Search Results (11)

Background: Long-acting drug delivery strategies could augment pediatric human immunodeficiency virus (HIV) treatment effectiveness by bypassing population-specific challenges such as adherence. We harnessed pharmacokinetic (PK) modeling to develop a biodegradable, subcutaneous (SQ), reservoir-style implant for HIV treatment in 2–5-year-old children. Methods: Plasma was collected from New Zealand White rabbits over 30 h after a single intravenous (IV) bolus of bictegravir (BIC, 0.75 mg/kg), islatravir (ISL, 5 mg/kg) and/or emtricitabine (FTC, 30 mg/kg) then over a year after subcutaneous insertion of two to three implants eluting these antiretrovirals. Plasma antiretrovirals were quantified by HPLC-MS/MS and population PK models were fit to the IV PK profile to derive a mean unit impulse response (UIR). UIR was used to numerically deconvolve SQ absorption rate from the implant PK profile. SQ dosing rates were translated to pediatric plasma concentrations using published clinical PK parameters. Results: BIC, FTC, and ISL PK profiles were best described by two-compartment models. Each implant achieved quantifiable plasma concentrations for >360 days. Median SQ absorption rates (μg/day) at 3, 6 and 12 months of implantation were 116, 98 and 71 for BIC; 116, 37 and 5 for ISL; and 236, 116 and 24 for FTC. These 6-month dosing rates translated to pediatric plasma concentrations of 24 ng/mL BIC, 0.14 ng/mL ISL, and 0.7 ng/mL FTC. Conclusions: Our novel long-acting delivery platform exhibited antiretroviral SQ dosing rates for ≥6 months that are anticipated to achieve plasma concentrations in children within an efficacious range warranting further development for pediatric HIV treatment. Full article

Background: Islatravir (ISL) is a first-in-class nucleoside reverse transcriptase translocation inhibitor with high potency and long half-life in peripheral blood mononuclear cells (PBMCs). However, treatment and prevention of HIV with oral ISL in humans has been associated with decreases in total lymphocytes, CD4 T-cells, and B-cells in a dose-dependent manner. We investigated in macaques the effects of oral ISL on lymphocytes, monocytes, granulocytes, and gene expression in PBMCs. Methods: Female pig-tailed macaques (n = 5) received an HIV pre-exposure prophylaxis dose of oral ISL adjusted allometrically once a week for 12 weeks. Complete blood counts and B- and T-cells were monitored prior to, during, and after ISL treatment, and changes in counts were evaluated by using a repeated measures model. Changes in gene expression were investigated in PBMCs during treatment and following treatment discontinuation. Results: ISL treatment was associated with declines in lymphocytes (11.9%, p = 0.0015) and monocytes (22.4%, p = 0.0003), but not granulocytes (0.3%, p = 0.9781). Total lymphocytes and monocytes returned to pre-treatment levels 6 weeks after treatment cessation (p = 0.8244 and p = 0.4620, respectively). Lymphocyte subpopulation analyses showed a significant decline in CD8 (−18.4%, p = 0.0364) and CD20 (−35.3%; p = 0.0002) cells but not CD4 cells (−7.4%; p = 0.3470). Gene set enrichment analysis showed negative enrichment (p_adj < 0.05) of gene pathways associated with immune regulation, cell proliferation, and inflammation. Conclusions: ISL treatment resulted in significant reductions in lymphocytes reproducing clinical toxicity. This effect was reversed after treatment cessation as observed in humans. Our results highlight the value of the macaque model to study immune alterations at the preclinical stage. Full article

Long-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) demonstrates superior efficacy to oral PrEP but faces a critical implementation challenge: 47% of patients fail to receive their first injection during the “bridge period” between prescription and initiation. We developed a clinical decision support tool with an external configuration architecture synthesizing evidence from major LAI-PrEP trials (HPTN 083, HPTN 084, PURPOSE) and implementation studies. The tool provides population-specific risk stratification, barrier identification, and evidence-based intervention recommendations from a library of 21 interventions with mechanism diversity scoring to prevent redundant recommendations. We conducted progressive validation on four scales: 1000 (functional), 1,000,000 (large-scale), 10,000,000 (ultra-large-scale) and 21,200,000 patients (UNAIDS PrEP target), with comprehensive unit testing achieving a test pass rate of 100% (18/18 edge cases). Progressive validation demonstrated convergence and increasing precision: 1K (±2.6 pp), 1M (±0.09 pp), 10M (±0.028 pp), and 21.2M (±0.018 pp). At UNAIDS 2025 PrEP target (21.2 million) scale, the tool predicted baseline bridge period success rate of 23.96% (95% CI: 23.94–23.98%), with evidence-based interventions improving success to 43.50% (95% CI: 43.48–43.52%)—an absolute improvement of 19.54 pp (or 81.6% relative improvement), representing 4.1 million additional successful transitions globally. Population disparities were substantial: People who inject drugs (PWID) showed 10.36% baseline success versus 33.11% for men who have sex with men (MSM)—a 22.75 pp gap. Regional disparities were equally significant: Sub-Saharan Africa (serving 62% of global patients) achieved 21.69% baseline versus 29.33% in Europe/Central Asia—a 7.64 pp gap. However, evidence-based interventions disproportionately benefited vulnerable populations. PWID experienced +265% relative improvement, and adolescents experienced +147% relative improvement, demonstrating that systematic implementation support can narrow rather than widen health equity gaps at UNAIDS 2025 PrEP target (21.2 million) scale. The tool demonstrates predictive validity with policy-grade statistical precision. Using published epidemiologic parameters (HIV incidence 2–5% among indicated users, LAI-PrEP efficacy 96%), our model translates the 4.1 million additional successful transitions into approximately 80,000–100,000 prevented HIV infections annually (midpoint: 100,000), corresponding to an estimated USD 40 billion in averted lifetime treatment costs. Full article

Islatravir (ISL) is a novel antiretroviral that inhibits HIV-1 reverse transcriptase translocation. The M184V mutation, known to reduce ISL’s viral susceptibility in vitro, could arise from prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTI) (3TC). This study evaluated the predictive efficacy of ISL and identified potentially active antiretrovirals in combination among treatment-experienced patients in Cameroon, where NRTIs (3TC) have been the backbone of ART for decades now. Although ISL is a long-acting antiretroviral, it will provide other therapeutic options in combination with other reverse transcriptase inhibitors that remain effective. We analyzed 1170 HIV-1 sequences from patients failing first-, second-, and third-line ART using the CIRCB Antiviral Resistance Evaluation (CIRCB-CARE) database. Drug resistance mutations (DRMs) were interpreted using Stanford HIVdb.v9, and covariation patterns between M184V and major NRTI/NNRTI DRMs were assessed. The study population, with a median age of 40 years, showed a high prevalence of resistance to NRTIs (77.4%) and NNRTIs (49.2%). The most frequent NRTI DRMs were M184V/I (83.3%), M41L (25.0%), and T215FY (36.8%), while common NNRTI DRMs included K103NS (53.3%), Y181CIV (27.7%), and G190ASE (22.2%). In first-line ART failure, M184V significantly covaried with K70R, L74I, and M41L for NRTIs and K103N and G190A for NNRTIs. In second-line failure, the covariation with M184V extended to T215Y, M41L, and D67N for NRTIs and G190A, K103N, and K103S for NNRTIs. No significant covariation with M184V was observed in third-line treatment failures. Based on these covariations and on the effect of these mutations on available anti-HIV drugs, TDF (partial efficacy) and Doravirine (fully active) were identified as potentially suitable candidates in combination with ISL among patients failing the first, second, and third lines, and could serve as a valuable therapeutic option in LMICs facing similar treatment challenges. Full article

Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance are currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistant mutations in HIV-1 subtype C for their phenotypic resistance to ISL. Prevalent single and combinations of NRTI-resistant mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI-resistant mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, and K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, and M184V). Combinations of M184V with one or more additional NRTI-resistant mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens, but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens. Full article

Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL’s unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r² = 0.95) and Ritger–Peppas (r² = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp’s PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted. Full article

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0–2.5], 1.9 [1.2–6.3] and 2.8 [2.3–11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229–1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model. Full article

Tenofovir disoproxil fumarate (TDF) and islatravir (ISL, 4′-ethynyl-2-fluoro-2′-deoxyadensine, or MK-8591) are highly potent nucleoside reverse transcriptase inhibitors. Resistance to TDF and ISL is conferred by K65R and M184V, respectively. Furthermore, K65R and M184V increase sensitivity to ISL and TDF, respectively. Therefore, these two nucleoside analogs have opposing resistance profiles and could present a high genetic barrier to resistance. To explore resistance to TDF and ISL in combination, we performed passaging experiments with HIV-1 WT, K65R, or M184V in the presence of ISL and TDF. We identified K65R, M184V, and S68G/N mutations. The mutant most resistant to ISL was S68N/M184V, yet it remained susceptible to TDF. To further confirm our cellular findings, we implemented an endogenous reverse transcriptase assay to verify in vitro potency. To better understand the impact of these resistance mutations in the context of global infection, we determined potency of ISL and TDF against HIV subtypes A, B, C, D, and circulating recombinant forms (CRF) 01_AE and 02_AG with and without resistance mutations. In all isolates studied, we found K65R imparted hypersensitivity to ISL whereas M184V conferred resistance. We demonstrated that the S68G polymorphism can enhance fitness of drug-resistant mutants in some genetic backgrounds. Collectively, the data suggest that the opposing resistance profiles of ISL and TDF suggest that a combination of the two drugs could be a promising drug regimen for the treatment of patients infected with any HIV-1 subtype, including those who have failed 3TC/FTC-based therapies. Full article

The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the HIV-1 replication cycle and is an attractive drug target for developing therapies against MDR HIV-1 infection. Lenacapavir (LEN) is the first-in-class HIV-1 capsid inhibitor approved by the USFDA, EMA, and Health Canada for treating MDR HIV-1 infection. This article highlights the development, pharmaceutical aspects, clinical studies, patent literature, and future directions on LEN-based therapies. The literature for this review was collected from PubMed, authentic websites (USFDA, EMA, Health Canada, Gilead, and NIH), and the free patent database (Espacenet, USPTO, and Patent scope). LEN has been developed by Gilead and is marketed as Sunlenca (tablet and subcutaneous injection). The long-acting and patient-compliant LEN demonstrated a low level of drug-related mutations, is active against MDR HIV-1 infection, and does not reveal cross-resistance to other anti-HIV drugs. LEN is also an excellent drug for patients having difficult or limited access to healthcare facilities. The literature has established additive/synergistic effects of combining LEN with rilpivirine, cabotegravir, islatravir, bictegravir, and tenofovir. HIV-1 infection may be accompanied by opportunistic infections such as tuberculosis (TB). The associated diseases make HIV treatment complex and warrant drug interaction studies (drug–drug, drug–food, and drug–disease interaction). Many inventions on different aspects of LEN have been claimed in patent literature. However, there is a great scope for developing more inventions related to the drug combination of LEN with anti-HIV/anti-TB drugs in a single dosage form, new formulations, and methods of treating HIV and TB co-infection. Additional research may provide more LEN-based treatments with favorable pharmacokinetic parameters for MDR HIV-1 infections and associated opportunistic infections such as TB. Full article

Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens. Full article

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors. Full article