October 30, 2004
Enfuvirtide (T-20, Fuzeon) is the first and only entry inhibitor currently on the market. It disrupts the gp41 function and prevents the fusion of HIV with the T-cell membrane. Because of this unique mechanism of action, which works at a completely different site than other antiretrovirals, there is no cross-resistance with other HIV mutants. Therefore, enfuvirtide is effective against HIV-1 that is very resistant to all other drug classes. This characteristic makes it a highly valuable option for the treatment of the therapy-experienced population who have drug-resistant virus.
Recap of TORO Study Results
The efficacy and safety of enfuvirtide, when taken in combination with an optimized background of other antiretrovirals, have been demonstrated in several studies, including the international Phase III studies TORO 1 and TORO 2. In those studies, patients who were randomized to take enfuvirtide plus an optimized background regimen were more likely to achieve virologic suppression, larger reduction in viral counts and better immune reconstitution than patients who took an optimized background regimen alone.
Patients in the TORO studies who experienced virologic failure on the optimized background-only regimen were then allowed to switch to an enfuvirtide plus optimized background regimen. The question is: Were those patients better off adding the enfuvirtide in this second round, or does doing so lead ultimately to a higher treatment-failure rate?
Results of This Study
Cal Cohen of the Community Research Initiative of New England in Boston, Mass., presented the results of this retrospective study. This analysis was conducted to explore the development of resistance and the antiretroviral efficacy of all arms of the studies: (1) optimized background alone, (2) enfuvirtide plus optimized background and (3) optimized background alone followed by a switch to enfuvirtide plus optimized background.
The study population (intent-to-treat) included 661 patients who received enfuvirtide plus optimized background and 334 patients who received optimized background alone. Of these, 346 (52%) of the enfuvirtide plus optimized background patients vs. 260 (78%) of the optimized background-only patients met the definition for virologic failure.
When the researchers analyzed the change in genotypic score between baseline and time of virologic failure, the number and percentage of patients who lost genotypic-sensitive agents was higher for patients on the optimized background-only regimen.
In fact, approximately 50% of the patients in the optimized background-only group with a baseline Genotypic Susceptibility Score greater than or equal to 1 lost an active agent that had been included in their optimized background. This loss of active agents from the optimized background translated into poorer efficacy of the subsequent enfuvirtide plus optimized background regimen.
When the researchers compared the enfuvirtide plus optimized background arm to the optimized background-only arm, the difference in the loss of active agents was greater when the analysis included patients who did not meet the definition for virologic failure. This larger difference is explained by the fact that the proportion of enfuvirtide plus optimized background patients who experienced virologic failure was smaller. However, the investigators believe (and I agree) that the inclusion of the patients who did not experience virologic failure is a better method of analysis, since this reflects the overall proportion of patients who lost active agents.
This analysis clearly demonstrates that patients who initially received enfuvirtide had improved virologic outcomes compared to patients who used enfuvirtide only after virological failure.
These results are consistent with previously reported efficacy findings, which showed that patients with fewer active agents in their optimized background had poorer responses than patients with a greater number of active agents in their optimized background.
I think that by now everyone will agree that treatment with regimens that do not contain enfuvirtide is associated with higher virological failure rates and a greater loss of active background agents than treatment with enfuvirtide-containing regimens. What remains a challenge is determining the right cutoff at which the benefits of adding enfuvirtide are greater than the potential consequences and treatment inconveniences.
It is clear that the goal of switching regimens should be to achieve undetectability. The results of this analysis reinforce the concept that regimens that maximize the chances of earlier suppression also have a better chance of continuing their success over time.
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