Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates

Abstract

The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP. In rhesus macaques, the islatravir-eluting implants achieved constant concentrations of islatravir in plasma (median 3.14 nM) and islatravir triphosphate in peripheral blood mononuclear cells (median 0.16 picomole per 10 6 cells) for more than 20 months. These drug concentrations were above the established PrEP protection threshold. In two unblinded, placebo-controlled studies, islatravir-eluting implants conferred 100% protection against infection with SHIV SF162P3 after repeated low-dose rectal or vaginal challenge in male or female rhesus macaques, respectively, compared to placebo control groups. The islatravir-eluting implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month study period. This refillable islatravir-eluting implant has potential as a long-acting drug delivery system for HIV PrEP.

Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques

“…Compared with human studies, including the nonerodable ISL implant, we observed lower ISL-TP concentrations at equivalent plasma ISL values [ 15 , 16 , 44 , 45 ]. However, we calculated the ISL-TP:ISL ratios in other macaque studies and found a similar trend of lower ISL-TP in macaques compared to humans [ 14 , 36 , 46 , 47 ]. This could be attributed to differential rates of phosphorylation between species or possibly the sample processing method [ 36 ].…”

“…Recently, a refillable ISL implant was evaluated as PrEP in both vaginal and rectal SHIV challenge models. Although complete protection was achieved, the ISL levels were well above the limit deemed to be safe in humans [ 46 ]. Next-generation PCL implants releasing ISL at levels that are predicted to be safe were assessed as PrEP in the vaginal SHIV challenge model, and the threshold of protection is very close to the human PrEP benchmark of 50 fmol/10 6 PBMCs [ 48 ].…”

A Bilayer Microarray Patch (MAP) for HIV Pre-Exposure Prophylaxis: The Role of MAP Designs and Formulation Composition in Enhancing Long-Acting Drug Delivery

“…Additionally, a monthly dapivirine vaginal ring has been approved for the prevention of HIV in several countries [ 8 ], and other regimens, such as a twice-yearly subcutaneous injection of lenacapavir, have been recently approved [ 9 ]. Long-acting drug delivery technologies such as implants are also under development for HIV PrEP [ 10 , 11 , 12 , 13 ].…”

“…and other regimens, such as a twice-yearly subcutaneous injection of lenacapavir, have been recently approved [9]. Long-acting drug delivery technologies such as implants are also under development for HIV PrEP [10][11][12][13].…”

Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subdermal implant

“…The investigational drug islatravir (ISL, MK-8591 or EFdA) may have considerable potential for LA-PrEP, 1/27 due to its antiviral potency (sub-nanomolar range), long intracellular half-life and high barrier to drug resistance [13,14]. So far, the pharmacokinetics and antiviral potency of ISL have been assessed for daily, weekly and monthly oral dosing, and as a subdermal implant, which may need to be replaced every 3-6 months.…”