RESUMO
Hepatic focal nodular hyperplasia (FNH) is a nonmalignant condition rarely affecting children previously treated for cancer, especially those who received hematopoietic SCT (HSCT). Some aspects of its pathogenesis still remain unclear and a strong association with specific risk factors has not yet been identified. We report here a single institution's case series of 17 patients who underwent HSCT and were diagnosed with FNH, analyzing retrospectively their clinical features and the radiological appearance of their hepatic lesions. We aimed to compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) and to explore the role of transient elastography (FibroScan) to evaluate the degree of hepatic fibrosis in FNH patients. Our analysis showed an association of FNH with age at transplant ⩽12 years (hazard ratio (HR) 9.10); chronic GVHD (HR 2.99); hormone-replacement therapy (HR 4.02) and abdominal radiotherapy (HR 4.37). MRI proved to be a more accurate diagnostic tool compared with US. Nine out of 12 patients who underwent FibroScan showed hepatic fibrosis. Our study points out that FNH is an emerging complication of HSCT, which requires a lifelong surveillance to follow its course in cancer patients.
Assuntos
Hiperplasia Nodular Focal do Fígado/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Hiperplasia Nodular Focal do Fígado/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosRESUMO
In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/µL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Prolina/análogos & derivados , RNA Viral/sangue , Ribavirina/uso terapêutico , Carga Viral , Adulto , Idoso , Quimioterapia Combinada/métodos , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Espanha , Resultado do TratamentoRESUMO
In chronic hepatitis C (CHC), treatment duration may be individualized according to time to first undetectable hepatitis C virus (HCV) RNA, with patients who attain undetectable HCV RNA early in treatment being candidates for shorter regimens. The aim of this study was to determine the relapse rate in patients with CHC genotype (G) 1 infection and low baseline viral load who achieved undetectable HCV RNA by week 4 [rapid virologic response (RVR)] when treated for 24 weeks. This was an open-label, multicentre, noninterventional study. Adult patients with G1 CHC infection and baseline viral load <600,000 IU/mL who attained RVR were treated with peginterferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800-1200 mg/day) for 24 weeks, then followed for a further 24 weeks. The primary endpoint was relapse rate, defined as the proportion of patients with undetectable HCV RNA at treatment week 24 and detectable HCV RNA at week 24 follow-up. The secondary efficacy endpoint was sustained virologic response (SVR). Overall, 170 patients were included in the efficacy-evaluable population. The relapse rate was 9.7% (16/165, 95% confidence interval: 0.06-0.15), and SVR was attained by 149 of 170 patients (87.6%). Virologic outcomes were consistent regardless of age, gender, body weight and genotype. Seven patients reported treatment-emergent serious adverse events (AEs), and four patients discontinued treatment because of an AE. This study further demonstrates that peginterferon alfa-2b plus weight-based ribavirin for 24 weeks is an effective treatment strategy for treatment-naive patients with G1 CHC and low viral load who attain RVR.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/classificação , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Carga Viral , Adolescente , Adulto , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Recidiva , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The serpin squamous cell carcinoma antigen (SCCA, SERPINB3) has been found over-expressed in primary liver cancer and at lower extent in cirrhosis and chronic hepatitis. A novel SCCA-1 variant (SCCA-PD), presenting a single mutation in the reactive centre (Gly351Ala), has been recently identified (rs3180227). AIM: To explore SCCA-1 polymorphism in patients with HCV infection as single etiologic factor and different extent of liver disease. METHODS: One hundred and fourty-eight patients with chronic HCV infection (45 chronic hepatitis, 53 cirrhosis, 50 HCC) and 50 controls were evaluated. SCCA-1 polymorphism was studied by restriction fragment length polymorphism and confirmed randomly by direct sequencing. Circulating SCCA-IgM complex was determined by ELISA. RESULTS: SCCA-PD was detected with higher frequency in cirrhotic patients (45.3%, odds ratio=2.62; 95%CI 1.13-6.10, p=0.038) than in patients with chronic hepatitis or in controls (24.4% and 24%, respectively). Intermediate figures were found in hepatocarcinoma (36.0%). SCCA-IgM in serum was lower in patients carrying SCCA-PD than in wild type patients and the difference was statistically significant in cirrhotic patients (mean+/-S.D.=117.45+/-54.45 U/ml vs. 268.52+/-341.27 U/ml, p=0.026). CONCLUSIONS: The newly identified SCCA-PD variant was more frequently found in liver cirrhosis, suggesting that patients carrying this polymorphism are more prone to develop progressive liver fibrosis.
Assuntos
Antígenos de Neoplasias/genética , Hepatopatias/genética , Polimorfismo de Fragmento de Restrição , Serpinas/genética , Adulto , Antígenos de Neoplasias/imunologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Serpinas/imunologiaRESUMO
About 30% of the patients with chronic hepatitis develop a progressive liver disease and one of the most intriguing issues is the detection of noninvasive markers for fibrosis stage and disease progression. High levels of squamous cell carcinoma antigen (SCCA)-immunoglobulin M (IgM) are detectable in hepatocellular carcinoma and their increase in cirrhotic patients can predict tumour development. As SCCA-IgM can also be detectable at low percentages in patients with chronic hepatitis, the aim of this study was to assess SCCA-IgM complexes in relation to disease outcome in this group of patients. An ELISA assay was used to determine the presence of SCCA-IgM in 188 patients with chronic hepatitis and in 100 controls. An additional serum sample was available after a median period of 6 years in 57 untreated patients: these patients were subdivided in group A, including eight patients with a fibrosis score increase > or =2 in a second liver biopsy and group B, including 49 patients without fibrosis progression during a similar follow up. SCCA-IgM complexes were detectable in 63 of 188 (33%) patients but in none of the controls. A significant increase of SCCA-IgM levels over time was observed in patients with fibrosis progression (mean +/- SD: 117 +/- 200 U/mL/year), but not in those without histologic deterioration (mean +/- SD: -8.8 +/- 31 U/mL/year, P < 0.0001). In conclusion, monitoring SCCA-IgM levels over time appears a useful approach to identify patients with chronic hepatitis at higher risk for cirrhosis development.
Assuntos
Complexo Antígeno-Anticorpo/sangue , Antígenos de Neoplasias/imunologia , Hepatite Crônica/complicações , Imunoglobulina M/imunologia , Cirrose Hepática/diagnóstico , Serpinas/imunologia , Adulto , Biomarcadores , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hepatite Crônica/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess whether pegylated interferon alpha (PEG-IFNalpha) may induce peripheral neuropathy or antibodies to peripheral nerve antigens in patients with hepatitis C virus (HCV) infection. METHODS: We studied 52 patients with HCV (38 men, 14 women; mean age 44.6 +/- 10.6 years) treated with IFNalpha. Before therapy (T(0)), patients underwent quantitative viral RNA determination, HCV genotype analysis, and neurologic and electrophysiologic evaluation. At the end (T(1)) and after therapy (T(2)), patients were neurologically and electrophysiologically re-evaluated. Antibodies to gangliosides and sulfatides were assayed by ELISA at T(0) and T(1). Twenty-three patients with HCV with comparable age, viral load, and genotype, not treated with IFNalpha, were studied as controls. RESULTS: Seven patients (six in IFNalpha, one control) had peripheral neuropathy at recruitment. No significant differences in the electrophysiologic measures were detected between T(0) and T(1) (repeated-measures analysis of variance [ANOVA]) in any of the 52 patients or in those with neuropathy at T(0). No changes were found at T(2), independent of the viral response to treatment. Two patients, one with neuropathy, had antiganglioside antibodies at recruitment. Two patients, one not treated with IFNalpha, developed low antibody titers during follow-up, without symptoms or signs of neuropathy. CONCLUSIONS: Pegylated interferon alpha therapy was not associated with the occurrence (or worsening) of peripheral neuropathy or antibodies to peripheral nerve antigens in patients with hepatitis C virus.
Assuntos
Antivirais/efeitos adversos , Interferon-alfa/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Polietilenoglicóis/efeitos adversos , Adolescente , Adulto , Idoso , Anticorpos/metabolismo , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gangliosídeos/imunologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Exame Neurológico/métodos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estudos Prospectivos , RNA Viral/isolamento & purificação , Proteínas Recombinantes , Estudos Retrospectivos , Ribavirina/uso terapêutico , Estatísticas não Paramétricas , Sulfoglicoesfingolipídeos/imunologia , Fatores de TempoRESUMO
BACKGROUND AND AIMS: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. PATIENTS AND METHODS: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. RESULTS: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01). CONCLUSIONS: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.
Assuntos
Antivirais/uso terapêutico , Anticorpos Anti-Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Adulto , Alanina Transaminase/sangue , D-Alanina Transaminase , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/imunologia , Humanos , Interferons/uso terapêutico , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
AIM: To assess the efficacy of different schedules of human leucocyte interferon alpha in chronic hepatitis C. PATIENTS AND METHODS: A total of 213 naive patients with chronic hepatitis C were treated with 4 different schedules of human leucocyte interferon alpha. Sustained response was defined as persistently normal alanine amino transferase values with negative serum hepatitis C virus-RNA up to 12 months after therapy withdrawal. RESULTS: Rates of sustained response were 16% with 3 MU tiw for 6 months, 33% with 6 MU tiw for 5 months after a priming dose of 9 MU tiw for a month, 32% with 3 MU tiw for 12 months and 20% with 3 MU daily for 6 months. The major factors affecting the response rate were age and the hepatitis C virus genotype, as a sustained response was significantly higher in patients under 45 years and infected by hepatitis C virus types other than hepatitis C virus-1. Treatment was well tolerated and side-effects and drop-out events were similar to those described with other types of alpha-interferons. CONCLUSIONS: Human leucocyte interferon alpha appears to be equivalent to recombinant interferon-alpha in the treatment of chronic hepatitis C.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Viral/sangue , Fatores de TempoRESUMO
BACKGROUND/AIMS: In chronic hepatitis C, interferon-alpha (alpha-IFN) and ribavirin combination therapy improves sustained response compared to alpha-IFN monotherapy, both in naive patients and in previous alpha-IFN relapsers, but the efficacy of such therapy remains limited in non-responder cases. The aim of this study was to assess whether the pattern of response to alpha-IFN alone may predict sustained response to combination therapy during retreatment. METHODS: Fifty previous alpha-IFN relapsers and 50 previous alpha-IFN non-responders were retreated with a high alpha-IFN dose (6 MU/thrice weekly for 2 months; induction phase) and then randomised to continue with alpha-IFN alone (3 MU/thrice weekly) or to receive combination therapy (3 MU/thrice weekly of alpha-IFN and 1000-1200 mg/daily of ribavirin) for an additional 6 months according to the biochemical response to alpha-IFN shown after the induction phase. All patients were also evaluated for virological and histological response. RESULTS: Eleven of 25 (44%) relapsers treated with combination therapy and 4/25 (16%) treated with alpha-IFN alone achieved a sustained response. The corresponding figures among non-responders were 1/25 (4%) and 0/25, respectively. Among 26 patients with a complete ALT and HCV-RNA response after 2 months of alpha-IFN, sustained response was seen in 11/14 (79%) treated with combination therapy and in 4/12 (33%) treated with alpha-IFN alone (p=0.05). On the other hand, of 74 cases still HCV-RNA positive after 2 months of alpha-IFN alone, biochemical and virological end of therapy response was better with combination therapy (11/36; 30.5%) compared to alpha-IFN alone (4/38; 10.5%), but only one patient developed a sustained response (1/36; 3%). CONCLUSIONS: The retreatment with a 6-month combination therapy was associated with a high rate of sustained response only in patients showing a complete biochemical and virological response to alpha-IFN alone. Longer retreatment with combination therapy may be needed to achieve a sustained response in patients without a prompt virological response to alpha-IFN.
Assuntos
Antivirais/administração & dosagem , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Adulto , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/efeitos adversos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de Remissão , Retratamento , Ribavirina/efeitos adversos , Resultado do TratamentoRESUMO
In hepatitis C virus (HCV) infection, mechanisms responsible for liver cell damage are still poorly understood and both necrosis and apoptosis may be operative. By using terminal deoxynucleotydil transferase-mediated d-UTP-biotin nick-end labeling (TUNEL) we have evaluated and quantified apoptosis in liver biopsy specimens from 61 patients with chronic hepatitis C. All patients had detectable apoptotic cells in the liver. Presence of increased apoptotic activity was confirmed in selected cases by electron microscopy and by DNA gel electrophoresis. The amount of liver cell apoptosis expressed as apoptotic index, ranged between 0.01% to 0.54% and showed a positive correlation with histological activity grading (P <.0005) and with the amount of infiltrating CD8-positive cells (P =. 01). Apoptosis did not correlate with transaminase levels or with HCV load and genotype. These results support the concept that immune-mediated apoptosis may play a role in the pathogenesis of chronic hepatitis C and indicate that this type of reaction may occur in the absence of significant alanine transaminase (ALT) elevation, thus explaining the lack of correlation between biochemical activity and liver histological damage.
Assuntos
Apoptose , Hepatite C Crônica/patologia , Fígado/patologia , RNA Viral/sangue , Adolescente , Adulto , Alanina Transaminase/sangue , Feminino , Hepacivirus/genética , Hepatite C Crônica/metabolismo , Hepatite C Crônica/virologia , Humanos , Marcação In Situ das Extremidades Cortadas , Fígado/ultraestrutura , Masculino , Microscopia Eletrônica , Pessoa de Meia-IdadeRESUMO
Standard treatment for chronic hepatitis C currently consists of 3-6 million units (MU) of interferon-alpha (IFN-alpha) given thrice weekly (t.i.w.) for 12 months, obtaining rates of sustained response (SR) that usually do not exceed 15-25%. Some recent reports have suggested that daily administration of IFN-alpha may be more efficacious. More than 7 years ago, when standard therapy for hepatitis C was usually given for 6 months, we conducted a randomized clinical trial comparing daily vs t.i.w. treatment. In this study, 149 patients with chronic hepatitis C were randomized to received 3 MU of IFN-alpha either t.i.w. for 6 months or daily for 3 months followed by t.i.w. for 3 months. All patients were treated with human leucocyte IFN-alpha and were followed-up for up to 72 months after inclusion. Overall, patients treated daily or t.i.w. had similar rates of virological response after 3 months of induction [24/49 (50%) vs 40/100 (40%)], at the end of therapy [15/49 (31%) vs 36/100 (36%)] and at the end of follow-up [6/49 (12%) vs 9/100 (9%)]. However, when patients infected with HCV types other than HCV-1 were studied, there was a trend favouring the daily schedule that was associated with a higher [5/20 (25%) vs 5/48 (10%)] rate of long-term SR. All patients with a virological response - hepatitis C virus (HCV) RNA negative in serum as determined using the polymerase chain reaction - at 6 months after therapy remained in biochemical and virological remission at long-term follow-up, while seven of eight subjects who had normal alanine aminotransferase (ALT) levels but were serum positive for HCV RNA at 6 months, relapsed later, indicating that serum HCV RNA is better than ALT at predicting long-term cure after IFN-alpha therapy in chronic hepatitis C.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Adulto , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Esquema de Medicação , Feminino , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Leucócitos/imunologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Resultado do TratamentoRESUMO
Resistance of the hepatitis C virus (HCV) to interferon-alpha (IFN-alpha) therapy in patients with hepatitis C may be genetically controlled by an IFN sensitivity-determining region (ISDR) within the non-structural 5A (NS5A) gene. To assess whether HCV 1b strains carrying a 'resistant' type of ISDR are selected during unsuccessful IFN therapy, we analysed the evolution of the NS5A quasispecies, as detected by the clonal frequency analysis technique, and of the ISDR sequence by nucleotide sequence determination, in 11 patients showing no virological response during two consecutive cycles of IFN-alpha therapy. IFN-resistant patients had a homogeneous ISDR quasispecies with sequences identical to those described as 'resistant-' or 'intermediate-' type ISDR. After retreatment with IFN, further selection towards a homogeneous viral population was observed and 10 out of 11 patients had only one variant of HCV with no or just one single amino acid mutation within the ISDR sequence. Treatment and retreatment with IFN was associated in our non-responder patients with evolution of the ISDR quasispecies towards a rather homogeneous viral population carrying a conserved or minimally mutated ISDR motif, supporting the idea that this motif may be relevant for IFN resistance in HCV 1b-infected individuals.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferon-alfa/farmacologia , Proteínas não Estruturais Virais/genética , Adulto , Sequência de Aminoácidos , Antivirais/uso terapêutico , Resistência Microbiana a Medicamentos/genética , Feminino , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência de DNA , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacosRESUMO
Relapse after interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection occurs in 50% of patients after the initial response. The benefit of retreatment with IFN alone has not been assessed in large controlled studies. To assess the effectiveness and the tolerability of IFN retreatment and to identify the optimal second course regimen, we performed a meta-analysis of individual patient's data on a set of 549 patients (mean age 43.8 years; 12.2 SD, men: 65%) who had an end-of-treatment biochemical response to a first IFN course and then relapsed. Retreatment was started within 24 months after the end of the first course. Biochemical end-of-treatment responses (ETR) and sustained responses (SR) were observed in 405 of 549 (73.8%; 95% confidence interval [CI] 70.1-77.5) and in 124 of 549 (22.6%; CI 19.1-26.1) patients, respectively. One hundred seventy-five of 404 patients (43.3%; CI 38.6-48.2) developed an end-of-treatment, biochemical, and virological response when retreated. A biochemical and virological SR to retreatment occurred in 73 of 494 (14.8%; CI 11.7-18) patients. Thirty-two patients (5. 8%; CI 3.5-7.8) stopped retreatment for adverse effects. Biochemical and virological SR was predicted independently by logistic regression analysis using a negative HCV RNA at the end of the first cycle of IFN (P =.01) and by retreatment with a high IFN dose (P =. 03). Age, cirrhosis, genotype, and gamma-glutamyl transferase levels before retreatment were not significant by multivariate analysis. The excellent tolerability of IFN monotherapy retreatment makes it an option for patients who transiently cleared HCV-RNA during their first IFN course. Patients should be retreated with a high IFN dose regardless of the strength of the dose received during the previous course of treatment.
Assuntos
Hepatite C Crônica/terapia , Interferons/uso terapêutico , Adulto , Idoso , Feminino , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , RecidivaRESUMO
Alpha interferon (IFN-alpha) treatment is effective on a long-term basis in only 15 to 25% of patients with chronic hepatitis C. The results of recent trials indicate that response rates can be significantly increased when IFN-alpha is given in combination with ribavirin. However, a large number of patients do not respond even to combination therapy. Nonresponsiveness to IFN is characterized by evolution of the hepatitis C virus (HCV) quasispecies. Little is known about the changes occurring within the HCV genomes when nonresponder patients are retreated with IFN or with IFN plus ribavirin. In the present study we have examined the genetic divergence of HCV quasispecies during unsuccessful retreatment with IFN or IFN plus ribavirin. Fifteen nonresponder patients with HCV-1 (4 patients with HCV-1a and 11 patients with HCV-1b) infection were studied while being retreated for 2 months (phase 1) with IFN-alpha (6 MU given three times a week), followed by IFN plus ribavirin or IFN alone for an additional 6 months (phase 2). HCV quasispecies diversification in the E2 hypervariable region-1 (HVR1) and in the putative NS5A IFN sensitivity determining region (ISDR) were analyzed for phase 1 and phase 2 by using the heteroduplex tracking assay and clonal frequency analysis techniques. A major finding of this study was the relatively rapid evolution of the HCV quasispecies observed in both treatment groups during the early phase 1 compared to the late phase 2 of treatment. The rate of quasispecies diversification in HVR1 was significantly higher during phase 1 versus phase 2 both in patients who received IFN plus ribavirin (P = 0.017) and in patients who received IFN alone (P = 0. 05). A trend toward higher rates of quasispecies evolution in the ISDR was also observed during phase 1 in both groups, although the results did not reach statistical significance. However, the NS5A quasispecies appeared to be rather homogeneous and stable in most nonresponder patients, suggesting the presence of a single well-fit major variant, resistant to antiviral treatment, in agreement with published data which have identified an IFN sensitivity determinant region within the NS5A. During the entire 8 months of retreatment, there was no difference in the rate of fixation of mutation between patients who received combination therapy and patients who were treated with IFN alone, suggesting that ribavirin had no major effects on the evolution of the HCV quasispecies after the initial 2 months of IFN therapy.
Assuntos
Antivirais/uso terapêutico , Variação Genética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genética , Adulto , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND & AIMS: The aim of this study was to compare interferon (IFN)-ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with particular focus on its efficacy in cirrhosis. METHODS: A multivariate analysis of individual patient data of all randomized controlled trials using an IFN-ribavirin arm, reported between 1991 and March 1998, was performed. Centers included 1 Asian and 5 European university-based referral centers for liver disease. A total of 197 patients with chronic hepatitis C received IFN-alpha (3 MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147 patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were characterized according to previous IFN therapy, presence of cirrhosis, and genotype 1. Efficacy of therapy was evaluated by assessing the sustained response rate by logistic regression analysis. RESULTS: Patients without cirrhosis treated with IFN-ribavirin had a significantly higher sustained response rate than those treated with IFN, approximately 3-fold for previously untreated patients (IFN-ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority of combination therapy over IFN monotherapy was also observed for relapse; the same trend was observed for nonresponders. Tolerance for IFN-ribavirin was similar for patients with or without cirrhosis. CONCLUSIONS: Combination with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN-ribavirin combination is likely to become the antiviral therapy of choice for cirrhosis caused by hepatitis C.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Ribavirina/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Humanos , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversosRESUMO
Fluctuations of hepatitis C virus (HCV)-RNA serum levels were monitored in a multicenter study in 76 chronic HCV carriers who had been followed longitudinally without receiving antiviral therapy to assess their relation with the course of liver disease activity. Forty-four patients had normal transaminases over more than 2 years, while 32 additional patients had fluctuating levels. Viral load was measured in serial serum samples prospectively collected for 10 to 12 months in 54 patients and in sera stored yearly up to 8 years in an additional 22 patients. In patients tested monthly, a lesser extent of fluctuations was detected in cases with constantly normal transaminases as compared with those with fluctuating transaminases. In the former group, the mean difference between maximum and minimum values observed in each individual patient was 0.7 Log, while in the latter group, it was 1.3 Log (P =.0004). Most of these patients experienced, on average, three peaks of viremia over 1 year. The range of variation observed upon yearly testing was between 0.2 and 2.2 Log and did not reach statistical significance between the two groups. In conclusion, a careful viral replication profile can be achieved only by monthly testing, because longer time intervals could miss viremia fluctuations. HCV-RNA levels are more stable in asymptomatic HCV carriers than in patients with biochemical activity of liver disease.
Assuntos
Hepacivirus/genética , Hepatite C Crônica/fisiopatologia , Hepatite C Crônica/virologia , Fígado/fisiopatologia , RNA Viral/sangue , Adulto , Idoso , Alanina Transaminase/sangue , Portador Sadio , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , ViremiaRESUMO
Ten years after the discovery of the hepatitis C virus (HCV) and its association with NANB hepatitis as a major cause of chronic liver disease worldwide, our knowledge of the natural history of hepatitis C is still limited. The asymptomatic course of the disease in most patients, its slow and silent progression and heterogeneous outcome and the widespread use of interferon therapy during the past decade explain why many questions are still unsolved. The changing epidemiological pattern of HCV and the significant contribution of several cofactors to the severity of liver disease also complicate the development of a general model describing the natural history of hepatitis C. Available data indicate that HCV infection may resolve without any clinical signs of liver disease in individuals exposed to low dose inoculum and that these cases may develop T cell immunity even in the absence of anti-HCV seroconversion. Rates of complete biochemical and virological resolution of acute hepatitis C range between 10 and 50%, and are probably affected by the route of infection, size and type of inoculum and acute phase clinical features. Chronic HCV infection may develop with or without ALT abnormalities and with or without chronic inflammation and increasing fibrosis in the liver. Studies conducted in patients who acquired hepatitis C by blood transfusion 15-25 years ago indicate that 20-30% of them have now progressed to cirrhosis, including 5-10% with end stage liver disease and 4-8% who died of liver-related causes. Similar studies conducted in patients infected by other routes have shown a more benign course of hepatitis C, with little evidence of cirrhosis and no liver-related mortality during the first two decades. Outcomes after longer follow-up need to be assessed. In patients presenting with chronic hepatitis C, fibrosis progression is extremely variable over time and can be partially predicted by the age at infection, disease duration, liver histologic activity and stage of fibrosis and by the ALT profile. However, it is often difficult to predict clinical outcomes in individual cases. In patients who have developed cirrhosis, the 5-year risk of decompensation is between 15 and 20% and that of hepatocellular carcinoma around 10%. Several variables have been shown to influence the natural course of shown C, the most significant being age at infection, alcohol consumption and coinfection with HBV and HIV Studies are being performed to assess the role of host genetics. Viral factors, such as the HCV type and load, seem to have inconsistent or marginal effects.
Assuntos
Hepatite C/complicações , Hepatite C/diagnóstico , Doença Aguda , Progressão da Doença , Hepatite C/epidemiologia , Hepatite C/imunologia , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Cirrose Hepática/virologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fatores de TempoRESUMO
BACKGROUND/AIMS: Few data are available concerning the short and long-term effects of beta-IFN in patients with chronic hepatitis C. METHODOLOGY: We randomized 61 consecutive patients with HCV-related cirrhosis to receive: a) natural beta-IFN with a 6 MU/tiw for 6 months followed by 3 MU/tiw for 6 months schedule or b) no treatment. Biochemical and virological response was defined by normalization of ALT and negativization of serum HCV-RNA. Patients were followed-up for 5 years. RESULTS: A biochemical end-of-therapy response (ETR) was observed in 5/38 patients (13%) who received beta-IFN compared to 2/23 (9%) of untreated cases, but a virological ETR appeared only in 4/38 (11%) treated cases. At long-term follow-up, 6 cases (16%) who received beta-IFN and 4 untreated (17%) developed a persistent normalization of alanine aminotransferase (ALT) but only 2 (5%) and 1 (4%), respectively, were also HCV-RNA negative. The cumulative probability of liver decompensation (variceal bleeding ascites or hepatic encephalopathy) at 60 months was 24% in treated and 35% in untreated cases. Hepatocellular carcinoma developed in 2 treated and in 1 untreated patients. CONCLUSIONS: beta-IFN therapy was not associated with a significant improvement either in biochemical or virological response in cirrhotic patients with chronic hepatitis C. No significant reduction of cirrhosis related clinical events was linked to treatment.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/terapia , Interferon beta/uso terapêutico , Cirrose Hepática/complicações , Alanina Transaminase/sangue , Feminino , Seguimentos , Hepacivirus/genética , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/análise , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/terapia , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Antivirais/uso terapêutico , Crioglobulinemia/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Antivirais/administração & dosagem , Crioglobulinemia/etiologia , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Hepatite C Crônica/complicações , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ribavirina/administração & dosagemRESUMO
BACKGROUND: Recent data suggest that interferon therapy (IFN) can reduce the risk of progression to hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis. METHODS: A cohort of 189 patients with Child's Stage A cirrhosis of viral etiology followed prospectively were analyzed retrospectively to assess the effects of IFN on the clinical course and development of HCC. RESULTS: During a mean follow-up of 71.5+/-23.6 months, 7.9% of 88 treated and 21.8% of 101 untreated patients showed worsening of the Child's disease stage (P < 0.01); 5.6% of treated and 26.7% of untreated patients developed HCC (P < 0.001); and 3.4% of treated and 19.8% of untreated patients died of liver disease or underwent orthotopic liver transplantation (OLT) (P < 0.005). Using Cox's regression analysis, no treatment with IFN, high bilirubin and alkaline phosphatase (ALP) levels, and low leukocyte counts and prothrombin activity (PT) were associated significantly with worsening of Child's disease stage; no treatment with IFN, long term disease, low albumin and PT, and high gamma-glutamyl transpeptidase (GGT) were related significantly to HCC development; and no treatment with IFN, low albumin and PT, and high GGT and ALP were associated significantly with reduced survival. After adjustment for independent risk factors identified by multivariate analysis, the estimated cumulative probability of worsening of cirrhosis (P < 0.05), development of HCC (P < 0.001), and death or OLT (P < 0.005) was significantly lower in IFN-treated patients compared with untreated patients. This beneficial effect of therapy was statistically evident only in HCV positive patients. CONCLUSIONS: These results support the hypothesis that IFN improves clinical outcomes and reduces progression to HCC in patients with HCV-related cirrhosis. These conclusions, based on retrospective data, should be confirmed prospective.