Drug Database: Islatravir

Pharmacology

Pharmacology

Mechanism of Action

Nucleoside reverse transcriptase translocation inhibitor (NRTTI). Islatravir (ISL), a deoxyadenosine analog, belongs to a new class of ARV drugs called NRTTIs. It has potent activity against HIV-1 and is also active against HIV-2 and multidrug-resistant HIV strains.^8,9

Intracellularly, ISL is converted to its active triphosphate form (ISL-TP). ISL-TP inhibits HIV reverse transcriptase (RT) through multiple modes of action. Primarily, ISL-TP functions as an immediate chain terminator—after ISL is incorporated into viral DNA, it blocks RT translocation and prevents nucleotide attachment onto the viral DNA chain. In instances where RT translocation does occur and additional nucleotides are allowed to incorporate onto the viral DNA chain, ISL-TP can act as a delayed chain terminator by causing structural changes to the viral chain. Furthermore, ISL can be misincorporated by RT, resulting in mismatched primers that cannot be extended or excised.^8-11

Half-life (T_½)

Following single-dose oral administration of ISL in adults without HIV, the apparent plasma half-life of ISL ranged from 49 to 61 hours.^12,13 ISL-TP, the active form of ISL, has an intracellular half-life of 177 to 209 hours.¹³

Metabolism/Elimination

ISL undergoes adenosine deaminase-mediated metabolism and renal excretion; hepatic metabolism does not appear to have a significant role in ISL elimination.¹⁴ Following a single oral dose of radiolabeled ISL administered to healthy male participants, unchanged ISL was the predominant compound in plasma and 4′-ethynyl-2-fluorodeoxyinosine (M4) was the major metabolite in plasma. Ninety-one percent of the total radioactive dose was recovered in urine (with the majority as M4 and a significant amount as unchanged drug) and 6% was recovered in feces.¹³

Resistance

A Phase 2b trial (NCT03272347) evaluated three doses of ISL that were administered in combination with doravirine (DOR) in treatment-naive individuals. By Week 48, five participants who received ISL plus DOR had experienced protocol-defined virologic failure; however, all of these participants had HIV-1 RNA <80 copies/mL, and none met the criteria for resistance testing.¹⁵ No participants met the criteria for resistance testing through Week 144 of the trial.¹⁶

A Phase 3 trial (NCT04223778) evaluated a switch to a fixed-dose combination (FDC) containing DOR/ISL in participants who had virological suppression on a stable ART regimen. Through Week 96, no participants receiving DOR/ISL had virologic failure.^17-19

A separate Phase 3 trial (NCT04223791) evaluated a switch to an FDC containing DOR/ISL in participants with virological suppression on bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy). Two participants receiving DOR/ISL had virologic failure through Week 96; however, no resistance was detected to either DOR or ISL in testing of plasma samples.^20-22

In a Phase 3 study (NCT04233879) of a DOR/ISL FDC versus Biktarvy in treatment-naive adults, one participant receiving DOR/ISL experienced virologic failure at Week 24, which appeared to be attributed to study drug nonadherence. Genotypic testing revealed the emergence of the V106A and P225Y NNRTI mutations and the M184I NRTI mutation. Phenotypic analysis showed that the participant’s virus was resistant to DOR.²³

Select Clinical Trials

Select Clinical Trials

On December 13, 2021, the U.S. FDA placed clinical holds on studies of ISL for HIV treatment and prevention. The FDA’s decision was based on reports of decreases in total lymphocyte and CD4 counts in some participants receiving ISL in trials. Please refer to the drug developer’s December 13, 2021 press release for more information about the ISL clinical hold.²⁴

Subsequently, on September 20, 2022, the drug developer announced initiation of a new Phase 3 program evaluating a once-daily oral combination of DOR and a lower dose of ISL (DOR/ISL) for HIV treatment. Once-daily oral treatment studies of DOR/ISL that use doses higher than what will be studied in the new Phase 3 program remain under a partial clinical hold. The development of once-monthly oral ISL for pre-exposure prophylaxis (PrEP) has been discontinued. Please refer to this September 20, 2022 press release for more information.⁵

Islatravir for HIV treatment

Study Identifiers: MK-8591-011; NCT03272347

Sponsor: Merck Sharp & Dohme LLC
Phase: 2b
Status: This study has been completed.
Study Purpose: The purpose of this trial was to evaluate the safety and efficacy of a regimen consisting of ISL (at three different dose levels) plus DOR and lamivudine (3TC) over 24 weeks in treatment-naive participants. After 24 weeks, investigators evaluated the safety and efficacy of ISL (at three different dose levels) plus DOR. In both cases, the active comparator group received DOR/3TC/TDF.
Study Population:

• Participants were treatment-naive adults with HIV.
• Participants had HIV RNA ≥1,000 copies/mL and CD4 counts ≥200 cells/mm³.
• Participants had no known resistance to any approved NRTI, NNRTI, PI, INSTI, or any study drug.^25,26

Selected Study Results: Results published in Lancet HIV (2021) showed that treatment regimens containing ISL and DOR were highly effective in suppressing viral load levels. A high proportion of participants in all treatment groups (ISL plus DOR and comparator groups) achieved HIV RNA <50 copies/mL at Week 24 and Week 48.²⁶ Safety results through Week 144 presented at EAC 2021 showed that rates of discontinuations due to adverse events (AEs) were low and rates of drug-related AEs with ISL plus DOR were lower than rates of drug-related AEs with the comparator regimen.¹⁶

Study Identifiers: IMAGINE-DR; MK-8591-013; NCT04564547

Sponsor: Merck Sharp & Dohme LLC
Phase: 2b
Status: This study has been completed. (See note below.)
Study Purpose: The purpose of this study was to evaluate the safety of oral weekly ISL plus the investigational NNRTI MK-8507 (also known as ulonivirine) based on review of accumulated safety data in participants who were virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy).
Study Population:

• Participants are adults with HIV who have been virologically suppressed on Biktarvy for at least 6 months.
• Participants have HIV RNA <50 copies/mL and CD4 counts >200 cells/mm³ at screening.^27,28

Note: The developers of ISL announced in a November 18, 2021 press release that they were stopping dosing of participants in the MK-8591-013 trial. This decision was based on findings of reduced total lymphocyte and CD4 counts in study participants receiving ISL and MK-8507.²⁸ As of December 1, 2021, the MK-8591-013 study protocol was amended and all participants discontinued study treatment.²⁷

Study Identifiers: GS-US-563-6041; NCT05052996

Sponsor: Gilead Sciences
Phase: 2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the efficacy of weekly oral ISL (2 mg) in combination with the capsid inhibitor lenacapavir (LEN) in participants who are virologically suppressed on Biktarvy.
Study Population:

• Participants are adults with HIV who have been virologically suppressed (HIV RNA <50 copies/mL) on Biktarvy for at least 24 weeks before and at screening.
• Participants have CD4 counts ≥350 cells/mm³ and have no history of virologic failure. ^29,30

Selected Study Results: Results presented at CROI 2024 showed that participants switching to weekly oral ISL plus LEN maintained a high rate (94.2%) of viral suppression at Week 24, which was comparable to the rate of viral suppression in participants who remained on Biktarvy. Only one (1.9%) participant in the ISL plus LEN group had HIV RNA ≥50 copies/mL at Week 24. Notably, this participant resuppressed at Week 30 on ISL plus LEN.³⁰
Additional Published Material:

• HIV Glasgow 2024: Once-weekly islatravir plus lenacapavir in virologically suppressed PWH: Week 48 safety, efficacy, and metabolic changes

Study Identifiers: ILLUMINATE SWITCH A; MK-8591A-017; NCT04223778

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate the safety and efficacy of a switch to a once-daily DOR/ISL (100 mg/0.75 mg) FDC tablet versus continuing baseline ART.
Study Population:

• Participants were adults with HIV who had been receiving a continuous, stable 2- or 3-drug ART regimen for at least the past 3 months.
• Participants had viral suppression on ART with HIV RNA <50 copies/mL for at least the past 3 months.
• Participants had no history of virologic treatment failure on any past or current ART regimen.¹⁷

Selected Study Results: Results presented at CROI 2023 and published in Lancet HIV (2024) indicated that DOR/ISL was as effective as baseline ART regimens in maintaining suppression of participants’ viral load levels through 48 weeks of treatment. DOR/ISL had a safety profile that was similar to that of the comparator ART regimens. However, due to decreases in CD4 cell counts and total lymphocyte counts from baseline to Week 48, the development of the 100 mg/0.75 mg DOR/ISL FDC tablet was stopped.^18,31
Additional Published Material:

• EACS 2023: Switch to fixed-dose doravirine (100 mg) with islatravir (0.75 mg) once daily in adults with HIV-1 virologically suppressed on antiretroviral therapy: Week 96 results of a randomized, open-label, Phase 3 trial
• CROI 2024: Switching to doravirine/islatravir maintains viral suppression regardless of archived mutations

Study Identifiers: ILLUMINATE SWITCH B; MK-8591A-018; NCT04223791

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a switch to a once-daily DOR/ISL (100 mg/0.75 mg) FDC tablet versus continuing Biktarvy.
Study Population:

• Participants are adults with HIV who have been receiving Biktarvy for at least the past 3 months.
• Participants have had viral suppression on Biktarvy with HIV RNA <50 copies/mL for at least the past 3 months.
• Participants have no history of virologic treatment failure on any past or current ART regimen.^20,24

Selected Study Results: Results presented at CROI 2023 and published in Lancet HIV (2024) indicated that DOR/ISL was as effective as Biktarvy in maintaining suppression of participants’ viral load levels through 48 weeks of treatment. The safety profile of DOR/ISL was similar to that of Biktarvy. However, due to decreases in CD4 cell counts and total lymphocyte counts from baseline to Week 48, the development of the 100 mg/0.75 mg DOR/ISL FDC tablet was stopped.^21,32
Additional Published Material:

• EACS 2023: Switch to fixed-dose doravirine/islatravir (100/0.75 mg) once daily in adults with HIV-1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide: Week 96 results of a Phase 3, randomized, double-blind, non-inferiority trial
• CROI 2024: Switching to doravirine/islatravir maintains viral suppression regardless of archived mutations

Study Identifiers: ILLUMINATE HTE; MK-8591A-019; NCT04233216

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study has been completed.
Study Purpose: The purpose of this trial was to evaluate the safety and efficacy of ISL, DOR, and a DOR/ISL (100 mg/0.75 mg) FDC tablet, each compared to placebo, in heavily treatment-experienced participants.
Study Population:

• Participants were heavily treatment–experienced children and adults with HIV who had been receiving the same ART regimen for at least the past 3 months.
• Participants had resistance to at least one drug within three different ARV drug classes (NRTI, NNRTI, and either PI or INSTI) and had limited treatment options available to form a viable ART regimen.
• Participants had HIV RNA ≥500 copies/mL at screening and within the past 10 days prior to randomization.^33,34

Selected Study Results: Results presented at EACS 2023 showed that virologic response from baseline to Day 8 was greatest among participants in the DOR/ISL plus ART group. Of note, enrollment in the MK-8591A-019 study was stopped early due to findings of decreased CD4 cell counts and lymphocyte counts in other ISL studies, and hypothesis testing for efficacy was not performed. DOR/ISL was generally well tolerated through Week 49.³⁴

Study Identifiers: ILLUMINATE NAIVE; MK-8591A-020; NCT04233879

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a once-daily DOR/ISL (100 mg/0.75 mg) FDC tablet versus Biktarvy in treatment-naive participants.
Study Population:

• Participants are treatment-naive adults with HIV.
• Participants have no known resistance to any approved HIV-1 reverse transcriptase inhibitor or any study intervention.^24,35

Selected Study Results Week 48 results presented at IAS 2023 showed that DOR/ISL was as effective as Biktarvy in suppressing viral load in treatment-naive participants. Treatment-related AEs occurred with similar frequency in both groups. More participants receiving DOR/ISL discontinued treatment due to an AE than participants receiving Biktarvy.²³

Study Identifiers: MK-8591A-051; NCT05631093

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label trial is to evaluate the safety and efficacy of a switch to a once-daily DOR/ISL (100 mg/0.25 mg) FDC tablet versus continuing baseline ART.
Study Population:

• Participants are adults with HIV who have been receiving a continuous, stable 2- or 3-drug ART regimen for at least the past 3 months.
• Participants have had viral suppression on ART with HIV RNA <50 copies/mL for at least the past 3 months and at screening.
• Participants have no history of virologic treatment failure on any past or current regimen and have no known resistance to DOR.³⁶

Selected Study Results: Week 48 results were released in a company press release (December 2024) and indicated that DOR/ISL was as effective as baseline ART in controlling viral load levels in virologically suppressed adults. The safety profile of DOR/ISL was generally comparable to baseline ART regimens. The company reported that detailed results to this study would be presented at future scientific conferences.³⁷

Study Identifiers: MK-8591A-052; NCT05630755

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a switch to a once-daily DOR/ISL (100 mg/0.25 mg) FDC tablet versus continuing Biktarvy.
Study Population:

• Participants are adults with HIV who have been receiving Biktarvy for at least the past 3 months.
• Participants have had viral suppression on Biktarvy with HIV RNA <50 copies/mL for at least the past 3 months.
• Participants have no history of virologic treatment failure on any past or current ART regimen and have no known resistance to DOR.
• Participants have never received long-acting HIV therapy (such as cabotegravir or lenacapavir).³⁸

Selected Study Results: Week 48 results were released in a company press release (December 2024) and indicated that DOR/ISL was as effective as Biktarvy in controlling viral load levels in virologically suppressed adults. DOR/ISL, however, did not demonstrate superiority over Biktarvy. The safety profile of DOR/ISL was generally comparable to Biktarvy. The company reported that detailed results to this study would be presented at future scientific conferences.³⁷

Study Identifiers: MK-8591A-053; NCT05705349

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a once-daily DOR/ISL (100 mg/0.25 mg) FDC tablet versus Biktarvy in treatment-naive participants.
Study Population:

• Participants are treatment-naive adults with HIV.
• Participants have HIV RNA ≥500 copies/mL at screening.³⁹

Study Identifiers: MK-8591A-054; NCT05766501

Sponsor: Merck Sharp & Dohme LLC
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label trial is to evaluate the safety and tolerability of a once-daily DOR/ISL (100 mg/0.25 mg) FDC tablet in participants who have previously been treated in earlier clinical studies with DOR/ISL (100 mg/0.75 mg).
Study Population: Participants are adults with HIV who are currently receiving DOR/ISL in one of the following clinical studies: MK-8591A-017, MK-8591A-018, MK-8591A-020, or MK-8591A-033.⁴⁰

Study Identifiers: ISLEND-1; GS-US-563-5925; NCT06630286

Sponsor: Gilead Sciences
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the efficacy of a switch to a once-weekly islatravir/lenacapavir (ISL/LEN) FDC tablet versus continuing Biktarvy.
Study Population:

• Participants are adults with HIV who have been receiving Biktarvy for at least the past 6 months prior to screening.
• Participants have HIV RNA <50 copies/mL for at least the past 6 months prior to screening and at screening.
• Participants have no history of virologic treatment failure and have no prior exposure to ISL or LEN.⁶

Study Identifiers: ISLEND-2; GS-US-563-5926; NCT06630299

Sponsor: Gilead Sciences
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label trial is to evaluate the efficacy of a switch to a once-weekly ISL/LEN FDC tablet versus continuing standard-of-care ART.
Study Population:

• Participants are adults with HIV who have been receiving standard-of-care ART for at least the past 6 months prior to screening.
• Participants have HIV RNA <50 copies/mL for at least the past 6 months prior to screening and at screening.
• Participants have no history of virologic treatment failure and have no prior exposure to ISL or LEN.⁷

Additional trials evaluating DOR/ISL for HIV treatment have been or are being conducted, including:

• ILLUMINATE YOUTH (MK-8591A-028; NCT04295772):
  A Phase 2 open-label study that evaluated once-daily DOR/ISL (100 mg/0.75 mg) as an HIV treatment in pediatric participants who were virologically suppressed on ART or treatment-naive. This study has been completed.⁴¹
• MK-8591A-033 (NCT04776252): A Phase 3 open-label rollover study evaluating the safety of once-daily DOR/ISL (100 mg/0.75 mg) in adult and pediatric participants who received DOR/ISL in a previous clinical trial. This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)^24,42

Adverse Events

Adverse Events

MK-8591-011 (NCT03272347)

In this Phase 2b study, 90 participants received ISL (in doses of 0.25 mg, 0.75 mg, or 2.25 mg) plus DOR and 3TC and 31 participants received DOR/3TC/TDF for 24 weeks (Part 1). After 24 weeks, eligible participants who were receiving ISL, DOR, and 3TC switched to a two-drug regimen of ISL plus DOR (Part 2). The Week 48 analysis found that 73% of participants who received any dose of ISL and 77% of participants who received DOR/3TC/TDF experienced at least one AE. Drug-related AEs occurred in 8% of participants who received ISL and 19% of participants who received DOR/3TC/TDF. No serious drug-related AEs were reported with ISL. Two participants who received the 2.25-mg dose of ISL discontinued treatment because of an AE; one participant experienced diarrhea, nausea, and vomiting, and one participant had HBV reactivation. Headache was more common in the combined ISL groups (11%) than in the DOR/3TC/TDF group (6%), and diarrhea was more common in the DOR/3TC/TDF group (16%) than in the combined ISL groups (7%). Most of the cases of headache and diarrhea were mild, transient, and unrelated to treatment.^25,26

Results through Week 144 of the MK-8591-011 study include data from the open-label maintenance phase of the trial where all participants in the ISL plus DOR groups transitioned to the selected ISL dose of 0.75 mg plus DOR 100 mg (Part 3). The rate of drug-related AEs continued to be lower in the ISL groups (7.8%) than in the DOR/3TC/TDF group (22.6%). There were no additional participants who discontinued treatment because of an AE.¹⁶

GS-US-563-6041 (NCT05052996)

In this Phase 2 study, adults with viral suppression on Biktarvy were randomized to either weekly oral ISL plus LEN (n = 52) or continue daily oral Biktarvy (n = 52). Safety results at Week 24 showed that 76.9% of participants on ISL plus LEN and 73.1% of participants on Biktarvy had at least one AE. Treatment-related AEs, all of which were Grade 1 or 2, occurred in 17.3% of participants receiving ISL plus LEN and 5.8% of participants receiving Biktarvy. The most common treatment-related AEs with ISL plus LEN were dry mouth (3.8%) and nausea (3.8%). There were no Grade 3 or 4 treatment-related AEs in either group. Two participants discontinued ISL plus LEN because of AEs unrelated to the study drugs.^29,30

ILLUMINATE SWITCH A (MK-8591A-017; NCT04223778)

In the Phase 3 ILLUMINATE SWITCH A trial, participants were randomized to continue their baseline ART (bART) regimen (n = 366) or switch to a an FDC containing DOR/ISL (n = 366). Results through Week 48 showed that DOR/ISL had a similar safety profile to that of bART. Approximately 80% of participants in the DOR/ISL arm and 70% of participants in the bART arm had at least one AE. Drug-related AEs occurred in 19.6% of DOR/ISL participants and 8.9% of bART participants. The most common drug-related AEs were insomnia (2.1% DOR/ISL; 0.3% bART), abnormal dreams (1.8% DOR/ISL; 0.3% bART), headache (1.8% DOR/ISL; 0.6% bART), nausea (1.5% DOR/ISL; 0.3% bART), pruritus (1.5% DOR/ISL; 0.0% bART), and weight increase (1.5% DOR/ISL; 0.0% bART). A drug-related serious adverse event (SAE)—paranoia—occurred in one participant receiving DOR/ISL. Five participants discontinued DOR/ISL and no participants discontinued bART due to a drug-related AE. Decreases in total lymphocyte counts and CD4 counts in the DOR/ISL group were modest and were not associated with infection-related AEs.^17,18

After Week 48, all participants received open-label DOR/ISL, which was generally well tolerated. The majority of treatment-related AEs and discontinuations due to AEs that occurred after Week 48 were attributed to protocol-defined decreases in CD4 or total lymphocyte counts. Investigators determined that the decreases in CD4 and/or lymphocyte counts were generally not clinically significant. No treatment-related SAEs occurred.¹⁹

ILLUMINATE SWITCH B (MK-8591A-018; NCT04223791)

In the Phase 3 ILLUMINATE SWITCH B trial, participants were randomized to continue Biktarvy (n = 319) or switch to an FDC containing DOR/ISL (n = 322). Results through Week 48 showed that DOR/ISL had a similar safety profile to that of Biktarvy. Seventy-one percent of participants receiving DOR/ISL and 75% of participants receiving Biktarvy experienced at least one AE. Drug-related AEs occurred in 10% of DOR/ISL participants and 12% of Biktarvy participants. The most common drug-related AEs included nausea (3% DOR/ISL; 1% Biktarvy), dizziness (0% DOR/ISL; 2% Biktarvy), and myalgia (0% DOR/ISL; 2% Biktarvy). No SAEs were reported in either group. Six participants discontinued DOR/ISL, and five participants discontinued Biktarvy due to a drug-related AE. Decreases in total lymphocyte counts and CD4 counts in the DOR/ISL group were modest and were not associated with infection-related AEs.^20,21

Results at Week 96 showed that a greater proportion of participants receiving DOR/ISL than participants receiving Biktarvy had treatment-related AEs and discontinued treatment due to AEs. Most of the treatment-related AEs and discontinuations due to AEs in the DOR/ISL group were attributed to protocol-defined decreases in CD4 and/or total lymphocyte counts. The decreases in CD4 and/or lymphocyte counts were not considered clinically significant. No treatment-related SAEs occurred through 96 weeks.²²

ILLUMINATE HTE (MK-8591A-019; NCT04233216)

In the Phase 3 ILLUMINATE HTE study, 35 heavily treatment-experienced participants received at least one dose of study drug and completed Part 1 of the trial where ISL (n = 7), DOR (n = 14), an FDC containing DOR/ISL (n = 7), or placebo (n = 7) was added on to a baseline failing ART regimen from Day 1 to Day 8. In Part 2 of the trial, all participants received DOR/ISL plus optimized background therapy (OBT) starting on Day 8. Results at Week 49 showed that the majority of participants in the study experienced at least one AE. Drug-related AEs, most of which were attributed to DOR/ISL, occurred in 48.6% of participants. Two participants receiving DOR plus ART and one participant receiving DOR/ISL plus ART discontinued treatment due to a drug-related AE. No drug-related SAEs were reported. CD4 counts at Week 49 were only modestly different between treatment groups.^33,34,43

ILLUMINATE NAIVE (MK-8591A-020; NCT04233879)

In the Phase 3 ILLUMINATE NAIVE study, treatment-naive participants received either an FDC containing DOR/ISL (n = 298) or Biktarvy (n = 299). Through Week 48, 91% of participants on DOR/ISL and 86% of participants on Biktarvy had at least one AE. Drug-related AEs occurred in 26% of DOR/ISL participants and 25% of Biktarvy participants. The most common drug-related AEs that occurred in either group included decreased lymphocyte count (11.7% DOR/ISL; 6.4% Biktarvy), headache (10.7% DOR/ISL; 10.7% Biktarvy), diarrhea (8.7% DOR/ISL; 6.4% Biktarvy), insomnia (4.4% DOR/ISL; 6.4% Biktarvy), and increased weight (3.4% DOR/ISL; 5.0% Biktarvy). There were no drug-related SAEs associated with DOR/ISL. Twenty-two participants in the DOR/ISL group and 10 participants in the Biktarvy group discontinued treatment due to an AE. The higher rate of AE-related discontinuations seen with DOR/ISL was due to protocol-required withdrawals for decreased CD4 counts or total lymphocyte counts. Infection-related AE rates were similar in both groups.^23,44

Drug Interactions

Drug Interactions

In vitro, ISL does not interact with renal or hepatic drug transporters or major enzymes involved in drug metabolism, including CYP enzymes and UGT1A1.^14,45 Although ISL was shown to be a substrate of BCRP in vitro, this finding is unlikely to be clinically significant.¹⁴

Drug-drug interaction studies in adults without HIV indicate no significant interactions between ISL and either DOR or LEN.^46,47 Additionally, ISL does not appear to have any clinically meaningful interaction with dolutegravir and TDF.⁴⁸

The pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) were not affected when an oral contraceptive that contained these drugs was coadministered with ISL.⁴⁹ Additionally, an exploratory substudy in people of childbearing potential at low risk of acquiring HIV found that once-monthly ISL appeared to have no meaningful impact on exposure to long-acting reversible contraceptives.⁵⁰

Results from a two-way interaction study found that the coadministration of ISL and methadone did not significantly affect the pharmacokinetics of either drug.⁵¹

A drug-drug interaction study of a single oral dose of ISL on atorvastatin and metformin pharmacokinetics in healthy adults found that ISL has no clinically significant impact on the pharmacokinetic profiles of either atorvastatin or metformin.⁵²

References

References

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2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed February 19, 2025
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4. Jefferys R. PrEP and microbicides pipeline 2024. Treatment Action Group Pipeline Report 2024. Accessed February 19, 2025
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6. Gilead Sciences. A Phase 3, randomized, double-blind, active-controlled study to evaluate a switch to an oral weekly islatravir/lenacapavir regimen in people with HIV-1 who are virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 4, 2024. NLM Identifier: NCT06630286. Accessed February 19, 2025
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8. Michailidis E, Huber AD, Ryan EM, et al. 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms. J Biol Chem. 2014;289(35):24533-24548. doi:10.1074/jbc.M114.562694. Accessed February 19, 2025
9. Grobler J. Efficacy of MK-8591 against diverse HIV-1 subtypes and NRTI-resistant clinical isolates. Webcast presented at: International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 28-31, 2018; Glasgow, United Kingdom. Accessed February 19, 2025
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17. Merck Sharp & Dohme LLC. A Phase 3 randomized, active-controlled, open-label clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV-1 virologically suppressed on antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2020. NLM Identifier: NCT04223778. Accessed February 19, 2025
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24. Merck: Press release, dated December 13, 2021. Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 infection. Accessed February 19, 2025
25. Merck Sharp & Dohme LLC. A Phase 2B, randomized, double-blind, active-comparator-controlled, dose-ranging clinical trial to evaluate the safety, tolerability, antiretroviral activity, and pharmacokinetics of MK-8591 given in combination with doravirine (DOR) and lamivudine (3TC) in HIV-1-infected treatment-naïve adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 1, 2017. NLM Identifier: NCT03272347. Accessed February 19, 2025
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29. Gilead Sciences. A Phase 2 randomized, open-label, active-controlled study evaluating the safety and efficacy of an oral weekly regimen of islatravir in combination with lenacapavir in virologically suppressed people with HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 13, 2021. NLM Identifier: NCT05052996. Accessed February 19, 2025
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31. Molina JM, Rizzardini G, Orrell C, et al. Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial. Lancet HIV. 2024;11(6):e369-e379. doi:10.1016/S2352-3018(24)00031-6. Accessed February 19, 2025
32. Mills AM, Rizzardini G, Ramgopal MN, et al. Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial. Lancet HIV. 2024;11(6):e357-e368. doi:10.1016/S2352-3018(24)00030-4. Accessed February 19, 2025
33. Merck Sharp & Dohme LLC. A Phase 3, randomized, clinical study in HIV-1-infected heavily treatment-experienced participants evaluating the antiretroviral activity of blinded islatravir (ISL), doravirine (DOR), and doravirine/islatravir (DOR/ISL), each compared to placebo, and the antiretroviral activity, safety, and tolerability of open-label DOR/ISL. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2020. NLM Identifier: NCT04233216. Accessed February 19, 2025
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36. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, open-label clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL 100 mg/0.25 mg) once-daily in participants with HIV-1 who are virologically suppressed on antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 18, 2022. NLM Identifier: NCT05631093. Accessed February 19, 2025
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39. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the antiretroviral activity, safety, and tolerability of doravirine/islatravir (DOR/ISL 100 mg/0.25 mg) once-daily in HIV-1 infected treatment-naïve participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2023. NLM Identifier: NCT05705349. Accessed February 19, 2025
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41. Merck Sharp & Dohme LLC. A Phase 2 clinical study to evaluate the pharmacokinetics, safety, and efficacy of doravirine/islatravir in pediatric participants with HIV-1 infection who are virologically suppressed or treatment-naïve, are less than 18 years of age, and weigh greater than or equal to 35 kg. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2020. NLM Identifier: NCT04295772. Accessed February 19, 2025
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Last Reviewed: February 19, 2025