• K65R is the 'signature' tenofovir resistance mutation. 1 2
  • K65R confers cross-resistance to abacavir, ddI, 3TC and FTC.
  • K65R can make virus more susceptible to the thymidine analogues AZT and d4T.

The K65R mutation decreases sensitivity to all NRTIs except AZT and d4T. Pairing tenofovir with 3TC may provide additional selective pressure favouring the development of K65R. 3 Pairing tenofovir with ddI is not recommended because of an increased risk of side-effects and CD4 cell count declines.

K65R significantly reduces viral fitness 4 and appears to reduce resistance associated with thymidine associated mutations (TAMs). Virus with both K65R and TAMs has been associated with only low level AZT resistance. Therefore, tenofovir and AZT may be an effective NRTI pair. 5 Furthermore, the use of AZT in combination with tenofovir may slow the emergence of K65R. 3

Studies have shown that the likelihood of developing the K65R mutation is reduced when thymidine analogues are used in a regimen, as several agents select for the K65R pathway.6

Several large trials have found that only 3% developed the K65R mutation after at least a year of tenofovir-containing treatment.7 8  These studies showed that TAMs at codons 67, 70, 215 or 219 did not compromise response to tenofovir. Only those at 41 or 210 (associated with higher level NRTI resistance) showed a reduced response.

Tenofovir has been found to be active against viruses with three or fewer TAMs and maintains activity against the Q151M mutation.9 Greater reductions in susceptibility are associated with four or more TAMs, particularly the multi-nucleoside mutations 69SS and Q151M.8 10 11 IAS-USA guidelines state that three or more TAMs, if they include M41L or L210W, reduce response to tenofovir.2

Second-line therapy after first-line use of tenofovir has been shown to have a relatively high response rate when both the K65R and M184V mutations are present, and virus remains fully susceptible to AZT and d4T.12 Other tenofovir resistance mutations appear to develop slowly and infrequently after K65R has developed.13

Tenofovir response begins to decline after a 1.4-fold reduction in susceptibility, and a fourfold reduction in susceptibility is associated with no clinical response, according to an analysis of 112 patients in the Gilead 907 study.

K65R-related tenofovir resistance has been seen to develop more rapidly and frequently in African countries with a high prevalence of HIV subtype C.14 15


  1. Stanford HIV Drug Resistance Summaries. Stanford HIV Drug Resistance Summaries Online at http://hivdb.stanford.edu/pages/drugSummaries.html, accessed 2007
  2. IAS-USA Drug Resistance Mutations Group. Update of the drug resistance mutations in HIV-1: 2007. Topics in HIV Medicine 15(4):119-125, 2007
  3. MacArthur RD et al. Factors associated with selection of the K65R mutation: a retrospective chart review. Antivir Ther 8: S419, 2003
  4. Weber J et al. Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation. J Clin Microbiol 43: 1395-1400, 2005
  5. Parikh S et al. Antimalarial activity of HIV-1 protease inhibitors. 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Washington, 2005
  6. Winston A et al. Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase AIDS 18(6): 949-951, 2004
  7. Margot NA et al. Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquired Immune Defic Syndr 20 (33):15-21, 2003
  8. Margot NA et al. Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS 16: 1227-1235, 2002
  9. Miller MD et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 189: 837-846, 2004
  10. Masquelier B et al. Identification of genotypic determinants of the virological response to tenofovir-including regimens in nucleoside reverse transcriptase inhibitor-experienced patients. Antivir Ther 7: S105, 2002
  11. Lo CM et al. Efficacy of tenofovir combination therapy and its genotypic resistance in multifailure HIV-1-infected subjects. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P142, 2004
  12. Landman R et al. Low genetic barrier to resistance is a possible cause of early virologic failure in once-daily regimen of abacavir, lamivudine, and tenofovir: the Tonus Study. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 52, 2005a
  13. Brandi C J et al. Long-term follow-up of patients taking tenofovir DF with low-level HIV-1 viremia and the K65R substitution in HIV-1 RT. AIDS 21:761-763, 2007
  14. Doualla-Bell F et al. High Prevalence of the K65R Mutation in Human Immunodeficiency Virus Type 1 Subtype C Isolates from Infected Patients in Botswana Treated with Didanosine-Based Regimens. Antimicrob Agents Chemother 50(12): 4182–4185, 2006
  15. BG Brenner BG et al. Facilitated selection of K65R resistance with tenofovir pressure in subtype C HIV-1 isolates. Fifteenth International Workshop on HIV Drug Resistance, Sitges, Spain, abstract 150, 2006
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.