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O Weiland

Publications and source records attributed to O Weiland.

At least 37 records · Page 2Linked to original sources

Treatment of naive patients with chronic hepatitis C.

Treatment of chronic hepatitis C virus (HCV) infection in naive patients with interferon alpha alone or in combination with ribavirin is reviewed. Two placebo-controlled randomised studies including 150 patients have shown that ribavirin as single therapy at standard dosage (15 mg/kg bodyweight in two divided doses daily) only reduces ALT levels transiently during therapy, whereas HCV RNA levels are not substantially reduced. Interferon alpha (IFN) alone at standard dosage (3 MU t.i.w.) given for 12 months results in sustained virological response (SR) rates of some 15-25% depending on the genotype and baseline HCV RNA levels. Ribavirin in combination with alpha interferon, in standard doses for 6-12 months significantly improves the sustained biochemical and virological response rates 2-3 times compared with IFN alone for 12 months. In the future, combination therapy will become standard therapy for most naive patients, at least those with unfavourable viral parameters such as a high baseline viral load (>2-3 million gE/ml serum) and genotype 1a+1b. In patients with favourable baseline viral characteristics (genotypes 2 and 3, irrespective of viral load) 6 months of combination therapy is likely to be sufficient, whereas those with unfavourable viral baseline characteristics will need longer combination treatment. Both genotype and baseline viral load need to be assessed to optimise the choice of therapy. Many questions must still be answered, such as the optimal dose of ribavirin and IFN in combination regimens, and the optimal treatment length. Furthermore, should induction treatment be used in combination regimens? What regimen should be used for patients with more advanced disease such as those with cirrhosis and decompensation?

Antiviral Agents↗

Histological and virological long-term outcome in patients treated with interferon-alpha2b and ribavirin for chronic hepatitis C.

Long-term virological and histological outcome following interferon-alpha2b (IFN-alpha2b) and ribavirin treatment for 24 weeks was studied in 20 patients with chronic hepatitis C who were without a lasting response to IFN as monotherapy. Following combination therapy, sustained virological response (SR) was achieved in 12 patients (i.e. hepatitis C virus (HCV) RNA negative in serum 6 months post-treatment). Eleven of these patients remained HCV RNA negative in serum 2 years post-treatment. A virological long-term response (LTR) was more frequent in patients with a previous end-of-treatment response to IFN monotherapy than in non-responders. Liver histology at follow-up, >/=24 months post-treatment, showed substantial improvement in patients with a virological LTR to the combination treatment. In all nine patients biopsied at the 2-year follow-up, liver inflammation had disappeared totally (grade=0), and the stage (fibrosis) had improved. In contrast, no significant changes in grade or stage were noted in patients with a virological non-LTR to combination treatment. A significant improvement in inflammation was noted, in patients with a virological LTR, from 3.6 to 0.2 (P<0.01) and in fibrosis from 2.0 to 1.4 (P<0.05) whereas the corresponding scores for patients with a virological non-LTR did not change significantly, from 3.1 to 1.5 for inflammation and for fibrosis from 1.3 to 1.3. We conclude that patients with chronic hepatitis C who achieve a virological sustained response 6 months post-treatment with IFN-alpha2b and ribavirin will remain virological responders for a follow-up period of least 24 months, concomitant with a disappearance of inflammatory activity and a marked improvement of fibrosis in the liver.

Adult↗

Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials. Eurohep Study Group for Viral Hepatitis.

BACKGROUND & AIMS: The aim of this study was to compare interferon (IFN)-ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with particular focus on its efficacy in cirrhosis. METHODS: A multivariate analysis of individual patient data of all randomized controlled trials using an IFN-ribavirin arm, reported between 1991 and March 1998, was performed. Centers included 1 Asian and 5 European university-based referral centers for liver disease. A total of 197 patients with chronic hepatitis C received IFN-alpha (3 MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147 patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were characterized according to previous IFN therapy, presence of cirrhosis, and genotype 1. Efficacy of therapy was evaluated by assessing the sustained response rate by logistic regression analysis. RESULTS: Patients without cirrhosis treated with IFN-ribavirin had a significantly higher sustained response rate than those treated with IFN, approximately 3-fold for previously untreated patients (IFN-ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority of combination therapy over IFN monotherapy was also observed for relapse; the same trend was observed for nonresponders. Tolerance for IFN-ribavirin was similar for patients with or without cirrhosis. CONCLUSIONS: Combination with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN-ribavirin combination is likely to become the antiviral therapy of choice for cirrhosis caused by hepatitis C.

Adult↗

The anti-HBs response after 2 different accelerated intradermal and intramuscular schemes for hepatitis B vaccination.

To study early seroconversion rates after hepatitis B vaccination intramuscular (i.m.) and low-dose intradermal (i.d.) vaccination was compared when given either according to the registered 0, 4, 8 weeks scheme (scheme A), or to an accelerated 0, 2, 6 weeks scheme (scheme B). Medical staff received either 2 microg i.d. or 20 microg i.m. of a recombinant hepatitis B vaccine, in a non-randomized open trial. Two weeks after the third dose i.m. vaccinees overall had significantly higher rates of protective anti-HBs levels (anti-HBs > or = 10 IU/I), (23/30, 77%) compared with i.d. vaccinees (75/166, 45%) (p < 0.001). We conclude that when rapid protection against hepatitis B virus (HBV) infection is desirable, such as for post-exposure prophylaxis, an accelerated low-dose i.d. vaccination schedule cannot be used.

Administration, Cutaneous↗

Influence of pre-treatment factors on outcome of interferon-alpha treatment of patients with chronic hepatitis C.

A total of 172 Swedish patients treated with interferon-alpha for at least 24 weeks and followed-up > or =24 weeks after treatment was stopped were analysed for pre-treatment factors of importance for achieving a virological sustained response (SR). Furthermore, the predictive value for a virological SR of a positive or negative HCV RNA test at week 12 of treatment was evaluated. A low baseline viral load and genotype non-1b were pre-treatment factors indicating a favourable response. Thus, 44% (38/86) of patients with a low baseline viral load vs. only 16% (14/86) of those with a high viral load had a virological SR (p<0.0001). Of patients with a negative qualitative HCV RNA test after 12 weeks of interferon treatment, 46% (44/95) had virological SR, whereas only 5.9% (4/68) of those with a positive test had (p<0.0001). Prolonged ( > 6 months) treatment with interferon-alpha tended to increase the chance of virological SR (p<0.052).

Adolescent↗

Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.

BACKGROUND: Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon alpha-2b and ribavirin than with interferon alpha-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon alpha-2b and ribavirin compared with interferon alpha-2b alone. METHODS: In this double-blind trial 100 patients were randomly assigned to treatment with interferon alpha-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. FINDINGS: 18 (36%) of the 50 patients in the interferon alpha-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon alpha-2b and placebo group (p = 0.047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon alpha-2b and ribavirin group than the interferon alpha-2b and placebo group (42 vs 20%, p = 0.03), respectively. More patients with baseline HCV-RNA concentrations greater than 3 x 10(6) genome equivalents (Eq) per mL had a sustained response with interferon alpha-2b and ribavirin than with interferon alpha-2b and placebo (12/29 vs 1/26, p = 0.009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3 x 10(6) Eq per mL (6/21 vs 8/24, p = 0.67), respectively. INTERPRETATION: More patients with chronic hepatitis C have a sustained virological response with interferon alpha-2b and ribavirin than with only interferon alpha-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon alpha-2b and ribavirin.

Adult↗

[Treatment response in chronic hepatitis C. Content of virus in serum is decisive for the outcome].

The article consists in a brief review of pre-treatment evaluation and antiviral treatment of chronic hepatitis C (HCV) infection. Patients with viraemia (i.e. HCV RNA seropositive with the PCR technique) should be evaluated historically if they lack contraindications for interferon alpha (IFN-alpha) treatment. Patients with depression, autoimmune and thyroid disorders, decompensated cirrhosis, or solid organ transplants, are ineligible for-IFN-alpha treatment. If the histological evaluation shows moderate to severe chronic hepatitis, and the HCV RNA level is < 3 million Eq/mL serum as measured by bDNA, naive (i.e. formerly untreated) patients should be given an initial 12-week course of IFN-alpha to evaluate treatment response. Those who become HCV-negative should continue the treatment for 48 weeks to increase the likelihood of sustained virological response after treatment cessation. Treatment should be discontinued in the case of patients still HCV-positive at 12 weeks, as the chances of obtaining sustained response are remote. Patients with higher pre-treatment HCV RNA levels (> or = 3 million Eq/mL) and patients manifesting unsustained response to earlier IFN treatment should receive combination treatment with ribavirin and IFN-alpha, as treatment with IFN alone is associated with poor chances of sustained response. This treatment approach is associated with an estimated sustained response rate in naive patients of 40-50 per cent.

Antiviral Agents↗

GBV-C/HGV infection in hepatitis C virus-infected deferred Swedish blood donors.

Sera from 62 hepatitis C virus (HCV)-infected Swedish blood donors were tested by a nested polymerase chain reaction using primers targeting the 5'-noncoding region of the GB virus-C/hepatitis G (GBV-C/HGV) genome and an enzyme-linked immunosorbent assay that detects antibodies to the envelope protein E2 of GBV-C/HGV (anti-E2). Fourteen (22%) and 21 (34%) of the 62 blood donors were found to be GBV-C/HGV RNA and anti-E2 positive, respectively. None of the blood donors was positive for both GBV-C/HGV RNA and anti-E2. Thus, 35 of 62 (56%) HCV-infected donors had been exposed to GBV-C/HGV infection. At sequencing of the 14 GBV-C/HGV isolates, 12 were identified as subtype 2a and 2 as subtype 2b. One of 7 (14%) donors with mild liver disease such as steatosis and nonspecific reactive hepatitis had been exposed to GBV-C/HGV vs. 34 of 55 (62%) with chronic hepatitis with or without cirrhosis (P = 0.04). All other differences in histology were small between HCV and dual HCV GBV-C/HGV-infected donors. In conclusion, more than half of HCV-infected Swedish blood donors in this study were positive for either GBV-C/HGV RNA or anti-E2. GBV-C/HGV viremia and seropositivity were mutually exclusive.

Adult↗

Variation in the hepatitis C virus NS5a region in relation to hypervariable region 1 heterogeneity during interferon treatment.

The putative interferon sensitivity determining region (ISDR) in the NS5a region of the hepatitis C virus (HCV) was analyzed in 13 interferon alpha (IFN-alpha) treated patients representing genotypes 1a, 1b, and 2b. These patients had previously been followed longitudinally during treatment with respect to viral load and to virus heterogeneity using the hypervariable region 1 (HVR1) sequence as a marker. In the present study, the NS5a region was analyzed for nonresponders and sustained responders using direct DNA sequencing. While the previous results of analyzing viral composition and load showed evidence of selection, no corresponding selection of specific NS5a ISDR sequences was observed in the nonresponders, and identical ISDR sequences were observed among both sustained responders and nonresponders. Thus, we cannot verify a correlation between ISDR sequence and the observed selection of IFN-alpha-resistant quasispecies demonstrated as a restriction of HVR1 heterogeneity. This indicates that the potential for using ISDR as a diagnostic or prognostic marker during IFN-alpha treatment is limited.

Amino Acid Sequence↗

Human and murine antibody recognition is focused on the ATPase/helicase, but not the protease domain of the hepatitis C virus nonstructural 3 protein.

The hepatitis C virus (HCV) nonstructural (NS) 3 protein has been shown to possess at least two enzymatic domains. The amino terminal third contains a serine-protease domain, whereas the carboxy terminal two thirds is comprised of an adenosine triphosphatase (ATPase)/helicase domain. These domains are essential for the maturation of the carboxy-terminal portion of the HCV polyprotein and catalyze the cap synthesis of the RNA genome. In this report, human and murine antibody responses induced by NS3 were characterized using a recombinant full-length NS3 (NS3-FL) protein, or the isolated protease or ATPase/ helicase domains, expressed and purified from Escherichia coli. Sera from 40 patients with chronic HCV infection were assayed in enzyme-linked immunoassays (EIAs) for antibody binding to the panel of NS3 proteins. Virtually all patient sera contained antibodies specific for NS3-FL and the ATPase/helicase domain, whereas only 10% of sera reacted with the protease domain of NS3. Human antibodies reactive with NS3-FL were highly restricted to the immunoglobulin G1 (IgG1) isotype and were inhibited by soluble ATPase/helicase, but not by the protease domain. The anti-NS3 (ATPase/helicase) reactivity decreased on denaturation by sodium dodecyl sulfate (SDS) and beta-mercaptoethanol (2ME), suggesting the recognition of nonlinear or conformational B-cell determinants. Similar to infected humans, mice immunized with NS3-FL developed high-titered primary antibody responses to the NS3 ATPase/ helicase domain, whereas an anti-NS3 protease response was not observed after primary or secondary immunizations. Thus, the human and murine humoral immune responses to the HCV NS3 protein are focused on the ATPase/helicase domain, are restricted to the IgG1 isotype in humans, and are conformationally dependent. Unexpectedly, in both species, the NS3 protease domain, present in the context of the full-length NS3, appears to possess low intrinsic immunogenicity in terms of antibody production.

Adenosine Triphosphatases↗

Comparison of 3 quantitative HCV RNA assays--accuracy of baseline viral load to predict treatment outcome in chronic hepatitis C.

The correlation between 3 assays for hepatitis C virus (HCV) RNA quantification and their respective accuracy in predicting the response to interferon and interferon/ribavirin therapy was evaluated by analysing pre-treatment sera from 100 patients. A total of 97%, 100%, and 98% of the patients tested positive by the branched DNA 2.0 assay (Quantiplex), a multi-cycle reversed transcriptase polymerase chain reaction quantitative assay (Superquant) and the Roche Amplicor Monitor assay, respectively. The correlations between the assays, in all patients and in the major genotypes 1, 2, and 3, were significant, although the levels detected by the Amplicor Monitor assay were more than 1 log lower than by the other assays. Sustained virological responders to interferon therapy, but not to combination therapy, had lower baseline viral levels than long-term non-responders (p = 0.002 by Quantiplex 2.0; p = 0.008 by Superquant; p = 0.06 by Roche Amplicor Monitor). Pre-treatment viral load greater than 3 x 10(6) Eq or copies/ml by the Quantiplex 2.0 and Superquant assays and greater than 100,000 copies/ml by the Amplicor Monitor assay predicted long-term non-response in 94%, 93% and 91% of the interferon treated patients, respectively. In conclusion, acceptable correlations between available commercial quantitative assays were found. High baseline viral load predicted long-term non-response to interferon monotherapy, whereas it did not to interferon/ribavirin combination therapy.

Antiviral Agents↗

The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses.

Ribavirin is effective in combination therapies against chronic hepatitis C virus (HCV) infection, although its direct antiviral properties are unclear. We therefore studied the immune-modulatory effects of ribavirin on hepatitis B virus (HBV)- and HCV-specific immune responses. During a 24 week placebo-controlled ribavirin trial in ten patients with chronic HCV infection, HCV antibodies and alanine aminotransferase (ALT) levels decreased transiently whereas the serum levels of HCV RNA remained stable. Effects of ribavirin on human and murine phytohaemagglutinin (PHA)-activated T cells included inhibition of in vitro proliferation and modulation of IL-2, IL-4, IFN-gamma and TNF-alpha levels. HBcAg- and HBeAg-specific IL-2 and IFN-gamma levels were > or = 25-fold higher in mice immunized with HBV core- or e-antigens (HBcAg, HBeAg) while receiving ribavirin compared to untreated mice, but IL-4 and IL-6 remained constant. Concordantly, a slight shift was observed in the IgG subclass distribution of the humoral responses of ribavirin-treated mice to HBeAg and HCV NS3 protein. Ribavirin treatment of HBeAg-transgenic (HBeAg-Tg) mice induced a dose-dependent down-regulation of T helper (Th)2-mediated antibody production to HBeAg. In ribavirin-treated HBeAg-Tg mice anti-HBe IgG1 (positively regulated by Th2 cytokines) decreased simultaneously as both anti-HBe IgG2a (positively regulated by Th1 cytokines) levels and in vitro T-cell IFN-gamma production increased, indicating a change in the Th1/Th2 balance. Thus, the present data suggest that ribavirin is not strictly an antiviral compound, but rather it alters the T-cell balance in the immune system.

Animals↗

Therapy of hepatitis C: alpha interferon and ribavirin.

Ribavirin is a nucleoside analogue that has been evaluated as a therapy of chronic hepatitis C alone and in combination with alpha interferon. Ribavirin is well absorbed orally and is typically given in doses of 1,000 to 1,200 mg/d. Three randomized, placebo-controlled studies comprising more than 150 patients have shown that therapy with ribavirin alone for 24 to 48 weeks resulted in a significant reduction in serum alanine aminotransferase (ALT) levels during therapy. However, ribavirin therapy did not lead to a substantial reduction in hepatitis C virus (HCV) RNA levels; almost all patients remained viremic, and serum aminotransferase levels increased to pretreatment values when therapy was stopped. The most common adverse event was a moderate and reversible hemolysis during treatment that caused a decrease in hemoglobin by 10% to 20% of baseline levels. Combination therapy of ribavirin with alpha interferon has demonstrated promise both in pilot studies and a recently completed randomized controlled trial. Ribavirin in standard doses combined with alpha interferon in doses of 3 million units (MU) three times weekly for 6 months was found to significantly improve the sustained biochemical and virological response rates compared with interferon alone. Combination therapy offers a promise to become standard therapy for patients with nonsustained response to alpha interferon alone, because the majority of such patients achieve a durable response after treatment with combination therapy. However, nonresponders to alpha interferon alone rarely achieve a sustained beneficial response to combination treatment. For interferon-naive patients, combination therapy is superior to therapy with alpha interferon alone in achieving sustained biochemical and virological responses, but the combination demonstrates clear-cut superiority only in patients with unfavorable profiles for a response to interferon, in particular patients with high levels of HCV RNA. The optimal use and regimen of combination therapy awaits further investigation. New antiviral agents are still needed for the proportion of patients who do not respond to alpha interferon, even in combination with ribavirin.

Antiviral Agents↗

Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers.

BACKGROUND/AIMS: This study aimed to obtain a more precise estimation of the efficacy and tolerability of interferon-ribavirin combination therapy for chronic hepatitis C. METHODS: A meta-analysis was carried out of individual patient data comprising about 90% of the published experience with combination therapy. The study was set in four European university-affiliated liver referral centers. A total of 186 individuals with chronic hepatitis C who had participated in three randomized controlled trials and one open study were selected for the study. Fifty-one had received ribavirin monotherapy (1000-1200 mg/day), 37 interferon monotherapy (3 MU 3x/week) and 78 interferon-ribavirin combination therapy (dosage as for monotherapy) for 6 months. Twenty patients served as controls. Follow-up after therapy was 6 months. Data analysis was by the multivariate logistical regression method. RESULTS: The primary outcome measure for efficacy was the percentage with a sustained response (ALT normalization and HCV RNA negativity 6 months after therapy). The sustained response rate was significantly higher for interferon-ribavirin combination therapy than for interferon or ribavirin monotherapy (odds ratio IFN-Riba vs IFN = 9.8, 95% CI 1.9-50). The estimated probability of sustained response following interferon-ribavirin combination therapy was 51% for patients without previous IFN therapy, 52% for patients with previous IFN therapy and response-relapse, and 16% for previous IFN non-responders. No serious adverse events were observed and less than 10% withdrew. CONCLUSIONS: The efficacy of interferon-ribavirin therapy appears to be enhanced two- to threefold over interferon monotherapy in all major subgroups of chronic hepatitis C patients tested. In view of its acceptable toxicity profile, interferon-ribavirin combination therapy is a candidate for the new standard therapy for chronic hepatitis C.

Adult↗

Interferon-alpha treatment induces delayed CD4 proliferative responses to the hepatitis C virus nonstructural protein 3 regardless of the outcome of therapy.

The proliferative responses to a hepatitis C virus (HCV) recombinant nonstructural protein 3 (rNS3) were analyzed in 9 patients with chronic HCV infection before, during, and after 24 weeks of treatment with interferon-alpha (IFN-alpha) alone or in combination with ribavirin. Regardless of the therapy and the subsequent outcome, all patients showed an increased rNS3-specific proliferative response in peripheral blood mononuclear cells in vitro within 48 weeks from the start of therapy (P < .01). The proliferating cell phenotype was CD4 and was dependent on HLA-DP/DQ/DR class II antigen presentation. rNS3 induced in vitro detectable interleukin (IL)-2, IL-10, and IFN-gamma production in some patients before or after therapy (or both). No significant differences existed between responders and relapsed responders plus nonresponders with respect to the NS3-specific CD4 T helper (Th) cell responses. Thus, IFN-alpha therapy induces HCV NS3-specific CD4 Th cell proliferation regardless of the outcome of therapy.

Adult↗