Increased prevalence of reduced estimated glomerular filtration rate in chronic hepatitis C patients.

BACKGROUND: To investigate the prevalence and severity of reduced estimated glomerular filtration rate (eGFR) in patients with chronic hepatitis C (CHC). METHODS: Medical record review of 831 consecutive CHC patients seen in our clinic between July 2000 and August 2003; eGFR was estimated using the abbreviated Modification of Diet in Renal Disease (aMDRD) equation. The stage of kidney disease was determined based on eGFR expressed in milliliters per minute per 1.73 m(2): stage 1 (signs of kidney damage but normal or elevated (eGFR >or= 90), stage 2 (eGFR 60-89), stage 3 (30-59), stage 4 (eGFR 15-29), stage 5 (eGFR < 15 or dialysis-dependent). RESULTS: A total of 522 patients had available data with using the aMDRD equation, 51% had abnormal eGFR (stage 1, 4.6%; stage 2, 36.4%; stage 3 or 4, 6.1%; stage 5, 3.8%). Of 190 patients with stage 2 kidney disease, 189 patients (99.5%) had normal serum creatinine and only one patient (0.5%) had elevated creatinine concentrations (>1.4 mg/dl). Of the 32 patients with stage 3 or 4 disease, 20 (62.5%) had a normal serum creatinine concentration. Of 349 patients without diseases known to cause renal insufficiency, 38% had stage 2-4 renal disease. In a subset of these patients, 95/522 (18%) the measured creatinine clearance showed good correlation with their aMDRD (R = 0.47, (p < 0.0001). CONCLUSIONS: In CHC patients, a normal serum creatinine concentration does not assure normal kidney function. Estimation of eGFR with the aMDRD equation is a more accurate method of identifying patients with chronic kidney disease and reduced eGFR. Therefore, CHC patients should be screened more rigorously for chronic kidney disease because of the high prevalence of reduced eGFR. Lastly, in all CHC patients, the aMDRD eGFR should be used in each encounter with these patients when assessing their renal function irrespective of their serum creatinine.

Global transcriptional effects of PEG-IFN-alpha and ribavirin on peripheral blood cells obtained from patients with chronic hepatitis C.

The global transcriptional profile during the first 4 weeks of treatment with pegylated interferon alfa (PEG-IFN-alpha) therapy for chronic hepatitis C (CHC) was evaluated. cDNA array technology was used to assess expression of 10,918 human genes in peripheral blood cells obtained from 17 CHC patients at days 0, 7, and 28 following treatment with PEG-IFN-alpha and ribavirin. Hierarchical average linkage clustering identified seven temporal profiles of differential expression comprising 148 genes. Gene expression profiles were comparable between the PEG-IFN-alpha-2a and PEG-IFN-alpha-2b therapy. Genes representing a broad range of molecular functions were differentially regulated with distinct temporal patterns of expression. The initial global response to interferon treatment appears to be a net up-regulation of genes, consistent with gene responses identified previously in vitro, though by 4 weeks an overall down-regulation of genes was observed. Novel transcription factors potentially involved in secondary gene regulation cascades, a potential dsRNA receptor and members of the ubiquitin signaling, including a novel predicted deubiquitinating peptidase were all identified as being up-regulated upon treatment with IFN. The overall findings provide new light on possible physiological effects of IFN-alpha and open new lines of investigations on the mode of action of PEG-IFN-alpha combination therapy.

Persistence of hepatitis C virus in peripheral blood mononuclear cells of sustained viral responders to pegylated interferon and ribavirin therapy.

The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression.

Selective serotonin reuptake inhibitors in the context of hepatitis C infection: reexamining the risks of bleeding.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are used to treat interferon-associated depression in patients receiving hepatitis C virus therapy. Prior studies have cautioned against the combined use of SSRIs and interferon due to increased risk of hemorrhage. Given the morbidity of depression and its impact on interferon compliance, we sought to reexamine the data. METHOD: In a retrospective analysis of our database of hepatitis C virus patients, a consecutive series of 303 patients (receiving treatment between January 2001 and January 2005) were evaluated for any evidence of bleeding. On the basis of our standard practice of care, patients were treated prophylactically with antidepressants for 3 to 4 weeks before beginning combination therapy with interferon and ribavirin. Patients were evaluated every 4 weeks during antiviral treatment with physical examinations and complete blood cell counts with differentials and platelets. RESULTS: The overall rate of bleeding in our study was 0.3%, representing a single case of hemophilia. CONCLUSIONS: The bleeding risk of SSRIs is lower than previously reported.

Modafinil's use in combating interferon-induced fatigue.

Interferon (IFN) is an effective agent in the treatment of chronic viral hepatitis C. A variety of adverse neuropsychiatric effects including anxiety, depression, delirium, psychoses, and mania complicates its usage. IFN-alpha-induced depression is presumed to be composed of two overlapping syndromes: a depression-specific syndrome characterized by depressed mood, anxiety, and cognitive complaints, and a neurovegetative syndrome consisting of fatigue, anorexia, somatic pain complaints, and psychomotor retardation [1]. Our results show that depression-specific symptoms peak at 12 weeks of IFN therapy and respond well to serotoninergic antidepressants [2]. We conclude that neurovegetative symptoms are relatively treatment refractory to antidepressants, occur early in the course of treatment, and tend to persist for the duration of therapy [1].

Pegylated interferon and ribavirin failures: is retreatment an option?

Currently, there are limited therapeutic options available for chronic hepatitis C (HCV) patients who fail treatment with peginterferon alpha (PEG IFN) + ribavirin (RBV). An option is retreatment with a second course PEG-IFN + RBV. However, the virologic clearance with this option is unknown. Thus, we evaluated the outcome of our cohort of patients with chronic HCV who achieved a sustained viral response when retreated with PEG IFN plus RBV after having no response to an initial course of PEG IFN plus RBV. Nonresponse to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of PEG-IFN + RBV therapy. Twenty patients (12 [60%] men; 8 [40%] women) were treated with PEG IFN alpha-2b plus RBV and PEG IFN alpha-2a plus RBV. The mean age of the patients was 50 years, 85% were white, 95% had genotype 1, and 35% had cirrhosis. Prior to the first course of PEG IFN plus RBV, 12 (60%) of 20 patients had no prior treatment for Hepatitis C. After the second course of PEG IFN plus RBV, 2 (10%) of 20 patients achieved a sustained virologic response. These results suggest marginal benefit of retreatment of patients with chronic HCV with another course of PEG IFN plus RBV after they have not responded to an initial course of PEG IFN plus RBV.

Successful treatment with novel triple drug combination consisting of interferon-gamma, interferon alfacon-1, and ribavirin in a nonresponder HCV patient to pegylated interferon therapy.

Despite major advances in therapy of hepatitis C over the past decade, nearly half of the patients treated with the currently available regimens do not clear the virus. Therefore, there is a large unmet need for more effective therapy for patients who have failed pegylated interferon plus ribavirin therapy. We describe a case of a HCV genotype 1b patient who had failed previous combination therapies of interferon plus ribavirin and pegylated interferon plus ribavirin and was subsequently successfully treated with a novel triple drug combination consisting of interferon-gamma plus interferon alfacon plus ribavirin with the outcome of a sustained virologic response. This triple drug therapy combination could be an option for patients who have failed therapies with currently available pegylated interferons plus ribavirin. Prospective randomized studies are required to evaluate the effectiveness and tolerability of this regimen in this patient population.

Hepatic steatosis in hepatitis C virus genotype 3 infection: does it correlate with body mass index, fibrosis, and HCV risk factors?

Hepatic steatosis is a recognized feature of hepatitis C viral infection, particularly in genotype 3. The demographics and the associations contributing to moderate to severe steatosis in genotype 3 are not very well studied. The aim of this study is to determine the demographics and association of steatosis with fibrosis, obesity, diabetes, lipid levels, and risk factors among patients with hepatitis C virus (HCV) genotype 3. Two hundred ninety-three consecutive HCV patients (genotype 1, n = 218; genotype 2, n = 43; genotype 3, n = 32) at our institution were studied retrospectively. Demographic information such as height, weight, genotype, risk factors, serum cholesterol and triglyceride, and liver biopsy was collected. Steatosis was graded using the Brunt classification. HCV genotype 3-infected patients were younger (P < 0.04) and had lower serum cholesterol levels (P < 0.02) compared to nongenotype 3 patients. Moderate to severe steatosis was more prevalent in HCV genotype 3 patients (P < 0.001) with intravenous drug abuse as a risk factor (P = 0.04). Genotype 3 was the independent predictor of steatosis in all patients. There was no statistical association between grade of steatosis and body mass index, fibrosis, necroinflammation, or hyperlipidemia when only HCV genotype 3 patients were included in the multivariate logistic model. Hepatic steatosis is a feature of genotype 3. Patients with HCV genotype 3 are younger and have lower serum cholesterol levels. Genotype 3 is the independent predictor for steatosis in HCV patients. HCV genotype 3 patients with moderate to severe steatosis are more likely to have intravenous drug use as a risk factor.