July 16, 2003
Enfuvirtide (also know as T-20 and marketed as Fuzeon) is the first drug to be licensed in the U.S. that targets the entry of HIV into the cell. It was approved by the FDA earlier this year based on early data from two almost identical studies (TORO 1 and TORO 2 -- for The Body's coverage of these studies, click here).
This study reports the 48-week data along with additional analyses.
To recap the TORO studies, as presented in Barcelona and published in the New England Journal of Medicine, these two parallel studies enrolled patients with at least six months of previous treatment with all three classes of antiretroviral drugs. The participants had resistance testing with both genotype and phenotype tests. An optimal regimen based on history and resistance testing was chosen (optimal background or OB). Participants were then randomized to receive the OB plus injections of enfuvirtide twice daily or OB only in a two to one fashion.
For the purpose of the 48-week analysis, the two studies were combined. A total of 661 patients received enfuvirtide plus OB and 334 patients received OB only. At baseline, the median CD4 count was about 90 and the median viral load was over 100,000. The duration of previous therapy averaged almost seven years. Thus, it was clearly a group with advanced disease and extensive treatment.
The single take-home message from the 48-week analysis was that the treatment benefits, if they existed at 24 weeks, tended to last at least through the 48-week point. This is good news for patients. At 24 weeks, 47 percent of the patients in the enfuvirtide plus OB group had at least a one log drop in viral load, compared to 25 percent in the OB-only group. At 48 weeks the proportions were 37 versus 17 percent. At 24 weeks, 32 percent versus 15 percent had a viral load of less than 400 copies/mL and at 48 weeks the proportions were 30 versus 12. Sixteen percent in the enfuvirtide arm had a viral load of less than 50 copies/mL at week 24 compared to only 6 percent in the OB-only arm.
Interestingly, the proportion had gone up slightly by week 48 to 18 percent. While viral load responses are a marker of clinical benefit, it is more important to know whether the immune system has improved and whether patients have remained healthy. At 24 weeks, the average increase in CD4 cells in the enfuvirtide plus OB group was 71 cells, which increased to 91 cells at 48 weeks. This was roughly twice the response as seen in the OB only group.
Patients who persisted with the enfuvirtide for the first few months seemed to be able to stick with it. As reported in the early data, the major side effect was injection site reactions, which were seen in most patients. In about 60 percent of the patients with site reactions, the reactions were described as mild; they were moderate in about 20 percent. The reactions required pain meds or limited activities in only 2-3 percent of patients.
The only other effects that appeared to be higher in the enfuvirtide group were swollen lymph nodes and "pneumonia." The pneumonia cases remain perplexing. Most were not pneumonias confirmed by chest x-ray, and very few of the patients with pneumonia were hospitalized. Thus, it is unclear to me what this finding represents. It could be a chance finding, or it could reflect some subtle effect on the immune system that makes someone more susceptible to infection. Both of these seem unlikely and don't fit the data. Two more interesting explanations are the possibility that there was more immune reconstitution in the enfuvirtide arm or that a few patients have some type of allergic or hypersensitivity response to enfuvirtide. The overall safety of enfuvirtide seems very reasonable, but we need to explain this finding.
Perhaps the most interesting finding from the TORO studies was the degree to which resistance testing could predict response. Using either genotype or phenotype testing, the number of drugs in the background regimen that were predicted to be active was one of the most important predictors of response. The implication of this is that enfuvirtide is best used when there are still one or two new drugs to pair it with, not when all options are gone and the situation is gloomy. For example, patients whose genotypic sensitivity score predicted that there were no active drugs in the OB regimen had a 50 cell CD4 benefit with enfuvirtide, but if they had two or more drugs that were predicted to work, the benefit with enfuvirtide was an impressive 116 cells at 48 weeks.
The durability of enfuvirtide's benefit combined with its optimized background is similar to that of other effective salvage regimens. Another study, presented by Julio Montaner at this conference, looked in more detail at predictors of response. The hope is that we can better learn how to balance the efficacy of enfuvirtide with the expense and the need for injections.
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