Giancarlo Serra

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy

BackgroundMood and anxiety symptoms in chronic hepatitis C (CHC) may be related to the patient awareness of the diagnosis and prognosis, to side effects induced by interferon (IFN)-alpha treatment, as well as to substance abuse. However, the observation of metabolic alterations in patients with CHC has led to hypothesize a direct effect of hepatitis C virus (HCV) on brain function. This study was aimed at elucidating whether CHC is associated with specific anxiety or mood disorders independently of confounding factors.MethodsPatient cohort: consecutive patients, 135 with CHC and 76 with chronic hepatitis B (CHB). Exclusion criteria: previous treatment with IFN-alpha, co-infection with HCV and hepatitis B virus, infection with human immunodeficiency virus, drug or alcohol abuse, or malignancies. Controls: subjects without evidence of hepatitis randomly extracted from the database of a previous epidemiological study; they were divided into two groups of 540 (332 males) and 304 (220 males) as controls for patients with CHC and CHB, respectively. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified carried out by a physician according to DSM-IV criteria.ResultsA higher lifetime prevalence of major depressive disorder (MDD) was observed among CHC compared to CHB or controls. The risk of MDD was not statistically different between CHB and controls. Both the CHC and CHB groups showed a significantly higher frequency of panic disorder when compared to controls. No statistical differences were observed in the prevalence of general anxiety disorder and social phobia when CHC or CHB were compared to controls.ConclusionThe present study provides the first evidence of an association between CHC and MDD, diagnosed on the basis of well-defined international criteria. This association is independent of treatment with IFN-alpha and is not influenced by substance or alcohol abuse. By contrast, anxiety disorders do not appear to be specifically associated with CHC.

Treatment of chronic hepatitis D.

Summary.  Despite recent advances in the treatment of chronic viral hepatitis, therapy of chronic hepatitis D is not yet satisfactory. The only option currently available is interferon‐α (IFN), whose efficacy is related to the dose and duration of treatment. However, the rate of sustained hepatitis D virus (HDV) clearance after a 1‐year course with high doses of standard IFN is low. Better results have recently been reported with pegylated IFN both in IFN‐naïve and in previous nonresponders to standard IFN, suggesting the use of pegylated IFN as a first‐line therapy in chronic hepatitis D. Nucleoside analogues that inhibit hepatitis B virus (HBV) are ineffective against HDV and combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated IFN. Because the ultimate goal of treatment is eradication of both HDV and HBV, in responders IFN therapy should be continued as long as possible until the loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. However, because side‐effects are common, continuous monitoring is mandatory. Although the first results obtained with pegylated IFN have been encouraging, the rate of sustained virological response is still low and the rate of relapse high, emphasizing the need for developing novel classes of antivirals specifically interfering with the life cycle of this unique virus.

Association of chronic hepatitis C with recurrent brief depression

BACKGROUND Depressive syndromes, including recurrent brief depression (RBD), have frequently been observed in association with chronic diseases characterized by immune activation, such as autoimmune thyroiditis or celiac disease. However, the association of RBD with chronic hepatitis C (CHC), a disease with an increased incidence of major depressive disorders, is unknown. METHODS CASES 135 (83 males, 52 females) consecutive treatment-naïve patients with CHC. EXCLUSION CRITERIA previous treatment with IFN-alpha, co-infection with hepatitis C virus (HCV) and hepatitis B virus, infection with human immunodeficiency virus (HIV), drug or alcohol abuse, or malignancy. CONTROLS 540 (332 males, 208 females) subjects without evidence of hepatitis, randomly extracted from the database of a previous epidemiological study. The psychiatric diagnosis was based on the Composite International Diagnostic Interview Simplified (CIDI-S), containing a specific section on RBD. RESULTS A significantly higher rate of RBD was observed among both male and female patients with CHC (n=21, 15.5%) as compared to controls (n=34, 6.3%) (OR=2.6, CI 95% from 1.37 to 4.93). CONCLUSION The present study provides the first evidence of an association between CHC and RBD, independent of treatment with IFN-alpha and not influenced by substance or alcohol abuse. The results are similar to those found in other conditions with immune activation. RBD may be another expression of mood disorders in such conditions.

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

Background Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. Methods and Findings KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. Conclusions The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Can antiretroviral therapy modify the clinical course of HDV infection in HIV-positive patients?

BACKGROUND Infection with hepatitis delta virus (HDV) affects approximately 6-14.5% of patients coinfected with HIV-1 and HBV, showing a more aggressive clinical course compared with an HIV-negative population. There is no universally approved treatment for chronic hepatitis D (CHD) in HIV-infected patients. Antiretroviral therapy (ART) containing tenofovir has been recently associated with HDV suppression. Our aim was to evaluate whether the outcome of CHD in HIV-infected patients can be favourably influenced by ART including reverse transcriptase inhibitors. METHODS The clinical course of four HBV/HDV/HIV-coinfected patients receiving ART were retrospectively examined. RESULTS HDV RNA became undetectable in all patients after a variable period of ART along with the disappearance of hepatitis B surface antigen in two of them, and an increase in CD4(+) T-cell count. In all patients, virological changes were associated with improved liver function tests and clinical features. CONCLUSIONS We suggest that ART regimens including drugs active against HBV could have beneficial effects on the clinical course of CHD in patients with HIV-1 by favouring immunological reconstitution.

P09.19: Fetal loss and complications after genetic amniocentesis

Objectives: To evaluate the rate of preterm delivery (PTD) following late amniocentesis (>24 weeks of gestation). Methods: A retrospective cohort of all women with singleton pregnancy who underwent late amniocentesis in one tertiary center between 2005–2009, due to various indications, excluding cases of suspected amnionitis or premature rupture of membranes. Results: The initial cohort included 182 women. Pregnancy outcome was validated in 158 women who underwent amniocentesis at 24–36 weeks of gestation (mean, 31.4 ± 1.9). 13 women were excluded due to premature labor induction or cesarean section for suspected IUGR. Indications for late amniocentesis included abnormal ultrasonographic findings (n = 98), suspected intrauterine CMV or toxoplasmosis infection (n = 19), maternal age (n = 13), abnormal first or second trimester biochemical markers (n = 8) and others (n = 7). The rate of spontaneous PTD (<37 weeks) was 8.9% (13/145), mean gestational age at delivery 34.7 ± 1.3 (32–36 weeks). In only 5 (3.4%) delivery occurred ≤34 weeks of gestation. In one case (0.68%) of amniocentesis performed at 32 weeks of gestation, delivery occurred within 48 hours. In 4 cases (2.75%) delivery occurred within 10 day. The rate of PTD and mean gestational age at delivery stratified by grouped gestational age at amniocentesis is presented at Table 1. If cases of amniocentesis performed for ultrasonographic findings to rule out chromosomal abnormalities (n = 117/182), abnormal karyotype was found in 3 cases (2.56%). Conclusions: The risk of significant prematurity following late amniocentesis is low.

P16.06: Nuchal translucency and other US markers in cases of trisomy 18

(n = 134). Over a total of 134 fetuses with increased NT, karyotype was analysed in 129 cases (96,3%) and pregnancy outcome was available in 124 cases (92.5%). A chromosomal anomaly was detected in 57 fetuses (44.2%). In 72 (55.8%) fetuses, the karyotype was normal. The overall incidence of an adverse pregnancy outcome in the latter subset was 25% (18/72). Anomalies were detected, at the time of ultrasound, in 12 cases (16%) with 4 isolated cardiac defects and 8 other structural defects. Genetic syndromes occurred in 5 (6.9%) fetuses with normal karyotype. An adverse neonatal outcome was recorded in 1 case in which there were normal findings at the 20-week scan. Conclusion: After exclusion of chromosomal anomalies, 18/72 of the fetuses with increased NT had an adverse pregnancy outcome diagnosed in utero in 17/72 cases. Counselling should stress that, if the karyotype is normal and no fetal structural malformations were missed prenatally, a favourable outcome can be expected.

P26.21: Multiple congenital anomalies syndrome with urorectal septum malformation, absent radii, cerebellar vermis aplasia: case report

routine ultrasound. A bilateral renal disease with oligohydramnios was diagnosed in her first pregnancy and the baby was stillborn with Potter sequence. In the actual pregnancy the ultrasound done at 26 + 4 weeks of gestation showed right pyelocalicial and proximal ureteral dilatation with narrowing. In the neonatal period a 3D scan with multiplanar views demonstrated a megaureter associated with ureteral valve and a distal ureteral stenosis. The diagnosis was confirmed via surgical exploration and histology. While rare this might be a cause of ureteral obstruction with progressive upper tract dilatation. We emphasize the value of multiplanar 3D which allowed a diagnosis that only few years ago was privative of excretory urography.

P01.39: Experience on 1,282 cases of genetic amniocentesis: fetal loss and complications

Objective: The purpose of this study was to measure the fetal nasal bone between 11–14 weeks of gestation in order to elaborate a reference range for the Brazilian population. Methods: In this prospective and transversal study, crown-rump length, nuchal translucency, and nasal bone length were measured in 171 singleton pregnancies between 11 and 14 weeks of pregnancy. For statistical analysis the linear regression was used. Results: 171 singleton pregnancies which newborns had a normal phenotype were included in this study. A reference range of fetal nasal bone was elaborated. Median and percentiles 5 and 95 were also determined. The reference range was done after adjusting the coefficient of determination (R2) was 59.4% (p < 0.001). Conclusion: The length of the nasal bone showed a linear growth between 11–14 weeks of gestation.