Pharmacokinetics, Pharmacodynamics, Efficacy and Drug Resistance Selection of Injectable Long‐Acting Lenacapavir Pre‐Exposure Prophylaxis ( <scp>PrEP</scp> ) Against <scp>HIV</scp>

ABSTRACT 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 us 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 4.7 ng/mL and 5 ng/mL, respectively. The latter was reached within 23 h after the first 927 mg LEN SC injection and maintained up to 50.5 weeks after the last dose in an ‘average’ individual. Considering PK‐variability, concentrations of 5 ng/mL were not consistently maintained at all times especially considering lower concentration ranges, but were surpassed at steady‐state. Full protection was achieved at 21, 59, 1108, 142, 538, 107, 1142 ng/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 206, 170, 138, 160, 106, 191, 235 days 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.