Prevention of hepatitis B virus infection: from the past to the future.

About 3-5 % of the world's population is chronically infected by hepatitis B virus (HBV) and is at risk of developing liver cirrhosis or hepatocellular carcinoma. The risk of dying prematurely because of chronic HBV infection is higher in younger people. The current strategies to prevent HBV infection involve immunization (active and/or passive) and antiviral chemoprophylaxis. The vaccines available for active immunization, containing hepatitis B surface antigen, are safe and confer long-term immunity in most healthy subjects. Since the vaccination is unsatisfactory in some patients, e.g., those with chronic kidney disease, human immunodeficiency virus infection, type I diabetes mellitus, and celiac disease, new strategies of vaccination are required. The neonatal, infant, and adolescent routine program vaccination in about 180 countries has greatly decreased the disease burden. Passive immunization with specific HBV immunoglobulins is recommended after single acute exposure, in infants born to infected mothers, and in HBV-infected patients undergoing liver transplantation combined with nucleoside/nucleotide analogues (chemoprophylaxis). Chemoprophylaxis is also indicated in HBV carrier candidates for immunosuppressive treatment and in patients with occult B infection undergoing immunosuppressive therapy or hematopoietic stem cell transplantation. Since HBV is not eradicable by an immune response or by antiviral drugs developed so far, the only preventive strategy remains global neonatal vaccination in all countries, firstly in HBV-endemic countries.

Immunocompromised patients with HBsAg a determinant mutants: comparison of HBsAg diagnostic assays.

Hepatitis B surface antigen (HBsAg) is considered the best marker for the diagnosis of hepatitis B virus (HBV) infection. Mutations of the s gene involving amino acid substitutions within the a determinant could affect the sensitivity of diagnostic tests. In the present study, HBsAg mutants were detected in 3 immunocompromised patients, previously found to be HBsAg negative and anti-HBs positive. All patients had high levels of HBV-DNA, whereas HBsAg tests gave discordant results. Immunosuppression can cause viral reactivation of occult HBV infection in these patients and favour the selection of HBsAg a determinant mutants.

Isolated laryngeal leishmaniasis in an immunocompetent patient: a case report.

Visceral leishmaniasis, a protozoan disease caused by Leishmania infantum, is endemic in the Mediterranean basin, especially southern and Tyrrhenian Italy. Its aetiological agent can also sporadically cause isolated laryngeal localization in at-risk patients (i.e., heavy smokers, immunocompromised patients). This rare localization is often pauci-symptomatic and thus can easily escape diagnosis. A case of isolated leishmaniasis limited to the left vocal cord in an immunocompetent Italian male without significant risk factors, randomly discovered upon histological examination, is described herein. We inquire how many patients affected by non-specific symptoms such as dysphonia and live in countries where Leishmania infantum infection is reported, could be truly affected by Leishmania spp infection.

Prolonged persistence of lamivudine-resistant mutant and emergence of new lamivudine-resistant mutants two years after lamivudine withdrawal in HBsAg-positive chronic hepatitis patient: a case report.

Lamivudine can select resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate aminoacid motif (YMDD) mutants, which usually disappear in few months after lamivudine withdrawal. We report an unusual case of a male adult patient who showed a prolonged persistence of the M204I mutation up to 24 months after lamivudine withdrawal followed by the emergence of new distinct YMDD mutants (namely M204V, V207L). Only 42 months after lamivudine withdrawal wild-type YMDD motif became dominant over the YMDD mutants. To our knowledge, a so prolonged persistence of a YMDD mutant and also the emergence of new YMDD mutants many months after drug withdrawal are unusual.

A case of pegylated interferon alpha-related diabetic ketoacidosis: can this complication be avoided?

We report the case of a 42-year-old woman with chronic hepatitis C (genotype 1), who in June 2004 started therapy with pegylated interferon alpha (PEG-IFNalpha) plus ribavirin. Two months later, she discontinued treatment because of polydipsia, polyuria and vomiting leading to a marked dehydration. Biochemical data showed type 1 diabetes mellitus with ketoacidosis, and insulin therapy was started. The patient, who before starting PEG-IFN alpha plus ribavirin therapy tested negative for glutamic acid decarboxylase antibodies (GADAb) and islet cell (ICAb) antibodies, became strongly positive for both autoimmune markers. This case confirms that patients with chronic hepatitis C who do not have baseline markers of pancreatic autoimmunity may develop severe ketoacidosis during treatment with PEG-IFNalpha, as well as with standard IFNalpha. In order to avoid this complication, as no guidelines are available and the pancreatic autoimmunity markers are not routinely analysed, we suggest frequent monitoring (e.g., every one to two weeks) of glycaemic values: e.g., every one to two weeks during the first 3 months (when this complication occurs most frequently) and monthly thereafter so as to identify diabetes at an early stage and before the onset of the appearance of severe ketoacidosis, which is life-threatening.

Severe reactivation of hepatitis B virus infection in a patient with hairy cell leukemia: Should lamivudine prophylaxis be recommended to HBsAg-negative, anti-HBc-positive patients?

The reverse seroconversion to hepatitis B virus infection has been sporadically described in onco-haematological patients receiving cytotoxic therapy or allogeneic bone marrow transplantation and can be associated with the development of acute icteric hepatitis. We present a male HBsAg-negative, anti-HBc-positive patient with Hairy Cell Leukemia who developed acute B hepatitis more than 1 year after the last course of 2-CdA and 6 months after splenectomy, while the patient was receiving therapy with alphaIFNr. The acute B hepatitis promptly responded to lamivudine therapy followed by viral clearance.

Myocardial ischemia caused by an hydatid cyst of the interventricular septum successfully treated with albendazole.

We report the case of a 33-year-old patient with clinical history of echinococcosis admitted to our Hospital for the appearance of chest pain and electrocardiographic findings of anterior ischemia. The cardiac enzymogram was in the normal range, the chest roentgengram did not show any pathological findings, but two-dimensional echocardiography revealed the presence of a small circular area in the interventricular septum. Transesophageal echocardiography and cardiac nuclear magnetic resonance confirmed the presence of a small hydatid cyst in the middle ventricular septum; in addition, a myocardial scintigraphy revealed an apical stress defect with late reperfusion. Besides cardiologic therapy, the patient was treated with albendazole, an antiparasitic drug, 400 mg bid, for cycles of 28 days with 14 day withdrawal. After two cycles of albendazole therapy, two-dimensional echocardiography showed the absence of the round cystic mass of the interventricular septum previously described. In conclusion, in the case described, long-term therapy with albendazole determined the complete recovery from the illness with the simultaneous disappearance of the cyst and of clinical and electrocardiographic findings of myocardial ischemia.

Safety and immunogenicity of hepatitis A vaccine in infants: a candidate for inclusion in the childhood vaccination programme.

Forty-eight infants received a single dose (720 ELISA units = 0.5 ml) of inactivated hepatitis A vaccine at the fifth month of age with booster at the 11th month of age, together with the second and third doses of the vaccines compulsory under Italian law (diphtheria, tetanus, oral polio and hepatitis B). Overall, the seroconversion rate was 100%. The anti-HAV geometric mean titre (GMT) reached 3,021 mIU/ml in infants born to anti-HAV-negative mothers, but only 399 mIU/ml in infants born to anti-HAV-positive mothers. Hepatitis A vaccine was immunogenic, safe and well tolerated without significant side-effects. There seems to be no reason for not including it in childhood vaccination programmes particularly in low endemic HAV areas.

Prophylaxis of hepatitis C with intramuscular immunoglobulin: clinical and economic appraisal.

Hepatitis C virus (HCV) affects millions of individuals worldwide. In most cases, HCV infection progresses to chronic liver disease and, subsequently, to liver cirrhosis and hepatocellular carcinoma. HCV is transmitted by the parenteral route, for example by transfusion of blood or blood products, injection during drug abuse, etc., and by the inapparent parenteral route (penetration of the virus through difficult-to-identify microlesions present on the skin or mucosae), for example, sexual exposure or household exposure to infected contacts, etc. The cost of chronic hepatitis C and its sequelae is high in both financial and human terms. At present, only anti-HCV screening of blood/organ/tissue donors and universal precautions for the prevention of blood-borne infections are recommended for HCV prevention. Before the discovery of the main aetiological agent of non-A, non-B hepatitis (HCV), several randomised controlled clinical trials demonstrated that standard intramuscular immunoglobulin exerted a preventive effect on post-transfusional and sexual and /or horizontal transmission of non-A, non-B hepatitis. When serological tests for HCV infection became available, bimonthly inoculation of standard unscreened intramuscular immunoglobulin (prepared from plasma pools containing about 2% of anti-HCV-positive units) was demonstrated to significantly prevent sexually transmitted HCV infection. The immunoglobulin used contained high titres of anti-HCV neutralising antibodies (anti-E2 neutralisation of binding assay), whereas currently available commercial screened immunoglobulin (prepared from anti-HCV-negative blood units) did not. This finding suggested that anti-HCV neutralising antibodies are concentrated only in anti-HCV-positive units (which are currently discarded). Thus, anti-HCV hyperimmune globulin (HCIg) can be produced only from anti-HCV-positive units. The neutralising titre can be increased by the exclusive use of units with higher titres of neutralising antibodies. Unlike other hyperimmune globulins, which are produced from a limited number of selected donors, HCIg should be produced from a large number of units so as to contain neutralising antibodies to the different HCV strains. HCIg will have a number of advantages: (i) it is easy to produce and inexpensive; (ii) it has a long half-life, allowing infrequent administration; (iii) new additional viral inactivation procedures have been introduced to eradicate transmission of infection, and (iv) it may be possible to neutralise all the emerging HCV strains. HCIg could be used in all individuals at risk of HCV infection (sexual partners, haemodialysis patients, etc), in preventing reinfection of transplanted livers, and perhaps also in the treatment of chronic hepatitis C, alone or associated with other drugs.

Evolution of hypervariable region 1 of hepatitis C virus in primary infection.

The hypervariable region 1 (HVR-1) of the putative envelope encoding E2 region of hepatitis C virus (HCV) RNA was analyzed in sequential samples from three patients with acute type C hepatitis infected from different sources to address (i) the dynamics of intrahost HCV variability during the primary infection and (ii) the role of host selective pressure in driving viral genetic evolution. HVR-1 sequences from 20 clones per each point in time were analyzed after amplification, cloning, and purification of plasmid DNA from single colonies of transformed cells. The intrasample evolutionary analysis (nonsynonymous mutations per nonsynonymous site [Ka], synonymous mutations per synonymous site [Ks], Ka/Ks ratio, and genetic distances [gd]) documented low gd in early samples (ranging from 2. 11 to 7.79%) and a further decrease after seroconversion (from 0 to 4.80%), suggesting that primary HCV infection is an oligoclonal event, and found different levels and dynamics of host pressure in the three cases. The intersample analysis (pairwise comparisons of intrapatient sequences; rKa, rKs, rKa/rKs ratio, and gd) confirmed the individual features of HCV genetic evolution in the three subjects and pointed to the relative contribution of either neutral evolution or selective forces in driving viral variability, documenting that adaptation of HCV for persistence in vivo follows different routes, probably representing the molecular counterpart of the viral fitness for individual environments.

Sexual transmission of hepatitis C virus and prevention with intramuscular immunoglobulin.

The sexual transmission of hepatitis C virus (HCV) has long been debated. The prevalence of infected at-risk partners varies from 0% to 30%. In a prospective study, the risk of infection was quantified in steady heterosexual partners and the prophylactic effect of normal human polyvalent immune serum globulin (ISG) was evaluated. A total of 899 at-risk partners of HCV-infected patients were enrolled in a single-blind randomized controlled trial and assigned to receive every 2 month 4 mL of intramuscular ISG from unscreened donors (450 partners) or placebo (499 partners). Seven partners developed acute HCV infection (increased aminotransferase levels and appearance of HCV-RNA): six of the placebo group (incidence density [ID] 12.00/1,000 person year; 95% confidence interval [CI] 3.0 to 21.61), and only one of the ISG-treated group (ID 1.98/1,000 person year; 95% CI 0 to 5.86). The risk of infection was significantly higher in controls versus treated individuals (p = 0.03). Six couples had genotype 1b (85%), and one couple had genotype 1a; HCV sequence homology strongly supported sexual transmission. Our trial demonstrates that HCV infection can be sexually transmitted and quantifies the risk of sexual transmission: for every year of at-risk sexual relationship, almost 1% of the partners became infected. Intramuscular ISG is safe and well tolerated. Unlike ISG from screened donors, ISG from donors unscreened for anti-HCV contains high titers of anti-gpE1/gpE2 neutralizing antibodies and high neutralizing activity. Anti-HCV hyperimmune globulin could be prepared from anti-HCV-positive blood units and could be used to protect sexual partners and in other at-risk situations of exposure to HCV infection.

Long-term interferon-alpha therapy does not affect sex hormones in males with chronic hepatitis C.

The effects of interferon-alpha (IFN-alpha), given at a dosage of 6 MU thrice weekly for 12 months, on gonadal function were investigated in 18 males affected by chronic hepatitis C. Periodically, all patients were clinically monitored and questioned about sexual function. Gonadotropin and serum androgen concentrations (follicle-stimulating hormone, luteinizing hormone, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and sex hormone binding globulin) were tested every 3 months. Ten of 18 patients (55%) responded to IFN-alpha therapy. Serum total testosterone and sex hormone binding globulin values decreased slightly at the third month of treatment, then returned to baseline values. Serum free testosterone and other sex hormones remained essentially unchanged during IFN-alpha therapy. Four patients (22.2%) complained of sexual dysfunction (impaired libido, erectile failure, and impaired ejaculation), which was unrelated to any significant hormonal change and resolved after IFN therapy was stopped. Serum sex hormones values did not differ between responders and nonresponders to IFN-alpha. This study indicates that 12 months treatment with 6 MU of IFN-alpha thrice weekly does not significantly affect gonadal function in men with chronic hepatitis C. The sexual dysfunction observed could be ascribed to such other side effects of IFN as asthenia, fatigue, or anxiety, or it could have a psychologic basis.

Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. A randomized controlled trial.

OBJECTIVE: To estimate the risk of sexual transmission of hepatitis C and to assess the value of prophylaxis with periodic intramuscular immune serum globulin administration. METHODS: Of 1102 steady heterosexual partners of patients with antibodies to the hepatitis C virus (HCV), 899 were enrolled in a single-blind, randomized, controlled trial. All the partners tested negative for antibodies to HCV and had normal baseline serum aminotransferase concentrations. The partners were assigned to receive 4 mL of 16% polyvalent immune serum globulin prepared from unscreened donors every 2 months (n = 450) or a placebo (n = 449). Tests for HCV infection were performed every 4 months. RESULTS: Eight hundred eighty-four partners completed the study. Seven partners became infected with HCV: 6 in the control group (incidence density, 12.00 per 1000 person-years; 95% confidence interval, 3.0 21.61) and 1 in the immune serum globulin group (incidence density, 1.98 per 1000 person-years; 95% confidence interval, 0-5.86). The risk of infection was significantly higher for partners in the control group (P = .03): for each year approximately 1% of the partners became infected. Sequence homology studies strongly suggest the sexual transmission of HCV. All immune serum globulin lots used had high enzyme-linked immunosorbent assay titers of neutralizing antibodies to HCV envelope glycoproteins and high neutralization titers in the neutralization of binding assay. CONCLUSIONS: Hepatitis C can be sexually transmitted. Immune serum globulin prepared from unscreened donors significantly reduced the risk. The treatment was safe and well tolerated. Because only immune serum globulin from unscreened donors (and not from those screened for HCV) contain anti-HCV neutralizing antibodies, hyperimmune anti-HCV immune serum globulin should be prepared from blood testing positive for antibodies to HCV, which is currently discarded.

Treatment of chronic hepatitis C with recombinant interferon alfa-2b.

In a study of 87 patients with chronic hepatitis C, 12 months' treatment with interferon alfa-2b at a dose of 6 million units (MU) three times per week seemed to be more effective than treatment with 3 MU three times a week for two months plus 1.5 MU three times a week for 10 months in increasing the percentage of long term responders. The percentage of patients in whom alanine amino-transferase activities returned to normal was highest in the 6 MU group, as was the percentage of responders who sustained this normal activity after treatment. Side effects were moderate and self-limited in most patients.

[Malaria prevention: new indications]. / Profilassi malarica: nuove indicazioni.

Malaria chemoprophylaxis must be continuously modified because of drug-resistant Plasmodium strains. The authors report the most recent regimens in all travelers including infants and pregnant women. The side effects of these drugs are pointed out.

[An update on the therapy of malaria]. / Aggiornamenti in tema della terapia della malaria.

The authors analyze the recent treatment regimens of malaria, related to Plasmodium strains and clinical manifestation. Chloroquine is the first choice drug for uncomplicated chloroquine-sensitive P. falciparum, whereas for P. malariae, P. vivax and P. ovale infections treatment with chloroquine plus primaquine is also recommended. For uncomplicated chloroquine-resistant P. falciparum infections many treatment regimens are available. Management of complications is also analyzed.

[Malaria epidemiology]. / Epidemiologia della malaria.

The investigators examine the worldwide epidemiological aspects of malaria infection, stressing the importance of possible alternative pathways of Plasmodium transmission in countries considered free of infection. The potential danger due to the persistence in Italy of the Anopheles mosquito, which could resume its role as a vector of Plasmodium in the future, is pointed out.