Bruno Cacopardo

Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C.

OBJECTIVES:Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its accuracy for milder stages of fibrosis is much less satisfactory. The objective of this study was to compare the performance and the discordance rate of acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of chronic hepatitis C (CHC) patients.METHODS:One hundred thirty-nine consecutive patients with CHC were enrolled in two tertiary centers, and evaluated for histological (Metavir score) and biochemical features. All patients underwent TE and ARFI.RESULTS:TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI invalid measurements recorded (P=0.029). By area under receiver operating characteristic curve (AUROC), the best cutoff values for TE and ARFI for significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s (AUROC: 0.86), respectively. For severe fibrosis (F3–F4), these cutoff values were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at ≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis (P=0.024 and P=0.002, respectively), while this difference was only marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance results significantly higher for all three stages of fibrosis. The average concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%, respectively. By multivariate analysis, ARFI was not associated with alanine aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis, while TE was significantly correlated with the ALT value (P=0.027).CONCLUSIONS:In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.

Hepatic echinococcosis: Clinical and therapeutic aspects

Echinococcosis or hydatid disease (HD) is a zoonosis caused by the larval stages of taeniid cestodes belonging to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoccus multilocularis (E. multilocularis) and Echinococcus granulosus (E. granulosus) infection, respectively. Cystic echinococcosis (CE) has a worldwide distribution, while hepatic alveolar echinococcosis (AE) is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the pericyst; old cysts typically present internal septations and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration (PAIR)] and more effective drugs (such as benzoimidazoles) have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis.

Slower Progression of HIV-1 Infection in Persons with GB Virus C Co-Infection Correlates with an Intact T-Helper 1 Cytokine Profile

Context Patients infected with HIV-1 progress to AIDS more slowly if they are co-infected with hepatitis G virus, also called GB virus C (GBV-C), than if they are not. The mechanism of this effect of GBV-C infection is not known. Contribution Among 80 asymptomatic HIV-1infected patients, T-helper 1 cytokine profiles changed unfavorably in those without GBV-C infection and remained stable in those with GBV-C infection. Implications Co-infection with GBV-C may slow progression of HIV-1 infection through a mechanism related to T-helper 1 cytokines. The Editors Hepatitis G virus, also called GB virus C (GBV-C), is a recently identified RNA virus belonging to the Flaviviridae family (1, 2). It is usually transmitted parenterally (2, 3). The prevalence of GBV-C viremia ranges from 20% to 24% among persons who use intravenous drugs (4, 5). Higher rates have been seen in patients with HIV-1 infection, regardless of intravenous drug use (4, 6). In recent surveys, HIV-1infected persons with GBV-C co-infection had better AIDS-free survival rates and higher CD4+ cell counts than HIV-1infected patients who were GBV-C negative (7-10). It has also been shown that GBV-C inhibits HIV-1 replication in vitro (11). Our objective was to evaluate AIDS-free survival rates, plasma HIV-1 viral load, and selected immunologic variables in 80 HIV-1seropositive patients with and without GBV-C co-infection. We sought to determine possible immunologic mechanisms involved in these co-infection scenarios. Methods The study was initiated between January and March 1989 at the Institute of Infectious Diseases, University of Catania, Catania, Italy. Institutional review boards at the Institute of Infectious Diseases, University of Catania, approved the follow-up protocol. Signed informed consent was obtained from each patient. Among 319 HIV-1seropositive patients, 240 used intravenous drugs, 60 were homosexual men, and 19 had received many blood transfusions. Eighty of these 319 patients (25%), all of whom used intravenous drugs, were asymptomatic and were enrolled in a prospective follow-up study to evaluate the progression of HIV-1related disease. All 80 patients underwent physical examination and routine blood biochemistry examinations every 6 months. Blood samples were obtained annually from each patient, and serum was stored at 80 C until use. The analyses for the current study were begun in January 1997. Quantitative plasma HIV-1 RNA levels and circulating levels of specific interleukins (ILs)IL-2, IL-4, IL-10, and IL-12were retrospectively determined in all serum samples. We determined GBV-C RNA levels in all serum specimens collected at the beginning of the study and at the end of follow-up. Analyses were repeated in January 2001. Anti-E2 antibodies were detected by using the Enzymun-Test Anti-HGenv (Boehringer Mannheim Corp., Indianapolis, Indiana). Plasma HIV-1 RNA copy numbers were determined by using the nucleic acid sequence-based amplification method (NASBA, Organon Teknika, Boxtel, the Netherlands). The sensitivity limit of the assay was 400 copies/mL. Interleukin-2 was analyzed by using a quantitative enzyme immunoassay (Predicta, Genzyme Diagnostics, Cambridge, Massachusetts) with a sensitivity limit of 4 pg/mL. Interleukin-4 was tested by using a quantitative enzyme immunoassay (InterTest, Genzyme Diagnostics) with a sensitivity limit of 0.045 ng/mL. Interleukin-10 was measured by using a competitive enzyme immunoassay (Cytokit Red 10, Genzyme Diagnostics), which had a range of detection between 0.195 and 200 ng/mL. Interleukin-12 levels were determined by using an enzyme immunoassay provided by R&D Systems (Oxon, United Kingdom) that had a lower sensitivity limit of 5 pg/mL. We measured GBV-C RNA level by using reverse transcriptase polymerase chain reaction, as described elsewhere (12). Statistical Analysis Plasma HIV-1 RNA levels were logarithmically transformed to normalize their distribution. Categorical variables were analyzed by using the Fisher exact test. The group means were compared by using the Student t-test. Variations of all interim values of plasma HIV-1 RNA level, CD4+ cell count, and IL levels were analyzed within each group by using two-way analysis of variance. We compared GBV-C RNApositive and GBV-C RNAnegative groups by using the MannWhitney U test to examine percentage variations from baseline values to values at the end of follow-up. Curves reflecting variations by time in immunologic and virologic variables were compared by using univariate repeated-measures analysis that followed an analysis-of-variance structure (13). Progression to AIDS was defined as the development of an opportunistic infection or malignant condition. We used the Kaplan-Meier method to evaluate the effect of GBV-C infection on AIDS-free survival by assuming that GBV-C and HIV-1 infection status was fixed at the beginning of follow-up. A P value less than 0.05 was considered statistically significant. Statistical analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no direct control over the analysis of the study. Results The mean age of the study patients (SD) was 24.6 2.2 years. Fifty-two patients were men, and 28 were women. Mean duration of intravenous drug use (SD) was 24.2 1.8 months, and mean duration of known HIV-1 seropositivity (SD) was 9.2 1.6 months. The mean baseline CD4+ cell count (SD) was 471 55 109 cells/L. Fifty-eight patients declined to take any antiretroviral drug, and 6 were treated with zidovudine alone throughout the follow-up period. In 16 patients, didanosine was added to zidovudine, starting in 1993. In January 1997, follow-up was interrupted and all 80 patients began to receive different highly active antiretroviral therapy (HAART). At this time, 6 patients were asymptomatic, 24 had stage B disease, and 50 had stage C disease, according to stages defined by the U.S. Centers for Disease Control and Prevention. At the end of follow-up, the mean CD4+ cell count (SD) was 77 33 109 cells/L. Seventeen of the 80 serum specimens collected at the beginning of follow-up (21%) were positive for GBV-C RNA. All of these 17 patients maintained GBV-C viremia to the end of the follow-up period, and none of the 63 patients who were GBV-C RNA negative acquired the infection. Patients who were GBV-C negative and those who were GBV-C positive did not significantly differ in age, sex, duration of intravenous drug use and HIV-1 seropositivity, or rate of hepatitis C virus and hepatitis B virus infection (Table). Table. Epidemiologic and Virologic Variables Measured at Baseline and at the End of Follow-up Clinical Outcomes At the end of the 8-year follow-up, 3 of 17 GBV-Cpositive patients (18%) remained asymptomatic (stage A), 7 (41%) had stage B disease, and 7 (41%) had stage C disease. In the 7 patients with stage C disease, the following AIDS-defining diseases were observed: AIDS dementia complex (n = 7 [100%]), Pneumocystis carinii pneumonia (n = 4 [57%]), esophageal candidiasis (n = 3 [43%]), and Toxoplasma encephalitis infection (n = 1 [14%]). Three of 63 GBV-C RNAnegative patients (5%) had stage A disease, 17 (27%) had stage B disease, and 43 (68%) had stage C disease. Among those with stage C disease, the following diseases were observed: P. carinii pneumonia (n = 18 [42%]), esophageal candidiasis (n = 11 [26%]), Toxoplasma encephalitis infection (n = 5 [12%]), cryptococcal meningitis (n = 4 [9%]), intestinal cryptosporidiosis (n = 3 [7%]), Kaposi sarcoma (n = 2 [5%]), AIDS dementia complex (n = 2 [5%]), and disseminated cytomegalovirus disease (n = 1 [2%]). According to Kaplan-Meier curves showing progression to AIDS in HIV-1infected persons, cumulative AIDS-free survival rates at 24 and 48 months, respectively, were 0.5 (95% CI, 0.3 to 0.6) and 0.4 (CI, 0.3 to 0.5) in the GBV-Cnegative group and 0.9 (CI, 0.7 to 1.0) and 0.7 (CI, 0.5 to 0.9) in the GBV-Cpositive group (P = 0.02 for between-group comparisons). Mean AIDS-free survival time was 73 months (CI, 59 to 87 months) among GBV-Cpositive persons and 45 months (CI, 35 to 54 months) among GBV-Cnegative persons. Immunologic and Virologic Evaluations The Figure shows the cross-sectional averages of IL levels, CD4+ cell counts, and HIV RNA levels during the follow-up period. Annual plasma HIV-1 RNA levels significantly increased during follow-up in both the GBV-Cnegative and GBV-Cpositive groups, whereas CD4+ cell counts significantly decreased (P < 0.01 for all comparisons). In the GBV-Cnegative group, IL-4 and IL-10 levels increased significantly from baseline (P = 0.01 and P = 0.004, respectively) but IL-2 and IL-12 concentrations decreased significantly throughout the entire follow-up period (P = 0.005 and P = 0.01, respectively). In contrast, in the GBV-Cpositive group, none of the measured cytokine levels changed significantly during follow-up. The Table shows the percentage variation from baseline to the end of follow-up in plasma HIV-1 RNA levels, CD4+ cell counts, and cytokine concentrations between the two groups. Figure. Cross-sectional averages of interleukin ( IL ) levels, CD4+ cell counts, and HIV-1 RNA levels in GB virus C ( GBV-C )-positive and GBV-Cnegative patients during 8 years of follow-up. P P Response to HAART In January 1997, all 80 patients began taking HAART. Among the 17 GBV-Cpositive patients, 10 received zidovudine, lamivudine, and saquinavir and 7 received zidovudine, lamivudine, and indinavir. Among the 63 GBV-Cnegative patients, 20 were treated with zidovudine, lamivudine, and saquinavir; 20 were treated with zidovudine, lamivudine, and indinavir; 13 were treated with zidovudine, didanosine, and indinavir; and 10 were treated with zidovudine, lamivudine, and ritonavir. Fourteen patients, 2 in the GBV-Cpositive group and 12 in the GBV-Cnegative group, stopped taking HAART between 1997 and 2001 because of personal preference, lack of adh

A Placebo-Controlled Treatment Trial of Blastocystis hominis Infection with Metronidazole

Blastocystis hominis, previously considered a harmless yeast, is now classified as a protozoan inhabiting the human intestinal tract. The pathogenicity of B. hominis remains controversial and is currently the subject of extensive debate.1- 5 As a result of the uncertainty surrounding the pathogenic role of B. hominis, large-scale treatment trials of B. hominis infection have so far been lacking. In spite of this, several drugs have been reported to be active against the parasite.6-8 The present study was carried out in order to evaluate the efficacy of metronidazole treatment in inducing clinical remission and parasitologic eradication in immunocompetent individuals with B. hominis as the only evident cause of diarrhea.

Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard

PURPOSE Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. The aims of this study were to describe HCC tumor characteristics and different therapeutic approaches, to evaluate patient survival time from HCC diagnosis, and to identify clinical prognostic predictors in patients with and without HIV infection. PATIENTS AND METHODS A multicenter observational retrospective comparison of 104 HIV-infected patients and 484 uninfected patients was performed in four Italian centers. HCC was staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria. RESULTS Tumor characteristics of patients with and without HIV were significantly different for age, Eastern Cooperative Oncology Group performance status (PS) score ≤1, and etiology of chronic liver disease. Despite the similar potentially curative option rate and better BCLC stage at diagnosis, the median survival time was significantly shorter in HIV(+) patients. HIV(+) patients were less frequently retreated at relapse. Independent predictors of survival were: BCLC stage, potentially effective HCC therapy, tumor dimension ≤3 cm, HCC diagnosis under a screening program, HCC recurrence, and portal vein thrombosis. Restricting the analysis to HIV(+) patients only, all positive prognostic factors were confirmed together with HAART exposure. CONCLUSION This study confirms a significantly shorter survival time in HIV(+) HCC patients. The less aggressive retreatment at recurrence approach does not balance the benefit of younger age and better BCLC stage and PS score of HIV(+) patients. Thus, considering the prognosis of HIV(+) HCC patients, effective screening techniques, programs, and specific management guidelines are urgently needed.

Acute hepatitis E in Catania (eastern Sicily) 1980-1994. The role of hepatitis E virus.

SummaryBetween 1980 and 1994, 540 patients with acute viral hepatitis were admitted to hospital at the Department of Infectious Diseases of Catania (eastern Sicily). Twenty-five patients out of 540 were assessed as having non-A, non-B, non-C hepatitis. These subjects were studied for anti-HEV IgM and IgG seroprevalence by testing serial serum samples collected 1, 4, 12 and 24 weeks after the onset of acute disease. Fourteen of 25 samples (56%) seroconverted to anti-HEV IgG antibodies. No sample was positive for anti-HEV IgG at week 1, ten samples were positive at week 4 and the remainder at week 12. Anti-HEV reactivity was maintained until week 24 in all cases. In 11 of the 14 patients seroconverting to anti-HEV, the presence of IgM anti-HEV was found, which appeared in the sample from week 1 and gradually disappeared thereafter. Identified risk factors for HEV transmission included travel in the tropics and shellfish ingestion (anti-HEV positive versus anti-HEV negative: p<0.05). HEV-related hepatitis is not yet a major public health problem in Sicily but, from our data, the trend of its incidence is clearly upwards. The high incidence of faecally-orally transmitted diseases in Sicily, the crucial position of Sicily in the middle of the Mediterranean Sea (where HEV largely circulates) and the increase of migration from developing countries are all factors which should increase awareness for a more active surveillance of the spread of HEV in our area.

Microbial Translocation in Chronic Liver Diseases

The intestinal microflora is not only involved in the digestion of nutrients, but also in local immunity, forming a barrier against pathogenic microorganisms. The derangement of the gut microflora may lead to microbial translocation, defined as the passage of viable microorganisms or bacterial products (i.e., LPS, lipopeptides) from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites. The most recent evidence suggests that microbial translocation (MT) may occur not only in cirrhosis, but also in the early stage of several liver diseases, including alcoholic hepatopathy and nonalcoholic fatty liver disease. Different mechanisms, such as small intestinal bacterial overgrowth, increased permeability of intestinal mucosa, and impaired immunity, may favor MT. Furthermore, MT has been implicated in the pathogenesis of the complications of cirrhosis, which are a significant cause of morbidity and mortality in cirrhotic subjects. Therapeutic strategies aiming at modulating the gut microflora and reducing MT have focused on antibiotic-based options, such as selective intestinal decontamination, and nonantibiotic-based options, such as prokinetics and probiotics. In particular, probiotics may represent an attractive strategy, even though the promising results of experimental models and limited clinical studies need to be confirmed in larger randomized trials.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Reduction of Serum Melatonin Levels in HIV-1- Infected Individuals' Parallel Disease Progression: Correlation with Serum Interleukin-12 Levels

Abstract.Background:During the natural history of human immunodeficiency virus type I (HIV-1) infection, an impairment of interleukin-12 (IL-12) production precedes a switch from a T-helper 1 (Th1) to a T-helper 2 (Th2) stage of cellular immunity. Melatonin, the main hormone produced by the pineal gland, seems to promote a Th1 response by increasing the production of IL-12 in vitro. The aim of this study was to measure and correlate serum levels of melatonin and IL-12 in a cohort of HIV-1-infected individuals.Patients and Methods:77 anti-HIV-1-positive subjects were enrolled: 20 were in CDC stage A, 25 in CDC stage B and 32 in CDC stage C. 30 healthy HIV-1-seronegative subjects were recruited as controls. IL-12 and melatonin concentrations were quantitated in serum samples.Results:Mean levels of serum melatonin were significantly lower in HIV-1-infected individuals in comparison with controls (p < 0.001). Within the HIV-1-seropositive group, mean melatonin and IL-12 concentrations were significantly lower in patients in CDC stage C, as compared with patients in CDC stages B and A (p < 0.01).Conclusion:During the natural history of HIV-1 disease, serum melatonin levels are progressively reduced. This reduction may be related to the impairment of Th1 immunoresponses.

Hepatocellular carcinoma in HIV positive patients.

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV-1-infected patients leading to increased survival and a better quality of life. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are common among HIV-1-infected subjects and represent the most important risk factors for hepatocellular carcinoma (HCC). Whether HIV plays a direct role in hepatocellular carcinoma (HCC) pathogenesis remains to be established.HCC clinical course depends on stage of cancer disease, performance status and comorbidities. Therapeutic options include liver transplantation, local antiblastic chemotherapy and biological drugs. In the HIV setting few data are available about treatment options. The increased longevity of patients with HIV imposes new strategies for prevention and therapeutic management of patients. The aim of this article is to provide an up-to-date review of HIV-related HCC in the HAART era.