islatravir (MK-8591) / Merck (MSD) - LARVOL DELTA

Kinetic Insights into the Enhanced Antiviral Activity of Islatravir against Doravirine Resistance-Associated Substitution Mutations in HIV-1 Reverse Transcriptase. (PubMed, Biochemistry) - "Alongside this, the F227C mutation decreased dATP's binding affinity with both templates. Our data established a kinetic basis for the published cell-based resistance selection assay results, underscoring the significant potential of the ISL/DOR combination therapy in treating HIV-1 infected patients."

Journal • Human Immunodeficiency Virus • Infectious Disease

Population Pharmacokinetic Analysis of Islatravir and the Impact of Intrinsic Factors in Participants with HIV-1 (IDWeek 2025) - No abstract available

Clinical • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Modeling Confirms Islatravir 0.25 mg Administered Daily Has No Adverse Effect on Total Lymphocyte or CD4+ T-cell Counts in People Living with HIV (IDWeek 2025) - No abstract available

Adverse events • Human Immunodeficiency Virus • Infectious Disease • CD4

Evaluation of Relative Bioavailability and Food Effect of a Fixed-Dose Combination Tablet of Islatravir and Lenacapavir (IDWeek 2025) - No abstract available

Human Immunodeficiency Virus • Infectious Disease

Modeling Confirms Islatravir 0.25 mg Administered Daily Has No Adverse Effect on Total Lymphocyte or CD4+ T-cell Counts in People Living with HIV (IDWeek 2025) - No abstract available

Adverse events • Human Immunodeficiency Virus • Infectious Disease • CD4

A double-blind, active-controlled, phase 2b study to evaluate the efficacy and safety of ulonivirine in combination with islatravir in virologically suppressed adults living with HIV-1 (IAS-HIV 2025) - P2 | "This double-blind, phase 2b trial evaluated the efficacy and safety of ISL+ULO QW in virologically suppressed adults living with HIV-1 (MK-8591-013; NCT04564547). Participants without known NNRTI resistance who were virologically suppressed for =6 months on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), were randomized (1:1:1:1) to receive ISL 20 mg plus ULO (100, 200, or 400 mg) QW, or remain on BIC/FTC/TAF once-daily. ISL+ULO showed efficacy in maintaining viral suppression through Week 24. Consistent with previous studies of ISL, decreases in TLC and CD4+ counts were observed with ISL 20 mg + ULO QW followed by a trend to recovery after discontinuation. Development of ISL 2 mg + ULO QW is ongoing."

Clinical • Combination therapy • P2b data • Human Immunodeficiency Virus • Infectious Disease • CD4

Kinetic investigation of resistance to Islatravir conferred by mutations in HIV-1 reverse transcriptase (ACS-Fall 2025) - "The M184V mutation, commonly associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) such as lamivudine and emtricitabine, and the M184V/A114S mutations, both located within the hydrophobic pocket, were shown to reduce Islatravir susceptibility in cell-based viral resistance selection assays. These reductions were primarily attributable to corresponding decreases in EFdA-TP incorporation rate constants of 18-fold and 105-fold, respectively. These results suggest that, unlike FDA-approved NRTIs, the clinical efficacy of Islatravir, may not be substantially compromised by the M184V mutation alone but could be significantly reduced by the M184V/A114S mutations."

Human Immunodeficiency Virus • Infectious Disease

A Study of Islatravir (ISL) and Ulonivirine (ULO) Once Weekly (QW) in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8591B-060) (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

Phase 2 once-weekly dose optimization for ulonivirine in combination with Islatravir 2 mg (IAS-HIV 2025) - P3 | "ULO data from Phase 1 and the previous Phase 2 studies were used to predict a safe and efficacious Phase 2 ULO dose to be combined with ISL 2 mg QW, which is the lower ISL dose used in ongoing clinical trials in combination with oral lenacapavir [NCT06630286; NCT06630299] and is expected to be safe and efficacious. Reduction in viral load (measured as log10 plasma HIV-1 RNA copies/mL]) and ULO pharmacokinetics (PK) from a Phase 1b study where treatment-naïve participants living with HIV-1 received single oral doses of ULO (40, 80, or 600 mg) were used to establish a wild-type (WT) efficacy PK threshold. Dose selection factors weighed PK coverage and virological efficacy. Weekly 200 mg ULO in combination with ISL 2 mg was selected for Phase 2 for continued clinical development."

Combination therapy • P2 data • Human Immunodeficiency Virus • Infectious Disease

Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016) (clinicaltrials.gov) - P2 | N=242 | Completed | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P2a ➔ P2

Phase classification • Human Immunodeficiency Virus • Infectious Disease

ISLEND-2: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Active, not recruiting | Sponsor: Gilead Sciences | Trial primary completion date: Jun 2027 ➔ Apr 2026

Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease

An open-label Phase 1 study to evaluate drug interactions between multiple weekly doses of ulonivirine (MK-8507) and single doses of islatravir in adults without HIV (IAS-HIV 2025) - "No clinically meaningful DDI was observed when ULO and ISL were co-administered."

Clinical • P1 data • Human Immunodeficiency Virus • Infectious Disease • CD4

Patient-Reported Outcomes From People With HIV-1 Receiving Once-Weekly Oral Islatravir in Combination With Lenacapavir: Phase 2 Week 48 Results (EACS 2025) - No abstract available

Clinical • Combination therapy • P2 data • Patient reported outcomes • Human Immunodeficiency Virus • Infectious Disease

A double-blind, placebo-controlled, Phase 1 study to evaluate extended multiple dosing of ulonivirine (MK-8507) in adults without HIV (IAS-HIV 2025) - "BACKGROUND: Ulonivirine (ULO, MK-8507), an NNRTI with a favorable safety profile and pharmacokinetic properties that support once-weekly (QW) dosing, is in development in combination with islatravir (ISL) for the treatment of HIV-1. ULO 200 mg QW demonstrated an AE profile similar to that of placebo and did not decrease total lymphocyte or CD4+ T-cell counts to a clinically significant degree in adults without HIV."

Clinical • P1 data • Human Immunodeficiency Virus • Infectious Disease • CD4

Effectiveness of islatravir post-exposure prophylaxis after intravenous challenge with simian immunodeficiency virus in rhesus macaques. (PubMed, J Int AIDS Soc) - "Two weekly oral doses of ISL 3.9 mg/kg, administered 24 hours post IV SIV exposure, prevents infection of rhesus macaques. These results support further investigation of a long-acting oral NRTTI for PEP."

Journal • Infectious Disease • IGFBP7

ISLEND-1: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=609 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

ISLEND-2: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

A Study of Islatravir (ISL) and Ulonivirine (ULO) Once Weekly (QW) in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8591B-060) (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease

Safety, Tolerability, and Pharmacokinetics of Once-Monthly Oral Islatravir: a Phase 2a Study in Participants at Low Risk for Acquiring HIV-1. (PubMed, J Infect Dis) - P2a | "Oral islatravir 60 mg and 120 mg once monthly demonstrated similar tolerability and AE profiles to placebo, except for dose-dependent decreases in total lymphocyte counts. A partial recovery in total lymphocyte counts was observed. In most participants, both islatravir doses achieved PBMC islatravir-triphosphate exposure levels projected to be effective for once-monthly oral HIV-1 pre-exposure prophylaxis."

Journal • P2a data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Exploratory Substudy of a Phase 2 Trial to Evaluate the Pharmacokinetic Effect of Once-Monthly Islatravir on Long-Acting Reversible Contraceptives. (PubMed, J Acquir Immune Defic Syndr) - P2a | "Coadministration with once-monthly islatravir does not appear to affect exposure to LARCs in people at low risk of HIV-1 infection. Due to the exploratory nature of this substudy, prospective studies are needed to verify these findings."

Journal • P2 data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • Long-acting Reversible Contraceptives

Kinetic investigation of resistance to Islatravir conferred by mutations in HIV-1 reverse transcriptase. (PubMed, J Mol Biol) - "The M184V mutation, commonly associated with resistance to NRTIs such as lamivudine and emtricitabine, and the M184V/A114S mutations, both located within the hydrophobic pocket, were shown to reduce Islatravir susceptibility in cell-based viral resistance selection assays. These reductions were primarily attributable to corresponding decreases in EFdA-TP incorporation rate constants of 18-fold and 105-fold, respectively. These results suggest that, unlike FDA-approved NRTIs, the clinical efficacy of Islatravir, may not be substantially compromised by the M184V mutation alone but will be significantly reduced by the M184V/A114S mutations."

Journal • Human Immunodeficiency Virus • Infectious Disease

A Study of Islatravir (ISL) and Ulonivirine (ULO) Once Weekly (QW) in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8591B-060) (clinicaltrials.gov) - P2 | N=150 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P2 trial • Human Immunodeficiency Virus • Infectious Disease

A Biodegradable Implant Releasing Low-Dose Islatravir Protects Macaques From Rectal SHIV Infection (CROI 2025) - "The ISL-TP levels in PBMCs remained below the clinical toxicity threshold and provided complete protection to macaques against rectal SHIV infection. Our study supports the development of a PCL implant that can deliver safe and effective ISL concentrations for ultra-long-acting HIV prevention."

Human Immunodeficiency Virus • Infectious Disease

Dose-Ranging Pharmacokinetics and Efficacy of a 90-Day Multipurpose IVR Delivering Islatravir (CROI 2025) - "Systemic ISL concentration remained below the clinical toxicity threshold and prevented SHIV acquisition in macaques. These results warrant further development of the 3D printed IVR as a three-month MPT for prevention of HIV and unintended pregnancy using an already optimized hormones dose."

Clinical • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • Vaginitis

Resistance Analysis of Weekly Islatravir Plus Lenacapavir in People With HIV at 48 Weeks (CROI 2025) - P2 | "Methods Participants received either ISL (2 mg QW from Day [D] 1) + LEN (600 mg D1 and D2; then 300 mg QW) orally (n=52) or remained on once-daily oral bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; n=52). No participants with VF developed study drug resistance. These findings support the ongoing evaluation of ISL+LEN as an oral, QW treatment for HIV-1 infection."

Human Immunodeficiency Virus • Infectious Disease