February 25, 2005
Currently the 2 most popular nucleoside backbone regimens are 1) abacavir (ABC, Ziagen) + lamivudine (3TC, Epivir) and 2) tenofovir (TDF, Viread) + lamivudine. Each 1 of these combinations has characteristic genotypic patterns of resistance when treatment fails.
The goal of this study by Mark Underwood et al was to look at the phenotypic sensitivity of HIV with specific mutations that are typically associated with the above mentioned regimens. Using the Virologic database, the researchers specifically looked at viruses that harbor the following mutations: K65R, K65R/M184V, L74V, L74V/M184V, M184V and M184I.
Typically, K65R has been associated with tenofovir, L74V with abacavir and didanosine (ddI, Videx), and M184V with lamivudine and emtricitabine (FTC, Emtriva). Viruses with K65R/M184V mutations are sensitive to zidovudine (AZT, Retrovir), stavudine (d4T, Zerit) and surprisingly to tenofovir. Viruses that have the L74V/M184 mutations are also sensitive to the same drugs. K65R alone is associated with resistance to lamivudine, didanosine and tenofovir, while L74V seems to leave all the nucleosides available.
If you believe the results of this analysis, it seems that the L74V and M184V mutations will leave someone with more options down the road. This would favor the use of abacavir + lamivudine first. Some other people would use didanosine + lamivudine as another possibility, which is much less popular at the present time.
Last year, during the XIII International HIV Drug Resistance Workshop in Tenerife, Spain, Gilead presented results in a similar study with opposite conclusions.1 In that study, having L74V was associated with low-level frequency of K65R and decreased subsequent virologic response to tenofovir.
However, the problem is that when the time comes for a patient to initiate treatment, there are many things to take into account besides future options. Critical considerations include: tolerability, safety and cost of possible regimens.
In addition, we need to ascertain which of these 2 regimens is better. The combination of tenofovir + lamivudine versus abacavir + lamivudine has never been compared one against the other head to head. Fortunately, the AIDS Clinical Trials Group (ACTG) is designing exactly this -- a trial that will compare both regimens and evaluate tolerability, metabolic complications and response to subsequent therapy. It is only in doing this kind of large randomized trial that we will learn which 1 of the 2 combinations is really better. My sense is that both are pretty darn good.
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