OA03.01
Background: Vaginal HIV transmission accounts for the majority of new infections worldwide. Prevention efforts have demonstrated mixed success due to lack of adherence to drug regimens. New efforts to prevent HIV transmission have focused on long–acting (LA) antiretroviral drug formulations to circumvent this issue.
Methods: We first established critical pharmacokinetic parameters of intramuscular (IM) injection of TMC–278 LA in mice and demonstrated sustained drug release for 4 weeks. Humanized BLT mice were then vaginally challenged with HIV–1 transmitted founder viruses (T/F) after IM administration of TMC–278 LA and the extent of protection from HIV acquisition was determined. In the 1st experiment, challenges with the T/F virus CHO40 were performed 1 week after drug administration (600mg/kg). In a 2nd experiment, BLT mice were challenged 1 week after drug administration with 1 of 3 different viruses (CHO40, RHPA, or JR-CSF). These mice were exposed to a second challenge 3 weeks after drug administration with a different T/F virus (THRO). Infection was determined using viral load assay and PCR analysis for vDNA in tissues. Identity of the infecting viruses was confirmed by DNA sequencing.
Results: In the first experiment, a single IM dose of TMC–278 LA (600 mg/kg) one week before vaginal challenge provided significant protection from CHO40 infection (6/6 mice protected) (p=0.0047). In contrast, 3/3 animals that received saline became infected. In the second experiment, 6/7 BLT mice that received saline before exposure became infected. Whereas 6/8 BLT mice that received TMC-278 LA before the first viral challenge were protected from infection (p=0.026). All mice exposed 3 weeks post–drug administration to a 2nd challenge with THRO became infected.
Conclusions: TMC-278 LA offers significant protection from vaginal HIV infection against T/F viruses. Although a wane in protection over time was observed. These results demonstrate the potential of long–acting antiretroviral formulations for HIV prevention.
