Enea Spada

Correlation between virus genotype and chronicity rate in acute hepatitis C

BACKGROUND/AIMS Forty-two patients with the diagnosis of acute hepatitis C virus hepatitis were studied to investigate the relationship between hepatitis C virus genotype and progression to chronic infection. METHODS The patients were followed for more than 1 year (mean age 29 years, male/female ratio 2.5). Intravenous drug use was documented in 15 cases, blood transfusion in four, surgical intervention, dental therapy or other parenteral exposure in 15, and unknown factors in the remaining eight. The evolution to chronicity was diagnosed on the basis of a persistent increase in transaminase levels, the presence of HCV-RNA and the histological pattern of chronic hepatitis. RESULTS The majority of cases presented hepatitis C virus infection of subtype 1a (38.1%) or 1b (33.9%). Six cases showed the presence of genotype 3a (14.3%). Subtype 2c was observed in three out of four cases infected with genotype 2. No significant association was demonstrated with documented risk factors. The overall chronicity rate was 59.5%. This value increased to 92% in individuals infected with genotype 1b. By multivariate analysis the age-adjusted odds ratio for infection with genotype 1b as compared with all other genotypes was 14.4 (95% confidence interval; 1.52-137). Moreover, significant differences (p= 0.0002) were present in this group for histological activity index (8.7 as compared with 5-7). CONCLUSIONS The results of this prospective study are consistent with an independent association between hepatitis C virus genotype 1b and a poor prognosis.

Risk of parenterally transmitted hepatitis following exposure to surgery or other invasive procedures: results from the hepatitis surveillance system in Italy

BACKGROUND/AIMS To evaluate the strength of association between parenterally transmitted viral hepatitis and specific types of invasive procedures. METHODS Data from the surveillance system for type-specific acute viral hepatitis (SEIEVA) during the period 1994-1999 were used. The association of acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with the potential risk factors (odds ratios (OR)) was estimated comparing 3120 hepatitis B and 1023 hepatitis C cases with 7158 hepatitis A cases, used as controls, by multiple logistic regression analysis. RESULTS Most procedures resulted in being associated with the risk of acquiring acute HBV or HCV. The strongest associations were: for HBV infection, abdominal surgery (adjusted OR = 3.9; 95% confidence intervals (CI) = 2.0-7.5), oral surgery (OR = 2.7; 95% CI = 1.6-4.5) and gynaecological surgery (OR = 2.6; 95% CI = 1.2-5.5); for HCV infection, obstetric/gynaecological interventions (OR = 12.1; 95% CI = 5.6-26.3), abdominal surgery (OR = 7.0; 95% CI = 3.2-14.9) and ophthalmological surgery (OR = 5.2; 95% CI = 1.1-23.2). Biopsy and/or endoscopy were associated with HCV, but not with HBV infection. CONCLUSIONS Invasive procedures represent an important mode of HBV and HCV transmission. Since a large proportion of the adult general population is exposed to these procedures and an effective HCV vaccine is not yet available, non-immunological means of controlling iatrogenic modes of transmission are extremely important.

Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearance

Background/Aims: Hepatitis C virus (HCV) infection results in a high frequency of chronic disease. The aim of this study was to identify early prognostic markers of disease resolution by performing a comprehensive analysis of viral and host factors during the natural course of acute HCV infection. Methods: The clinical course of acute hepatitis C was determined in 34 consecutive patients. Epidemiological and virological parameters, as well as cell mediated immunity (CMI) and distribution of human leukocyte antigens (HLA) alleles were analysed. Results: Ten out of 34 patients experienced self-limiting infection, with most resolving patients showing fast kinetics of viral clearance: at least one negative HCV RNA test during this phase predicted a favourable outcome. Among other clinical epidemiological parameters measured, the self-limiting course was significantly associated with higher median peak bilirubin levels at the onset of disease, and with the female sex, but only the latter parameter was independently associated after multivariate analysis. No significant differences between self-limiting or chronic course were observed for the distribution of DRB1 and DQB1 alleles. HCV specific T cell response was more frequently detected during acute HCV infection, than in patients with chronic HCV disease. A significantly broader T cell response was found in patients with self-limiting infection than in those with chronic evolving acute hepatitis C. Conclusion: The results suggest that host related factors, in particular sex and CMI, play a crucial role in the spontaneous clearance of this virus. Most importantly, a negative HCV RNA test and broad CMI within the first month after onset of the symptoms represent very efficacious predictors of viral clearance and could thus be used as criteria in selecting candidates for early antiviral treatment.

Early impairment of hepatitis C virus specific T cell proliferation during acute infection leads to failure of viral clearance

Background and aims: Cellular mediated immunity (CMI) is thought to play a key role in resolution of primary hepatitis C virus (HCV) infection. However, CD4+ and CD8+ T cell responses are also generated during acute infection in individuals who become chronic, suggesting that they developed a defective CMI. The aim of this study was to verify if and when such immune dysfunction is established by measuring the breadth, magnitude, function, and duration of CMI in a large cohort of subjects during the natural course of acute HCV infection. Methods: CMI was comprehensively studied by prospective sampling of 31 HCV acutely infected subjects enrolled at the onset of infection and followed for a median period of one year. Results: Our results indicated that while at the onset of acute HCV infection a measurable CMI with effector function was detected in the majority of subjects, after approximately six months less than 10% of chronically infected individuals displayed significant CMI compared with 70% of subjects who cleared the virus. We showed that progressive disappearance of HCV specific T cells from the peripheral blood of chronic patients was due to an impaired ability to proliferate that could be rescued in vitro by concomitant exposure to interleukin 2 and the antigen. Conclusion: Our data provide evidence of strong and multispecific T cell responses with a sustained ability to proliferate in response to antigen stimulation as reliable pharmacodynamic measures of a protective CMI during acute infection, and suggest that early impairment of proliferation may contribute to loss of T cell response and chronic HCV persistence.

Changing epidemiology of parenterally transmitted viral hepatitis: results from the hepatitis surveillance system in Italy

BACKGROUND In 1991, compulsory hepatitis B virus vaccination and screening for anti-hepatitis C virus of blood banks were introduced in Italy. AIM To evaluate the impact of preventive measures on the incidence and risk factors for parenterally transmitted viral hepatitis. METHODS Data from the surveillance system for acute viral hepatitis for the period 1985-99 were used. Temporal trends in distribution of reported risk factors were analysed by comparing three-year periods: 1987-89 and 1997-99. RESULTS The incidence (no. cases per 100,000 population) of hepatitis B was 12 in 1985 and 3 in 1999; the incidence of hepatitis non-A, non-B decreased from 5 to 1 in the same period. These decreases were more evident among young adults and before rather than after 1991. Multiple sexual partners, other parenteral exposures and dental treatment remain the most common risk factors for parenterally transmitted viral hepatitis. An increase in frequency over time was observed for other parenteral exposures, whereas a marked decrease was evident for blood transfusion and household contact with an HB-sAg carrier. Invasive medical procedures continue to represent an important source of infection. Intravenous drug use was reported particularly by young adults with non-A, non-B hepatitis, with increased frequency over time. CONCLUSIONS Non-immunologic measures for preventing hepatitis B and non-A, non B due to iatrogenic and other parenteral exposures, combined with hepatitis B virus vaccination, could further reduce parenteral transmission.

Acute Hepatitis Delta Virus Infection in Italy: Incidence and Risk Factors after the Introduction of the Universal Anti-Hepatitis B Vaccination Campaign

BACKGROUND Updates on the incidence of and risk factors for acute hepatitis delta virus infection in Italy, as well as in other countries, are lacking, and the impact of the mandatory anti-hepatitis B vaccination has not been evaluated. METHODS We performed a case-control study within a population-based surveillance for acute viral hepatitis. RESULTS During 1993-2004, 344 cases of acute hepatitis delta virus infection were reported. After a peak in 1993 (2.8 cases per 1 million population), the incidence decreased from 1.7 to 0.5 cases per 1 million population. Coinfections were prevalent. The decrease in incidence particularly affected young adults, and it paralleled the decrease in incidence of acute hepatitis B. In 1993, being an injection drug user (adjusted odds ratio [OR(adj)], 67.9; 95% confidence interval [CI], 18.1-254.5) or being a member of a household with a carrier of hepatitis B surface antigen (OR(adj,) 14.8; 95% CI, 3.0-72.9) were the only independent predictors of infection. During 1994-2004, being an injection drug user (OR(adj), 36.8; 95% CI, 20.7-65.4), cohabitation with an injection drug user (OR(adj), 4.2, 95% CI, 1.7-12.3), hospitalization (OR(adj), 3.5; 95% CI, 1.9-6.6), receipt of dental therapy (OR(adj), 2.3; 95% CI, 1.4-3.6), promiscuous sexual activity (OR(adj), 2.2; 95% CI, 1.4-3.6), and receipt of beauty treatment (OR(adj), 2.0; 95% CI, 1.3-3.2) were independently associated with infection. CONCLUSIONS Incidence of acute hepatitis delta infection is markedly decreasing in Italy. Undergoing invasive medical procedures, engaging in promiscuous sexual activity, and receiving beauty treatments are emerging, in addition to injection drug use, as important risk factors for infection. Further efforts are needed to increase vaccine coverage in high-risk groups and to implement the safety of invasive procedures performed both inside and outside health care facilities.

Estimating the incidence, prevalence and clinical burden of hepatitis C over time in Italy

Our objective was to estimate HCV clinical burden over time in Italy. A national age-specific HCV prevalence in 1995 was obtained from studies conducted in general population samples and intravenous drug users. Age profile of new HCV infections and trend of incidence since 1985 were derived from a database of reported acute HCV infections. These incidence and prevalence data were used to estimate HCV burden from 1950 to 2030 by mathematical modelling. Different rates of HCV related liver disease progression were tested to assess the robustness of estimates. It is estimated that HCV had a major spread in Italy in 1945–1969. HCV RNA-positive subjects peaked around 1970; their prevalence in 2005 was 3.2%, 58% of them being >65 y of age. The number of individuals with HCV related cirrhosis and that of HCV liver related deaths peaked in 1980–1985. In 2005, they were ~230,000 (range 150,000–240,000, according to lower or higher disease progression rates) and ~7,000 (range 2200–12,300), respectively: both will be halved by 2025. In conclusion, unlike other industrialized countries, the burden of clinically relevant HCV-positive cases in Italy is already on the decline and will further reduce in the future. This is due to differences in the age-specific prevalence, most of HCV-positive Italians currently being >65 y of age.

Case fatality rate of acute viral hepatitis in Italy: 1995-2000. An update.

BACKGROUND Fulminant hepatic failure is the most serious complication of viral hepatitis. Although this event occurs rarely, it may be fatal. AIMS To evaluate the case fatality rate (several deaths divided by number of cases x 100) for each viral hepatitis type in Italy from 1995 to 2000. PATIENTS Acute hepatitis cases identified by the surveillance system for acute viral hepatitis, which covers approximately 58% of the Italian population. RESULTS Twenty-five deaths (0.1%) occurred among the 18 460 acute viral hepatitis cases observed from 1995 to 2000, a rate threefold lower than the 0.3% reported during the period 1985-1994. The highest case fatality rate (0.4%) was seen for acute hepatitis B (18 deaths among 4257 cases). Only one death (0.01%) occurred among the 11 063 acute hepatitis A cases and two deaths (0.1%) among the 1536 acute hepatitis C cases. No deaths were observed among the 309 acute hepatitis A cases superimposed on chronic HBsAg carriers and the 166 superimposed on chronic HCV carriers. Intravenous drug use (22.2% of cases) and other parenteral exposures (22.2% of cases) were the most frequent non-mutually exclusive sources of infection reported by subjects who died of acute hepatitis B. CONCLUSIONS Analysis of surveillance system data from 1995 to 2000 indicates that, in Italy, deaths due to acute viral hepatitis are rare, but most commonly observed with acute hepatitis B. There is no evidence that acute hepatitis A may be fatal in chronic HBsAg or HCV carriers. The overall better survival rate may probably reflect improvements in the treatment of fulminant hepatitis in the last few years in Italy.

Positive selection of cytotoxic T lymphocyte escape variants during acute hepatitis C virus infection.

Cellular immune responses are induced during hepatitis C virus (HCV) infection and acute‐phase CD8+ T cells are supposed to play an important role in controlling viral replication. In chimpanzees, failure of CD8+ T cells to control HCV replication has been associated with acquisition of mutations in MHC class I‐restricted epitopes. In humans, although selection of escape mutations in an immunodominant CTL epitope has been recently described, the overall impact of immune escape during acute HCV infection is unclear. Here, by performing an in depth analysis of the relationship between early cellular immune responses and viral evolution in a chronically evolving HCV acutely infected individual, we demonstrate: (i) the presence of a potent and focused CD8+ T cell response against a novel epitope in the NS3 protein, (ii) the elimination of the quasi‐species harboring the original amino acid sequence within this epitope, and (iii) the selection for a virus population bearing amino acid changes at a single residue within the cytotoxic T cell epitope that strongly diminished T cell recognition. These results support the view that acute‐phase CD8+ T cell responses exert a biologically relevant pressure on HCV replication and that viruses escaping this host response could have a significant survival advantage.

Acute hepatitis A in Italy: incidence, risk factors and preventive measures

Summary.  The incidence of, and risk factors for, acute hepatitis A (AHA) were assessed by using data collected from the Italian surveillance system of acute viral hepatitis (SEIEVA). To this end, a case–control study within a population‐based surveillance for acute viral hepatitis was performed. AHA incidence has been estimated since 1991; the association with considered risk factors was analysed from 2001 to 2006 employing cases of acute hepatitis B (AHB) as controls. The incidence of AHA declined from 4 / 100 000 in 1991 to 1.4/100 000 in 2006, with a peak during 1996–1998 due to an outbreak in southern Italy. The incidence of AHA was highest among persons aged 15–24 years. The case‐fatality rate was 2.9 / 10 000. Contact with individuals with AHA [adjusted OR (ORadj) = 3.8, 95% CI 2.7–5.5; population‐attributable risk (PAR) = 7.5%], travelling to endemic areas (ORadj = 3.1, 95% CI = 2.6–3.8; PAR = 19.5%), ingestion of raw shellfish (ORadj = 1.8, 95% CI = 1.6–2.1; PAR = 26.6%), and cohabitation with day care children (ORadj = 1.3, 95% CI = 1.01–1.7; PAR = 2.3%) were the main important risk factors. In 2003, an outbreak, with high case‐fatality rate occurred among intravenous drug users, in a central Italian town. A weak association was found for male homosexuality when acute hepatitis C cases were employed as controls (ORadj = 1.4 CI, 95% CI = 1.1–1.9). Hepatitis A virus infections are currently occurring more frequently in adults, in whom the disease is most severe. In conclusion, looking at the attributable risks, at present most of the AHA infections are due to shellfish consumption, travel to endemic areas and contact with patients with AHA. Vaccination of individuals at increased risk of infection, as well as persons with underling liver disease and those at increased risk of complications, combined with surveillance of shellfish retail outlets are efficient control measures.