Luisa Romanò

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.

Lack of Evidence of Sexual Transmission of Hepatitis C among Monogamous Couples: Results of a 10-Year Prospective Follow-Up Study

The risk of sexual transmission of hepatitis C virus (HCV) infection was evaluated among 895 monogamous heterosexual partners of HCV chronically infected individuals in a long-term prospective study, which provided a follow-up period of 8,060 person-years. Seven hundred and seventy-six (86.7%) spouses were followed for 10 yr, corresponding to 7,760 person-years of observation. One hundred and nineteen (13.3%) spouses (69 whose infected partners cleared the virus following treatment and 50 who ended their relationship or were lost at follow-up) contributed an additional 300 person-years. All couples denied practicing anal intercourse or sex during menstruation, as well as condom use. The average weekly rate of sexual intercourse was 1.8. Three HCV infections were observed during follow-up corresponding to an incidence rate of 0.37 per 1,000 person-years. However, the infecting HCV genotype in one spouse (2a) was different from that of the partner (1b), clearly excluding sexual transmission. The remaining two couples had concordant genotypes, but sequence analysis of the NS5b region of the HCV genome, coupled with phylogenetic analysis showed that the corresponding partners carried different viral isolates, again excluding the possibility of intraspousal transmission of HCV. Our data indicate that the risk of sexual transmission of HCV within heterosexual monogamous couples is extremely low or even null. No general recommendations for condom use seem required for individuals in monogamous partnerships with HCV-infected partners.

Identification of a novel variant of hepatitis E virus in Italy

Hepatitis E infection is typically associated with areas in which hepatitis E virus (HEV) is endemic. Except for a few cases in Europe and in the United States, acute hepatitis E is usually associated with travel to endemic areas. We set out to determine the etiologic role of HEV in acute non‐A‐C hepatitis in Italy. The presence of HEV‐RNA and antibody was determined in 218 patients diagnosed with acute viral non‐A‐C hepatitis. Acute hepatitis E infection was defined by the presence of HEV‐RNA in sera and positivity for IgM anti‐HEV and seroconversion to IgG anti‐HEV. Acute hepatitis E was found in 10.1% of the patients with acute non‐A‐C, with 95.5% exhibiting a benign course. A more severe course was observed in a patient co‐infected with HAV and HEV. Most cases were travelers to endemic areas, although 18.2% reported no travel. One patient was from a household with an infected patient. Sequence analyses of the polymerase chain reaction (PCR) product derived from a patient who never visited endemic areas, identified an isolate that is divergent significantly from all reported isolates of HEV (79.5–85.8% nucleotide identity). Evidence from this study suggests that HEV accounts for approximately 10% of acute non‐A‐C viral hepatitis in Italy, diagnosed generally in travelers returning from endemic areas. However, the identification of a new HEV variant in an individual who never indicated travel or contact with individuals associated with endemic areas, suggests that this virus may be native to Italy. J. Med. Virol. 57:356–360, 1999.

Perinatal transmission and manifestation of hepatitis C virus infection in a high risk population.

We studied the perinatal transmission of hepatitis C virus (HCV) in 70 high risk mother/infant pairs. Seventy-six percent of the mothers (53 of 70) were coinfected with human immunodeficiency virus (HIV) and 79% (55 of 70) had a history of drug addiction. During the follow-up HCV RNA was detected in 14 of 70 (20%) infants: 12% (2 of 17) in infants born to HIV-negative mothers; and 23% (12 of 53) in infants to HIV-positive mothers. The rate of vertical transmission was significantly higher in vaginally delivered infants than in those delivered by cesarean section (32% vs. 6%; P < 0.05). All 56 uninfected infants lost passively acquired anti-HCV by age 9 \pm 4 months and only 2 of 56 infants (4%) had evidence of HIV infection. Four of 14 HCV RNA-positive infants (29%) had evidence of HTV coinfection. We observed 3 clinical patterns of HCV infection: a transient viremia in 2 infants; an acute pattern in 2 infants; and a chronic pattern in 10 infants. All 4 HIV-coinfected infants had chronic HCV infection. All infants with a chronic pattern, had increased alanine aminotransferase values for more than 6 months and 5 had a liver biopsy that showed signs of chronic persistent hepatitis. HCV perinatal transmission was more frequent in infants born to HIV-coinfected mothers than in infants born to HIV-noninfected women, particularly when delivered vaginally.

Long‐term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth

Long‐term follow up studies of hepatitis C virus (HCV) infection rarely exceed 20–25 yr. We studied the outcome of HCV infection in 35‐yr‐old adults infected at birth (1968) through mini transfusions of blood. A retrospective‐prospective study was carried out. The cohort included 31 individuals who were given mini blood transfusions (21–30 ml) collected from a donor subsequently revealed to be HCV infected. At enrollment (1998), 18 of 31 (58.1%) recipients had anti‐HCV antibody and 16 (88.9%) of them were HCV‐RNA positive. All viremic recipients and the infectious donor had the same genotype 1b. Sequence analysis of E1/E2 and NS5b regions, coupled with phylogenetic analysis, indicated that HCV isolates from donor/recipients were linked. Eleven of the 16 viremic recipients gave consent to liver biopsy. Nine had no fibrosis or mild portal fibrosis and 2 had either discrete (Ishaks staging 3) or marked (Ishaks staging 4) fibrosis. During the prospective follow‐up period (1998–2003), 2 patients were given therapy, one of whom achieved sustained clinical and virologic response. A second biopsy, performed in 5 patients at a 5 yr interval, revealed no substantial modifications in 4 cases and progression from absence of fibrosis to mild portal fibrosis in the fifth. In conclusion, taking into account the limited study sample, these findings suggest that HCV infection acquired early in life shows a slow progression and mild outcome during the first 35 yr of infection. (HEPATOLOGY 2004;39:90–96.)

A 2010 update on occult hepatitis B infection

Occult hepatitis B virus infection is a challenging issue whose virological and clinical relevance has been a source of long-lasting debate. By definition, OBI is characterized by the persistence of HBV-DNA in the liver tissue (and in some cases also in the serum) in absence of HBsAg. According to the HBV serological profile, OBI may be antibody (anti-HBc alone or together with anti-HBs) positive (seropositive OBI) or antibody negative (seronegative OBI). OBI is a complex biological entity with possible relevant clinical implications, mainly related to the intrahepatic persistence of viral cccDNA and to a strong suppression of viral replication and gene expression. Clinical observations suggest that OBI carriers may be a source of HBV transmission through blood transfusion or orthotopic liver transplantation (OLT). The state of suppression of viral replication and gene expression may be discontinued when an immunosuppressive status occurs, leading to typical hepatitis B with severe - and some times - fulminant course. The long-lasting persistence of the virus in the liver may provoke a very mild but continuing necro-inflammation that (if other causes of liver damage cohexist) may contribute over time to the progression of the chronic liver damage towards cirrhosis. In addition, OBI is supposed to be an important risk factor to HCC development since it maintains the pro-oncogenic properties typical of the overt infection.

Effectiveness of Hepatitis B Vaccination in Babies Born to Hepatitis B Surface Antigen-Positive Mothers in Italy

This study examined 522 children born to hepatitis B surface antigen (HBsAg)-positive mothers from 1985 through 1994 and evaluated the protection provided by anti-hepatitis B virus (HBV) immunization at birth. Babies were given hepatitis B immunoglobulin and hepatitis B vaccine at birth. At 5-14 years after immunization, 17 children (3.3%) were anti-HB core antigen positive, and 3 also were HBsAg positive. One carrier child had a double mutation, with substitution of proline-->serine at codons 120 (P120S) and 127 (P127S) within the a determinant of HBsAg. Of the 522 children, 400 (79.2%) of 505 still had protective anti-HBsAg titers > or =10 mIU/mL. Thus, HBV vaccination of children born to HBsAg-positive mothers is effective and confers long-term immunity. There is no evidence that the emergence of HBV escape mutants secondary to the immune pressure against wild-type HBV is of concern.

A Prospective Study on Mother-to-Infant Transmission of Hepatitis C Virus

To assess the rate of mother-to-infant transmission of hepatitis C virus (HCV) and to identify potential risk factors for transmission, we followed up (mean 22.4 months, range 1–7.5 years) a cohort of 291 babies born to anti-HCV-positive mothers, 40 of whom were also HIV coinfected. Seventeen (5.8%) babies acquired HCV infection, but none became icteric. All babies developed chronic HCV infection with 16 babies showing elevated levels of ALT. The rate of transmission was higher in babies born to mothers coinfected with HIV than in those born to mothers with HCV alone (22.5 vs. 3.2%, p < 0.0001). No association was seen between a specific maternal HCV genotype and an increased risk of neonatal infection. The median level of HCV-RNA was higher in mothers who transmitted infection than in those who did not, although the ranges overlapped. In this study, maternal history of chronic liver disease, mode of delivery and type of feeding were not predictive of HCV infection.

Impact of nucleic acid testing for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus on the safety of blood supply in Italy: a 6‐year survey

BACKGROUND: Nucleic acid testing (NAT) for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) has been implemented in several European countries and in the United States, while hepatitis B virus (HBV) NAT is still being questioned by opinions both in favor and against such an option, depending on the HBV endemicity, health care resources, and expected benefits.

Hepatitis E in Italy: A long-term prospective study

BACKGROUND & AIMS In developed countries, hepatitis E is usually associated with travelling to endemic areas, but a growing number of sporadic cases are also seen in patients with no travel history. The aim of this study was to assess the impact and the molecular epidemiology of hepatitis E in Italy. METHODS Between January 1994 and October 2009, we analyzed 651 patients with acute non-A-C hepatitis. Diagnosis of hepatitis E was based on the presence of IgM anti-HEV and/or the detection of HEV RNA by RT-PCR. Viral isolates were sequenced and phylogenetically characterized. RESULTS A total of 134 out of 651 (20.6%) patients tested had acute hepatitis E. All were anti-HEV IgM and IgG positive and 96 (71.6%) were also positive for HEV RNA. Moreover, 39 (6%) patients were anti-HEV IgG positive but negative for both IgM anti-HEV and HEV RNA. A total of 109 (81.3%) patients developed hepatitis E travelling to endemic areas, 3 (2.3%) acquired intra-familial infection from relatives who developed travel-related disease, while 22 (16.4%) patients denied having travelled abroad. In all patients, acute disease had a self-limited course with ALT normalization within 3-6 weeks. Phylogenetic analysis of 39 isolates from patients with a travel-related disease showed that they belonged to genotype 1, while sequences from five patients with autochthonous hepatitis E belonged to genotype 3. CONCLUSIONS In Italy, most cases of hepatitis E are travel related, caused by viral genotype 1, while autochthonous cases are caused by genotype 3. The prevalence of genotype 3 among pigs and boars suggests that HEV infection may have zoonotic origins in non-endemic countries.