Andrea Mariano

Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study

BACKGROUND Universal anti-hepatitis-B vaccination of infants and adolescents was implemented in Italy in 1991. We undertook a multicentre study in previously vaccinated individuals to assess the duration of immunity and need for booster, over 10 years after vaccination. METHODS In 1212 children and 446 Italian Air Force recruits vaccinated as infants and adolescents, respectively, we measured the concentrations of antibodies to hepatitis-B surface antigen (anti-HBs) and the presence of antibodies to hepatitis-B core antigen (anti-HBc) at enrollment; postimmunisation values were not available. Individuals positive for anti-HBc were tested for hepatitis B surface antigen (HBsAg) and hepatitis B viral DNA. Individuals with anti-HBs concentrations at 10 IU/L or more were regarded as protected; those with antibody less than 10 IU/L were given a booster dose and retested 2 weeks later. Individuals showing postbooster anti-HBs concentrations of less than 10 IU/L were offered two additional vaccine doses and retested 1 month after the third dose. FINDINGS Protective anti-HBs concentrations were retained in 779 (64%, 95% CI 61.6-67) children and 398 (89%, 86.4-92.1) recruits. We recorded antibody amounts of less than 10 IU/L in 433 children (36%, 33-38.4) and 48 (11%, 7.9-13.6) recruits. One child and four recruits were positive for anti-HBc, but negative for HBsAg and hepatitis B viral DNA. Antibody concentrations were higher in recruits than in children (geometric mean titre 234.8 IU/L vs 32.1 IU/L, p=0.0001). 332 (97%) of 342 children and 46 (96%) of 48 recruits who received a booster showed an anamnestic response, whereas ten (3%) children and two (4%) recruits remained negative for anti-HBs or had antibody concentrations of less than 10 IU/L. Prebooster and postbooster antibody titres were strongly correlated with each other in both groups. All individuals given two additional vaccine doses (eight children and two recruits) showed anti-HBs amounts of more than 10 IU/L at 1 month after vaccination. INTERPRETATION Strong immunological memory persists more than 10 years after immunisation of infants and adolescents with a primary course of vaccination. Booster doses of vaccine do not seem necessary to ensure long-term protection.

Prevalence and etiology of altered liver tests: a population-based survey in a Mediterranean town.

Serum biochemical liver tests (LTs) (ALT, AST, GGT) and platelet counts are often used to screen for chronic liver disease. Population‐based data on abnormal LTs in Mediterranean areas are lacking. The prevalence and etiology of abnormal LTs were assessed from 2002 to 2003 in a 1 in 5 systematic random sample of the general population who were 12 years of age or older in Cittanova, a southern Italian town with 10,600 inhabitants. LTs, indices of metabolism, and markers of HBV and HCV infection were assayed and alcohol intake was recorded in the selected population. In virus‐free individuals with abnormal LTs, LTs were retested, and upper abdominal echography and tests for other causes of liver damage were undertaken. Among the 1,645 individuals screened, the prevalence of anti‐HCV was 6.5%; the prevalence was particularly high in individuals over 50 years of age. The corresponding prevalence for HBsAg was 0.8%. The overall prevalence of individuals with abnormal LTs was 12.7% (95% CI: 11.1‐14.3). The probable cause of abnormal LTs was excessive alcohol in 45.6%, HCV in 18.6%, HBV in 1%, alcohol plus HCV and/or HBV in 8.8%, and rare diseases in 2%. In 24% of individuals with abnormal LTs, the probable cause was nonalcoholic fatty liver disease (NAFLD); in this subgroup, increased body weight, hypercholesterolemia, and hyperglycemia were common, and 63.3% of them had a bright liver at echography. In conclusion, in southern Italy, a Mediterranean area where dietary habits are different from those in industrialized areas, one eighth of the general population has abnormal LTs suggestive of possible liver damage; NAFLD appears to be emerging as a potentially important etiology of this presumed liver injury. (HEPATOLOGY 2005;41:1151–1159.)

Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy

BACKGROUND Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. METHODS Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. RESULTS With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. CONCLUSIONS TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

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.

Hepatitis A, Italy.

To the Editor: Hepatitis A virus (HAV) infection rates are very low in industrialized countries. A noticeable fall in the prevalence of HAV antibodies (anti-HAV) has been reported in southern European and Mediterranean countries such as Spain (1) and Greece (2), reflecting improvements in hygiene standards in the last decades.

Effect of HIV co-infection on mutation patterns of HBV in patients with lamivudine-resistant chronic hepatitis B.

A retrospective review was performed comparing lamivudine‐resistance mutation patterns between patients infected with hepatitis B virus (HBV) with or without human immunodeficiency virus (HIV) co‐infection. Medical records that included a genotypic test of patients infected with HBV and treated with lamivudine as the only anti‐HBV drug were reviewed. Pol gene mutations were assessed by direct sequencing of the reverse transcriptase fragment 125–213 aa. Eighty‐nine patients infected with HBV (29 co‐infected with HIV) with rtM204V or rtM204I mutations were included. Multiple mutations associated with the YMDD motif were observed in 33 (55%) of 60 patients infected with HBV only and in 28 (96.6%) of patients co‐infected with HIV/HBV. In this latter group, the prevalence of the rtV173L + rtL180M + rtM204V triple mutation was 31% versus a prevalence of 3.4% observed among patients infected with HBV only. All patients with the triple mutational pattern showed sE164D + sI195M changes in the envelope gene. Multivariate analysis demonstrated that HIV co‐infection (adjusted OR 11.2, 95% CI 2.0–61.0) and HBV genotype A (adjusted OR 7.2, 95% CI 1.5–34.8) were the only independent variables associated with the chance of harboring rtM204V. Patients with HBV genotype A or HIV co‐infection were more likely to harbor the rtM204V mutation. Patients co‐infected with HIV showed multiple mutations more frequently, including the triple mutation that may elicit a vaccine escape phenotype. Among patients co‐infected with HIV/HBV, strict HBV DNA monitoring is essential to detect treatment failure and adapt therapy to avoid limitations of future therapeutic options or the emergence of a public health threat. J. Med. Virol. 81:1151–1156, 2009.

Risk factors for and incidence of acute hepatitis C after the achievement of blood supply safety in Italy: results from the national surveillance system.

Surveillance systems for acute hepatitis C allow monitoring of disease incidence trends and transmission patterns. This study aimed to describe the epidemiological profile of reported cases of symptomatic acute hepatitis C in Italy after the achievement of blood supply safety. The incidence of symptomatic acute hepatitis C since 1991 was estimated. Risk factors for acute hepatitis C were analyzed for the period 2003–2010 through a case–control study within a population‐based surveillance for acute viral hepatitis. From 1991 to 2010, the incidence decreased from 2 to 0.2 per 100,000, with a more evident decrease among persons aged 15–24 years. During 2003–2010, 1,053 cases were reported. Intravenous drug use (adjusted odds ratio [adjOR], 30.5; 95% confidence interval [CI], 18.9–49.1), cohabitation or sexual partnership with an hepatitis C virus (HCV) carrier (adjOR, 11.2; 95% CI, 6.6–19.2), nosocomial exposure (adjOR, 6.6; 95% CI, 4.6–9.4); unsafe sexual practices (adjOR, 3.1; 95% CI, 1.9–5.2), and cosmetic treatments with percutaneous exposure (adjOR, 1.7; 95% CI, 1.2–2.4) were independently associated with acute hepatitis C. Population attributable risk estimates indicated nosocomial exposure (39.6%) and intravenous drug use (30.5%) as responsible for most cases. In conclusion, the incidence of symptomatic acute hepatitis C is declining in Italy. Currently, the most important risk factors are: having an HCV‐positive household or sexual partner, unsafe sexual practices, cosmetic percutaneous treatments, intravenous drug use, and nosocomial exposure; the latter two factors are responsible for most cases. Effective prevention programs for intravenous drug users and strict adherence to universal precautions in healthcare settings are needed. J. Med. Virol. 85:433–440, 2013.

Incidence of Parenterally Transmitted Acute Viral Hepatitis Among Healthcare Workers in Italy

In Italy during 1995-2004, no significant difference was observed in the incidence rate of acute hepatitis B virus infection in the general population and in healthcare workers, with a downward trend noted in both groups. In contrast, the incidence rate of acute hepatitis C virus infection was significantly higher in healthcare workers than in the general population. In Italy, despite the strong recommendation since 1985 for healthcare workers (HCWs) to receive the hepatitis B virus (HBV) vaccine , the incidence of hepatitis B in HCWs continued to be higher than that in the general population during 1986-1991, likely reflecting poor vaccination coverage. Hepatitis C virus (HCV) is less infective than HBV. Studies published between 1992 and 2002 involving more than 11,000 HCV-exposed HCWs in 6 countries indicate that the average rate of HCV transmission after a single needlestick exposure is 0.5%. According to the Studio Italiano Rischio Occupazionale da HIV, a nationwide study on the occupational risk of acquiring human immunodeficiency virus (HIV) in Italy, the largest and most standardized study in the world, since 1995 there have been 3,795 exposures to anti-HCV–positive patients and a transmission rate as low as 0.4%. This rate increases to 0.9% in exposures with large inocula (eg, from hollow needles full of blood), whereas it is 0.3% for conjunctival exposure. Similar to hepatitis B, the incidence of acute hepatitis C in Italy during 1991-1994 was significantly higher in HCWs than in the general population. The Sistema Epidemiologico Integrato dell’Epatite Virale Acuta (SEIEVA) is Italy’s national surveillance system for acute viral hepatitis, which has been operating since 1985. Using SEIEVA data, we evaluated the incidence trends of acute hepatitis B and hepatitis C in HCWs and compared the incidence of these 2 infections in HCWs and members of the general population of the same age during 1995-2004. The SEIEVA data also served as the basis for the previously performed evaluations.

Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000–14

Background Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. Methods In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Results Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005-14: 19.5%-38.5%, P < 0.0001), particularly among Italians (<2005-14: 6.5%-28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (<2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. Conclusions The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.