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[PMID]:28463753
[Au] Autor:Walker A; Bergmann M; Camdereli J; Kaiser R; Lübke N; Timm J
[Ad] Endereço:Institute of Virology, Heinrich-Heine-University, University Hospital, Düsseldorf, Germany.
[Ti] Título:A genotype independent, full-genome reverse-transcription protocol for HCV genotyping and resistance testing.
[So] Source:J Clin Virol;91:42-48, 2017 06.
[Is] ISSN:1873-5967
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: HCV treatment options and cure rates have tremendously increased in the last decade. Although a pan-genotype HCV treatment has recently been approved, most DAA therapies are still genotype specific. Resistance-associated variants (RAVs) can limit the efficacy of DAA therapy and are associated with increased risk for therapy failure. With the approval of DAA regimens that recommend resistance testing prior to therapy, correct assessment of the genotype and testing for viruses with RAVs is clinically relevant. However, genotyping and resistance testing is generally done in costly and laborious separate reactions. OBJECTIVE: The aim of the study was to establish a genotype-independent full-genome reverse transcription protocol to generate a template for both genotyping and resistance testing and to implement it into our routine diagnostic setup. STUDY DESIGN: The complete HCV genome was reverse transcribed with a pan-genotype primer binding at the 3'end of the viral RNA. This cDNA served as template for transcription of the genotyping amplicon in the core region as well as for the resistance testing of NS3, NS5A, and NS5B. RESULTS: With the established RT-protocol the HCV core region was successfully amplified and genotyped from 124 out of 125 (99.2%) HCV-positive samples. The amplification efficiency of RAV containing regions in NS3, NS5A, NS5B was 96.2%, 96.6% and 94.4%, respectively. CONCLUSIONS: We developed a method for HCV full-genome cDNA synthesis and implemented it into a routine diagnostic setup. This cDNA can be used as template for genotyping amplicons covering the core or NS5B region as well as for resistance testing amplicons in NS3, NS5A and NS5B.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
Genoma Viral/genética
Técnicas de Genotipagem
Hepacivirus/efeitos dos fármacos
Hepacivirus/genética
Transcrição Reversa
[Mh] Termos MeSH secundário: Antivirais/farmacologia
Antivirais/uso terapêutico
DNA Complementar
Genoma Viral/efeitos dos fármacos
Genótipo
Hepacivirus/isolamento & purificação
Hepatite C Crônica/sangue
Hepatite C Crônica/diagnóstico
Hepatite C Crônica/tratamento farmacológico
Seres Humanos
Reação em Cadeia da Polimerase
RNA Viral/sangue
RNA Viral/genética
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (DNA, Complementary); 0 (RNA, Viral)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28463369
[Au] Autor:Ndagi U; Mhlongo NN; Soliman ME
[Ad] Endereço:Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. soliman@ukzn.ac.za.
[Ti] Título:The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design.
[So] Source:Mol Biosyst;13(6):1157-1171, 2017 May 30.
[Is] ISSN:1742-2051
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The emergence of a drug resistant non-receptor tyrosine kinase (c-Src) in triple-negative breast cancer (TNBC) remains a prime concern in relation to the burden of TNBC among people living with breast cancer and drug development. Thr91 mutation was found to induce a complete loss of protein conformation required for drug fitness. Herein, we provide the first account of the molecular impact of the Thr91 mutation on c-Src resistance to experimental drug UM-164 using various computational approaches, namely molecular dynamics simulation, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, hydrogen bond occupancy, thermodynamics calculation, ligand-residue interaction and residue interaction networks (RINs). Findings from this study revealed that Thr91 mutation leads to a steric conflict between UM-164 and the side chain of methionine (Met91); this mutation distorts the UM-164 optimum orientation on the conformational space of mutant c-Src compared to the wild-type; decreases hydrogen bond formation between the residues in the mutant protein structure; decreases the UM-164 binding energy in the mutant by -13.416 kcal mol ; reduces the residue correlation in the mutant protein structure; induces a change in the overall protein structure conformation from an inactive to active conformation; and distorts the ligand atomic interaction network and the residue interaction network. This report provides important insights that will assist in the further design of novel dual kinase inhibitors to minimise the chances of drug resistance in triple negative breast cancer.
[Mh] Termos MeSH primário: Simulação de Dinâmica Molecular
Neoplasias de Mama Triplo Negativas/genética
[Mh] Termos MeSH secundário: Desenho de Drogas
Farmacorresistência Viral/genética
Seres Humanos
Ligações de Hidrogênio
Mutação
Análise de Componente Principal
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1039/c6mb00848h


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[PMID]:28453848
[Au] Autor:Kakiuchi S; Tsuji M; Nishimura H; Yoshikawa T; Wang L; Takayama-Ito M; Kinoshita H; Lim CK; Fujii H; Yamada S; Harada S; Oka A; Mizuguchi M; Taniguchi S; Saijo M
[Ad] Endereço:Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.
[Ti] Título:Association of the Emergence of Acyclovir-Resistant Herpes Simplex Virus Type 1 With Prognosis in Hematopoietic Stem Cell Transplantation Patients.
[So] Source:J Infect Dis;215(6):865-873, 2017 03 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Antiviral-resistant herpes simplex virus type 1 (HSV-1) has been recognized as an emerging clinical problem among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A prospective observational study was conducted at a hematological center over a 2-year period. Oropharyngeal swab samples were serially collected each week from 1 week before and up to 100 days after HSCT and were tested for virus isolation. The HSV-1 isolates were tested for sensitivity to acyclovir (ACV). The prognosis of patients with ACV-resistant (ACVr) HSV-1 and the genetic background of the ACVr HSV-1 isolates were assessed. Results: Herpes simplex virus type 1 was isolated in 39 of 268 (15%) HSCT patients within 100 days after transplantation. Acyclovir-resistant HSV-1 emerged in 11 of these 39 patients (28%). The 100-day death rates of HSCT patients without HSV-1 shedding, those with only ACV-sensitive HSV-1 shedding, and those with ACVr HSV-1 shedding were 31%, 39%, and 64%, respectively. Patients with HSV-1, including ACVr HSV-1, shedding showed a significantly higher mortality rate. Relapsed malignancies were a significant risk factor for the emergence of ACVr HSV-1. Acyclovir resistance was attributable to viral thymidine kinase and DNA polymerase mutations in 6 and 5 patients, respectively. Conclusions: Herpes simplex virus type 1, including ACVr HSV-1, shedding was associated with poorer outcome in HSCT patients, even if HSV disease did not always occur. Patients with relapsed malignancies were at especially high risk for the emergence of ACVr HSV-1.
[Mh] Termos MeSH primário: Aciclovir/uso terapêutico
Antivirais/uso terapêutico
Farmacorresistência Viral
Transplante de Células-Tronco Hematopoéticas/mortalidade
Herpes Simples/tratamento farmacológico
Herpesvirus Humano 1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
DNA Polimerase Dirigida por DNA/genética
Feminino
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Herpes Simples/virologia
Herpesvirus Humano 1/isolamento & purificação
Seres Humanos
Japão
Masculino
Testes de Sensibilidade Microbiana
Meia-Idade
Análise Multivariada
Complicações Pós-Operatórias/virologia
Prognóstico
Modelos de Riscos Proporcionais
Estudos Prospectivos
Recidiva
Taxa de Sobrevida
Timidina Quinase/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Antiviral Agents); EC 2.7.1.21 (Thymidine Kinase); EC 2.7.7.7 (DNA-Directed DNA Polymerase); X4HES1O11F (Acyclovir)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix042


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[PMID]:28453836
[Au] Autor:Margot NA; Wong P; Kulkarni R; White K; Porter D; Abram ME; Callebaut C; Miller MD
[Ad] Endereço:Gilead Sciences, Foster City, California, USA.
[Ti] Título:Commonly Transmitted HIV-1 Drug Resistance Mutations in Reverse-Transcriptase and Protease in Antiretroviral Treatment-Naive Patients and Response to Regimens Containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide.
[So] Source:J Infect Dis;215(6):920-927, 2017 03 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: The presence of transmitted drug resistance mutations (TDRMs) in antiretroviral treatment (ART)-naive patients can adversely affect the outcome of ART. Methods: Resistance testing was conducted in 6704 ART-naive subjects predominantly from the United States and Europe in 9 clinical studies conducted by Gilead Sciences from 2000 to 2013. Results: The presence of TDRMs increased during this period (from 5.2% to 11.4%), primarily driven by an increase in nonnucleoside reverse-transcriptase (RT) inhibitor (NNRTI) resistance mutations (from 0.3% to 7.1%), particularly K103N/S (increase from 0.3% to 5.3%). Nucleoside/nucleotide RT inhibitor mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 had M184V/I (0.1%), despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. At least 1 thymidine-analogue mutations was present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L + L210W + T215rev showed full human immunodeficiency virus RNA suppression while receiving a TDF- or tenofovir alafenamide-containing regimen. Conclusions: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013, driven primarily by an increase in NNRTI resistance. However, the presence of common TDRMs, including thymidine-analogue mutations/T215rev, showed no impact on response to TDF- or tenofovir alafenamide-containing regimens.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Fármacos Anti-HIV/uso terapêutico
Farmacorresistência Viral/genética
Infecções por HIV/tratamento farmacológico
HIV-1/genética
Tenofovir/uso terapêutico
[Mh] Termos MeSH secundário: Adenina/uso terapêutico
Adulto
Emtricitabina/uso terapêutico
Europa (Continente)
Feminino
HIV-1/efeitos dos fármacos
Seres Humanos
Lamivudina/uso terapêutico
Masculino
Mutação de Sentido Incorreto
Inibidores da Transcriptase Reversa/uso terapêutico
Timidina/análogos & derivados
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (GS-7340); 0 (Reverse Transcriptase Inhibitors); 2T8Q726O95 (Lamivudine); 99YXE507IL (Tenofovir); G70B4ETF4S (Emtricitabine); JAC85A2161 (Adenine); VC2W18DGKR (Thymidine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix015


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[PMID]:29390377
[Au] Autor:Trifan A; Stanciu C; Gheorghe L; Iacob S; Curescu M; Cijevschi Prelipcean C; Stefanescu G; Girleanu I; Chiriac S; Mihai C; Brisc C; Goldis A; Sporea I; Miftode E; Bataga S; Rogoveanu I; Preda C; Caruntu FA; Singeap AM
[Ad] Endereço:"Grigore T. Popa" University of Medicine and Pharmacy Iasi.
[Ti] Título:Efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with ribavirin for the treatment of HCV genotype 1b compensated cirrhosis in patients aged 70 years or older.
[So] Source:Medicine (Baltimore);96(50):e9271, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advanced age has been a major limitation of interferon-based treatment for chronic hepatitis C virus (HCV) infection because of its poor response and tolerability. Direct-acting antiviral (DAA) drug regimens are safe and highly effective, allowing administration of treatment also in elderly. This study aims to assess the efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with ribavirin for the treatment of patients aged ≥70 years with HCV genotype 1b compensated cirrhosis.A total of 1008 patients with HCV genotype 1b compensated cirrhosis were prospectively treated with PrOD + ribavirin for 12 weeks, between December 2015 and July 2016. Sustained virologic response 12 weeks after the end of treatment (SVR12), adverse effects (AEs), comorbidities, discontinuation, and death rates were recorded. Efficacy and safety of therapy were assessed in patients aged ≥70 years and compared with data from patients <70 years.There were 117 patients aged ≥70 years, preponderantly females (58.9%), mean age 73.3 ±â€Š2.8 years (range 70-82), and 37 (31.6%) were treatment-experienced. Comorbidities were reported in 60.6% of patients ≥70 years and in 39.8% of those <70 years (P < .001). SVR12 rates based on intention-to-treat and per-protocol analyses were 97.4% and 100%, respectively, in patients ≥70 years, compared to 97.8% and 99.6%, respectively, in patients <70 years (P = ns and P = ns). Severe AEs were reported in 4 (3.4%) patients ≥70 years, compared to 23 (2.6%) in those <70 years (P = ns). One death was recorded in a patient aged 79 years (0.9%) and 6 deaths (0.8%) in those <70 years (P = ns).Treatment with PrOD + ribavirin in patients 70 years of age or older with HCV genotype 1b compensated cirrhosis proved as effective, safe, and well tolerated, as it did in younger patients.
[Mh] Termos MeSH primário: Antivirais/uso terapêutico
Hepatite C Crônica/tratamento farmacológico
Cirrose Hepática/tratamento farmacológico
Cirrose Hepática/virologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Anilidas/uso terapêutico
Carbamatos/uso terapêutico
Farmacorresistência Viral
Quimioterapia Combinada
Feminino
Genótipo
Seres Humanos
Compostos Macrocíclicos/uso terapêutico
Masculino
Estudos Prospectivos
Ribavirina/uso terapêutico
Ritonavir/uso terapêutico
Sulfonamidas/uso terapêutico
Resposta Viral Sustentada
Uracila/análogos & derivados
Uracila/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-267); 0 (ABT-333); 0 (ABT-450); 0 (Anilides); 0 (Antiviral Agents); 0 (Carbamates); 0 (Macrocyclic Compounds); 0 (Sulfonamides); 49717AWG6K (Ribavirin); 56HH86ZVCT (Uracil); O3J8G9O825 (Ritonavir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009271


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[PMID]:29370196
[Au] Autor:Kearney MF; Spindler J; Wiegand A; Shao W; Haubrich R; Riddler S; Lalama CM; Hughes MD; Coffin JM; Mellors JW
[Ad] Endereço:HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, United States of America.
[Ti] Título:Lower pre-ART intra-participant HIV-1 pol diversity may not be associated with virologic failure in adults.
[So] Source:PLoS One;13(1):e0190438, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Identifying pre-ART factors associated with the emergence of HIV-1 drug resistance is critical for optimizing strategies to prevent virologic failure. A previous study reported that lower pre-ART HIV-1 pol diversity was associated with higher risk of virologic failure in HIV-1-infected children. To investigate this association in adults, we measured HIV-1 diversity with deep sequencing in pre-ART samples from adults with well-characterized virologic outcomes in a study (A5142) of initial ART conducted by the AIDS Clinical Trials Group (ACTG). METHODS: We identified 22 cases in ACTG A5142 who experienced virologic failure with drug resistance mutations in RT and 44 matched controls who did not experience virologic failure. cDNA was synthesized from plasma HIV-1 RNA. Each cDNA molecule was tagged with a unique primer ID and RT codons 41-103 were amplified and deep sequenced. Sequences with the same tag were aligned and a consensus was generated to reduce PCR and sequencing errors. Diversity was calculated by measuring average pairwise distance (APD) of the consensus sequences. An exact conditional logistic regression model with percent APD as the risk factor estimated the odds ratio for VF and the corresponding 95% confidence interval. RESULTS: Consensus single-genome sequences and diversity estimates of pol were obtained for pre-ART samples from 21 cases and 42 controls. The median (IQR) pre-ART percent APD was 0.71 (0.31-1.13) in cases and 0.58 (0.32-0.94) in controls. A possible trend was found for higher diversity being associated with greater risk of virologic failure in adults (OR = 2.2 per one percent APD increase, 95% CI = [0.8, 7.2]; p = 0.15). CONCLUSIONS: This study in adults suggests there is a positive association between higher pre-ART pol diversity and the risk of virologic failure in adults rather than an inverse relationship reported in children.
[Mh] Termos MeSH primário: Genes pol
Variação Genética
Infecções por HIV/tratamento farmacológico
Infecções por HIV/genética
HIV-1/genética
[Mh] Termos MeSH secundário: Contagem de Linfócito CD4
Estudos de Casos e Controles
Farmacorresistência Viral/genética
Seres Humanos
Reação em Cadeia da Polimerase
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190438


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[PMID]:29447145
[Au] Autor:Budd AP; Wentworth DE; Blanton L; Elal AIA; Alabi N; Barnes J; Brammer L; Burns E; Cummings CN; Davis T; Flannery B; Fry AM; Garg S; Garten R; Gubareva L; Jang Y; Kniss K; Kramer N; Lindstrom S; Mustaquim D; O'Halloran A; Olsen SJ; Sessions W; Taylor C; Xu X; Dugan VG; Katz J; Jernigan D
[Ad] Endereço:Influenza Division, National Center for Immunization and Respiratory Diseases, CDC.
[Ti] Título:Update: Influenza Activity - United States, October 1, 2017-February 3, 2018.
[So] Source:MMWR Morb Mortal Wkly Rep;67(6):169-179, 2018 Feb 16.
[Is] ISSN:1545-861X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Influenza activity in the United States began to increase in early November 2017 and rose sharply from December through February 3, 2018; elevated influenza activity is expected to continue for several more weeks. Influenza A viruses have been most commonly identified, with influenza A(H3N2) viruses predominating, but influenza A(H1N1)pdm09 and influenza B viruses were also reported. This report summarizes U.S. influenza activity* during October 1, 2017-February 3, 2018, and updates the previous summary (1).
[Mh] Termos MeSH primário: Vírus da Influenza A Subtipo H1N1/isolamento & purificação
Vírus da Influenza A Subtipo H3N2/isolamento & purificação
Vírus da Influenza B/isolamento & purificação
Influenza Humana/epidemiologia
Vigilância da População
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Assistência Ambulatorial/estatística & dados numéricos
Antivirais/farmacologia
Criança
Mortalidade da Criança
Pré-Escolar
Farmacorresistência Viral
Feminino
Hospitalização/estatística & dados numéricos
Seres Humanos
Lactente
Recém-Nascido
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos
Vírus da Influenza A Subtipo H1N1/genética
Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos
Vírus da Influenza A Subtipo H3N2/genética
Vírus da Influenza B/efeitos dos fármacos
Vírus da Influenza B/genética
Influenza Humana/mortalidade
Influenza Humana/virologia
Masculino
Meia-Idade
Pneumonia/mortalidade
Gravidez
Estações do Ano
Estados Unidos/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180216
[St] Status:MEDLINE
[do] DOI:10.15585/mmwr.mm6706a1


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[PMID]:29329305
[Au] Autor:Lee HJ; Kim SJ; Kweon YO; Park SY; Heo J; Woo HY; Hwang JS; Chung WJ; Lee CH; Kim BS; Suh JI; Tak WY; Jang BK
[Ad] Endereço:Department of Internal Medicine, Yeungnam University College of Medicine Daegu, South Korea.
[Ti] Título:Evaluating the efficacy of switching from lamivudine plus adefovir to tenofovir disoproxil fumarate monotherapy in lamivudine-resistant stable hepatitis B patients.
[So] Source:PLoS One;13(1):e0190581, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear. METHODS: In this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96. RESULTS: Patients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000). CONCLUSIONS: Stable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function. TRIAL REGISTRATION: ClinicalTrials.gov NCT01732367.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Antivirais/administração & dosagem
Hepatite B Crônica/tratamento farmacológico
Lamivudina/administração & dosagem
Organofosfonatos/administração & dosagem
Ácidos Fosforosos/administração & dosagem
[Mh] Termos MeSH secundário: Adenina/administração & dosagem
Adulto
DNA Viral/sangue
Farmacorresistência Viral
Quimioterapia Combinada
Feminino
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (9-(2-((bis(pivaloyloxymethoxy)phosphinoyl)methoxy)propyl)adenine); 0 (Antiviral Agents); 0 (DNA, Viral); 0 (Organophosphonates); 0 (Phosphorous Acids); 2T8Q726O95 (Lamivudine); 6GQP90I798 (adefovir); JAC85A2161 (Adenine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190581


  9 / 11182 MEDLINE  
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[PMID]:28467359
[Au] Autor:Yoshida K; Hai H; Tamori A; Teranishi Y; Kozuka R; Motoyama H; Kawamura E; Hagihara A; Uchida-Kobayashi S; Morikawa H; Enomoto M; Murakami Y; Kawada N
[Ad] Endereço:Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. m2028081@med.osaka-cu.ac.jp.
[Ti] Título:Long-Term Follow-Up of Resistance-Associated Substitutions in Hepatitis C Virus in Patients in Which Direct Acting Antiviral-Based Therapy Failed.
[So] Source:Int J Mol Sci;18(5), 2017 May 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
Hepacivirus/genética
Hepatite C Crônica/tratamento farmacológico
Serina Proteases/genética
Proteínas não Estruturais Virais/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Antivirais/farmacologia
Antivirais/uso terapêutico
Quimioterapia Combinada
Feminino
Seguimentos
Hepacivirus/efeitos dos fármacos
Hepatite C Crônica/virologia
Seres Humanos
Imidazóis/farmacologia
Imidazóis/uso terapêutico
Interferon-alfa/uso terapêutico
Isoquinolinas/farmacologia
Isoquinolinas/uso terapêutico
Masculino
Meia-Idade
Polietilenoglicóis/uso terapêutico
Inibidores de Proteases/farmacologia
Inibidores de Proteases/uso terapêutico
Proteínas Recombinantes/uso terapêutico
Ribavirina/farmacologia
Ribavirina/uso terapêutico
Simeprevir/farmacologia
Simeprevir/uso terapêutico
Sulfonamidas/farmacologia
Sulfonamidas/uso terapêutico
Fatores de Tempo
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (BMS-790052); 0 (Imidazoles); 0 (Interferon-alpha); 0 (Isoquinolines); 0 (NS-5 protein, hepatitis C virus); 0 (Protease Inhibitors); 0 (Recombinant Proteins); 0 (Sulfonamides); 0 (Viral Nonstructural Proteins); 30IQX730WE (Polyethylene Glycols); 49717AWG6K (Ribavirin); 9WS5RD66HZ (Simeprevir); EC 3.4.- (NS3-4A serine protease, Hepatitis C virus); EC 3.4.- (Serine Proteases); G8RGG88B68 (peginterferon alfa-2b); S9X0KRJ00S (asunaprevir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  10 / 11182 MEDLINE  
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[PMID]:29324781
[Au] Autor:Tewawong N; Marathe BM; Poovorawan Y; Vongpunsawad S; Webby RJ; Govorkova EA
[Ad] Endereço:Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
[Ti] Título:Neuraminidase inhibitor susceptibility and neuraminidase enzyme kinetics of human influenza A and B viruses circulating in Thailand in 2010-2015.
[So] Source:PLoS One;13(1):e0190877, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amino acid substitutions within or near the active site of the viral neuraminidase (NA) may affect influenza virus fitness. In influenza A(H3N2) and B viruses circulating in Thailand between 2010 and 2015, we identified several NA substitutions that were previously reported to be associated with reduced inhibition by NA inhibitors (NAIs). To study the effect of these substitutions on the enzymatic properties of NA and on virus characteristics, we generated recombinant influenza viruses possessing either a wild type (WT) NA or an NA with a single I222V, S331G, or S331R substitution [in influenza A(H3N2) viruses] or a single D342S, A395T, A395V, or A395D NA substitution (in influenza B viruses). We generated recombinant (7:1) influenza A and B viruses on the genetic background of A/Puerto Rico/8/1934 (A/PR/8, H1N1) or B/Yamanashi/166/1998 (B/YAM) viruses, respectively. In contrast to the expected phenotypes, all the recombinant influenza A(H3N2) and B viruses carrying putative NA resistance substitutions were susceptible to NAIs. The Km and Vmax for the NAs of A/PR8-S331G and A/PR8-S331R viruses were higher than for the NA of WT virus, and the corresponding values for the B/YAM-D342S virus were lower than for the NA of WT virus. Although there was initial variation in the kinetics of influenza A and B viruses' replication in MDCK cells, their titers were comparable to each other and to WT viruses at later time points. All introduced substitutions were stable except for B/YAM-D342S and B/YAM-A395V which reverted to WT sequences after three passages. Our data suggest that inferring susceptibility to NAIs based on sequence information alone should be cautioned. The impact of NA substitution on NAI resistance, viral growth, and enzymatic properties is viral context dependent and should be empirically determined.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Farmacorresistência Viral/genética
Vírus da Influenza A/enzimologia
Influenza Humana/virologia
Influenzavirus B/enzimologia
Neuraminidase/antagonistas & inibidores
Neuraminidase/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Cães
Inibidores Enzimáticos/farmacologia
Estabilidade Enzimática/genética
Instabilidade Genômica
Seres Humanos
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos
Vírus da Influenza A Subtipo H1N1/enzimologia
Vírus da Influenza A Subtipo H1N1/genética
Vírus da Influenza A Subtipo H1N1/fisiologia
Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos
Vírus da Influenza A Subtipo H3N2/enzimologia
Vírus da Influenza A Subtipo H3N2/genética
Vírus da Influenza A Subtipo H3N2/fisiologia
Vírus da Influenza A/efeitos dos fármacos
Vírus da Influenza A/genética
Vírus da Influenza A/fisiologia
Influenzavirus B/efeitos dos fármacos
Influenzavirus B/genética
Influenzavirus B/fisiologia
Cinética
Células Madin Darby de Rim Canino
Neuraminidase/genética
Tailândia
Proteínas Virais/antagonistas & inibidores
Proteínas Virais/genética
Proteínas Virais/metabolismo
Replicação Viral/efeitos dos fármacos
Replicação Viral/genética
Replicação Viral/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Enzyme Inhibitors); 0 (Viral Proteins); EC 3.2.1.18 (Neuraminidase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190877



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