The first two integrase strand transfer inhibitors (INSTIs) approved for treatment of patients infected with human immunodeficiency virus (HIV) were raltegravir and elvitegravir. Both raltegravir and elvitegravir are now guideline-preferred agents as part of an antiretroviral regimen for treatment-naive patients. However, raltegravir is dosed twice/day. Elvitegravir is available in a single-tablet regimen and dosed once/day because it is administered with the pharmacokinetic booster cobicistat, a potent CYP3A4 inhibitor that can lead to clinically significant drug-drug interactions. In addition, raltegravir and elvitegravir have a low genetic barrier to resistance and are associated with cross-resistance. Dolutegravir is a new-generation INSTI administered once/day without a pharmacokinetic booster and can be coformulated in a single-tablet regimen. Phase III studies have demonstrated the efficacy and safety of dolutegravir for treatment-naive and treatment-experienced patients. Compared with other INSTIs, dolutegravir has a higher genetic barrier to resistance. Dolutegravir was approved by the U.S. Food and Drug Administration in August 2013 and joins raltegravir and elvitegravir as guideline-preferred agents for the management for HIV-infected treatment-naive patients.
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Major role of dolutegravir in the emergence of the S147G integrase resistance mutation.
J Antimicrob Chemother
December 2024
Department of Virology, Sorbonne Université, INSERM, UMR-S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, 83 Boulevard de l'Hôpital 39, F-75013 Paris, France.
Background: The S147G mutation is associated with high-level resistance to the integrase strand transfer inhibitor (INSTI) elvitegravir. In several poorly documented cases, it was also selected in patients on dolutegravir. Given the widespread use of dolutegravir, further studies of S147G are required.
View Article and Find Full Text PDFPredictive Efficacy of Dual Therapies Combining Integrase Strand Transfer Inhibitors with Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Following HIV-1 Treatment Failure in Cameroon: Implications for the Use of a Long-Acting Therapeutic Strategy in Low- and Middle-Income Countries.
Viruses
November 2024
Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon.
Dual therapies (DT) combining integrase strand transfer inhibitors (INSTIs) with second-generation non-nucleoside reverse transcriptase inhibitors (2nd-Gen-NNRTIs) offer new possibilities for HIV treatment to improve adherence. However, drug resistance associated mutations (RAMs) to prior antiretrovirals may jeopardize the efficacy of DT. We herein describe the predicted efficacy of DT combining INSTIs + 2nd-Gen-NNRTI following treatment failure among Cameroonian patients.
View Article and Find Full Text PDFEffectiveness of dolutegravir-based regimens compared to raltegravir-, elvitegravir-, bictegravir, and darunavir-based regimens among older adults with HIV in the Veterans Aging Cohort Study (VACS).
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Veterans Affairs (VA) Connecticut Healthcare System Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), 950 Campbell Avenue, West Haven, CT, 06516-2770, USA.
Background: Real-world data on treatment patterns and clinical outcomes for newer drugs, including integrase strand transfer inhibitors, among older people with human immunodeficiency virus (PWH) are limited.
Methods: This cohort study included PWH enrolled in the Veterans Aging Cohort Study (VACS) who were prescribed a standard 3-drug antiretroviral therapy (ART) regimen containing dolutegravir (DTG), bictegravir (BIC), cobicistat boosted elvitegravir (EVG), raltegravir (RAL), or darunavir/ritonavir (DRV) plus 2 nucleoside reverse transcriptase inhibitors between January 1, 2014, and March 31, 2020, and who were ≥50 years at regimen initiation. The association between regimen and virologic effectiveness or discontinuation was assessed using logistic regression models with inverse probability of treatment weights.
Low prevalence of archived integrase strand transfer inhibitors resistance associated mutations in Botswana before the roll out of dolutegravir based first line antiretroviral therapy.
Front Microbiol
October 2024
Botswana Harvard Health Partnership, Gaborone, Botswana.
Article Synopsis
- - The study assessed the prevalence of drug resistance mutations (DRMs) to integrase strand transfer inhibitors (INSTIs) just before Botswana switched to dolutegravir (DTG) for first-line HIV treatment in 2016, analyzing over 5,000 HIV-1 sequences from various individuals.
- - Results indicated that the overall prevalence of significant INSTI DRMs was 1.11%, with higher rates found in those who had not received antiretroviral treatment (ART-naïve individuals) compared to those who had (ART-experienced individuals).
- - Notable mutations associated with INSTI resistance included E138K and G140R, but high-level resistance to newer drugs like dolutegravir
Prevalence of integrase strand transfer inhibitor resistance in people living with HIV and virological failure.
J Chin Med Assoc
November 2024
Division of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.
Article Synopsis
- This study investigates the resistance profiles of integrase strand transfer inhibitors (INSTIs) in patients from southern Taiwan who experienced failure in antiretroviral therapy (ART), particularly focusing on those previously treated with highly active ART (HAART).
- It analyzes data from patients who failed an INSTI-containing regimen between 2009 and 2022, with genotypic drug resistance tested against established guidelines, revealing insights into mutations associated with treatment failure.
- Among 21 patients who failed INSTI therapy, 40% showed INSTI drug resistance, with specific mutations identified, highlighting the challenges in treating individuals with resistant strains in a treatment-experienced population.
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