RESUMO
INTRODUCTION: During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. AIM AND METHOD: Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. RESULTS: In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. CONCLUSIONS: With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374.
Assuntos
Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Prolina/análogos & derivados , Estudos de Coortes , Farmacorresistência Viral , Quimioterapia Combinada , Hepacivirus/genética , Humanos , Hungria , Interferon-alfa/administração & dosagem , Cirrose Hepática/virologia , Prolina/administração & dosagem , Prolina/efeitos adversos , Resultado do TratamentoRESUMO
Approximately 70,000 people are infected with hepatitis C virus in Hungary, and more than half of them are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy. Furthermore, these could from prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity, as a socioeconomic aspect. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can clear the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained viral response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antivirals and interferon-free combination therapies have been registered for the treatment of chronic hepatitis C with a potential efficacy over 90% and typically with a short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. Non-invasive methods (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations therapy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained viral response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co-financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option.
Assuntos
Antivirais/uso terapêutico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Cobertura do Seguro , Inibidores de Proteases/uso terapêutico , Antivirais/economia , Consenso , Progressão da Doença , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Hepatite C/complicações , Hepatite C/economia , Hepatite C/reabilitação , Humanos , Hungria , Seguro Saúde , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Falência Hepática/prevenção & controle , Falência Hepática/virologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , Oligopeptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/administração & dosagem , Prolina/análogos & derivados , Proteínas Recombinantes/administração & dosagem , Sistema de Registros , Ribavirina/administração & dosagem , Resultado do TratamentoRESUMO
Approximately 70 000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. Early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases (liver cirrhosis and liver cancer) and its complications. In addition, it may increase work productivity and life expectancy of infected individual, and can prevent further viral transmission. Early recognition can substantially reduce the long term financial burden of related morbidity from socioeconomic point of view. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can kill the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of two direct acting first generation protease inhibitor drugs (boceprevir and telaprevir) to the dual therapy increased the chance of sustained clearance of virus to 63-75% and 59-66%, respectively. These two protease inhibitor drugs are available and financed for a segment of Hungarian patients since May 2013. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. For initiation of treatment as well as for on-treatment decisions accurate and timely molecular biology tests are mandatory. Staging of liver damage (fibrosis) non-invasive methods (transient elastography and biochemical methods) are acceptable to avoid concerns of patients related to liver biopsy. Professional decision for treatment is balanced against budget limitations in Hungary, and priority is given to those with urgent need using a national Priority Index system reflecting stage of liver disease as well as additional factors (activity and progression of liver disease, predictive factors and other special circumstances). All naïve patients are given a first chance with dual therapy. Those with genotype 1 infection and with on-treatment or historic failure to dual therapy are eligible to receive protease inhibitor based triple therapy provided, they reach financial cutoff eligibility based on Priority Index. Duration of therapy is usually 48 weeks in genotype 1 with a response-guided potential to reduce duration for non-cirrhotic patients. Patients with non-1 genotypes are treated with dual therapy (without protease inhibitors) for a genotype and response driven duration of 16, 24, 48, or 72 week. Careful monitoring for early recognition and management of side-effects as well as viral response and potential breakthrough during protease-inhibitor therapy are recommended.
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Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Interferons/uso terapêutico , Inibidores de Proteases/uso terapêutico , Ribavirina/uso terapêutico , Algoritmos , Antivirais/administração & dosagem , Comorbidade , Consenso , Esquema de Medicação , Quimioterapia Combinada , Diagnóstico Precoce , Medicina Baseada em Evidências , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/epidemiologia , Humanos , Hungria/epidemiologia , Interferon-alfa/uso terapêutico , Interferons/administração & dosagem , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Polietilenoglicóis/uso terapêutico , Inibidores de Proteases/administração & dosagem , RNA Viral/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection.
Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite D Crônica/diagnóstico , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/isolamento & purificação , Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/administração & dosagem , Consenso , Esquema de Medicação , Quimioterapia Combinada , Medicina Baseada em Evidências , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Hepatite D Crônica/complicações , Hepatite D Crônica/epidemiologia , Humanos , Hungria/epidemiologia , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Neoplasias Hepáticas/prevenção & controle , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , TenofovirRESUMO
INTRODUCTION: In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. AIM: The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. METHOD: Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. RESULTS: The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.
Assuntos
Antivirais/metabolismo , Citocinas/metabolismo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/metabolismo , Interferons/uso terapêutico , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Substâncias Protetoras/metabolismo , Ribavirina/uso terapêutico , Fatores de Transcrição/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Humanos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Polietilenoglicóis/uso terapêutico , Valor Preditivo dos Testes , Fatores de Transcrição/biossínteseRESUMO
More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines - since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority.
Assuntos
Antivirais/uso terapêutico , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite D/diagnóstico , Hepatite D/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Comorbidade , Consenso , Esquema de Medicação , Quimioterapia Combinada , Genótipo , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepacivirus/genética , Humanos , Hungria , Interferon-alfa/uso terapêutico , Interferons/uso terapêutico , Lamivudina/uso terapêutico , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , RNA Viral/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Tenofovir , Fatores de Tempo , Resultado do TratamentoRESUMO
Chronic hepatitis C virus (HCV) infection is the major etiology and the reason of chronic liver disease, liver cirrhosis, hepatic decompensation, hepatocellular cancer and liver transplantation. Less than half of patients with HCV-related chronic hepatitis achieve sustained viral clearance with current pegylated interferon and ribavirin (P+R) combination therapy. Due to the insufficient treatment success, an extended search for new, direct acting anti-HCV agents (DAAs) is ongoing, already leading to submissions of applications for marketing authorization of the protease-inhibitors boceprevir and telaprevir. Both are effective only in triple combinations with P+R. Studies demonstrate a 50% success rate advantage for triple therapies above current standards. In addition, treatment duration can be shortened, and half of the patients who failed previous therapy with P+R can be cured with triple therapies. A major concern with new DAAs is rapid development of DAA-resistant viral mutants, a reason as well as a consequence of insufficient triple therapy. Clinical studies with boceprevir and telaprevir are reviewed in this paper.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Farmacorresistência Viral , Quimioterapia Combinada , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacologia , RNA Viral/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
Hepatitis C virus (HCV) infection affects 2-3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15-20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10-15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts - with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients.
Assuntos
Anemia Hipocrômica/induzido quimicamente , Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Inibidores de Proteases/efeitos adversos , Ribavirina/efeitos adversos , Afeto/efeitos dos fármacos , Antivirais/administração & dosagem , Doenças Autoimunes/induzido quimicamente , Autoimunidade/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Toxidermias/etiologia , Sinergismo Farmacológico , Quimioterapia Combinada , Doenças do Sistema Endócrino/induzido quimicamente , Olho/efeitos dos fármacos , Humanos , Infecções/imunologia , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Neutropenia/induzido quimicamente , Oligopeptídeos/efeitos adversos , Polietilenoglicóis/administração & dosagem , Prolina/efeitos adversos , Prolina/análogos & derivados , Inibidores de Proteases/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Sistema Respiratório/efeitos dos fármacos , Ribavirina/administração & dosagem , Fatores de Risco , Trombocitopenia/induzido quimicamenteRESUMO
UNLABELLED: Since oxidative stress may play a pathogenetic role in chronic hepatitis C, and sustained virological response to antiviral therapy is limited in HCV1 genotype infection, a double blind study was performed in HCV1 patients treated with pegylated interferon + ribavirin, to assess the efficacy of supplementation with the antioxidant flavonoid silymarin. PATIENTS AND METHODS: Thirty-two naive HCV1 positive patients with biopsy proven chronic hepatitis C, to be treated with pegylated interferon + ribavirin, have been randomized: group A): 16 patients have been given the antiviral therapy for 6-12 months plus placebo for the first 3 months; group B): 16 patients have been treated with pegylated interferon + ribavirin for 6-12 months plus silymarin, 2 x 166 mg/day, was given for 3 months. Serum alanine aminotransferase and HCV-RNA levels as well as parameters of oxidative stress such as plasma or red blood cell hemolysate, malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase and myeloperoxidase were determined after 0, 1, 3, 6 and 12 months during the treatment. Sustained virological response as undetectable serum HCV RNA was evaluated 24 weeks after the end of therapy. RESULTS: In the silymarin group, a more rapid decrease in the malondialdehyde level as well as a marked decrease in superoxide dismutase and an increase in myeloperoxidase activity after month 12 were found, alanine aminotransferase normalized in 6/16 (vs control 9/16) cases, and sustained virological response occurred in 3/16 (vs 7/16) patients. DISCUSSION/CONCLUSION: Although silymarin supportation to antiviral therapy improved oxidative stress, it was able to affect favourably neither the alanine aminotransferase nor the sustained virological response. These contradictory findings may be related to randomization bias as patients in study group B had more negative predictors of response: they were older with higher fibrosis score and even with more severe pretreatment baseline oxidative stress. Regarding the recently published in vitro experiments with silybinin on HCV replication as well as the newest convincing clinical observations, we do suggest further studies with more than three times higher doses of silymarin in controlled trials to assess the value of this supplementation in antivirally treated HCV patients.
Assuntos
Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Substâncias Protetoras/uso terapêutico , Ribavirina/uso terapêutico , Silimarina/uso terapêutico , Adulto , Idoso , Alanina Transaminase/sangue , Método Duplo-Cego , Feminino , Hepacivirus/genética , Hepatite C Crônica/metabolismo , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/sangue , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , RNA Viral/isolamento & purificação , Superóxido Dismutase/sangue , Resultado do TratamentoRESUMO
BACKGROUND: The outcome of HCV infection and the response to antiviral treatment depend on both viral and host factors. Host immune response contributes not only to viral control, clinical recovery and protective immunity, but also to chronic hepatitis and liver cirrhosis. Establishing immunological status and identifying pretreatment immunological factors associated with better response to therapy might be of importance in the understanding of the successful immune response and in the future of combination therapy to HCV infection. AIMS: The authors delivered a review on the immunology of HCV infection and characterized the cause of impaired cellular immune response in chronic HCV infection. Natural killer (NK) cell activity, perforin and the inhibitory CD81 HCV co-receptor expression, and Th1/Th2 cytokine production of the monocytes and lymphocytes have been investigated. PATIENTS AND METHODS: 42 patients with chronic hepatitis C, out of them 25 being on interferon (PEG-IFN) + ribavirin (RBV) therapy, 12 sustained virological responders, 26 HCV carriers with normal transaminase values and 22 healthy controls were studied. NK cell activity, perforin and CD81 expression, the IFNgamma, TNFalpha, IL-2 (Th1) and IL-4, IL-6, IL-10 (Th2) production of LPS stimulated monocytes and PMA + ionomycine stimulated lymphocytes were measured by flow-cytometry. RESULTS: In patients with chronic hepatitis C we demonstrated decreased NK cell activity associated with increased CD81 expression. The perforin expression of lymphocytes was also impaired in HCV patients. The pretreatment capacity of the macrophages to produce TNFalpha was predictive for sustained virological response. This increased TNFalpha production of the monocytes counteracted the observed impaired Th1 type cytokine production of the lymphocytes. IL-10 and IL-4 production showed positive correlation with HCV RNA levels, and negative correlation with histological activity index was noted. PEG-IFN + RBV treatment increased NK activity, perforin expression, Th1 type cytokine production of thr lymphocytes and downregulated CD81 expression inducing effective cellular immune response against HCV. The author's results provide further data to understand the causes of impaired cellular immune response in chronic HCV hepatitis and may be useful in the developement of immunotherapy as an adjunctive treatment to cure patients with chronic hepatitis C.
Assuntos
Antivirais/uso terapêutico , Citocinas/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Adulto , Idoso , Antígenos CD/metabolismo , DNA Viral/isolamento & purificação , Quimioterapia Combinada , Feminino , Citometria de Fluxo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/patologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferon gama/metabolismo , Interleucinas/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Perforina , Polietilenoglicóis , Proteínas Citotóxicas Formadoras de Poros , RNA Viral/isolamento & purificação , Proteínas Recombinantes , Ribavirina/uso terapêutico , Tetraspanina 28 , Células Th1/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: The authors described their experience with the therapy with pegylated interferon and its safety in patients with hepatitis C virus (HCV) induced liver cirrhosis treated at First Department of Medicine, Medical School, University of Pécs and at Tawam Hospital, Al Ain, United Arab Emirates. PATIENTS AND METHODS: Twenty four (12 male, 12 female, average: 55.66 +/- 7. 02 years) anti-HCV and/or HCV-RNA PCR positive cirrhotic patients were examined. Liver cirrhosis was diagnosed by abdominal ultrasound and/or histological examination of liver biopsy. RESULTS: Different genotypes of HCV were detected: genotype 1 in 7 cases, genotype 2 in 1 person, genotype 3 in 3 cases. Genotype 4 was detected in 10 patients, all of them were treated out of Hungary. Thirteen of 24 patients were not treated earlier, 6 persons were non-responders to previous interferon monotherapy, pegylated interferon was administered to 5 patients because of relapse. Biochemical parameters showed improvement in 16 cases (16/24, 66.66%), but did not in 5 patients. Until now, virological response was achieved in 13 patients (13/24, 54.16%), while three patients remained HCV-PCR positive. Temporary dose reduction was needed in 13/24 cases (54.16%). Withdrawal of therapy became necessary in only 2 patients due to severe neutropenia, thrombocytopenia and/or signs of decompensation. CONCLUSIONS: Pegylated interferon treatment is well tolerated by patients with compensated liver cirrhosis (Child-Pough stage A). Frequent side-effects (half of all cases) were usually mild or moderate requiring discontinuation only in 2 of 24 patients. The incidence of neutropenia and thrombocytopenia emphasizes the need of frequent blood cell count tests and patients follow up.
Assuntos
Antivirais/efeitos adversos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Interferon-alfa/efeitos adversos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/virologia , Polietilenoglicóis/efeitos adversos , Antivirais/administração & dosagem , DNA Viral/isolamento & purificação , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/genética , Humanos , Hungria , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Polietilenoglicóis/administração & dosagem , Reação em Cadeia da Polimerase , Proteínas Recombinantes , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Emirados Árabes UnidosAssuntos
Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite D/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Biópsia , Guanina/análogos & derivados , Guanina/uso terapêutico , Infecções por HIV/complicações , Hepatite B/diagnóstico , Hepatite B/patologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite D/diagnóstico , Hepatite D/patologia , Hepatite D/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferons/uso terapêutico , Lamivudina/uso terapêutico , Cirrose Hepática/diagnóstico , Nucleotídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , TenofovirRESUMO
BACKGROUND: Previous studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment. METHODS: A total of 748 chronic HCV1 infected patients (365 male, 383 female; 18-82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24-72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R -1087 (also known as IL10R -1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis. RESULTS: The IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p<0.001). P/R treated patients with the IL28B CC genotype achieved higher SVR rate, as compared to patients with CT (58.6% vs 40.8%, p=0.002). The prevalence of IL10R -1087 GG genotype was lower in patients than in controls (31.8 % vs 52.2%, p<0.001). Among patients achieving SVR, the IL10R -1087 GG genotype occurred with higher frequency than the AA (32.0% vs 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combination was found with higher prevalence in patients than in controls (52% vs 20.7%, p<0.001). The IL28B CC plus IL10R A allele combination occurred with higher frequency among patients with SVR than in non-responders (21.3% vs 12.8%, p=0.026). Both the IL28B CC plus IL10R GG and the IL28B CC plus IL10R A allele combinations occurred with lower frequency in patients than in controls. CONCLUSIONS: In our HCV1 patients, both the IL28B CC and IL10R GG genotypes are associated with clearance of HCV. Moreover, distinct IL28B and IL10R allele combinations appear to be protective against chronic HCV1 infection and predictors of response to P/R therapy.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/prevenção & controle , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-10/genética , Ribavirina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Farmacorresistência Viral Múltipla , Quimioterapia Combinada , Feminino , Frequência do Gene , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/genética , Humanos , Hungria , Interferon alfa-2 , Interferons , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto JovemAssuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Algoritmos , Protocolos Clínicos , Hepacivirus/genética , Hepacivirus/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Ribavirina/uso terapêuticoAssuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Algoritmos , Quimioterapia Combinada , Hepatite C Crônica/diagnóstico , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferons/administração & dosagem , Polietilenoglicóis , Proteínas Recombinantes , Recidiva , Ribavirina/administração & dosagemAssuntos
Antivirais/uso terapêutico , Hepatite Crônica/tratamento farmacológico , Hepatite Viral Humana/tratamento farmacológico , Algoritmos , Hepatite C Crônica/tratamento farmacológico , Hepatite Crônica/diagnóstico , Hepatite Crônica/enzimologia , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/enzimologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Ribavirina/uso terapêuticoRESUMO
HCV infects approximately 2-3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ribavirin can eradicate HCV infection in 40-90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10-15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.