Gabriella Verucchi

Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. METHODS We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24weeks. Fifty-nine patients had previous HCC. RESULTS DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99-10.84): 17 of 59 patients (28.81%, 95% CI: 17.76-42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45-5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p=0.03, OR: 4.18, 95% CI: 1.17-14.8) and history of HCC (p<0.0001, OR: 12.0, 95% CI: 4.02-35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. CONCLUSIONS In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. LAY SUMMARY New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

Long-Term Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease

BACKGROUND & AIMS The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4 + cell count

Objectives:We investigated the significance of microbial translocation measured on average 3 years after HIV seroconversion in driving disease progression in HIV+ untreated patients with high CD4+ cell count. Design:We included ICONA patients with documented last HIV-negative and first HIV-positive test, at least one plasma sample stored while antiretroviral therapy (ART)-naive and CD4+ cell count greater than 200 cells/&mgr;l. Methods:Microbial translocation [lipopolysaccharide (LPS), sCD14 and EndoCAb] and immune activation (IL-6 and TNF-&agr;) were measured. Correlation between immune activation, microbial translocation, CD4+ and plasma HIV-RNA was evaluated by linear regression and nonparametric Spearmans rho. The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, death, CD4+ cell count less than 200 cells/&mgr;l or start of antiretroviral therapy (ART) was assessed using survival analysis. Results:We analysed 1488 biomarker measures from 379 patients. A median of 3.1 years after the estimated seroconversion date [interquartile range (IQR) 1.6–5.4], median (IQR) markers values were LPS, 110 pg/ml (IQR 75–215), sCD14, 3.3 &mgr;g/ml (2.2–4.8), IL-6, 1.1 pg/ml (0.6–1.9) and TNF-&agr;, 2.4 pg/ml (1.8–3.4). Two hundred and sixty progression events were recorded over a median of 1.6 years from the first sample (2% AIDS, 84% ART initiation, 12% CD4+ cell count less than 200 cells/&mgr;l and 2% death). LPS was the only biomarker associated with this primary composite outcome independently of age, HIV-RNA and CD4+ (relative hazard = 1.40 per loge higher, 95% confidence interval 1.18–1.66, P < 0.001). Conclusion:Circulating LPS in the first years of chronic HIV infection is a strong predictor of disease progression independent of CD4+ cell count and HIV viraemia and may be considered a candidate biomarker for HIV monitoring and evaluation in clinical trials.

Non—Organ-Specific Autoantibodies in Children with Chronic Hepatitis C: Clinical Significance and Impact on Interferon Treatment

We evaluated the prevalence and clinical significance of non-organ-specific autoantibodies (NOSAs) in 47 hepatitis C virus (HCV)-positive children with abnormal alanine transaminase levels and analyzed the association between NOSAs and virus level, genotype, human leukocyte antigen status, and interferon (IFN) response. Forty-two hepatitis B virus (HBV)-positive children and 25 age- and sex-matched healthy children served as control subjects. NOSAs were found in 34% of the HCV-positive children, 12% of the HBV-positive controls, and none of the healthy control subjects. Liver-kidney microsomal antibody type 1 (LKM1) was detected in 11% of the HCV-positive children but in none of the controls. The HCV load was significantly higher in NOSA-negative than in NOSA-positive children. HCV genotype distribution and human leukocyte antigen alleles were similar, irrespective of NOSA status. Long-term response to IFN therapy was achieved by 18% of the NOSA-positive and 55% of the NOSA-negative subjects. Two LKM1-positive children developed acute, self-limited hepatocellular necrosis while receiving IFN therapy. NOSAs are frequently present in children with hepatitis C, who are less likely to benefit from IFN therapy.

Epidemiology and outcomes of bloodstream infection in patients with cirrhosis

BACKGROUND & AIMS Bloodstream infections (BSIs) in cirrhotic patients are 10-fold more common than in non-cirrhotic patients and increasingly caused by resistant pathogens. We examined 162 BSI episodes in cirrhotic patients to describe the etiology and risk factors for 30-day mortality. METHODS We retrospectively analyzed all consecutive BSIs in patients with liver cirrhosis at our 1350-bed teaching hospital (January 2008 to June 2012). Cox-proportional hazard regression was used to analyze the impact of disease and treatment-related variables on the crude 30-day mortality. RESULTS BSI episodes were identified in 162 patients, including 29 mixed infections. Most of episodes were classified as hospital acquired or healthcare associated (93%). Gram-negative bacteria (GNB), Gram-positive bacteria and Candida spp. caused 64%, 38%, and 10% of episodes, respectively. GNB were classified as multi-drug resistant (MDR) and extensively drug resistant (XDR) in 25% and 21% of cases, respectively. The overall crude 30-day mortality rate was 29%. Four risk factors were independently associated with 30-day crude mortality: worsening of MELD score from baseline (the last MELD score available in the 2 weeks prior BSI) to that at BSI onset (HR 1.11 per point increase, 95% CI 1.07-1.15, p<0.0001), spontaneous bacterial peritonitis as BSI source (HR 4.42, 2.04-9.54, p=0.002), sepsis grading (HR 2.18, 1.39-3.43, p=0.0007), and inappropriate antibiotic therapy within 24h from blood cultures (HR 2.82, 1.50-5.41, p=0.002). CONCLUSION An increasing proportion of BSIs in cirrhotic patients are caused by resistant GNB and Candida spp. Accurate evaluation of risk factors for mortality may improve early appropriate therapeutic management.

HLA DR13 and HCV vertical infection.

Risk factors affecting vertical hepatitis C virus (HCV) transmission are not completely known, if we exclude maternal HIV coinfection. We hypothesized that immunogenetic factors related to maternal or neonatal HLA profiles may affect HCV vertical transmission. HLA typing (microcytotoxicity assay on blood samples) was performed in 18 infants affected by vertically transmitted HCV infection and in 17 serum-reverted infants. (Serum-reversion is defined as antibody negative by 1 year of age and persistently HCV-RNA negative.) Moreover, HLA typing was performed in 20 mothers. Logistic regression analysis showed a significant negative association between childrens HLA-DR13 antigens and risk of HCV vertical transmission (p < 0.01). This association persisted in a model including the maternal HIV status: HLA DR13 and maternal HIV coinfection showed a separate, opposite effect on vertical HCV infection (p < 0.01 and p < 0.001, respectively). The relative risk estimate for the ratio of not-infected to infected children in the presence of DR13 was 8.4 (95% confidence bounds, 1.1–60.8). Breast-feeding did not affect the risk of vertical HCV transmission. Maternal HLA profile did not relate to vertical infection. The present study reveals a significant association between HLA-DR13 and the likelihood of seroreversion in infants born to HCV-infected mothers. The findings of the present study could help in better understanding the pathogenesis of vertical HCV infection and in better identifying the cases at higher risk, which would be useful for the development of prevention strategies. It is possible that DR13 modulates the immune response to viruses, enhancing their clearance and, thus, in the case of HCV, exerting a protective role against the development of vertical infection.

Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome

Background and aim: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. Methods: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. Results: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. Conclusion: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.

Hepatitis B virus infection in native versus immigrant or adopted children in Italy following the compulsory vaccination.

AbstractBackground: Compulsory vaccination of children against hepatitis B virus (HBV) infection was introduced in Italy in 1991. Patients and Methods: To evaluate the current importance of pediatric HBV infection, we studied 359 HBsAg-positive children admitted to 16 centers in Italy from 1991 to 1998. 185 patients were natives of Italy and 174 (39 immigrants and 135 adopted) came from highly endemic countries (eastern Europe: 60.9%, Asia: 16.7%, Africa: 14.9% and Central and South America: 5.7%). Results: Transaminase levels were moderately altered in both Italian (mean 134 UI/l) and foreign children (mean 168 UI/l). In total, 77% of Italian children and 88% of foreign children tested HBeAg postive. High transaminase levels and HBeAg positivity were more frequent in adopted children. Follow-up of 317 patients showed that the incidence of HBeAg/anti-HBe serum conversion was similar in all cohorts, but in adopted children it occurred at an earlier age and was associated with HBsAg clearance in 5%. Conclusion: HBV is not frequent in Italian children today, but it is common among children comming from highly endemic areas. The vaccination of nonimmune native populations must be strongly recommended.

An Epidemiological Survey of Hepatitis C Virus Infection in Italian Children in the Decade 1990–1999

Background A retrospective–prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. Methods Anti-HCV–positive patients (or HCV RNA–positive infants) aged 1 month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. Results From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). Conclusions Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Despite the excellent efficacy of direct‐acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance‐associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real‐life DAA failures.