Evidence of hepatitis C virus viremia without detectable antibody to hepatitis C virus in a blood donor.
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Blood Donors↗
Biomedical subjects
P Marcellin
Publications and source records attributed to P Marcellin.
A new step toward standardization of serum hepatitis C virus-RNA quantification in patients with chronic hepatitis C.
The need to improve efficacy of antiviral therapy for chronic hepatitis C has prompted the development of quantitative assays, which allows the assessment of viral load before therapy. The aim of our study was to evaluate the clinical relevance of 3 serum HCV-RNA quantitative assays in 87 patients with chronic hepatitis C, the noncommercially available SuperQuant assay (National Genetic Institute), recently used in large international controlled trials, the most early and widely used Quantiplex HCV RNA v2.0 assay (branched DNA [bDNA] v2.0; Bayer Diagnostics, Puteaux, France), and the new generation Cobas Amplicor HCV Monitor assay (COBAS v2.0; Roche Diagnostics Systems, Meylan, France), which is a semiautomated reverse transcription-polymerase chain reaction (RT-PCR) assay. The level and range of quantification were similar between all assays and a strong correlation was observed over all HCV genotypes among the assays. Recent publications have suggested that the baseline cut-off level of 2 x 10(6) copies/mL, as determined by the SuperQuant assay, is able to discriminate between patients with low viral load from those with high viral load and can be used to predict responses to therapy. Because all 3 assays use different testing technologies we examined how many of our patients fell above this defined cut-off level when tested by the other assays; of 22 patients measured below 2 x 10(6) copies/mL with the SuperQuant assay, 17 of 22 and 19 of 22 patients were eligible with the bDNA v2. 0 and the COBAS v2.0 assays, respectively (P >.05). Our results indicate that the 2 commercial assays can be used to determine treatment schedules in patients with chronic hepatitis C, providing a flexibility in multicenter controlled trials by offering better accessibility of test results.
Enzyme-Linked Immunosorbent Assay↗
Lessons from a multicentre study of the detectability of viral genomes based on a two-round quality control of GB virus C (GBV-C)/hepatitis G virus (HGV) polymerase chain reaction assay.
The aim of this study was to determine whether multicentre quality controls for the detectability of viral genomes could contribute to the improvement of diagnostic performance in the participating laboratories. The study was carried out during two successive rounds, during which 18 laboratories specialized in nucleic acid testing analyzed, through a polymerase chain reaction (PCR) assay, a common panel of GB virus C (GBV-C)/hepatitis G virus (HGV) RNA-positive and -negative samples. During the first round, the laboratories used either an 'in-house' PCR procedure or a partly standardized commercial test. After decoding the results of the first round, the procedures of the participating laboratories were compared in order to establish a consensus procedure deduced from those of the laboratories which provided the best results. During the second round, each participating laboratory could use the resulting consensus procedure, or its own procedure, or both. The results of this quality control study indicated that, whatever method used, even specialized and trained laboratories may give false-negative or false-positive results. The commercial assay did not guarantee a systematic high quality level of results. The striking heterogeneity of results observed among laboratories using the same commercial assay confirm that molecular biology methods need skilled technicians. The results of this quality control study suggest that full standardization of viral genome detection, including all steps of the procedure, is necessary and that the laboratories performing PCR should participate in repeated quality control studies, whatever technique is being used.
Flaviviridae↗
Decrease in serum ALT and increase in serum HCV RNA during pregnancy in women with chronic hepatitis C.
BACKGROUND/AIMS: The natural history of chronic hepatitis C infection during pregnancy has not been clearly established, and thus our aim was to assess serum alanine aminotransferase levels and serum HCV RNA levels during pregnancy. METHODS: Twenty-six pregnant women with chronic hepatitis C were studied. Serum alanine aminotransferase was assessed within the 3 months before, monthly during and within the 3 months after pregnancy. In 12 women, serum HCV RNA levels were quantified by the branched DNA assay. Twenty-six age-matched non-pregnant women with chronic hepatitis C were followed up for 1 year, and used as a comparison group. RESULTS: During pregnancy, serum alanine aminotransferase levels decreased in the second and third trimesters. The third trimester levels were significantly lower than serum alanine aminotransferase levels before pregnancy (p=0.0001). Seventy-seven percent of the pregnant women with increased pre-pregnancy levels had normalization of serum alanine aminotransferase levels. In the second or third trimesters, serum HCV RNA levels increased. The third trimester serum HCV RNA levels were significantly higher than levels before pregnancy (p=0.01). No significant change in serum alanine aminotransferase or HCV RNA levels was observed in the control group. CONCLUSION: In pregnant women with chronic hepatitis C, serum alanine aminotransferase levels decrease, and serum HCV RNA levels increase during the second and third trimesters.
Adult↗
A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.
BACKGROUND/AIMS: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/kg b.w., n=16) of recombinant human (rHu) IL-12 given s.c. once a week for 12 consecutive weeks. METHODS: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. RESULTS: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: at the end of the study HBV DNA clearance was greater in patients treated with 0.50 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-gamma, IL-10, neopterin and beta2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. CONCLUSIONS: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.
Adjuvants, Immunologic↗
Impact of TT virus infection in acute and chronic, viral- and non viral-related liver diseases.
BACKGROUND/AIMS: The prevalence and pathogenicity of TT virus, recently identified in patients with non A-non G post-transfusional hepatitis, are questioned. METHODS: We investigated the impact of this new viral infection in a large series of patients with non A-non G, cryptogenic, non-viral and viral-related, acute and chronic liver diseases (n=577) and blood donors (n=300). TTV DNA was detected in serum by hemi-nested polymerase chain reaction. Phylogenetic analysis was performed in 13 isolates. RESULTS: TTV DNA was detected in 6/25 and 15/127 patients with cryptogenic non A-non G acute and chronic liver disease, respectively. TTV DNA positive subjects with post-transfusional acute hepatitis scored negative before transfusion. TTV prevalence was increased in patients with cryptogenic non A-non G acute and chronic liver disease compared to blood donors (6/300; p<0.001) and non-viral-related chronic liver diseases (6/137; p<0.05). TTV/HBV coinfection was frequently identified (35/147), but this was not the case for HCV-infected subjects (4/77). Transaminase activity or liver histological score was not significantly increased among TTV positive, HBV infected or non A-non G patients. The HBV infection and Mediterranean origin were the risk factors associated with TTV infection. The majority of analysed sequences clustered in genotype 1 (8=1b; 3=1a). Two isolates showed homology to genotype 2. CONCLUSIONS: These results support the view that TTV is a widely spread infectious agent with a weak pathogenicity. It raises the possibility, however, that TTV might be implicated in a few cases of acute and chronic non A-non G hepatitis. TTV-DNA-analysed sequences are related to genotypes 1 and 2 described in Europe.
Acute Disease↗
Pathogenesis, diagnosis and management of hepatitis C.
The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. It is estimated that about 170 million people are chronically infected with HCV. Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma and HCV-related end-stage liver disease is, in many countries, the first cause of liver transplantation. HCV infection is characterized by its propensity to chronicity. Because of its high genetic variability, HCV has the capability to escape the immune response of the host. HCV is not directly cytopathic and liver lesions are mainly related to immune-mediated mechanisms, which are characterized by a predominant type 1 helper cell response. Co-factors influencing the outcome of the disease including age, gender and alcohol consumption are poorly understood and other factors such as immunologic and genetic factors may play an important role. Recent studies have shown that the combination therapy with alpha interferon and ribavirin induces a sustained virological response in about 40% of patients with chronic hepatitis C. The sustained response rates are mainly dependent on the viral genotype (roughly 60% in genotype non-1 and 30% in genotype 1). Reliable diagnostic tools are now available and useful for detecting HCV infection, to quantify viral load and to determine the viral type. The assessment of the viral quasispecies and the characterization of viral sequences might be clinically relevant but standardized and simple techniques are needed. The lack of animal models and of in vitro culture systems hampers the understanding of the pathogenesis of chronic hepatitis C and the development of new antivirals. New therapeutic schedules with higher and/or daily doses of alpha interferon do not seem to improve the efficacy greatly. The conjugation with polyethylene glycol (PEG) improved the pharmacodynamics and the efficacy of alpha interferon. Emerging new therapies include inhibitors of viral enzymes (protease, helicase and polymerase), cytokines (IL-12 and IL-10), antisense oligonucleotides and ribozymes. The first candidate compounds should be available in the next few years. The development of an effective vaccine remains the most difficult and pressing challenge. Because of the high protein variability of HCV, protective vaccines could be extremely difficult to produce and therapeutic vaccines seem more realistic. Considerable progress has been made in the field of HCV since its discovery 10 years ago but a major effort needs to be made in the next decade to control HCV-related liver disease.
Antiviral Agents↗
[Discovery of a chronic HVC infection without seroconversion in a blood donor in France during 28 months].
The HCV-RNA screening technique developed by the French Fractionation and Biotechnology Laboratory singled out in March 1998 a case of positive HCV-RNA viremia in a blood donor without any anti-HCV antibody. That donor was a 46-year-old woman who had made 54 donations of blood products from 1988 to 1997. She had no history of blood transfusion, no history of hepatitis and no life-style risk factor. Clinical examination was normal. Liver tests (serum alanine amino transferases, gamma glutamyl transpeptidase , alkaline phosphatase, bilirubin , prothrombin and albumin) were normal. Total blood count was normal. Lymphocyte count was normal as well as in vitro functional analysis of lymphocytes (stimulation with different antigens). All screening HCV Elisa tests and immunoblot System available on the French market were unable to detect anti-HCV antibodies. Quantification of serum HCV-RNA (Amplicor Monitor Roche) showed 294,000 copies/mL and HCV genotype 1b determination was performed using Innolipa assay. Further examination of the HCV genotype by direct sequencing of the PCR product showed a classical 1b genotype sequence. The hemovigilance inquiry identified 25 labile products distributed since 1988. Analyzing the records of the recipients that have so far been traced and identified revealed three periods: 1997 to 1995: three recipients were found to be positive for anti-HCV antibodies; two are now cured of hepatitis C. In one recipient, direct sequencing after specific PCR of the hypervariable region coding for the envelope domain showed 100% homology with the donor; 1993 to 1990: four recipients were identified and traced without contamination; in 1988: three of four blood product recipients were anti-HCV negative without HCV-RNA viremia. The forth carried anti-HCV antibodies and genotype 1b HCV-RNA but had a history of multiple surgery. Alter et al. [4] and Bush et al. [5] have previously suggested the possibility of a chronic, immunologically silent state of infection. The case described herein, is the first evidence for this hypothesis. Indeed, the donor has not yet seroconverted 28 months after viremia was discovered. This blood donor was identified by HCV-RNA screening of plasma products. The identification of the same sequence in a recipient of blood from this donor clearly establishes the transmission of the virus by transfusion. The prevalence of such cases of infectious silent chronic HCV carriers has to be determined and the mechanisms responsible for the absence of antibody production need to be clarified.
Amino Acid Sequence↗
Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis.
UNLABELLED: Response to treatment with alpha interferon with or without concomitant ribavirin varies according to the viral genotype in patients with chronic hepatitis C. AIM: This study was undertaken in order to determine the response of genotype 4 chronic hepatitis C to interferon and ribavirin combination compared to interferon alone in patients without cirrhosis. METHODS: Fifty-two patients were given interferon alone at a dose of 5 million units, 3 times a week and another 60 patients were administered with interferon combined with ribavarin (1,000-1,200 mg/ day) for 24 weeks. Sustained biochemical response was defined as normal ALT, 6 months after end of therapy. Sustained virologic response was defined as negative HCV RNA, 6 months after the end of therapy. RESULTS: Only 10/52 (19%) patients showed sustained biochemical response after interferon alone, while 31/60 (52%) showed sustained biochemical response after interferon combined with ribavirin (p<0.01). Only 4/52 (8%) patients showed sustained virologic response after interferon alone, while 25/60 (42%) showed sustained virologic response after interferon combined with ribavirin (p<0.001). CONCLUSION: These results show that patients with chronic hepatitis due to hepatitis C virus type 4 show a poor response to interferon alone but a better response to interferon combined with ribavirin.
Adult↗
A pilot study of recombinant interferon beta-1a for the treatment of chronic hepatitis C.
AIMS: Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and tolerance of recombinant interferon beta-la administered subcutaneously. METHODS: Twenty-one drug-naive patients with chronic hepatitis C were treated with recombinant interferon beta-la administered, subcutaneously, for 24 weeks using two different regimens: 9 MU, three times per week (n=11) and 12 MU, three times per week (n=10). RESULTS: At the end of the treatment period, nine (43%) patients had a biochemical and virological response (i.e. normal ALT and absence of hepatitis C virus RNA by PCR). Four of these patients were in the 9 MU group and five in the 12 MU group. A biochemical and virological sustained response occurred in four (19%) patients, all in the 9 MU dose group. The 4 patients with a sustained response maintained their response during a follow-up period of 33 to 58 months. Side effects were mild and 19 (90%) patients completed the treatment period. CONCLUSIONS: The results of this pilot study indicate that interferon beta-la administered subcutaneously is an effective therapy for some patients with chronic hepatitis C, and suggest that interferon beta-1a deserves further evaluations in larger trials especially in combination with ribavirin.
Adult↗
Serum alanine transaminase level is a good predictor of response to interferon alfa therapy for chronic hepatitis B in human immunodeficiency virus-infected patients.
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Acquired Immunodeficiency Syndrome↗
A la carte interferon for hepatitis C?
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Antiviral Agents↗
A randomized, placebo-controlled study to evaluate the efficacy of 12-month famciclovir treatment in patients with chronic hepatitis B e antigen-positive hepatitis B.
We conducted a randomized, placebo-controlled clinical study evaluating famciclovir (500 mg 3 times daily and 1.5 g once daily) for 1 year (6 months post-treatment follow-up) in patients with chronic hepatitis B e antigen (HBeAg)-positive hepatitis B virus (HBV) infection. The study was conducted in 80 centers in North America, Europe, and Australia/New Zealand. A total of 417 patients with histologically documented chronic hepatitis B (histologic activity index [HAI] 9.5-11.0) received famciclovir (500 mg 3 times daily or 1.5 g once daily) or placebo. Famciclovir 500 mg 3 times daily significantly reduced HBV DNA and median HAI scores versus placebo. By week 8, median HBV DNA decreased from 1,645 to 283 MEq/mL (famciclovir 500 mg 3 times daily) and from 1,147 to 304 MEq/mL (famciclovir 1.5 g once daily), while increasing for placebo (1,617 to 1,685 MEq/mL). Median change in HBV DNA at the end of therapy was -76% (famciclovir 500 mg 3 times daily; P <.01) and -60% (famciclovir 1.5 g once daily; P =.25) versus -37% for placebo. Median change in HAI was -1.5 points (famciclovir 500 mg 3 times daily; P =.02) and -1.0 point (famciclovir 1.5 g once daily; P =.35) and zero for placebo. Fifty percent of patients receiving famciclovir 500 mg 3 times daily (P =.07) and 43% receiving 1.5 g once daily (P =.41) experienced >/=2 points improvement in HAI versus 37% for placebo. Nine percent of patients treated with famciclovir 500 mg 3 times daily underwent anti-HBeAg seroconversion with undetectable HBV DNA at end of follow-up versus 3% in the placebo group (P =.05). Famciclovir was well tolerated; the incidence of post-treatment alanine transaminase (ALT) elevations was comparable with placebo. In conclusion, famciclovir 500 mg 3 times daily gave modest suppression of viral replication, but translated into significant histologic improvement in median HAI score at 1 year.
2-Aminopurine↗
Assessment of viral loads in patients with chronic hepatitis C with AMPLICOR HCV MONITOR version 1.0, COBAS HCV MONITOR version 2.0, and QUANTIPLEX HCV RNA version 2.0 assays.
The correlation between response to antiviral therapy and pretreatment viral load in patients with chronic hepatitis C has prompted the development of quantitative assays to measure viral load. The aim of our study was to assess the clinical relevance of the newly developed semiautomated PCR system COBAS HCV MONITOR version 2.0 in comparison with (i) the AMPLICOR HCV MONITOR version 1.0 assay, which underestimates RNA concentration of hepatitis C virus (HCV) genotypes 2 to 6, and (ii) the QUANTIPLEX HCV RNA version 2.0 assay, which achieves equivalent quantification for each HCV genotype, with samples from 174 patients diagnosed with chronic hepatitis C before therapy. The level and range of quantification measured with AMPLICOR HCV MONITOR version 1.0 were 1 log lower than when measured with the COBAS HCV MONITOR version 2.0, at 0.261 x 10(6) RNA copies/ml (range, 0.001 x 10(6) to 2.50 x 10(6) RNA copies/ml) and 4.032 x 10(6) RNA copies/ml (range, 0.026 x 10(6) to 72.6 x 10(6) RNA copies/ml), respectively. The two assays showed a poor correlation (r(2) = 0.175). The level and range of quantification were similar when measured with the COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays, at 3.03 x 10(6) RNA copies/ml (range, 0.023 x 10(6) to 72.6 x 10(6) RNA copies/ml) and 4.91 Meq/ml (range, 0.200 to 49.5 Meq/ml), respectively. The two assays showed a strong correlation (r(2) = 0. 686) for each HCV genotype. The duration of treatment (6 or 12 months) is modulated according to HCV genotype and viral load. Our results indicate that COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays showing an equal dynamic range for each HCV genotype are suitable tools to assess patients before therapy.
Evaluation Studies as Topic↗
[Alpha interferon-induced eczema in atopic patients infected by hepatitis C virus: 4 case reports].
OBJECTIVES: We report four cases of eczema induced by alpha interferon in atopic patients treated for chronic hepatitis C. CASE REPORTS: Eczema developed in 4 patients with certain (3 cases) or possible (1 case) atopy treated by subcutaneous injections of alpha interferon for hepatitis C virus infections. Delay to onset was 3 weeks to 6 months. Interferon was highly likely the causal agent: lesions started at site of interferon injection, followed the rhythm of interferon injections (three cases), disappeared at interferon withdrawal. In two patients, the lesions diffused to other sites. Both Introna and Roféron were used. Three patients also took ribavirine. The possible role of a contact factor (antiseptic.) was ruled out. Skin tests (patch tests, prick tests, intradermal reactions) were negative for interferon alpha and for a standard battery. DISCUSSION: The role of interferon in the induction of skin diseases or its influence on the course of certain dermatoses is well known. In atopic patients, interferon might induce eczema via an immunomodulator rather than an allergic mechanism since skin tests (performed in one patient) were negative. This observation is similar to that in psoriasis induced by interferon in predisposed subjects who develop skin lesions at injection sites which sometimes diffuse to distant localizations. The role of other factors (hepatitis C virus infection, ribavirine) remains unknown; they might participate in this mechanism by aggravating skin dryness.
Adrenal Cortex Hormones↗
[Genetic variability of the hepatitis C virus: clinical implications].
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Genetic Variation↗
Prevalence of hepatitis C virus infection in patients hospitalized for hepatitis A.
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Hepatitis A↗
Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men.
The aim of this study was to assess the influence of human immunodeficiency virus (HIV) infection on chronic hepatitis B. In a series of 132 (65 anti-HIV positive) homosexual non-drug addicted men with chronic hepatitis B, the liver function was assessed with biochemical tests; the degree of hepatitis B virus (HBV) replication was assessed with serum HBV DNA level and with immunoperoxidase staining of hepatitis B core (HBc) antigen on liver specimens; and the severity of liver lesions was assessed with an histology activity index. Anti-HIV-positive and anti-HIV-negative patients were not different for serum aspartate transaminase activity, bilirubin, prothrombin, and histology activity index. Anti-HIV-positive patients had lower serum alanine transaminase activity levels (P =.0001), lower serum albumin levels (P =.0009), and higher serum HBV DNA levels (P =.01). There was a higher prevalence of cirrhosis in anti-HIV-positive patients (P =.04). In homosexual men with chronic hepatitis B, HIV infection is associated with a higher level of HBV replication and a higher risk for cirrhosis without increased liver necrotico-inflammatory process.
Alanine Transaminase↗