Failure to bictegravir and development of resistance mutations in an antiretroviral-experienced patient

2020 ◽  
Vol 179 ◽  
pp. 104717 ◽  
Author(s):  
Ana Belén Lozano ◽  
Natalia Chueca ◽  
Adolfo de Salazar ◽  
Elisa Fernández-Fuertes ◽  
Antonio Collado ◽  
...  
Keyword(s):  
Resistance Mutations ◽  
Experienced Patient ◽  
Development Of Resistance

scholarly journals Evolution of the Insecticide Target Rdl in African Anopheles Is Driven by Interspecific and Interkaryotypic Introgression

2020 ◽  
Vol 37 (10) ◽  
pp. 2900-2917 ◽  
Author(s):  
Xavier Grau-Bové ◽  
Sean Tomlinson ◽  
Andrias O O’Reilly ◽  
Nicholas J Harding ◽  
Alistair Miles ◽  
...  
Keyword(s):  
Large Scale ◽  
Sequence Data ◽  
Management Strategies ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Malaria Vectors ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Evolution Of Resistance

Abstract The evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across nonconcordant karyotypes of the 2La chromosomal inversion. Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticide-based intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors.

scholarly journals Evolution of the insecticide target Rdl in African Anopheles is driven by interspecific and interkaryotypic introgression

2019 ◽  
Author(s):  
Xavier Grau-Bové ◽  
Sean Tomlinson ◽  
Andrias O. O’Reilly ◽  
Nicholas J. Harding ◽  
Alistair Miles ◽  
...  
Keyword(s):  
Large Scale ◽  
Sequence Data ◽  
Management Strategies ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Malaria Vectors ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Evolution Of Resistance

AbstractThe evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across non-concordant karyotypes of the 2La chromosomal inversion. Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticide-based intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors.

scholarly journals Contribution of rpoB Mutations to Development of Rifamycin Cross-Resistance in Mycobacterium tuberculosis

1998 ◽  
Vol 42 (7) ◽  
pp. 1853-1857 ◽  
Author(s):  
D. L. Williams ◽  
L. Spring ◽  
L. Collins ◽  
L. P. Miller ◽  
L. B. Heifets ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cross Resistance ◽  
In Vitro Mutagenesis ◽  
Missense Mutations ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
High Level ◽  
The Impact ◽  
Level Resistance

ABSTRACT The contributions of 23 insertion, deletion, or missense mutations within an 81-bp fragment of rpoB, the gene encoding the β-subunit of the DNA-dependent RNA polymerase of Mycobacterium tuberculosis, to the development of resistance to rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) in 29 rifampin-resistant clinical isolates were defined. Specific mutantrpoB alleles led to the development of cross-resistance to all rifamycins tested, while a subset of mutations were associated with resistance to rifampin and rifapentine but not to KRM-1648 or rifabutin. To further study the impact of specific rpoBmutant alleles on the development of rifamycin resistance, mutations were incorporated into the rpoB gene of M. tuberculosis H37Rv, contained on a mycobacterial shuttle plasmid, by in vitro mutagenesis. Recombinant M. tuberculosis clones containing plasmids with specific mutations in either codon 531 or 526 of rpoB exhibited high-level resistance to all rifamycins tested, whereas clones containing a plasmid with a mutation in codon 516 exhibited high-level resistance to rifampin and rifapentine but were susceptible to both rifabutin and KRM-1648. These results provided additional proof of the association of specificrpoB mutations with the development of rifamycin resistance and corroborate previous reports of the usefulness of rpoB genotyping for predicting rifamycin-resistant phenotypes.

scholarly journals Nucleocapsid Protein Precursors NCp9 and NCp15 Suppress ATP-Mediated Rescue of AZT-Terminated Primers by HIV-1 Reverse Transcriptase

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Moisés A. Árquez ◽  
Samara Martín-Alonso ◽  
Robert J. Gorelick ◽  
Walter A. Scott ◽  
Antonio J. Acosta-Hoyos ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nucleocapsid Protein ◽  
Inhibitory Effect ◽  
Rnase H ◽  
Resistance Mutations ◽  
Site Mutation ◽  
Development Of Resistance ◽  
Transcription Process ◽  
Dna Primers ◽  
Hiv 1

ABSTRACT In HIV-1, development of resistance to AZT (3′-azido-3′-deoxythymidine) is mediated by the acquisition of thymidine analogue resistance mutations (TAMs) (i.e., M41L, D67N, K70R, L210W, T215F/Y, and K219E/Q) in the viral reverse transcriptase (RT). Clinically relevant combinations of TAMs, such as M41L/T215Y or D67N/K70R/T215F/K219Q, enhance the ATP-mediated excision of AZT monophosphate (AZTMP) from the 3′ end of the primer, allowing DNA synthesis to continue. Additionally, during HIV-1 maturation, the Gag polyprotein is cleaved to release a mature nucleocapsid protein (NCp7) and two intermediate precursors (NCp9 and NCp15). NC proteins interact with the viral genome and facilitate the reverse transcription process. Using wild-type and TAM-containing RTs, we showed that both NCp9 and NCp15 inhibited ATP-mediated rescue of AZTMP-terminated primers annealed to RNA templates but not DNA templates, while NCp7 had no effect on rescue activity. RNase H inactivation by introducing the active-site mutation E478Q led to the loss of the inhibitory effect shown by NCp9. NCp15 had a stimulatory effect on the RT’s RNase H activity not observed with NCp7 and NCp9. However, analysis of RNase H cleavage patterns revealed that in the presence of NCp9, RNA/DNA complexes containing duplexes of 12 bp had reduced stability in comparison with those obtained in the absence of NC or with NCp7 or NCp15. These effects are expected to have a strong influence on the inhibitory action of NCp9 and NCp15 by affecting the efficiency of RNA-dependent DNA polymerization after unblocking DNA primers terminated with AZTMP and other nucleotide analogues.

scholarly journals Antiviral-resistant cytomegalovirus infections in solid organ transplantation in the Netherlands

2019 ◽  
Vol 74 (8) ◽  
pp. 2370-2376 ◽  
Author(s):  
Coretta C Van Leer Buter ◽  
Danielle W K de Voogd ◽  
Hans Blokzijl ◽  
Anoek A E de Joode ◽  
Stefan P Berger ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Response To Treatment ◽  
Antiviral Resistance ◽  
Solid Organ ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
High Level

Abstract Objectives Antiviral resistance in cytomegalovirus (CMV) may result from mutations in the molecular targets of antiviral agents. The aim of this study was to investigate both the prevalence of resistance-associated mutations and the factors associated with antiviral resistance in solid organ transplant (SOT) patients with repeated high CMV loads during antiviral treatment. Methods SOT patients were selected retrospectively, based on CMV loads of >30000 IU/mL at least twice in a period during which treatment was given. Patient samples were tested for antiviral resistance by Sanger sequencing the UL97 and UL54 genes of CMV, which code for the viral kinase and polymerase. Factors predisposing to and resulting from the development of antiviral resistance mutations were analysed. Results Multiple samples from 113 SOT patients were tested, showing resistance-associated mutations in 25 patients (22%). A further 20 (18%) patients showed mutations that were not known to be associated with antiviral resistance. Several factors were associated with development of resistance-associated mutations in UL97 as well as UL54, including human leucocyte antigen (HLA) mismatch, which occurred more frequently in the group of patients with resistance mutations. High-level resistance mutations were most frequently seen in UL97. Conclusions This study shows that by selecting patients solely on the basis of virological response to treatment, more patients with antiviral resistance mutations are identified. In this study we confirm findings by other groups that primary infections are associated with resistance development. Moreover, we show that HLA mismatch is associated with the development of antiviral resistance, which suggests a role for host immunity in the development of resistance.

scholarly journals Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

2004 ◽  
Vol 48 (6) ◽  
pp. 2116-2123 ◽  
Author(s):  
Michelle L. Gatton ◽  
Laura B Martin ◽  
Qin Cheng
Keyword(s):  
Drug Resistance ◽  
Half Life ◽  
Drug Dosage ◽  
Parasite Resistance ◽  
Resistance Mutations ◽  
Correct Treatment ◽  
Development Of Resistance ◽  
Elimination Half ◽  
Treatment Dosage ◽  
Selection Of

ABSTRACT The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of P. falciparum malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-P. falciparum EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage, clinical treatment failure becomes prevalent as the parasites develop sufficient resistance mutations to survive therapeutic doses of the drug combination. Therefore, the model output reaffirms the importance of correct treatment of confirmed malaria cases in slowing the development of parasite resistance to sulfadoxine-pyrimethamine.

Genetic background for development of resistance mutations within the HCV NS3 protease-helicase in patients naive to direct antivirals

2014 ◽  
Vol 19 (5) ◽  
pp. 455-461 ◽  
Author(s):  
Georgios Grammatikos ◽  
Cassandra B Jabara ◽  
Monazza Q Ahmad ◽  
Eva Herrmann ◽  
Stefan Zeuzem ◽  
...  
Keyword(s):  
Genetic Background ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Ns3 Protease

scholarly journals Influenza A/H4N2 mallard infection experiments further indicate zanamivir as less prone to induce environmental resistance development than oseltamivir

2020 ◽  
Vol 101 (8) ◽  
pp. 816-824
Author(s):  
Viktoria Tepper ◽  
Marie Nykvist ◽  
Anna Gillman ◽  
Erik Skog ◽  
Michelle Wille ◽  
...  
Keyword(s):  
Influenza A ◽  
Wastewater Treatment Plants ◽  
Water Environment ◽  
Resistance Mutations ◽  
Pandemic Preparedness ◽  
Drug Pressure ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Different Characteristics

Neuraminidase inhibitors (NAIs) are the gold standard treatment for influenza A virus (IAV). Oseltamivir is mostly used, followed by zanamivir (ZA). NAIs are not readily degraded in conventional wastewater treatment plants and can be detected in aquatic environments. Waterfowl are natural IAV hosts and replicating IAVs could thus be exposed to NAIs in the environment and develop resistance. Avian IAVs form the genetic basis for new human IAVs, and a resistant IAV with pandemic potential poses a serious public health threat, as NAIs constitute a pandemic preparedness cornerstone. Resistance development in waterfowl IAVs exposed to NAIs in the water environment has previously been investigated in an in vivo mallard model and resistance development was demonstrated in several avian IAVs after the exposure of infected ducks to oseltamivir, and in an H1N1 IAV after exposure to ZA. The N1 and N2 types of IAVs have different characteristics and resistance mutations, and so the present study investigated the exposure of an N2-type IAV (H4N2) in infected mallards to 1, 10 and 100 µg l−1 of ZA in the water environment. Two neuraminidase substitutions emerged, H274N (ZA IC50 increased 5.5-fold) and E119G (ZA IC50 increased 110-fold) at 10 and 100 µg l−1 of ZA, respectively. Reversion towards wild-type was observed for both substitutions in experiments with removed drug pressure, indicating reduced fitness of both resistant viruses. These results corroborate previous findings that the development of resistance to ZA in the environment seems less likely to occur than the development of resistance to oseltamivir, adding information that is useful in planning for prudent drug use and pandemic preparedness.

scholarly journals In VitroResistance Profile of the Candidate HIV-1 Microbicide Drug Dapivirine

2011 ◽  
Vol 56 (2) ◽  
pp. 751-756 ◽  
Author(s):  
Susan M. Schader ◽  
Maureen Oliveira ◽  
Ruxandra-Ilinca Ibanescu ◽  
Daniela Moisi ◽  
Susan P. Colby-Germinario ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Sexual Transmission ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Development Of Resistance ◽  
Sexual Transmission Of Hiv ◽  
Hiv 1

ABSTRACTAntiretroviral-based microbicides may offer a means to reduce the sexual transmission of HIV-1. Suboptimal use of a microbicide may, however, lead to the development of drug resistance in users that are already, or become, infected with HIV-1. In such cases, the efficacy of treatments may be compromised since the same (or similar) antiretrovirals used in treatments are being developed as microbicides. To help predict which drug resistance mutations may develop in the context of suboptimal use, HIV-1 primary isolates of different subtypes and different baseline resistance profiles were used to infect primary cellsin vitroin the presence of increasing suboptimal concentrations of the two candidate microbicide antiretrovirals dapivirine (DAP) and tenofovir (TFV) alone or in combination. Infections were ongoing for 25 weeks, after which reverse transcriptase genotypes were determined and scrutinized for the presence of any clinically recognized reverse transcriptase drug resistance mutations. Results indicated that suboptimal concentrations of DAP alone facilitated the emergence of common nonnucleoside reverse transcriptase inhibitor resistance mutations, while suboptimal concentrations of DAP plus TFV gave rise to fewer mutations. Suboptimal concentrations of TFV alone did not frequently result in the development of resistance mutations. Sensitivity evaluations for stavudine (d4T), nevirapine (NVP), and lamivudine (3TC) revealed that the selection of resistance as a consequence of suboptimal concentrations of DAP may compromise the potential for NVP to be used in treatment, a finding of potential relevance in developing countries.

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