Thank you for your question.
This topic is one of considerable interest and debate.
One key issue here is that the combination of ddI and TDF has not been well studied; other than pharmacokinetic studies among non-infected individuals, we have no data to date about the safety, efficacy or resistance of this dual nucleoside backbone. Hence, any summaries about these points are speculative.
The point that has been raised by the Lanier poster (CROI #586) is that since TDF and ddI can select for either of these mutations in vitro, that at time of treatment failure, the combination would be expected to select virus with either of these two mutations. There is data that suggests that the use of thymidine analogs will change the mutational distribution in selected viruses- favoring the emergence of thymidine analog mutations; this data does not directly relate to the RATE of emergence of resistance, per se, since this is undoubtedly related to the entire drug regimen (i.e., the third drug in the regimen).
So the key issue to me isn't the time to emergence of resistance, but rather the time to first evidence of treatment failure-- and the temporal relationship of the appearance of subsequent mutations. I think that experience has shown us to be very wary of predictions of this, since data from in vivo selected virus often does not match data from laboratory selected and lab-adapted virsu.
You raise a question about the possibility of a 3TC-based regimen influencing the potential for 65R or 74V-- this is a very interesting point; one partially addressed in the Gilead 903 trial where TDF and 3TC were co-administered. Here, the emergence of 65R was rare, though data on the temporal releationship between the 3TC resistance mutation 184V, NNRTI resistance and 65R was not presented. One might look at the effect of 184V on TDF or ddI resistance as another metric of whether 3TC (and 3TC resistance) might affect the emergence of resistance to either TDF or ddI. Last year's presentation by Whitcomb at CROI suggests that there is slight hypersusceptibility to TDF after the emergence of 184V; in contrast, ddI susceptibility is actually reduced. This would suggest a beneficial relationship between 3TC resistance and TDF and a potential antagonistic relationship with ddI.
Bear in mind that the above is mere speculation and I'll await both clinical virology and clinical outcomes before codifying this into my clinical practice. -BY
