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Enfuvirtide-Plus-Raltegravir Salvage Trial Cuts Off Recruitment Early
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Targeting HIV Entry: 4th International Workshop, December 8-9, 2008, Rio Grande, Puerto Rico
Mark Mascolini
A small salvage study pairing the fusion inhibitor enfuvirtide with the integrase inhibitor raltegravir recorded a good virologic response rate at week 12, and an even better rate at week 16 [1]. But investigators closed enrollment early because of poor recruitment, another signal that enfuvirtide is finding few takers as more oral salvage drugs fill pharmacy shelves.
This Roche-sponsored trial conducted at Boston's Community Research Initiative of New England launched as a two-phase study of enfuvirtide plus raltegravir and an optimized background regimen in highly treatment-experienced adults. Plans called for a 12-week first phase with a sub-50-copy viral load goal aimed at allowing an early confirmation of efficacy. In phase 2 participants with an undetectable load got randomized from twice-daily enfuvirtide dosing to once- or twice-daily dosing. People without an undetectable load at week 12 were followed for an additional 4 weeks.
The investigators aimed to recruit 238 people to attain the statistical power needed to discriminate between once- and twice-daily enfuvirtide in phase 2. But sluggish enrollment encouraged trial planners to cap enrollment at 30 patients and analyze 12- and 16-week results.
All study participants had experience with the first three antiretroviral classes or virus resistant to those classes. No one had taken enfuvirtide or raltegravir, and all had a genotypic sensitivity score of 3 or more, excluding nucleosides and considering enfuvirtide and raltegravir as active drugs. In other words, besides enfuvirtide and raltegravir, everyone would have at least one other active drug that was not a nucleoside.
The analysis involved 29 people who received at least one dose of study drugs, 14 who had an undetectable viral load by week 12 and 15 who did not. Study participants had a median age of 47 years (range 21 to 66), a median CD4 count of 115 (range 2 to 675), and a median viral load of 40,000 copies. Eight people (28%) entered the trial with a viral load above 100,000 copies. Only 13 people (45%) had virus that used the CCR5 coreceptor, so maraviroc was not a background regimen option for most people.
Two of 15 people in the group without an undetectable load at week 12 stopped treatment early because of protocol violations, 3 dropped out for reasons other than virologic failure, and 1 had no virologic assessment after entering the trial. After 16 weeks of treatment, 6 people in this group reached a viral load below 50 copies, so 20 of 29 people who took at least one dose (69%) reached a load below 50 copies at this point.
Seven of eight people who took the nonnucleoside etravirine as their third active drug had a 16-week viral load under 50 copies. By week 16, 13 of 17 people with a protease inhibitor (PI) in their regimen had a viral load under 50 copies, as did 7 of 8 without a PI. It's hard to make much of these third-drug correlations because of the small numbers. Clearly, being able to supplement enfuvirtide and raltegravir with drugs like etravirine and darunavir, which 12 people took, virtually guarantee an undetectable viral load, though perhaps not in 12 weeks.
Safety results suggest why people showed little enthusiasm for this trial. Twenty-four of 29 participants (83%) had injection site reactions, and 18 (62%) had grade 3 or 4 injection site reactions, though no one dropped out by week 16 because of tender injection sites.
Reference
1. Cohen CJ, Guittari CJ. The efficacy and safety of enfuvirtide in combination with raltegravir and an optimized background antiviral regimen in triple-class experienced HIV-1 infected patients. Targeting HIV Entry: 4th International Workshop. December 8-9, 2008. Rio Grande, Puerto Rico. Abstract 14.
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