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1.
J Hepatol ; 76(3): 568-576, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34748893

RESUMO

BACKGROUND & AIMS: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening. METHODS: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation. RESULTS: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 µg/L, and liver iron concentration (LIC) 166±77 µmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37). CONCLUSION: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice. LAY SUMMARY: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing.


Assuntos
Proteínas de Transporte de Cátions/análise , Hemocromatose/diagnóstico , Projetos de Pesquisa/normas , Idoso , Proteínas de Transporte de Cátions/sangue , Estudos de Coortes , Feminino , Hemocromatose/sangue , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/complicações , Modelos Logísticos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Curva ROC , Projetos de Pesquisa/estatística & dados numéricos
2.
Clin Gastroenterol Hepatol ; 17(3): 518-526, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29857143

RESUMO

BACKGROUND & AIMS: In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas. METHODS: We collected follow-up data from a prospective international multicenter cohort study of 148 patients with symptomatic HCV-CryoVas (53.7% with cirrhosis and 49.3% naive to treatment with DAAs). All patients received DAA (sofosbuvir plus daclatasvir, n = 53; sofosbuvir plus ribavirin, n = 51; sofosbuvir plus ledipasvir, n = 23; or sofosbuvir plus simeprevir, n = 18), for 12 or 24 weeks, from 2014 through 2017; the median follow-up time was 15.3 months. A complete clinical response was defined as improvement of all organs involved at baseline and the absence of clinical relapse; a partial response was defined as improvement in some but not all organs involved at baseline. The primary end point was clinical response of CryoVas symptoms at week 12 after stopping DAA therapy. RESULTS: A complete response was reported for 106 patients (72.6%), a partial response for 33 patients (22.6%), and no response for 7 patients (4.8%). Cryoglobulins were no longer detected in blood samples from 53.1% of patients, and 97.2% of the patients had a sustained virologic response to therapy. Premature DAA withdrawal was reported for 4.1% of patients. Factors associated with no or partial response to therapy included a severe form of CryoVas (odds ratio, 0.33; 95% CI, 0.12-0.91; P = .03) and peripheral neuropathy (odds ratio, 0.31; 95% CI, 0.11-0.84; P = .02). After a median follow-up time of 15.3 months, 4 patients (2.8%) died. The CryoVas manifestation of purpura was cleared from 97.2% of patients, renal involvement from 91.5% of patients, arthralgia from 85.7% of patients, neuropathy from 77.1% of patients, and cryoglobulinemia from 52.2%. CONCLUSIONS: In a long-term follow-up analysis of data from a clinical trial, we found that more than 95% of patients with HCV-CryoVas have a full or partial response of symptoms to different DAA treatment regimens. Fewer than 5% of patients stop therapy prematurely and less than 3% die. A severe form of CryoVas and peripheral neuropathy were associated with a lack of response of HCV-CryoVas to DAA therapy.


Assuntos
Antivirais/uso terapêutico , Crioglobulinemia/complicações , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Vasculite/patologia , Idoso , Antivirais/efeitos adversos , Ensaios Clínicos como Assunto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento
3.
Ann Hepatol ; 18(5): 708-714, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164266

RESUMO

INTRODUCTION AND OBJECTIVE: Hepatitis C virus (HCV) infection and treatment impact the patient's daily life and work productivity. Until recently, treatments were associated with side effects and insufficient virologic and hepatic results. This study evaluated fatigue, work productivity, and treatment modalities in patients with HCV infection. MATERIALS AND METHODS: This cross-sectional, non-interventional, multicenter study was conducted in real-life settings between March and December 2015 at 109 sites in France. RESULTS: Data from 1269 patients were evaluable. The mean patient age was 55.8±12.5 years; 53.3% (676) patients were male. A total of 80.1% (1015) of patients were Caucasian and 62.3% (791) had a genotype 1 infection, 34.2% (433) had at least one comorbidity and 15.6% (198) had ≥1 clinical sign/symptom. Illicit drug use was the main route of HCV transmission and accounted for 36.8% (466) of all infections. Fibrosis stage F0/F1 was reported in 41.4% (525) of patients. A majority of patients (60.4%, 764) had never been treated. In patients previously treated, 85.8% (430) received ribavirin and pegylated interferon and only 13.4% (67) direct-acting antivirals. The mean percent of global impairment due to health was highest (34.8±30.9%) in patients 18-45 years of age. The prevalence of active employed patients with a total fatigue score≥its median value (45/160) was 38.6%. The mean percent work time missed due to health was 9.6±23.6% for working patients of 18-45 years of age and 7.3±21.8% for working patients of 45-65 years of age. The mean overall prevalence of employed patients with impairment due to health issues was 21.8±26.8%. The prevalence of patients with a reduced work activity of ≥50% due to their health status was 32.1%. CONCLUSION: These data reinforce the request for improved disease management in France, allowing patients with HCV infection to increase work productivity, reduce fatigue, and, hopefully, cure their disease.


Assuntos
Antivirais/uso terapêutico , Eficiência/fisiologia , Fadiga/etiologia , Nível de Saúde , Hepatite C Crônica/complicações , Trabalho , Idoso , Estudos Transversais , Feminino , Seguimentos , França/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Índice de Gravidade de Doença
4.
Gastroenterology ; 152(8): 2052-2062.e2, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28274850

RESUMO

BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.


Assuntos
Antivirais/uso terapêutico , Subpopulações de Linfócitos B/efeitos dos fármacos , Crioglobulinemia/tratamento farmacológico , Hepatite C/tratamento farmacológico , Vírus de Hepatite/efeitos dos fármacos , Imidazóis/uso terapêutico , Tolerância Imunológica/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Ribavirina/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Subpopulações de Linfócitos T/efeitos dos fármacos , Vasculite/tratamento farmacológico , Idoso , Antivirais/efeitos adversos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/virologia , Biomarcadores/sangue , Carbamatos , Estudos de Casos e Controles , Crioglobulinemia/diagnóstico , Crioglobulinemia/imunologia , Crioglobulinemia/virologia , Citocinas/sangue , Quimioterapia Combinada , Feminino , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/imunologia , Vírus de Hepatite/imunologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Pirrolidinas , Ribavirina/efeitos adversos , Simeprevir/efeitos adversos , Sofosbuvir/efeitos adversos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/virologia , Fatores de Tempo , Resultado do Tratamento , Valina/análogos & derivados , Vasculite/diagnóstico , Vasculite/imunologia , Vasculite/virologia , Carga Viral
5.
Gastroenterology ; 153(1): 49-52.e5, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28288791

RESUMO

Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.


Assuntos
Antivirais/uso terapêutico , Crioglobulinemia/tratamento farmacológico , Crioglobulinas/metabolismo , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Sofosbuvir/uso terapêutico , Vasculite/tratamento farmacológico , Antivirais/efeitos adversos , Linfócitos B/química , Linfócitos T CD4-Positivos/química , Carbamatos , Crioglobulinemia/sangue , Crioglobulinemia/virologia , Quimioterapia Combinada , Feminino , Hepatite C/sangue , Hepatite C/complicações , Humanos , Imidazóis/efeitos adversos , Imunoglobulina M/análise , Interleucinas/análise , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirrolidinas , Receptores CXCR5/análise , Receptores de Complemento 3d/análise , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Linfócitos T Reguladores , Células Th17 , Valina/análogos & derivados , Vasculite/sangue , Vasculite/virologia
6.
J Gen Virol ; 97(1): 69-81, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26519381

RESUMO

There is growing evidence that virus particles also contain host cell proteins, which provide viruses with certain properties required for entry and release. A proteomic analysis performed on double-gradient-purified hepatitis C virus (HCV) from two highly viraemic patients identified the phosphatidylinositol 3,5-bisphosphate 5-phosphatase FIG4 (KIAA0274) as part of the viral particles. We validated the association using immunoelectron microscopy, immunoprecipitation and neutralization assays in vitro as well as patient-derived virus particles. RNA interference-mediated reduction of FIG4 expression decreased cholesteryl ester (CE) levels along with intra- and extracellular viral infectivity without affecting HCV RNA levels. Likewise, overexpressing FIG4 increased intracellular CE levels as well as intra- and extracellular viral infectivity without affecting viral RNA levels. Triglyceride levels and lipid droplet (LD) parameters remained unaffected. The 3,5-bisphosphate 5-phosphatase active site of FIG4 was found to strongly condition these results. Whilst FIG4 was found to localize to areas corresponding to viral assembly sites, at the immediate vicinity of LDs in calnexin-positive and HCV core-positive regions, no implication of FIG4 in the secretory pathway of the hepatocytes could be found using either FIG4-null mice, in vitro morphometry or functional assays of the ERGIC/Golgi compartments. This indicates that FIG4-dependent modulation of HCV infectivity is unrelated to alterations in the functionality of the secretory pathway. As a result of the documented implication of CE in the composition and infectivity of HCV particles, these results suggest that FIG4 binds to HCV and modulates particle formation in a CE-related manner.


Assuntos
Ésteres do Colesterol/metabolismo , Flavoproteínas/metabolismo , Hepacivirus/química , Hepacivirus/fisiologia , Interações Hospedeiro-Patógeno , Monoéster Fosfórico Hidrolases/metabolismo , Montagem de Vírus , Internalização do Vírus , Linhagem Celular , Flavoproteínas/isolamento & purificação , Hepatócitos/virologia , Humanos , Imunoprecipitação , Microscopia Imunoeletrônica , Testes de Neutralização , Monoéster Fosfórico Hidrolases/isolamento & purificação , Vírion/química
7.
Ann Rheum Dis ; 75(10): 1777-82, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26567178

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is the aetiological agent for most cases of cryoglobulinaemia vasculitis. Interferon-containing regimens are associated with important side effects and may exacerbate the vasculitis. OBJECTIVE: To evaluate safety and efficacy of an oral interferon-free regimen, sofosbuvir plus ribavirin, in HCV-cryoglobulinaemia vasculitis. PATIENTS AND METHODS: We enrolled 24 consecutive patients (median age of 56.5 years and 46% of women) with HCV-cryoglobulinaemia vasculitis. Sofosbuvir (400 mg/day) was associated with ribavirin (200-1400 mg/day), for 24 weeks. The primary efficacy end point was a complete clinical response of the vasculitis at the end of treatment (week 24). RESULTS: Main features of HCV-cryoglobulinaemia vasculitis included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%) and skin ulcers (12%). Twenty-one patients (87.5%) were complete clinical response at week 24. Complete clinical response was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16 and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16-0.83) at baseline to 0.15 (0.05-0.45) g/L at week 24. The C4 serum level increased from 0.10 (0.07-0.19) to 0.17 (0.09-0.23) g/L at week 24. Seventy-four per cent of patients had a sustained virological response at week 12 post treatment. The most common side effects were fatigue, insomnia and anaemia. Two serious adverse events were observed. CONCLUSIONS: Sofosbuvir plus ribavirin combination was associated with a high rate of complete clinical response and a low rate of serious adverse events in HCV-cryoglobulinaemia vasculitis.


Assuntos
Antivirais/administração & dosagem , Crioglobulinemia/tratamento farmacológico , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Vasculite/tratamento farmacológico , Crioglobulinemia/virologia , Quimioterapia Combinada , Feminino , Hepacivirus , Hepatite C/complicações , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Vasculite/virologia
8.
World J Gastrointest Oncol ; 14(8): 1510-1527, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36160737

RESUMO

BACKGROUND: Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available. AIM: To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time. METHODS: A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups. RESULTS: Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors. CONCLUSION: This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

9.
ESMO Open ; 2(4): e000238, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29104762

RESUMO

BACKGROUND: Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC. PATIENTS AND METHODS: Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints. RESULTS: In phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m2, giving MTD at 30 mg/m2. Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p<0.05). CONCLUSION: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen. TRIAL REGISTRATION NUMBER: EUDRACT 2006-004088-77; Results.

10.
Gastroenterol Clin Biol ; 29(1): 63-8, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15738897

RESUMO

AIM: The survey conducted in the Provence-Alpes-Cote d'Azur region in France in 1999 showed that 38% of patients infected with the hepatitis C virus (HCV) receiving interferon injections in their home were aware of the recommendations concerning the disposal of injection material and that 41% of the needles were discarded with household waste after use. The purpose of our study conducted in the Centre region of France was to ascertain how injection material used by HCV-positive patients for interferon treatment are disposed of in comparison with material used by patients injecting insulin for insulin-dependent diabetes mellitus (IDDM) or low-molecular-weight heparin (LMWH) for thromboembolism. MATERIAL AND METHODS: A questionnaire to be completed by patients was proposed to HCV-positive patients attending hepatogastroenterology clinics in the Centre region hepatitis C network for therapeutic follow-up (N=113 patients) between October 2001-January 2002. The same questionnaire was proposed to patients attending follow-up consultations for insulin-dependent diabetes mellitus (N=85 patients) or thromboembolism (N=23 patients) between March-June 2002. RESULTS: Significantly more patients stated they were aware of recommendations for disposal of injection material in the HCV group (89%) than in the IDDM (67%) or LMWH (26%) groups (P<0.01). Injection material was discarded with household waste less often by patients in the HCV group (6%) than in the IDDM (32%) or LMWH (29%) groups (P<0.001) and more often collected in a safety box prior to incineration (73% in the HCV group versus 63% and 14% in the IDDM and LMWH groups respectively). The safety box was discarded with household garbage more often by patients in the IDDM (54%) or LMWH (50%) groups than in the HCV group (0%) (P<0.001). Equivalent proportions of the patients said they recapped the needle after use (HCV 83%; IDDM 93%; LMWH 84%). DISCUSSION: Information concerning use of safety boxes for disposal of injection material should be provided to patients in order to comply with regulatory recommendations on proper disposal of used injection material. Moreover, the habit of recapping needles (89% of all patients in this study) is still widespread.


Assuntos
Anticoagulantes/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Heparina de Baixo Peso Molecular/administração & dosagem , Hepatite C/tratamento farmacológico , Insulina/administração & dosagem , Eliminação de Resíduos de Serviços de Saúde , Educação de Pacientes como Assunto , Seringas , Tromboembolia/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários
11.
Gastroenterol Clin Biol ; 29(2): 117-21, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15795657

RESUMO

AIM: About 45% of patients with chronic hepatitis C are unresponsive to the present reference treatment combining pegelated interferon plus ribavirin; before pegylated interferon was available the non-response rate was around 60%. This open multicenter pilot study, initiated before pegylated interferon became available, was designed to evaluate, in patients unresponsive to interferon monotherapy, the rate of biological and virological response and side-effects of the ribivirin-alpha 2b interferon combination. METHODS: The combination protocol was ribavirin (1 to 1.2 g/d) plus alpha 2b interferon at induction doses (9 MU/d the first week; 4.5 MU/d the eleven following weeks; 3 MU/2 days the 36 following weeks). RESULTS: Among the 27 included patients, 17 (63%) were viremia-negative (PCR) after 12 weeks of treatment, 9 (33%) were complete responders (undetectable viremia and normal transaminases) at the end of treatment (48 weeks) and of follow-up (72 weeks). Patients with non-1, non-4 genotypes who derived full benefit from this therapeutic strategy (6/7 (86%) were complete responders: 4/5 with genotype 3 and 2/2 with genotype 5). Quality-of-life was impaired during treatment, especially during the first 12 weeks of high-dose interferon therapy. CONCLUSION: While waiting for new therapeutic possibilities, these good results suggest interferon induction at the beginning of treatment remains a valid option.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes , Retratamento , Falha de Tratamento
12.
Eur J Gastroenterol Hepatol ; 26(2): 146-54, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24025974

RESUMO

BACKGROUND AND OBJECTIVE: Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analog (NA)-naive chronic hepatitis B patients with a very low rate of resistance (≤1.2%) over 5 years. The aim of this study was to assess the efficacy of ETV treatment in routine clinical practice and to investigate whether persistence of residual viral replication was the result of the emergence and selection of drug-resistant mutants. PATIENTS AND METHODS: Chronic hepatitis B patients treated with ETV were consecutively recruited from the Department of Hepatology, Hospices Civils de Lyon, France, and were monitored regularly within their routine clinical follow-up. Virological, biochemical, clinical, and tolerance findings were assessed prospectively. RESULTS: A total of 79 patients were studied, of whom 58% received ETV as a first-line therapy. During ETV therapy (median follow-up 42 months), hepatitis B virus (HBV) DNA became undetectable in 95% of patients. Time to HBV DNA undetectability was significantly shorter in patients with an HBV DNA level less than 4 log10 IU/ml at baseline and in HBeAg-negative patients. Moreover, time to undetectability was significantly shorter in patients with no or only one lamivudine-resistance (LAMr) mutation than in patients with two or more LAMr mutations (P=0.050). No patient had renal-function impairment during ETV therapy. CONCLUSION: In routine clinical practice, ETV is effective in both NA-naive and NA-experienced patients, except in patients with HBV strains harboring at least two LAMr mutations. The analysis of viral genome sequence at the time of treatment adaptation could prove useful to personalize antiviral therapy in patients failing a previous line of treatment.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Mutação , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , DNA Viral/sangue , Feminino , França , Genótipo , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Estimativa de Kaplan-Meier , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Replicação Viral/efeitos dos fármacos
14.
Antiviral Res ; 92(1): 90-5, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21767570

RESUMO

BACKGROUND AND AIMS: The combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus (HBV) infection. The aim of this study was to assess the efficacy and tolerance of TDF + FTC in patients with chronic hepatitis B (CHB). METHODS: Seventy eight consecutive CHB patients from five European centers were included. All started a TDF + FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF + FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. RESULTS: TDF + FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4 log10 IU/mL, and median alanine-transaminase (ALT) was 1.10 × ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (≥ F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76 weeks (interquartile range 60-116). Kaplan-Meier analysis showed that, 48 weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1 log10 IU/mL, median ALT 0.79 × ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76 weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. CONCLUSIONS: After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF + FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Desoxicitidina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Idoso , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Quimioterapia Combinada , Emtricitabina , Europa (Continente) , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Tenofovir
16.
Expert Rev Anti Infect Ther ; 7(3): 309-20, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19344244

RESUMO

HBV is the leading cause of liver cancer and frequently leads to cirrhosis and liver failure. The goals of nucleos(t)ide analog treatments are to suppress viral replication to as low as possible, to halt disease progression and to prevent the onset of complications. Due to the mechanism of viral genome persistence, chronic hepatitis B requires long-term therapy that exposes patients to the risk of selection of resistant mutants and treatment failure. Genotypic resistance is defined as the detection of resistant mutations that are known to confer resistance to antiviral drugs. Virologic rebound is defined as an increase in viral load of at least 1 log(10) copies/ml compared with the lowest value during therapy. Clinical breakthrough is defined as a rise in alanine aminotransferase levels and liver disease progression following the emergence of resistant mutants and the rise in viral load. Currently, the management of antiviral therapy should be based on precise virologic monitoring to enable an early diagnosis of partial response and treatment failure. An early treatment adaptation is recommended at least at the time of virologic breakthrough or in the case of insufficient viral suppression. The choice of drug for second-line therapy should be based on cross-resistance data to tailor therapy to the virologic situation of the patient. The addition of a complementary drug is the preferred strategy. Clinical experience shows that an optimal management of antiviral therapy allows the control of viral replication in the majority of patients in whom liver disease progression is halted.


Assuntos
Farmacorresistência Viral , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Farmacorresistência Viral/fisiologia , Genótipo , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Humanos , Mutação , Fenótipo , Resultado do Tratamento , Carga Viral , Replicação Viral/efeitos dos fármacos
17.
J Hepatol ; 44(3): 484-90, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16426697

RESUMO

BACKGROUND/AIMS: To determine whether addition of amantadine to pegylated interferon/ribavirin improved response rates among chronic hepatitis C patients, non-responders to interferon/ribavirin and study the dynamic of response. METHODS: In a double blind, multicenter, randomized trial, 200 non-responder patients received pegylated interferon 1.5 microg/kg per week and ribavirin 800-1200 mg/day, plus either amantadine 200 mg/day or placebo for 48 weeks. Endpoints were virological responses, ALT normalization, and histological benefit overtime. RESULTS: Twenty percent of all patients achieved a sustained virological response (SVR). This rate was 8% higher in the triple therapy group (24%) compared with the double therapy group (16%) (P = 0.22). A better virological response rate at week 24 was observed in the triple regimen group (43 vs 29%; P = 0.06), which was lost at week 48 suggesting viral escape. The biochemical response rate was also significantly higher with triple therapy at week 12 (63 vs 49%; P = 0.05) and week 24 (64 vs 49%; P = 0.03). Fibrosis stabilized or improved in 77% of all patients. CONCLUSIONS: Re-treatment of interferon/ribavirin non-responder patients should be encouraged since a substantial proportion benefits from re-treatment with pegylated interferon/ribavirin +/- amantadine. In triple therapy involving amantadine, a time wise response and an increased SVR rate in subgroups less prone to viral breakthrough suggest clues for existing controversies.


Assuntos
Amantadina/uso terapêutico , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Biópsia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/patologia , Hepatite C/virologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Estudos Prospectivos , RNA Viral/genética , Proteínas Recombinantes , Resultado do Tratamento
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