RESUMO
Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Ácidos Aminoisobutíricos , Ciclopropanos , Interpretação Estatística de Dados , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Pirrolidinas , Resposta Viral Sustentada , Resultado do Tratamento , Adulto JovemRESUMO
Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (≥10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. CONCLUSION: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260).
Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Ciclopropanos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
In AGATE-II, treatment with ombitasvir coformulated with paritaprevir/ritonavir plus ribavirin (RBV) in Egyptians infected with hepatitis C virus genotype 4 resulted in high rates of sustained virologic response at post-treatment week 12. This subanalysis examined the effects of treatment in AGATE-II on liver biomarkers in patients with compensated cirrhosis. AGATE-II was a phase 3, open-label, partly randomized trial of ombitasvir/paritaprevir/ritonavir with weight-based RBV daily once in treatment-naive or treatment-experienced patients. Patients without cirrhosis received treatment for 12 weeks and patients with compensated cirrhosis were randomized 1:1 to the same regimen for either 12 or 24 weeks. Sixty patients with compensated cirrhosis were randomized to treatment for 12 weeks (n = 31) or 24 weeks (n = 29). In the 12-week arm, significant improvements were observed in biomarkers of liver injury (alanine aminotransferase: -53.7 U/L, P < 0.001; aspartate aminotransferase: -35.9 U/L, P < 0.001) and liver fibrosis (aspartate aminotransferase to platelet ratio index: -0.987, P < 0.001; fibrosis-4 index: -1.165, P < 0.001). Similar results were reported in the 24-week arm. Treatment with ombitasvir/paritaprevir/ritonavir plus RBV in hepatitis C virus genotype, 4-infected Egyptians with compensated cirrhosis resulted in improvements in certain biomarkers of liver synthetic function, injury, and fibrosis, independent of treatment duration.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/patologia , Adulto , Idoso , Alanina Transaminase/sangue , Anilidas/uso terapêutico , Aspartato Aminotransferases/sangue , Carbamatos/uso terapêutico , Ciclopropanos , Quimioterapia Combinada/métodos , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Lactamas Macrocíclicas , Fígado/patologia , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas , Resposta Viral Sustentada , Resultado do Tratamento , ValinaRESUMO
The antiquated system used to manufacture the currently licensed inactivated influenza virus vaccines would not be adequate during an influenza virus pandemic. There is currently a search for vaccines that can be developed faster and provide superior, long-lasting immunity to influenza virus as well as other highly pathogenic viruses and bacteria. Recombinant vectors provide a safe and effective method to elicit a strong immune response to a foreign protein or epitope. This review explores the advantages and limitations of several different vectors that are currently being tested, and highlights some of the newer viruses being used as recombinant vectors.
Assuntos
Vetores Genéticos/genética , Vacinas contra Influenza/imunologia , Vacinas Sintéticas/imunologia , Adenoviridae/genética , Animais , Humanos , Vírus da Doença de Newcastle/genética , Orthomyxoviridae/genética , Poxviridae/genética , Vesiculovirus/genéticaRESUMO
Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3-99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6-98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection.
Assuntos
Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Idoso , Ácidos Aminoisobutíricos , Ciclopropanos , Quimioterapia Combinada , Feminino , Hepatite C Crônica/virologia , Humanos , Rim/patologia , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Prolina/análogos & derivados , Pirrolidinas , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. METHODS: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug. RESULTS: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. CONCLUSIONS: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit.
RESUMO
There is a substantial need to develop better influenza virus vaccines that can protect populations that are not adequately protected by the currently licensed vaccines. While live attenuated influenza virus vaccines induce superior immune responses compared to inactivated vaccines, the manufacturing process of both types of influenza virus vaccines is time consuming and may not be adequate during a pandemic. Adjuvants would be particularly useful if they could enhance the immune response to live attenuated influenza virus vaccines so that the amount of vaccine needed for a protective dose could be reduced. The glycolipid, alpha-galactosylceramide (alpha-GalCer), has recently been shown to have adjuvant activity for both inactivated and replicating recombinant vaccines. The goal of these experiments was to determine whether a derivative of alpha-GalCer, alpha-C-galactosylceramide (alpha-C-GalCer) can enhance the immune response elicited by a live attenuated influenza virus vaccine containing an NS1 protein truncation and reduce the amount of vaccine required to provide protection after challenge. Our results indicated that the adjuvant reduced both morbidity and mortality in BALB/c mice after challenge with wild type influenza virus. The adjuvant also increased the amount of influenza virus specific total IgG, IgG1, and IgG2a antibodies as well as IFN-gamma secreting CD8(+) T cells. By using knockout mice that are not able to generate NKT cells, we were able to demonstrate that the mechanism of adjuvant activity is dependent on NKT cells. Thus, our data indicate that stimulators of NKT cells represent a new avenue of adjuvants to pursue for live attenuated virus vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Galactosilceramidas/farmacologia , Vacinas contra Influenza/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Embrião de Galinha , Feminino , Galactosilceramidas/administração & dosagem , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Índice de Gravidade de Doença , Análise de Sobrevida , Vacinas Atenuadas/imunologiaRESUMO
The severe acute respiratory syndrome coronavirus (SARS-CoV) is highly pathogenic in humans, with a death rate near 10%. This high pathogenicity suggests that SARS-CoV has developed mechanisms to overcome the host innate immune response. It has now been determined that SARS-CoV open reading frame (ORF) 3b, ORF 6, and N proteins antagonize interferon, a key component of the innate immune response. All three proteins inhibit the expression of beta interferon (IFN-beta), and further examination revealed that these SARS-CoV proteins inhibit a key protein necessary for the expression of IFN-beta, IRF-3. N protein dramatically inhibited expression from an NF-kappaB-responsive promoter. All three proteins were able to inhibit expression from an interferon-stimulated response element (ISRE) promoter after infection with Sendai virus, while only ORF 3b and ORF 6 proteins were able to inhibit expression from the ISRE promoter after treatment with interferon. This indicates that N protein inhibits only the synthesis of interferon, while ORF 3b and ORF 6 proteins inhibit both interferon synthesis and signaling. ORF 6 protein, but not ORF 3b or N protein, inhibited nuclear translocation but not phosphorylation of STAT1. Thus, it appears that these three interferon antagonists of SARS-CoV inhibit the interferon response by different mechanisms.
Assuntos
Interferon beta/antagonistas & inibidores , Proteínas do Nucleocapsídeo/metabolismo , Fases de Leitura Aberta/fisiologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , Proteínas Virais/metabolismo , Apoptose , Linhagem Celular , Humanos , Fator Regulador 3 de Interferon/antagonistas & inibidores , Interferon beta/biossíntese , Microscopia Confocal , NF-kappa B/antagonistas & inibidores , Proteínas do Nucleocapsídeo/genética , Fases de Leitura Aberta/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Transfecção , Proteínas Virais/genéticaRESUMO
The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis.
Assuntos
Núcleo Celular/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Fases de Leitura Aberta/fisiologia , Fator de Transcrição STAT1/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Replicação Viral/fisiologia , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Células CACO-2 , Núcleo Celular/genética , Núcleo Celular/imunologia , Chlorocebus aethiops , Retículo Endoplasmático/genética , Retículo Endoplasmático/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Complexo de Golgi/genética , Complexo de Golgi/imunologia , Humanos , Imunidade Inata/genética , Interferons/imunologia , Interferons/metabolismo , Mutação , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Vero , alfa Carioferinas/genética , alfa Carioferinas/imunologia , alfa Carioferinas/metabolismo , beta Carioferinas/genética , beta Carioferinas/imunologia , beta Carioferinas/metabolismoRESUMO
It was recently shown that the 7a protein of severe acute respiratory syndrome coronavirus induces biochemical changes associated with apoptosis. In this study, the mechanism by which the 7a protein induces apoptosis was examined. The 7a protein was tested for the ability to inhibit cellular gene expression because several proapoptotic viral proteins with this function have previously been identified. 7a protein inhibited expression of luciferase from an mRNA construct that specifically measures translation, whereas inhibitors of transcription and nucleocytoplasmic transport did not. The inhibition of translation and other cellular processes of gene expression have been associated with the induction of a stress response in cells. Western blot analysis using phosphospecific antibodies indicated that 7a protein activated p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal protein kinase/stress-activated protein kinase. Taken together, these data indicate that the induction of apoptosis by the 7a protein may be related to its ability to inhibit cellular translation and activate p38 MAPK.
Assuntos
Proteínas de Membrana/fisiologia , Biossíntese de Proteínas/fisiologia , Proteínas Virais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose , Linhagem Celular , Células , Regulação para Baixo , Ativação Enzimática , Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Luciferases/metabolismo , Proteínas de Membrana/metabolismo , Proteínas da Matriz Viral , Proteínas Virais/metabolismoRESUMO
Reovirus infection is initiated by interactions between the attachment protein sigma1 and cell surface carbohydrate and junctional adhesion molecule A (JAM-A). Expression of a JAM-A mutant lacking a cytoplasmic tail in nonpermissive cells conferred full susceptibility to reovirus infection, suggesting that cell surface molecules other than JAM-A mediate viral internalization following attachment. The presence of integrin-binding sequences in reovirus outer capsid protein lambda2, which serves as the structural base for sigma1, suggests that integrins mediate reovirus endocytosis. A beta1 integrin-specific antibody, but not antibodies specific for other integrin subunits, inhibited reovirus infection of HeLa cells. Expression of a beta1 integrin cDNA, along with a cDNA encoding JAM-A, in nonpermissive chicken embryo fibroblasts conferred susceptibility to reovirus infection. Infectivity of reovirus was significantly reduced in beta1-deficient mouse embryonic stem cells in comparison to isogenic cells expressing beta1. However, reovirus bound equivalently to cells that differed in levels of beta1 expression, suggesting that beta1 integrins are involved in a postattachment entry step. Concordantly, uptake of reovirus virions into beta1-deficient cells was substantially diminished in comparison to viral uptake into beta1-expressing cells. These data provide evidence that beta1 integrin facilitates reovirus internalization and suggest that viral entry occurs by interactions of reovirus virions with independent attachment and entry receptors on the cell surface.
Assuntos
Integrina beta1/metabolismo , Orthoreovirus de Mamíferos/patogenicidade , Sequência de Aminoácidos , Animais , Células CHO , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Moléculas de Adesão Celular/metabolismo , Cricetinae , Células HeLa , Humanos , Moléculas de Adesão Juncional , Células L , Orthoreovirus Mamífero 3/patogenicidade , Camundongos , Dados de Sequência Molecular , Receptores Virais/metabolismoRESUMO
Persistent reovirus infections of murine L929 (L) fibroblast cells select mutant (LX) cells that do not support proteolytic disassembly of reovirus virions within the endocytic pathway. To better understand the function and regulation of endocytic proteases, we conducted experiments to define the block to reovirus disassembly displayed by LX cells. In contrast to parental L cells, mutant LX cells harbor defects that interfere with the maturation and activity of cathepsin B and cathepsin L but not cathepsin H. The cDNAs encoding cathepsin B and cathepsin L in L cells are identical to those in LX cells, indicating that LX cells manifest an extrinsic block to the function of these enzymes. Mixed lysates of L cells and LX cells lack activity of both cathepsin B and cathepsin L, suggesting the presence of an inhibitor of cathepsin function in LX cells. A cathepsin B-green fluorescent protein (GFP) fusion protein expressed in L cells and purified by immunoprecipitation retains cathepsin B activity, whereas cathepsin B-GFP expressed in LX cells does not. However, activity of cathepsin B-GFP expressed in LX cells can be recovered by incubating the immunoprecipitate with L cell lysate followed by immunoprecipitation, providing further evidence that LX cells express a cathepsin inhibitor. Native-gel electrophoresis and gel filtration chromatography demonstrate that, in both cell lines, the double-chain form of cathepsin B is sequestered in a large molecular weight complex that renders this form of the enzyme inactive. Alteration of this sequestration complex appears to be responsible for inhibition of cathepsin B in LX cells. These findings suggest that cathepsins can be regulated within the endocytic pathway. Moreover, this regulation influences host cell susceptibility to intracellular pathogens.