RESUMO
In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Fatores Etários , Índice de Massa Corporal , Feminino , Genótipo , Hepacivirus/genética , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , RNA Viral/sangue , Proteínas Recombinantes , Fatores Sexuais , Fatores de Tempo , Falha de Tratamento , Carga ViralRESUMO
The concept of antiviral therapy with interferon for chronic hepatitis B emerged in the middle of the seventies and was supported by the suppressive effect of human interferon on HBV-DNA polymerase levels in 3 patients. This effect of leukocyte interferon was confirmed in a small controlled study of patients with HBeAg-positive chronic hepatitis B; however, no effect was found on other indices of hepatitis B. More than 10 years elapsed before one large RCT demonstrated clinically relevant virological responses in 35% vs. < 10% in placebo and led to registration of interferon for hepatitis B. Responses in HBeAg-negative chronic hepatitis B were very high during treatment but high relapse rates eliminated most of the long-time treatment effect. Interferon has now to compete with highly effective nucleoside analog therapy, but still has a prominent place as a limited duration therapy leading to sustained and sometimes complete responses. In the middle of the eighties, interferon was tested in 10 patients with non-A, non-B chronic hepatitis and ALT normalization was observed in the majority. After the discovery of the hepatitis C virus and the introduction of the HCVRNA PCR test it became clear that interferon therapy can cure hepatitis C infections. Widespread therapy was introduced after a co-drug ribavirin was found to reduce relapse rates and two pivotal trials with recombinant interferon showed sustained virological responses in about 50% of patients, with much higher positive outcomes in genotype 2 and 3. Therapy-induced sustained virological remission has been shown to reduce liver-related death, liver failure and to a lesser extent hepatocellular carcinoma. Interferon has become the key drug for hepatitis C.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Humanos , Recidiva , Resultado do Tratamento , Carga ViralRESUMO
The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.
Assuntos
Antivirais/uso terapêutico , Guias como Assunto/normas , Hepatite B Crônica/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Humanos , Países BaixosRESUMO
The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.
Assuntos
Antivirais/uso terapêutico , Guias como Assunto/normas , Hepatite C Crônica/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Humanos , Países BaixosRESUMO
The treatment of chronic viral hepatitis B and C is now so effective that the efforts of health care workers should now be concentrated on tracing infected persons and determining antiviral therapies. It is for these reasons in particular that this revision from the Dutch College of General Practitioners' practice guideline 'Viral hepatitis and other liver diseases' is so necessary. It is estimated that there are 46 patients with chronic viral hepatitis in each general practice of 2300 people, and that only 1 in 64 is registered as such. This calls for active case finding. If a risk factor is present, a feasible approach might be to ask about symptoms and complaints and to establish serum transaminase levels.
Assuntos
Gastroenterologia/normas , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/epidemiologia , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Busca de Comunicante , Hepatite Viral Humana/prevenção & controle , Humanos , Países Baixos/epidemiologia , Fatores de Risco , Sociedades MédicasRESUMO
Only in a minority of patients with chronic hepatitis B (CHB) will treatment with interferon (IFN)-alpha or nucleoside analogues lead to sustained virological response. In vivo immunization (IVI) following virus suppression aims to optimize conditions for an effective immune response: following rapid and profound virus suppression by interferon-lamivudine combination therapy, lamivudine is withdrawn intermittently during continued interferon therapy. It is thought that withdrawal of lamivudine will lead to increased viral replication and increased antigen expression with subsequent immune stimulation. The aim of this prospective pilot study was to evaluate IVI as a therapeutic approach for CHB. Fourteen HBeAg-positive CHB patients were treated for 42 weeks with a combination of pegylated interferon-alpha 2b and lamivudine. After 12 weeks of combination therapy lamivudine was withdrawn intermittently for three consecutive periods of 4 weeks until it was permanently stopped on week 36. At the end of follow-up (week 52) all patients had remained HBeAg positive and the median viral load was similar to baseline. During the initial 12 weeks of treatment, there was a reduction of both the hepatitis B virus (HBV)-specific proliferation capacity of Th-cells and the frequencies of IFNgamma-producing cells. During the lamivudine interruption-cycle there was an inverse relation between the increase of HBV-DNA, and the decrease in proliferation capacity and frequency of IFN-gamma-producing cells. The intrahepatic fraction of CD8(+) T-cells increased during lamivudine withdrawal. In conclusion, IVI was able to transiently stimulate the HBV-specific immune responsiveness of T-cells, but the magnitude of the response was insufficient to cause a beneficial virological effect.
Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Esquema de Medicação , Quimioterapia Combinada , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Interferon alfa-2 , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes , Resultado do Tratamento , Carga ViralAssuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Quimioterapia Combinada , Seguimentos , Antígenos E da Hepatite B/sangue , Humanos , Interferon alfa-2 , Polietilenoglicóis , Proteínas Recombinantes , Recidiva , Fatores de RiscoRESUMO
To prevent transmission of hepatitis B virus (HBV) from health care workers (HCWs) to patients, highly viraemic HCWs are often advised to restrict performing exposure prone procedures (EPPs). To prevent loss of highly qualified medical personnel and simultaneously minimize transmission risk to patients, we offered highly viraemic HCWs antiviral therapy and evaluated the effects of this strategy. Eighteen chronic HBV-infected HCWs have been monitored every 3-6 months for a median period of 5.6 years (range 1.1-12.5 years). Antiviral therapy was offered if HBV DNA was above 10(5) copies/mL and EPPs were performed or active liver disease was present. Median HBV DNA levels, the percentage of days with HBV DNA above 10(3), 10(4) and 10(5) copies/mL, and reduction of HBV DNA during antiviral treatment have been analysed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative HCWs separately. Prolonged viral suppression was achieved in both HBeAg-positive, as well as HBeAg-negative HCWs. In HBeAg-negative HCWs treatment with interferon or lamivudine maintained HBV DNA levels below 10(5) copies/mL. For HBeAg-positive HCWs continuous treatment with tenofovir or entecavir was essential for reaching low viraemia persistently. In 2004, median HBV DNA levels in both HBeAg-negative and HBeAg-positive HCWs were below 10(3) copies/mL and all HCWs executed their professional work full-range. For both HBeAg-positive and HBeAg-negative HCWs, antiviral treatment is effective in persistent suppression of virus levels below 10(5) copies/mL. This observation supports antiviral therapy as a viable management option instead of work restriction, with the provision of regular expert monitoring including quantification of HBV DNA.
Assuntos
Antivirais/uso terapêutico , Pessoal de Saúde , Hepatite B Crônica/prevenção & controle , Hepatite B Crônica/transmissão , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , DNA Viral/análise , Dosagem de Genes , Hepatite B Crônica/genética , Humanos , Carga Viral , ViremiaRESUMO
Since hepatitis C can be treated more and more successfully, treatment should be considered in every patient. In some of the patients infected by viral genotype I, the duration of treatment can be shortened: 24 weeks instead of 48 weeks. Maintaining the optimal dosage of ribavirin and peginterferon alpha is of great importance for successful treatment. For this purpose, new guidelines are proposed with reference to the haematological side effects, recommending more restraint with the reduction of the dosage and treatment in case of complaints. Treatment with peginterferon alpha frequently causes psychiatric problems, particularly depressive symptoms that are sometimes severe. Adequate treatment and support, including the use of antidepressants, are necessary in such cases and are often effective.
Assuntos
Antivirais/efeitos adversos , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Genótipo , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Proteínas RecombinantesRESUMO
Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.
Assuntos
Antivirais/uso terapêutico , Fígado Gorduroso/complicações , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Biópsia , Fígado Gorduroso/virologia , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Estimativa de Kaplan-Meier , Cinética , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: Health-related quality of life of patients with chronic liver disease has been shown to be impaired in numerous studies. However, the factors which influence health-related quality of life in treated chronic liver patients are not quite known. This is the first study to assess the impact of physical and psychosocial determinants on a weighted score of health-related quality of life in patients with chronic liver disease. METHODS: The data of 1175 chronic liver patients were used to assess the relationship between items of the disease-specific Liver Disease Symptom Index 2.0 and the Short Form (SF)-6D weighted utility score by means of linear regression analyses. RESULTS: Health-related quality of life was most strongly related to disease severity (B = -0.029) and joint pain (B = -0.023). Depression (B = -0.014), pain in the right upper abdomen (B = -0.014), decreased appetite (B = 0.014) and fatigue (B = -0.013) were also strongly related to health-related quality of life. In hepatitis C virus patients, disease severity (B = -0.037) and depression (B = -0.030) were strong determinants of health-related quality of life. CONCLUSIONS: This study shows that health-related quality of life in chronic liver patients is clearly determined by disease severity, joint pain, depression, decreased appetite and fatigue. These patients may benefit most from interventions aimed at improving adaptation to the symptoms described.
Assuntos
Hepatopatias/psicologia , Qualidade de Vida , Atividades Cotidianas , Adaptação Psicológica , Adulto , Apetite/fisiologia , Artralgia/etiologia , Doença Crônica , Transtorno Depressivo/etiologia , Feminino , Humanos , Hepatopatias/terapia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Índice de Gravidade de DoençaRESUMO
Based on virological and biochemical parameters patients with chronic hepatitis B virus (HBV) are divided into distinct clinical phases: the immune-tolerance phase, the immune-clearance phase, and the inactive carrier state. Unclear is whether these phases have characteristic intrahepatic immune responses. The composition of liver-derived lymphocytes in patients with chronic HBV infection was studied. In 47 patients the composition of liver-derived lymphocytes was analyzed by flow cytometry of fine needle aspiration biopsies of the liver. The proportion natural killer (NK) cells in the liver was significantly higher in immune-tolerant than in immune-clearance patients and inactive carriers. No differences were found in proportion CD4+ T-cells and CD8+ T-cells, in these phases. However, when patients in the immune-clearance phase, with similar alanine transaminase (ALT), were grouped according to viral load, the proportion CD8+ T-cells was higher in those with high viral load. In contrast, the proportion CD4+ T-cells was increased in patients with low HBV-DNA. These differences were absent in the peripheral blood (PB). Intrahepatic HBV-specific CD8+ T-cells were mainly found in immune-clearance patients with low viral load. In conclusion, clear differences in the intrahepatic cellular infiltrate were found between the various clinical phases of chronic HBV infection. These findings are relevant to the design of new, individualized anti-viral strategies.
Assuntos
Convalescença , Hepatite B Crônica/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Biópsia por Agulha Fina , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Portador Sadio/imunologia , DNA Viral/sangue , Feminino , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
To reduce unnecessary exposure to treatment, physicians must decide at an early stage whether continuation of treatment has a reasonable chance of success for the individual patient. The objectives of our study were to evaluate the previously described quantitative hepatitis B e antigen (HBeAg) measurements vs quantitative hepatitis B virus (HBV) DNA measurements for prediction of nonresponse and response in interferon (IFN)-alpha treated HBeAg positive chronic HBV patients. Serum HBV DNA and HBeAg levels were assessed at baseline and weeks 8 and 12. For each test (HBV DNA level at baseline, HBV DNA decrease between baseline and weeks 8 and 12, or the combination of these two, as well as HBeAg level at baseline, HBeAg decrease between baseline and weeks 8 and 12, and the combination of these two), we calculated the positive predictive value, negative predictive value, sensitivity and specificity. Monitoring with quantitative HBV DNA levels (area under ROC 0.87) was superior to monitoring with quantitative HBeAg levels (0.76, P < 0.05). Step-wise logistic regression identified HBV DNA at baseline and decrease in HBV DNA from baseline to week 12, as independent predictors of response. The overall test performance of predicting nonresponse (predictive value 100%) was best for log HBV DNA testing at week 12 compared with testing at week 8 due to a better prediction of sustained response (46%vs 38%) and lower misidentification of nonresponse (39%vs 54%). This study showed that quantitative HBV DNA testing at baseline in combination with a decrease between baseline and week 12 has a high predictive value for identifying patients who have virtually no chance of reaching a sustained response with IFN therapy.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adolescente , Adulto , Idoso , DNA Viral/sangue , Feminino , Marcadores Genéticos/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Resultado do Tratamento , Carga ViralRESUMO
Different guidelines exist for the management of hepatitis B virus (HBV)-infected health care workers (HCWs). Various HBV DNA levels are used as a cutoff level to determine whether an HBV-infected HCW is allowed to perform exposure-prone procedures (EPPs) or not. In this paper we discuss the factors that determine HBV DNA levels and the implications of different HBV DNA cutoff levels for EPP performing HCWs. If the level of HBV DNA in the serum of HCWs is used to determine acceptability for the conduct of EPPs, it is necessary to take into account the variability in time of HBV DNA levels in HBV carriers and the reliability and reproducibility of the molecular diagnostic test involved. The issue of standardization has to be addressed, before a universal, maximum level of viraemia for EPP performing HCWs can be introduced.
Assuntos
DNA Viral/sangue , Vírus da Hepatite B/genética , Hepatite B/sangue , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , Pessoal de Saúde , Hepatite B/diagnóstico , Hepatite B/transmissão , Hepatite B/virologia , Antígenos E da Hepatite B/sangue , Humanos , Viremia/virologiaRESUMO
SUMMARY: Information about the character and grade of the intrahepatic immune response in viral hepatitis is important for the evaluation of disease stage and effect of therapy. Complications like haemorrhage limit the frequent performance of tissue-needle biopsies (TB), and the cells of peripheral blood have to be used as surrogate markers instead. Fine-needle-aspiration biopsy (FNAB) of the liver represents a safe and atraumatic method that allows frequent cytological sampling. Our aim was to investigate whether flow cytometry of FNAB specimens allows co-analysis of phenotype, function and specificity of key populations of liver-infiltrating lymphocytes (LIL). In 20 consecutive patients with chronic viral hepatitis [10 hepatitis B virus (HBV), 10 hepatitis C virus (HCV)], flow cytometry was performed on FNAB cytology, and simultaneously on lymphocytes isolated from a TB and peripheral blood mononuclear cells (PBMC). The ratio of CD8+/CD4+ lymphocytes in FNAB correlated well with LIL from TB (r =0.78, P < 0.05) but differed from PBMC (mean ratio: 2.6, 2.1 and 0.7, respectively). Similarly, a correlation was observed for percentage CD56+ natural killer (NK) cells (mean %: 29.9, 32.3 and 14.5, respectively; r = 0.69, P < 0.05). The percentage of interferon (IFN)-gamma-producing CD3+ lymphocytes in both FNAB and TB was higher than in PBMC (mean %: 41, 44 and 22, respectively; P < 0.05). Furthermore, tetrameric complexes allowed analysis of HBV-specific T cells in FNAB specimens. In conclusion, flow cytometry of FNAB allows easy, atraumatic and reliable analysis of lymphocytes obtained from the intrahepatic compartment. Therefore, the FNAB is a valuable tool in the study of the immunopathology of viral hepatitis, and it may contribute to the improved clinical evaluation of chronic viral liver disease.
Assuntos
Biópsia por Agulha Fina/métodos , Linfócitos T CD8-Positivos/imunologia , Citometria de Fluxo/métodos , Hepatite/patologia , Subpopulações de Linfócitos/imunologia , Células Sanguíneas/efeitos dos fármacos , Complexo CD3/análise , Antígenos CD8/análise , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Doença Crônica , Hepatite/tratamento farmacológico , Hepatite/imunologia , Humanos , Imunofenotipagem , Resultado do TratamentoRESUMO
The treatment of chronic hepatitis C forms a considerable burden for society. The present standard treatment with PEG-Interferon and Ribavirin is costly, has side effects and is not always effective. The current trend is to prolong treatment from 24 to 48 or even 72 weeks in patients infected with genotypes 1 and 4 virus, in order to prevent relapses after cessation of therapy. There are, however, suggestions that treatment of relapses gives a response rate similar to that of first-time treatment. We, therefore, compared the sustained response rates and the mean treatment durations of one-time treatment and cyclic treatment in a model that incorporates the rates of non-response to antiviral therapy, of breakthrough during and of relapse after cessation of treatment. Our calculations show that, even under the most unfavourable assumptions, repeated 6-month treatment lowers the mean treatment duration from 9.6 to 7.5 months when compared to a single 12-month treatment, without jeopardising the overall effectiveness. If the results of our model calculations can be confirmed, current guidelines for the treatment of infections with genotype 1 hepatitis C virus ought to be reconsidered.
Assuntos
Hepatite C/terapia , Antivirais/farmacologia , Doença Crônica , Humanos , Interferons/farmacologia , Modelos Teóricos , Polietilenoglicóis/química , Recidiva , Ribavirina/farmacologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Tenofovir, an antihuman immunodeficiency virus (HIV) drug, has activity against lamivudine-resistant hepatitis B virus (HBV) mutants. To describe the efficacy of tenofovir in patients with lamivudine-resistant hepatitis B we applied two investigative approaches based on mathematical models of viral dynamics: the individual nonlinear fitting and the mixed-effect group fitting approaches. Eleven chronic HBV patients on lamivudine for a median of 176 weeks (range: 72-382) with YMDD mutation-related HBV-DNA breakthrough received 'add-on' tenofovir 300 mg once-daily, while maintaining their existing therapy. Sequential sera were taken at day 1 (t = 0 and t = 8 h), days 2, 4, 7, 10, 14, 21, 28 and every 4 weeks thereafter, and HBV-DNA levels were assessed using a validated quantitative polymerase chain reaction (PCR) assay. Median baseline log HBV-DNA was 8.62 (range: 6.48-9.76 log HBV-DNA). Tenofovir treatment resulted in a mean (+/-SD) log HBV-DNA decline of 1.37 +/- 0.51 in the first phase, 2.54 +/- 0.91 after 4 weeks, and 4.95 +/- 0.90 log HBV-DNA after 24 weeks. The median effectiveness of blocking viral replication in the individual fit model was 93% (range: 73-99) for eta = 0 and 93% (range: 59-99) for eta = 1. There was only a small difference between the efficacy parameter 'epsilon' of the individual nonlinear fitting and mixed-effect group fitting on the biphasic exponential model. These data show that tenofovir has good efficacy in blocking viral replication in HBV patients with lamivudine-induced drug-resistant HBV mutants, but effectiveness varies greatly among individuals. Both models can be used to describe viral decay during tenofovir therapy.
Assuntos
Adenina/análogos & derivados , Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Lamivudina/farmacologia , Organofosfonatos/farmacologia , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/farmacologia , Adulto , DNA Viral/sangue , Farmacorresistência Viral , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Tenofovir , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss). PATIENTS: A total of 266 patients, participating in a global randomised controlled study, were assigned to 52 weeks of 100 mug pegylated (Peg)-interferon alpha-2b weekly, combined with either daily lamivudine 100 mg or placebo. RESULTS: Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (38%) patients the flare was preceded by an increase in HBV DNA (virus induced flare). In 17 (26%) patients the flare did not meet one of these criteria (indeterminate flare). Of patients with host induced flare, 58% responded whereas only 20% of patients with virus induced flares responded (p = 0.008). Hepatitis B surface antigen loss (n = 8) was exclusively seen in patients experiencing a host induced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043). CONCLUSION: Flares are not more common in responders than in non-responders to Peg-interferon alpha-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most probably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adulto , Alanina Transaminase/sangue , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Interferon alfa-2 , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. AIM: To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. METHODS: Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. RESULTS: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. CONCLUSION: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.
Assuntos
Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Adulto , Antivirais/administração & dosagem , Infecções Bacterianas/complicações , Método Duplo-Cego , Feminino , Hemorragia/etiologia , Hepatite B Crônica/complicações , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Polietilenoglicóis , Proteínas Recombinantes , Fatores de RiscoRESUMO
BACKGROUND: Current guidelines for stopping treatment of chronic hepatitis C are based on hepatitis C ribonucleic acid measurements at 12 and 24 weeks. AIM: To explore an alternative approach for making individualized recommendations about treatment duration, based on simple alanine aminotransferase tests and on cost-per-cure. METHODS: We analysed individual patient data from 13 randomized, controlled trials with interferon alone or combined with ribavirin. Using multiple logistic regression, we built a model that estimated the probability of sustained virological response for treatment durations of 24 and 48 weeks. Decisions to prolong treatment were based on an increase in probability of sustained virological response. If the increase was 10%, the cost-per-cure became decisive with a limit of 50,000. RESULTS: Noncirrhotics with genotype 2 or 3 did not benefit when treatment was continued beyond 24 weeks. Sustained virological response rates in cirrhotic patients increased by 14-47% if treatment was continued up to 48 weeks. In noncirrhotic genotype 1 or 4 patients who had elevated alanine aminotransferase levels at week 4, the probability of sustained virological response increased by <10% if treatment was continued up to 48 weeks; the cost-per-cure for these patients would exceed 50,000. CONCLUSION: The dynamics of alanine aminotransferase levels and cost-per-cure provides a useful alternative to determine the duration of therapy in chronic hepatitis C.