Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors
Open accessAbstract
Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97).
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Dolutegravir, bictegravir, and cabotegravir are second-generation INSTIs with reduced susceptibility to viral mutations that render raltegravir and elvitegravir ineffective.
“The latter three, classified as second-generation compounds, are characterized by reduced susceptibility to viral mutations that render the first-generation drugs, raltegravir and elvitegravir, ineffective151–153.”
From Structure and function of retroviral integrase (2022) · cites this paper as [153]
The Results report that viruses with G140S/Q148H were highly resistant to raltegravir and elvitegravir but had relatively small susceptibility changes to dolutegravir, bictegravir, and cabotegravir. The claim is broader than that finding: the Results also show that additional mutations produced substantial resistance to all three newer inhibitors. (LLM, conf=0.85)
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Targeting HIV-1 integrase: A review of options, challenges and future directions
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BindingDB (2026) · UC San Diego · doi:10.7270/q22v2mzm
BindingDB (2026) · UC San Diego · doi:10.7270/q2pg1xnq
- Authors
- Zhang, W. W., Cheung, P. K., Oliveira, N., Robbins, M. A., Harrigan, P. R., & Shahid, A.
- Affiliations
- University of British Columbia (CA)
- BC Centre for Excellence in HIV/AIDS (CA)
- Corresponding author
- Harrigan, P Richard
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-07-16
- Volume
- 218
- Issue
- 11
- Pages
- 1773-1776
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- OpenAlex
- W2884916801
- Cited by
- 44
- References
- 14
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 1
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- HIV integrase inhibitors, drug resistance, cross-resistance, bictegravir, cabotegravir, dolutegravir, raltegravir, elvitegravir
- MeSH terms
- Dolutegravir, Amides, Cell Line, Heterocyclic Compounds, 3-Ring, Heterocyclic Compounds, 4 or More Rings, Humans, Oxazines, Piperazines, Pyridones, HIV-1, HIV Infections, HIV Integrase Inhibitors, Drug Resistance, Viral, Diketopiperazines
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