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K65R HIV Drug Mutation: resistance, prevalence, & associations
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"Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase"
AIDS: Volume 18(6) 9 April 2004 pp 949-951
Winston, Alana; Pozniak, Antona; Mandalia, Sundhiyaa; Gazzard, Briana; Pillay, Deenanb; Nelson, Marka
aDepartment of GU and HIV Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; and bDepartment of Virology, Royal Free and University College Medical School, Windeyer Institute, 46 Cleveland Street, London W1T 4JF, UK.
The K65R mutation has been reported to be associated with the use of abacavir, didanosine and tenofovir. With the advent of tenofovir we have assessed the change in the prevalence of this mutation. The prevalence of the K65R mutation remains low, but has significantly increased over a 2-year period. Although not associated with a specific drug, it is associated with the dual use of tenofovir, didanosine and the triple combination of tenofovir, didanosine and abacavir.
(Note from Jules Levin: studies suggest that use of AZT, when used with drugs associated with development of the K65R resistance mutation, slows or prevents development of K65R mutation).
The long-term efficacy of combination antiretroviral therapy is compromised by the emergence of drug-resistant viral isolates that may confer cross-class resistance. This is the case when the K65R mutation arises in reverse transcriptase, which confers in-vivo resistance to abacavir, didanosine, lamivudine and tenofovir [1].
We have previously reported the prevalence of the K65R mutation in tenofovir-naive individuals [2], in which the K65R mutation occurred in 1.7% of individuals failing antiretroviral therapy and was associated with current abacavir use. Furthermore, individuals on abacavir without concomitant thymidine analogue use were more likely to develop the K65R variant, whereas those on abacavir with a thymidine analogue were more likely to develop nucleoside analogue mutations (NAM).
Tenofovir, a newly licensed nucleotide reverse transcriptase inhibitor, selects for the K65R mutation in vivo [3]. Studies in antiretroviral-experienced individuals have shown that 3% of individuals failing tenofovir contained regimens to develop this mutation [4]. However, in antiretroviral-naive individuals, 22% failing a tenofovir-containing regimen developed the K65R mutation [5].
With the widespread use of tenofovir, the prevalence of the K65R mutation outside of clinical trials is unknown. The aim of this study was to assess the changes in prevalence of the K65R mutation over 2 years from a large clinical database and to assess any associations with particular treatment strategies and virological correlates.
Genotypes from individuals on a failing antiretroviral regimen at Chelsea and Westminster Hospital NHS Trust, UK, were analysed from October 2000 to October 2002. As historical controls these were compared with genotypes before October 2000 in tenofovir-naive individuals. Genotypes were matched to the patients' drug histories and laboratory parameters.
Data were analysed using SAS statistical analysis software. Comparisons between two groups with quantitative data were assessed using the Mann-Whitney test, whereas between three groups data were assessed using the Kruskal-Wallis test. Chi-squared statistics were used to test for associations between two qualitative variables, and when samples of subjects were small in strata, Yate's correction was applied. All P values presented are two-tailed.A total of 997 resistance tests had been performed before October 2000 in tenofovir-naive individuals. In 17 of these isolates the K65R mutation was present, representing a prevalence of 1.7%. In the 2-year period from October 2000 to October 2002, a total of 733 resistance tests were performed in individuals failing antiretroviral therapy. The K65R variant was newly identified in 28 isolates, representing a prevalence of 4%. This represents a significant increase in the prevalence of this mutation between the two time periods (P = 0.004).
Laboratory and drug history was compared between the 28 isolates with the K65R mutation and the 705 isolates without this mutation from the time period when tenofovir had been in use. There was no difference in the CD4 lymphocyte count, HIV viral load or time on antiretroviral therapy at the time of resistance testing. When adjusting for the use of other drugs, there was no difference in the use of didanosine, abacavir or tenofovir as single agents between each group.
Reviewing dual-drug combinations in the nucleoside backbone of the antiretroviral regimens between each group, the use of tenofovir and didanosine in combination was commoner in isolates with the K65R variant (14.3 versus 3.8%, P = 0.007). No other dual nucleoside combination in antiretroviral regimens was commoner in isolates with the K65R mutation.The triple nucleoside combination of tenofovir, abacavir and didanosine together, either as a single regimen or as part of an antiretroviral regimen, was also associated with the development of this mutation, with 32% of individuals with the K65R variant being on a combination containing these agents (nine of the 28 isolates).
Individuals concurrently receiving a thymidine analogue were significantly less likely to develop the K65R mutation as were individuals with pre-existing NAM. The fewer NAM present the more likely the K65R variant was to develop. (note from Jules Levin: studies suggest use of AZT slows or prevents K65R mutation from developing).
The prevalence of the K65R mutation in reverse transcriptase in our clinic has increased from 1.7% before October 2000 to 4% in a subsequent 2-year period. The widespread use of tenofovir, especially in combination with other drugs that select for this mutation, may be associated with the upward trend.The K65R variant is less likely to develop in individuals who are on concomitant thymidine analogues and less likely to develop in those with pre-existing NAM.
From our data, we could not identify any single drug associated with the development of K65R. We identified statistically significant associations with the dual use of tenofovir and didanosine as part of a highly active antiretroviral therapy regimen, and the triple combination of tenofovir, didanosine and abacavir either as part of or as highly active antiretroviral therapy, associated with its development. This may be due to several components of these regimens exerting a selective pressure for the development of this single codon mutation. It appears that the concurrent use of thymidine analogues reduces the emergence of K65R in patients receiving a combination of tenofovir, abacavir and didanosine.
It has recently been suggested that the development of the K65R mutation may reduce the primer unblocking effect of the NAM, and therefore lower the resistance to zidovudine in isolates with NAM [6]. Our clinical data would support this mechanism, with a reduced likelihood of developing the K65R variant when thymidine analogues are used in a regimen in which several agents select for the K65R pathway.
References
1. Gu Z, Arts EJ, Parniak MA, Wainberg MA. Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2',3'-dideoxycytidine 5'-triphosphate and other drugs. Proc Natl Acad Sci U S A 1995, 92:2760-2764.
2. Winston A, Mandalia S, Pillay D, Gazzard B, Pozniak A. The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients. AIDS 2002, 16:2087-2089.
3. Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, et al. In vitro selection and characterisation of HIV-1 with reduced susceptibility to PMPA. Antiviral Ther 1999, 4:87-94.
4. Margot NA, Issacson E, McGowan I, Cheng A, Miller MD. Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquired Immune Defic Syndr 20 2003, 33:15-21.
5. Miller MD, Margot NA, McColl DJ, Coakley DF. Cheng AK. Characteristics of virological failure through 96 weeks among treatment naïve patients taking tenofovir DF or stavudine in combination with lamivudine and efavirenz. In: 2nd International AIDS Society Conference. Paris, 2003 [Abstract 553].
6. Parikh U, Koontz D, Hammond J, Bacheler L, Schinazi R, Meyer P, et al. K65R: a multi-nucleoside resistance mutation of low but increasing frequency. Antiviral Ther 2003, 8 (Suppl.):S152.
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