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1.
J Hepatol ; 60(1): 54-61, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23994382

RESUMO

BACKGROUND & AIMS: The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms. METHODS: We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360 µg Pegasys [PegIFNα] n=11, daily dose of 300 mg Viread [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 µg Pegasys injected subcutaneously, weekly). RESULTS: PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF. CONCLUSIONS: We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Replicação Viral/efeitos dos fármacos , Adolescente , Adulto , Estudos de Coortes , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Recombinantes/uso terapêutico , Linfócitos T/imunologia
2.
Antimicrob Agents Chemother ; 58(2): 1136-45, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24295986

RESUMO

Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a-ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a-ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a-ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a-ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a-ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.).


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Lactamas/administração & dosagem , Polietilenoglicóis/administração & dosagem , RNA Viral/antagonistas & inibidores , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Ciclopropanos , Esquema de Medicação , Farmacorresistência Viral/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/efeitos adversos , Isoindóis , Lactamas/efeitos adversos , Lactamas Macrocíclicas , Masculino , Pessoa de Meia-Idade , Mutação , Polietilenoglicóis/efeitos adversos , Prolina/análogos & derivados , RNA Viral/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversos , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais/genética
3.
Nucleic Acids Res ; 40(22): 11189-201, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23066108

RESUMO

The study of cell-population heterogeneity in a range of biological systems, from viruses to bacterial isolates to tumor samples, has been transformed by recent advances in sequencing throughput. While the high-coverage afforded can be used, in principle, to identify very rare variants in a population, existing ad hoc approaches frequently fail to distinguish true variants from sequencing errors. We report a method (LoFreq) that models sequencing run-specific error rates to accurately call variants occurring in <0.05% of a population. Using simulated and real datasets (viral, bacterial and human), we show that LoFreq has near-perfect specificity, with significantly improved sensitivity compared with existing methods and can efficiently analyze deep Illumina sequencing datasets without resorting to approximations or heuristics. We also present experimental validation for LoFreq on two different platforms (Fluidigm and Sequenom) and its application to call rare somatic variants from exome sequencing datasets for gastric cancer. Source code and executables for LoFreq are freely available at http://sourceforge.net/projects/lofreq/.


Assuntos
Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Simulação por Computador , Vírus da Dengue/genética , Escherichia coli/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Mutação , Sensibilidade e Especificidade , Neoplasias Gástricas/genética , Proteínas Virais/química , Proteínas Virais/genética
4.
J Infect Dis ; 207(9): 1442-50, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22807519

RESUMO

BACKGROUND: Dengue is the most common arboviral infection of humans. There are currently no specific treatments for dengue. Balapiravir is a prodrug of a nucleoside analogue (called R1479) and an inhibitor of hepatitis C virus replication in vivo. METHODS: We conducted in vitro experiments to determine the potency of balapiravir against dengue viruses and then an exploratory, dose-escalating, randomized placebo-controlled trial in adult male patients with dengue with <48 hours of fever. RESULTS: The clinical and laboratory adverse event profile in patients receiving balapiravir at doses of 1500 mg (n = 10) or 3000 mg (n = 22) orally for 5 days was similar to that of patients receiving placebo (n = 32), indicating balapiravir was well tolerated. However, twice daily assessment of viremia and daily assessment of NS1 antigenemia indicated balapiravir did not measurably alter the kinetics of these virological markers, nor did it reduce the fever clearance time. The kinetics of plasma cytokine concentrations and the whole blood transcriptional profile were also not attenuated by balapiravir treatment. CONCLUSIONS: Although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule. CLINICAL TRIALS REGISTRATION: NCT01096576.


Assuntos
Antivirais/administração & dosagem , Dengue/tratamento farmacológico , Nucleosídeos/administração & dosagem , Administração Oral , Adulto , Antígenos Virais/sangue , Antivirais/efeitos adversos , Dengue/patologia , Dengue/virologia , Vírus da Dengue/isolamento & purificação , Método Duplo-Cego , Febre/tratamento farmacológico , Humanos , Masculino , Nucleosídeos/efeitos adversos , Placebos/administração & dosagem , Resultado do Tratamento , Carga Viral , Viremia/tratamento farmacológico , Adulto Jovem
5.
J Dermatol ; 48(11): 1652-1664, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34396569

RESUMO

Apremilast is an orally available phosphodiesterase 4 inhibitor used for the treatment of moderate to severe psoriasis. The aims of this analysis were to develop a population pharmacokinetic (PPK) model of apremilast based on observed data from phase 1 studies combined with clinical trial data from subjects with moderate to severe psoriasis, and to develop exposure-response (E-R) models to determine whether Japanese subjects with moderate to severe psoriasis achieve response to apremilast treatment similar to that observed in non-Japanese, predominantly Caucasian subjects with moderate to severe psoriasis. The PPK model demonstrated that apremilast plasma concentrations and overall apparent clearance rate were comparable between the Japanese and Caucasian subgroups. The E-R analyses of ≥75% or ≥50% improvement from baseline in Psoriasis Area and Severity Index score and achievement of static Physician Global Assessment score of 0 (clear) or 1 (almost clear) at week 16 indicated that apremilast treatment in Japanese subjects approached the maximal effect with response rates comparable to those in predominantly Caucasian subjects. Overall, the analyses confirm that the approved apremilast 30 mg b.i.d. dose is appropriate for Japanese subjects with moderate to severe psoriasis, with an efficacy profile similar to that previously observed in Caucasian subjects.


Assuntos
Psoríase , Anti-Inflamatórios não Esteroides/uso terapêutico , Método Duplo-Cego , Humanos , Japão , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Talidomida/análogos & derivados , Resultado do Tratamento
6.
J Dermatol ; 48(1): 80-84, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32909643

RESUMO

We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long-term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman's rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)-17A, IL-17F and IL-22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor-α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL-17A, IL-17F and IL-22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis.


Assuntos
Psoríase , Talidomida , Adulto , Método Duplo-Cego , Humanos , Japão , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Resultado do Tratamento
7.
J Dermatol ; 44(8): 873-884, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28391657

RESUMO

Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, works intracellularly within immune cells to regulate inflammatory mediators. This phase 2b randomized, placebo-controlled study evaluated efficacy and safety of apremilast among Japanese patients with moderate to severe plaque psoriasis. In total, 254 patients were randomized to placebo, apremilast 20 mg b.i.d. (apremilast 20) or apremilast 30 mg b.i.d. (apremilast 30) through week 16; thereafter, all placebo patients were re-randomized to apremilast 20 or 30 through week 68. Efficacy assessments included achievement of 75% or more reduction from baseline in Psoriasis Area and Severity Index score (PASI-75; primary) and achievement of static Physician Global Assessment (sPGA; secondary) score of 0 (clear) or 1 (minimal) at week 16. Safety was assessed through week 68. At week 16, PASI-75 response rates were 7.1% (placebo), 23.5% (apremilast 20; P = 0.0032 vs placebo) and 28.2% (apremilast 30; P = 0.0003 vs placebo); sPGA response rates (score of 0 or 1) were 8.8% (placebo), 23.9% (apremilast 20; P = 0.0165 vs placebo) and 29.6% (apremilast 30; P = 0.0020 vs placebo). Responses were maintained with apremilast through week 68. Most common adverse events (AEs) with placebo, apremilast 20 and apremilast 30 (0-16 weeks) were nasopharyngitis (8.3%, 11.8%, 11.8%), diarrhea (1.2%, 8.2%, 9.4%), and abdominal discomfort (1.2%, 1.2%, 7.1%), respectively. Exposure-adjusted incidence of these AEs did not increase with continued apremilast treatment (up to 68 weeks). Apremilast demonstrated efficacy and safety in Japanese patients with moderate to severe plaque psoriasis through 68 weeks that was generally consistent with prior studies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/tratamento farmacológico , Talidomida/análogos & derivados , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Nasofaringite/epidemiologia , Inibidores da Fosfodiesterase 4/farmacologia , Placebos , Psoríase/patologia , Índice de Gravidade de Doença , Talidomida/farmacologia , Talidomida/uso terapêutico , Resultado do Tratamento
8.
Leuk Res ; 29(11): 1253-7, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15916806

RESUMO

INTRODUCTION: : Studies with flavopiridol have demonstrated that this agent has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. Based upon this pre-clinical data, a phase I/II study of 24h flavopiridol was performed. PATIENTS AND METHODS: : Patients with previously treated CLL patients were enrolled on two sequentially performed cohorts of 13 patients. Patients in the first cohort received flavopiridol (80 mg/m(2) as a 24-h continuous infusion [24h CI]) every 2 weeks. Patients in the second cohort received flavopiridol (80 mg/m(2) as a 24h CI) for week 1 and then were dose escalated by 20mg/m(2) every 2 weeks to a maximal dose of 140 mg/m(2) in the absence of symptoms. Patients received up to 12 doses of therapy. RESULTS: : Thirteen patients with fludarabine-refractory or intolerant CLL enrolled in each cohort. Patients received a median of five treatments in each cohort with only two patients completing all 12 courses of therapy. There were no partial or complete responses noted. Toxicity was manageable in most patients and included anemia, thrombocytopenia, infections, diarrhea, and fatigue. CONCLUSIONS: : Flavopiridol as a 24-h continuous infusion has no clinical activity in relapsed, fludarabine-refractory CLL.


Assuntos
Flavonoides/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/administração & dosagem , Adulto , Idoso , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Flavonoides/efeitos adversos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
9.
Antivir Ther ; 19(3): 259-67, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24256626

RESUMO

BACKGROUND: We studied whether hepatitis B surface antigen (HBsAg)/anti-HBs immune complex levels in chronic hepatitis B (CHB) patients receiving antiviral therapy could be used as a response marker at baseline (BL) or early during treatment to predict treatment outcome. METHODS: An experimental array-based assay (immunological multi-parameter chip technology [IMPACT]; Roche Diagnostics, Penzberg, Germany) served to determine HBsAg, anti-HBs and complex levels. We tested a panel of serum samples of 40 hepatitis B e antigen (HBeAg)-positive and 44 HBeAg-negative patients who received pegylated interferon and adefovir for 48 weeks. RESULTS: HBsAg loss occurred in 4 of 40 HBeAg-positive and 4 of 44 HBeAg-negative patients. A total of 14 of 40 HBeAg-positive patients lost HBeAg and 12 of them formed anti-HBe. At BL, complexes were present in 83 (99%) patients, whereas free anti-HBs levels were detectable in 5 patients. Complex levels at BL and week 12 were higher in HBeAg-positive patients with HBeAg loss, compared to patients who retained HBeAg (P=0.002 and P=0.005, respectively). Receiver operating characteristic analysis for HBeAg loss in HBeAg-positive patients at BL and week 12 showed area-under-the-curve values of 0.79 (P=0.002) and 0.82 (P=0.003) for complex levels. We found no correlation in either HBeAg-positive or -negative patients between complex levels and HBsAg loss. CONCLUSIONS: We demonstrated for the first time that before and during treatment HBsAg/anti-HBs immune complex levels can predict HBeAg loss in HBeAg-positive CHB patients treated with pegylated interferon and adefovir. Complexes were present in almost all patients at BL and were higher in patients who lost HBeAg. In conclusion, determining HBsAg/anti-HBs immune complex levels before and early during treatment could aid in selecting CHB patients with an optimal chance to achieve HBeAg loss.


Assuntos
Adenina/análogos & derivados , Complexo Antígeno-Anticorpo/sangue , Antivirais/uso terapêutico , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adenina/uso terapêutico , Adulto , Área Sob a Curva , DNA Viral/sangue , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise Serial de Proteínas , Ligação Proteica , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
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