Islatravir (MK-8591): A Comprehensive Analysis of a First-in-Class NRTTI from Clinical Promise to Regulatory Relaunch

I. Executive Summary

Islatravir (MK-8591, DB15653) is a first-in-class, investigational small molecule antiretroviral agent developed by Merck (known as MSD outside the U.S. and Canada) for the treatment and prevention of Human Immunodeficiency Virus Type 1 (HIV-1) infection.[1] It is classified as a Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI), a novel class of drug that distinguishes it from all currently approved antiretrovirals. The development of Islatravir represents a significant narrative in modern pharmacology, characterized by immense initial promise, a critical safety-related setback, and a subsequent strategic realignment. The drug's unique mechanism of action and exceptionally long intracellular half-life positioned it as a potential cornerstone for future long-acting HIV treatment and prevention regimens. However, its development was fundamentally reshaped by the discovery of a dose-dependent safety signal—decreases in lymphocyte and CD4+ T-cell counts—which compelled a strategic pivot away from ambitious long-acting applications toward a more conservative once-daily oral treatment regimen.

Islatravir exerts its potent antiviral activity through a multi-pronged mechanism that includes both immediate and delayed termination of viral DNA synthesis, a process distinct from conventional nucleoside reverse transcriptase inhibitors (NRTIs).[4] This unique mechanism confers a high barrier to the development of drug resistance.[7] In extensive clinical trials, Islatravir, in a fixed-dose combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR/ISL), demonstrated non-inferior efficacy in maintaining viral suppression compared to standard-of-care three-drug regimens.[9]

The trajectory of Islatravir's development was significantly altered in December 2021, when the U.S. Food and Drug Administration (FDA) placed full and partial clinical holds on its investigational new drug applications. The decision was based on observed dose-dependent decreases in total lymphocyte and CD4+ T-cell counts in trial participants.[11] This led to the discontinuation of programs evaluating Islatravir for pre-exposure prophylaxis (PrEP), including once-monthly oral and once-yearly implantable formulations.[14] Following an extensive investigation, Merck initiated a new Phase 3 program in 2022, focusing on a lower, once-daily oral dose of Islatravir (0.25 mg) in combination with doravirine for HIV-1 treatment.[15]

This relaunched program yielded positive results, forming the basis of a New Drug Application (NDA) for the DOR/ISL (100 mg/0.25 mg) combination, which was accepted for review by the FDA in July 2025. The agency has set a Prescription Drug User Fee Act (PDUFA) target action date of April 28, 2026.[17] If approved, DOR/ISL would be the first once-daily, two-drug, complete regimen for HIV-1 treatment that does not contain an integrase strand transfer inhibitor (InSTI). This positions Islatravir to fill a specific clinical niche for patients who may benefit from an InSTI-sparing regimen, contingent upon final regulatory approval and continued validation of its long-term safety profile at the lower dose.

II. Islatravir: Profile of a Novel Nucleoside Reverse Transcriptase Translocation Inhibitor

2.1. Chemical Identity and Molecular Structure

Islatravir is identified by several names, including its generic name, the chemical name 4'-ethynyl-2-fluoro-2'-deoxyadenosine, and the developmental codes EFdA and MK-8591.[1] It is registered under DrugBank Accession Number DB15653 and CAS Number 865363-93-5.[19]

As a small molecule, Islatravir is classified pharmacologically as a deoxyadenosine analog and structurally as a purine nucleoside.[7] Its chemical formula is

C12​H12​FN5​O3​, with an average molecular weight of 293.258 Da.[19] Predicted physicochemical properties indicate a water solubility of 0.744 mg/mL and a logP of -0.34, suggesting a degree of hydrophilicity.[19] The synthesis of 4'-ethynyl purine derivatives with anti-HIV activity was first reported in the early 2000s, with the specific synthesis and potent activity of the compound now known as Islatravir being detailed in 2006. Its development was the result of a deliberate, structure-guided design process involving the HIV-1 reverse transcriptase (RT) enzyme complexed with DNA.[21]

2.2. Unique Mechanism of Action as an NRTTI

Islatravir's primary distinction is its novel mechanism of action as a Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI). It suppresses HIV-1 replication through multiple, synergistic mechanisms that differ fundamentally from conventional NRTIs.[4] After being converted to its active triphosphate form within the host cell, Islatravir is incorporated into the growing viral DNA chain by the HIV-1 RT enzyme. Its inhibitory actions then proceed via two main pathways:

1. Translocation Inhibition and Immediate Chain Termination: The core of its mechanism lies in translocation inhibition. After incorporation, the unique 4'-ethynyl group on the Islatravir molecule sterically hinders the RT enzyme, physically preventing it from sliding, or "translocating," along the DNA template to the next position. This blockade prevents the enzyme's nucleotide-binding site from opening to accept the next incoming nucleotide, resulting in an immediate termination of DNA chain elongation.[5]
2. Delayed Chain Termination: In addition to the physical blockade, the presence of Islatravir in the viral DNA chain induces conformational changes in the DNA structure. These structural alterations also prevent the efficient incorporation of subsequent nucleotides, leading to what is described as delayed chain termination.[5]

A critical structural feature underpins this unique mechanism: Islatravir retains a 3'-hydroxyl (3'OH) group on its ribose sugar ring.[21] All approved NRTIs function as obligate chain terminators precisely because they lack this 3'OH group, which is chemically necessary for the formation of the phosphodiester bond that extends the DNA chain. Islatravir's ability to terminate elongation despite possessing a 3'OH group represents a paradigm shift in NRTI design. It moves beyond simple chemical chain termination to a more complex, physical "jamming" of the RT replication machinery, providing a more robust blockade of viral replication.

2.3. Differentiated Resistance Profile

Islatravir's multi-faceted mechanism of action translates to a favorable resistance profile, characterized by a high genetic barrier to the development of clinically significant resistance.[7] In vitro resistance selection studies demonstrated that the most frequently observed mutations were M184I and M184V, which are commonly associated with resistance to other NRTIs like lamivudine and emtricitabine. However, these mutations conferred only a modest reduction in Islatravir susceptibility (defined as >2-fold change).[7]

Further studies revealed a differentiated resistance pathway involving the emergent A114S substitution in the RT enzyme. While this mutation, in combination with others, could further reduce susceptibility to Islatravir, it had a notable and strategically important secondary effect: it increased the virus's susceptibility to currently approved NRTIs.[7] This phenomenon is a direct consequence of Islatravir's distinct mechanism of action compared to traditional NRTIs. The potential for a resistance mutation to one drug to re-sensitize the virus to another is highly unusual and clinically valuable. It suggests that Islatravir could play a unique role in future treatment sequencing and salvage regimens for patients with multi-drug resistant HIV. In clinical trials, the development of resistance to Islatravir has been rare and typically observed in the context of documented nonadherence to the treatment regimen.[24]

III. Pharmacokinetic and Pharmacodynamic Profile: The Foundation for Long-Acting Potential

3.1. Absorption, Metabolism, and Elimination

Following oral administration, Islatravir is rapidly and well absorbed, with peak plasma concentrations (Tmax​) achieved within 30 to 60 minutes.[4] The parent drug circulates in the plasma and is readily taken up by target cells, such as CD4+ T lymphocytes and peripheral blood mononuclear cells (PBMCs). Inside the cell, a critical activation process occurs: endogenous cellular kinases, including deoxycytidine kinase, phosphorylate Islatravir into its mono-, di-, and ultimately its pharmacologically active triphosphate form, islatravir-triphosphate (ISL-TP).[4]

The primary metabolic pathway for Islatravir is not hepatic but rather involves deamination by the enzyme adenosine deaminase (ADA), which is widely distributed in tissues. This process converts Islatravir to its major circulating metabolite, 4′-ethynyl-2-fluoro-2′deoxyinosine (M4), which is inactive and cannot be phosphorylated.[4] Importantly, Islatravir is not a significant substrate, inhibitor, or inducer of cytochrome P450 (CYP) enzymes, which minimizes its potential for many common drug-drug interactions.[8] This "clean" interaction profile is a significant clinical advantage, particularly for people living with HIV who may require multiple medications for comorbidities. Elimination of Islatravir and its M4 metabolite occurs primarily through renal excretion.[4]

3.2. The Defining Feature: Extended Intracellular Half-Life

The pharmacokinetic profile of Islatravir is defined by a stark contrast between its plasma and intracellular behavior. Plasma concentrations of the parent drug decline in a biphasic manner, featuring an initial rapid phase followed by a slow terminal phase.[4] The slow phase is thought to result from the gradual redistribution of Islatravir from the intracellular compartment back into the plasma as ISL-TP is slowly dephosphorylated.

The plasma half-life (t1/2​) of Islatravir is approximately 73 hours, or about 3 days.[4] However, the defining characteristic of the drug is the exceptionally long intracellular half-life of its active form, ISL-TP, within PBMCs. Robust measurements from studies with extended sampling periods place the intracellular

t1/2​ of ISL-TP at approximately 195 to 209 hours, which translates to 8.1 to 8.7 days.[4] This prolonged intracellular residence time leads to a significant accumulation of ISL-TP (approximately 10-fold) with repeated dosing, allowing therapeutic concentrations to be maintained for extended periods well after the parent drug has declined in the plasma.[25]

This unique pharmacokinetic property is a "double-edged sword." It was the very foundation for Islatravir's potential as a long-acting agent suitable for weekly or monthly oral dosing, or even yearly implants. The slow clearance from target cells is precisely what enables sustained antiviral activity. However, this same property—the persistent high-level accumulation of ISL-TP within lymphocytes—is also the direct pharmacological driver of the dose-dependent toxicity (lymphopenia) that ultimately curtailed those ambitious long-acting programs. The drug's greatest strength proved to be inextricably linked to its greatest liability.

3.3. Dose Proportionality and Tissue Distribution

Islatravir exhibits predictable, dose-proportional pharmacokinetics across a very wide range of oral doses, from 0.25 mg to 400 mg.[4] This linearity simplifies dose selection and modeling. Furthermore, the drug demonstrates broad tissue distribution, achieving potentially therapeutic concentrations in key anatomical compartments relevant to HIV transmission and persistence, including rectal and vaginal tissues.[8] This characteristic provided strong support for its initial investigation as a PrEP agent.

IV. Clinical Efficacy in HIV-1 Treatment Regimens

4.1. Combination Therapy with Doravirine (DOR/ISL)

The primary treatment strategy for Islatravir has been its co-formulation with doravirine, an approved NNRTI, to create a potent, two-drug, once-daily regimen.[6] Early Phase 2b trials, such as NCT03272347, successfully established the efficacy and safety of this combination, demonstrating high rates of viral suppression and leading to the selection of the 0.75 mg dose of Islatravir for initial Phase 3 development.[27]

The initial wave of pivotal Phase 3 trials, known as the ILLUMINATE program, evaluated the DOR/ISL (100 mg/0.75 mg) combination in both treatment-naive and virologically suppressed "switch" populations. These trials successfully demonstrated that the two-drug regimen was non-inferior to standard-of-care three-drug regimens, including Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide).[11] However, these trials were ultimately halted due to the emergence of the lymphocyte safety signal associated with the 0.75 mg dose.[11]

Following a program-wide review and consultation with the FDA, Merck relaunched its Phase 3 program with a lower 0.25 mg dose of Islatravir. The subsequent pivotal trials, MK-8591A-051 and MK-8591A-052, produced positive results. At Week 48, the DOR/ISL (100 mg/0.25 mg) regimen was proven to be non-inferior to both baseline antiretroviral therapy and Biktarvy in maintaining viral suppression (defined as HIV-1 RNA <50 copies/mL).[9] In trial MK-8591A-052, 91.5% of participants on DOR/ISL maintained viral suppression, compared to 94.2% on Biktarvy.[10] In trial MK-8591A-051, 95.6% on DOR/ISL maintained suppression compared to 91.9% on their baseline ART.[9] These successful outcomes formed the basis for the regulatory submission to the FDA. The consistent demonstration of non-inferiority, rather than superiority, positions DOR/ISL not as a replacement for the most potent first-line therapies, but as a crucial alternative. Its clinical value lies in being a highly effective regimen that is fundamentally different, offering an InSTI-sparing option for patients where that class of drugs may not be ideal due to concerns about weight gain, neuropsychiatric side effects, or other long-term tolerability issues.

Table 1: Overview of Key Phase 3 Clinical Trials for Doravirine/Islatravir (DOR/ISL) in HIV-1 Treatment
Trial ID (NCT Number)
NCT04223778
NCT04223791
NCT04233879
NCT05631093
NCT05630755

4.2. Investigational Weekly Regimens

The long half-life of Islatravir made it an ideal candidate for less-frequent dosing regimens. A Phase 2 study (NCT05052996) was initiated to evaluate a once-weekly oral regimen combining Islatravir with Gilead's long-acting capsid inhibitor, lenacapavir. Early results were highly promising, with 94% of participants who switched to the weekly regimen maintaining viral suppression at 24 weeks, a rate comparable to those who remained on daily Biktarvy.[11] This program was also temporarily paused during the clinical hold but was restarted with a lower weekly Islatravir dose (2 mg) and is now advancing to Phase 3 trials, reflecting the strong clinical desire for regimens that can alleviate the burden of daily pill-taking.[16]

In contrast, a separate program evaluating a once-weekly combination of Islatravir with an investigational NNRTI, ulonivirine (MK-8507), in the IMAGINE-DR trial was stopped early. It was in this trial that the lymphocyte decline was first clearly identified and linked to the combination treatment, leading to the discontinuation of ulonivirine's development.[2]

4.3. Efficacy in Heavily Treatment-Experienced (HTE) Populations

The potency of Islatravir was also tested in a difficult-to-treat population. The ILLUMINATE HTE study (MK-8591A-019) evaluated the addition of DOR/ISL to a failing antiretroviral regimen in heavily treatment-experienced individuals. Results showed that this combination yielded the greatest virologic response compared to placebo, demonstrating its robust antiviral activity even in the presence of extensive pre-existing resistance.[11] Although enrollment was stopped prematurely due to the broader safety concerns, the data provided valuable proof-of-concept for the regimen's efficacy in a high-need population.

V. The Critical Safety Signal: Dose-Dependent Lymphocyte Declines

5.1. Characterization of the Adverse Event

The pivotal safety concern that reshaped the Islatravir development program was the observation of dose-dependent decreases from baseline in mean total lymphocyte and CD4+ T-cell counts.[32] These findings first emerged from trials of weekly combination regimens, such as IMAGINE-DR, and were subsequently confirmed through a comprehensive review across all company-sponsored trials.[2] The hematological effect was broad, impacting total lymphocytes, CD4+ T-cells, CD8+ T-cells, and B-cells.[23]

5.2. The Dose-Response Relationship

A clear dose-response relationship was established for this adverse event:

• High-Dose Regimens: The most pronounced declines were observed in studies using higher, less-frequent doses. The once-monthly oral PrEP regimens (60 mg and 120 mg) resulted in mean total lymphocyte count reductions of approximately 21% to 36%.[34] A weekly 20 mg treatment dose led to declines of up to 30%.[33]
• Mid-Dose Regimens: The once-daily 0.75 mg dose used in the initial Phase 3 treatment trials produced more modest but still statistically significant declines of 5-10%, which appeared to stabilize after 48 weeks of treatment.[33]
• Low-Dose Regimens: Crucially, data from Phase 2b dose-ranging studies and subsequent analyses showed that a lower once-daily dose of 0.25 mg did not have a negative effect on lymphocyte or CD4 counts while retaining comparable antiviral efficacy to the higher doses.[15]

Importantly, the lymphocyte count decreases were observed to be generally reversible, with counts returning toward baseline levels after Islatravir was discontinued.[15]

5.3. Clinical Significance and Infection Risk

A critical element of the safety investigation was to determine the clinical relevance of these laboratory findings. A drop in CD4 cells is a classic and serious warning sign in HIV management, historically linked to disease progression and an increased risk of opportunistic infections. However, in the case of Islatravir, this link was not observed. Comprehensive analyses of adverse events across the clinical trials, presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2023, revealed that despite the laboratory-observed decreases in lymphocyte counts, there was no associated increase in the rate of clinical infections (including COVID-19) in participants receiving Islatravir compared to those in control arms.[33]

This disconnect between the surrogate marker (lymphocyte count) and the clinical outcome (infection rate) is a crucial nuance. The mechanism of lymphocyte reduction with Islatravir is believed to be related to the inhibition of cellular proliferation due to the high intracellular accumulation of ISL-TP, which is fundamentally different from the immunodestructive depletion of T-cells caused by uncontrolled HIV replication. Consequently, the clinical consequences were not the same. In the trials, CD4 counts rarely fell below the clinically significant threshold of 200 cells/mm³, and the effect was largely deemed a subclinical laboratory finding.[33] This distinction was likely the key factor that allowed for a path forward for the treatment indication, while the risk was considered too great for a prevention indication in healthy individuals.

5.4. The Path to Mitigation: Rationale for the Lower Dose

In response to the safety signal, Merck conducted extensive pharmacokinetic and pharmacodynamic (PK/PD) modeling. These analyses predicted that the 0.25 mg once-daily dose would achieve intracellular ISL-TP concentrations sufficient for robust antiviral efficacy while remaining below the threshold associated with significant lymphocyte effects.[15] The modeling projected that this lower dose would allow for CD4+ T-cell increases over 48 weeks that were similar to those seen with comparator regimens, effectively mitigating the safety concern.[31] This data-driven rationale formed the scientific basis for the program's relaunch.

VI. A Tumultuous Regulatory Journey: Clinical Holds and Program Realignment

6.1. The December 2021 FDA Clinical Hold

On December 13, 2021, Merck announced that the U.S. FDA had placed clinical holds on the Investigational New Drug (IND) applications for Islatravir, citing the observed decreases in total lymphocyte and CD4+ T-cell counts.[11] The regulatory action was bifurcated, reflecting a nuanced risk-benefit assessment for different indications:

• Full Clinical Hold: This was applied to all programs for HIV prevention, including the oral and implantable formulations for PrEP, as well as the injectable formulation for treatment and prophylaxis. A full hold meant that all dosing in ongoing trials was stopped, and no new studies could be initiated.[12]
• Partial Clinical Hold: This was applied to the seven ongoing trials of the once-daily DOR/ISL combination for HIV treatment. This allowed participants already on the study drug to continue receiving it with enhanced safety monitoring, but it prohibited the enrollment of any new participants.[12]

6.2. Discontinuation of the PrEP Program

In September 2022, Merck announced the formal discontinuation of the development of once-monthly oral Islatravir and the subdermal implant for PrEP.[1] This strategic decision was based on a careful risk-benefit analysis. For a prevention indication in a healthy population, the tolerance for any significant safety risk is extremely low. It was determined that a lower dose of Islatravir might not provide the robust, long-lasting protection required for a monthly or yearly PrEP regimen, while the higher doses carried an unacceptable risk of immune cell modulation.[14] Final data from the halted IMPOWER PrEP trials confirmed both the lymphocyte declines and the high efficacy of the drug while it was being taken, as no participants acquired HIV during the blinded phase of the study.[35]

6.3. The Strategic Relaunch for HIV Treatment

Concurrent with the discontinuation of the PrEP program, Merck announced on September 20, 2022, that it would, in consultation with the FDA, initiate a new Phase 3 clinical program for HIV treatment. This relaunched program would evaluate the DOR/ISL combination using the lower, 0.25 mg dose of Islatravir.[11] The partial clinical hold remained in effect for any studies using higher doses of the drug.[16] The once-weekly oral program in combination with lenacapavir was also re-initiated with a lower Islatravir dose.[16] This careful, science-driven approach allowed Merck to salvage a promising treatment asset from what could have been a complete program termination.

6.4. Current Regulatory Status

The relaunched Phase 3 program with the 0.25 mg dose was successful, leading to a major regulatory milestone. In July 2025, Merck announced that the FDA had accepted its New Drug Application (NDA) for the fixed-dose combination of doravirine/islatravir (100 mg/0.25 mg) for the treatment of virologically suppressed adults with HIV-1.[17] The FDA has set a PDUFA target action date of

April 28, 2026, by which it is expected to complete its review and make a decision on approval.[17]

In parallel, Merck has engaged with the European Medicines Agency (EMA). In July 2024, the EMA accepted a modification to an agreed paediatric investigation plan (PIP) for the doravirine/islatravir combination, indicating ongoing regulatory processes in Europe.[39]

VII. Formulations and Dosing: From Daily Pills to Investigational Implants

The development of Islatravir was marked by an ambitious exploration of diverse formulations, leveraging its unique pharmacokinetic profile to target a wide range of clinical needs. This demonstrated the immense initial confidence Merck had in the drug's potential to serve as a "pipeline in a molecule."

7.1. Oral Formulations

• Once-Daily: The primary formulation for HIV treatment has been an oral, fixed-dose combination tablet with doravirine. Clinical trials have evaluated Islatravir doses of 0.25 mg, 0.75 mg, and 2.25 mg, with the 0.25 mg dose ultimately being selected for the NDA submission following the identification of the dose-dependent safety signal.[6]
• Once-Weekly: To further reduce dosing burden, once-weekly oral regimens were investigated for treatment. This included a combination with lenacapavir (using a 2 mg Islatravir dose) and a discontinued combination with ulonivirine.[4]
• Once-Monthly: For PrEP, a once-monthly oral regimen was studied at high doses of 60 mg and 120 mg. This program aimed to provide a highly convenient alternative to daily PrEP but was discontinued due to the lymphocyte safety concerns.[11]

7.2. Long-Acting Implantable Technology

Perhaps the most innovative formulation explored was a subdermal implant for PrEP. This was a small, polymer-based device designed to be placed under the skin of the upper arm, where it would continuously release Islatravir for at least one year.[1] Phase 1 results presented at CROI 2021 were highly promising, showing that implants containing 48 mg to 56 mg of Islatravir successfully achieved and maintained intracellular ISL-TP concentrations above the predefined pharmacokinetic threshold for antiviral efficacy for the entire 12-week study period.[42]

Despite this successful proof-of-concept for the delivery technology, the development of the implant was halted as part of the broader discontinuation of the PrEP program.[14] The failure of this long-acting formulation, driven by the pharmacology of the drug itself, underscores a critical challenge in the field: the biological consequences of sustained, high-level drug exposure within specific cell compartments are not yet fully understood and require novel approaches for preclinical safety assessment.

VIII. Conclusion and Expert Outlook

8.1. Synthesis of Findings: A Story of Promise, Peril, and Pivot

The developmental saga of Islatravir is a seminal chapter in modern antiretroviral therapy. It is the story of a drug born from immense promise, defined by a novel mechanism of action, ultrapotent activity, and a pharmacokinetic profile seemingly perfect for the next generation of long-acting HIV treatment and prevention. This promise encountered significant peril with the discovery of a dose-dependent effect on lymphocyte counts—a safety signal directly linked to the very intracellular accumulation that made it so attractive. The subsequent response was a masterful strategic pivot: a shift away from the high-dose, long-acting ambitions for prevention to a focused, data-driven relaunch of a lower-dose daily regimen for treatment. Islatravir's journey is a powerful illustration of the delicate balance between efficacy and safety, the different standards of risk tolerance for treatment versus prevention, and the resilience of a scientifically-grounded development program.

8.2. Future Role in HIV Therapy

Contingent on FDA approval in 2026, the fixed-dose combination of doravirine/islatravir (100 mg/0.25 mg) is poised to occupy a specific and important niche in the HIV treatment landscape. As the first potential once-daily, two-drug, single-tablet regimen that is free of an integrase inhibitor, it will offer a valuable alternative to the current standard of care.[12] This will be particularly relevant for patients with pre-existing resistance to InSTIs, or for whom there are clinical concerns about the long-term side effects of the InSTI class, such as weight gain or potential neuropsychiatric effects. While it is not expected to be superior in efficacy to leading InSTI-based regimens, its differentiated profile will be its key clinical advantage in a competitive market.

Furthermore, the continued development of a once-weekly oral combination of Islatravir and lenacapavir holds the potential for a paradigm shift in HIV management. If successful, this regimen would be a major innovation, significantly reducing treatment burden and potentially improving long-term adherence and quality of life for people living with HIV.

8.3. Lessons for Antiretroviral Development

The Islatravir program offers several profound lessons for the future of drug development. First, it highlights the critical importance of the therapeutic index—the window between the dose required for efficacy and the dose that causes toxicity. For drugs with long intracellular half-lives and a tendency to accumulate, this window may be narrower than anticipated. Second, it provides a clear example of indication-specific risk-benefit assessment, where the same safety signal can be deemed acceptable for treating a life-threatening disease but unacceptable for preventing it in a healthy population. Finally, it serves as a cautionary tale about the challenges of long-acting intracellular agents, underscoring the need for more sophisticated preclinical models and safety endpoints to predict and monitor potential long-term cellular effects. The story of Islatravir, with its near-failure and strategic rebirth, will undoubtedly inform and influence the development of novel antiretroviral therapies for years to come.

Works cited

1. Islatravir - Wikipedia, accessed September 5, 2025, https://en.wikipedia.org/wiki/Islatravir
2. Merck Provides Update on Phase 2 Clinical Trial of Once-Weekly Investigational Combination of MK-8507 and Islatravir for the Treatment of People Living with HIV-1, accessed September 5, 2025, https://www.merck.com/news/merck-provides-update-on-phase-2-clinical-trial-of-once-weekly-investigational-combination-of-mk-8507-and-islatravir-for-the-treatment-of-people-living-with-hiv-1/
3. Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial - PubMed, accessed September 5, 2025, https://pubmed.ncbi.nlm.nih.gov/34608329/
4. Intracellular islatravir-triphosphate half-life supports extended dosing intervals | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed September 5, 2025, https://journals.asm.org/doi/10.1128/aac.00458-24
5. doravirine/islatravir (Pending FDA Approval) - Medscape Reference, accessed September 5, 2025, https://reference.medscape.com/drug/doravirine-islatravir-4000566
6. Islatravir in Combination With Doravirine Maintains HIV-1 Viral Suppression Through 96 Weeks, accessed September 5, 2025, https://www.hivglasgow.org/wp-content/uploads/2020/11/O415-HIV-DTG-ePoster-Molina.pdf
7. Islatravir Has a High Barrier to Resistance and Exhibits a Differentiated Resistance Profile from Approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - PubMed, accessed September 5, 2025, https://pubmed.ncbi.nlm.nih.gov/35546110/
8. Islatravir (ISL) - LAPaL - Medicines Patent Pool, accessed September 5, 2025, https://lapal.medicinespatentpool.org/compounds/islatravir-isl
9. Merck Announces Positive Data from Phase 3 Trials that Show the ..., accessed September 5, 2025, https://www.merck.com/news/merck-announces-positive-data-from-phase-3-trials-that-show-the-investigational-once-daily-oral-two-drug-regimen-of-doravirine-islatravir-dor-isl-maintained-hiv-1-viral-suppression-at-week-48/
10. Studies confirm non-inferiority of doravirine / islatravir to standard HIV treatment - Aidsmap, accessed September 5, 2025, https://www.aidsmap.com/news/mar-2025/studies-confirm-non-inferiority-doravirine-islatravir-standard-hiv-treatment
11. Islatravir Patient Drug Record | NIH - Clinical Info HIV.gov, accessed September 5, 2025, https://clinicalinfo.hiv.gov/en/drugs/islatravir/patient
12. Trials of long-acting islatravir for HIV treatment and prevention placed on hold - Aidsmap, accessed September 5, 2025, https://www.aidsmap.com/news/dec-2021/trials-long-acting-islatravir-hiv-treatment-and-prevention-placed-hold
13. Merck Announces Clinical Holds on Studies Evaluating Islatravir for ..., accessed September 5, 2025, https://www.merck.com/news/merck-announces-clinical-holds-on-studies-evaluating-islatravir-for-the-treatment-and-prevention-of-hiv-1-infection/
14. Merck restarts islatravir HIV treatment studies, but abandons monthly PrEP - Aidsmap, accessed September 5, 2025, https://www.aidsmap.com/news/sep-2022/merck-restarts-islatravir-hiv-treatment-studies-abandons-monthly-prep
15. Islatravir returns to clinical trials - CATIE.ca, accessed September 5, 2025, https://www.catie.ca/treatmentupdate-247/islatravir-returns-to-clinical-trials
16. Merck to resume testing of closely watched HIV drug, but at lower dose | BioPharma Dive, accessed September 5, 2025, https://www.biopharmadive.com/news/merck-islatravir-hiv-lower-dose-phase-3-fda-hold/632233/
17. FDA accepts New Drug Application for Merck's HIV investigational treatment regimen doravirine/islatravir, accessed September 5, 2025, https://www.eatg.org/hiv-news/fda-accepts-new-drug-application-for-mercks-hiv-investigational-treatment-regimen-doravirine-islatravir/
18. U.S. FDA Accepts New Drug Application for Merck's Doravirine ..., accessed September 5, 2025, https://www.merck.com/news/u-s-fda-accepts-new-drug-application-for-mercks-doravirine-islatravir-an-investigational-once-daily-oral-two-drug-regimen-for-treatment-of-adults-with-virologically-suppressed-hiv-1-infe/
19. Islatravir: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 5, 2025, https://go.drugbank.com/drugs/DB15653
20. Nonclinical and clinical characterization of the absorption ... - PubMed, accessed September 5, 2025, https://pubmed.ncbi.nlm.nih.gov/39807886/
21. Islatravir: evaluation of clinical development for HIV and HBV - Taylor & Francis Online, accessed September 5, 2025, https://www.tandfonline.com/doi/pdf/10.1080/13543784.2024.2305130
22. Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters - PMC, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8402619/
23. Pharmacokinetics of islatravir in participants with moderate hepatic impairment - PMC, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11963540/
24. Doravirine/Islatravir (100/0.75 mg) Once-Daily Compared With ..., accessed September 5, 2025, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf077/8074956
25. Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV | Request PDF - ResearchGate, accessed September 5, 2025, https://www.researchgate.net/publication/352773343_Safety_and_Pharmacokinetics_of_Once-Daily_Multiple-Dose_Administration_of_Islatravir_in_Adults_Without_HIV
26. Intracellular islatravir-triphosphate half-life supports extended dosing intervals - PubMed, accessed September 5, 2025, https://pubmed.ncbi.nlm.nih.gov/39105584/
27. Doravirine Completed Phase 2 Trials for Human Immunodeficiency Virus Type 1 (HIV-1) Infection Treatment - DrugBank, accessed September 5, 2025, https://go.drugbank.com/drugs/DB12301/clinical_trials?conditions=DBCOND0045921&phase=2&purpose=treatment&status=completed
28. Merck Presents New Data from Ongoing Phase 2b Clinical Trial Evaluating Efficacy and Safety of Investigational Islatravir in Combination With Doravirine Through 144 Weeks for HIV-1 Treatment at EACS 2021, accessed September 5, 2025, https://www.natap.org/2021/EACS/EACS_02.htm
29. Merck announces results from Phase 3 trials evaluating investigational regimen of doravirine/islatravir - European AIDS Treatment Group, accessed September 5, 2025, https://www.eatg.org/hiv-news/press-release-merck-announces-results-from-phase-3-trials-evaluating-investigational-regimen-of-doravirine-islatravir/
30. Islatravir plus lenacapavir could be the first once-weekly oral HIV treatment | aidsmap, accessed September 5, 2025, https://www.aidsmap.com/news/mar-2024/islatravir-plus-lenacapavir-could-be-first-once-weekly-oral-hiv-treatment
31. TS2023 - LEAP, accessed September 5, 2025, https://longactinghiv.org/LEAPWRKSHP2023-Text_Summary-JayG
32. Islatravir Effects on Lymphocyte Counts in HIV Treatment and Prevention - CCO, accessed September 5, 2025, https://clinicaloptions.com/activities/hiv/isl-effect-on-lymphocytes/23413
33. White blood cell changes on islatravir do not lead to a higher risk of ..., accessed September 5, 2025, https://www.aidsmap.com/news/feb-2023/white-blood-cell-changes-islatravir-do-not-lead-higher-risk-infections
34. Safety, Tolerability, and Pharmacokinetics of Once-Monthly Oral Islatravir - Oxford Academic, accessed September 5, 2025, https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiaf222/63070100/jiaf222.pdf
35. It's the end of the road for monthly oral islatravir as HIV PrEP, accessed September 5, 2025, https://www.eatg.org/hiv-news/its-the-end-of-the-road-for-monthly-oral-islatravir-as-hiv-prep/
36. Modeling of HIV‐1 prophylactic efficacy and toxicity with islatravir shows non‐superiority for oral dosing, but promise as a subcutaneous implant - PubMed Central, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11494919/
37. Merck Announces Clinical Holds on Studies Evaluating Islatravir for the Treatment and Prevention of HIV-1 Infection | American Pharmaceutical Review, accessed September 5, 2025, https://www.americanpharmaceuticalreview.com/1315-News/581948-Merck-Announces-Clinical-Holds-on-Studies-Evaluating-Islatravir-for-the-Treatment-and-Prevention-of-HIV-1-Infection/
38. FDA accepts Merck's NDA for doravirine/islatravir to treat suppressed HIV-1, accessed September 5, 2025, https://clival.com/news/fda-accepts-mercks-nda-for-doravirineislatravir-to-treat-suppressed-hiv-1
39. European Medicines Agency decision P/0268/2024 of 17 July 2024 on the acceptance of a modification of an agreed paediatric inves, accessed September 5, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-0268-2024-ema-decision-17-july-2024-acceptance-modification-agreed-paediatric-investigation-plan-doravirine-islatravir-emea-002707-pip01-19-m02_en.pdf
40. HIV Preexposure Prophylaxis Terminated Phase 3 Trials ... - DrugBank, accessed September 5, 2025, https://go.drugbank.com/indications/DBCOND0068733/clinical_trials/DB15653?phase=3&status=terminated
41. A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection, accessed September 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9936965/
42. Merck Presents Results from Phase 1 Trial Evaluating Investigational Islatravir Subdermal Implant for the Prevention of HIV-1 Infection at CROI 2021, accessed September 5, 2025, https://www.merck.com/news/merck-presents-results-from-phase-1-trial-evaluating-investigational-islatravir-subdermal-implant-for-the-prevention-of-hiv-1-infection-at-croi-2021/