Biomedical subjects
Publications and source records attributed to Martin Lagging.
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BACKGROUND: We investigated associations between interferon (IFN)-gamma-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4. METHODS: Plasma IP-10 was monitored before, during, and after treatment with pegylated IFN- alpha 2a and ribavirin in 265 HCV-infected patients. RESULTS: In univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively. CONCLUSION: Baseline IP-10 levels are predictive of the response to HCV treatment.
BACKGROUND/AIMS: Phase I/II studies of 4 weeks duration have confirmed the ALT lowering effect of glycyrrhizin in Western chronic hepatitis C patients. Our aim was to determine the dose frequency of glycyrrhizin required to maintain the ALT response beyond 4 weeks and evaluate its effect on liver histology and quality of life. METHODS: HCV-RNA-positive patients with elevated ALT and marked fibrosis or necro-inflammation who were not eligible for interferon therapy were treated for 4 weeks with six infusions weekly of glycyrrhizin. Patients with an ALT response at week 4 were randomized to continue treatment for 22 weeks in three dose frequency groups: 6x, 3x or once weekly. RESULTS: 72/121 (60%) patients were randomized. At the end of treatment the ALT response was maintained in 60%, 24% and 9% of patients in the 6x, 3x, and once weekly groups, respectively (p<0.001). In ALT responders the necro-inflammation score improved non-significantly compared to ALT non-responders. Quality of life assessed by SF-36 increased in patients treated with the study drug, albeit unrelated to the occurrence of ALT response. CONCLUSIONS: ALT responses induced by 4 weeks glycyrrhizin therapy can be maintained in a subset of chronic hepatitis C patients receiving at least three injections weekly. The observed ALT response did not translate in a significant histological improvement after 6 months treatment.
Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-alpha-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P < .0001), even in those with body mass index (BMI) > or = 25 kg/m2 (P = .004) and with baseline viral load > or = 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P < .05), higher viral load (P = .0005), and both higher BMI and viral load (P < .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCV-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.
BACKGROUND/AIMS: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. METHODS: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180 microg/week) and ribavirin (1000-1200 mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1 mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360 microg/week) plus ribavirin for NUR patients. RESULTS: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. CONCLUSIONS: An improvement in virologic efficacy was not achieved with the available individualized treatment options.
OBJECTIVE: Assessment of liver histology is pivotal in prognostication and decision-making regarding therapeutic intervention in patients with chronic hepatitis C virus (HCV). Being an invasive procedure, the liver biopsy is associated with complications, and a non-invasive alternative would be preferable. MATERIAL AND METHODS: Sera samples from 179 patients with chronic HCV infection collected at the time of liver biopsy were analyzed using routinely available biochemical markers of liver disease, and liver histology was evaluated using the Ishak protocol. The relationship between the serum biochemical markers and cirrhosis (Ishak stage > or = 5) as well as bridging fibrosis (Ishak stage > or = 3) was examined. RESULTS: A strong association was found in the multivariate logistic regression analysis between fibrosis stage and aspartate aminotransferase (AST), platelet count and prothrombin-INR (international normalized ratio). An index (the Göteborg University Cirrhosis Index (GUCI)) was calculated using these variables: normalized ASTxprothrombin-INRx100/platelet count (x 10(9)/l). Using a cut-off value of 1.0, the sensitivity was 80% and the specificity 78% for diagnosis of cirrhosis, and the negative predictive values (NPV) and positive predictive values (PPV) were 97% and 31%, respectively. The GUCI score proved slightly superior for sensitivity, specificity, NPV, PPV, and the area under the receiver operating characteristic (ROC) curve for prediction of cirrhosis and bridging fibrosis compared with the AST to platelet ratio index (APRI), which has been reported as a predictor of significant fibrosis and cirrhosis. CONCLUSION: An index using routinely available biochemical markers can with a high degree of accuracy discriminate patients with from those without hepatitis C-related cirrhosis.
It has previously been reported that singular reactivity against NS5 in the third generation hepatitis C virus (HCV) confirmatory recombinant immunoblot assay (RIBA-3) is not associated with detectable HCV RNA in sera. In order to investigate the significance of indeterminate HCV RIBA-3 results with particular regard to NS5, 165 sera with indeterminate RIBA-3 results were analysed for the presence of HCV RNA. Sera from blood donors constituted 58 of the 165 samples, whereas 11 were from immunocompromized patients. The remaining 96 sera were from non-immunosuppressed clinical patients. Of the 107 RIBA-3 indeterminate samples from clinical patients, 19 were HCV RNA positive (18%), with 3 of the 57 (5%) NS5 reactive samples having detectable HCV RNA. None of the 58 indeterminate samples obtained from blood donors had detectable HCV RNA. Thus, having an indeterminate RIBA-3, including singular reactivity against NS5, may be associated with the presence of detectable levels of HCV RNA in clinical patients but not necessarily in blood donors.
BACKGROUND/AIMS: Steatosis is common in patients with hepatitis C virus (HCV) infection. Its influence on disease progression is only partially understood. The aim of this study was to evaluate the impact of steatosis on fibrosis progression over time in relation to HCV genotype. METHODS: We retrospectively analyzed 98 patients who underwent dual liver biopsies prior to antiviral treatment. The median follow-up time was 5.8 years. Biopsy specimens were assessed for necroinflammatory activity, fibrosis and steatosis. RESULTS: The prevalence and grade of steatosis were strongly associated with HCV genotype 3, independent of sex, age, body mass index and alcohol consumption. Progressive fibrosis was more prevalent in patients whose initial biopsy showed steatosis, an effect seen mainly in genotype 3 infected patients. Low-grade steatosis was observed in overweight patients, but high-grade steatosis was associated with genotype 3, independent of body mass index. CONCLUSIONS: Our data confirm the association between HCV genotype 3 and steatosis. Furthermore, we showed that steatosis in genotype 3 infected patients is a risk factor for progression of fibrosis. Therefore, patients with genotype 3 and steatosis ought to be recommended for early therapeutic intervention.