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Fuzeon Once vs Twice Daily Injections, and Predictors of Failure

Excerpted from: Glasgow Meeting: Part 5
8th International Congress on Drug Therapy in HIV Infection
November 12-16, 2006, Glasgow

Mark Mascolini

Once- vs twice-daily enfuvirtide, and predictors of failure
Enfuvirtide remains the only licensed antiretroviral requiring injection, and having to poke oneself twice a day doesn't make this fusion inhibitor any more popular. To see if two shots at the same time would control HIV as well as two shots in the morning and the evening, US and Canadian clinicians randomized 64 treatment-experienced people to inject 180 mg of enfuvirtide once daily or the standard 90 mg twice daily when starting additional salvage drugs [3]. People in the once-daily group gave themselves two separate injections at different body sites, one right after the other.

Study participants began their enfuvirtide-based salvage regimen with a median CD4 count of 115 (range 2 to 662) and a median viral load of 4.9 log (just under 100,000 copies). About one quarter also started tipranavir in their salvage regimen, and 87% already had an AIDS diagnosis. Twelve people dropped out of the once-daily arm and 10 quit the twice-daily arm before week 48, mostly for reasons unrelated to side effects.

Week 48 intent-to-treat analyses showed that similar proportions in the two study arms reached a viral load below 400 copies, but the twice-daily arm did better in getting their loads under 50 copies and in cutting their loads at least 10-fold (1 log) (Table 2). Twelve of 30 people (40%) in the once-daily arm and 11 of 31 (36%) in the twice-daily arm had a virologic failure, defined as confirmed failure to push the viral load down a half-log at or after week 4. CD4 gains did not differ significantly between the once-daily and twice-daily groups.

Table 2. 48-Week responses to once- versus twice-daily enfuvirtide




After 48 weeks of treatment 28 of 30 people (93%) in the once-daily group versus 25 of 31 (81%) in the twice-daily group reported at least 85% adherence to enfuvirtide (measured by 4-day recall); that difference fell short of statistical significance (P = 0.14). Twenty-four of 30 people (80%) in the once-daily group versus 18 of 31 (58%) in the twice-daily group reported enfuvirtide adherence of 95% or better, but that difference also fell just shy of statistical significance (P = 0.06). These differences in adherence did not correlate with virologic suppression at the 400-copy level.

Among people who reported at least one injection site reaction, injection site ecchymoses (purple patches), induration (skin hardening), and erythema (redness) were moderately less severe with twice-daily dosing. One person quit the once-daily group because of injection site reactions, while none quit the twice-daily arm for that reason.

Results of this small pilot trial must be judged equivocal because the authors note that the study did not have enough statistical power to demonstrate noninferiority between once- and twice-daily dosing. Injecting two loads of enfuvirtide at the same time may be just as burdensome to some people as injecting the drug at two different times of day. The needle-free Biojector system, not yet available in the US or Europe, proved more acceptable than standard needle injection in a Canadian study [4] and may make two shots at the same time more tolerable.

Having two or more mutations from a set of only six mutations at five protease positions predicted lack of virologic response to salvage regimens including enfuvirtide and ritonavir-boosted tipranavir [5]. But this response predictor rests on analysis of only 24 triple-class-experienced people starting enfuvirtide salvage, so it must be validated in larger groups of patients.

Rodger MacArthur (Wayne State University, Detroit) focused on 24 people with a median pre-enfuvirtide viral load above 100,000 copies and an average CD4 count of 113. That group comprised 13 "responders," including 10 who met the full-response definition (reaching a viral load under 400 copies on enfuvirtide/tipranavir) and 3 who met the partial-response definition (at least a 10-fold drop in viral load). No single mutation predicted lack of virologic response, but two or more from a protease mutation subset--L33F, I47V, I54A/M, V82T, and I84V--had a 100% positive predictive value and a 68% negative predictive value for lack of response (P = 0.006) (Table 3).

Table 3. Six PI mutations predicting response to enfuvirtide/tipranavir



Responders had a higher presalvage CD4 count (mean 151, range 6 to 360) than did nonresponders (mean 69, range 2 to 324), a bigger CD4 gain with enfuvirtide/tipranavir (mean 131, range 29 to 353) than nonresponders (mean -10, range -159 to 41), and a lower presalvage viral load (median 60,000 copies, range 1500 to >100,000) than nonresponders (median >100,000, range 15,000 to >100,000).

Link to detailed report of Fuzeon once vs twice daily injection poster:
A PILOT 48-WEEK STUDY OF ONCE-DAILY (180 MG QD) VERSUS TWICE-DAILY (90 MG BID) ENFUVIRTIDE (11/28/06)

References
3. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in study TMC125-C227. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract PL5.6.
4. Harris M, Joy R, Larsen V, et al. Enfuvirtide plasma levels and injection site reactions using a needle-free gas-powered injection system (Biojector). AIDS. 2006;20:719-723.
5. MacArthur RD, Richmond D, Crane LR. Lack of virologic response to the combination of tipranavir/ritonavir + enfuvirtide in treatment-experienced HIV-infected persons with multi-drug resistant virus can be predicted by the presence of two or more of six mutations from five positions in protease. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P205.


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