Drug information

Audio
Pronounce:
Other Names
EFdA, ISL, MK-8591
Drug Class
Nucleoside Reverse Transcriptase Translocation Inhibitors
Molecular Formula:

C12 H12 F N5 O3

Registry Number
865363-93-5 (CAS)
Chemical Name

4'-Ethynyl-2-fluoro-2'-deoxyadenosine

Chemical Class
Purine Nucleosides
Organization
Merck Sharp & Dohme Corp.
Phase of Development

Islatravir is in Phase 3 development for HIV treatment. It is being developed as a stand-alone agent and as part of a fixed-dose combination containing doravirine and islatravir (DOR/ISL).  Islatravir is also in Phase 3 development for HIV prevention.

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Treatment Action Group Pipeline Report 20213,4)

 
What is islatravir?What is 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.5

Islatravir may be effective against certain HIV strains that are resistant to other HIV drugs.6

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.

 

Which clinical trials are studying islatravir?Which clinical trials are studying islatravir?

Which clinical trials are studying 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.

Participants who started treatment in ongoing studies of doravirine/islatravir will continue receiving study drugs; however, no new participants will be screened or randomized in doravirine/islatravir studies. Participants receiving islatravir in prevention studies will no longer receive study drug; however, their CD4 and lymphocyte counts will continue to be monitored. For more information about the clinical holds on trials evaluating islatravir, please refer to the drug developer’s December 13, 2021 press release.7

 

Islatravir for HIV treatment

Study Names:  MK-8591-011; NCT03272347
Phase: 2b
Status: This study was placed on partial clinical hold in December 2021. (A clinical hold is an order given by FDA to a drug sponsor to delay or suspend clinical trial work under an investigational new drug application (IND). A clinical hold can be either complete [“full”] or partial.) Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Locations: Chile, France, United Kingdom, United States
Purpose: The purpose of this trial is 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 adults with HIV who have never taken HIV medicines before. After 24 weeks, investigators will evaluate the safety and effectiveness of islatravir (given at three different dose levels) plus doravirine.7,8
Selected Study Results: Results published in Lancet HIV showed that treatment regimens containing islatravir and doravirine were highly effective in reducing participants’ viral load levels. There were few reports of drug-related side effects or discontinuations due to side effects associated with islatravir plus doravirine.9


Study Names: IMAGINE-DR; MK-8591-013; NCT04564547
Phase: 2b
Status: See note below. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Locations: United States, France, Switzerland
Purpose: The purpose of this study is to evaluate a switch to islatravir plus the investigational non-nucleoside reverse transcriptase Inhibitor (NNRTI) MK-8507 given once weekly in participants with viral suppression on bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy).10,11
Note: The developers of islatravir 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 islatravir and MK-8507.11  As of December 1, 2021, 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.10


Study Names: GS-US-563-6041; NCT05052996
Phase: 2
Status: See note below. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Location: United States
Purpose: The purpose of this study is to evaluate the efficacy of oral weekly islatravir in combination with the investigational capsid inhibitor lenacapavir in participants with viral suppression on Biktarvy.12
Note: The developers of islatravir and lenacapavir announced in a December 13, 2021 press release that they were stopping dosing of participants in the GS-US-563-6041 trial. Participants will discontinue study treatment and will restart their prior ART regimen.7


Study Names:  ILLUMINATE SWITCH A; MK-8591A-017; NCT04223778
Phase: 3
Status: This study was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Locations: Multiple countries, including United States
Purpose: The purpose of this trial is to evaluate the safety and effectiveness of a switch from a current ART regimen to a fixed-dose combination (FDC) containing doravirine/islatravir.7,13
Selected Study Results: Results announced in an October 25, 2021 press release indicated that the doravirine/islatravir FDC was as effective as other ART regimens in controlling participants’ viral load levels. The safety of doravirine/islatravir was similar to what had previously been reported in Phase 2 studies.14


Study Names: ILLUMINATE SWITCH B; MK-8591A-018; NCT04223791
Phase: 3
Status: This study was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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.7,15
Selected Study Results: Results announced in an October 25, 2021 press release indicated that the doravirine/islatravir FDC was as effective as Biktarvy in controlling participants’ viral load levels. The safety of doravirine/islatravir was similar to what had previously been reported in Phase 2 studies.14


Study Names: ILLUMINATE HTE; MK-8591A-019; NCT04233216
Phase: 3
Status: This study was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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 participants with antiretroviral drug resistance.7,16


Study Names: ILLUMINATE NAIVE;  MK-8591A-020; NCT04233879
Phase: 3
Status: This study was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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 adults with HIV who have never taken HIV medicines before.7,17


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 (less than 18 years of age and weighing at least 35 kg) who have viral suppression on ART or who have never taken HIV medicines before. This study was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.7,18
  • 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 was placed on partial clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.7,19

 

Islatravir for HIV prevention

Study Names: MK-8591-016; NCT04003103
Phase: 2a
Status: This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Locations: United States, Israel, South Africa
Purpose: The purpose of this study is to evaluate the safety and pharmacokinetics of two different doses of oral islatravir given once a month to participants who have a low risk of getting HIV.7,20
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.21


Study Names: MK-8591-043; NCT05115838
Phase: 2a
Status: This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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.7,22


Study Names: MK-8591-035; NCT05130086
Phase: 2
Status: This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Location: Not available
Purpose: The purpose of this study is to evaluate the safety and tolerability of oral islatravir given once monthly in trans and gender diverse participants who are receiving gender-affirming hormone therapy and are at low risk of getting HIV.7,23


Study Names: IMPOWER 22; MK-8591-022; NCT04644029
Phase: 3
Status: This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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 pre-exposure prophylaxis (PrEP) in cisgender women who are at high risk of getting HIV,7,24


Study Names: IMPOWER 24; MK-8591-024; NCT04652700
Phase: 3
Status: This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
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.7,25


Additionally, an injectable formulation of islatravir is being evaluated in a Phase 1 trial (MK-8591-034). This study was placed on full clinical hold in December 2021. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.7

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

 

What side effects might islatravir cause?What side effects might islatravir cause?

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. For more information about the clinical holds on trials evaluating islatravir, please refer to the drug developer’s December 13, 2021 press release.7


MK-8591-011 (NCT03272347):

In this Phase 2b study, 8% of participants who received islatravir reported experiencing 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.8,9

ILLUMINATE SWITCH A (MK-8591A-017; NCT04223778) and ILLUMINATE SWITCH B (MK-8591A-018; NCT04223791):

Results for both of these Phase 3 trials trials evaluating the doravirine/islatravir FDC in participants with viral suppression were announced in a company press release. The doravirine/islatravir FDC was reported to have a comparable safety profile to what has already been seen in previous Phase 2 trials.13-15

MK-8591-016 (NCT04003103):

In this Phase 2a trial evaluating 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.20,21

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

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

More information about islatravir-related research studies is available from ClinicalTrials.gov.

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.

 

ReferencesReferences

References

  1. United States National Library of Medicine. ChemIDplus Advanced: Islatravir. https://chem.nlm.nih.gov/chemidplus/rn/865363-93-5. Accessed January 13, 2022
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed January 13, 2022
  3. Jefferys R. The antiretroviral therapy pipeline 2021. Treatment Action Group Pipeline Report 2021. https://www.treatmentactiongroup.org/wp-content/uploads/2021/07/pipeline_2021_hiv_ARV_final.pdf. Accessed January 13, 2022
  4. Jefferys R. The PrEP and microbicides pipeline. Treatment Action Group Pipeline Report 2021. https://www.treatmentactiongroup.org/wp-content/uploads/2021/07/pipeline_2021_hiv_PrEP_final.pdf. Accessed January 13, 2022
  5. 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
  6. 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. https://vimeo.com/298576925. Accessed January 13, 2022
  7. Merck: Press release, dated December 13, 2021. Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 infection. https://www.merck.com/news/merck-announces-clinical-holds-on-studies-evaluating-islatravir-for-the-treatment-and-prevention-of-hiv-1-infection/. Accessed January 13, 2022
  8. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT03272347. Accessed January 13, 2022
  9. 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
  10. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04564547. Accessed January 13, 2022
  11. 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. 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/. Accessed January 13, 2022
  12. 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. https://clinicaltrials.gov/ct2/show/NCT05052996. Accessed January 13, 2022
  13. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/study/NCT04223778. Accessed January 13, 2022
  14. Merck: Press release, dated October 25, 2021. Week 48 data met safety and efficacy endpoints in adults with HIV-1 infection currently on antiretroviral therapy. https://www.merck.com/news/merck-announces-positive-top-line-results-from-pivotal-phase-3-trials-evaluating-investigational-once-daily-oral-fixed-dose-combination-of-doravirine-islatravir-for-the-treatment-of-people-with-hiv-1/. Accessed January 13, 2022
  15. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04223791. Accessed January 13, 2022
  16. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04233216. Accessed January 13, 2022
  17. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04233879. Accessed January 13, 2022
  18. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04295772. Accessed January 13, 2022
  19. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04776252. Accessed January 13, 2022
  20. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04003103. Accessed January 13, 2022
  21. 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. https://natap.org/2021/IAS/IAS_50.htm. Accessed January 13, 2022
  22. Merck Sharp & Dohme Corp. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT05115838. Accessed January 13, 2022
  23. Merck Sharp & Dohme Corp. A Phase 2 open-label study to evaluate the safety and pharmacokinetics of oral islatravir once-monthly in trans and gender diverse individuals on gender-affirming hormone therapy and at low-risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2021. NLM Identifier: NCT05130086. https://clinicaltrials.gov/ct2/show/NCT05130086. Accessed January 13, 2022
  24. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04644029. Accessed January 13, 2022
  25. Merck Sharp & Dohme Corp. 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. https://clinicaltrials.gov/ct2/show/NCT04652700. Accessed January 13, 2022

 

 

Last Reviewed: January 13, 2022