Philip L Tzou1, Soo-Yon Rhee1, Diane Descamps2, Dana S Clutter3, Bradley Hare4, Orna Mor5, Maxime Grude6, Neil Parkin7, Michael R Jordan8, Silvia Bertagnolio9, Jonathan M Schapiro10, P Richard Harrigan11, Anna Maria Geretti12, Anne-Geneviève Marcelin6, Robert W Shafer1. 1. Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA. 2. Université de Paris, IAME, INSERM, F-75018, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, F-75018, Paris, France. 3. Kaiser-Permanente Medical Care Program - Northern California, South San Francisco, CA, USA. 4. Kaiser-Permanente Medical Care Program - Northern California, San Francisco, CA, USA. 5. Central Virology Laboratory, Sheba Medical Center, Ministry of Health, Ramat-Gan, Israel and Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Israel. 6. Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Department of Virology, F-75013, Paris, France. 7. Data First Consulting Inc., Sebastopol, CA, USA. 8. Tufts University School of Medicine, Boston, MA, USA. 9. Department of HIV and Global Hepatitis Programme, WHO, Geneva, Switzerland. 10. National Hemophilia Center, Shaba Medical Center, Ramat Gan, Israel. 11. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 12. Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
Abstract
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. OBJECTIVES: We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. METHODS: To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. RESULTS: Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. CONCLUSIONS: A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. OBJECTIVES: We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. METHODS: To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. RESULTS: Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. CONCLUSIONS: A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.
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