Islatravir Explained

Islatravir (4′-ethynyl-2-fluoro-2′-deoxyadenosine, EFdA, or MK-8591) is an investigational drug for the treatment of HIV infection.[1] It is classified as a nucleoside reverse transcriptase translocation inhibitor (NRTTI).[2] Merck is developing a subdermal drug-eluting implant to administer islatravir.[3] [4]

In 2021, FDA placed a partial clinical hold for several studies under Islatravir.[5] The reason was a decline in CD4 T cells under therapy. Merck announced to restart the study program in 2023 with a decreased dose, however studies of islatravir for pre-exposure prophylaxis (PrEP) will be discontinued.[6]

In 2024, results from a phase II study combining islatravir with lenacapavir indicated that the regimen shows promise as a possible weekly oral regimen.[7]

Biological activity

Islatravir has activity against HIV in animal models,[8] and is being studied clinically for HIV treatment and prophylaxis.[9] Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that unlike other such inhibitors, inhibits HIV through multiple mechanisms,[8] providing rapid suppression of the virus, when tested in macaques and mice.[10] Nevertheless, there are HIV strains resistant to islatravir and research is ongoing.[11] [12]

Notes and References

  1. Kawamoto . A . Kodama . E . Sarafianos . SG . Sakagami . Y . Kohgo . S . Kitano . K . Ashida . N . Iwai . Y . Hayakawa . H . Nakata . H . Mitsuya . H . Arnold . E . Matsuoka . M . 2'-deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants . The International Journal of Biochemistry & Cell Biology . 2008 . 40 . 11 . 2410–20 . 10.1016/j.biocel.2008.04.007 . 18487070.
  2. Top Antivir Med . 2018 . 25 . 4 . 127–132 . 5935216 . 29689540 . Investigational Antiretroviral Drugs: What is Coming Down the Pipeline . Roy M. Gulick .
  3. News: Someday, an Arm Implant May Prevent H.I.V. Infection for a Year . New York Times . July 23, 2019 .
  4. Merck Presents Early Evidence on Extended Delivery of Investigational Anti-HIV-1 Agent Islatravir (MK-8591) via Subdermal Implant . July 23, 2019 .
  5. Web site: Merck restarts islatravir HIV treatment studies, but abandons monthly PrEP . 2023-05-02 . aidsmap.com . en.
  6. Web site: 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 . Merck . 10 March 2024.
  7. Web site: Highleyman . Liz . Islatravir plus lenacapavir could be the first once-weekly oral HIV treatment . Aidsmap . 10 March 2024 . 6 March 2024.
  8. Michailidis . Eleftherios . Huber . Andrew D. . Ryan . Emily M. . Ong . Yee T. . Leslie . Maxwell D. . Matzek . Kayla B. . Singh . Kamalendra . Marchand . Bruno . Hagedorn . Ariel N. . Kirby . Karen A. . Rohan . Lisa C. . Kodama . Eiichi N. . Mitsuya . Hiroaki . Parniak . Michael A. . Sarafianos . Stefan G. . 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms . Journal of Biological Chemistry . 289 . 35 . 24533–48 . 2014 . 24970894 . 4148878 . 10.1074/jbc.M114.562694 . free .
  9. Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis . Grobler. Jay . February 22–25, 2016. Conference on Retroviruses and Opportunistic Infections . Boston, Massachusetts . 98.
  10. Stoddart . Cheryl A. . Galkina . Sofiya A. . Joshi . Pheroze . Kosikova . Galina . Moreno . Mary E. . Rivera . Jose M. . Sloan . Barbara . Reeve . Aaron B. . Sarafianos . Stefan G. . Murphey-Corb . Michael . Parniak . Michael A. . Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque . Antimicrobial Agents and Chemotherapy . 59 . 7 . 4190–8 . 2015 . 25941222 . 4468726 . 10.1128/AAC.05036-14 .
  11. Web site: The Crystal Structure of EFdA‐Resistant HIV‐1 Reverse Transcriptase Reveals Structural Changes in the Polymerase Active Site . Bruno Marchand.
  12. Salie . Zhe Li . Kirby . Karen A. . Michailidis . Eleftherios . Marchand . Bruno . Singh . Kamalendra . Rohan . Lisa C. . Kodama . Eiichi N. . Mitsuya . Hiroaki . Parniak . Michael A. . Sarafianos . Stefan G. . Structural basis of HIV inhibition by translocation-defective RT inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) . Proceedings of the National Academy of Sciences . 16 August 2016 . 113 . 33 . 9274–9279 . 10.1073/pnas.1605223113. 27489345 . 4995989 . free .

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