ArticleAntimicrobial agents and chemotherapy2011
Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers, 3 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
104 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Pooled it
- Current ART, determinants for virologic failure and implications for HIV drug resistance: an umbrella review.AIDS research and therapy · 2023Pooled it
- Dolutegravir(DTG, S/GSK1349572) combined with other ARTs is superior to RAL- or EFV-based regimens for treatment of HIV-1 infection: a meta-analysis of randomized controlled trials.AIDS research and therapy · 2016Pooled it
- Trial
- Pharmacokinetics and safety of dolutegravir in children receiving rifampicin tuberculosis treatment in South Africa (ORCHID): a prospective cohort study.The lancet. HIV · 2025Trial
- 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.Antimicrobial agents and chemotherapy · 2022Trial
- Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.Clinical pharmacology in drug development · 2020Trial
- Effects of Low- and High-Mineral Content Water on the Relative Bioavailability of a Coformulated Abacavir/Dolutegravir/Lamivudine Dispersible Tablet in Healthy Adults.Journal of acquired immune deficiency syndromes (1999) · 2018Trial
- Targeting Human Immunodeficiency Virus Integrase Beyond the Active Site: The Discovery and Development of Allosteric Integrase Inhibitors.ChemMedChem · 2026Review
- Non-integrase mechanisms for dolutegravir resistance.Retrovirology · 2026Review
- HIV Resistance to Dolutegravir Varies With Coadministered Agents.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026Article
- A model-based comparison of dose reduction strategies for fixed-dose dolutegravir-containing regimens.The Journal of antimicrobial chemotherapy · 2026Article
- Dolutegravir-associated hyperglycemia: a narrative review.AIDS research and therapy · 2025Review
- Pharmacogenetics of plasma dolutegravir exposure during 1-month rifapentine/isoniazid treatment of latent tuberculosis.Pharmacogenetics and genomics · 2025Article
- The population pharmacokinetics of dolutegravir co-administered with rifampicin in Thai people living with HIV: Assessment of alternative dosing regimens.CPT: pharmacometrics & systems pharmacology · 2025Article
- Brief Histories of Retroviral Integration Research and Associated International Conferences.Viruses · 2024Review
- Epistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors.Science advances · 2024Article
- Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants.Science advances · 2023Article
- Dolutegravir once daily with rifampicin for HIV and tuberculosis.The lancet. HIV · 2023Article
- Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes.Antimicrobial agents and chemotherapy · 2023Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10(-6) s(-1) and a dissociative half-life (t(1/2)) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t(1/2), at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.
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