1. Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study
- Author
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Eugene L. Stewart, Mark R. Underwood, Joseph Horton, Michael Aboud, Keith Nangle, Judy Hopking, Kimberly Y. Smith, Ruolan Wang, Brian Wynne, and Jörg Sievers
- Subjects
Adult ,Pyridones ,Population ,Integrase inhibitor ,HIV Infections ,integrase strand transfer inhibitor ,HIV Integrase ,Drug resistance ,HIV-1 infection ,Antiviral Agents ,Piperazines ,Nucleoside Reverse Transcriptase Inhibitor ,chemistry.chemical_compound ,Oxazines ,medicine ,Humans ,Pharmacology (medical) ,HIV Integrase Inhibitors ,education ,Genotyping ,Pharmacology ,education.field_of_study ,business.industry ,Nucleosides ,Lopinavir ,Virology ,antiretroviral agents ,dolutegravir ,Infectious Diseases ,Viral replication ,chemistry ,Dolutegravir ,HIV-1 ,Reverse Transcriptase Inhibitors ,barrier to resistance ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
At week 48 in the phase IIIb DAWNING study, the integrase strand transfer inhibitor (INSTI) dolutegravir plus 2 nucleoside reverse transcriptase inhibitors demonstrated superiority to ritonavir-boosted lopinavir in achieving virologic suppression in adults with HIV-1 who failed first-line therapy. Here, we report emergent HIV-1 drug resistance and mechanistic underpinnings among dolutegravir-treated adults in DAWNING. Population viral genotyping, phenotyping, and clonal analyses were performed on participants meeting confirmed virologic withdrawal (CVW) criteria on dolutegravir-containing regimens. Dolutegravir binding to and structural changes in HIV-1 integrase-DNA complexes with INSTI resistance-associated substitutions were evaluated. Of participants who received dolutegravir through week 48 plus an additional 110 weeks for this assessment, 6 met CVW criteria with treatment-emergent INSTI resistance-associated substitutions and 1 had R263R/K at baseline but not at CVW. All 7 achieved HIV-1 RNA levels of 10-fold and reduced viral replication capacity versus baseline levels. This study demonstrates that the pathway to dolutegravir resistance is a challenging balance between HIV-1 phenotypic change and associated loss of viral fitness. (This study has been registered at ClinicalTrials.gov under identifier NCT02227238.)
- Published
- 2022