G. Teuber

Randomized, double‐blind, placebo‐controlled trial of interferon Alfa2a with and without amantadine as initial treatment for chronic hepatitis C

Although the antiviral effects of amantadine sulphate (1‐aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health‐related quality of life (HRQOL) of interferon alfa (IFN‐α) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN‐α2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24‐week follow‐up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN‐α plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN‐α alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN‐α worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN‐α plus amantadine is as effective as IFN‐α monotherapy in previously untreated patients with chronic hepatitis C.

Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

ABSTRACT The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). Baseline HCV RNA levels maximally declined on average by −0.8 or −0.1 log10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.

Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy

BACKGROUND/AIMS Studies from Japan showed that HCV-1b isolates with at least four amino acid changes within NS5A2209-2248 compared with the prototype sequence HCV-J are more sensitive to interferon than isolates with a prototype sequence. However, the data were not unequivocally confirmed in studies from other geographical areas. These discrepancies may be explained by differences in the prevalence of multiple mutations within the NS5A2209-2248 and/or the treatment efficacy. METHODS In the present study, we therefore investigated the correlation between NS5A2209-2248 sequences of HCV-1b isolates and sustained virological response in 72 European patients treated with 3x6 MU interferon-a per week with (n = 26) and without (n = 46) ribavirin (1000-1200 mg/day). Serum HCV RNA was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the NS5A2209-2248 region was analyzed by sequencing of PCR products or individual clones. RESULTS Compared with HCV-1b prototype sequences, 19 patients (26%) had no amino acid changes (prototype), 47 patients (65%) had 1-3 mutations (intermediate type) and six patients (8%) had at least 4 mutations in the NS5A2209-2248 region (mutant type). Nine of the 12 patients with sustained virological response were infected with an intermediate type HCV-1b, the remaining three patients revealed a mutant type HCV-1b. A sustained virological response was achieved in three of four patients with a mutant type HCV-1b treated with interferon-alpha and ribavirin, but in none of the mutant type HCV-1b infected patients treated with interferon-a alone. Quasispecies analysis of HCV in the NS5A2209-2248 region showed only minor heterogeneity of the amino acid sequence. CONCLUSIONS The prevalence of mutant type HCV-1b isolates in European patients is low. In patients treated with combination therapy interferon-a and ribavirin, a correlation between mutant type HCV-1b isolates and sustained virological response was observed. The discrepancies between previous studies appear to be related to the efficacy of antiviral treatment and to the low prevalence of mutant type HCV-1b isolates in Western countries.

Pulmonary dysfunction in non-cirrhotic patients with chronic viral hepatitis

Background: Hepatopulmonary syndrome (HPS), defined as hypoxemia and functional intrapulmonary right-to-left shunts in the presence of chronic liver disease, is a frequent complication of end-stage liver disease. The aim of this study was to determine the extent of pulmonary dysfunction and the prevalence of HPS in non-cirrhotic patients with chronic viral hepatitis. Methods: Lung function tests were carried out in 178 patients with chronic viral hepatitis (mean age 43.2 years, 95 smokers). To demonstrate intrapulmonary shunting, contrast echocardiography was performed in all patients with hypoxemia (paO(2)<70 mmHg) or a reduced diffusion capacity (DLCO<70% predicted). Results: The median results of lung function parameters (FVC, FEV(1), FEV(1)/FVC, TLC, DLCO, and blood gas analysis) were normal. Despite normal lung function, hypoxemia and/or DLCO reduction were observed in 17 of 178 patients (9.6%). A correlation with inflammatory activity, extent of fibrosis, or etiology was not found. Intrapulmonary shunting was observed in three of 17 patients. Two of these patients fulfilled the diagnostic criteria of HPS. Conclusions: Impaired gas exchange is a common finding even in non-cirrhotic patients with chronic viral hepatitis. HPS, however, was present in 1.1% of patients with chronic viral hepatitis and is thus not restricted to patients with liver cirrhosis, portal hypertension, or acute liver failure.

Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response†

The benefit of extending treatment duration with peginterferon (PEG‐IFN) and ribavirin (RBV) from 48 weeks to 72 weeks for patients with chronic hepatitis C genotype 1 infection has not been well established. In this prospective, international, open‐label, randomized, multicenter study, 1,428 treatment‐naïve patients from 133 centers were treated with PEG‐IFN alfa‐2b (1.5 μg/kg/week) plus RBV (800‐1,400 mg/day). Patients with detectable hepatitis C virus (HCV) RNA and a ≥2‐log10 drop in HCV RNA levels at week 12 (slow responders) were randomized 1:1 to receive 48 weeks (n = 86) or 72 weeks (n = 73) of treatment. Sustained virologic response (SVR) rates were 43% in slow responders treated for 48 weeks and 48% in slow responders treated for 72 weeks (P = 0.644). Relapse rates were similar in slow responders treated for 48 or 72 weeks (47% versus 33%, P = 0.169). The safety profile was similar in both treatment arms; serious adverse events leading to discontinuation of treatment were observed in 3.5% of slow responders treated for 48 weeks and 8.2% of those treated for 72 weeks. Among slow responders with a <2‐log drop in HCV RNA at week 8, SVR was 39% in the 72‐week arm and 19% in the 48‐week arm. Conclusion: These data suggest that 48 weeks of therapy with PEG‐IFN alfa‐2b plus RBV (800‐1,400 mg/day) should remain a standard‐of‐care treatment for treatment‐naïve G1 slow responders. (Hepatology 2010)

Comparison of new faecal antigen test with 13C-urea breath test for detecting Helicobacter pylori infection and monitoring eradication treatment: prospective clinical evaluation

The 13C-urea breath test is currently regarded as the best non-invasive diagnostic method for detecting Helicobacter pylori infection, even when monitoring efficacy of treatment.1–2 Serological methods are not appropriate for such monitoring as antibodies stay for months after successful eradication.3 A newly developed immunoassay that detects bacterial antigens in a faeces specimen might constitute a non-invasive technique for evaluating the efficacy of eradication regimens shortly after treatment is stopped. In this prospective study we compared a new antigen test for H pylori in faeces4 with the reference method of monitoring treatment, the 13C-urea breath test. We intended to evaluate the clinical validity of the test for first diagnosis of H pylori infection and for monitoring efficacy of eradication treatment. Ninety participants (46 men, 44 women; age range 18-82 years) complaining about dyspeptic symptoms were screened for H pylori infection with …

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.

Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients.

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1–infected patients represents one possible strategy. Four hundred thirty‐three patients were randomly assigned to receive either 1.5 μg/kg peginterferon alfa‐2b weekly plus 800‐1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18‐48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription‐mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009.)

Severity of HCV-Induced Liver Damage Alters Glucose Homeostasis in Noncirrhotic Patients with Chronic HCV Infection

Background/Aims: To investigate the link between hepatitis C infection and glucose intolerance, we measured insulin sensitivity, glucose effectiveness and β-cell secretion in noncirrhotic HCV-infected patients with normal glucose tolerance according to WHO criteria as assessed by oral glucose tolerance tests. Methods: Glucose, insulin and C-peptide data from frequently sampled intravenous glucose tolerance tests were analyzed using the minimal modeling technique for glucose and C-peptide to determine insulin sensitivity, glucose effectiveness, first and second phase insulin secretion in noncirrhotic HCV-infected patients (n = 10) and in healthy control subjects (n = 10). Histological activity index (HAI) as well as the extent of fibrosis were evaluated by scoring liver biopsies. Results: Insulin sensitivity (2.72 ± 1.63 vs. 6.84 ± 1.20 10–4 min–1 per µU/ml, p < 0.01) and glucose effectiveness (2.29 ± 0.45 vs. 2.89 ± 0.39 10–2 min–1, p < 0.05) ere significantly lower in patients with HCV-induced liver disease. Insulin sensitivity was negatively related to serum alanine aminotransferase (r = –0.47, p < 0.05) and aspartate aminotransferase concentrations (r = –0.65, p < 0.05). Multiple linear regression analysis revealed a strong relation of insulin sensitivity with fibrosis score and HAI (r = –0.82, p < 0.02 for both). Second phase insulin secretion was significantly enhanced in HCV-infected patients (14.30 ± 2.04 vs. 8.29 ± 1.65 min–1, p < 0.05). Conclusions: HCV-infected patients with normal glucose tolerance are insulin and glucose resistant. The impairment of glucose tolerance appears to be closely related with the severity of HCV-induced liver damage.

Improved Responses to Pegylated Interferon Alfa-2b and Ribavirin by Individualizing Treatment for 24–72 Weeks

BACKGROUND & AIMS Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS We treated 398 treatment-naïve patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P < .0001 for noninferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P < .0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders.