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Schürmann D, Jackson Rudd D, Schaeffer A, et al. Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. J Acquir Immune Defic Syndr. 2022;89(2):191-198doi: 10.1097/QAI.0000000000002834.
Schürmann, D., Jackson Rudd, D., Schaeffer, A., De Lepeleire, I., Friedman, E. J., Robberechts, M., Zhang, S., Liu, Y., Kandala, B., Keicher, C., Däumer, M., Hofmann, J., Grobler, J. A., Stoch, S. A., Iwamoto, M., & Ankrom, W. (2022). Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. Journal of acquired immune deficiency syndromes (1999), 89(2), 191-198. https://doi.org/10.1097/QAI.0000000000002834
Schürmann, Dirk, et al. "Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week." Journal of acquired immune deficiency syndromes (1999) vol. 89,2 (2022): 191-198. doi: https://doi.org/10.1097/QAI.0000000000002834
Schürmann D, Jackson Rudd D, Schaeffer A, De Lepeleire I, Friedman EJ, Robberechts M, Zhang S, Liu Y, Kandala B, Keicher C, Däumer M, Hofmann J, Grobler JA, Stoch SA, Iwamoto M, Ankrom W. Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. J Acquir Immune Defic Syndr. 2022 Feb 01;89(2):191-198. doi: 10.1097/QAI.0000000000002834. PMID: 34654041.
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J Acquir Immune Defic Syndr. 2022 Feb 01;89(2):191-198. doi: 10.1097/QAI.0000000000002834.

Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week.

Journal of acquired immune deficiency syndromes (1999)

Dirk Schürmann, Deanne Jackson Rudd, Andrea Schaeffer, Inge De Lepeleire, Evan J Friedman, Martine Robberechts, Saijuan Zhang, Yang Liu, Bhargava Kandala, Christian Keicher, Martin Däumer, Jörg Hofmann, Jay A Grobler, S Aubrey Stoch, Marian Iwamoto, Wendy Ankrom

Affiliations

  1. Charité Research Organisation GmbH, Berlin, Germany.
  2. Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  3. Merck & Co., Inc., Kenilworth, NJ.
  4. MSD, Brussels, Belgium.
  5. Seq-IT GmbH & Co. KG, Kaiserslautern, Germany; and.
  6. Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

PMID: 34654041 DOI: 10.1097/QAI.0000000000002834

Abstract

BACKGROUND: MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing.

SETTING: A phase 1, open-label, proof-of-concept study was conducted in treatment-naive adults with HIV-1 infection to assess monotherapy antiviral activity.

METHODS: In 3 sequential panels, participants aged 18-60 years with baseline plasma HIV-1 RNA ≥10,000 copies/mL and CD4+ T-cell count >200/mm3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PKs for 14 days, and safety and tolerability for 21 days postdose.

RESULTS: A total of 18 participants were enrolled (6 per panel). The mean 7-day postdose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of an F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days postdose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PKs were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half life was 56-69 hours in this study. MK-8507 was generally well tolerated at all doses.

CONCLUSIONS: The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

References

  1. AIDSMAP. Types of antiretrovial medications. 2020. Available at: https://www.aidsmap.com/about-hiv/types-antiretroviral-medications. Accessed April 1, 2021. - PubMed
  2. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet. 2013;382:1525–1533. - PubMed
  3. Smith DE, Woolley IJ, Russell DB, et al. HIV in practice: current approaches and challenges in the diagnosis, treatment and management of HIV infection in Australia. HIV Med. 2018;19(suppl 3):5–23. - PubMed
  4. Marcus JL, Leyden WA, Alexeeff SE, et al. Comparison of overall and comorbidity-free life expectancy between insured adults with and without HIV infection. JAMA Netw Open. 2020;3:e207954. - PubMed
  5. Iacob SA, Iacob DG, Jugulete G. Improving the adherence to anti-retroviral. therapy, a difficult but essential task for a successful HIV treatment-clinical points of view and practical considerations. Front Pharmacol. 2017;8:831. - PubMed
  6. Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol. 2015;79:182–194. - PubMed
  7. Bangsberg DR, Perry S, Charlebois ED, et al. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS. 2001;15:1181–1183. - PubMed
  8. Harrigan PR, Hogg RS, Dong WW, et al. Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. J Infect Dis. 2005;191:339–347. - PubMed
  9. Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002;16:1051–1058. - PubMed
  10. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. 2019. Available at: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Accessed June 1, 2021. - PubMed
  11. Solomon DA, Sax PE. Current state and limitations of daily oral therapy for treatment. Curr Opin HIV AIDS. 2015;10:219–225. - PubMed
  12. Polonsky WH, Henry RR. Poor medication adherence in type 2 diabetes: recognizing the scope of the problem and its key contributors. Patient Prefer Adherence. 2016;10:1299–1307. - PubMed
  13. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23:1296–1310. - PubMed
  14. Rintamaki L, Kosenko K, Hogan T, et al. The role of stigma management in HIV treatment adherence. Int J Environ Res Public Health. 2019;16:5003. - PubMed
  15. Shubber Z, Mills EJ, Nachega JB, et al. Patient-reported barriers to adherence to antiretroviral therapy: a systematic review and meta-analysis. Plos Med. 2016;13:e1002183. - PubMed
  16. Cabenuva. Prescribing information. Viiv Healthcare; 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf. Accessed November 2, 2021. - PubMed
  17. European Medicines Agency. Assessment Report: Vocabria. Published October 15, 2020. Available at: https://www.ema.europa.eu/en/documents/assessment-report/vocabria-epar-public-assessment-report_en.pdf. Accessed February 17, 2021. - PubMed
  18. Iglay K, Cao X, Mavros P, et al. Systematic literature review and meta-analysis of medication adherence with once-weekly versus once-daily therapy. Clin Ther. 2015;37:1813–1821.e1. - PubMed
  19. Qiao Q, Ouwens MJ, Grandy S, et al. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany. Diabetes Metab Syndr Obes. 2016;9:201–205. - PubMed
  20. Diamond TL, Lai MT, Feng M, et al. Resistance profile of MK-8507, a novel NNRTI suitable for weekly oral HIV treatment. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2021 (virtual); March 6–10, 2021. Abstract #129. - PubMed
  21. Ankrom W, Schürmann D, Jackson Rudd D, et al. Oral presentation: Single doses of MK-8507, a novel HIV-1 NNRTI, reduced HIV viral load for at least a week. HIV Glasgow 2020; October 5–8, 2020 (Virtual). - PubMed
  22. Stanford University. Stanford University HIV Drug Resistance Database: HIVdb Program. Available at: https://hivdb.stanford.edu/hivdb/by-mutations/. Accessed August 13, 2020. - PubMed
  23. Shafer RW, Jung DR, Betts BJ. Human immunodeficiency virus type 1 reverse transcriptase and protease mutation search engine for queries. Nat Med. 2000;6:1290–1292. - PubMed
  24. Xu Y, Li YF, Zhang D, et al. Characterizing class-specific exposure-viral load suppression response of HIV antiretrovirals using a model-based meta-analysis. Clin Transl Sci. 2016;9:192–200. - PubMed
  25. Acosta EP, Limoli KL, Trinh L, et al. Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data. Antimicrob Agents Chemother. 2012;56:5938–5945. - PubMed
  26. Preston SL, Piliero PJ, Bilello JA, et al. In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours. Antimicrob Agents Chemother. 2003;47:3393–3399. - PubMed
  27. Rizk ML, Hang Y, Luo WL, et al. Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients. Antimicrob Agents Chemother. 2012;56:3101–3106. - PubMed
  28. ClinicalTrials.gov. NCT04564547: Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013]. Available at: https://clinicaltrials.gov/ct2/show/NCT04564547. Accessed August 5, 2020. - PubMed
  29. Soulie C, Santoro MM, Storto A, et al. Prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients from two large databases in France and Italy. J Antimicrob Chemother. 2020;75:1026–1030. - PubMed
  30. Calvez V, Marcelin AG, Vingerhoets J, et al. Systematic review to determine the prevalence of transmitted drug resistance mutations to rilpivirine in HIV-infected treatment-naive persons. Antivir Ther. 2016;21:405–412. - PubMed
  31. Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr. 2012;59:39–46. - PubMed
  32. Orkin C, Squires K, Molina J, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis. 2018;68:535–544. - PubMed
  33. Stanford University. Major Non-Nucleoside RT Inhibitor (NNRTI) Resistance Mutations. 2021. Available at: https://hivdb.stanford.edu/dr-summary/resistance-notes/NNRTI/. Accessed August 13, 2021. - PubMed
  34. European AIDS Clinical Society (EACS). European Guidelines for the Treatment of HIV-Positive Adults in Europe Version 10.1. 2020. Available at: https://www.eacsociety.org/files/guidelines-10.1.finalsept2020.pdf. Accessed April 1, 2021. - PubMed
  35. Pennings PS. HIV drug resistance: problems and perspectives. Infect Dis Rep. 2013;5(suppl 1):e5. - PubMed

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