scholarly journals A systematic review of the genetic mechanisms of dolutegravir resistance

2019 ◽  
Vol 74 (11) ◽  
pp. 3135-3149 ◽  
Author(s):  
Soo-Yon Rhee ◽  
Philip M Grant ◽  
Philip L Tzou ◽  
Geoffrey Barrow ◽  
P Richard Harrigan ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Resistance Mutations ◽  
First Line Therapy ◽  
Highly Effective ◽  
Active Viral Replication ◽  
Drug Regimens ◽  
Genetic Mechanisms ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Background Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. Methods We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons. Results and conclusions We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir’s companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir’s companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

National Landscape of HIV+ Deceased Organ Donors in the United States

2021 ◽  
Author(s):  
William A Werbel ◽  
Diane M Brown ◽  
Oyinkansola T Kusemiju ◽  
Brianna L Doby ◽  
Shanti M Seaman ◽  
...  
Keyword(s):  
The United States ◽  
Organ Donors ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Hiv Diagnosis ◽  
Hiv Viral Load ◽  
Drug Resistance Mutations ◽  
Transfer Inhibitor ◽  
A Prospective Study ◽  
Integrase Strand Transfer Inhibitor

Abstract Background Organ transplantation from donors with HIV to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV+ donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) testing within the HOPE in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262; NCT03500315; NCT03734393). We compared clinical characteristics in HIV+ versus FP donors. We measured CD4+ T cells, HIV viral load (VL), drug resistance mutations (DRMs), co-receptor tropism, and serum antiretroviral therapy (ART) detection using mass spectrometry in HIV+ donors. Results Between 03/2016-03/2020, 92 donors (58 HIV+, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidney, 46 liver). Each year the number of donors increased. Prevalence of hepatitis B (16% vs. 0%), syphilis (16% vs. 0%), and cytomegalovirus (91% vs. 58%) was higher in HIV+ versus FP donors; hepatitis C viremia was similar (2% vs. 6%). Most HIV+ donors (71%) had known HIV diagnosis, of whom 90% were prescribed ART and 68% had VL<400 copies/mL. Median CD4 count was 194 cells/uL (IQR=77-331); median CD4% was 27.0 (IQR=16.8-36.1). Major HIV DRMs were detected in 42%, including non-nucleoside reverse transcriptase inhibitors (33%), integrase strand transfer inhibitor (INSTI, 4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. Conclusion Utilization of HIV+ donor organs is increasing. HIV DRMs are common, yet resistance that would compromise INSTI-based regimens is rare, which is reassuring regarding safety.

scholarly journals Dolutegravir impairs stem cell-based 3D morphogenesis models in a manner dependent on dose and timing of exposure: an implication for its developmental toxicity

2021 ◽  
Author(s):  
Lauren Kirkwood-Johnson ◽  
Nana Katayama ◽  
Yusuke Marikawa
Keyword(s):  
Stem Cells ◽  
Animal Studies ◽  
Expression Profiles ◽  
Developmental Toxicity ◽  
Strand Transfer ◽  
In Vitro Morphogenesis ◽  
Transfer Inhibitor ◽  
Timing Of Exposure ◽  
Integrase Strand Transfer Inhibitor

Abstract Dolutegravir is an anti-retroviral drug of the integrase strand transfer inhibitor class used to treat HIV infection. It is the recommended first-line regimen for most people, including women of childbearing age. However, some human and animal studies have suggested that dolutegravir causes birth defects, although its developmental toxicity remains controversial. Here, we investigated the adverse effects of dolutegravir using pluripotent stem cell-based in vitro morphogenesis models that have previously been validated as effective tools to assess the developmental toxicity of various chemicals. Dolutegravir diminished the growth and axial elongation of the morphogenesis model of mouse pluripotent stem cells at exposures of 2 μM and above in a concentration-dependent manner. Concomitantly, dolutegravir altered the expression profiles of developmental regulator genes involved in embryonic patterning. The adverse effects were observed when the morphogenesis model was exposed to dolutegravir at early stages of development, but not at later stages. The potency and molecular impact of dolutegravir on the morphogenesis model were distinct from other integrase strand transfer inhibitors. Lastly, dolutegravir altered the growth and gene expression profiles of the morphogenesis model of human embryonic stem cells at 1 μM and above. These studies demonstrate that dolutegravir impairs morphological and molecular aspects of the in vitro morphogenesis models in a manner dependent on dose and timing of exposure through mechanisms that are unrelated to its action as an integrase strand transfer inhibitor. This finding will be useful for interpreting the conflicting outcomes regarding the developmental toxicity of dolutegravir in human and animal studies.

scholarly journals HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Dario Oliveira Passos ◽  
Dmitry Lyumkis ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Strand Transfer ◽  
First Line ◽  
Preclinical Development ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

scholarly journals Might dolutegravir be part of a functional cure for HIV?

2016 ◽  
Vol 62 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Mark A. Wainberg ◽  
Ying-Shan Han ◽  
Thibault Mesplède
Keyword(s):  
First Generation ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Functional Cure ◽  
Viral Reservoirs ◽  
Genetic Barrier ◽  
Clinical Resistance ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.

scholarly journals In SilicoandIn VitroComparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Xiaoju Ni ◽  
Safwat Abdel-Azeim ◽  
Elodie Laine ◽  
Rohit Arora ◽  
Osamuede Osemwota ◽  
...  
Keyword(s):  
Structural Features ◽  
Strand Transfer ◽  
Binding Modes ◽  
Medical Treatments ◽  
Sequence Variations ◽  
Transfer Inhibitor ◽  
Dna Substrate ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1

Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors—raltegravir (RAL), elvitegravir (ELV) and L731,988—were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Ourin silicoandin vitrostudies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.

scholarly journals Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis

2019 ◽  
Vol 6 (3) ◽  
Author(s):  
Kimia Kamelian ◽  
Katherine J Lepik ◽  
William Chau ◽  
Benita Yip ◽  
Wendy W Zhang ◽  
...  
Keyword(s):  
British Columbia ◽  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Transfer Inhibitor ◽  
Inhibitor Resistance ◽  
Integrase Strand Transfer Inhibitor ◽  
Human Immunodeficiency Virus 1

AbstractBackgroundIntegrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations.MethodsHuman immunodeficiency virus-1-positive individuals ≥19 years were included if they received ≥1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ≥1 sample with a combined, cumulative score ≥30 by Stanford HIV Drug Resistance Algorithm version 7.0.1.ResultsAlthough most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P < .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263.ConclusionsThe prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

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