• Baseline and On-Treatment Susceptibility to Enfuvirtide Seen in TORO 1 and TORO 2 to 24 Weeks (Oral 141)
  Authored by M.L. Greenberg, T. Melby, P. Sista, R. DeMasi, N. Cammack, M. Salgo, J. Whitcomb, C. Petropoulos, T.J. Matthews
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This presentation addressed the issue of resistance from the TORO 1 and TORO 2 studies of enfuvirtide (ENF, formerly T-20, Fuzeon). For a previous report on this study, click here. These were large studies of more than 500 patients each that looked at the use of ENF in a highly drug-experienced population.

Individuals with triple-class experience received genotypic and phenotypic resistance testing of the RT and protease and had their regimen optimized based on the results. The study arm then received ENF, in addition to the optimized therapy, and results were compared at week 24.

Both studies showed a significant advantage in the ENF arms. Here the investigators (led by the makers of ENF) looked at resistance to ENF in samples from baseline and at treatment failure. Since no standard assays are available for fusion inhibitors, they used an investigational susceptibility test developed by Virologic for determining ENF resistance and sequencing of the gp41 -- amino acids 36-45 positions believed to be important in ENF resistance (binding area of the drug).

First they looked at the ability of this susceptibility assay to determine which patients had baseline resistance that might predict subsequent drug failure. They found a very large variation in the baseline susceptibility to ENF -- a range of about 1,000 fold. PEC50 values were approximately log-normally distributed with a geometric mean of 0.259 mg/ml (range 0.007-7.526) and a standard deviation of approximately 2.7 fold. Sixteen patients with the greatest baseline values were identified and their virological response compared to the rest of the group. They were not found to have any diminished response. Therefore, despite the enormous differences in baseline susceptibility this assay shows, it did not help predict which patients will fail ENF if administered per the TORO protocols.

Next, they looked at the differences between susceptibility at baseline and after failure. Once again a very large variation was found in the increased fold resistance to ENF after failure 1-422 fold. The mean fold change was 21. In other words, patients failing ENF had on the average a 21-fold drop in susceptibility to the drug.

Genotypic resistance was examined in the failing patients and a large number of mutations in the gp41 -- amino acids 36-45 -- were seen. Mutations at these positions were found alone or in combination and resulted in varying degrees of ENF-reduced susceptibility if compared with the phenotypic assay results. Many mutations were seen, in particular positions 36, 38 and 43 seemed to be common and produce reduced susceptibility, although others were also often present and may be important.

The authors also report that HIV subtype (Clade) or baseline viral tropism did not appear to impact virological success in this study population.

Obviously we are very eager to see such interesting results regarding resistance to this new class of drugs -- especially with the possibility that many of us might be considering using ENF soon. But how can this study help us optimize the drugs clinical use?

As clinicians, our first concern is that some patients may have baseline resistance to ENF and therefore will not benefit (or not benefit as much) from the drug. Here the questions are: Are there patients with less baseline susceptibility to ENF? Do we have the proper tests to identify them? And if so, does this translate into poorer clinical response? If the answer is yes to all of these, we may need to consider performing this test before using the drug.

Current and previous studies suggest that patients vary in their laboratory susceptibility to ENF, but nothing has yet shown that this translates into clinical failure. This study suggests that the very large variability shown in the assay used here did not predict clinical failure. It may be that indeed the assay is accurately measuring clinical resistance and that all samples in this large range do respond equally well to the drug.

Another possibility is that the assay is either not measuring that right parameter or is not accurate enough. Either way, the take home message for clinicians is that at this point there is no need to perform this assay before starting a patient on ENF. Further study of this and maybe other assays of ENF resistance may provide different results -- we will keep our eyes open.

The other concern will relate to cross resistance between ENF and other fusion or entry inhibitors. Will these mutations preclude or reduce the efficacy of a subsequent agent of the class? Since this is the only agent right now available, the immediate clinical relevance is limited. Some preliminary results on cross-resistance between ENF and T-1249 were presented at the meeting (abstract 14lb, G.D. Miralles, et al.), but we have a long way to go in determining which assays should be used and if and how they can improve our patient management. For patients failing ENF therapy, we do not yet know if keeping them on the drug will result in accumulating mutations and reduce future entry inhibitor options, but this is a question we would like future studies to address.