Articles Related to drug resistance

Objective: To determine the prevalence of minority drug resistance variants in the protease and Gag regions among patients failing a protease inhibitor (PI) based regimen with or without a susceptible genotype based on Sanger sequencing technology. Methods: Samples were obtained from patients who were failing on a protease inhibitor-based regimen (n = 500). Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was grouped into two categories: those failing a PI based with mutations in the protease region (n = 100) and those failing on a PI based regimen without mutations in the protease region (n = 128). These samples were then analyzed in the protease and Gag regions using Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cutoffs. Results: An initial analysis of the protease region for patients failing with drug resistance mutations revealed that most patients harbored mutations that confer resistance to Lopinavir and Atazanavir, but these mutations had little effect on Darunavir. Furthermore, NGS revealed that in patients failing with and without drug resistance mutations, minority drug resistance mutations were present at each of the drug resistance codons and at codons that confer multi-drug resistance to protease inhibitors. Further analysis of the Gag gene revealed more genetic diversity among patients failing with no mutations in the protease as evidenced by the proportion of polymorphisms at each codon. Conclusion: Based on Sanger sequencing, a proportion of patients fail a PI based regimen with a susceptible genotype. However, these patients harbor minority variants in the protease and numerous polymorphisms in the Gag region which when combined these could explain their poor response to therapy. Therefore, in order to improve patient care in low resource settings, there is need to adapt NGS as the standard genotyping technique so that minority variants are captured much earlier. In addition, since mutations in the Gag region also play a role in response to PIs, this region should be included in the routine monitoring for response to therapy in patients on a PI based regimen.

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Background:The extensive use of antiretroviral therapy has favored the emergence of multiple patterns of drug resistance mutations. These mutations evolve over time and are only detected by the conventional Sanger sequencing technology when they exceed 20% at which time there may be cross resistance. Unfortunately, the controversy surrounding the significance of these minority drug resistance mutations is still overwhelming. Methods: Samples were obtained from patients who were failing on an NRTI based regimen between 2010 and 2019. For the subtype A and D analysis, 1000 patient samples were analyzed while the subtype C sub-analysis was comprised of 363 samples. Sanger based sequencing was performed as part of the standard of care. A subset of these samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off to determine the prevalence of minority multi-drug resistant variants. Results: Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. On the other hand, the Q151M mutation complex was significantly more predominant among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion: Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex more predominant among patients harboring subtype C viruses. Even in patients with a fully susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that if their early detection is missed, cross resistance is inevitable.

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Regular whole-flock treatments and long-term repeated use of similar anthelmintics has led to the development of anthelmintic resistance and widespread epidemic of sheep nematodiasis. The current work was carried out to understand the prevalence of gastrointestinal nematodes in Ordos fine-wool sheep and to evaluate the efficacy of currently used anthelmintics.

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Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4) epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.

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The distribution of different human immunodeficiency virus type 1 (HIV-1) genotypes and the prevalence of transmitted drug resistance (TDR) mutations vary greatly across different Brazilian regions. This study aimed to describe the HIV-1 molecular diversity and TDR prevalence among treatment-naïve HIV-1 infected individuals in an urban area of Northeastern Brazil. DNA samples from 97 infected individuals were obtained and pol sequences were generated by Polimerase Chain Reaction (PCR) and direct sequencing. Bioinformatics tools were used to identify the presence of associated mutations with drug resistance, to reconstruct the phylogeny and to detect recombination.

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The high mortality associated with ovarian cancer is generally related to the development of drug-resistant disease. HMGA2 protein, a member of the high-mobility group AT-hook (HMGA) family of non-histone chromatin binding factors, is overexpressed in high-grade serous ovarian and tubal carcinomas, though little is known about its contribution to disease progression and drug resistance. We sought to assess whether compositional changes in HMGA2 production were associated with ovarian cancer progression.

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