Background:
Pre-exposure prophylaxis (PrEP) is an important strategy for HIV prevention among people at risk. Long-acting antiretroviral agents circumvent the requirement for daily dosing to achieve maximal protection and represent an alternative to daily oral regimens. Lenacapavir (LEN) is a long-acting HIV capsid inhibitor recently approved in the European Union for the treatment of multi-drug-resistant HIV infection in combination with other antiretrovirals. Here, we assessed the relationship between LEN plasma concentration following a single subcutaneous (SC) administration and PrEP efficacy using a single high-dose SHIV rectal challenge macaque model.
Methods:
LEN antiviral activity against SHIV and HIV was measured in activated PBMCs and adjusted for plasma protein binding. The SHIV stock was titrated over 8 cycles of escalating (0.625 to 100 TCID50) rectal challenge (n=8 macaques/cycle) to define a suitable high-dose inoculum. Twenty naïve rhesus macaques received a single SC injection of LEN at 5, 10, 20, 50 or 75 mg/kg (n=4/group). Eleven animals with LEN exposures above its paEC95 were challenged rectally with SHIV 7 weeks post-dose. Blood was collected weekly through study week 25 for the evaluation of drug levels, viral loads, and p27 ELISA.
Results:
LEN inhibited SHIV replication in rhesus PBMCs with an EC50 of 390 pM, resulting in a projected 4.4-fold lower LEN activity against SHIV in vivo in rhesus as compared to HIV in humans (rhesus and human PBMC paEC95 values of 8.8 and 2.0 nM, respectively). A SHIV inoculum resulting in 10 infections out of 16 rectal challenges of untreated macaques (62.5 % infection per challenge) was selected for the LEN efficacy study. Animals dosed with LEN exhibited a dose proportional increase in plasma Cmax and AUC and a half-life ranging from 17-53 days. Of 11 SHIV-challenged animals, 3 became infected and 8 remained protected as confirmed by plasma PCR, cell-associated proviral DNA assay, and serology. Adjusting for the 4.4-fold LEN potency difference between HIV and SHIV, we computed protection above and below the clinical efficacy target LEN plasma concentration in this model (70 nM). In animals with LEN above this target, LEN demonstrated complete protection and was superior to the untreated group (p=0.012, one-tailed Fisher’s exact test).
Conclusions:
These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the ongoing clinical evaluation of long-acting LEN for HIV PrEP.