November 21, 2002
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.
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.
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