Drug Database: Islatravir

What is islatravir?

Islatravir is an investigational drug that is being studied to treat and prevent HIV infection.^3,4

Islatravir belongs to a group of HIV drugs called nucleoside reverse transcriptase translocation inhibitors (NRTTIs). NRTTIs use several different methods to block an HIV enzyme called reverse transcriptase. By blocking reverse transcriptase, NRTTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.⁶

Islatravir may be effective against certain HIV strains that are resistant to other HIV drugs.⁷

To learn about how investigational drugs are tested during clinical trials, read the HIVinfo  What is an Investigational HIV Drug? and HIV and AIDS Clinical Trials fact sheets.

Select clinical trials of islatravir

On December 13, 2021, the U.S. Food and Drug Administration (FDA) placed clinical holds on studies of islatravir 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 islatravir in trials. Please refer to the drug developer’s December 13, 2021 press release for more information about the islatravir clinical hold.⁸

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

Islatravir for HIV treatment

Study Names: MK-8591-011; NCT03272347

Phase: 2b
Status: This study has been completed.
Locations: Chile, France, United Kingdom, United States
Purpose: The purpose of this clinical trial was to evaluate the safety and effectiveness of a treatment regimen consisting of islatravir (given at three different dose levels) plus doravirine (brand name: Pifeltro) and lamivudine (brand name: Epivir) over 24 weeks in treatment-naive adults with HIV. After 24 weeks, investigators evaluated the safety and effectiveness of islatravir (given at three different dose levels) plus doravirine.⁹
Selected Study Results: Results published in Lancet HIV (2021) showed that treatment regimens containing islatravir and doravirine were highly effective in reducing participants’ viral load levels.¹⁰ Safety results through Week 144 of the study presented at EAC 2021 showed that there were few reports of discontinuations due to side effects associated with islatravir plus doravirine. Additionally, drug-related side effects occurred less frequently in the islatravir plus doravirine arms than in the control arm.¹¹

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

Phase: 2b
Status: This study is ongoing, but not recruiting participants. (See note below.)
Locations: United States, France, Switzerland
Purpose: The purpose of this study is to evaluate the safety of islatravir plus the investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) MK-8507 based on review of accumulated safety data in participants who have had viral suppression on bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy).^12,13
Note: The developers of islatravir announced in a November 18, 2021 press release that they are 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 islatravir and MK-8507.¹³  As of December 1, 2021, the MK-8591-013 study protocol was updated and all participants have discontinued study treatment and will be switched to non-study antiretroviral therapy (ART). Participants who received islatravir and MK-8507 will be followed for at least 6 months.¹²

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

Phase: 2
Status: This study is ongoing, but not recruiting participants. (See note below.)
Location: United States
Purpose: The purpose of this study is to evaluate the efficacy of oral weekly islatravir in combination with the capsid inhibitor lenacapavir in participants with viral suppression on Biktarvy.¹⁴
Note: This study is under a partial clinical hold. The developers of islatravir announced plans to resume the GS-US-563-6041 trial under an updated protocol utilizing a lower dose of islatravir. For more information, please refer to the September 20, 2022 press release.⁵

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

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Locations: Multiple countries, including United States
Purpose: The purpose of this trial is to evaluate the safety and effectiveness of a switch from a baseline ART regimen to a fixed-dose combination (FDC) containing doravirine/islatravir.^8,15
Selected Study Results: Results presented at CROI 2023 indicated that doravirine/islatravir was as effective as baseline ART regimens in maintaining suppression of participants’ viral load levels through 48 weeks of treatment. The safety profile of doravirine/islatravir was similar to that of the baseline ART regimens.¹⁶

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

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Locations: Multiple countries, including United States
Purpose: The purpose of this trial is to evaluate the safety and effectiveness of a switch from Biktarvy to an FDC containing doravirine/islatravir.^8,17
Selected Study Results: Results presented at CROI 2023 indicated that doravirine/islatravir was as effective as Biktarvy in maintaining suppression of participants’ viral load levels through 48 weeks of treatment. The safety profile of doravirine/islatravir was similar to that of Biktarvy.¹⁸  

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

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Locations: Multiple countries, including United States
Purpose: The purpose of this trial is to evaluate the safety and efficacy of islatravir, doravirine, and an FDC containing doravirine/islatravir, each compared to placebo, in heavily treatment-experienced participants.^8,19

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

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold.)
Locations: Multiple countries, including United States
Purpose: The purpose of this trial is to evaluate the safety and efficacy of an FDC containing doravirine/islatravir versus Biktarvy in treatment-naive participants.^8,20

Study Names: MK-8591A-051; NCT05631093

Phase: 3
Status: This study is currently recruiting participants. 
Locations: United States, Australia, Canada, Japan, Switzerland
Purpose: The purpose of this trial is to evaluate the safety and efficacy of a switch from a current ART regimen to an FDC containing doravirine/islatravir in participants with viral suppression.²¹

Study Names: MK-8591A-052; NCT05630755

Phase: 3
Status: This study is currently recruiting participants. 
Locations: United States, Australia, Israel
Purpose: The purpose of this trial is to evaluate the safety and efficacy of a switch from Biktarvy to an FDC containing doravirine/islatravir in participants with viral suppression.²²

Study Names: MK-8591A-053; NCT05705349

Phase: 3
Status: This study is currently recruiting participants. 
Locations: United States, Israel, Puerto Rico
Purpose: The purpose of this trial is to evaluate the safety and efficacy of an FDC containing doravirine/islatravir as compared to Biktarvy in treatment-naive participants.²³ 
 

Additional trials evaluating doravirine/islatravir for HIV treatment are being conducted, including:

• ILLUMINATE YOUTH (MK-8591A-028; NCT04295772): A Phase 2 study evaluating doravirine/islatravir as an HIV treatment in pediatric participants who have viral suppression on ART or who are treatment-naive. This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on partial clinical hold. As of February 8, 2022, all participants have discontinued study treatment and will be switched to non-study ART. Certain participants may be followed for up to 6 months for extended monitoring.)^8,24
• MK-8591A-033 (NCT04776252): A Phase 3 rollover study evaluating the safety of doravirine/islatravir in adult and pediatric participants who received doravirine/islatravir in a previous clinical trial. This study is currently recruiting participants. (In December 2021, this study was placed on partial clinical hold.)^8,25

Islatravir for HIV prevention

Study Names: MK-8591-016; NCT04003103

Phase: 2a
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on full clinical hold.)
Locations: United States, Israel, South Africa
Purpose: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of two different doses of oral islatravir given once a month to participants who have a low risk of getting HIV.^8,26
Selected Study Results: Results presented at IAS 2021 showed that both doses of oral islatravir given once monthly were well-tolerated over 24 weeks. The majority of side effects that occurred were mild, and less than 1% of participants discontinued due to side effects. No serious drug-related side effects were reported.²⁷
Additional Published Material:

• CROI, 2022: Phase IIA trial of islatravir QM for HIV PrEP: Week 24 metabolic and renal outcomes

Study Names: MK-8591-043; NCT05115838

Phase: 2a
Status: See the ClinicalTrials.gov record for this study’s status. (In December 2021, this study was placed on full clinical hold.)
Location: Not available
Purpose: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of different doses of a once-yearly islatravir implant in participants who are at low risk of getting HIV.^8,28

Study Names: IMPOWER 22; MK-8591-022; NCT04644029

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on full clinical hold.)
Locations: United States, South Africa, and Uganda
Purpose: The purpose of this study is to evaluate the safety and efficacy of oral islatravir given once monthly as PrEP in cisgender women who are at high risk of getting HIV.^8,29

Study Names: IMPOWER 24; MK-8591-024; NCT04652700

Phase: 3
Status: This study is ongoing, but not recruiting participants. (In December 2021, this study was placed on full clinical hold.)
Locations: Multiple countries, including United States
Purpose: The purpose of this study is to evaluate the safety and efficacy of oral islatravir given once monthly as PrEP in cisgender men who have sex with men and transgender women who have sex with men and who are at high risk of getting HIV.^8,30

Additionally, an injectable formulation of islatravir is being evaluated in a Phase 1 trial (MK-8591-034). In December 2021, this study was placed on full clinical hold.⁸

For more details on the studies listed above, see the Health Professional version of this drug summary.

What side effects might islatravir cause?

One goal of HIV research is to identify new drugs that have fewer side effects. The following side effects were observed in some of the studies of islatravir listed above.

On December 13, 2021, the FDA placed clinical holds on studies of islatravir for HIV treatment and prevention. The FDA’s decision was based on safety concerns over decreases in total lymphocyte and CD4 counts in some participants receiving islatravir in trials.⁸

MK-8591-011 (NCT03272347)

In this Phase 2b study, 8% of participants who received islatravir had a drug-related side effect. No serious drug-related side effects occurred with islatravir treatment. Two participants who received the highest dose of islatravir stopped treatment early because of a side effect; one participant experienced diarrhea, nausea, and vomiting, and one participant had an existing hepatitis B virus infection reactivate. Headache was more common in the combined islatravir groups than in the  control arm. Most of the cases of headache were mild, temporary, and unrelated to treatment.^9,10

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

In this Phase 3 trial, participants continued their baseline antiretroviral therapy (ART) regimen or switched to a fixed-dose combination (FDC) containing doravirine/islatravir. Results through Week 48 showed that doravirine/islatravir had a similar safety profile to that of baseline ART. Approximately 80% of participants in the doravirine/islatravir arm and 70% of participants in the baseline ART arm had at least one side effect. Drug-related side effects occurred in 19.6% of doravirine/islatravir participants and 8.9% of baseline ART participants. Overall, the most common drug-related side effects were insomnia, abnormal dreams, headache, nausea, itching skin, and weight gain. A drug-related serious side effect—paranoia—occurred in one participant receiving doravirine/islatravir. Five participants discontinued doravirine/islatravir because of a drug-related side effect.^15,16

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

In this Phase 3 trial, participants continued Biktarvy or switched to an FDC containing doravirine/islatravir. Results through Week 48 showed doravirine/islatravir had a similar safety profile to that of Biktarvy. Seventy-one percent of participants receiving doravirine/islatravir and 75% of participants receiving Biktarvy experienced at least one side effect. Drug-related side effects occurred in 10% of doravirine/islatravir participants and 12% of Biktarvy participants. Overall, the most common drug-related side effects included nausea, dizziness, and muscle aches and pain. Six participants discontinued doravirine/islatravir because of a drug-related side effect.^17,18

MK-8591-016 (NCT04003103)

In this Phase 2a trial evaluating once-monthly oral islatravir for PrEP, 60% of the participants who received islatravir experienced at least one side effect. The majority of side effects were mild in intensity, with the most common side effects overall being headache, diarrhea, and nausea. Drug-related side effects were all mild or moderate. Two participants discontinued study drug because of a side effect — one due to a mild foreign body sensation in the throat and one due to moderate rash and itching skin.^26,27

Because islatravir is still being studied, information on possible side effects of the drug is not complete. As testing of islatravir continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying islatravir?

More information about islatravir-related research studies is available from ClinicalTrials.gov. (The ClinicalTrials.gov search can be modified so that you can get results that better match your interests. To learn more about the ClinicalTrials.gov search features, please see How to Search.)

Some clinical trials may be looking for volunteer participants. Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

1. National Center for Biotechnology Information. PubChem compound summary for CID 6483431, 4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine. Accessed March 31, 2023
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed March 31, 2023
3. Jefferys R. The antiretroviral therapy pipeline 2022. Treatment Action Group Pipeline Report 2022. Accessed March 31, 2023
4. Jefferys R. The PrEP and microbicides pipeline 2022. Treatment Action Group Pipeline Report 2022. Accessed March 31, 2023
5. Merck: Press Release, dated September 20, 2022. Merck to initiate new Phase 3 clinical program with lower dose of daily oral islatravir in combination with doravirine for treatment of people with HIV-1 infection. Accessed March 31, 2023
6. Markowitz M, Sarafianos SG. EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine, MK-8591): a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS. 2018;13(4):294-299. doi:10.1097/COH.0000000000000467. Accessed March 31, 2023
7. 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 March 31, 2023
8. 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 March 31, 2023
9. 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 March 31, 2023
10. Molina JM, Yazdanpanah Y, Afani Saud A, et al. Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. Lancet HIV. 2021;8(6):e324-e333. doi:10.1016/S2352-3018(21)00021-7. Accessed March 31, 2023
11. Molina J-M, Yazdanpanah Y, Afani A, et al. Efficacy and safety of islatravir in combination with doravirine through 144 weeks for treatment-naïve adults with HIV-1 infection in a Phase 2b trial. European AIDS Conference; October 27-30, 2021; Virtual and United Kingdom. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2021. Accessed March 31, 2023
12. Merck Sharp & Dohme LLC. A Phase 2b, randomized, active-controlled, double-blind, dose-ranging clinical study to evaluate a switch to islatravir (ISL) and MK-8507 once-weekly in adults with HIV-1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once-daily. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 21, 2020. NLM Identifier: NCT04564547. Accessed March 31, 2023
13. Merck: Press release, dated November 18, 2021. 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 March 31, 2023
14. 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 March 31, 2023
15. 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 March 31, 2023
16. Molina J-M, Rizzardini G, Orell C, et al. Switch to DOR/ISL (100/0.75mg) QD: Week 48 results from an open-label Phase 3 trial. Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22; Seattle, WA. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2023. Accessed March 31, 2023
17. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, double-blind clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV- 1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2020. NLM Identifier: NCT04223791. Accessed March 31, 2023
18. Mills AM, Rizzardini G, Ramgopal M, et al. Switch to DOR/ISL (100/0.75 mg) QD from B/F/TAF: Week 48 results from a Phase 3 trial. Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22; Seattle, WA. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2023. Accessed March 31, 2023
19. 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 March 31, 2023
20. 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 once-daily in HIV-1 infected treatment-naïve participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2020. NLM Identifier: NCT04233879. Accessed March 31, 2023
21. 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 March 31, 2023
22. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, double-blind 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 bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 18, 2022. NLM Identifier: NCT05630755. Accessed March 31, 2023
23. 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 March 31, 2023
24. 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 March 31, 2023
25. Merck Sharp & Dohme LLC. A Phase 3 open-label rollover clinical study of doravirine/islatravir (DOR/ISL) once-daily for the treatment of HIV-1 infection in participants who previously received DOR/ISL in a Phase 2 or Phase 3 DOR/ISL clinical study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 26, 2021. NLM Identifier: NCT04776252. Accessed March 31, 2023
26. Merck Sharp & Dohme LLC. A Phase 2a, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral MK-8591 once-monthly in participants at low-risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 27, 2019. NLM Identifier: NCT04003103. Accessed March 31, 2023
27. Hillier S, Bekker L-G, Riddler SA, et al. Safety and pharmacokinetics of oral islatravir once monthly for HIV pre-exposure prophylaxis (PrEP): Week 24 analysis of a Phase 2a trial. IAS Conference on HIV Science; July 18-22, 2021; Virtual and Berlin, Germany. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2021. Accessed March 31, 2023
28. Merck Sharp & Dohme LLC. A Phase 2a, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of a radiopaque matrix MK-8591 implant in participants at low-risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 2, 2021. NLM Identifier: NCT05115838. Accessed March 31, 2023
29. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly as preexposure prophylaxis in cisgender women at high risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 23, 2020. NLM Identifier: NCT04644029. Accessed March 31, 2023
30. Merck Sharp & Dohme LLC. A Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly as preexposure prophylaxis in cisgender men and transgender women who have sex with men, and are at high risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 2, 2020. NLM Identifier: NCT04652700. Accessed March 31, 2023