The Body PRO Covers: The 6th International Congress on Drug Therapy in HIV Infection

The Development of Mutations in Antiviral-Treated Patients

November 21, 2002

  • The Development of K65R Versus Thymidine Analogue-Associated Mutations (TAMs) in Antiviral-Treated Patients
    Authored by D.J. McColl


Two studies on the use of tenofovir (TDF, Viread) in salvage therapy, studies 902 and 907, have been previously reported. Study 902 was a trial in which the participants who were failing their current regimens, with viral loads below 100,000 copies/ml, were randomized to receive either tenofovir at three separate doses or a placebo. Study 907 followed and utilized the 300 mg dose of tenofovir. This study was another add-on study in which tenofovir or placebo was added to a pre-existing therapy which was failing, with low level viral replication of less than 10,000 copies. Genotypic resistance analysis was performed for all patients in study 902 and a randomly selected population in study 907.


The aim of this study was to characterize the pattern of nucleoside-associated resistance mutations that developed in individuals undergoing therapy with tenofovir in studies 902 and 907.


The mean reduction in viral load due to the addition of tenofovir in the failing regimen was 0.6 log at 24 weeks, maintained to 96 weeks. Because the patients were extensively pre-treated and were on a failing regimen, there was a high level of nucleoside, non-nucleoside and protease inhibitor resistance. Indeed 94 percent of patients had nucleoside resistance of some kind, 57 percent resistance to protease inhibitors and 40 percent to non-nucleosides. Only 1.3 percent of individuals had the signature mutation to tenofovir -- K65R -- at baseline.

Individuals were more likely to develop new nucleoside mutations, presumably selected by other drugs in their regimes, with a total of 40 percent developing more thymidine analogue mutations. Only 3 percent of patients (14 individuals) developed the K65R mutation over 96 weeks, while 175 patients developed one or more new TAMs. Other nucleoside analogue mutations also developed at a low rate, with only 2.9 percent of patients in the study developing the mutation M184V (3TC [lamivudine, Epivir]) and 3.2 percent developing the mutation L74V (ddI [didanosine, Videx]).

Interestingly, among the 14 individuals developing the K65R mutation, virological response was highly variable. Although five individuals were classified as non-responders -- defined by a less than 0.5 log decrease in viral load -- seven individuals continued to have a sustained response defined as a greater than 0.5 log decrease up to week 96. Two other individuals who were initial responders rebounded secondary to the development of non-nucleoside resistance. In individuals developing the mutation K65R, there was continuing phenotypic sensitivity to AZT (zidovudine, Retrovir) in fact, there was hypersensitivity, d4T (stavudine, Zerit)/ddI/abacavir (ABC, Ziagen), and continuing sensitivity overall to tenofovir when a biological cut off of three times the sensitivity of wild type virus was used. In the presence of the mutation M184V, there was a loss of sensitivity to abacavir and clearly 3TC, but an increase in the sensitivity to tenofovir.

One patient developed a Q151M, which is a multi-nucleoside resistance mutation that wipes out the activity of all nucleoside analogues apart from tenofovir. However, in the presence of a K65R mutation with a Q151M mutation the virus became resistant to tenofovir.


This study would suggest the development of a K65R mutation was infrequent (3.2 percent of patients). This should be compared with the results from the 902 study, which showed that 24 percent of patients virologically failing tenofovir developed this mutation. Interestingly, despite the presence of the K65R mutation, continued reduction in HIV replication occurred. It is possible that the K65R mutation may protect against future TAM development, and maintain reduced plasma HIV RNA by re-sensitization to AZT. Additionally there has been increased interest in fitness assays and evidence that replication capacity may be a useful measure of viral fitness. Indeed, the K65R mutation reduces the viral fitness to 53 percent of wildtype, and in the presence of the M184V mutation will reduce it even further to approximately 24 percent of wild type.

Implications for Clinical Practice

The addition of a single drug to a failing regime cannot be recommended, even though it appears to be the FDA's preferred method of investigating new agents. The development of the K65R mutation in this intensification study was rare, and the development of thymidine analogue mutations presumably driven by other drugs in the regimen was much more common. Clearly, this shows the need in clinical practice to try and develop fully effective regimens wherever possible, including the treatment of late stage rescue patients.

A few tricks which may be useful in clinical practice, came out from this study. Firstly, that the K65R mutation may re-sensitize virus to AZT. Secondly, that the reduced fitness of the virus in the presence of K65R, may mean the continued antiviral effect of tenofovir and 3TC in virologically failing regimens.

It is important to realize that resistance testing is not all or nothing. Clearly in this study and also in the 902 study, some individuals continued to respond to tenofovir despite the presence of the K65R mutation.

Previous | Next Tell us what you think of The Body's conference coverage!

This article was provided by TheBodyPRO. It is a part of the publication The 6th International Congress on Drug Therapy in HIV Infection.

Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.