Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study.

BACKGROUND: Data on HCV-related hepatocellular carcinoma (HCC) early recurrence in patients whose HCC was previously cured, and subsequently treated by direct-acting antivirals (DAAs), are equivocal. AIM: To assess the risk of HCC early recurrence after DAAs exposure in a large prospective cohort of HCV-cirrhotic patients with previous successfully treated HCC, also looking for risk factors for cancer early recurrence. METHODS: We enrolled 143 consecutive patients with complete response after curative treatment of HCC, subsequently treated with DAAs and monitored by the web-based RESIST-HCV database. Clinical, biological, and virological data were collected. The primary endpoint was the probability of HCC early recurrence from DAA starting by Kaplan-Meier method. RESULTS: Eighty-six per cent of patients were in Child-Pugh class A and 76% of patients were BCLC A. Almost all patients (96%) achieved sustained virological response. Twenty-four HCC recurrences were observed, with nodular or infiltrative pattern in 83% and 17% of patients, respectively. The 6-, 12- and 18-month HCC recurrence rates were 12%, 26.6% and 29.1%, respectively. Main tumour size and history of prior HCC recurrence were independent risk factors for HCC recurrence by Cox multivariate model. CONCLUSIONS: Probability of HCC early recurrence in patients who had HCC previously cured remains high, despite HCV eradication by DAAs. Risk was comparable but not higher to that reported in literature in DAA-untreated patients. Previous HCC recurrence and tumour size can be used to stratify the risk of HCC early recurrence. Further studies are needed to assess impact of DAAs on late recurrence and mortality.

Does the margin width influence recurrence rate in liver surgery for hepatocellular carcinoma smaller than 5 cm?

OBJECTIVE: Liver surgery is considered a curative treatment for hepatocellular carcinoma (HCC) but the importance of resection margin width remains controversial. The aim of this study is to clarify the role of 5-10 mm surgical margin width on post-operative recurrence and overall survival after resection. PATIENTS AND METHODS: We analyzed recurrence rate and overall survival rate of 72 patients who underwent curative hepatic resection for HCC smaller than 5 cm with 5-10 mm surgical margin width between January 2005 and December 2014. RESULTS: The mean follow-up period was 36 months. Among the seventy-two patients, thirty-one (31/72; 43%) developed recurrence but only eleven (11/31; 15.3%) along the resection margin. The disease-free survival was 77.2%, 50%, 41.4% at 1, 3 and 5 years respectively, and the overall survival was 89.9%, 78.8%, 60% at 1, 3 and 5 years respectively. CONCLUSIONS: 5-10 mm surgical resection margin for HCC smaller than 5 cm seems to be safe as a wider surgical margin because does not increase the risk of marginal recurrence and does not decrease overall survival rate. Further prospective and randomized studies are required to definitively clarify the importance of surgical margin width in hepatic resection for HCC.

IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. AIM: To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC). METHODS: Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. RESULTS: Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR=0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age <40 years (OR=4.79; 1.50-15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR=6.26; 1.98-19.74) and age <40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67). CONCLUSIONS: In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.

A 2010 update on occult hepatitis B infection.

Occult hepatitis B virus infection is a challenging issue whose virological and clinical relevance has been a source of long-lasting debate. By definition, OBI is characterized by the persistence of HBV-DNA in the liver tissue (and in some cases also in the serum) in absence of HBsAg. According to the HBV serological profile, OBI may be antibody (anti-HBc alone or together with anti-HBs) positive (seropositive OBI) or antibody negative (seronegative OBI). OBI is a complex biological entity with possible relevant clinical implications, mainly related to the intrahepatic persistence of viral cccDNA and to a strong suppression of viral replication and gene expression. Clinical observations suggest that OBI carriers may be a source of HBV transmission through blood transfusion or orthotopic liver transplantation (OLT). The state of suppression of viral replication and gene expression may be discontinued when an immunosuppressive status occurs, leading to typical hepatitis B with severe - and some times - fulminant course. The long-lasting persistence of the virus in the liver may provoke a very mild but continuing necro-inflammation that (if other causes of liver damage cohexist) may contribute over time to the progression of the chronic liver damage towards cirrhosis. In addition, OBI is supposed to be an important risk factor to HCC development since it maintains the pro-oncogenic properties typical of the overt infection.

An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers.

Liver biopsy is frequently required in HBeAg-negative disease to determine the stage of fibrosis. It can be difficult to distinguish cohorts with undetectable HBeAg who may have varying degrees of fibrosis due to different stages of disease. We have assessed the utility of transient elastography (TE) to evaluate differences in HBeAg-negative patients. A total of 220 HBsAg-positive individuals were studied: 125 (group 1) had an inactive HBsAg carrier state and 95 (group 2) were HBeAg-negative, anti-HBe-positive patients with persistently or intermittent elevation of alanine aminotransferase (ALT) and/or HBV DNA >10(5) copies/mL. Mean stiffness was 4.83 +/- 1.2 kPa in group 1 vs 8.53 +/- 6 kPa in group 2 (P < 0.001); statistically significant differences were also found between AST/ULN ALT/ULN ratios, HBV DNA in group 1 vs group 2, respectively (P < 0.001). In the multivariate analysis, the only variable independently associated with the stage of fibrosis was the stiffness. This study shows that mean hepatic stiffness by elastography is significantly lower in patients with inactive hepatitis B compared to those with HBeAg-negative disease. The procedure is a useful adjunct to diagnosis to confirm a clinical pattern of disease, and for more selective use of liver biopsy before considering antiviral therapy.

Is there a downgrading in the alert about the hepatitis B virus infection in Italy?

BACKGROUND AND AIM: There is suspicion of a decrease in warning regarding the hepatitis B virus as a health problem both by the infected individuals and their doctors. The aim of this study was to investigate whether the clinical/virology investigation of chronic hepatitis B virus infected individuals is at present accurate. METHODS: The chronic hepatitis B virus surface antigen carriers consecutively attending 13 different hospital divisions in Calabria from July to December 2005 were evaluated to investigate the available information on the grade of their liver disease, their virologic profile and the hepatitis B virus status of their family members. RESULTS: Four-hundred-thirty hepatitis B virus surface antigen positive individuals were enrolled, 417 of whom were Calabrians. Most of them had a diagnosis of chronic liver disease, but a liver biopsy had been performed only in 13.5% of the cases, whereas more than 1/3 of them had not been tested for hepatitis Delta virus co-infection. The majority of these individuals were unaware of the hepatitis B virus status of their family members. Moreover, anti-hepatitis B virus vaccination procedures were not performed in most of the hepatitis B virus surface antigen carrier families. CONCLUSIONS: This study revealed that fundamental clinical, virological, and epidemiological aspects of chronic hepatitis B virus infection are not investigated in many hepatitis B virus surface antigen carriers, suggesting that the general knowledge as regards hepatitis B virus is mostly inadequate.

Correlates of total homocysteine plasma concentration in type 2 diabetes.

BACKGROUND: Although well-defined in the general population, correlates of total homocysteine (tHcy) plasma concentration have not been sufficiently evaluated in diabetes. We investigated factors potentially associated with tHcy concentration in a cohort of type 2 diabetic subjects. MATERIALS AND METHODS: The common methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism, fasting tHcy, vitamin B12 and folate plasma levels were assessed in 312 diabetic subjects, whose clinical, metabolic and lifestyle information was also available. RESULTS: The MTHFR genotype distribution was comparable to the Hardy-Weinberg equilibrium, with an overall TT homozygous frequency of 22%. Fasting tHcy concentration was significantly higher in men than in women (P < 0.001). Multivariate-adjusted tHcy concentration was significantly different across the quartiles of age (P < 0.001), folate (P = 0.01), vitamin B12 (P = 0.03), creatinine concentrations (P = 0.001) and smoking (P = 0.02). Overall, significant trends were noted for creatinine clearance (P for trend = 0.02) and systolic blood pressure (BP) (unadjusted P for trend = 0.01), whereas no differences were noted according to BMI, diastolic BP, presence of hypertension, and diabetes-related variables, such as diabetes duration, fasting glucose and glycated haemoglobin concentrations, current treatment and diabetes long-term complications. Total homocysteine levels significantly correlated with age, systolic BP, vitamin B12, creatinine and creatinine clearance, but only age, creatinine, folate and vitamin B12 levels were independently associated with tHcy concentration in stepwise regression analysis. CONCLUSIONS: Age, creatinine, folate, vitamin B12, and to a minor extent, sex, smoking, TT genotype and systolic BP were significantly associated with Hcy plasma concentration in type 2 diabetes, whereas no significant associations were noted with diabetes-related variables.

Candida infections in children treated with conventional chemotherapy for solid tumors (transplant recipients excluded): The Institut Gustave Roussy Pediatrics Department experience.

INTRODUCTION: Advances in medical therapy have greatly improved the survival of children suffering from cancer. Although progress has been made in the eradication of malignant disease there is growing concern for the development of fungal infections in patients treated with chemotherapy. MATERIALS AND METHODS: We reviewed all episodes of pediatric candidemia that occurred between January 1988 and December 2000. We analyzed the general characteristics of this population, risk factors, microbiology features, treatment, complications, and outcome. RESULTS: Seventeen cases of candidemia were observed during the 12 years of the study at an estimated incidence of 0.4%. Neutropenia occurred at the onset of infection in 13/17 (76.5%) children. A central venous device was present in all cases. Seventy-seven percent of the infections were caused by Candida albicans and in 85% of patients, yeasts had colonized the gastrointestinal tract. In 9/17 patients visceral dissemination was documented. Overall, in 77% of the episodes the outcome was favorable. CONCLUSIONS: Candidemia is a rare but severe complication in pediatric oncology. Even if the prognosis is better in children than in adults, Candida septicemia remains of great concern since a high percentage of these infections result in visceral dissemination and mortality is still elevated.

Occult HBV infection and suppression of HCV replication in the early phase of combination therapy for chronic hepatitis C.

BACKGROUND: Occult HBV infection in subjects with chronic hepatitis C is related to more severe disease outcome. It has been suggested that it might reduce sensitivity to antiviral treatment. AIMS: To assess in HBsAg negative subjects with chronic hepatitis C any effect of the presence of HBV genomes in the liver on the early kinetics of HCV-RNA under PEG-IFN plus ribavirin. PATIENTS AND METHODS: Twenty-two anti-HCV and HCV-RNA positive subjects, with biopsy-proven chronic hepatitis C (M/F 15/7; 50 +/- 8.6 years, 16 genotype 1b) were given PEG-IFN alpha 2b 1.0 microg qw plus ribavirin (800 to 1,200 mg daily according to body weight) for an intended 52 week period. Early virological response was assessed over the first 4 weeks of therapy by quantifying HCV-RNA. Occult HBV infection was assessed by testing for HBV-DNA in the liver before therapy. RESULTS: HBV genomes were found in the liver of 7 of 22 (31.4%) patients, unrelated to anti-HBc status. Kinetics of HCV-RNA during the first 4 weeks of antiviral treatment was unaffected by occult HBV infection, both in terms of absolute reduction of viral load and of number of cases with a reduction of > or = 2 log10 on treatment. CONCLUSIONS: Occult HBV infection does not affect the early phase of response to combination therapy. Further follow-up of patients into the maintenance phase of antiviral treatment and after stopping it will clarify if and when occult HBV has a role in reducing sustained virological response.

Neuropsychological outcome in long-term survivors of a childhood extracranial solid tumor who have undergone autologous bone marrow transplantation.

The purpose of this study was to evaluate neuropsychological and adaptive functioning of children who have undergone bone marrow transplantation (BMT) without previous cranial irradiation. In total, 76 children treated for an extracranial tumor with BMT without total body irradiation (TBI) were evaluated at least 5 years after the end of the treatment.Overall, their performance and skills were in the normal range and their professional and academic outcomes were satisfactory. Nevertheless, we observed a deleterious effect of deafness on verbal IQ associated with the previous administration of cisplatin during conventional chemotherapy. In addition, reading difficulties had arisen. This could be related to absence from kindergarten or primary school during hospitalization. Finally, in the younger subgroup, visual-perceptual skills were found to be more fragile.

TT virus has a ubiquitous diffusion in human body tissues: analyses of paired serum and tissue samples.

The tissue tropism and possible correlation with liver disease of the TT virus (TTV) as well as its prevalence and genotype distribution remain undefined. TTV-DNA was investigated in paired sera and tissue samples from 144 patients, and sera and cerebrospinal fluids (CSF) from additional six subjects. Of the 144 tissue samples, 128 were liver biopsy specimens from subjects with hepatic disease while 16 were surgically obtained nonliver specimens from patients with extrahepatic disease. TTV cloning, sequencing and genotype analyses were performed on isolates from sera, tissue specimens and peripheral blood mononuclear cells of two patients with hepatic and four patients with extrahepatic pathologies, as well as from sera and CSFs of two subjects. TTV was found in 100% of the examined tissues and in 60.1 and 50% of sera from patients with hepatic and extrahepatic pathologies, respectively. Moreover, TTV was detected in four of the six CSFs analysed but only in two correspondent sera. Genotyping revealed the coexistence of multiple TTV genotypes and genetic variants in each infected individual, and the analysis of TTV mRNA showed the presence of transcripts in all the six different tissues studied. These results indicate that the entire adult population in our area is more likely infected by TTV, although several subjects are not viraemic and that TTV infects many different human tissues and is able to invade the central nervous system.

[Pseudotumoral diseases: ten years of experience in a pediatric oncology department]. / Affections pseudotumorales: dix ans d'expérience dans un service d'oncologie pédiatrique.

PURPOSE: Among the 350 new patients per year treated in the pediatric oncology department of the Gustave-Roussy Institute, about 2% have no tumor. This study analyzes these children presenting a pseudotumoral disease. PATIENTS AND METHODS: Ten-year-retrospective study. Patients for which no follow up in oncology was necessary after one consultation or hospitalization were selected. OUTCOME: Between 1990 and 2000, 64 patients were seen in the pediatric department for pseudotumoral disease. The reasons of orientation were mainly a soft tissue mass (15 cases), an abdominal mass (14 cases), or a bone lesion (13 cases). Diagnosis was most often infectious diseases (33 cases), or post-traumatic lesions (10 cases). Diagnosis was established following several consultations or an hospitalization for 29 of 64 patients. In 75% of the cases new investigations were necessary to determine the diagnosis. A biopsy was performed in 19. For two children, diagnosis was corrected after the beginning of chemotherapy. CONCLUSION: Pseudotumoral diseases leading to a consultation in pediatric oncology are rare and represent two per cent of the patients. For these difficult cases, only a pluridisciplinary discussion may lead to diagnosis.

[Discovery of a neuroblastoma producing cardiogenic shock in a 2-month-old child]. / Découverte d'un neuroblastome lors d'un choc cardiogénique chez un enfant de deux mois.

CASE REPORT: A two-month-old male child presented a severe heart failure associated with a malignant hypertension. Abdominal ultrasound revealed a mass connected to the left adrenal gland. CT scan showed a tumor of 7 x 6 x 8 cm, forcing back both the left kidney and the aorta. A biopsy allowed the diagnosis of neuroblastoma without MYCN oncogene amplification. Intensive care stabilized the hemodynamic situation. Under chemotherapy the tumor volume decreased significantly and complete surgical excision became possible. Three years after diagnosis, the patient remained in complete remission. CONCLUSION: Clinical presentation of this neuroblastoma was extremely uncommon. The catecholamines produced by the tumoral cells could induce an increase of the myocardiac work following the left ventricule post charge increase. Theses mechanisms could be synergistic for a myocardial exhaustion.

[Metastatic osteosarcoma: prognosis factors and treatment]. / Les ostéosarcomes métastatiques; facteurs pronostiques et traitements.

Long term outcome and prognosis factors of patients with metastatic osteosarcoma were evaluated on 29 observations from 3 centres reviewed retrospectively. Twenty-nine patients less than 18 years old were treated from 1990 to 1998. Only 29 of these patients had received similar treatments associating chemotherapy and surgery, adapted according to histological and clinical response to treatment, as recommended by the SFOP. Overall survival at five years was 26%, and disease free survival 14%. Eight patients are alive, four in first complete remission (CR) and four in second CR. Three of the four patients alive in first CR had bone metastases at diagnosis. On univariate analysis, factors predicting survival are: the numbers of organs affected by metastatic lesions, the number of lung nodules and the type of surgery. This is, to our knowledge, the first report of long term survivors with bone metastases at diagnosis. Metastatic osteosarcoma prognosis remain poor. A randomised study would help to define the best possible treatment for this disease.

Analysis of haemochromatosis gene mutations in a population from the Mediterranean Basin.

BACKGROUND/AIMS: The C282Y mutation in the haemochromatosis gene (HFE) located on chromosome 6 has been identified as the main genetic basis of hereditary haemochromatosis (HH). Two more mutations of that gene, H63D and S65C, appear to be associated with milder forms of HH. A high allele frequency for C282Y and H63D mutations was reported in populations from North Europe, while incomplete information is available for individuals from the Mediterranean Basin where C282Y homozygotes comprise a smaller percentage of HH cases. In this study we investigated the allele frequency of HFE mutations and the association between HFE mutations and cases of HH in a population from the South of Italy (Sicily and Calabria). In addition, we evaluated a possible association between HFE mutations and either chronic liver disease or type II diabetes. PATIENTS AND METHODS: Three hundred and twenty-seven individuals (654 chromosomes) were tested for C282Y, H63D and S65C mutations of the HFE gene by restriction fragment length polymorphism. Four had HH, 23 had hepatocellular carcinoma, 100 had chronic liver disease, 100 had type II diabetes, and 100 were healthy controls. RESULTS: Both C282Y and S65C mutations were each detected in one of the 654 chromosomes analysed (allele frequency=0.15%), while H63D change was found in 122 chromosomes (allele frequency=18.6%) and was equally distributed in all the categories examined. One healthy individual had compound heterozygosity for C282Y and H63D mutations. The frequency of C282Y in this Southern Italian sample was the lowest yet reported for a population of European origin. None of the four HH patients was either homozygous or heterozygous for C282Y. CONCLUSIONS: In Mediterranean populations from Southern Italy the C282Y mutation occurs sporadically and HFE polymorphisms seem to have little diagnostic relevance.

Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection?

Our aims were to develop a noninvasive predictive tool to identify cirrhotic patients with esophageal varices and to evaluate whether portal Doppler ultrasonographic parameters may improve the value of other predictors. One hundred forty-three consecutive compensated cirrhotic patients underwent upper gastrointestinal endoscopy. Fourteen clinical, biochemical, ultrasonographic, and Doppler ultrasonographic parameters of each patient were also recorded. Esophageal varices were detected in 63 of the 143 patients examined (44%; 95% confidence interval [CI] 36.2-52.6). Medium and large esophageal varices were observed in 28 subjects (44%; 95% CI 31.4-58.4). Using stepwise logistic regression, presence of esophageal varices was independently predicted by prothrombin activity less than 70% (odds ratio [OR]: 5.83; 95% CI: 2.6-12.8), ultrasonographic portal vein diameter greater than 13 mm (OR: 2.92; 95% CI: 1.3-6.4), and platelet count less than 100 x 10(9)/L (OR: 2.83; 95% CI: 1.27-6.28). Variables included in the model were used to generate a simple incremental rule to evaluate each individual patient. The discriminating ability of the prediction rule was relevant (area under the curve: 0.80) and did not change by replacing ultrasonographic portal vein diameter with congestion index of portal vein. We concluded that compensated cirrhotic patients should be screened by upper gastrointestinal endoscopy when prothrombin activity less than 70%, platelet count less than 100 x 10(9)/L, and ultrasonographic portal vein diameter greater than 13 mm are observed, whereas those without any of these predictors should not undergo endoscopy. The contribution provided by portal Doppler ultrasonographic parameters does not appear of practical utility.

Occult hepatitis B virus infection.

Many studies have shown that hepatitis B virus infection may also occur in hepatitis B surface antigen-negative patients. This occult infection has been identified both in patients with cryptogenic liver disease and in patients with hepatitis C virus-related chronic hepatitis, and much evidence suggests that it may be a risk factor of hepatocellular carcinoma development. However several aspects of this occult infection remain unclear such as its prevalence and the factor(s) involved in the lack of circulating hepatitis B surface antigen. Moreover, it is uncertain whether the occult hepatitis B virus infection may contribute to chronic liver damage, considering that it is usually associated with a suppressed viral replication. Evidence and hypotheses concerning this fascinating field of bio-medical research are reviewed.

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study.

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: deltaF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) deltaF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.

Efficacy of high dose of recombinant alpha 2b interferon on long term response in chronic hepatitis C and cirrhosis: prospective randomized multicentre study.

BACKGROUND/AIMS: The long-term response to alpha-Interferon in HCV-related chronic liver diseases is disappointing. A randomized controlled trial was conducted to investigate: 1) if doubling the standard regimen of 3 MU recombinant alpha 2b-interferon thrice weekly for one year could improve the long-term response, and 2) the efficacy of these two schedules in cirrhotic patients. PATIENTS AND METHODS: A series of 80 anti-HCV positive patients with biopsy proven liver disease (52 chronic hepatitis and 28 cirrhosis) were randomized to receive either 3 MU or 6 MU alpha 2b-interferon. RESULTS: Based on "intention-to-treat analysis", 38% in the 3 MU group and 53% in the 6 MU group had end-of-treatment response. After 24 months, 18% had long-term response: 5% in 3 MU group and 30% in 6 MU group (p < 0.008). HCV genotype had no influence on the response rate. Thirty-eight percent of the cirrhotics treated with 6 MU had long-term response, while none of those treated with 3 MU had long-term response (difference 38%; 95% confidence internal 10%-67%; p = 0.03). At the end of treatment, 38% of patients lost HCV-RNA. After 24 months only 19% remained HCV-RNA negative: 12 patients (31%) in the 6 MU group and 2 (6%) in the 3 MU group (p < 0.05). CONCLUSIONS: 6 MU of alpha 2b-interferon thrice weekly for 12 months is significantly better than 3 MU in inducing a long-term response and permanent loss of HCV-RNA. This result is particularly striking in the subgroup of cirrhotics.