Biomedical subjects

M von Wagner

Publications and source records attributed to M von Wagner.

7 recordsLinked to original sources

PubMed2006

Impaired health-related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels.

A significant impact of hepatitis C virus (HCV) infection on health-related quality of life (HRQOL) has been previously described. However, comprehensive data on the quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels (PNAL) are currently not available. One hundred fifteen patients with chronic hepatitis C (45 with persistently normal aminotransferases and 70 with elevated aminotransferases) and 50 healthy subjects were enrolled. Emotional and psychological states were assessed by Profile of Mood States (POMS) scale and HRQOL was assessed by the 'Everyday Life' questionnaire (EDLQ), a validated questionnaire related to the SF-36 Health Survey. An impairment in HRQOL was observed in patients with chronic hepatitis C showing PNAL compared with healthy subjects with significant differences for the factor scores depression and anger in the POMS scale as well as for the items body, relationship to partner, self-confidence and zest of life in the EDLQ. No differences in any questionnaire were observed between patients with chronic hepatitis C showing PNAL or elevated aminotransferase levels except of a worse mean level for factor score anger in POMS scale in patients with persistently normal aminotransferases. No association of quality of life with severity of liver disease was found. Impairment of HRQOL by chronic infection with HCV is similar in patients with PNAL and those with elevated aminotransferase levels.

Adult↗

PubMed2004

Mutations in the putative HCV-E2 CD81 binding regions and correlation with cell surface CD81 expression.

The hepatitis C virus (HCV) envelope (E)2 protein interacts with the cellular receptor CD81 leading to modulation of B and T cell function. Recently, a higher binding affinity of subtype 1a in comparison with 1b derived E2 proteins for CD81 in vitro was described. The importance of mutations within the putative CD81 binding regions of different HCV geno-/subtypes in correlation with CD81 expression is unknown. In the present study, CD81 expression on blood lymphocytes of patients with chronic hepatitis C infected with different HCV geno-/subtypes were analysed by fluorescence activated cell sorter analyses. In addition, the putative CD81 binding regions on the E2 gene comprising the hypervariable region (HVR)2 were analysed by direct sequencing. CD81 expression on CD8(+) T-lymphocytes from patients infected with subtype 1a (n = 6) was significantly higher in comparison with subtype 1b (n = 12) and 3 (n = 5) infected patients before and during antiviral therapy (P = 0.006; P = 0.021, respectively). Sequencing of the putative CD81 binding regions in the E2 protein comprising the HVR2 (codon 474-495 and 522-552 according to the HCV-1a prototype HCV-H) showed a highly conserved motif within HVR2 for subtype 1a isolates and an overall low number of mutations within the putative CD81 binding regions, whereas numerous mutations were detected for subtype 1b isolates (12.0 vs 23.6%). HCV-3 isolates showed an intermediate number of mutations within the putative binding sites (19.2%; P = 0.022). In conclusion, the highly conserved sequence within HVR2 and putative CD81 binding sites of subtype 1a isolates previously associated with a high CD81 binding affinity in vitro is correlated with high CD81 expression on CD8(+) T-lymphocytes in vivo.

Adult↗

PubMed2003

Dynamics of hepatitis C virus quasispecies turnover during interferon-alpha treatment.

Interferon-alpha (IFN) has been shown to accelerate the evolution of hepatitis C virus (HCV) variants (quasispecies) in nonresponder patients. Different sensitivities of HCV variants to IFN are discussed as a possible mechanism. In the present study, quasispecies were investigated in detail by a newly established and validated direct solid-phase sequencing of the hypervariable region 1 (HVR1), during the initial 3 months of IFN therapy. According to single strand conformation polymorphism (SSCP) analysis, 14 of 26 (54%) virologic nonresponders with quasispecies evolution were identified. Six representative patients with SSCP changes were selected for frequent HVR1 sequencing. Pre-existing variants were identified by cloning and sequencing of the pretreatment serum HCV sample. In one patient the major type was substituted by a minor variant within 3 days of treatment while in the majority of patients the pretreatment major type did not decline before days 26-57 of treatment. Total serum HCV RNA levels remained constant in all patients. In conclusion, although quasispecies evolution during IFN therapy is common, it occurs after a wide range of time intervals after initiation of therapy. Thus, nonresponse to IFN cannot exclusively be explained by changes in the quasispecies.

Adult↗

PubMed2003

Response predictors and results of a long-term treatment with lamivudine in patients with chronic hepatitis B.

INTRODUCTION: European data on outcome and follow-up of long-term lamivudine treatment are sparse. Moreover, little is known about predictors for sustained virologic response and for development of drug resistance in patients with lamivudine monotherapy. Patients and methods : 39 patients (17 HBeAg+, 22 HBeAg-) were treated with lamivudine for a median duration of 2.5 years (range: 0.5-4). Outcome to therapy and predictors for response and drug resistance were analyzed retrospectively. RESULTS: None of the patients lost HBsAg. In 14 of 17 initially HBeAg positive patients the HBeAg status was available at the end of treatment. Loss of HBeAg was observed in 8 patients and 7 of these 8 patients seroconverted to anti-HBe. Five of 6 patients with HBeAg seroconversion and a post-treatment follow-up period showed sustained HBeAg seroconversion. In HBeAg negative patients virologic response (serum HBV DNA< or =1 x 10(5) copies/ml) was observed in 12 of 22 patients after a median treatment period of 2.5 years. Post-treatment follow-up data were available in only 2 patients, one of which remained below 1 x 10(5) HBV DNA copies/ml for one year. Resistance emerged in 15 of 36 patients with available serum HBV DNA data after a median treatment period of 2 years. CONCLUSION: The present retrospective study confirms international data for lamivudine treatment in a central European setting. Lamivudine therapy achieved disease control in more than 50 % of patients treated for chronic hepatitis B. Baseline predictors could neither be identified for sustained virologic response nor for the development of drug resistance.

Adolescent↗

PubMed2000

Antiviral effect of human recombinant interleukin-12 in patients infected with hepatitis C virus.

The heterogeneity of hepatitis C virus (HCV) is due to the continuous and high replication rate, the low fidelity of the RNA-dependent RNA polymerase, and the immune surveillance of the host. Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The effect of IL-12 on hepatitis C viremia and the HCV quasispecies population is unknown. In this study, 12 patients (9 males, 3 females; mean age: 44 +/- 11 years), all virological non-responders to previous IFN-alpha treatment, received recombinant human IL-12 s.c. once weekly for 10 weeks stratified to three dose schedules (0.03 microg/kg, 0.1 microg/kg, and 0.5 microg/kg body weight, respectively). Fourteen IFN-alpha non-responders and 14 untreated patients served as age- and sex-matched controls. Serum HCV RNA concentrations and HCV quasispecies distribution were measured serially by quantitative reverse transcription - polymerase chain reaction and single strand conformation polymorphism analysis of the hypervariable region of the second envelope gene, respectively. Serum ALT and median HCV RNA levels before treatment (52.7 +/- 21.7 U/L; 2.6 x 10(6) copies/mL) showed no significant changes during IL-12 treatment (57.3 +/- 58.8 U/L and 3.2 x 10(6) copies/mL, 50.3 +/- 46.2 U/L and 3.1 x 10(6) copies/mL, and 46.8 +/- 35.3 U/L and 3.9 x 10(6) copies/mL at weeks 1, 4, and 10, respectively). Similar results were observed in 14 IFN-alpha non-responders and 14 untreated patients. However, changes in HCV quasispecies occurred in 10/12 (83%) and 9/14 (64%) patients treated with interleukin-12 and interferon-alpha, respectively, but only in 3/14 (21%) untreated subjects (P < 0.003 and P < 0.03). These results imply that interleukin-12 exerts only limited antiviral activity against certain HCV quasispecies in vivo.

Adult↗

PubMed1998

Hepatitis C virus dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover.

Treatment of patients with chronic hepatitis C with recombinant interferon alfa (rIFN-alpha) can cause a decrease of serum transaminases and hepatitis C virus (HCV) RNA. Recent trials evaluating combination therapy of IFN-alpha and ribavirin suggested a potential synergistic effect. From serial measurements of serum HCV RNA concentrations following treatment-induced perturbation of the balance between virus production and clearance, we compared the antiviral efficacy of both IFN-alpha alone and IFN-alpha in combination with ribavirin. Chronically HCV-infected patients were treated with either 3 x 3 MU or 3 x 6 MU rIFN-alpha per week or 3 x 6 MU rIFN-alpha plus 14 mg/kg of body weight ribavirin per day. The time-dependent HCV RNA concentrations during antiviral treatment were analyzed by iterative least-squares regression. After initiation of antiviral therapy, HCV RNA declined exponentially below the detection limit of the reverse-transcription polymerase chain reaction assay (1,000 HCV RNA molecules per milliliter) in 10 of 26 (39%), 10 of 19 (53%), and 10 of 18 patients (56%) treated with 3 x 3 MU, 3 x 6 MU rIFN-alpha without and with ribavirin, respectively. Viral clearance from serum was faster in patients treated with 3 x 6 MU rIFN-alpha (t1/2 = 0.23 +/- 0.15) compared with patients treated with 3 x 3 MU rIFN-alpha per week (0.67 +/- 0.36 days) (P < .004). However, half-lives of viral clearance were similar in patients treated with rIFN-alpha or rIFN-alpha plus ribavirin. For virus release from infected hepatocytes, absence and presence of ribavirin yielded half-lives of t1/2 = 2.54 +/- 2.10 and t1/2 = 1.99 +/- 1.70, respectively, indicating that ribavirin does not significantly inhibit HCV production. In conclusion, the data of the present study indicate that higher rIFN-alpha doses accelerate viral clearance from serum. Ribavirin (14 mg/kg/d), however, lacks synergistic antiviral effects in the treatment of chronic hepatitis C with 3 x 6 MU rIFN-alpha per week.

Adult↗

PubMed1998

Effect of ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus.

BACKGROUND/AIMS: The combination of ribavirin and interferon alfa has potent synergistic effects in the treatment of chronic hepatitis C. The antiviral mechanism of ribavirin is unknown. We investigated whether a transient initial antiviral effect of ribavirin was sufficient to improve the response to interferon. METHODS: Fifteen HCV-infected patients (ten male, five female; mean age 45.4+/-11.0 years) treated with ribavirin (1000-1200 mg) and 17 untreated patients with chronic hepatitis C (11 male, six female; mean age 45.6+/-9.9 years) were investigated. All patients were either non-responders to (n=19) or relapsed after (n=13) previous interferon treatment. Serum HCV-RNA concentrations and HCV quasispecies distribution were serially measured over 4 weeks by quantitative reverse transcription-polymerase chain reaction and single-strand conformation polymorphism analysis, respectively. RESULTS: In six of the 15 patients treated with ribavirin, but in none of the controls, serum alanine aminotransferase levels declined by at least 30%. Pretreatment HCV-RNA levels ranged from 5.0x10(5)-5.0x10(7) copies/ml. After initiation of ribavirin treatment, minor (0.5-1.0 log) or no changes (<0.5 log) in total hepatitis C viremia were observed in ten and five patients, respectively. In HCV-infected patients without treatment 7/17 patients had minor and 10/17 no changes in viremia. Polymerase chain reaction amplification of the hypervariable region-1 of HCV was successful in 13/15 treated and in 17/17 untreated patients. Changes in HCV quasispecies according to the single-strand conformation polymorphism band pattern occurred in only one patient treated with ribavirin and in three of the untreated patients. CONCLUSIONS: Ribavirin monotherapy has no initial antiviral effect on total hepatitis C viremia nor on HCV quasispecies. Unlike the rapid emergence of antiviral drug-resistant strains in HIV-infected patients, no viral escape phenomena are observed in HCV-infected patients treated with ribavirin.

Adult↗