Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes

Author:

Giammarino Federica1,de Salazar Adolfo234ORCID,Malet Isabelle5,Viñuela Laura234,Fuentes Ana234ORCID,Saladini Francesco1ORCID,Bartolini Niccolò1,Charpentier Charlotte6,Lambert-Niclot Sidonie7ORCID,Sterrantino Gaetana8ORCID,Colao Maria Grazia9,Micheli Valeria10,Bertoli Ada1112,Fabeni Lavinia13,Teyssou Elisa5,Delgado Rafael14ORCID,Falces-Romero Iker415ORCID,Aguilera Antonio16,Gomes Perpetua1718,Paraskevis Dimitrios19ORCID,Santoro Maria M12,Ceccherini-Silberstein Francesca12,Marcelin Anne-Genevieve5,Moreno Cristina420,Zazzi Maurizio1,García Federico234ORCID

Affiliation:

1. Department of Medical Biotechnologies, University of Siena , Siena , Italy

2. Clinical Microbiology, Hospital Universitario Clinico San Cecilio , Granada , Spain

3. Instituto de Investigación Biosanitaria (ibs.Granada) , Granada , Spain

4. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC) , Instituto de Salud Carlos III, Madrid , Spain

5. Laboratoire de Virologie, Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié-Salpêtrière , Paris , France

6. Service de Virologie, Université Paris Cité, INSERM, IAME, UMR 1137, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard , Paris , France

7. Laboratoire de Virologie, Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine , Paris , France

8. Department of Clinical and Experimental Medicine, University of Florence , Florence , Italy

9. Laboratory of Microbiology and Virology, Careggi Hospital , Florence , Italy

10. Department of Clinical Microbiology, Virology, and Bioemergencies, Sacco University Hospital , Milan , Italy

11. Laboratory of Virology, University Hospital Tor Vergata , Rome , Italy

12. Department of Experimental Medicine, University of Rome Tor Vergata , Rome , Italy

13. Virology and Biosafety Laboratories Unit, Lazzaro Spallanzani-IRCCS, National Institute for Infectious Diseases , Rome , Italy

14. Clinical Microbiology Service, Instituto de Investigación, Hospital 12 de Octubre , Madrid , Spain

15. Clinical Microbiology Service, Hospital La Paz , Madrid , Spain

16. Clinical Microbiology Service, Hospital Clínico Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago (IDIS) , Santiago de Compostela , Spain

17. Egas Moniz Center for Interdisciplinary Research, Egas Moniz School of Health and Science , Almada , Portugal

18. Laboratório de Biología Molecular, Centro Hospitalar Lisboa Ocidental-Hospital Egas Moniz , Lisboa , Portugal

19. Department of Hygiene, Epidemiology, and Medical Statistics, National and Kapodistrian University of Athens , Athens , Greece

20. National Centre for Epidemiology, Institute of Health Carlos III , Madrid , Spain

Abstract

Abstract Background Limited data are available regarding the susceptibility of the reverse transcriptase V106 polymorphism to doravirine. Methods Doravirine susceptibility was measured in site-directed mutants (SDMs) containing V106I, V106A, V106M, and Y188L mutations in subtype B (NL4-3, HXB2) and CRF02_AG background and in recombinant viruses with RT harboring V106I alone derived from 50 people with HIV. Results HIV-1 B subtype was detected in 1523 of 2705 cases. Prevalence of V106I was 3.2% in B and 2.5% in non-B subtypes, and was higher in subtype F (8.1%) and D (14.3%). Fold-changes (FC) in susceptibility for SDMs were below doravirine biological cutoff (3.0) for V106I, but not for V106A, V106M, and Y188L. Clinically derived viruses tested included 22 B (median FC, 1.2; interquartile range [IQR], 0.9–1.6) and 28 non-B subtypes (median FC, 1.8; IQR, 0.9–3.0). Nine (18%) viruses showed FC values equal or higher than the doravirine biological FC cutoff. Conclusions The prevalence of the HIV-1 RT V106I polymorphism in MeditRes HIV consortium remains low, but significantly more prevalent in subtypes D and F. V106I minimally decreased the susceptibility to doravirine in SDMs and most clinical isolates. Reduced susceptibility seems to occur at increased frequency in subtype F1; however, the clinical impact remains to be investigated. Clinical Trials Registration NCT04894357.

Funder

Merck Sharp and Dohme, LLC

Plan Nacional de I + D + I

Fondo

Europeo de Desarrollo Regional

Fundacion Progreso y Salud

Junta de Andalucia

Instituto de Salud Carlos III

Publisher

Oxford University Press (OUP)

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