 |
|
|
| |
Tenofovir & Correlates of the K65R Mutation
|
| |
| |
"Clinical and genotypic correlates of K65R mutation in an unselected cohort of HIV-infected persons naive for tenofovir"
ABSTRACT 152
Antiviral Therapy 2004; 9:S168.
MP Trotta, S Bonfigli, F Ceccherini Silberstein, D Zinzi, R D'Arrigo, F Soldani, M Zaccarelli, P Marconi, U Visco Comandini, E Boumis, F Forbici, V Tozzi, P Narciso, CF Perno and A Antinori
National Institute for Infectious Diseases 'Lazzaro Spallanzani'IRCCS, Rome, Italy
BACKGROUND: Mutation RT-K65R confers resistance to tenofovir (TDF), so the identification of clinical and genotypic factors related with the occurrenceof K65R could be useful in selecting patients who had greatest probability of response to TDF-based regimens.
METHODS: Clinical, viro-immunological and genotypic data of all persons failing HAART who underwent genotypic resistance test (GRT) during 1999--2003 werecollected in a database and retrospectively analysed for this study.
RESULTS: Out of 1392 GRT performed on 771 patients, 12 TDF-naive patients had the K65R mutation with an overall prevalence of 1.6%, ranged between 0.59% and 2.08% without a significantly change in K65R prevalence over the study period (P at Chi-square for linear trend = 0.842).
At multivariate analysis, previous AIDS (OR 4.54; 95%CI 1.04--19.82) and use of abacavir (13.50; 2.57--70.82) and of efavirenz at GRT (14.32; 3.33--61.61) were associated with a greater risk of developing K65R, while patients with longer exposure to lamivudine were less likely to present the mutation (0.94;0.89--0.98 for each more month of therapy).
In a separate multivariate logistic model, presence of M184V (0.06; 0.01--0.86) and TAMs (0.35; 0.16--0.82 for each more mutation among TAMs) seems to be protective for the emergence of K65R, while a strong positive correlation was found with the cluster of mutations associated with Q151M (3.47; 2.07--5.80).
Moreover, NNRTI-induced L100I-mutation was independently associated with an higher probability of presentingK65R (16.87; 2.59--110.02).
CONCLUSIONS:
In this large unselected cohort of antiretroviral-experienced patients naïve for TDF, the prevalence of the K65R mutation remains low.
RT-K65R mutation is more common in patients with more advanced HIV stage disease.
K65R was also strongly independently associated with the use of EFV and the presence of L100I mutation.
1) In antiretroviral-experienced patients, selection and sequencing of the best nucleoside-backbone should be based on patients' clinical history and genotypic test; 2) caution should be used in starting TDF in patients who are failing an abacavir-containing regimen; 3) longer exposure to lamivudine and presence of M184V seems protective for K65R suggesting the utility to incorporate lamivudine in TDF-based regimens; 3) K65R was inversely associated with TAMs indicating that these patterns could representantagonistic ways of viral evolution; the total number of NAMS/TAMS seems to decrease the risk of selection for K65R mutation, suggesting that thymidine analogue use could protect from the development of K65R; 4) the strong association between K65R and Q151M-complex confirm the utility of performing systematically GRT in therapy failure before initiation of TDF; 3) since nucleoside and non-nucleoside inhibitors bind to different sites on reverse transcriptase in a non-exclusive way, cross-resistance should be further investigated.
|
| |
|
|
|
|
|
