G.B. Gaeta

Tamoxifen in treatment of hepatocellular carcinoma: A randomised controlled trial

BACKGROUND Results from small randomised trials on tamoxifen in the treatment of hepatocellular carcinoma (HCC) are conflicting. We studied whether the addition of tamoxifen to best supportive care prolongs survival of patients with HCC. METHODS Patients with any stage of HCC were eligible, irrespective of locoregional treatment. Randomisation was centralised, with a minimisation procedure accounting for centre, evidence of disease, and time from diagnosis. Patients were randomly allocated best supportive care alone or in addition to tamoxifen. Tamoxifen was given orally, 40 mg per day, from randomisation until death. RESULTS 496 patients from 30 institutions were randomly allocated treatment from January, 1995, to January, 1997. Information was available for 477 patients. By Sept 15, 1997, 119 (50%) of 240 and 130 (55%) of 237 patients had died in the control and tamoxifen arms, respectively. Median survival was 16 months and 15 months (p=0.54), respectively. No differences were found within subgroups defined by prognostic variables. Relative hazard of death for patients receiving tamoxifen was 1.07 (95% CI 0.83-1.39). INTERPRETATION Our findings show that tamoxifen is not effective in prolonging survival of patients with HCC.

Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients.

OBJECTIVE The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. METHODS Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. RESULTS An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. CONCLUSION Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

Hepatic resection and percutaneous ethanol injection as treatments of small hepatocellular carcinoma. A Cancer of the Liver Italian Program (CLIP 08)retrospective case-control study

Background Patients with small hepatocellular carcinoma (HCC) are usually treated with hepatic resection or percutaneous ethanol injection (PEI). Goals To compare the effects of hepatic resection versus PEI on survival in a matched case–control study. Study Patients with single-nodule HCC (≤5 cm) who were treated with hepatic resection (cases) or PEI (controls) were eligible. Matching criteria were date of diagnosis, Child–Pugh stage, and age at diagnosis. Kaplan–Meier survival curve of the control group was drawn weighing each stratum by the inverse of its size. Treatments were compared by a stratified Coxs model, adjusted by CLIP score. Results Of 912 patients, 197 were eligible and 82 (17 cases and 65 controls) were matched, creating 17 strata. Nine (53%) cases and 41 (63%) controls died. Cox model showed no survival difference between the two groups; hazard ratio of PEI versus hepatic resection was 1.04 (95% CI = 0.43–2.52). One- and 3-year survival rates in the hepatic resection and PEI groups were 82% versus 91% and 63% versus 65%, respectively. Conclusions Patients with small HCC treated with hepatic resection or PEI have similar survival rates. In view of the higher cost and morbidity of hepatic resection, a prospective randomized study is warranted.

Does an 'autoimmune' profile affect the clinical profile of chronic hepatitis C? An Italian multicentre survey.

Summary.  Nonorgan‐specific autoantibodies (NOSA) are common in patients with chronic hepatitis C virus infection. It is unclear whether serological markers of autoimmunity segregate in a cohort of cases with more severe liver damage. We assessed the relationship between NOSA and demographic, biochemical and histological features in 502 subjects with anti‐HCV positive, HCV‐RNA positive, HBsAg negative chronic hepatitis consecutively referred to four Italian liver units. Percutaneous liver biopsy was performed in all subjects. A single pathologist scored the biopsies using histology activity index classification. The overall prevalence of positivity for any NOSA was 36.9%. Antinuclear antibodies, anti‐smooth muscle antibodies, and anti‐liver/kidney microsomal antibodies were found in 15.7, 27.3 and 2.2% of cases. Multivariate analysis showed that γ‐globulin >2 g/dL was the only independent predictor of the likelihood of NOSA positivity (OR, 2.1; 95% CI, 1.3–3.4). No other clinical (age, gender, ALT, HCV genotype) or histological features (grading and staging score, bile ductular damage) were linked to NOSA. Antiviral therapy in 155 subjects with NOSA did not cause any adverse events related to autoimmunity during and after treatment. The presence of NOSA in patients with chronic HCV hepatitis is not related to specific demographic features and has no impact on the biochemical and histological profile of the liver disease at presentation and the response to antiviral treatment.

Management of infections in cirrhotic patients: Report of a Consensus Conference

The statements produced by the consensus conference on infection in end-stage liver disease promoted by the Italian Association for the Study of the Liver, are here reported. The topics of epidemiology, risk factors, diagnosis, prophylaxis, and treatment of infections in patient with compensated and decompensated liver cirrhosis were reviewed by a scientific board of experts who proposed 26 statements that were graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. By systematic literature search of available evidence, comparison and discussion of expert opinions, pertinent statements answering specific questions were presented and approved. Short comments were added to explain the basis for grading evidence particularly on case of controversial areas.

Hepatitis C virus infection in households of anti-HCV chronic carriers in Italy: A multicentre case-control study

To test the hypothesis that households of anti-HCV positive subjects might be at increased risk of HCV infection, a case-control study was carried out comparing 518 family members of 205 anti-HCV positive subjects (index carriers) with 281 family members of 100 anti-HCV negative subjects (index controls), consecutively observed in ten gastroenterology units in different Italian regions. The index carriers were age and sex matched to the index controls and their households were similar with respect to the main sociodemographic characteristics. Anti-HCV antibodies were found in 6.9% (36/518) of household members of index carriers and in 3.2% (9/281) of household members of index controls (p<0.05). The results of multiple logistic regression analysis showed that being over 50 years of age was the sole independent predictor for a household contact of the likelihood of being anti-HCV positive (O.R. 3.6; C.I. 95%=1.5−8.2). Being in the household of an anti-HCV index carrier was marginally associated to anti-HCV positivity (O.R. 2.0; C.I. 95%=0.9−4.6). No association was found for sex, area of residence, family size, lowest level of schooling, or any type of family relationship. These findings are not in compliance with the statement that household contacts of HCV carriers are at increased risk of HCV infection. The 3.2% anti-HCV prevalence rate observed among household contacts of anti-HCV negative index controls may suggest that the true anti-HCV prevalence in the general population in Italy is nearly 2.5 times as high as the 1.3% found in Italian blood donors.SummaryTo test the hypothesis that households of anti-HCV positive subjects might be at increased risk of HCV infection, a case-control study was carried out comparing 518 family members of 205 anti-HCV positive subjects (index carriers) with 281 family members of 100 anti-HCV negative subjects (index controls), consecutively observed in ten gastroenterology units in different Italian regions. The index carriers were age and sex matched to the index controls and their households were similar with respect to the main sociodemographic characteristics. Anti-HCV antibodies were found in 6.9% (36/518) of household members of index carriers and in 3.2% (9/281) of household members of index controls (p<0.05). The results of multiple logistic regression analysis showed that being over 50 years of age was the sole independent predictor for a household contact of the likelihood of being anti-HCV positive (O.R. 3.6; C.I. 95%=1.5−8.2). Being in the household of an anti-HCV index carrier was marginally associated to anti-HCV positivity (O.R. 2.0; C.I. 95%=0.9−4.6). No association was found for sex, area of residence, family size, lowest level of schooling, or any type of family relationship. These findings are not in compliance with the statement that household contacts of HCV carriers are at increased risk of HCV infection. The 3.2% anti-HCV prevalence rate observed among household contacts of anti-HCV negative index controls may suggest that the true anti-HCV prevalence in the general population in Italy is nearly 2.5 times as high as the 1.3% found in Italian blood donors.

Interferon-α plus amantadine in chronic hepatitis C resistant to interferon alone: a pilot randomized study

The optimal therapy for patients with chronic hepatitis C who have not responded to interferon (IFN) is still an unsolved issue. The aim of this study was to evaluate the efficacy and tolerability of a high dose of IFN‐α2a plus amantadine for chronic hepatitis C patients who were non‐responders to a previous course of IFN.

Who is more likely to respond to dual treatment with pegylated‐interferon and ribavirin for chronic hepatitis C? A gender‐oriented analysis

We assessed, in real‐life practice, viral, demographic, genetic and metabolic factors influencing the sustained virologic response (SVR), with a gender‐oriented analysis, in patients with chronic hepatitis C virus (HCV) treated with pegylated interferon and ribavirin. Six hundred and seventy naïve patients were treated with dual therapy and evaluated by gender and HCV genotype. Associations between baseline variables and SVR were assessed by multivariate logistic regression analysis. Among 362 genotype 1 patients, SVR was achieved in 158 patients (44%), and SVR was independently associated with age less than 50 years (OR 2.12; 95% CI 1.09–4.30; P = 0.039) and C/C genotype rs12979860 SNP (OR 2.83; 1.19–6.74; P = 0.002) in 163 females, while absence of visceral obesity (OR 2.491; 1.131–5.487; P = 0.023), HCV‐RNA lower than 400 000 IU/mL (OR 2.66; 1.273–5.558; P = 0.009) and C/C genotype rs12979860 SNP (OR 4.969; 2.401–10.283; P < 0.001) were independently associated with SVR in 199 males. Combining favourable baseline variables, the probability of obtaining SVR ranged from 27.6% to 84.2% in females, and from 14.3% to 85.7% in males. The rate of SVR was 81.1% in 175 genotype 2 patients, and 69% in 100 genotype 3 patients. Rapid virologic response was the only valid predictor of SVR regardless of other features. In conclusions, in the setting of HCV genotype 1, chronic hepatitis, combining rapid virologic response and predictive factors, which are different for females and males, allows clinicians to single out a group of patients whose likelihood of SVR exceeds 80%. For these patients, triple therapy with first‐generation protease inhibitors may be unwarranted.

Severe polymyositis due to Toxoplasma gondii in an adult immunocompetent patient: a case report and review of the literature.

Toxoplasmosis, a worldwide zoonosis caused by a coccidian parasite Toxoplasma gondii, is more often asymptomatic in immunocompetent patients. We report the case of a 38-year-old immunocompetent male with a polymyositis as the presenting manifestation of T. gondii infection. The patient was hospitalized for a 30-day history of fever (T max 39.5°C), muscle pain, and progressive weakness of the muscles. A diagnosis of polymyositis was made, and he was started on corticosteroid treatment, which caused no reduction of symptoms. After finding a positive polymerase chain reaction (PCR) assay for T. gondii, together with additional clinical findings, a diagnosis of acute toxoplasmosis was made. Specific treatment with pyrimethamine and sulfadiazine was started, with a progressive reduction of symptoms and normalization of laboratory tests.

Factors associated with access to antiviral treatment in a multicentre cross-sectional study of patients with chronic hepatitis B in Italy

Summary.  A multicentre cross‐sectional survey was performed to provide an accurate picture of patients with chronic hepatitis B (CHB) cared for by Italian Infectious Diseases Centers (IDCs). This analysis describes factors associated with access to the treatment of CHB in a country where barriers to treatment are not expected to exist because of comprehensive coverage under the National Health System (NHS). The study was performed in 74 IDCs. The analysis focused on 3305 patients with CHB of 3760 HBsAg‐positive patients enrolled from March to September, 2008. To account for missing values, a Multiple Imputation method was used. Treatment was reported in 2091 (63.3%) patients. In the multivariate analysis, an increased chance of getting treatment was independently associated with 10 years increase of age at diagnosis (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 1.1–1.3, P < 0.001), HBeAg positivity (aOR 1.8, 95% CI 1.1–2.8, P < 0.001), cirrhosis (aOR 3.6, 95% CI 2–6.3, P = 0.012), HDV (aOR 1.6, 95% CI 1.02–2.5, P = 0.042) and HIV positivity (aOR 6.5, 95% CI 4–10.8, P < 0.001). Conversely, a decreased chance was associated with female gender (aOR 0.6, 95% CI 0.5–0.7, P < 0.001), immigration (aOR 0.6, 95% CI 0.5–0.9, P = 0.009), alcohol consumption (aOR 0.7, 95% CI 0.5–0.98, P = 0.04) and HCV positivity (aOR 0.5, 95% CI 0.3–0.8, P = 0.005). Our study shows that Italian IDCs treat a high percentage of patients with CHB. Nevertheless, disparities exist which are not related to the severity of disease limiting access to antiviral therapy of CHB, even in a country with a universal healthcare system.