Introduction: Pre-exposure prophylaxis (PrEP) cannot meaningfully affect the HIV epidemic in the United States without improving access to PrEP and reducing PrEP disparities among gay, bisexual, and other men who have sex with men (GBM), especially GBM of color. A patient-centered approach to increase PrEP options will offer better PrEP solutions to GBM. We sought to understand how GBM prefer current and emerging PrEP modalities.

Methods: We conducted a national online survey among adult GBM to determine preferences for current and emerging PrEP modalities (daily, on-demand, and monthly oral, subcutaneous and intramuscular injectable, implantable, and rectal douche) and perceived barriers, based on their lived experiences. We determined PrEP modality preferences and associations using multivariable exploded logit regression model.

Results: In total, 723 GBM completed the survey. The largest proportion preferred monthly oral PrEP (n = 207, 28.6%), and more than half preferred some form of oral PrEP. Race was significantly associated with PrEP modality preference, and Black GBM preferred daily oral PrEP most. Side effects, health care visits, administration route, and frequency influenced PrEP preferences. PrEP and HIV knowledge, and HIV risk were associated with PrEP modality choice. GBM considered out-of-pocket cost and side effects as the significant barriers to PrEP care.

Conclusions: Monthly oral PrEP was most preferred with oral options preferred more than other modalities. Black GBM most preferred daily oral PrEP, which could be because of lack of familiarity with the emerging products. Future PrEP provision must include patient-centered prevention plans that include enhanced education and counseling to promote use of newer agents.

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) are potent antiretroviral agents that block HIV replication. A comprehensive lead optimization campaign was undertaken to develop a novel long-acting NRTTI with the potential for extended-duration dosing for HIV prophylaxis. Broad exploration of nucleoside structure-activity relationship (SAR), leveraging ribose core, periphery, and nucleobase modifications, along with systematic progression of compounds of interest through key in vitro and in vivo studies led to the discovery of MK-8527. MK-8527 is a novel deoxyadenosine analog that is phosphorylated intracellularly to its active triphosphate (TP) form, which inhibits reverse transcription. Iron footprinting and primer extension assays demonstrated that MK-8527-TP inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. MK-8527 inhibits viral replication in human peripheral blood mononuclear cells (PBMCs), with a half maximal inhibitory concentration (IC50) of 0.21 nM. The pharmacokinetic (PK) profile of MK-8527 in rats and rhesus monkeys was characterized by low-to-moderate clearance and volume of distribution, with good oral absorption (57% and 100% in rats and monkeys, respectively). Following oral administration of MK-8527 to monkeys, MK-8527-TP exhibited an intracellular half-life of approximately 48 h in PBMCs, significantly longer than the apparent plasma half-life of the parent compound (approximately 7 h). MK-8527 and MK-8527-TP demonstrated favorable in vitro off-target profiles, with IC50 values of ≥95 µM against human DNA polymerases tested, and no off-target activities at 10 μM against a panel of 114 enzyme and receptor binding assays. Collectively, the potent antiretroviral activity and favorable preclinical PK and off-target profiles make MK-8527 an attractive clinical candidate, and it is currently in clinical trials for once-monthly oral HIV-1 pre-exposure prophylaxis.

MK‐8527 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two Phase 1 trials evaluated single (trial A) and multiple (trial B) ascending doses of MK‐8527 in adults without HIV. In trial A, 34 participants were assigned to 1 of 4 panels and randomized to receive single oral doses of MK‐8527 (0.5–200 mg) or placebo after fasting, over 3 dosing periods; 25 mg was assessed after a high‐fat meal. In trial B, 32 participants were randomized to receive 3 once‐weekly (QW) oral doses of MK‐8527 (between 5 and 40 mg) or placebo. Safety and pharmacokinetics (PK) of MK‐8527 and MK‐8527‐triphosphate (TP) were assessed. MK‐8527 was generally well tolerated with no serious adverse events. Plasma exposure of MK‐8527 increased approximately dose‐proportionally, and intracellular exposure of MK‐8527‐TP was slightly less than dose‐proportional over administered doses between 5 and 200 mg. Participants who received MK‐8527 with a meal showed a 41% decrease in C _max with no effect on AUC_0–168, and a 20%, 22%, and 58% increase in intracellular MK‐8527‐TP C _max, C ₁₆₈, and AUC_0–168, respectively. Across QW doses, plasma MK‐8527 median T _max ranged from 0.5 to 1 h, and t _1/2 was 24–81 h; MK‐8527‐TP median T _max ranged from 10 to 24 h on Day 15, and geometric mean apparent t _1/2 was 216–291 h. Accumulation of intracellular MK‐8527‐TP was modest (accumulation ratios [Day 15/Day 1] for C _max and AUC_0–168 ranged from 1.1 to 1.6; C ₁₆₈ from 1.2 to 2.4). Single and multiple QW doses of MK‐8527 were generally well tolerated in adults without HIV. The safety and PK profiles of MK‐8527 support continued clinical development.

Trial Registration: EudraCT numbers: 2016‐004647‐36 (trial A); 2018‐000846‐20 (trial B)

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) are potent antiretroviral agents that block HIV replication. A comprehensive lead optimization campaign was undertaken to develop a novel long-acting NRTTI with the potential for extended-duration dosing for HIV prophylaxis. Broad exploration of nucleoside structure-activity relationship (SAR), leveraging ribose core, periphery, and nucleobase modifications, along with systematic progression of compounds of interest through key in vitro and in vivo studies led to the discovery of MK-8527. MK-8527 is a novel deoxyadenosine analog that is phosphorylated intracellularly to its active triphosphate (TP) form, which inhibits reverse transcription. Iron footprinting and primer extension assays demonstrated that MK-8527-TP inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. MK-8527 inhibits viral replication in human peripheral blood mononuclear cells (PBMCs), with a half maximal inhibitory concentration (IC50) of 0.21 nM. The pharmacokinetic (PK) profile of MK-8527 in rats and rhesus monkeys was characterized by low-to-moderate clearance and volume of distribution, with good oral absorption (57% and 100% in rats and monkeys, respectively). Following oral administration of MK-8527 to monkeys, MK-8527-TP exhibited an intracellular half-life of approximately 48 h in PBMCs, significantly longer than the apparent plasma half-life of the parent compound (approximately 7 h). MK-8527 and MK-8527-TP demonstrated favorable in vitro off-target profiles, with IC50 values of ≥95 µM against human DNA polymerases tested, and no off-target activities at 10 μM against a panel of 114 enzyme and receptor binding assays. Collectively, the potent antiretroviral activity and favorable preclinical PK and off-target profiles make MK-8527 an attractive clinical candidate, and it is currently in clinical trials for once-monthly oral HIV-1 pre-exposure prophylaxis.