears to occur more rarely. In our analysis, K65R was particularly frequent among patients failing tenofovir/didanosine-based combinations, but this may indirectly reflect the fact that a large group of patients in our institution have been exposed to this combination during the past 2 years.

The frequent selection of M184V along with K65R results in a novel multi-nucleoside-resistant genotype, although it may provide in vitro an increased susceptibility to zidovudine and perhaps to stavudine.

Clinical data are needed to clarify to what extent the K65R+M184V genotype compromises the activity of nucleoside analogues. This information may be particularly relevant given that tenofovir is now widely used with lamivudine, and single pills containing tenofovir and emtricitabine (Emtriva) are expected to be available soon.

Conclusions

In conclusion, the authors write, “The rate of K65R has increased significantly over the past 5 years among treatment-experienced patients, and currently is above 10%. This fact is directly related to the wide use of tenofovir in clinical practice.”

“Given the antagonism between K65R and TAM, further clinical studies assessing the benefit of using combination nucleoside analogues driving these different resistance pathways should be conducted.”

Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

10/18/04

Reference
L Valer and others. Predictors of selection of K65R: tenofovir use and lack of thymidine analogue mutations. AIDS 18(15): 2094-2096. October 21, 2004.