RESUMO
Mycobacterium tuberculosis (Mtb) infection remains a major health problem worldwide. Although the Bacillus Calmette-Guérin (BCG) vaccine is the most widely used vaccination for preventing tuberculosis (TB), its efficacy is limited. We previously developed a new recombinant BCG (rBCG)-based vaccine encoding the Ag85B protein of M. kansasii (Mkan85B), termed rBCG-Mkan85B, and its administration is followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). Previously, we identified MHC-I (H2-Kd)-restricted epitopes that highly cross-react with those of Mtb in BALB/c (H2d) and CB6F1 (H2b/d) mice. We also reported that the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol protected CB6F1 mice against M. kansasii infection. In this study, to investigate the protective effect of our novel rBCG against Mtb infection, CB6F1 mice were either left unimmunized or immunized with the BCG, rBCG-Mkan85B, or rBCG-Mkan85B/DNA-Mkan85B vaccine for 10 weeks prior to inhalation exposure to the virulent Mtb Erdman strain for another 6 weeks. Compared with the BCG and rBCG-Mkan85B vaccinations, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol significantly reduced the numbers of pulmonary colony-forming units (CFUs). Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination induced antigen-specific polyfunctional CD4+ and CD8+ T cells. These results suggest that CD8+ T-cell immunity to immunodominant epitopes of Mtb is enhanced by rBCG vector-based immunization. Thus, rBCG vector-based vaccinations may overcome the limited ability of the current BCG vaccine to elicit TB immunity.
Assuntos
Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose , Animais , Camundongos , Vacina BCG , Linfócitos T CD8-Positivos , Antígenos de Bactérias , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/metabolismo , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75-84 years with chronic hepatitis C after HCV elimination. METHODS: This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75-84 versus 60-74 years. RESULTS: The median observational period was 3.5 years. Among patients aged 75-84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus <3.25 (2.16 per 100 PY) at 12 weeks after the end of treatment, unlike the results in those aged 60-74 years (3.61 and 1.51 per 100 PY, respectively) (adjusted hazard ratio, 2.20; P = .04). In 495 pairs matched by propensity score matching, in patients without cirrhosis, the cumulative HCC incidence was significantly higher in the 75-84-year than in the 60-74-year age group (P = .04). CONCLUSIONS: Older patients aged 75-84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to <3.25.
Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Humanos , Pessoa de Meia-Idade , Idoso , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Estudos de Coortes , Estudos Retrospectivos , Hepacivirus , Resposta Viral SustentadaRESUMO
Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.
Assuntos
Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Humanos , Pneumopatias/diagnóstico , Pneumopatias/epidemiologia , Pneumopatias/microbiologia , Mycobacterium/genética , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/genéticaRESUMO
A slowly growing mycobacteria, identified as strain TY59T, was isolated from sputum of an elderly man with pneumonia. Sequencing of the 16S rRNA gene indicated that this strain was similar to members of the Mycobacterium avium complex and closely related species. Strain TY59T has highest 16S rRNA gene sequence similarities to the type strains of Mycobacterium colombiense (99.80â% sequence similarity), Mycobacterium vulneris (99.74â%), Mycobacterium timonense (99.54â%), Mycobacterium avium subsp. avium (99.54â%) and Mycobacterium avium subsp. silvaticum (99.54â%). Analysis of the internal transcribed spacer (ITS) and DNA-directed RNA polymerase subunit beta (rpoB) sequences gave similar results to the 16S rRNA gene analysis. The closest species to strain TY59T were M. colombiense and M. vulneris with 97.90-98.25â% identity in ITS and 96.4-96.6â% in rpoB. The strain's 65 kDa heat shock protein (hsp65) gene was different from those of M. vulneris, M. colombiense and M. avium subsp. silvaticum with 72.4-74.2â% identity. Average nucleotide identity results showed a 93.4â% match to M. vulneris as the maximum value. Phenotypically, the non-chromogenicity, rough colonies, growth at 42 °C, negative results for nitrate reduction, ß-glucosidase and Tween 80 hydrolysis, and positive results for catalase activity set this strain apart from closely related species. We propose that Mycobacterium senriense sp. nov. is a novel species of slowly growing mycobacteria. The type strain is TY59T (RIMD 1371001T=CIP 111917T).
Assuntos
Infecções por Mycobacterium , Mycobacterium , Idoso , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , RNA Polimerases Dirigidas por DNA/genética , Ácidos Graxos/química , Humanos , Masculino , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/microbiologia , Complexo Mycobacterium avium , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Escarro/microbiologiaRESUMO
Recently, the efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination is being reassessed in accordance with the achievements of clinical tuberculosis (TB) vaccine research. However, the mechanisms ultimately determining the success or failure of BCG vaccination to prevent pulmonary TB remain poorly understood. In this study, we analyzed the protective effects of intradermal BCG vaccination by using specific pathogen-free cynomolgus macaques of Asian origin that were intradermally vaccinated with BCG (Tokyo strain) followed by Mycobacterium tuberculosis (Erdman strain) infection. Intradermal BCG administration generated TB Ag-specific multifunctional CD4 T cell responses in peripheral blood and bronchoalveolar lavage and almost completely protected against the development of TB pathogenesis with aggravation of clinical parameters and high levels of bacterial burdens in extrapulmonary organs. However, interestingly, there were no differences in bacterial quantitation and pathology of extensive granulomas in the lungs between BCG-vaccinated monkeys and control animals. These results indicated that the changes in clinical parameters, immunological responses, and quantitative gross pathology that are used routinely to determine the efficacy of TB vaccines in nonhuman primate models might not correlate with the bacterial burden and histopathological score in the lung as measured in this study.
Assuntos
Vacina BCG/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Animais , Antígenos de Bactérias/imunologia , Lavagem Broncoalveolar/métodos , Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Macaca fascicularis , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Pneumonia/imunologia , Vacinação/métodosRESUMO
BACKGROUND AND AIM: Early hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long-term trends and predictors of recurrence after HCV cure by direct-acting antivirals (DAAs). METHODS: This retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post-treatment early phase (24 weeks after SVR) were evaluated. RESULTS: The data of 326 patients were available for the final analysis. The median follow-up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5-year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log-rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2). CONCLUSIONS: The evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long-term surveillance strategies.
Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Recidiva , Estudos Retrospectivos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS: This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS: The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4 < 3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation. CONCLUSIONS: In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation.
Assuntos
Antivirais , Hepatite C , Cirrose Hepática , Idoso , Antivirais/uso terapêutico , Estudos de Coortes , Feminino , Hepatite C/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/fisiopatologia , Masculino , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF. METHODS: This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Differences in longitudinal parameters were compared by the generalized estimating equation method. RESULTS: In the prior ETV group (n = 191), the HBV DNA suppression rate at week 48 was significantly increased, from 75.9% to 96.9% (P < .001). Additionally, mean changes in the HBsAg level at week 48 in HBsAg ≥ 3.0 logIU/mL and < 3.0 logIU/mL groups were -0.09 and -0.13 logIU/mL respectively. In the prior NA combination group (n = 122), the mean changes in HBsAg level at week 48 in the HBsAg ≥ 3.0 logIU/mL and <3.0 logIU/mL groups were -0.08 and -0.11 logIU/mL respectively. For patients with CKD, the eGFR at week 48 was significantly improved compared to those with non-CKD (adjusted slope coefficient difference: 2.75 mL/min/1.73 m2 /48 weeks; P = .001). CONCLUSIONS: Switching from ETV or an NA combination to TAF was effective for HBV suppression and continued HBsAg reduction. Moreover, the renal glomerular function of patients in the prior NA combination group with CKD was significantly improved compared to those with non-CKD. LAY SUMMARY: Nucleos(t)ide analogues, such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, inhibit hepatitis B virus (HBV) replication and are recommended as first-line oral agents for chronic HBV infection. We evaluated the virological/biochemical effects and renal safety when patients are switched from entecavir or nucleoside-nucleotide analogue combination therapy to tenofovir alafenamide. Our findings suggest that switching to tenofovir alafenamide was effective for HBV suppression and the improvement in renal function for patients with chronic kidney disease.
Assuntos
Hepatite B Crônica , Adenina/análogos & derivados , Alanina , Antivirais/efeitos adversos , Estudos de Coortes , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Humanos , Estudos Retrospectivos , Tenofovir/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. CASE PRESENTATION: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. CONCLUSION: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.
Assuntos
Pneumopatias/diagnóstico , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Micobactérias não Tuberculosas/genética , Micobactérias não Tuberculosas/isolamento & purificação , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes Diagnósticos de Rotina , Feminino , Humanos , Pneumopatias/microbiologia , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus/métodos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Resultado do Tratamento , Sequenciamento Completo do Genoma/métodosRESUMO
AIM: Hepatitis C virus genotype 2 is common in East Asia, sub-Saharan Africa, and Latin America. However, many countries in these areas lag behind other areas of the world in government approval for new direct-acting antivirals. The aim of this study was to evaluate the treatment outcome of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C virus genotype 2 infection. METHODS: This is a two-part multicenter, real-world cohort study. Study 1 consisted of 58 consecutive patients who were treated with LDV/SOF for 12 weeks. Study 2 used propensity score matching for LDV/SOF (n = 58) and glecaprevir/pibrentasvir (n = 207) treatment groups (1:1) with a set of clinically important variables. Sustained viral response 12 weeks after the end of treatment (SVR12) and adverse events were evaluated in both studies. RESULTS: In study 1, the overall SVR12 rates of the intention-to-treat and modified intention-to-treat populations were 94.8% (55/58) and 96.5% (55/57), respectively. High SVR12 rates were observed in almost all subgroups, including older age, compensated cirrhosis, and treatment experience. In study 2, propensity score matching of the entire study population yielded 52 matched pairs with similar baseline characteristics. There were no statistically significant differences between the LDV/SOF (96.1%) and glecaprevir/pibrentasvir (98.0%) groups in the overall SVR12 rates of the modified intention-to-treat populations, and their rates of treatment discontinuation and adverse events were similar. CONCLUSIONS: Treatment with LDV/SOF for hepatitis C virus genotype 2 resulted in a high rate of SVR12 and excellent tolerability. The outcomes of LDV/SOF were very similar to those of glecaprevir/pibrentasvir.
RESUMO
AIM: Glecaprevir (GLE) and pibrentasvir (PIB) are new direct-acting antiviral agents (DAAs) with pangenotypic inhibitors that respectively target the hepatitis C virus (HCV) NS3/4 protease and NS5A. The aim of this study was to evaluate the effectiveness and safety of combining GLE and PIB for patients with HCV genotype (GT) 1 or 2 infection in the clinical setting, including patients DAA-experienced or on hemodialysis. METHODS: This multicenter, real-world, retrospective, cohort study consisted of 314 Japanese patients who were treated with GLE (300 mg) and PIB (120 mg) for a fixed 8- or 12-week duration. We evaluated the sustained virologic response rate 12 weeks after the end of treatment (SVR12) and adverse events. RESULTS: Among the treated patients, 122 had GT1 and 192 GT2 infection. The overall SVR12 rates in the per-protocol populations were 99.2% (119/120) for GT1 and 98.9% (183/185) for GT2. High SVR12 rates were observed in almost all subgroups, including cirrhosis, receiving hemodialysis, or previous all-oral DAA groups treated with asunaprevir and daclatasvir (GT1b), ledipasvir/sofosbuvir (GT1), or sofosbuvir and ribavirin (GT2). Virological relapse occurred in only 1.0% (3/305) of the patients who completed treatment. The most common adverse events were pruritus and fatigue (>5% of patients). Serious adverse events were rare and discontinuation due to an adverse event was required for 1.6% of the patients. CONCLUSIONS: In this real-world cohort study, treatment with GLE/PIB achieved high SVR12 rates with a low rate of serious adverse events among patients with HCV GT1 or 2 infection.
RESUMO
AIM: The aim of this study was to evaluate the efficacy and safety of 24-week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection. METHODS: This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon-ineligible/intolerant or non-responders to interferon-based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age. RESULTS: The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65-74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre-existent NS5A resistance-associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen. CONCLUSIONS: Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre-existent NS5A resistance-associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.
RESUMO
BACKGROUND: It is known that tooth loss is known to be a risk factor for Alzheimer's disease and soft diet feeding induces memory impairment. Recent studies have shown that brain-derived neurotrophic factor (BDNF) is associated with tooth loss or soft diet in young animal model, and that BDNF expression is decreased in patients with Alzheimer's disease. However, single or combined effect of tooth loss and/or soft diet on brain function has not fully understood. Here we examined the effect of molar loss and powder diet on memory ability and the expression of BDNF mRNA in the hippocampus of adult C57BL/6J mice. Twenty eight-weeks-old C57BL/6J mice were divided into intact molar group and extracted molar group. They were randomly divided into the I/S group (Intact upper molar teeth/Solid diet feeding), the E/S group (Extracted upper molar teeth/Solid diet feeding), the I/P group (Intact upper molar teeth/Powder diet feeding), and the E/P group (Extracted upper molar teeth/Powder diet feeding). The observation periods were 4 and 16-week. To analyze the memory ability, the step-through passive avoidance test was conducted. BDNF-related mRNA in the hippocampus was analyzed by real-time polymerase chain reaction (RT-PCR). RESULTS: At 4 weeks later, we performed memory test and isolated brains to analyze. There were no differences in memory function and BDNF mRNA level between these four groups. However, at 16 weeks later, E/S and E/P group showed memory impairment, and decreased level of BDNF mRNA. Whereas, the powder diet had no effect on memory function and BDNF mRNA level even at 16 weeks later. CONCLUSIONS: These results suggest that the effect of molar loss and powder diet on memory function and BDNF mRNA levels were different, molar loss may have a greater long-term effect on memory ability than powder diet does.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta/efeitos adversos , Hipocampo/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Perda de Dente/complicações , Animais , Aprendizagem da Esquiva/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Hipocampo/patologia , Hipotálamo/metabolismo , Masculino , Memória/fisiologia , Transtornos da Memória/patologia , Camundongos Endogâmicos C57BL , Dente Molar , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptor trkB/metabolismo , Fatores de Tempo , Perda de Dente/metabolismo , Perda de Dente/patologia , Perda de Dente/psicologiaRESUMO
AIM: Although there is much evidence of an antitumor effect of pegylated interferon (IFN)-α-based treatment, limited data is available about that of IFN-ß-based treatment. Our goal was to evaluate the impact of IFN-ß plus ribavirin (RBV) treatment on the suppression of hepatocellular carcinoma (HCC). METHODS: This retrospective, multicenter study consisted of 124 chronic hepatitis C patients who were treated with IFN-ß plus RBV treatment, including 61 with advanced fibrosis and five with pretreatment HCC. All participants were followed for a median of 2.8 years (range, 2.2-3.2) after the end of their antiviral treatment. The data of 112 patients who finished the treatment were available for analysis. Cox proportional hazard analyses were performed to determine factors significantly associated with HCC development. Cumulative incidence curves for HCC were plotted using the Kaplan-Meier method and differences between groups were assessed using the log-rank test. RESULTS: The 2.9% rate of HCC development of patients with sustained virological response (SVR) was significantly lower (P = 0.027) than the 15.9% of non-SVR patients. Interestingly, no significant difference was observed between the rates of HCC development of patients with and without advanced fibrosis (P = 0.733), even though the SVR rate of patients with advanced fibrosis was significantly lower than that of those without advanced fibrosis (P < 0.001). Stepwise multivariable Cox analysis extracted that only SVR was significantly associated with HCC development (hazard ratio, 0.20; 95% confidence interval, 0.03-0.84, P = 0.027). CONCLUSION: SVR was significantly associated with a lower risk of HCC development after IFN-ß plus RBV treatment.
RESUMO
A 63-year-old female and a 63-year-old male with resolved HBV infection suffered a relapse of malignant lymphoma. After bendamustine hydrochloride monotherapy, HBV reactivation occurred. Entecavir treatment was commenced immediately, with tests for HBV DNA negative without development of hepatitis. Regular monitoring of HBV DNA based on the guidelines from the Japan Society of Hepatology was useful.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Vírus da Hepatite B/fisiologia , Hepatite B/virologia , Linfoma/tratamento farmacológico , Ativação Viral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
BACKGROUND AND AIM: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated-interferon alpha (PEG-IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir-based or telaprevir-based triple therapy for non-cirrhotic patients in real-world clinical practice. METHODS: This multicenter study consisted of 835 consecutive Japanese HCV genotype 1b patients treated in a clinical setting, 716 of whom were enrolled (simeprevir = 256 and telaprevir = 460). Logistic regression was carried out after propensity score matching to assess the sustained virological response at week 12 after the end of treatment (SVR12). RESULTS: In the propensity-matched cohort (253 matched pairs), the SVR12 rates of the patients who underwent simeprevir-based or telaprevir-based triple therapy were 85.0% and 84.2%, respectively, by intention-to-treat analysis. Prior treatment response to PEG-IFNα/ribavirin and IL28B genotype was independently associated with SVR12 in both groups. No significant differences in the SVR12 rates stratified by prior treatment response to PEG-IFNα/ribavirin were found between the simeprevir (treatment-naïve 89.1%, prior relapse 94.3%, prior partial response 65.0%, and prior null response 33.3%) and telaprevir (treatment-naïve 87.8%, prior relapse 90.1%, prior partial response 68.4%, and prior null response 50.0%) groups. The incidence of adverse effects, such as anemia, severe rash, and the elevation of serum creatinine, was markedly higher in the telaprevir group. CONCLUSIONS: Considering the effectiveness and safety, simeprevir-based triple therapy will continue to be a useful treatment option in Japan for treatment-naïve or prior relapse patients with a favorable IL28B genotype.
Assuntos
Antivirais/administração & dosagem , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Oligopeptídeos/administração & dosagem , Farmacogenética , Inibidores de Proteases/administração & dosagem , Simeprevir/administração & dosagem , Idoso , Antivirais/efeitos adversos , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferons , Interleucinas/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Polietilenoglicóis/administração & dosagem , Pontuação de Propensão , Inibidores de Proteases/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Ribavirina/administração & dosagem , Simeprevir/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to the pegylated interferon (PEG-IFN) α and ribavirin combination regimen (triple therapy) has dramatically improved treatment outcome. Unfortunately, anemia remains a common adverse effect. This study was done to compare the development of severe anemia during simeprevir- or telaprevir-based triple therapy. METHODS: This retrospective multicenter study consisted of 837 consecutive Japanese HCV genotype 1 patients treated in a real-world clinical setting, 811 of whom were enrolled (simeprevir 281, telaprevir 530). The inosine triphosphate pyrophosphatase (ITPA) genotype at rs1127354 was determined for all studied patients. Logistic regression was done after propensity score matching to assess the risk of development of severe anemia. RESULTS: Propensity score matching of the entire study population yielded 266 matched pairs. Severe anemia (nadir hemoglobin < 9.0 g/dL) was developed during the treatment period by 81 (30.5%) and 144 (54.1%) patients treated with simeprevir and telaprevir, respectively. Treatment with simeprevir was independently associated with a lower risk of severe anemia (odds ratio 0.25, 95% confidence interval 0.16-0.38, P < 0.0001). Moreover, ITPA genotype, age, hemoglobin level, and estimated glomerular filtration rate at baseline were also independent factors associated with the development of severe anemia. CONCLUSIONS: Patients treated with simeprevir-based triple therapy have a lower risk of the development of severe anemia than those treated with telaprevir. Moreover, ITPA genotype and age may be useful for individualizing treatment to reduce the risk of anemia-related adverse effects.
Assuntos
Anemia/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Simeprevir/efeitos adversos , Fatores Etários , Idoso , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Feminino , Genótipo , Taxa de Filtração Glomerular , Hemoglobinas , Hepacivirus/genética , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Oligopeptídeos/administração & dosagem , Pirofosfatases/genética , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Risco , Índice de Gravidade de Doença , Simeprevir/administração & dosagem , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
BACKGROUND AND AIM: Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx). METHODS: This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin. RESULTS: The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P < 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P < 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups. CONCLUSION: The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/terapia , Cirrose Hepática/terapia , Oligopeptídeos/administração & dosagem , Esplenectomia , Trombocitopenia/terapia , Adulto , Idoso , Alelos , Quimioterapia Combinada , Feminino , Hepatite C Crônica/complicações , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferons , Interleucinas/genética , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Ribavirina/administração & dosagem , Índice de Gravidade de Doença , Trombocitopenia/sangue , Trombocitopenia/etiologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS: This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS: The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS: TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Oligopeptídeos/administração & dosagem , Adulto , Fatores Etários , Idoso , Antivirais/efeitos adversos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/classificação , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Prospectivos , RNA Viral/sangue , RNA Viral/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. METHODS: This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L. RESULTS: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). CONCLUSIONS: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.