Pharmacokinetics, pharmacodynamics, efficacy and drug resistance selection of injectable long-acting lenacapavir pre-exposure prophylaxis (PrEP) against HIV

Oral pre-exposure prophylaxis (PrEP) can substantially reduce HIV infection risk when taken as prescribed. However, many individuals struggle adhering to the daily regimen. Twice-yearly injections of the novel HIV capsid inhibitor lenacapavir (LEN) demonstrated potential in recent PrEP-trials. However, clinical trials may not enable to accurately estimate efficacy or protective concentration benchmarks. Moreover, while LEN can persist for more than a year, stopping PrEP may facilitate de novo drug resistance emergence. We developed an integrated PK-PD model of LEN, incorporating PK-variability to quantify prophylactic efficacy against wild-type virus and transmitted drug resistance and to estimate the probability of drug resistance emergence when LEN-PrEP is stopped. We estimated a 95% preventive and fully preventive plasma concentration of 4.7ng/mL and >5ng/mL, respectively. The latter was reached within 23hours after the first 927mg LEN SC injection and maintained up to 50.5weeks after the last dose in an 'average' individual. Considering PK-variability, concentrations of >5ng/mL were not consistently maintained at all times for lower concentrations, but were surpassed at steady-state. Full protection was achieved at 21, 59, 1108, 142, 538, 107, 1142ng/mL for viruses carrying mutations Q67H, N74D, Q67H+N74D, Q67H+T107N, M66I+T107A, Q67H+K70R, Q67H+K70R+T107N, respectively, and mutant selection windows for N74D, all double mutants and Q67H+K70R+T107N overlapped with LEN SC steady-state concentrations. In an 'average' individual, wild-type infection with subsequent de novo resistance emergence may occur within a period of approx. 206, 170, 138, 160, 106, 191, 235days for Q67H, N74D, Q67H+N74D, Q67H+T107N, M66I+T107A, Q67H+K70R, Q67H+K70R+T107N after stopping LEN-injections, calling for strategies to manage LEN-PrEP discontinuation.