Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques

Abstract

Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded a mean viral load reduction of -2.30 ± 0.53 log₁₀ copies/mL at week 2, compared to baseline. The antiviral potency of the ISL delivered from the nanofluidic implant was higher than oral ISL dosed either daily or weekly. At week 3, viral resistance to ISL emerged in 2 out of 8 macaques, attributable to M184V mutation, supporting the need of combining ISL with other ARV for HIV treatment. The ISL implant produced moderate reactivity in the surrounding tissue, indicating tolerability. Overall, we present the ISL subdermal implant as a promising approach for LA ARV treatment in PLWH.

Keywords: Drug delivery; HIV treatment; Implantable devices; Islatravir; Refillable.

Figure 1.. nISL_t implant and plasma, PBMC and tissue distribution of ISL from subcutaneous nISL_t.

(A) Rendering of nISL_t cross-section depicting solid drug loading via syringes. (B) Picture of open implant showing titanium casing, refill ports: drug loading (l) and venting (v), sintered titanium filter (f) and nanofluidic membrane (m). (C) SEM of array of nanofluidic channels. (D) AFM image of the nanochannels. (E) Plasma ISL and (F) intracellular ISL-TP PBMC concentrations in NHP over 4 weeks. (G) Tissue ISL-TP concentrations upon euthanasia after 1 month of nISL_t implantation. NHP, nonhuman primate, ILN, inguinal lymph nodes. N=8, tissue concentration analyzed using mixed effect analysis, *p < 0.05.

Figure 2.. Plasma viral load in nISL_t (n=8).

(A) Absolute value and (B) change in SHIV RNA from baseline (log₁₀ copies/mL) at weeks 1, 2, 3 and 4 of continuous subcutaneous ISL dosing via nISL_t. Data shows individual NHP.

Figure 3.. Viral load correlation with ISL dose, plasma and ISL-TP PBMC concentration.

Logarithmic viral load reduction from baseline at week 2 correlated with (A) ISL dose (mg/kg/day), (B) average plasma ISL (first 2 weeks), (C) ISL-TP AUC in PBMCs (first 2 weeks). Logarithmic viral load reduction from baseline up to week 3 were fitted using a one phase decay model: rate constant was correlated with (D) ISL dose, (E) average plasma ISL (first 3 weeks), and (F) ISL-TP AUC in PBMCs (first 3 weeks); Span was correlated with (G) ISL dose, (H) average plasma ISL (first 3 weeks), and (I) ISL-TP AUC in PBMCs (first 3 weeks). Data analyzed with Pearson correlation two-tailed P-value, *P<0.05. Each point in the graph represents one animal.

Figure 4.. Histological characterization of inflammatory response to nISL_t in NHPs.

(A) Total histological score of fibrotic capsule (FC) surrounding PBS and nISL_t implant. (B) Placebo-adjusted implant reactivity score (S_pair) of nISL_t FC after a month of subcutaneous ISL delivery. S_pair values 0.0–2.9 (no reaction, green), 3.0–8.9 (slight reaction, yellow), 9.0–15.0 (moderate reaction, orange), and >15.1 (severe reaction, red). (C) Representative Masson Trichrome image of FC showing the membrane side in contact with nISL implant (“M”) and the opposite side (“O”). (D) 40 × magnification of red box outline of M FC. Comparison of (E) FC thickness, (F) percentage of collagen and (G) quantification of blood vessel lumens in M and O of PBS and nISL_t. (H) Fluorescence recovery after photobleaching (FRAP) Fluorescein isothiocyanate (FITC) diffusivity coefficient between PBS, nISL_t, subcutaneous tissue and free FITC groups. Data presented as median ± IQR.

Figure 5.. Drug potency comparison in SHIV-infected NHP.

Drug potency was calculated as vRNA reduction / dose (mg/kg/day). The nISL_t subcutaneous (SQ) implant is compared to daily oral ISL (QD), weekly oral ISL (QW), Cabotegravir (CAB) LA intramuscular (IM) injections (3 injections 4 weeks apart) and, tenofovir alafenamide fumarate (TAF) SQ nanofluidic implant (nTAF_t). Data presented as mean ± SD.