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INFLUENCE OF DELTA INFECTION ON SEVERITY OF HEPATITIS B

The prevalence of serum markers of primary delta infection was determined in 532 patients with acute benign hepatitis B seen in Italy, and in 111 patients with fulminant hepatitis B seen in Italy, France and England. Patients with fulminant hepatitis had significantly higher prevalence of delta markers (43/111, 39%) than did those with benign hepatitis (101/532, 19%). In 25 of the 43 patients with delta-positive fulminant hepatitis, serum markers indicated a primary hepatitis B infection while in the remaining 18, IgM antibody to hepatitis B core antigen was absent, indicating that hepatitis B preceded superinfection with the delta agent. The increased morbidity of HBsAg hepatitis with delta infection may result from the cumulative simultaneous exposure to hepatitis B virus and delta, or from superinfection of HBsAg carriers with delta.

Infection with the delta agent in chronic HBsAg carriers

To establish the mechanism of progression to chronicity of the HBsAg-associated delta infection, serum hepatitis B virus and delta markers were tested in five babies born to HBsAg-positive mothers with anti-delta, in 42 follow-up patients with acute hepatitis B virus and delta hepatitis, and in collections of sera from 8 HBsAg carriers with anti-delta. Evidence of delta infection was found in the baby born to a mother with serum HBeAg and in none of the four babies born to mothers with anti-HBe. Hepatitis was self-limited in the 42 patients acutely infected by hepatitis B virus and delta agent; none developed persistent HBs-antigenemia and the majority displayed transient anti-delta of IgM class. In seven HBsAg carriers high titers of anti-delta developed during the follow-up; coincident with the rise of the antibody, aminotransferase elevation occurred in five previously asymptomatic carriers and persisted in three of them. No sign of infectious hepatitis B virus replication was detected in five of the carriers throughout the follow-up, and all of them had anti-HBe before the rise of anti-delta and of aminotransferase. HBsAg carriers with diminished hepatitis B virus synthesis appear to be at high risk of developing chronic delta infection and disease when exposed to the delta-infectious serum of other carriers.

Prevalence of Infected Patients and Understaffing Have a Role in Hepatitis C Virus Transmission in Dialysis

To assess hepatitis C virus (HCV) incidence rates and identify determinants of infection among hemodialysis patients, a multicenter study was conducted in 58 units in ITALY: An initial seroprevalence survey was conducted among 3,492 patients already on hemodialysis therapy as of January 1997 and among an additional 434 patients who began dialysis up to January 1998. HCV antibodies were assessed by third-generation enzyme immunoassays. Patients testing seronegative at baseline were enrolled into a 1-year incidence study with serological follow-up at 6 and 12 months. For patients who seroconverted, an HCV RNA assay was performed on stored baseline samples to confirm new infection. A nested case-control study was subsequently performed to investigate potential risk factors. For each incident case, three controls negative for both HCV antibodies and HCV RNA were randomly selected. At enrollment, HCV seroprevalence was 30.0%. During follow-up, 23 new HCV cases were documented, with a cumulative incidence of 9.5 cases/1,000 patient-years. By logistic regression analysis, an increased risk for HCV infection emerged for patients attending the dialysis units with a high prevalence of HCV-infected patients at baseline (odds ratio [OR], 4.6) and for those attending units with a low personnel-patient ratio (OR, 5.4). Among extradialysis factors, a history of surgical intervention in the previous 6 months (OR, 16.7) significantly increased HCV risk. These findings suggest that the combination of understaffing and a high level of infected patients in the dialysis setting increases the risk for HCV nosocomial transmission. This is likely related to an increased likelihood for breaks in infection control measures.

Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and a common occurrence in patients with liver cirrhosis in western and North American countries. Ultrasound screening is a powerful technique for HCC diagnosis, whereas the only available serologic test, alpha‐fetoprotein, has poor reliability. It has been reported that the squamous cell carcinoma antigen (SCCA) is overexpressed in HCC tissue. In our study, the expression of SCCA was investigated in tumoral and peritumoral tissues and in the serum of 52 HCC patients, as well as in the serum of 48 cirrhotic patients. The results show that SCCA expression is much stronger in the tumoral than in the peritumoral tissue of HCC. Moreover, it is also evident in metastatic nodules present in the peritumoral tissue. SCCA serum levels were significantly higher in HCC samples than in cirrhotic samples. However, no correlation was found between SCCA expression and the HCC histologic degree, nor did SCCA expression correlate with tumor size, presence of metastasis or clinical outcome. In conclusion, in HCC patients, the SCCA antigen could represent a useful marker for the detection of micro‐metastasis in the tissues and for large‐scale screening of serum in patients at risk.

CLINICAL SIGNIFICANCE OF ANTIBODY TO THE HEPATITIS DELTA VIRUS IN SYMPTOMLESS HBsAg CARRIERS

Antibody to the hepatitis delta virus (anti-delta) was detected in 112 out of 2487 (5%) individuals fortuitously found to have the hepatitis B surface antigen (HBsAg) in the blood. Liver function was impaired in 38% (43 of 112) of the anti-delta-positive carriers but in only 9% (215 of 2375) of the anti-delta-negative subjects (p less than 0.001). Liver biopsy specimens were obtained from 31 antibody-positive and 97 antibody-negative subjects with impaired liver function. Important histological changes were observed in 61% of the 31 antibody-positive carriers (7 chronic active hepatitis, 4 active cirrhosis, 8 inactive cirrhosis) but in only 19% of the 97 antibody-negative carriers (p less than 0.001). The presence of anti-delta in serum identifies a subpopulation of apparently healthy HBsAg carriers whose risk of underlying liver disease is four times higher than that in the ordinary carrier. The identification of anti-delta in a symptom-free HBsAg carrier with abnormal liver function is thus an indication for a diagnostic liver biopsy.

SCCA antigen combined with alpha-fetoprotein as serologic markers of HCC

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is α‐fetoprotein (α‐FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of α‐FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of α‐FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC.

Familiar clustering and spreading of hepatitis delta virus infection

The prevalence of hepatitis delta virus (HDV) infection was significantly higher among the relatives of 79 carriers of HBsAg with antibody to HDV (index cases) than among relatives of 111 carriers without serological evidence of HDV infection (controls). Antibody to HDV was found in 45 of the 80 (56%) carriers of HBsAg in families of index cases but only in 2 of 59 (3%) carriers in families of controls (P less than 0.0001). During follow-up new HDV infection developed in 31% of 13 susceptible carriers in families of index cases, but only in 1.2% of 162 susceptible carriers in families of controls (P less than 0.001). None of the family members previously unexposed to the hepatitis B virus had HDV markers in serum or developed this infection during the follow-up. Familial clustering shows that HDV is transmitted by personal contacts, presumably through the inapparent permucosal or percutaneous passage of virus during close or intimate contact. The family model indicates that endemic HDV is maintained and spread through the network of carriers in the community, and that HBsAg carriers in contact with HBsAg/HDV carriers are at high risk of contracting HDV.

Evaluation of the immunogenicity and reactogenicity of a DTPa-HBV-IPV Combination vaccine co-administered with a Hib conjugate vaccine either as a single injection of a hexavalent combination or as two separate injections at 3, 5 and 11 months of age.

A combined DTPa-HBV-IPV/Hib vaccine containing diphtheria (D), tetanus (T), acellular pertussis (Pa), hepatitis B (HBV) and types 1, 2 and 3 inactivated polioviruses (IPV) extemporaneously mixed with a conjugated Haemophilus influenzae type b (Hib) vaccine (Group 1) was compared to the DTPa-HBV-IPV and Hib vaccines (Group 2) administered separately at 3, 5 and 11 months of age (n=440). A microneutralization assay was used to detect antibodies against the 3 polio virus types (cut-off 1:8 dil), RIA for anti-HBs antibodies (cut-off 10 mIU/ml) and ELISA for antibodies against all other vaccine antigens (cut-off: 0.1 IU/ml for anti-tetanus and anti-diphtheria antibodies; 5 El.U/ml for antibodies against each of the 3 acellular pertussis antigens and 0.15 μg/ml for anti-PRP antibodies). Similar immune responses were observed in both groups 1 month after dose 2 as well as after dose 3. Six months after dose 2 however, the proportion of subjects maintaining an anti-tetanus antibody concentration ≥0.1 IU/ml was lower in Group 2 and a slight group difference in favour of Group 1 was also observed for anti-PRP, anti-diphtheria and anti-polio type 1 antibody persistence prior to the third dose. The overall incidence of local and general solicited symptoms was similar in both groups. One subject discontinued study vaccination following an SAE considered to be related to vaccination. The DTPa-HBV-IPV/Hib combined vaccine is immunogenic and well tolerated when administered according to a 3, 5 and 11 month vaccination schedule and can therefore be considered as a feasible alternative to the separate administration of the pentavalent DTPa-HBV-IPV and the monovalent Hib vaccines.

Anamnestic response to administration of purified non-adsorbed hepatitis B surface antigen in healthy responders to hepatitis B vaccine with long-term non-protective antibody titres

A clinical trial with four groups receiving either 0.6, 3.5, 10 or 20 micro g of purified non-adsorbed hepatitis B surface antigen (HBsAg) was performed to study the kinetics as well as the capacity of the immune memory to respond following exposure to HBsAg in responders to a complete course of hepatitis B vaccine, in whom anti-HBs titres had declined below the seroprotective level. The study population included 64 healthy individuals. All response parameters seropositivity, seroprotection rates, booster response rates and geometric mean titres (GMTs), consistently showed that the immune response was highly satisfactory and dose-dependent. A remarkable immune response was obtained even with a trace amount of HBsAg. This study further supports recent indication that booster hepatitis B vaccine doses may be unnecessary in healthy adult responders to a full course of hepatitis B vaccination.

Long term immunogenicity safety and efficacy of a recombinant hepatitis B vaccine in healthy adults

Two hundred healthy adults seronegative for HBV markers received three 10 or 20 mcg injections of a vaccine formulated from HBsAg produced by a recombinant strain of the yeastSaccharomyces cerevisiae. The vaccine was administered intramuscularly at 0, 1, and 6 months in the deltoid region. The seroconversion rates, expressed in GMT/IU/1 were determined at 1, 2, 6, 7, 12, 24, 36 and 48 months following the initial injection. No severe or serious adverse reactions attributable to the HB vaccines were observed in any subject. The seroconversion rates following the 20 mcg dose of recombinant vaccine were always higher than those observed after the 10 mcg dose, but the differences were not statistically significant. Also the GMT values were lower after the 10 mcg dose of vaccine. Females showed a higher anti-HBs response than males; an age-dependent effect was observed in the anti-HBs response as regards both the percentage of responders and the antibody concentrations in the serum. No adverse reactions to the vaccine were observed. The rDNA vaccine did not induce a response to yeast-derived impurities and did not increase anti-yeast IgE antibody titres. The results of this study have shown that the Amgen rDNA vaccine is safe and clinically well tolerated, and that it provides protection against infection and disease. A vaccination dose of 20 mcg appears more advantageous for healthy adult subjects.