Giovanni L. Ricci

Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48‐week treatment. Patients (n = 696) received peginterferon alfa‐2a, 180 mg/week, or peginterferon alfa‐2b, 1.5 mg/kg/week, plus ribavirin, 1000‐1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV‐RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8‐51.4] of the patients in the standard group and in 48.8% (CI 44.2‐53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (HEPATOLOGY 2007.)

Determinants of relapse after a short (12 weeks) course of antiviral therapy and re‐treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection

In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24‐week course of therapy. RVR patients received pegylated interferon (Peg‐IFN) alfa‐2b (1.5 μg/kg) and ribavirin (1000‐1200 mg/day) for 12 weeks; those who relapsed were re‐treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1‐85.8) attained SVR, and 67 (14.1%, CI 10.4‐16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm3 [odds ratio, 2.51; confidence interval (CI), 1.49‐4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03‐2.70) were independently associated with relapse. Forty‐three of 67 patients with relapse agreed to be re‐treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI. (HEPATOLOGY 2008.)

A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C.

Summary.  We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG‐IFN) α‐2a or conventional IFN α‐2a would improve sustained virological response (SVR) rates over dual therapy with IFN α‐2a and RBV in patients with chronic HCV infection. A total of 362 treatment‐naïve patients were randomized to 48 weeks of treatment with: PEG‐IFN α‐2a 180 μg/week (group A) or IFN α‐2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow‐up. At the end of therapy, 74.4% (95% CI 0.66–0.82) of patients in group A were HCV RNA‐negative compared with 42.5% (95% CI 0.33–0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40–0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53–0.56), 33.3% (95% CI 0.25–0.41) and 44.6% (95% CI 0.36–0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG‐IFN, female gender and age. In treatment‐naïve patients with chronic hepatitis C, triple therapy with PEG‐IFN α‐2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN α‐2a.

Acute and long‐term effects of inhaled iloprost in portopulmonary hypertension

Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 μg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 μg/day) for more than 1 year. The 6‐minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; −16% ± 8%, P < 0.001) and pulmonary vascular resistance (−18% ± 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long‐term evaluation, iILO improved FC by 1 or more in 7 patients (P = 0.04) and increased 6MWD by 67 ± 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long‐term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition. Liver Transpl 16:348–356, 2010.

Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3

BACKGROUND & AIMS The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established. METHODS Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration. RESULTS At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25). CONCLUSIONS HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks.

Amantadine and interferon in the combined treatment of hepatitis C virus in elderly patients

Background: Treatment of hepatitis C virus (HCV) infection with interferon (IFN) in older patients may not be feasible on account of side effects: we, therefore, attempted combined treatment with amantadine hydrochloride (AH) in order to improve not only the flu-like symptoms associated with IFN but also the anti-viral effect. Methods: Patients over 65 years of age, (n=165), who had failed to eradicate HCV infection after previous treatment with IFN were randomized into three groups and treated for 12 months, group A received AH 100 mg twice per day; group B received IFNalpha-n(3) 6 M units every other day for 3 months followed by 3 MU and group C the same dose of IFNalpha-n(3), as in B, and AH 200 mg per day. Results: Group A, 42 patients agreed to undergo treatment (genotype 1b n=39); at the end of treatment 21 patients (50%) had normal ALT and seven (17%) negative polymerase chain reaction (PCR). HCV-RNA was not detectable in seven patients at the sixth month follow-up and in six (14%) after 23plus minus2 months. Group B, 39 patients accepted the treatment (genotype 1b n=31); at the end of treatment, 17 patients (44%) had normal ALT and 13 negative PCR (13%). HCV-RNA was not detectable in nine patients (23%) at the sixth month of follow-up and in eight (21%) after 22plus minus4 months. Group C, 38 patients accepted the treatment (genotype 1b n=32); at the end of treatment, 20 (53%) patients had normal ALT and 15 negative PCR (39%). HCV-RNA was not detectable in 15 patients at the sixth month follow-up and in 11 after 21plus minus4 months (29%). Forty-six patients did not accept the scheme of treatment and 26 of them had a follow-up of 20plus minus3 months. HCV-RNA copies and prevalence of genotype 1b were comparable to the treated groups: HCV-RNA was fluctuating or unchanged during the entire follow-up. Conclusions: AH associated with IFN was able to improve the negativization of HCV-RNA and sustained response to IFN and decreased the malaise associated with IFN; an increase in viral copies was observed under AH in about 40%.

Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension

The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI2), and to investigate the acute effects of the oral vasodilator isosorbide‐5‐mononitrate (Is‐5‐MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI2 (2–12 μg/kg/minute) and 8 were tested with Is‐5‐MN (20–40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI2 elicited greater reductions in PAP (11.8%) and PVR (−24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is‐5‐MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI2 and Is‐5‐MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value ≤35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one‐third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI2 is more suitable than NO in PoPH. Is‐5‐MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI2. Liver Transpl 13:1506–1514, 2007.

Multiple viral infections in a group of intravenous drug users: hepatitis B virus exposure is the risk factor.

Objective Infection with hepatotropic viruses is associated with a variable degree of liver disease, and there is evidence that more severe lesions are related to the association with another viral infection. The aim of this investigation is to establish the relationship between different viral infections occurring in the same individual and the presence and progression of liver disease. Design The study population comprises 754 intravenous (IV) drug abusers exposed to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or cytomegalovirus (CMV). All individuals were followed for an average of 2 years. Liver disease was assessed by liver function tests, 99m-technetium (99mTc) liver scintigraphy, and also by liver biopsy in a subset (n = 136) of patients. The different viral patterns and presence of disease were analysed by logistic regression, and the risk factors were calculated. Contingency tables of patients with single or associated infections were drawn up to evaluate progression of liver disease. Results Association of HIV with at least one other viral infection was constant. Surface antigens of HBV (HBsAg) were always associated with HIV (n = 19); in this group, 18 patients had signs of liver disease. A past infection with HBV, as revealed by the presence of at least antibodies against the surface antigen (HBsAb) and antibodies against the core antigen of HBV (HBcAb), was detected in 463 patients (61.4%). The overall prevalence of HCV antibodies was 63.91% (n = 482). In 96.8% of the 406 patients tested, HCV-RNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The majority of patients with high alanine transaminase (ALT) had anti-HBV antibodies in the presence of HCV (56.1%). At the end of follow-up, all of these patients showed signs of active liver disease, and scoring was significantly worse than in patients with either HBV or HCV alone. An infection/reactivation of CMV was found in patients previously exposed to HBV and with increased ALT values. Conclusions Data emerging from this study reveal the association of HCV or CMV, or both, with a previous HBV infection, as demonstrated by HBsAb and HBcAb, and rapid progression of the disease in this group of patients. A previous HBV infection therefore appears to be an important risk factor for subsequent viral-related liver disease.

Patterns of chronic hepatitis B in Central Italy: a cross-sectional study.

We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of HBsAg-positive patients, in Central Italy, by collecting a screening form with demographic, clinical and laboratory data. Overall, 737 HBsAg-positive cases were included (70% male; median age 52 years): 30% were inactive HBsAg carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-related cirrhosis. Patients from non-European Union (EU) countries (n = 65) were significantly younger, had a higher prevalence of HBeAg-positive infection and hepatitis delta virus (HDV) co-infection than patients of Italian origin. Therefore, as immigration from non-EU countries continues to grow, we can expect a change in the landscape of HBV-related disease in our area.

Leucopenia is a side effect of combination therapy for hepatitis C infection

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