Background: Enfuvirtide (ENF) is derived from HIV-1 gp41. Most infected patients (pts) have antibodies to gp41 that could cross-react with ENF. When ENF is administered to pts, potential exits for neutralization and hypersensitivity. Here we analyze the effects of gp41 antibody that cross-react with ENF on the efficacy and safety of ENF in 2 Phase III trials.

Methods: An indirect ELISA assay measured antigen-specific serum antibody levels; results were presented as levels of antibody titer with categories of positive, negative, and non-quantifiable. Efficacy was assessed as change from baseline (BL) in HIV-1 RNA, proportion of pts with virological failure (VF), and reduction of 1.0 log₁₀ RNA from BL. All adverse events (AEs) and any event that could be a manifestation of hypersensitivity, and grade 3 or 4 lab toxicities were assessed for safety.

Results: At BL 77% of pts receiving ENF + optimized background (OB) and 74% of OB pts were antibody-positive; 1.3% of pts in either group were negative for antibody, the remainder being non-quantifiable. Mean BL antibody titers were 5.57 and 5.80 mg/mL for the ENF + OB and OB treatment groups, respectively. At 24 wks, 78% of pts on ENF + OB and 43% on OB had reduced antibody titers of ≥ 30%. The absolute decline in titer between treatment groups was significantly different (p < 0.0001). In the table below, we list efficacy parameters vs maximum change in antibody titer through 24 wks. A greater reduction in plasma HIV-1 RNA was associated with a greater reduction in gp41 antibody (r = 0.24; p < 0.0001). For pts with positive antibody at BL, 95% in ENF + OB and 88% in the OB arm had at least one AE, 3.6% of pts in ENF + OB and 3.2% in OB had an AE that might represent any hypersensitivity reaction, and 22% of ENF + OB pts and 15% of OB pts had a grade 3 or 4 lab abnormality. There was no correlation with antibody change and the incidence or severity of injection site reactions.

Conclusions: Cross-reacting gp41 antibodies to ENF declined in both treatment arms throughout 24 wks but to a greater extent in the ENF + OB group. There appears to be no negative influence of cross-reacting antibodies on the efficacy or safety of ENF.

 

	ENF + OB (N = 408)			OB (N = 219)
	Change from BL in antibody titer
	< -30% N = 264	-30 to +30% N = 111	> +30% N = 33	< -30% N = 29	-30 to +30% N = 167	> +30% N = 23
Change from BL HIV RNA (log10 )	-1.7	-1.4	-1.3	-1.2	-0.7	-0.6
VF	40%	56%	58%	59%	76%	78%
>1.0 log10 decrease from BL	55%	42%	33%	41%	23%	17%