Background:  Monoclonal antibodies 2F5, 2G12, and 4E10 have demonstrated broad, neutralizing potential in vitro and activity in passive transfer experiments in animals and humans. The 3 monoclonal antibodies were given to HIV-1-infected individuals on HAART in an open label, non-randomized, proof-of-concept study to evaluate their potential in preventing viral rebound after ART termination.

Methods:  We studied 10 HIV-1-infected individuals, all identified and treated during acute and early infection with HAART for 15 to 60 months (mean 29.1). In all subjects, virus was susceptible to 2G12 (mean IC₅₀ 13.7 μg/mL, range 0.7 to 34.6), 2F5 (mean IC₅₀ 6.3 μg/mL, range 1.0 to 18.9), and 4E10 (mean IC₅₀ 7.1 μg/mL, range 1.2 to 20.1). All had a viral load <50 copies/mL for at least 6 months on HAART. Patients had weekly monoclonal antibody infusions for 3 weeks, and discontinued HAART at week 4, following which infusions were continued for 12 weeks. The first 6 patients (group I) were administered 1 g of each of the 3 monoclonal antibodies. In the last 4 patients (group II), the dose of 2F5 and 4E10 was increased to 2 g, based on poor pharmacokinetics in group I.

Results:  Pre-HAART, the study subjects had a mean log₁₀ HIV-1 RNA of 5.7 (range 4.1 to 7.3 log₁₀ HIV-1 RNA) and CD4⁺ T cells count of 440 cells/mm³ (range 258 to 703 cells/mm³). Of 10 subjects, 5 received the full set of 16 infusions; 2 remained aviremic after 6 and 9 months of HAART discontinuation; and 7 of 8 had delayed time to rebound (mean 50 days, range 35 to 73 days vs 26 days in historic controls; p <0.05). In 7 of 8 patients with viral rebound, resistance to 2G12 emerged but susceptibility of sequential plasma virus to 2F5 and 4E10 did not change. In group I, trough plasma levels of 2G12 (mean 623±113 μg/mL) were significantly higher than trough levels of 2F5 (mean 50±24 μg/mL; p <0.01) and 4E10 (mean 105± 39 μg/mL; p <0.01). In group II, trough levels of 2G12 (mean 549±50 μg/mL) remained significantly higher than trough levels of 2F5 (mean 99±48 μg/mL; p <0.01) and 4E10 (mean 193±52 μg/mL; p <0.01). Monoclonal antibody infusions were well tolerated. In group II, PTT levels were slightly prolonged post-infusion. Anticardiolipin activity was detected in one patient tested.

Conclusions:  Monoclonal antibodies delay plasma viral rebound post ART-DC. In general, rebounding virus developed resistance to 2G12; 4E10 and 2F5 did not exert pressure on the virus likely due to rapid clearance and low trough levels of these antibodies in vivo. Testing of other monoclonal antibodies in combination with 2G12 should be evaluated.