scholarly journals Rapid Development of High-Level Resistance to Dolutegravir With Emergence of T97A Mutation in 2 Treatment-Experienced Individuals With Baseline Partial Sensitivity to Dolutegravir

2018 ◽  
Vol 5 (10) ◽  
Author(s):  
Jomy M George ◽  
Safia S Kuriakose ◽  
Nicola Dee ◽  
Pam Stoll ◽  
Tahaniyat Lalani ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Rapid Development ◽  
Fold Increase ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Strand Transfer Inhibitors ◽  
Single Addition ◽  
High Level ◽  
Level Resistance

Abstract HIV integrase mutation T97A emerges after suboptimal therapy with integrase strand transfer inhibitors (INSTIs), but the contribution of T97A to dolutegravir resistance remains uncertain. Here we report >10-fold increase in dolutegravir resistance after the single addition of T97A in 2 individuals with prior INSTI resistance receiving dolutegravir salvage therapy.

scholarly journals Virologic failure after 48 weeks of raltegravir-based regimen in low HIV-1 incidence setting

2020 ◽  
Vol 28 ◽  
pp. 204020662092790
Author(s):  
Wassim Chehadeh ◽  
Osama Albaksami ◽  
Shaikhah Al-Shammari
Keyword(s):  
Salvage Therapy ◽  
Virologic Failure ◽  
Strand Transfer ◽  
Adherence To Treatment ◽  
First Line ◽  
Transfer Inhibitor ◽  
High Level ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1 ◽  
Level Resistance

Background With the advent of next generation integrase strand transfer inhibitors, the rates of virologic failure in treated subjects are expected to decrease. In this study, we analyzed the mutation patterns leading to virologic failure before and after starting integrase strand transfer inhibitor-based regimen as first-line or salvage therapy. Methods Between 2016 and 2019, blood samples were received from 258 patients with HIV-1 infection. Plasma HIV-1 RNA concentrations, and pol gene sequences were determined at baseline, and 16–48 weeks of treatment with integrase strand transfer inhibitor-based regimen. Only patients who did not achieve viral suppression at 48 weeks of integrase strand transfer inhibitor-based treatment were eligible for the current study. Results Virologic failure was observed in seven patients on raltegravir-based regimen. All patients with virologic failure but one were infected with CRF01_AE virus subtype. Raltegravir based-regimen was offered as first-line therapy for four patients, and as salvage therapy for three patients. M184V mutation associated with high level resistance to lamivudine and emtricitabine was detected in six out of seven patients. Primary mutations (Y143C, N155H, T66I, G118R, E138K) conferring high level resistance to raltegravir were detected in only three patients. Pre-existing polymorphic integrase mutation (T97A) was detected in two patients. Furthermore, two patients reported low adherence to treatment. Conclusions Emergence of primary mutations in the integrase gene can account for virologic failure in less than half of patients on raltegravir-based regimen. Low adherence to treatment, pre-existing accessory mutations, and resistance to reverse transcriptase inhibitors may have some role in virologic outcome.

scholarly journals Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda

2020 ◽  
Vol 75 (12) ◽  
pp. 3525-3533
Author(s):  
Emmanuel Ndashimye ◽  
Mariano Avino ◽  
Abayomi S Olabode ◽  
Art F Y Poon ◽  
Richard M Gibson ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Cross Resistance ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Resistance Mutations ◽  
Middle Income ◽  
Subtype B ◽  
High Level ◽  
Hiv 1 ◽  
Level Resistance

Abstract Background Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs). Methods A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman’s correlation coefficient was used to determine cross-resistance between INSTIs. Results INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT. Conclusions In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.

scholarly journals The Terminal (Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissociation of HIV Integrase Strand Transfer Inhibitors

Biochemistry ◽  
2008 ◽  
Vol 47 (51) ◽  
pp. 13481-13488 ◽  
Author(s):  
David R. Langley ◽  
Himadri K. Samanta ◽  
Zeyu Lin ◽  
Michael A. Walker ◽  
Mark R. Krystal ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Strand Transfer Inhibitors ◽  
Kinetics Of

scholarly journals Phenotypic Characterization of Two Ancylostoma caninum Isolates with Different Susceptibilities to the Anthelmintic Pyrantel

2008 ◽  
Vol 52 (11) ◽  
pp. 3980-3986 ◽  
Author(s):  
Steven R. Kopp ◽  
Glen T. Coleman ◽  
James S. McCarthy ◽  
Andrew C. Kotze
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Resistance Mechanism ◽  
Fold Increase ◽  
Phenotypic Characterization ◽  
Gastrointestinal Helminths ◽  
Ancylostoma Caninum ◽  
High Level ◽  
Level Resistance

ABSTRACT The anthelmintic pyrantel plays an important role in the control of gastrointestinal helminths of humans and domestic animals. Despite the demonstration of pyrantel resistance in several helminth species over the last 20 years, the resistance mechanism remains unclear. It has been hypothesized that resistance may arise as a consequence of changes to the relative proportions of subpopulations of nicotinic acetylcholine receptors (nAchRs). To test this hypothesis, we examined the responses of two isolates of the canine hookworm Ancylostoma caninum with low-level resistance (isolate NT) and high-level resistance (isolate PR) to pyrantel to nicotinic agonist drugs reported to be selective for three nAchR subtypes. We used larval motility and conformation assays and force transduction experiments with adult worms. Pyrantel and levamisole were less potent against larvae of isolate PR than larvae of isolate NT (up to an 18-fold increase in the 50% inhibitory concentration); on the other hand, bephenium was more potent against larvae of isolate PR than larvae of isolate NT (twofold) and nicotine had the same potency against larvae of both isolates. In adults, pyrantel, levamisole, and nicotine were less potent against isolate PR than isolate NT (two- to threefold), but the potency of bephenium against the two isolates was equivalent. Our data indicate a complex pattern of nAchRs in this species and suggest that the two isolates differ in their relative sensitivities to agonists targeting different nAchRs.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide discontinuation and return to normal weight

2020 ◽  
pp. 095646242096434 ◽  
Author(s):  
Blake Max ◽  
Patricia DeMarais
Keyword(s):  
Weight Gain ◽  
Normal Weight ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Combination Antiretroviral Therapy ◽  
Excessive Weight ◽  
Integrase Strand Transfer Inhibitors ◽  
Baseline Weight ◽  
Tenofovir Alafenamide

HIV integrase strand transfer inhibitors (INSTI) are considered well tolerated with few treatment-limiting adverse effects. However, emerging data from clinical trials has identified excessive weight gain possibly due to INSTI alone or with tenofovir alafenamide as a new and possible long-term complication of combination antiretroviral therapy (cART). Identifying who is at greatest risk and whether the unintended weight gain is reversible remain unanswered questions. We report a return to baseline weight after switching back to tenofovir disoproxil/emtricitabine/efavirenz (Atripla®) in a woman who had profound weight gain due to tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (Genvoya®).

Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors

2020 ◽  
Vol 17 ◽  
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
In Silico ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Chromosomal Dna ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
In Vitro Evaluation ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

Aim:: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background:: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective:: To develop inhibitors against HIV integrase strand transfer step. Methods:: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4- oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. As shown in figure 2, prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13. Result:: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode. Conclusion:: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

scholarly journals Sustained HIV viral suppression with dolutegravir, tenofovir, and emtricitabine as initial therapy despite high-level transmitted multi-class resistance

2021 ◽  
Author(s):  
Ellen H Nagami ◽  
Kinna Thakarar ◽  
Paul E Sax
Keyword(s):  
Viral Suppression ◽  
Drug Class ◽  
Drug Regimen ◽  
Initial Therapy ◽  
Strand Transfer ◽  
Antiretroviral Drug ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv Viral Suppression ◽  
High Level ◽  
Selection Of

Abstract Multi-class high-level transmitted HIV drug resistance is uncommon, and the selection of the optimal initial antiretroviral drug regimen may be challenging. We report a case of extensive transmitted multi-class resistance successfully treated with dolutegravir, tenofovir, and emtricitabine even though the baseline genotype demonstrated full susceptibility to only one drug class, the integrase strand transfer inhibitors. Our case highlights both the high resistance barrier of dolutegravir and the residual antiviral activity of nucleoside reverse transcriptase inhibitors despite extensive resistance on genotype.

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