Psychological screening before interferon therapy.
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Antiviral Agents↗
Biomedical subjects
L Roffi
Publications and source records attributed to L Roffi.
A randomized 4-arm multicenter study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon alone.
To determine whether a higher dosage of interferon (IFN) associated with ribavirin and/or prolonged time of administration may improve therapeutic efficacy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN monotherapy. Group 1 (n = 139) received 3 million units (MU) IFN-alpha2b 3 times a week (t.i.w.) plus ribavirin 1,000 mg/d for 12 months; group 2 (n = 162) received 5 MU t.i.w. plus ribavirin for 12 months; group 3 (n = 142) received 3 MU t.i.w. plus ribavirin for 6 months; and group 4 (n = 151) received 5 MU t.i.w. plus ribavirin for 6 months. The primary end point was hepatitis C virus (HCV)-RNA clearance at the end of 6-month follow-up. HCV-RNA was negative in 15% of group 1, 23% of group 2, 11% of group 3, 16% of group 4 (group 2 vs. group 3, P =.04). Among patients with genotypes 1 and 4, sustained response was significantly higher in group 2 vs. group 3 (18% vs. 7%, P =.03; group 1 = 9%, group 4 = 12%, P = not significant [NS]). In patients with genotypes 2 and 3, sustained virologic response was not affected by the different regimens (group 1 = 32%, group 2 = 30%, group 3 = 30%, group 4 = 35%, P = NS). In conclusion, about 23% of nonresponders to IFN monotherapy may achieve a sustained response if re-treated by 5 MU t.i.w. IFN plus ribavirin 1,000 mg/d for 1 year. Patients with genotype 1 should receive a high dosage of IFN plus ribavirin for 12 months, whereas therapy for patients with genotype 2 or 3 should be less aggressive.
Adult↗
Treatment with interferon-alpha2b of naive non-cirrhotic patients with chronic hepatitis C according to viraemia and genotype. Results of a randomized multicentre study. The North West Italian Hepatological Group.
OBJECTIVE: To establish whether tailoring the dosage of interferon (IFN)-alpha2b in non-cirrhotic naive patients with chronic hepatitis C according to hepatitis C virus (HCV) genotype and viraemic level improves the rate of sustained response (normal alanine aminotransferase values and HCV-RNA negativity 6 months after the end of therapy). PATIENTS: A total of 538 consecutively collected HCV-positive patients with non-cirrhotic chronic hepatitis who had not been previously treated. METHODS: Quantitative viraemia and genotype were determined in each patient by a core laboratory. The patients were randomized to: Group 1, 86 patients with genotype non-1 and viraemia < 1,000,000 HCV genome equivalents/ml (GenEq/ml) treated with 3 Million Units (MU) IFN three times weekly (t.i.w.) for 1 year; Group 2, 42 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 3 MU IFN t.i.w. for 1 year; Group 3, 46 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 5 MU IFN t.i.w. for 1 year; Group 4, 85 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 5, 88 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN t.i.w. for 1 year; Group 6, 94 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 7, 97 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN daily for 2 months followed by 5 MU t.i.w. for a further 10 months. RESULTS: According to an intention-to-treat analysis, a sustained virological response (negative HCV-RNA by polymerase chain reaction 6 months after the end of therapy) was observed in 42% of Group 1 patients, in 21% of Group 2 patients versus 24% of Group 3 patients [P = not significant (NS)], in 28% of Group 4 patients versus 35% of Group 5 patients (P = NS), and in 8.5% of Group 6 patients versus 12% of Group 7 patients (P = NS). CONCLUSIONS: Even though a trend towards a therapeutic improvement is observed, the adoption of more aggressive IFN protocols, such as induction therapy, does not appear to significantly improve the rate of sustained response in patients with chronic hepatitis C associated with HCV genotype 1 and highly viraemic levels compared with standard therapy. Moreover, patients with only one unfavourable predictive factor (genotype 1 or high viraemia) do not gain major therapeutic benefits when treated with high doses of IFN.
Adult↗
Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype.
OBJECTIVE: To assess the influence of hepatitis C virus (HCV) genotypes on the clinical outcome of liver disease, we analysed 2,307 patients. RESULTS: The most frequently represented genotypes were 1b (40%) and 2 (28.1%). Patients with these genotypes had a median age higher than patients with other genotypes (P< 0.01). The overall survival of subjects with genotype 1b was poorer than the survival of patients with other genotypes (P< 0.01). Liver cirrhosis was found in 280 patients (12.1%), and type 1b was the most represented isolate among them (P< 0.01). Sixty-two patients (22%) developed hepatocellular carcinoma (HCC) during a follow-up of 1481.8 cumulative years (estimated crude incidence rate, 4.1 cases per 100 person-years for all cirrhotics; 5.9 cases for genotype 1a; 4.5 cases for genotype 1b; and 2.8 cases for genotypes non-1). Considering the whole population of 2,307 patients, only genotype 1b was associated significantly with both cirrhosis and the development of HCC. One hundred and nineteen cirrhotic patients underwent treatment with interferon in uncontrolled studies. Interferon therapy was associated with both better survival (P< 0.01) and a lower cumulative hazard for HCC (P< 0.01). CONCLUSIONS: Genotype 1b was associated with a poorer prognosis, probably because it leads to cirrhosis and consequently to HCC development. However, our data did not confirm genotype 1b as an independent risk factor for HCC in liver cirrhosis, which plays a major role in carcinogenesis. Interferon should be considered as a useful strategy in cirrhosis for improvement of survival and reduction of HCC risk.
Adolescent↗
Hepatocyte proliferation and risk of hepatocellular carcinoma in cirrhotic patients.
OBJECTIVES: High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics. METHODS: We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum alpha-fetoprotein (AFP) assays every 6 months. RESULTS: During a mean follow-up of 53 months (range, 12-120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5%+/-1.6 in patients who developed HCC and 0.9%+/-0.6 in those who did not (p < 0.0001). By univariate analysis, S-phase fraction 1.8% or higher and AFP higher than 20 ng/ml were the only two variables significantly correlated with the development of HCC (p < 0.0001, p < 0.0001). Multivariate analysis found that both variables were independently associated with HCC development (p < 0.003 and p < 0.005, respectively), with hazard ratios of 8.0 and 7.3 (confidence intervals, 2.1-31.2 and 1.8-29.2). Among patients with high AFP and/or high S-phase fraction, 11 (39%) developed HCC, compared with only one (1%) with a low S-phase fraction and normal AFP, corresponding to HCC yearly incidences of 9.5% and 0.3% (p < 0.00009). CONCLUSIONS: Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.
Adult↗
Hepatitis C virus genotypes in a non-cirrhotic Italian population with chronic hepatitis C: correlation with clinical, virological and histological parameters. Results of a prospective multicentre study.
To identify correlations between the distribution of hepatitis C virus (HCV) genotypes and demographic, pathological and virological parameters of HCV-infected patients, we prospectively recruited 650 patients with biopsy-proven chronic hepatitis C without histological aspects of cirrhosis; none had been treated with antiviral therapy. Data regarding gender, age, mode of HCV transmission, alanine aminotransferase (ALT) and HCV RNA levels, immunoglobulin M (IgM) anticore values, liver histology and histological activity were obtained from each patient and correlated on multivariate analysis with infecting HCV genotype. Fifty-five per cent of the patients were infected with HCV genotype 1, 20% with HCV genotype 2, 18% with HCV genotype 3 and 7% with HCV genotype 4. Non-transfusional HCV transmission, low ALT levels, IgM anticore reactivity and a low histological grading score were independent variables associated with HCV genotype 1. Older age, female gender, post-transfusional transmission and a high histological grading score were related to HCV genotype 2, whilst younger age, history of current/previous drug abuse, high ALT values, low IgM anticore reactivity and high viraemic levels were associated with HCV genotype 3. History of illicit use of intravenous drugs and low HCV RNA levels were the only independent variables correlated with HCV genotype 4. Genotype 1 remains predominant in Italy but the prevalence of HCV genotypes is changing in relation to age and mode of transmission: Italian patients with HCV genotype 3 are younger and exhibit higher levels of ALT and HCV RNA than patients with other genotypes.
Adolescent↗
Depression during interferon therapy for chronic viral hepatitis: early identification of patients at risk by means of a computerized test.
OBJECTIVES: At the doses used for the treatment of chronic viral hepatitis, interferon (IFN)-related side-effects are usually modest, even though in some cases they require the interruption of therapy. Neuropsychiatric disturbances that range from modest depression and irritability to forms of manic-depressive psychosis and attempted or successful suicides are among the most important side-effects. The aim of our study was to determine whether the Minnesota Multiphasic Personality Inventory (MMPI) is a sensitive and reliable test for the early identification of patients at risk of depression before IFN therapy is commenced, and whether it could be useful for the monitoring of these patients during treatment. METHODS: We prospectively studied 67 patients with chronic active liver diseases, consecutively enrolled in open studies and treated with r-IFNalpha2. Before starting therapy and after 3 months of treatment, all patients underwent a clinical neurological evaluation and MMPI. RESULTS: At baseline, the correlation between the clinical evaluation and the score of the depression scale of the MMPI was statistically significant (P< 0.0001). Nine of 14 (64.3%) patients with a baseline score > or = 60/100 showed a depressive mood after 3 months of therapy. Five of 44 patients (11.3%) with a baseline score < 60/100 showed a depression of medium level after 3 months of treatment. This difference was highly significant (P< 0.0001). CONCLUSIONS: According to our results, the MMPI is a reliable and sensitive test for the early identification of patients at risk of depression before and during IFN therapy for chronic viral liver diseases.
Adult↗
Early effects of total paracentesis and albumin infusion on muscle sympathetic nerve activity in cirrhotic patients with tense ascites.
BACKGROUND/AIMS: Cirrhotic patients with ascites are characterized by a marked activation of the sympathetic and the renin-angiotensin-aldosterone system. Total paracentesis is associated with a short-lived suppression of the renin-angiotensin-aldosterone system. Little information exists as to whether this favourable effect is parallelled by sympathoinhibition. METHODS: In 16 Child C cirrhotic patients (age: 57.1+/-6.2 years, mean+/-SEM) with tense ascites we assessed the time course of the effects of total paracentesis followed by intravenous albumin (6-8 g/l of ascites) on beat-to-beat mean arterial pressure (Finapres), heart rate, plasma norepinephrine, epinephrine (high performance liquid chromatography) and muscle sympathetic nerve activity (microneurography, peroneal nerve). Measurements were obtained under baseline conditions, during staged removal of ascitic fluid (250 ml/min) and 24 h later. The patient remained supine throughout the study period. RESULTS: Total paracentesis (10.6+/-1.3 l) induced a decrease in mean arterial pressure (from 95.0+/-2.6 mmHg to 88.2+/-3.2 mmHg, p<0.01), in heart rate (from 82.5+/-3.3 beats/min to 77.1+/-2.8 beats/min, p<0.01) and a reduction in plasma norepinephrine values (from 782+/-133 pg/ml to 624+/-103 pg/ml, p<0.01), which were substantially maintained 24 h later. In eight patients muscle sympathetic nerve activity did not change during paracentesis (from 65+/-7.1 bursts/min to 65+/-7.4 bursts/min, p=NS), but a marked reduction was observed 24 h later (48.4+/-5.6 bursts/min, p<0.01). CONCLUSIONS: These data provide the first evidence that total paracentesis exerts an acute marked sympathoinhibitory effect. Whether this is a long-lasting phenomenon and to what extent plasma expansion with albumin contributes to this effects need to be further addressed.
Adult↗
Prediction of relapse or sustained response in biochemical responders by serum hepatitis C virus RNA monitoring during interferon therapy.
Normalization of serum aminotransferase levels is achieved in approximately 50% of chronic hepatitis C patients treated with interferon (IFN); however, in about one-half of these patients the hepatitis relapses after therapy. In this study we investigated the efficacy of serum hepatitis C virus (HCV) RNA monitoring during IFN therapy to predict the outcome of a biochemical end-of-treatment (ETR) response. Eighty patients with chronic hepatitis C received leucocyte (natural) IFN-alpha (13 patients) or recombinant IFN-alpha2a (67 patients). Antiviral therapy was given for 12 months to 43 (53.7%) responders and this group was analysed further. During follow-up, 15 relapsed and 28 showed a sustained response (median follow-up 50 months, range 39-67 months). Viraemia was monitored at baseline, and at months 1, 3, 6, 9 and 12 of treatment, by nested polymerase chain reaction (PCR) (sensitivity 10-100 copies ml-1). A combination of positive nested PCR and HCV RNA values at the 3rd and 6th months of treatment was 100% predictive of relapse (sensitivity, 66.6%; specificity, 100%). A combination of negative nested PCR and HCV RNA values at the 1st and 3rd months of treatment was 100% predictive of sustained response (sensitivity, 39.3%; specificity, 100%). In conclusion, serum HCV RNA monitoring is an appropriate and reliable tool for predicting early outcome of the biochemical ETR response after IFN discontinuation. This could be useful in the modulation of therapeutic management of chronic hepatitis C.
Adult↗
Correlation of interferon-induced expression of MxA mRNA in peripheral blood mononuclear cells with the response of patients with chronic active hepatitis C to IFN-alpha therapy.
MxA, a protein with selective activity against certain viruses, is an accepted specific indicator of type I interferon (IFN) activity. We have developed an internally controlled quantitative-competitive PCR to measure the amounts of MxA mRNA expressed in peripheral blood mononuclear cells (PBMC). This assay is more sensitive, quantitative, and easily applied to serial clinical samples than previously described methods. We have applied this assay retrospectively to 27 patients with chronic active hepatitis C given IFN-alpha2. Most such patients gain no sustained benefit but nevertheless suffer from the side effects, expense, and inconvenience of the treatment. Fourteen of the 27 had been classified on clinical grounds as responders and 13 as nonresponders at the end of a 6 month treatment period. We measured MxA mRNA in PBMC obtained before and after 8 weeks of IFN-alpha2 treatment. All the patients expressed some level of mRNA before treatment began, and after 8 weeks of treatment, the level rose in 19. This increase was significant (p < 0.001) only in patients classified as responders. This strongly suggests that hepatitis C virus (HCV) patients who express increased amounts of MxA mRNA in their PBMC during IFN-alpha treatment are most likely to obtain long-term benefit. If this finding is confirmed in future prospective studies, it will provide an extremely important predictive marker for managing IFN-alpha therapy in patients with HCV.
Adult↗
Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study.
OBJECTIVE: After non-response to the initial course of therapy, retreatment with alpha-interferon is not effective. The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon. DESIGN: Prospective, multicentre clinical trial. SETTING: Twelve hospitals in Lombardy, Italy. PARTICIPANTS: 120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon, administered at the dosage of 3-6 million units (MU) three times a week (tiw) for 6 months. INTERVENTIONS: The patients were randomly assigned to one of two groups of treatment: group A, natural interferon-alphaN3, 6 or 9 MU tiw, when the body weight was < 60 kg or > or = 60 kg, respectively; group B, the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day. The period of treatment was 6 months in both groups. RESULTS: Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment, and in no case was clearance of the virus from serum observed. CONCLUSIONS: In this randomized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon, oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone.
Acetylcysteine↗
HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients.
BACKGROUND/AIMS: Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotype 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. METHODS: We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors. RESULTS: Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusions were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. CONCLUSION: The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes.
Adolescent↗
HCV genotypes and breakthrough in patients treated with recombinant alpha interferon.
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Adolescent↗
"Breakthrough" during interferon therapy for chronic hepatitis C. Overview on the diagnosis, possible aetiology and recommendations for management.
A relapse of serum aminotransferase levels after complete normalisation during alpha interferon therapy for chronic hepatitis C is diagnosed as Breakthrough. Its prevalence ranges between 14% and 21% of the responders, with no significant differences between the alpha interferons. Hepatitis C virus genotype and interferon dose do not seem to represent predisposing factors. The development of neutralising antibodies to interferon is associated with Breakthrough in about half of the patients; other aetiologic factors such as down-regulation of interferon receptors or development of virus resistance to interferon may be implicated in the remaining cases. The therapeutic switch from recombinant to lymphoblastoid alpha interferon has been demonstrated to be a successful strategy to overcome Breakthrough and to restore a complete response.
Antibody Formation↗
Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites.
Cirrhosis is associated with cardiovascular abnormalities. Scanty information is available as to whether these include left ventricle diastolic dysfunction and wall thickness increase. To this aim in 27 cirrhotic patients with tense ascites, 17 cirrhotic patients with previous episodes of ascites (not actual), and 11 controls we investigated by echocardiography and echocolor Doppler left ventricle diastolic function (E wave, A wave, E/A ratio, deceleration time of E wave), systolic function (ejection fraction), and wall thickness (left ventricle posterior wall thickness + interventricular septum thickness) along with neurohumoral variables. All measurements (supine position) were repeated after total paracentesis (10.7 +/- 0.6 L of ascites) in ascitic patients. Both in patients with and without ascites E/A ratio was reduced as compared with controls (0.93 +/- 0.07 and 0.97 +/- 0.06 vs. 1.18 +/- 0.08, P < .05) while left ventricle wall thickness was increased (18.6 +/- 0.6 and 20.1 +/- 0.8 vs. 17.2 +/- 0.7, P < .05 and P < .01, respectively), irrespective of the postviral or alcoholic cause of liver disease. In all cirrhotics both right and left atrial and right ventricle diameters were significantly greater. Ejection fraction was slightly but significantly (P < .01) reduced in ascitic patients. Paracentesis induced a reduction of the highly increased basal plasma renin activity, aldosterone, norepinephrine (P < .01), and epinephrine (P < .05) and improved diastolic function (E/A, P < .05). Systolic function was unaffected. Thus, irrespective of ascites and cause, advanced cirrhosis is associated with left ventricle diastolic dysfunction and wall thickness increase. We can speculate that neurohumoral overactivity, known to stimulate cardiac tissue growth, may challenge the heart, promoting fibrosis and exerting a further hindrance to ventricular relaxation in patients with cirrhosis experiencing episodes of ascites.
Aged↗
Prevalence of breakthrough in chronic hepatitis C patients undergoing antiviral therapy: role of type and schedule of alpha interferon C.H.S.G.
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Antiviral Agents↗
Antibodies to interferon (IFN) in hepatitis C patients relapsing while continuing recombinant IFN-alpha2 therapy.
A number of trials have demonstrated that IFN-alpha is effective in chronic hepatitis C virus infection. It is known, however, that a number of chronic hepatitis C patients experience, after an initial response to IFN, disease reactivation or relapse (also called 'breakthrough') while IFN therapy is still ongoing. Since in a number of clinical conditions a significant correlation between development of antibodies to IFN and failure of therapy has been established, we addressed the possibility that the development of antibodies to IFN may take part in the relapse occurring in hepatitis C patients during recombinant IFN-alpha (rIFN-alpha) therapy. The prevalence of neutralizing (NA) and binding antibodies (BA) to rIFN-alpha2 has been evaluated in 45 patients with chronic hepatitis C treated with rIFN-alpha2a who first normalized aminotransferase (ALT) levels, and subsequently showed disease reactivation while on treatment. The presence of NA and BA was tested before therapy, during the response to IFN treatment, and at the time when ALT started to rise again to abnormal levels. The results showed that no patients had detectable antibodies to IFN before therapy and during the period of response to the therapy, while most of them (88.9%) developed NA and/or BA to IFN-alpha2 concomitantly with disease reactivation. In particular, in 29 of the 45 patients (64.4%) ALT normalized on treatment and rose to abnormal levels when NA appeared in their serum, while in 11 of the 16 (68.8%) remaining patients the relapse was associated with BA development. The frequency of seroconversion in these patients is significantly higher than that observed in the control group. These data indicate that antibodies to IFN may be responsible for breakthrough in the majority of patients showing disease reactivation while rIFN-alpha therapy is still ongoing.
Adolescent↗
Iron stores, response to alpha-interferon therapy, and effects of iron depletion in chronic hepatitis C.
We studied 81 patients with chronic hepatitis C to investigate the relationship between iron and alpha-interferon response. Sixty-one patients (group A) were given alpha-interferon irrespective of iron status, whereas 20 (group B) with iron overload, were iron depleted before alpha-interferon therapy. In group A, 21 patients responded to alpha-interferon and 40 were non-responders. Increased iron indices were significantly more frequent in non-responders than responders. Multivariate analysis showed that among the independent variables evaluated, only gamma-GT and liver iron concentration predicted therapy outcome. After phlebotomy treatment, serum alanine aminotransferase fell significantly both in patients of group B (196 +/- 122 IU/l vs 82 +/- 37 IU/l, p < 10(-6)) and in 12 non-responders of group A (198 +/- 89 IU/l vs 107 +/- 81 IU/l, p < 10(-6)). In 16 iron depleted patients, eight from each group, subsequent treatment with alpha-interferon produced a response in only one patient. These results suggest that increased liver iron is a negative prognostic factor for alpha-interferon response in chronic hepatitis C. Iron depletion had a beneficial effect on serum alanine aminotransferase in all the patients treated, but did not improve the response to alpha-interferon.
Adult↗