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2.
Viruses ; 13(8)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34452507

RESUMO

An Emergency Use Authorization was issued in the United States and in Europe for a monoclonal antibody monotherapy to prevent severe COVID-19 in high-risk patients. This study aimed to assess the risk of emergence of mutations following treatment with a single monoclonal antibody. Bamlanivimab was administered at a single dose of 700 mg in a one-hour IV injection in a referral center for the management of COVID-19 in France. Patients were closely monitored clinically and virologically with nasopharyngeal RT-PCR and viral whole genome sequencing. Six patients were treated for a nosocomial SARS-CoV-2 infection, all males, with a median age of 65 years and multiple comorbidities. All patients were infected with a B.1.1.7 variant, which was the most frequent variant in France at the time, and no patients had E484 mutations at baseline. Bamlanivimab was infused in the six patients within 4 days of the COVID-19 diagnosis. Four patients had a favorable outcome, one died of complications unrelated to COVID-19 or bamlanivimab, and one kidney transplant patient treated with belatacept died from severe COVID-19 more than 40 days after bamlanivimab administration. Virologically, four patients cleared nasopharyngeal viral shedding within one month after infusion, while two presented prolonged viral excretion for more than 40 days. The emergence of E484K mutants was observed in five out of six patients, and the last patient presented a Q496R mutation potentially associated with resistance. CONCLUSIONS: These results show a high risk of emergence of resistance mutants in COVID-19 patients treated with monoclonal antibody monotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , SARS-CoV-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antivirais/administração & dosagem , COVID-19/complicações , Comorbidade , Farmacorresistência Viral/genética , França , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , SARS-CoV-2/efeitos dos fármacos , Índice de Gravidade de Doença
3.
Arch Virol ; 166(10): 2853-2857, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34373969

RESUMO

Strains of the HIV-1 circulating recombinant forms (CRFs) 06_cpx and 56_cpx were identified for the first time in Guangzhou, China. The nearly full-length genome (NFLG) sequence was amplified, and the PCR products were sequenced by the Sanger method. The CRF06_cpx and CRF56_cpx strains were identified using the Basic Local Alignment Search Tool (BLAST) and confirmed by neighbour-joining (NJ) phylogenetic analysis. Additionally, these strains were found to contain transmitted drug resistance mutations that have little effect on first-line efavirenz (EFV)-based treatment. Genetic analysis of the detailed sequence data will provide more information on the HIV-1 epidemic in China.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Adulto , China/epidemiologia , Cidades/epidemiologia , Farmacorresistência Viral/genética , Feminino , Genoma Viral/genética , Genótipo , Infecções por HIV/epidemiologia , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Masculino , Mutação , Filogenia , Recombinação Genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
4.
Ann Palliat Med ; 10(7): 7775-7785, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353064

RESUMO

BACKGROUND: It is largely unknown how frequently minor HIV drug-resistant variants at levels under limit of detection of conventional genotyping are present in patients experiencing virological failure (VF). Further, the clinical implications of minor drug-resistant variants at time of virologic failure are unknown. METHODS: Fifteen patients experiencing VF on a first-line regimen were evaluated by high-throughput sequencing and compared with the conventional Sanger genotype drug resistance detection method. RESULTS: NRTI drug resistant mutations (DRMs) were detected in a high proportion of subjects, with the most common being M184V and TAMs. Minor resistant mutations accounted for 19.27% of the total drug-resistant mutations in patients with VF. A mean of 1.7 additional mutations per subject were detected by high-throughput sequencing, the difference was statistically significant, and those additional low-abundance drug-resistant mutations increased the genotypic resistance scores in 10 of 11 subjects (90.9%). Among persons experiencing VF, minor variants possessing major PI (protease inhibitor) DRMs were present in a minority of cases, which was also the case in ARV-naive subjects, and suggests PIs may be effective in subjects experiencing VF on subsequent second-line PI-based antiretroviral regimen. The high-throughput sequencing results of mutations between ART failure subjects and treatment naïve subjects were also compared. Three novel mutations were then screened with higher frequencies in the ART failure subjects. CONCLUSIONS: It is important to guide the replacement of treatment programs and screening for new drug-resistant mutation sites, and the use of high-throughput sequencing methods can more comprehensively study the characteristics of drug-resistant viral variants of patients experiencing VF on a first-line regimen.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Preparações Farmacêuticas , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Carga Viral
5.
Nat Commun ; 12(1): 4996, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404793

RESUMO

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.


Assuntos
Antivirais/química , Antivirais/farmacologia , Microscopia Crioeletrônica , Infecções por HTLV-I/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Amidas , Domínio Catalítico , Deltaretrovirus , Farmacorresistência Viral/efeitos dos fármacos , Integrase de HIV/efeitos dos fármacos , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Naftiridinas/farmacologia , Piperazinas , Piridonas , Proteínas Recombinantes
6.
Adv Exp Med Biol ; 1322: 1-30, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34258735

RESUMO

The discovery of the nucleoside analogue, acyclovir, represented a milestone in the management of infections caused by herpes simplex virus and varicella-zoster virus. Ganciclovir, another nucleoside analogue, was then used for the management of systemic and organ-specific human cytomegalovirus diseases. The pyrophosphate analogue, foscarnet, and the nucleotide analogue, cidofovir, have been approved subsequently and constitute the second-line antiviral drugs. However, the viral DNA polymerase is the ultimate target of all these antiviral agents with a possible emergence of cross-resistance between these drugs. Recently, letermovir that targets the viral terminase complex was approved for the prophylaxis of human cytomegalovirus infections in hematopoietic stem cell transplant recipients. Other viral targets such as the protein kinase and the helicase-primase complex are also evaluated for the development of novel potent inhibitors against herpesviruses.


Assuntos
Antivirais , Farmacorresistência Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , Cidofovir/farmacologia , Citomegalovirus , Farmacorresistência Viral/genética , Humanos , Simplexvirus
7.
Braz J Infect Dis ; 25(3): 101596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270996

RESUMO

Brazil is a huge continental country with striking geographic differences which are well illustrated in the HIV/AIDS epidemic. Contrasting with the significant decline in the national AIDS detection rate in the last decade, a linear growth has been reported in the Northern region. Despite its public health and epidemiologic importance, there is scarce HIV-1 molecular data from Northern Brazil. This scoping review summarizes recent epidemiologic data with special emphasis on HIV-1 genetic diversity and antiretroviral drug resistance mutations in patients from the seven Northern states of Brazil. Studies from the Northern Brazil on different HIV-1 genomic regions, mostly pol (protease/reverse transcriptase) sequences of naïve/antiretroviral treated adults/children were retrieved from PubMed/MEDLINE electronic database. These studies indicate a consistent molecular profile largely dominated by HIV-1 subtype B with minor contribution of subtypes F1 and C and infrequent detection of other subtypes (A1, D, K), recombinants (BF1, BC), circulating recombinant forms (CRF) as the new CRF90_BF1 and CRF02_AG-like, CRF28-29_BF-like, CRF31_BC-like, and a potential new CRF_BF1. This pattern indicates a founder effect of subtype B and the introduction of non-B-subtypes and recombinants probably generated in the Southern/Southeastern regions. In naïve populations transmitted drug resistance (TDR) can impact the outcome of first-line antiretroviral treatment and prophylactic/preventive regimens. In the Northern region TDR rates are moderate while patients failing highly active antiretroviral therapy (HAART) showed high prevalence of acquired drug resistance mutations. The limited HIV-1 molecular data from Northern Brazil reflects the great challenges to generate comprehensive scientific data in isolated, underprivileged areas. It also highlights the need to invest in local capacity building which supported by adequate infrastructure and funding can promote robust research activities to help reduce the scientific asymmetries in the Northern region. Currently the impacts of the overwhelming COVID-19 pandemic on the expanding HIV/AIDS epidemic in Northern Brazil deserves to be closely monitored.


Assuntos
COVID-19 , Infecções por HIV , HIV-1 , Brasil , Resistência a Medicamentos , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Mutação , Pandemias , Filogenia , SARS-CoV-2 , Análise de Sequência de DNA
8.
Viruses ; 13(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208165

RESUMO

Affordable, sensitive, and scalable technologies are needed for monitoring antiretroviral treatment (ART) success with the goal of eradicating HIV-1 infection. This review discusses use of Sanger sequencing and next generation sequencing (NGS) methods for HIV-1 drug resistance (HIVDR) genotyping, focusing on their use in resource limited settings (RLS). Sanger sequencing remains the gold-standard method for detecting HIVDR mutations of clinical relevance but is mainly limited by high sequencing costs and low-throughput. NGS is becoming a more common sequencing method, with the ability to detect low-abundance drug-resistant variants and reduce per sample costs through sample pooling and massive parallel sequencing. However, use of NGS in RLS is mainly limited by infrastructure costs. Given these shortcomings, our review discusses sequencing technologies for HIVDR genotyping, focusing on common in-house and commercial assays, challenges with Sanger sequencing in keeping up with changes in HIV-1 treatment programs, as well as challenges with NGS that limit its implementation in RLS and in clinical diagnostics. We further discuss knowledge gaps and offer recommendations on how to overcome existing barriers for implementing HIVDR genotyping in RLS, to make informed clinical decisions that improve quality of life for people living with HIV.


Assuntos
Farmacorresistência Viral , Genótipo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Técnicas de Genotipagem , Infecções por HIV/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
9.
Euro Surveill ; 26(27)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34240696

RESUMO

BackgroundInfluenza virus presents a considerable challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid infection diagnosis, rationalising antimicrobial therapy, and supporting infection-control interventions.AimTo evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Oxford Nanopore Technologies (Oxford, United Kingdom (UK)) metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic standards (Xpert Xpress Flu/RSV assay; BioFire FilmArray Respiratory Panel 2 assay). We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsCompared to standard testing, Nanopore metagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses. Of 59 samples with haemagglutinin subtype determined, 40 were H1 and 19 H3. We identified an influenza A(H3N2) genome encoding the oseltamivir resistance S331R mutation in neuraminidase, potentially associated with an emerging distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in a ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant community-circulating strain. We also detected other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Full genome generation can help investigate and manage nosocomial outbreaks.


Assuntos
Infecção Hospitalar , Influenza Humana , Nanoporos , Antivirais/uso terapêutico , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Resistência a Medicamentos , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/diagnóstico , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Metagenoma , Neuraminidase/genética , Estações do Ano , Reino Unido
10.
J Gen Virol ; 102(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34292864

RESUMO

Hepatitis B virus surface antigen (HBsAg) encoded by the S gene is highly expressed during the replication cycle of hepatitis B virus (HBV). However, the frequent usage of tryptophan in HBsAg, which leads to a high cost of biosynthesis, is inconsistent with the high expression level of this protein. Tryptophan-truncated mutation of HBsAg, that is, a tryptophan to stop codon mutation resulting in truncated HBsAg, might help to maintain its high expression with lower biosynthetic cost. We aimed to investigate the prevalence of tryptophan-truncated S quasispecies in treatment-naïve patients with chronic hepatitis B (CHB) by applying CirSeq as well as a site-by-site algorithm developed by us to identify variants at extremely low frequencies in the carboxyl terminus of HBsAg. A total of 730 mutations were identified in 27 patients with CHB, varying from seven to 56 mutations per sample. The number of synonymous mutations was much higher than that of nonsynonymous mutations in the reverse transcriptase (RT) coding region and vice versa in the S coding region, implying that the evolutionary constraints on the RT and S genes might be different. We showed that 25 (92.6 %) of 27 patients had at least one S-truncated mutation, most of which were derived from tryptophan, indicating a high prevalence of tryptophan-truncated S mutations in treatment-naïve patients with CHB. In terms of the RT gene, 21 (77.8 %) patients had pre-existing drug-resistant mutations, while no truncated mutations were detected. Our findings that tryptophan-truncated S quasispecies and drug-resistant RT mutants were highly prevalent in treatment-naïve patients with CHB provide new insights into the composition of the HBV population, which might help optimize the treatment and management of patients with CHB.


Assuntos
Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Mutação , Triptofano/genética , Adolescente , Adulto , Algoritmos , Motivos de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Códon , Farmacorresistência Viral , Evolução Molecular , Feminino , Genes Virais , Antígenos de Superfície da Hepatite B/química , Vírus da Hepatite B/química , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Quase-Espécies , DNA Polimerase Dirigida por RNA/genética , Análise de Sequência de DNA , Adulto Jovem
11.
Arch Virol ; 166(9): 2451-2460, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34195923

RESUMO

Human immunodeficiency virus (HIV) with transmitted drug-resistance (TDR) limits the therapeutic options available for treatment-naive HIV patients. This study aimed to further our understanding of the prevalence and transmission characteristics of HIV with TDR for the application of first-line antiretroviral regimens. A total of 6578 HIV-1 protease/reverse-transcriptase sequences from treatment-naive individuals in China between 2000 and 2016 were obtained from the Los Alamos HIV Sequence Database and were analyzed for TDR. Transmission networks were constructed to determine genetic relationships. The spreading routes of large TDR clusters were identified using a Bayesian phylogeographic framework. TDR mutations were detected in 274 (4.51%) individuals, with 1.40% associated with resistance to nucleoside reverse transcriptase inhibitors, 1.52% to non-nucleoside reverse transcriptase inhibitors, and 1.87% to protease inhibitors. The most frequent mutation was M46L (58, 0.89%), followed by K103N (36, 0.55%), M46I (36, 0.55%), and M184V (26, 0.40%). The prevalence of total TDR initially decreased between 2000 and 2010 (OR = 0.83, 95% CI 0.73-0.95) and then increased thereafter (OR = 1.50, 95% CI 1.13-1.97). The proportion of sequences in a cluster (clustering rate) among HIV isolates with TDR sequences was lower than that of sequences without TDR (40.5% vs. 48.8%, P = 0.023) and increased from 27.3% in 2005-2006 to 63.6% in 2015-2016 (P < 0.001). While most TDR mutations were associated with reduced relative transmission fitness, mutation M46I was associated with higher relative transmission fitness than the wild-type strain. This study identified a low-level prevalence of TDR HIV in China during the last two decades. However, the increasing TDR HIV rate since 2010, the persistent circulation of drug resistance mutations, and the expansion of self-sustaining drug resistance reservoirs may compromise the efficacy of antiretroviral therapy programs.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Prevalência , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , China/epidemiologia , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Masculino , Mutação , Filogenia
12.
Nat Commun ; 12(1): 4181, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234136

RESUMO

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.


Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Pirofosfatases/genética , Aciclovir/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Antibioticoprofilaxia , Antivirais/uso terapêutico , Variação Biológica da População/genética , Linhagem Celular , Criança , Pré-Escolar , Cristalografia por Raios X , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/virologia , DNA Viral/sangue , DNA Viral/isolamento & purificação , Modelos Animais de Doenças , Farmacorresistência Viral , Feminino , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Muromegalovirus/isolamento & purificação , Muromegalovirus/patogenicidade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Pirofosfatases/metabolismo , Pirofosfatases/ultraestrutura , Resultado do Tratamento , Adulto Jovem
13.
BMC Infect Dis ; 21(1): 668, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243716

RESUMO

BACKGROUND: To assess transmitted drug resistance (TDR) to tenofovir (TDF)/emtricitabine (FTC), using as pre-exposure prophylaxis, among newly diagnosed human immunodeficiency virus-1 (HIV-1)-infected residents in Shenyang city, northeast China. METHODS: Demographic and epidemiological information of all newly diagnosed HIV-1 infected residents in Shenyang city from 2016 to 2018 were anonymously collected from the local HIV epidemic database. HIV-1 pol sequences were amplified from RNA in cryopreserved plasma samples and sequenced directly. Viral subtypes were inferred with phylogenetic analysis and drug resistance mutations (DRMs) were determined according to the Stanford HIVdb algorithm. Recent HIV infection was determined with HIV Limiting Antigen avidity electro immunoassay. RESULTS: A total of 2176 sequences (92.4%, 2176/2354) were obtained; 70.9% (1536/2167) were CRF01_AE, followed by CRF07_BC (18.0%, 391/2167), subtype B (4.7%, 102/2167), other subtypes (2.6%, 56/2167), and unique recombinant forms (3.8%, 82/2167). The prevalence of TDR was 4.9% (107/2167), among which, only 0.6% (13/2167) was resistance to TDF/FTC. Most of these subjects had CRF01_AE strains (76.9%, 10/13), were unmarried (76.9%, 10/13), infected through homosexual contact (92.3%, 12/13), and over 30 years old (median age: 33). The TDF/FTC DRMs included K65R (8/13), M184I/V (5/13), and Y115F (2/13). Recent HIV infection accounted for only 23.1% (3/13). Most cases were sporadic in the phylogenetic tree, except two CRF01_AE sequences with K65R (Bootstrap value: 99%). CONCLUSIONS: The prevalence of TDR to TDF/FTC is low among newly diagnosed HIV-infected cases in Shenyang, suggesting that TDR may have little impact on the protective effect of the ongoing CROPrEP project in Shenyang city.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Emtricitabina/uso terapêutico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Tenofovir/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Farmacorresistência Viral/genética , Epidemias , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto Jovem
14.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169908

RESUMO

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/farmacologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Progressão da Doença , Farmacorresistência Viral , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Inibidores de Janus Quinases/farmacologia , Recidiva
15.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071094

RESUMO

Three main approaches are used to combat severe viral respiratory infections. The first is preemptive vaccination that blocks infection. Weakened or dead viral particles, as well as genetic constructs carrying viral proteins or information about them, are used as an antigen. However, the viral genome is very evolutionary labile and changes continuously. Second, chemical agents are used during infection and inhibit the function of a number of viral proteins. However, these drugs lose their effectiveness because the virus can rapidly acquire resistance to them. The third is the search for points in the host metabolism the effect on which would suppress the replication of the virus but would not have a significant effect on the metabolism of the host. Here, we consider the possibility of using the copper metabolic system as a target to reduce the severity of influenza infection. This is facilitated by the fact that, in mammals, copper status can be rapidly reduced by silver nanoparticles and restored after their cancellation.


Assuntos
Cobre/metabolismo , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Ceruloplasmina/fisiologia , Proteínas de Transporte de Cobre/metabolismo , ATPases Transportadoras de Cobre/fisiologia , Farmacorresistência Viral , Interações Hospedeiro-Patógeno , Humanos , Vacinas contra Influenza , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Mamíferos/metabolismo , Nanopartículas Metálicas/uso terapêutico , Chaperonas Moleculares/metabolismo , Proteínas PrPC/fisiologia , RNA Viral/fisiologia , Prata/uso terapêutico , Superóxido Dismutase-1/fisiologia , Proteínas Virais/fisiologia , Replicação Viral
16.
Am J Gastroenterol ; 116(6): 1264-1273, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074829

RESUMO

INTRODUCTION: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL). RESULTS: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR. DISCUSSION: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Biomarcadores/sangue , Comorbidade , Farmacorresistência Viral , Feminino , Guanina/uso terapêutico , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069929

RESUMO

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008-2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/genética , Adenina/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Brasil/epidemiologia , Farmacorresistência Viral/fisiologia , Feminino , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tenofovir/uso terapêutico , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Zidovudina/uso terapêutico
19.
Virus Genes ; 57(4): 327-337, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091827

RESUMO

Argentina exhibits low serological prevalence for Hepatitis B virus (HBV); however, occult hepatitis B infection (OBI) has been reported in blood donors, Amerindians and individuals coinfected with hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV). The aim of this study was to analyze the genetic diversity of HBV and to evaluate serological marker associations and coinfections with HCV and HIV in patients attending and treated in a public hospital in the province of Buenos Aires, Argentina. A total of 189 HBV reactive samples (HBsAg and/or anti-HBc) were analyzed for HBV DNA characterization. All reactive samples were tested for anti-HCV and HIV-antigen/antibody using CMIA assays. Thirty-six samples exhibited detectable HBV DNA, 7 of which were OBI. HBV sequences were classified as subgenotypes A1, A2, B2, D3, F1b, F3 and F4. Mutations related to the ability to escape the host's immune response, resistance to antiviral therapy and progression to disease were found in patients, partly due to the variable sensitivity of HBsAg, the reverse transcriptase, the basal core promoter and the preCore. HCV and HIV prevalence was 10% and most of the genotypes found in the sequences were genotype 1 and B/F recombinant subtype, respectively. Of the total samples analyzed, 7 exhibited coinfections. This study shows the frequency of OBI, subgenotype distribution, HBV mutations and coinfections, which may have important clinical implications in public hospital patients. Planned prevention, detection and treatment adherence are needed to reduce transmission and morbidity in vulnerable populations.


Assuntos
Coinfecção/genética , Hepatite B Crônica/genética , Hepatite B/genética , Hepatite C/genética , Adolescente , Adulto , Idoso , Argentina/epidemiologia , Doadores de Sangue , Coinfecção/sangue , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/genética , Infecções por HIV/virologia , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Hospitais Públicos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Sangue Oculto , Adulto Jovem
20.
J Biomed Nanotechnol ; 17(5): 809-821, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082868

RESUMO

Human Immunodeficiency Virus (HIV) is a global pandemic that has contributed to the burden of disease, and the synergistic interaction between Herpes Simplex Virus (HSV) and HIV has assisted further in the spread of the HIV disease. Moreover, several chemotherapeutic treatment options from antiviral monotherapy to highly active antiretroviral therapy (HAART) have been adopted to manage the infection; however, HIV has developed new mechanisms against these active pharmaceutical agents (APAs), limiting the effect of the drugs. In this article, we reviewed different nanoparticles and their antiviral potency against HSV and HIV infection as well as the effect of drug encapsulated nanoparticles using different drug delivery systems as they palliate to some flaws or deficiencies that the stand-alone drugs present. Drug encapsulated nanoparticles show better treatment outcomes of HSV and HIV infection. The nanoparticles can transverse the anatomic privilege sites to exert their therapeutic effect, and a prolonged and higher dose of the encapsulated therapeutic agent can ease the dosage frequency, thus palliating low drug compliance which the stand-alone drugs fail to perform. Therefore, it is clear that nanoparticles prevent antiviral drug resistance by maintaining sustained drug release over an extended period, improving the therapeutic effect of the entrapped drug.


Assuntos
Infecções por HIV , Osteoporose , Antivirais , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Humanos , Nanotecnologia , Osteoporose/tratamento farmacológico
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