Bezafibrate maintenance therapy in patients with advanced chronic hepatitis C.

BACKGROUND: Bezafibrate exerts multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-α, which modulates the expression of key genes of lipid transport, lipoprotein metabolism as well as inflammation. The aim of the present study was to assess the efficacy and safety of bezafibrate in patients with advanced chronic hepatitis C. MATERIALS AND METHODS: A total of 34 patients received oral bezafibrate treatment (400 mg/day) on the basis of a prospective observational open-label study design. Clinical, biochemical and virological data were evaluated during a mean treatment duration of 19 months. In a subpopulation (n=8), cytokine expression analysis was carried out and compared with an hepatitis C virus treatment-naive control group (n=7). RESULTS: A significant improvement in aspartate aminotransferase (P=0.007), alanine aminotransferase (P<0.0001), alkaline phosphatase (P=0.001), γ-glutamyltranspeptidase levels (P=0.001) and aspartate aminotransferase-to-platelets ratio index Score (P=0.026) could be found at the end of observation. No significant effect on viral load was observed. Bezafibrate treatment for at least 4 months markedly increased interferon-γ expression compared with the treatment-naive patients (4.81 vs. 1.63 arbitrary units; P=0.005), whereas tumour necrosis factor-α and interleukin-6 levels were not significantly influenced. CONCLUSION: This observational study provides evidence that bezafibrate is effective for patients with advanced chronic hepatitis C by reducing liver enzymes significantly and should be further evaluated as a potentially beneficial maintenance therapy.

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection.

BACKGROUND: The critical analysis of baseline factors has been found to be useful to predict virologic nonresponse (NR), relapse, or sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) who receive antiviral therapy. In the present retrospective study we tried to find out whether gamma-glutamyltranspeptidase (GGT) may be one of the baseline factors which are of special predictive power. We analyzed, in patients with different treatment outcomes, the predictive power of established baseline factors either in combination with GGT or by evaluating the predictive value of GGT independently. METHODS: Individual data from 632 patients chronically infected with HCV type 1 (n = 561) or type 2/3 (n = 71) were analyzed. All patients had received their first course of antiviral therapy and were treated with pegylated interferon α-2a or -2b plus ribavirin. RESULTS: In patients with HCV type 1, a multivariate multinomial logistic regression analysis identified low GGT (p < 0.0001), high cholesterol (p < 0.0001), age ≤ 40 years (p < 0.0001), high alanine aminotransferase (p = 0.0006), low viremia (p = 0.0014), and absence of cirrhosis (p = 0.0164) as independent predictors. While these baseline factors heralded improved virologic response, high GGT, in contrast, was significantly associated with NR (p < 0.0001). A strong correlation was found between log(10) GGT and a scoring variable S (r = -0.26 for prediction of SVR, p < 0.001; r = 0.11 for prediction of NR, p = 0.016) summarizing predictive information from other baseline factors. CONCLUSIONS: These findings prove the predictive sensitivity of GGT as an independent indicator of nonresponsiveness even at levels that are slightly above the normal range. This new predictive parameter may help to improve individualized therapy in HCV type-1 infection.

Evaluation of complement factor 5 variants as genetic risk factors for the development of advanced fibrosis in chronic hepatitis C infection.

BACKGROUND/AIMS: Intercross studies in inbred mice susceptible or resistant to liver fibrosis revealed complement factor 5 as a quantitative trait gene associated with the development of fibrosis. In 277 patients with hepatitis C, two C5 SNPs, rs17611 and rs2300929, have been associated with advanced fibrosis. METHODS: We investigated the association of these C5 SNPs with advanced fibrosis in 1435 HCV infected patients and in 1003 patients with other liver diseases. We performed genotyping with melting curve analysis using fluorescence resonance energy transfer probes in the LightCycler. RESULTS: The defined high-risk genotypes (AA and TT) and alleles (A and T) were not associated with advanced fibrosis in HCV patients when Chi square testing and logistic regression analysis were applied (rs17611A 0.45 in F0-1 vs. 0.43 in F2-4, P=0.31; rs2300929T 0.91 F0-1 and 0.91 in F2-4, P=0.82). In the group of patients with liver diseases other than HCV we neither found an association of the C5 SNPs with advanced fibrosis nor an overrepresentation of the SNPs in patients with cirrhosis. CONCLUSIONS: We found no evidence that these C5 SNPs are genetic risk factors for the development of advanced fibrosis in chronic HCV infection or other chronic liver diseases.

The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection.

BACKGROUND/AIMS: The efficacy of pegylated interferon alpha and ribavirin in HBV/HCV co-infected patients is unknown. METHODS: Nineteen patients with chronic HBV/HCV co-infection (HBsAg and HCV-RNA positive; 10 HCV-genotype 1; 9 HCV-genotype 2 or 3) were included in this prospective multicenter pilot study. Baseline HBV-DNA was negative in 13 individuals. All patients received weight-adjusted PEG-IFN-alpha2b and ribavirin for 48 weeks. RESULTS: In the intent-to-treat analysis, a biochemical and an HCV-RNA response were observed in 12 and 14 patients, respectively (63% and 74%). At the end of the treatment as well as at the end of the follow-up the HCV-RNA response was 93% (14/15) in patients adherent to therapy (86% in genotype 1 and 100% in genotypes 2 and 3 infection). Two of the five initially HBV-DNA positive patients with follow-up available were HBV-DNA negative at follow-up week 24. In contrast, HBV-DNA became detectable after the clearance of HCV in four initially HBV-DNA negative patients. CONCLUSIONS: Combination therapy with PEG-IFN-a2b and ribavirin is highly effective in inducing a virological response concerning HCV in patients with HBV/HCV co-infection. However, HBV replication may increase after the clearance of HCV and thus close monitoring for both the viruses is recommended even in patients with initially undetectable HBV-DNA.

Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease.

BACKGROUND: CTLA4 is an inhibitory receptor expressed on a subset of T lymphocytes. Single nucleotide polymorphisms of the CTLA4 gene have been implicated in autoimmune diseases, including autoimmune hepatitis and primary biliary cirrhosis. In reverse form, CTLA4 variations are associated with chronic infections such as chronic hepatitis B. METHODS: CTLA4 variations -318C>T and +49A>G were analyzed in 2366 patients with chronic liver disease of various etiologies, including 323 patients with chronic hepatitis B virus (HBV) infection, 1181 patients with chronic hepatitis C virus infection, 180 patients with primary biliary cirrhosis, and 127 patients with autoimmune hepatitis, as well as 202 healthy control individuals. Genotyping was performed by melting curve analysis. RESULTS: The -318C>T variation was underrepresented in patients with chronic HBV infection compared with healthy controls (14.6 vs. 25.7%, P=0.002) and with patients with chronic liver disease of other origin (14.6 vs. 20.7%, P=0.011). Patients with cryptogenic cirrhosis also showed a lower frequency of the -318T allele than healthy controls (12.0 vs. 25.7%, P=0.014). No association of the +49G>A variation was found with any diagnosis, including autoimmune hepatitis and primary biliary cirrhosis. CONCLUSION: We describe the association of the CTLA4 -318C>T variation with chronic HBV infection and cryptogenic cirrhosis but find no association of the +49G>A variation with autoimmune liver disease.

Hepatitis-C patients have reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-alpha.

OBJECTIVES: In vitro and in vivo data indicate multiple, but contradictory effects of interferon on pituitary hormone secretion. We therefore investigated prospectively basal and stimulated pituitary hormone secretion in 21 patients with chronic hepatitis C virus (HCV) infection before and during antiviral therapy. METHODS: Twenty-one patients received pegylated interferon-alpha plus either ribavirin or levovirin. Baseline and stimulated growth hormone (GH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and thyroid-stimulating hormone (TSH) responses were measured using standard pituitary function tests, before therapy in all and during therapy in 17 out of the 21 patients. RESULTS: Before therapy 17 patients (81%) had severe GH insufficiency and 9 of these had low insulin-like growth factor-1 (IGF-1) concentrations. Basal and stimulated GH concentrations increased significantly during therapy, reducing the number of patients with severe GH insufficiency to four, but IGF-1 remained low. Basal PRL and TSH concentrations were normal before and during therapy, while thyroid-releasing hormone (TRH)-stimulated concentrations increased significantly during therapy. The adrenocorticotropic hormone (ACTH)/cortisol axis, basal and stimulated gonadotropin, and testosterone concentrations were normal throughout. Neither the HCV RNA level nor transaminases correlated with hormone concentrations before or during therapy. CONCLUSIONS: GH insufficiency is common in patients with chronic HCV infection. While GH secretion improves during antiviral therapy, IGF-1 remains low, indicating persistent GH resistance of hepatocytes. Whether improvement in GH secretion during treatment is due to a direct drug effect or related to the suppression of viral load could not be differentiated, as most patients demonstrated a positive virologic response.

A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection.

BACKGROUND/AIMS: HCV-infection leads to development of liver fibrosis, causing morbidity and mortality. Multiple factors influence the progression of fibrosis, including genetic factors. Since HCV is an RNA virus, a role for TLR7 in the immune response against HCV is likely. No systematic analysis of TLR7 single nucleotide polymorphisms (SNPs) has been published. METHODS: We sequenced TLR7 in 52 women and investigated SNPs with an allele frequency >5% in 807 patients with chronic HCV-infection by melting curve analysis. We analyzed the effect of TLR7 SNPs on grade of inflammation and stage of fibrosis as determined by liver biopsy. RESULTS: We detected five TLR7 SNPs, three of which showed a frequency >5%. One variant, c.1-120T>G, was more common in patients with no or little inflammation than in patients with grades 2-4 (10.7% vs. 6.1%; P=0.034). The variant was also enriched in patients with no or little fibrosis compared to those with higher stages (12.6% vs. 6.6%; P=0.005). The difference was fully attributable to male patients. CONCLUSIONS: This is the first analysis of TLR7 SNPs in patients with chronic HCV-infection. Our data suggest that the c.1-120G TLR7 allele offers protection from the development of inflammation and fibrosis in male patients with chronic HCV-infection.

Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection.

BACKGROUND/AIMS: A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease. METHODS: We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes. RESULTS: CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response. CONCLUSIONS: CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.

Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C.

BACKGROUND & AIMS: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-alpha and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown. METHODS: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-alpha-2a (180 microg/wk) plus ribavirin 800-1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patients with HCV RNA > or =600 IU/mL at week 4 (group C) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL). RESULTS: Only 11 of 153 patients (7%) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82%, (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively. In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85%, respectively; P = .003). CONCLUSIONS: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-alpha-2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.

Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection.

Adefovir dipivoxil was recently approved for the treatment of wild-type and lamivudine-resistant hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV infected patients, has recently been shown to also be effective in patients with lamivudine-resistant HBV infection. We therefore compared the two substances in a study of 53 patients defined by high HBV DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance. Thirty-five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir-treated patients showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variations in HBV DNA decline were observed in the adefovir group. Thus at week 48, only 44% of these patients had HBV DNA levels below 10(5) copies/mL in contrast to 100% of the tenofovir-treated patients (P = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir-treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection.