Chronic hepatitis delta cirrhosis cured by adapting PEG-IFNα-2a + tenofovir disoproxil fumarate treatment duration until HBsAg loss.

As the loss of HBsAg during treatment of chronic hepatitis delta (CHD) is mandatory for definitive clearance and durable response, the optimal target of therapy should be complete response (CR), defined as loss of HDV RNA and HBsAg, plus development of anti-HBs. The optimal treatment duration of CHD is not well established. We present 2 cases of patients with CHD cirrhosis who were treated with prolonged Peg-IFNα-2a + tenofovir disoproxil fumarate until HBsAg loss, and who achieved CR after 46 and 55 months of treatment respectively. A personalized approach and prolonged treatment duration determined by HBsAg loss may increase the likelihood of CR in CHD.

Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress.

Hepatitis delta virus (HDV) coinfection or superinfection in hepatitis B virus (HBV)-infected patients results in a more aggressive liver disease, with more often fulminant forms and more rapid progression to cirrhosis and hepatocellular carcinoma. The mechanism(s) for this pejorative evolution remains unclear. To explore a specific HDV pathogenesis, we used a model of transient transfection of plasmids expressing the small (sHDAg or p24) or the large (LHDAg or p27) delta antigen in hepatocyte cell lines. We found that the production of reactive oxygen species was significantly higher in cells expressing p27. Consequently, p27 activated the signal transducer and activator of transcription-3 (STAT-3) and the nuclear factor kappa B (NF-κB) via the oxidative stress pathway. Moreover in the presence of antioxidants (PDTC, NAC) or calcium inhibitors (TMB-8, BAPTA-AM, Ruthenium Red), p27-induced activation of STAT-3 and NF-κB was dramatically reduced. Similarly, using a mutated form of p27, where the cysteine 211-isoprenylation residue was replaced by a serine, a significant reduction of STAT-3 and NF-κB activation was seen, suggesting the involvement of isoprenylation in this process. Additionally, we show that p27 is able to induce oxidative stress through activation of NADPH oxidase-4. These results provide insight into the mechanisms by which p27 can alter intracellular events relevant to HDV-related liver pathogenesis.

HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis.

Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 (n = 25) as compared with those infected with other genotypes (n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48%vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups (P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively (P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development.

[Detection of HBV DNA by sensitive techniques and definition of chronic VHB infection by pre-C-C mutants]. / Détection de l'ADN du VHB par des techniques sensibles et définition de l'infection VHB chronique à mutants pré-C-C.

Our purpose is to assess the question of the definition of hepatitis B virus pre-C-C mutant-chronic infection, according to the level of the viral load at the era of very sensitive techniques of quantification of HBV DNA.

Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein.

Human MxA is an alpha/beta interferon-inducible intracytoplasmic protein that mediates antiviral activity against several RNA viruses. We had previously shown that overexpression of the hepatitis B virus (HBV) capsid led to selective downregulation of MxA gene expression, suggesting a mechanism by which the virus escapes from the host defense system (O. Rosmorduc, H. Sirma, P. Soussan, E. Gordien, P. Lebon, M. Horisberger, C. Brechot and D. Kremsdorf, J. Gen. Virol. 80:1253-1262, 1999). In the present study, we investigated the antiviral activity of MxA protein against HBV. MxA-expressing HuH7 clones were established and transiently transfected with HBV, and viral replication was then studied. Viral protein secretion was profoundly reduced in MxA-expressing clones by 80% for HBV surface antigen (HBsAg) and 70% for HBV e antigen (HBeAg). The levels of intracytoplasmic HBsAg and HBeAg were reduced by about 80 and 50% in the two MxA-positive clones tested. A nearly complete disappearance of HBV DNA replicative intermediates was observed in MxA-expressing clones. Although the expression of total viral RNAs was not modified, two- to fourfold reductions in HBV cytoplasmic RNAs were found in MxA-expressing clones. This suggests the inhibition of HBV replication at a posttranscriptional level. Indeed, using the well-characterized posttranscriptional regulation element (PRE) reporter system, we were able to demonstrate a marked reduction (three- to eightfold) in the nucleocytoplasmic export of unspliced RNA in MxA-expressing clones. In addition, MxA protein did not interact with HBV nucleocapsid or interfere with HBV nucleocapsid formation. Our results show an antiviral effect of MxA protein on a DNA virus for the first time. MxA protein acts, at least in part, by inhibiting the nucleocytoplasmic export of viral mRNA via the PRE sequence.

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.

An unique seroepidemiological situation for hepatitis B markers in Guadeloupe: results of a prospective study in blood donors - abstract

Screening for HBsAG, anti-HBc, anti-HCV and ALAT levels is now performed on donor blood to prevent post-transfusion hepatitis. A prospective study of 2368 blood donors was performed in Guadeloupe (French West Indies) to determine risk factors associated with serologic abnormalities: 571 blood donations (24 percent) were positive for at least 1 of the 4 markers with 3.2 percent positive for HBsAG, 22 percent for anti-HBc, 0.8 percent for anti-HCV and 1.4 percent for ALAT (<45 IU/L). The anti-HCV prevalence was significantly different according to ALAT levels (P<10). Transfusion histosry and employment status (worker or serviceman) were found to be risk factors, with an odds ratio (OR) of 1.94 for serviceman population. Other unexpected risk factors were: number of years' residency in Guadeloupe (progressively increased risk with increasing number of years); birthplace and residence in the southern part of the island as well as the existence of gastrointestinal discomfort unrelated to viral hepatitis (OR=2.91). The results of this study show a unique epidemiological situation for hepatitis B virus in Guadeloupe necessitating careful selection of blood donors (AU)

Epidemiologic comparison of human T-lymphotropic virus type I-infected blood donors from endemic and nonendemic regions over a 3-year period.

BACKGROUND: Screening for human T-lymphotropic virus type I (HTLV-I) infection became systematic in 1989 in the French West Indies for blood from all donors and in France for blood from natives of endemic areas; in 1990, it was extended to blood from donors with at-risk sex partners and in July 1991 to blood from all donors. STUDY DESIGN AND METHODS: The epidemiologic characteristics of individuals found through the screening of donated blood to be HTLV-I infected were compared for an endemic region (Guadeloupe, French West Indies) and a nonendemic region (Paris area) over a 3-year period (1989 through 1991). RESULTS: In Guadeloupe, 131 HTLV-I-infected individuals were detected in the screening of 28,801 units; in the Paris area, 38 HTLV-I-infected donors were detected in the screening of 109,824 units. All Guadeloupean HTLV-I-infected donors were natives of endemic areas. Among the 38 Parisian HTLV-I-infected donors, 21 were natives of endemic areas, 10 were natives of endemic areas and had received transfusions, 2 were whites who had received transfusions, and 5 were whites who had had heterosexual contact with natives of endemic areas. The percentage of HTLV-I-infected individuals whose blood would have been excluded because of positivity for one or more markers for other viruses did not significantly change over the study period and did not significantly differ between regions (41%). Among the eight Parisian HTLV-I-infected blood donors detected after July 1991, six would not have been detected without the biologic screening. CONCLUSION: The generalization of biologic screening of HTLV-I-infected donated blood in France was useful for the prevention of HTLV-I and HTLV type II infections through transfusion.

A unique seroepidemiologic situation for hepatitis B markers in Guadeloupe. Results of a prospective study in blood donors.

Screening for HBsAg, anti-HBc, anti-HCV and ALAT levels is now performed on donated blood to prevent post-transfusion hepatitis. A prospective study of 2,368 blood donors was performed in Guadeloupe (French West Indies) to determine risk factors associated with serologic abnormalities: 571 donations (24%) were positive for at least 1 of the 4 analyzed markers with 3.2% positive for HBsAg, 22% for anti-HBc, 0.8% for anti-HCV and 1.4% with ALAT > or = 45 IU/L. The anti-HCV prevalence was significantly different according to ALAT levels (P < 10(-4)). Transfusion history and work status (worker or serviceman) were found to be risk factors, with an odds ratio of 1.94 for serviceman population. Other unexpected risk factors were: number of years residency in Guadeloupe (progressively increased risk with the number of years), birthplace and residence in southern part of the island as well as the existence of gastrointestinal discomfort unrelated to viral hepatitis (odds ratio = 2.91). The results of this study show a unique epidemiologic situation for hepatitis B virus in Guadeloupe necessitating careful selection of blood donors.

Human T lymphotropic virus (HTLV) type I and II DNA amplification in HTLV-I/II-seropositive blood donors of the French West Indies.

To confirm the presence of DNA from human T lymphotropic virus type I (HTLV-I), HTLV-II, or both in individuals found HTLV-I/II-positive through systematic screening of blood donations in Guadeloupe (French West Indies), 42 blood donors repeatedly positive for HTLV-I/II by ELISA were studied by polymerase chain reaction (PCR). Three primer pairs (env, pol, tax) targeted on conserved regions of HTLV-I or -II sequences (or both) and six probes (two generic, two HTLV-I-specific, two HTLV-II-specific) were used in a multiplex PCR. HTLV-I sequences were detected in 31 individuals (74%). All 31 subjects positive by Western blot (WB) harbored HTLV-I sequences. Fifteen individuals (48%) were positive with the three primer pairs used, 10 (32%) with two, and 6 (20%) with one. Subjects indeterminate or negative by WB were all negative by PCR. No HTLV-II sequences were detected with specific probes. The results indicate the absence of HTLV-I and -II infection in individuals with indeterminate WB, the presence of HTLV-I DNA in individuals positive for WB in the French West Indies, and the absence of HTLV-II infection in the cohort.

Quantification of HTLV-1 proviral copy number in peripheral blood of symptomless carriers from the French West Indies.

The development of human T-cell leukemia type 1 (HTLV-1) diseases are related to an increase in the proviral copy number (VCN) in peripheral blood mononuclear cells (PBMCs). Twenty symptomless anti-HTLV-1-positive blood donors, as well as four symptomatic individuals, all from the French West Indies, were studied. The VCN in PBMCs was determined by quantitative PCR. The VCN values for asymptomatic HTLV-1 carriers (range of less than 100 to approximately 9,500/micrograms of DNA) was nearly always less than the values for symptomatic carriers (range of approximately 5,500 to approximately 29,000/micrograms of DNA). Consequently, the proportion of HTLV-1-infected PBMCs in symptomless and in symptomatic individuals ranged from less than 1/1,500 to approximately 1/16 and approximately 1/27 to approximately 1/5, respectively. No correlation could be found between VCN and age or sex, suggesting the importance of factors other than age and sex as influences on the VCN number.

No evidence of HTLV-I infection in French patients with multiple sclerosis using the polymerase chain reaction.

The polymerase chain reaction (PCR), using three primer pairs in the pol, tax, and env regions of the HTLV-I genome, was unable to detect HTLV-I in the blood samples of 54 caucasian subjects with multiple sclerosis who were seronegative for HTLV-I/II. Seventeen HTLV-I/II seropositive (by ELISA and Western blot) subjects used as positive controls were positive with the three primer pairs. The PCR was negative in 47 healthy HTLV-I/II seronegative (by ELISA) subjects at low risk of HTLV-I infection used as negative controls. These results suggest that there is no association between the occurrence of HTLV-I sequences and the development of multiple sclerosis.

[Prevention of post-transfusion hepatitis in Guadeloupe: results after application of new measures for detecting blood donors potentially at risk]. / Prévention des hépatites post-transfusionnelles en Guadeloupe: résultats obtenus après application des nouvelles mesures visant à détecter les donneurs de sang potentiellement à risque.

One of the main concerns of blood transfusion centers is viral hepatitis as a direct result of blood transfusion. Ninety-five percent of these cases are non-A, non-B hepatitis. In order to prevent this disease, blood collections were screened for antibody anti-HBc as well as the level of activity of the alanine aminotransferase in 3,051 blood donors in Guadeloupe. this revealed a particular epidemiological situation, which caused this French country to be rated among moderate endemic zones for hepatitis B virus. As a result of this new screening procedure, 25 percent of the blood collected had to be discarded and was classified with prevalence rates of 21.8 percent HBc antibody, 2.9 percent HBs antigen, and 2.6 percent alanine aminotransferase (45 IU/l). Differences were noted according to sex, age, social-economical level and geographical origin of the blood donors. These data raised many significant questions regarding the vertical transmission of hepatitis B virus, the epidemiological situation of hepatitis B virus in the Guadeloupe population as well as in the rest of the French West-Indies, and also the type of action which must be taken against non-A, non-B hepatitis in a moderate endemic zone for HBV.