Hepatitis C subtype distribution in chronically infected patients with mild liver fibrosis in France: the GEMHEP study.

Treatment options for Hepatitis C infection have greatly improved with direct-acting antiviral (DAA) combinations achieving high cure rates. Nevertheless, the cost of this treatment is still high and access to treatment in many countries has been preferentially reserved for patients with more severe fibrosis (F3 and F4). In this French nationwide study, we investigated the epidemiological characteristics and genotype distribution of hepatitis C virus (HCV) in treatment-naive patients with METAVIR fibrosis stages between F0 and F2 in order to identify patient profiles that became eligible for unrestricted treatment in a second period. Between 2015 and 2016 we collected data from nine French university hospitals on a total of 584 HCV positive patients with absent, mild or moderate liver fibrosis. The most represented genotypes were genotype 1b (159/584; 27.2%), followed by genotype 1a (150/584; 25.7%); genotype 3 (87/584: 14.9%); genotype 4 (80/584; 13.7%). Among genotype 4: 4a was predominantly encountered with 22 patients (27.5% of genotype 4). Genotypes 1b and 1a are currently the most frequent virus types present in treatment-naive patients with mild fibrosis in France. They can be readily cured using the available DAA. Nevertheless, non-a/non-d genotype 4 is also frequent in this population and clinical data on the efficacy of DAA on these subtypes is missing. The GEMHEP is the French group for study and evaluation of viral hepatitis on a national scale. Data collection on epidemiological and molecular aspects of viral hepatitis is performed on a regular basis in all main French teaching hospitals and serves as a basis for surveillance of these infections. Analysis and trends are regularly published on behalf of the GEMHEP group. Data collection was performed retrospectively over the 2015-2016 period, covering nine main university hospitals in France. A total of 584 hepatitis C positive patients were included in this study. Genotyping of the circulating viruses showed a high prevalence of genotypes 1b and 1a in our population. The epidemiology of hepatitis C is slowly changing in France, particularly as a consequence of the rise of 'non-a non-d' genotype 4 viruses mainly originating from African populations. More data concerning treatment efficacy of these genotypes is needed in order to guide clinical care.

The novel HBx mutation F30V correlates with hepatocellular carcinoma in vivo, reduces hepatitis B virus replicative efficiency and enhances anti-apoptotic activity of HBx N terminus in vitro.

OBJECTIVE: We aimed to investigate HBx genetic elements correlated with hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC) and their impact on (a) HBV replicative efficiency, (b) HBx binding to circular covalently closed DNA (cccDNA), (c) apoptosis and cell-cycle progression, and (d) HBx structural stability. METHODS: This study included 123 individuals chronically infected with HBV: 27 with HCC (77.9% (21/27) genotype D; 22.1% (6/27) genotype A) and 96 without HCC (75% (72/96) genotype D; 25.0% (24/96) genotype A). HepG2 cells were transfected by wild-type or mutated linear HBV genome to assess pre-genomic RNA (pgRNA) and core-associated HBV-DNA levels, HBx-binding onto cccDNA by chromatin immunoprecipitation-based quantitative assay, and rate of apoptosis and cell-cycle progression by cytofluorimetry. RESULTS: F30V was the only HBx mutation correlated with HCC (18.5% (5/27) in HCC patients versus 1.0% (1/96) in non-HCC patients, p 0.002); a result confirmed by multivariate analysis. In vitro, F30V determined a 40% and 60% reduction in pgRNA and core-associated HBV-DNA compared with wild-type (p <0.05), in parallel with a significant decrease of HBx binding to cccDNA and decreased HBx stability. F30V also decreased the percentage of apoptotic cells compared with wild-type (14.8 ± 6.8% versus 19.1 ± 10.1%, p <0.01, without affecting cell-cycle progression) and increased the probability of HBx-Ser-31 being phosphorylated by PI3K-Akt kinase (known to promote anti-apoptotic activity). CONCLUSIONS: F30V was closely correlated with HBV-induced HCC in vivo, reduced HBV replicative efficiency by affecting HBx-binding to cccDNA and increased anti-apoptotic HBx activity in vitro. This suggests that F30V (although hampering HBV's replicative capacity) may promote hepatocyte survival, so potentially allowing persistent production of viral progeny and initiating HBV-driven hepatocarcinogenesis. Investigation of viral genetic markers associated with HCC is crucial to identify those patients at higher risk of HCC, who hence deserve intensive liver monitoring and/or early anti-HBV therapy.

Optimizing hepatitis B vaccination in prison.

OBJECTIVE: We aimed to establish the current status of hepatitis B virus (HBV) vaccination in prison. METHODS: We carried out two evaluations within a 1-year interval with inmates incarcerated for 6 to 12 months. A monitoring process was introduced in-between the two evaluations. RESULTS: We included 231 inmates. Overall, 42.9% were immunized because of a previous vaccination and 14.3% because of a previous exposure. Inmates born in an area of medium or high endemicity for HBV were significantly more exposed to HBV. The proportion of non-immunized inmates was 42.8% at the time of incarceration and 27.5% after 6 to 12 months. Vaccination coverage with two doses, after 6 to 12 months, was 63% among patients who were initially non-immunized. CONCLUSION: The recently developed accelerated vaccination schedule should help improve HBV vaccination coverage.

Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients.

BACKGROUND: The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. OBJECTIVES: In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. STUDY DESIGN: We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. RESULTS: We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e(-5), thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). CONCLUSIONS: We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis.

Hepatitis E virus infection as a new probable cause of de novo membranous nephropathy after kidney transplantation.

Hepatitis E virus (HEV) has been identified as a cause of chronic viral hepatitis in immunocompromised patients. Some glomerular diseases were found to be associated with this infection. We report the first case, to our knowledge, of a kidney transplant recipient who developed an HEV infection and de novo membranous nephropathy (MN) concomitantly. The patient displayed a hepatic cytolysis first and a nephrotic syndrome occurred 3 months later. HEV infection was diagnosed upon positive polymerase chain reaction on plasma and stool samples, and renal allograft biopsy revealed de novo MN. Typical causes of MN were definitively excluded. A 3-month course of ribavirin monotherapy allowed the patient to mount a sustained viral response that was rapidly followed by complete remission of the nephrotic syndrome. The chronology of the onset and remission of both diseases is highly suggestive of a causal relationship between hepatitis E and MN.

Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients.

OBJECTIVES: Data on the natural selection of isolates harbouring mutations within the NS3 protease, conferring resistance to hepatitis C virus (HCV) protease inhibitors (PIs), are limited for HIV/HCV-coinfected patients. The aim of this study was to describe the natural prevalence of mutations conferring resistance to HCV PIs in HIV/HCV-coinfected patients compared with HCV-monoinfected patients. METHODS: The natural prevalences of HCV PI resistance mutations in 120 sequences from HIV/HCV-coinfected patients (58 genotype 1a, 18 genotype 1b and 44 genotype 4) and 501 sequences from HCV-monoinfected patients (476 genotype 1 and 25 genotype 4), retrieved from GenBank as a control group, were compared. RESULTS: Of 76 sequences from HIV/HCV genotype 1-coinfected patients, six (7.9%) showed amino acid substitutions associated with HCV PI resistance (V36L, n=1; V36M, n=2; T54S, n=2; R155K, n=1). In 31 of 476 (6.5%) HCV genotype 1 sequences retrieved from the GenBank database, HCV PI resistance mutations were found. The difference was not statistically significant (P=0.6). All of the sequences from HIV/HCV genotype 4-coinfected patients and those retrieved from the GenBank database had amino acid changes at position 36 (V36L). CONCLUSION: Our study suggests that the natural prevalence of strains resistant to HCV PIs does not differ between HCV-monoinfected and HIV/HCV-coinfected patients. Further studies on larger cohorts are needed to confirm these findings and to evaluate the impact of these mutations in clinical practice.

Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers.

BACKGROUND: Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. AIM: To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. METHODS: Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. RESULTS: TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. CONCLUSION: Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C.

BACKGROUND: The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated. AIM: To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin. PATIENTS AND METHODS: Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment. RESULTS: At week 4, a strong correlation was found between HCV-RNA and C(min) of ribavirin plasma level (r = -0.376, P = 0.002) and AUC(0-->12h) of ribavirin plasma level (r = -0.277, P = 0.018). At week 12, a strong correlation was found between HCV-RNA and C(min) of ribavirin plasma level (r = -0.384, P < 0.0001) and AUC(0-->12h) of ribavirin plasma level (r = -0.257, P = 0.002). In genotype 1 patients, AUC(0-->12h) ribavirin and C(min) were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12. CONCLUSION: C(min) of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.

Hepatic steatosis in HIV-HCV coinfected patients in France: comparison with HCV monoinfected patients matched for body mass index and HCV genotype.

BACKGROUND: Significance of steatosis in HIV-HCV coinfection remains controversial. AIM: To compare the prevalence and predictors of hepatic steatosis between HIV-HCV and HCV patients matched for steatosis known determinants. METHODS: A total of 564 HCV-naive patients undergoing liver biopsy were studied: 137 with HIV-HCV coinfection and 427 with HCV monoinfection, among whom 137 were matched for age, gender, body mass index and HCV genotype. RESULTS: Steatosis of any grade (67.1% vs. 41.6%, P < 0.0001), mixed steatosis (55.4% vs. 21.1%, P < 0.0001), severe histological activity (A2-A3: 78.1% vs. 55.5%, P < 0.0001) and severe fibrosis (F3-F4: 33.1% vs. 15.3%, P < 0.0001) were significantly more common in coinfected than in matched monoinfected patients. In multivariate analysis, steatosis was associated only with severe histological activity [odds ratio (OR): 3.1 (95% CI: 1.3-7.1)] in coinfected patients and with elevated body mass index [OR; 1.3 (1.1-1.5)], HCV genotype 3 [OR: 5.6 (2.3-13.9)], severe histological activity [OR: 3.1 (1.3-7.3)] and severe fibrosis [OR: 4.7 (1.3-17.3)] in monoinfected patients. CONCLUSIONS: Steatosis is significantly more common and severe in HIV-HCV coinfected than in HCV monoinfected French patients, even after matching for body mass index and HCV genotype. Steatosis is associated only with severe histological activity in coinfected patients and with previously reported factors in monoinfected patients, thus suggesting different underlying mechanisms.

Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study.

This cross-sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6-month period. HCV genotyping in the 5'-non-coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer-specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non-subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

[Efficacy and safety of pegylated-interferon plus ribavirin in HIV-infected patients co-infected with hepatitis C virus in clinical practice: a 32 cases observational follow-up]. / Efficacité et tolérance de l'association interféron pégylé-ribavirine chez les patients co-infectés VIH-VHC en pratique clinique: étude observationnelle de 32 patients.

OBJECTIVE: To describe efficacy and safety in clinical practice of pegylated interferon plus ribavirin (INFpeg-Riba) in the treatment of hepatitis C viral infection (HCV) in HIV infected patients. METHODS: Monocentric retrospective study with inclusion of all patients who received at least once INFpeg-Riba before April 1st 2003. All patients were followed up to six months after the end of HCV therapy. RESULTS: Thirty two HIV-positive patients (23 men and 9 women) with chronic hepatitis C treated by INFpeg-Riba were included. The mean age was 43 years. Fourteen patients carried HCV genotype 2 or 3 (43 %) and 18 patients carried genotype 1 or 4 (57%). The Metavir score of fibrosis showed fibrosis F1 (N =3), F2 (N =14), F3 (N =7) and F4 - cirrhosis (N =8). Twenty six patients (81%) were naive for anti hepatitis C drugs. Thirty one per cent of patients were at AIDS stage and 84% were receiving antiretroviral drugs. The mean CD4 cell count was 469 /ml and the plasma RNA HIV was less than 50 copies /ml in 57% of the cases. Adverse events leading to reduction of dose of drugs occurred in 40% and adverse events leading to discontinuation treatment occurred in 12%. A decline of CD4 cell count <200 CD4/ml was observed in 15%. Clearance of HCV-RNA in end of treatment was seen in 46 % and sustained virological response in 34 %. The main predictors of sustained virological response were HCV genotype 2 or 3 (P =0.04) and plasma HIV RNA less than 50 copies/ml (P =0.001). The predictive value of good virological response of a CD4 cell count >350/ml before treatment was very near the statistical significancy (p =0.07). CONCLUSIONS: The efficacy of pegylated interferon plus ribavirin in HIV-HCV co-infected patients is disappointing mainly due to a poor tolerance. In addition to HCV genotype, plasma HIV RNA level and CD4 cell count were essential to predict INFpeg-Riba response and should be taken into account in the process leading to the initiation of such therapy in HIV-HCV co-infected patients.

PCR-detected hepatitis C virus RNA associated with human zona-intact oocytes collected from infected women for ART.

BACKGROUND: The aim of this study was to investigate the susceptibility of human oocytes from hepatitis C virus (HCV) RNA-positive women to HCV contamination during assisted reproductive technology (ART). METHODS: A reverse transcriptase-PCR assay was used to test for the presence of HCV RNA associated with 24 unfertilized oocytes 48 h after follicular fluid aspiration in 10 IVF attempts (seven conventional IVF and three ICSI). Negative and positive controls (10 unfertilized oocytes from HCV-negative women and 20 unfertilized oocytes artificially contaminated with HCV RNA-positive plasma; HCV RNA was also quantified in plasma and follicular fluid) were included. RESULTS: HCV RNA was associated with 17/24 (70.8%) oocytes (6/7 after ICSI and 11/17 after conventional IVF) and was found in 19/20 (95%) follicular fluid samples. A weak correlation was found between plasma and follicular fluid HCV RNA loads (r = 0.73, P < 0.001). CONCLUSIONS: HCV associated with unfertilized oocytes surrounded by their intact zona pellucida from anti-HCV antibody-positive and viraemic women undergoing ART raises questions concerning the safe management of medically assisted procreation for these women and good practice of oocyte/embryo cryopreservation and donation.

Intrahepatic HCV RNA loads in 37 HIV-HCV co-infected patients with controlled HIV infection.

Serum and intrahepatic hepatitis C virus (HCV) RNA were measured in 37 HIV-HCV co-infected patients with controlled human immunodeficiency virus (HIV) infection and correlated with clinical, biological, and histological parameters. Thirty-seven interferon-naive patients underwent liver biopsy. HCV-induced activity (A) and fibrosis (F) were evaluated with METAVIR score. The 37 patients included had HIV plasma loads < 10,000 copies/ml, CD4(+) count > 250/microl. All the patients but two were receiving antiretroviral treatment. Liver tissue and sera were used for measurement of HCV RNA by the Cobas Amplicor HCV Monitor. All patients had serum and liver HCV RNA, and both levels were correlated (r = 0.47; P = 0.003). Intrahepatic HCV load did not depend on age, sex, duration of HCV infection, CD4(+), HCV genotype, or fibrosis. AST levels correlated with intrahepatic HCV load (r = 0.52; P = 0.001). Patients with METAVIR A1/A2 had significantly lower levels of liver HCV-RNA than were found in patients with METAVIR A3 (P = 0.026). Highly active antiretroviral therapy (HAART) including protease inhibitors(PI)-treated patients had significantly lower intrahepatic HCV load (P = 0.04). A weak but significant correlation between serum and liver HCV RNA was found. The amount of hepatic HCV RNA was correlated with AST levels, histological activity, but not with HCV genotype or fibrosis. The immune improvement associated with PI regimens could help reduce HCV load, supporting a protective effect of PI-induced immune restoration.

Impact of protease inhibitors on intrahepatic hepatitis C virus viral load.

During chronic hepatitis C, hepatitis C virus (HCV) load in plasma was shown to be higher in HIV-co-infected than in immunocompetent patients [1]. The reason for this increased HCV replication is not known. It may be as a result of HIV-induced immune deficiency [2], although some authors did not find any correlation with the CD4 cell count [3]. A direct interaction between HCV and HIV was also hypothesized [4]. Protease inhibitors (PI) used in highly active antiretroviral therapy (HAART) have no HCV reduction effect during the first months of treatment [5-8]. However, a decrease in HCV plasma load was recently described in patients treated with HAART for a year [9,10]. We therefore investigated the potential impact of HAART on intrahepatic HCV load.

Immunohistochemical detection of hcv in cirrhosis, dysplastic nodules, and hepatocellular carcinomas with parallel-tissue quantitative RT-PCR.

Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.

Hepatitis C virus genotyping based on 5' noncoding sequence analysis (Trugene).

Hepatitis C virus (HCV) genotyping of samples from 184 patients with chronic HCV infection by the Trugene 5'NC genotyping kit, based on sequence analysis of the 5' noncoding region (5' NCR), and the InnoLiPA assay was evaluated. In addition to these methods, the 184 samples were also analyzed by sequencing of part of the NS5B of the HCV genome after in-house PCR amplification, as a means of validating results obtained with the 5' NCR. The distribution of the genotypes typed by NS5B sequence analysis was as follows: 1a, 41 samples; 1b, 58 samples; 1d, 1 sample; 2a, 5 samples; 2b, 2 samples; 2c, 7 samples; 3a, 46 samples; 4a, 7 samples; 4c, 1 samples; 4e, 9 samples; 5a, 6 samples; 6a, 1 sample. The Trugene and InnoLiPA assays gave concordant results within HCV types in 100% of cases. The ability to discriminate at the subtype level was 76 and 74% for the Trugene and the InnoLiPA assays, respectively.

Hepatic porphyrin concentration and uroporphyrinogen decarboxylase activity in hepatitis C virus infection.

Previous studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT). The aim of this study was to assess hepatic porphyrin concentrations (HPC) and hepatic uroporphyrinogen decarboxylase (UROD) activity in HCV-infected patients free of PCT. Thirty-two HCV-infected patients (20 M, 12 F, mean age 51 years) and seven control patients (4 M, 3 F, mean age 59 years) free of liver disease, were studied. Knodell's score was determined on liver biopsy by two independent anatomopathologists. Measurement of HPC and hepatic UROD activity levels were carried out on liver biopsy. Relative to controls, HCV-infected patients had high HPC levels (mean +/- SD: 47 +/- 20 vs. 17 +/- 6 pmol/mg protein, P < 0.001) and low hepatic UROD activity levels (514 +/- 95 vs. 619 +/- 125 pmol Copro/h/mg protein, P < 0.05). HPC was not correlated with hepatic UROD activity and the increase was due to coproporphyrin accumulation. No correlation was observed between HPC or hepatic UROD activity values and HCV-RNA concentrations, Knodell's score, hepatic fibrosis, periportal necrosis, periportal inflammation or hepatic iron content in HCV-infected patients. Hepatocellular necrosis was significantly correlated with HPC value (P < 0.005). Hence, in HCV-infected patients, HPC is significantly increased and hepatic UROD activity is very slightly decreased as compared to controls. HPC values and UROD activity are not correlated with HCV-RNA concentrations, hepatic iron content and hepatic fibrosis. The small increase in HPC values in hepatitis C infection is linked with hepatic injury and not with a direct effect on hepatic UROD enzyme.

[Multicenter study of intrafamilial transmission of hepatitis C virus in human immunodeficiency virus infection]. / Etude multicentrique de la transmission intra-familiale du virus de l'hépatite C dans le contexte de l'infection par le virus de l'immunodéficience humaine.

OBJECTIVE: Intrafamilial transmission of hepatitis C virus in human immunodeficiency virus and hepatitis C virus co-infections is not well documented. This cross-sectional study evaluated the transmission of hepatitis C virus in the sexual partners of hepatitis C virus and human immunodeficiency virus co-infected patients. METHODS: Hemophiliacs and transfused hepatitis C virus and human immunodeficiency virus co-infected patients who were being seen in three French university hospitals, and their sexual partners were studied by a face-to-face interview using an epidemiological questionnaire and by biological tests: antibodies against hepatitis C virus, hepatitis C virus RNA, and ALT activity. RESULT: Fifty-two subjects were included: 26 cases and their 26 sexual partners. Three sexual partners (11.5 %) had anti-hepatitis C virus antibodies, two of whom had an undetermined RIBA test. All three had a risk factor for hepatitis C virus infection (transfusion, intra-muscular injections with re-usable needles). Two of these three partners were also human immunodeficiency virus antibody positive. Hepatitis C virus RNA was negative in all sexual partners. CONCLUSION: This study provides evidence of a low prevalence of anti-hepatitis C virus antibodies in sexual partners of hepatitis C virus and human immunodeficiency virus co-infected patients. It does not support intra-familial transmission of hepatitis C virus.

TT virus infection during chronic hepatitis C.

OBJECTIVE: The pathogenic role of TT virus (TTV) is not well known, especially during chronic hepatitis C virus (HCV) infection. We retrospectively investigated the presence of TTV DNA in the plasma of patients with chronic HCV infection and compared the characteristics of TTV-DNA-positive and -negative groups. METHODS: Between November 1996 and November 1998, 234 patients were included. Inclusion criteria were persistently elevated serum alanine aminotransferase (ALT) levels, anti-HCV and HCV-RNA positivity, and seronegativity for hepatitis B virus and human immunodeficiency virus markers. TTV DNA was amplified in nested polymerase chain reaction with TTV-specific primers, and products were analyzed by agarose-gel electrophoresis. Data were analyzed using the chi2, Fisher's exact test, or Mann-Whitney test, as appropriate. RESULTS: TTV DNA was detected in 19 (8.1%; 95% confidence interval: 4.6-11.6%) patients. TTV-DNA-positive and TTV-DNA-negative patients did not differ statistically for age, gender ratio, source of HCV infection, HCV disease duration, biological parameters, histological grade, HCV-RNA load, or HCV genotype. Although nonsignificant (p = 0.21), there was a trend for a higher prevalence of TTV DNA in patients with an unknown cause of HCV infection (4/22, 18.2%) than in intravenous drug users (4/84; 4.8%), in those exposed to potential risk factors (4/49; 8.2%), or in those having received blood transfusion (7/79; 8.9%). CONCLUSIONS: Because the rates of HCV replication and the severity of liver lesions in TTV-DNA-negative and -positive patients were similar, the hepatic pathogenicity of TTV in chronic hepatitis C patients is questionable.

New molecular assays to predict occurrence of cytomegalovirus disease in renal transplant recipients.

Thirty renal transplant recipients, after transplantation, were tested weekly with the following assays: cytomegalovirus (CMV) antigenemia (pp65 Ag), plasma qualitative Amplicor CMV (P-AMP), plasma and peripheral blood leukocyte quantitative Amplicor CMV monitor (P- and PBL-CMM), peripheral blood leukocyte (PBL) quantitative Quantiplex bDNA CMV, version 2.0 (bDNA), and whole-blood Nuclisens pp67 CMV (pp67). Eleven patients developed symptomatic CMV disease, and 7 developed asymptomatic CMV infection. For prediction of CMV disease, the sensitivity, specificity, and positive and negative predictive values, respectively, were as follows: 100%, 63%, 61%, and 100% for pp65 Ag; 100%, 42%, 50%, and 100% for bDNA; 91%, 47%, 50%, and 90% for PBL-CMM; 55%, 74%, 55%, and 74% for P-AMP; 55%, 74%, 55%, and 74% for P-CMM; and 64%, 79%, 64%, and 79% for pp67. First positive results in PBL were obtained 9-10 days before symptoms of CMV disease, compared with 5-6 days in plasma and 0 days in whole blood. PBL assays appear to be more appropriate than plasma assays when pre-emptive therapy is required to prevent the rapid progression from the first detection of the virus to CMV disease.