HBV core sequence: definition of genotype-specific variability and correlation with geographical origin

There are eight genotypes and nine subtypes of HBV. Small differences in geographical origin are associated with sequence changes in the surface gene. Here, we compared core gene sequences from different genotypes and geographical regions. Specific combinations of 24 amino acid substitutions at nine residues allowed allocation of a sequence to a subtype. Six of these nine residues were located in different T cell epitopes depending on HBV geographical area and/or genotype. Thirty-seven nucleotide changes were associated uniquely with specific genotypes and subtypes. Unique amino acid and nucleotide variants were found in a majority of sequences from specific countries as well as within subtype ayw2 and adr. Specific nucleotide motifs were defined for Korean, Indian, Chinese, Italian and Pacific region isolates. Finally, we observed amino acid motifs that were common to either South-east Asian or Western populations, irrespective of subtype. We believe that HBV strains spread within constrained ethnic groups, result in selection pressures that define sequence variability within each subtype. It suggests that particular T cell epitopes are specific for geographical regions, and thus ethnic groups; this may affect the design of immunomodulatory therapies.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naive adults with CHC.

Transmission dynamics of the Echinococcus granulosus sheep-dog strain (G1 genotype) in camels in Tunisia

Cystic echinococcosis, caused by Echinococcus grantilosus, is highly endemic in North Africa and the Middle East. This paper examines the abundance and prevalence of infection of E. granulosus in camels in Tunisia. No cysts were found in 103 camels from Kebili, whilst 19 of 188 camels from Benguerden (10.1%) were infected. Of the cysts found 95% were considered fertile with the presence of protoscolices and 80% of protoscolices were considered viable by their ability to exclude aqueous eosin. Molecular techniques were used on cyst material from camels and this demonstrated that the study animals were infected with the G1 sheep strain of E. granulosus. Observed data were fitted to a mathematical model by maximum likelihood techniques to define the parameters and their confidence limits and the negative binomial distribution was used to define the error variance in the observed data. The infection pressure to camels was somewhat lower in comparison to sheep reported in an earlier study. However, because camels are much longer-lived animals, the results of the model fit suggested that older camels have a relatively high prevalence rate, reaching a most likely value of 32% at age 15 years. This could represent an important source of transmission to dogs and hence indirectly to man of this zonotic strain. In common with similar studies on other species, there was no evidence of parasite-induced immunity in camels. (C) 2004 Elsevier B.V. All rights reserved.

Active and passive immunization against oral Candida albicans infection in a murine model

Background/aims: Clinical and laboratory studies are consistent with a major role for cell-mediated immunity in recovery from oral infection with Candida albicans, but the role of humoral immunity remains controversial. The purpose of this study was to establish the relative contributions of cellular and humoral immunity to protection against oral candidiasis in a murine model, and to determine whether host responses could be enhanced by different immunization strategies. Results: Active oral immunization was protective in BALB/c and CBA/CaH mice, reducing both fungal burden and duration of infection after secondary challenge, whereas systemic immunization failed to protect against subsequent oral challenge. Candida-specific IgM was the predominant antibody detected in serum following both primary and secondary oral challenge; however, Candida-specific salivary IgA was not detectable. Immunization by passive transfer of either lymphocytes or immune serum did not confer any significant protection against oral infection in either susceptible or resistant mouse strain. Conclusion: The data demonstrate a possible role for mucosa-associated immunity following active immunization by the oral route, most likely exerted by local T lymphocytes resident in the oral mucosa, but there was no evidence to support a role for humoral immunity in protection against oral candidiasis.

Isolates of Candida albicans that differ in virulence for mice elicit strain-specific antibody-mediated protective responses

Three distinct isolates of Candida albicans were used to establish systemic and oral infections in inbred mice that are genetically resistant or susceptible to tissue damage. Patterns of infection differed significantly between both yeasts and mouse strains. Systemic infection conferred significant protection against re-challenge with the homologous, but not the heterologous yeast; however, the protective effect was more evident in the tissue-susceptible CBA/CaH mice than in the resistant BALB/c strain. In contrast, oral infection induced protection against both homologous and heterologous oral challenge, although this was significant only in the CBA/CaH mice. CBA/CaH mice produced antibodies of both IgG1 and IgG2a subclasses, whereas BALB/c mice produced predominantly IgG1. Western blotting demonstrated considerable differences between epitopes recognised by serum antibodies from mice of both strains after immunisation with each of the three yeasts. Thus, different strains of yeast show considerable specificity in antibody responses elicited by either systemic or oral infection. (c) 2005 Elsevier SAS. All rights reserved.

Effector function of leucocytes from susceptible and resistant mice against distinct isolates of Candida albicans

Neutrophils and macrophages were generated in vitro from mice that display either high or low tissue susceptibilities to Candida albicans infection and their ability to phagocytose and kill three isolates of the yeast with different virulence characteristics was evaluated. In the absence of opsonization, phagocytosis by BALB/c and CBA/CaH neutrophils was comparable, but the killing was very poor. Opsonization with normal serum slightly decreased phagocytosis, but it had markedly different effects on killing, either enhancing or inhibiting candidacidal activity, depending on the combination of yeast isolate and mouse strain. In contrast, BALB/c macrophages showed high levels of phagocytosis and killing of both unopsonized yeasts and opsonized yeasts; whereas killing of unopsonized yeasts by CBA/CaH macrophages was poor, it was markedly enhanced by opsonization.

Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data

Background & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in :1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in :142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin

SUMMARY. We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon- alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.