Response to interferon in chronic hepatitis C due to mixed genotype infection

We examined the response to interferon (IFN) in patients with chronic hepatitis C (CHC) due to two different genotypes of hepatitis C virus (HCV) infection. Among 64 CHC patients studied, one (2%) had HCV-RNA genotype I, 36 (56%) had genotype II, 19 (30%) had genotype III, 2 (3%) had genotype IV and 6 (9%) had both genotypes II and III. There was no significant difference in age, sex, history of blood transfusion and liver histology among patients with genotypes II, III and II + III. The HCV-RNA titre of genotype II patients was significantly higher than that of genotype III patients (P < 0.05). However, there was no significant difference in the HCV-RNA titre between genotype II + III and the other groups. The complete response rate achieved with IFN therapy was significantly higher in genotype III patients (74%) than in genotype II patients (17%; P < 0.01). Of the six patients with genotype II + III, a complete response to IFN was only achieved by two patients (33%), both of whom had a low HCV-RNA titre (≦ 10^4,5 copies/mL) and HCV serotype 2. The remaining four patients had HCV serotype 1 and three of the patients had a high HCV-RNA titre (≧ 10⁵ copies/mL). The HCV genotype III was lost in two patients after IFN therapy. These data suggest that HCV-RNA titre and HCV serotype are important factors for predicting the efficacy of IFN therapy in patients with mixed genotype infection and show direct evidence of higher susceptibility towards CHC of patients with genotype III than genotype II.     

Magnitude of activity in chronic hepatitis C is influenced by apoptosis of T cells responsible for hepatitis C virus

BACKGROUND: The mechanisms of hepatitis C virus (HCV) persistence are unknown, but down-regulation of immune response in a host is likely to play a major role in it. METHODS: To investigate whether T cell apoptosis contributes to such down-regulation, we compared peripheral T cell apoptosis in patients with chronic hepatitis C (CHC) with the serum titre of HCV-RNA, serum alanine aminotransferase (sALT) levels and its change, or peripheral T cell proliferation to the recombinant core antigen of HCV, JCC-1. RESULTS: The percentage of apoptosis in T cells was 0.30 +/- 0.31% (mean +/- SD) in 44 patients with CHC and 0.10 +/- 0.05% in 10 normal volunteers (P < 0.05). In patients with CHC there was no statistical correlation between apoptosis in T cells and sALT levels, titre of HCV-RNA or T cell proliferation to JCC-1 antigen. But, in patients showing relatively more apoptosis in T cells (more than mean + 2SD of apoptosis in T cells from normal volunteers), sALT levels decreased. CONCLUSIONS: Thus, T cell apoptosis in patients with CHC is considered to cause a reduction in sALT, contributing to HCV persistence in patients with CHC.     

Hepatitis C virus genotypes in elderly patients with chronic hepatitis C

The importance of determination of hepatitis C virus (HCV) genotypes and subtypes has been demonstrated not only as epidemiological characteristics, but also as prognostic factors regarding the seriousness of the disease and response to interferon (IFN) in patients with chronic hepatitis C (CHC). Aim of this study was to determine HCV genotypes in a group of elderly patients with CHC, in order to acquire epidemiological data on the prevalence of HCV genotypes in Eastern Sicily, and to evaluate any relationship with the seriousness of the disease and with the response to IFN. The study was carried out on 22 patients with CHC, aged from 65 to 75 years. The prevalence of HCV-RNA subtypes in elderly patients (Group A) was compared with two other groups: Group B aged from 36 to 64 years; and Group C aged from 20 to 35 years. HCV-RNA proved to be positive in 20 of the 22 patients in Group A, and in 100% of these cases the prevalent subtype was 1b; in the other two groups the occurrence of other subtypes was more frequent, especially in the younger ages. In conclusion, the subtype 1b is indigenous in our region and it cannot be proposed as the only prognostic factor for seriousness of the disease and response to IFN, especially in elderly patients.     

Long-term follow up of chronic hepatitis C patients after alpha-interferon treatment: a functional study

AIM: To evaluate the long-term functional outcome of chronic hepatitis C (CHC) patients treated with interferon (IFN) therapy. METHODS: Thirty-six patients with CHC were followed up for a mean of 36 months (+/- 19, SD) after a course of IFN therapy. Biochemical, virological (qualitative hepatitis C virus (HCV)-RNA and HCV genotype), and functional (monoethylglycinexylidide (MEGX) test) evaluations were carried out at the time of liver biopsy. Patients were divided into long-term responders (LTR), relapsers (RR), or non-responders (NR) according to IFN therapy outcome. At the end of follow up, patients were non-invasively re-evaluated by means of biochemistry, qualitative HCV-RNA, MEGX test, and liver ultrasonography. RESULTS: A significant decrease in MEGX values was observed in all patients. However, when patients were examined according to treatment outcome, only NR and RR showed a significant decrease in liver function as compared to pretreatment levels (MEGX30, 80.5 +/- 26.8-62.9 +/- 24.2 ng/mL, P< 0.01; MEGX60, 72.9 +/- 18.1-60.5 +/- 19.7 ng/mL, P< 0.05; MEGXAUC, 3,816 +/- 1,243-3,095 +/- 1,205 ng/mL per h, P< 0.05). On the contrary, LTR patients showed no significant modifications in MEGX values at each sampling time (MEGX,5, 72.9 +/- 31.4-70.3 +/- 29.7 ng/mL; MEGX30, 84.0 +/- 27.6-71.5 +/- 21.8 ng/ mL; MEGX60, 69.5 +/- 26.8-63.2 +/- 14.4 ng/mL; MEGXAUC 4028 +/- 1,378-3,620 +/- 1,041 ng/mL per h). At the end of follow up, LTR patients showed normal liver biochemistry and negativity of serum HCV-RNA, while NR and RR patients showed a significant decrease in platelets. CONCLUSIONS: In CHC patients long-term response to IFN therapy, besides favoring positive clinical and virologic long-term outcome, results in maintaining preserved liver function. Furthermore, IFN therapy seems to determine a decrease in the rate of functional disease progression, even in NR and RR. The MEGX test may be considered as a useful tool for performing serial follow up of CHC patients.     

Long-term monitoring of platelet count, as a non-invasive marker of hepatic fibrosis progression and/or regression in patients with chronic hepatitis C after interferon therapy

Background: Platelet count has been shown to correlate with the hepatic fibrosis stage in chronic hepatitis C (CHC). The aim of the present study was to assess hepatic fibrosis progression or regression of CHC patients by long‐term monitoring of the platelet count. Methods: A total of 429 interferon (IFN)‐treated CHC patients were studied. Follow‐up data on the platelet count were collected every 6 months after IFN therapy. The IFN response was defined as follows: complete responders (CR, n = 121) demonstrating persistent clearance of serum hepatitis C virus (HCV) RNA; biochemical responders (BR, n = 94) demonstrating alanine aminotransferase (ALT) normalization for ≥6 months without eradication of HCV‐RNA; and non‐responder (NR, n = 214) demonstrating all other patterns. Results: In comparison with the baseline level, mean platelet count increased in the CR group from 0.5 years after IFN therapy (for each point, P < 0.01), but significantly decreased in the NR group from 1 year after IFN therapy (for each point, P < 0.01). In the BR group, an increase in mean platelet count was observed from 0.5 to 3.5 years following IFN therapy (for each point, P < 0.01), followed by a gradual decrease. Conclusion: An increase from baseline values in platelet count was observed, regardless of the presence of HCV‐RNA, in both the CR and BR groups, suggesting the importance of ALT normalization in preventing hepatic fibrosis progression in IFN‐treated CHC patients.     

Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV replication

Background We have reported that the presence of a mutation at the hepatitis C virus (HCV) nonstructural protein 5B (NS5B), defined as a change in amino acids at sites specific for a different reported genotype, was related to complete response (CR) to interferon (IFN) therapy in patients with chronic hepatitis C (CHC) with genotype 1b. The present study assessed the impact of the NS5B mutation on the replication of HCV in these patients.Methods Genotype-specific mutations of HCV NS5B were determined by direct sequencing. We measured HCV-RNA titers in serum by real-time detected polymerase chain reaction (PCR), and serum HCV core protein levels (as a marker of HCV-RNA replication) were measured using an enzyme immunoassay in patients with CHC genotype 1b. RNA-dependent RNA polymerase (RdRp) activity was measured by Behrens method in liver cirrhosis patients infected with HCV (n = 13) and in those infected with hepatitis B virus (HBV; n = 2).Results The titers of HCV-RNA (n = 44) and the levels of HCV core protein (n = 41) were significantly lower in patients with the HCV genotype 1b mutant compared with wild-type HCV (P < 0.05). RdRp activity in liver tissue did not show any correlation with the HCV NS5B mutation.Conclusions HCV NS5B genotype-specific mutations in HCV genotype 1b may influence HCV replication.     

Role of serum soluble Fas/soluble Fas ligand and TNF-alpha on response to interferon-alpha therapy in chronic hepatitis C

AIMS/BACKGROUND: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-alpha (TNF-alpha) were analyzed in 41 patients with chronic hepatitis C (CH-C) treated with IFN-alpha. METHODS: Serum levels of sFas, sFas ligand, and TNF-alpha were measured at 0, 4, and 24 weeks of IFN therapy. RESULTS: Eighteen patients were complete responders (CR) and 23 patients were non-responders (NR). Serum levels of sFas and TNF-alpha in patients with CHC were significantly higher than those in healthy controls (p<0.01 and p<0.01, respectively). Serum sFas ligand levels were significantly lower in CH-C patients than in healthy controls (p<0.01). Before IFN therapy, serum levels of sFas in NR were significantly higher than those in CR (p<0.05). At 4 weeks of IFN therapy, serum levels of sFas of CR were significantly elevated compared with levels before IFN therapy (p<0.05). Serum levels of sFas correlated with the histological activity of the liver (p<0.05) and alanine aminotransferase (p<0.05). None of the three parameters, serum sFas, sFas ligand, or TNF-alpha levels, correlated with each other, with HCV-RNA genotype or with serum HCV-RNA load. Multiple logistic regression analysis showed that serum sFas levels before IFN therapy were a contributive factor to predict efficacy of IFN therapy. CONCLUSIONS: Serum sFas/sFas ligand and TNF-alpha play a possible role in pathogenesis of CH-C and also in IFN therapy. Serum sFas levels before IFN therapy may be one of the host-related factors used for evaluating the response of CH-C patients to IFN therapy.     

Effects of bezafibrate in patients with chronic hepatitis C virus infection: combination with interferon and ribavirin

An association of hepatitis C virus (HCV) with low-density lipoproteins (LDL) in serum of patients with chronic hepatitis C (CHC) has been suggested. We conducted a prospective study in CHC patients complicated with hyperlipidaemia, to examine whether bezafibrate, which is commonly used for treatment of hyperlipidaemia, reduces serum HCV-RNA titre and improves liver dysfunction. Fifteen patients received daily oral bezafibrate treatment (400 mg/day) for 8 weeks, and its effects on serum lipids, transaminases, HCV-RNA titres, and HCV-RNA titres bound to LDL were evaluated. Fifteen untreated patients with CHC and hyperlipidaemia were used as controls. The mean serum alanine aminotransferase levels and HCV-RNA titres significantly decreased at the end of bezafibrate therapy in the treated group (105 +/- 34 to 80 +/- 32 IU/L, P = 0.02 and 2.23 +/- 2.71 to 1.78 +/- 2.38 x 10(7) copies/mL, P < 0.01 respectively), but no changes were observed in the control group. Serum HCV-RNA titres bound to LDL, as quantified by immunoprecipitation using anti-LDL antibody, also decreased in all 15 treated patients [5.55 +/- 6.59 to 1.07 +/- 1.58 x 10(6) copies/ml, P < 0.01 (mean reduction rate was -78.5 +/- 17.0%)]. Sucrose density-gradient ultracentrifugation study revealed that HCV-RNA-decreased density fractions after the bezafibrate were identical to LDL-density fractions (1.015-1.062 g/mL). Eight CHC patients were treated with bezafibrate, interferon, and ribavirin triple therapy for 32 weeks, and four patients achieved sustained virological response to therapy. This pilot study provides further evidence of an association between HCV and LDL in serum and suggests the potential usefulness of bezafibrate as an anti-HCV reagent for the treatment of CHC patients.     

聚乙二醇干扰素α-2a联合利巴韦林治疗老年慢性丙型肝炎的疗效和安全性

目的分析聚乙二醇干扰素（PEG—IFN）α-2a联合利巴韦林治疗老年慢性丙型肝炎（CHC）的疗效和安全性。方法老年CHC患者（〉t60岁）（N：16）与中青年CHC患者（〈60岁）（N=46）接受PEG—IFNα-2a 180μg／周,利巴韦林800—1000mg／d联合治疗。比较两组患者在基线、病毒应答和不良反应发生率等差异。结果老年患者中性粒细胞减少症和血小板减少症的发生率显著高于中青年患者[（P=0．044,OR（95％CI）=3．264（1．005～10．599）;P=0,000,OR（95％CI）=2．875（1．935-4．271）]。两组患者SVR率差异无统计学意义（P=0．131）。单因素分析结果提示CHC患者年龄与SVR率无明显关联。结论PEG—IFN α-2a联合利巴韦林治疗老年CHC是安全有效的。     

Randomized placebo-controlled trial of interferon alpha-2b plus ribavirin with and without lactoferrin for chronic hepatitis C.

Lactoferrin (LF), an iron-binding glycoprotein, exhibits several biological activities, including anti-viral activity and immunomodulatory functions. LF has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in low pretreatment HCV RNA titers of patients with chronic hepatitis C (CHC). However, the combination of interferon (IFN) alpha-2b plus ribavirin with LF for CHC has not been previously investigated. Thirty-six CHC patients, who were positive for HCV RNA with high serum levels of HCV RNA or who did not respond to or relapsed after interferon monotherapy, were randomly assigned to two groups: IFN alpha-2b and ribavirin plus LF for 24 weeks (18 patients), and IFN alpha-2b and ribavirin plus placebo (18 patients). Treatment was discontinued in three patients (17%) in the LF group and eight patients (44%) in the placebo group. For the 25 patients who finished the 24 weeks of treatment, virological sustained response was seen in 6 (40%) patients in the LF group and in 5 (50%) patients in the placebo group and there was no statistically significant difference between the two groups (p=0.7). Serum alanine aminotransferase concentrations remained normal throughout the follow-up period in nine patients (60%) in the LF group as compared with five patients (50%) in the placebo group (p=0.7). The proportion of patients with a virological or biochemical response at the end of the treatment period did not differ between the two groups. Furthermore, there were no statistically significant differences between the two groups in hemoglobin concentration, serum iron, ferritin, Th1/Th2 ratio or ribavirin concentration throughout the treatment and follow-up periods. In conclusion, we could not demonstrate that LF in combination with IFN alpha-2b and ribavirin increases the virological and biochemical response rate for CHC patients with high serum levels of HCV RNA or for CHC patients who do not response to or relapse after IFN monotherapy.     

Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C

BACKGROUND AND AIMS: Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy. METHODS: We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks. RESULTS: CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 +/- 5.34 vs 4.41 +/- 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake (P = 0.0213, r = 0.290), transaminase level (P = 0.0126, r = 0.247), platelet count (P = 0.0002, r = -0.369), histological grading (P = 0.0121, r = 0.248) and staging (P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 +/- 5.76 vs 4.39 +/- 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin (P = 0.0277). CONCLUSIONS: Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment.     

Clinical significance of TT virus in chronic hepatitis C

BACKGROUND AND AIMS: Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A-G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). METHODS: The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. RESULTS: TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5' untranslated region (5' UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5' UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. CONCLUSION: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV.     

Randomized trial of three different regimens for 24 weeks for re-treatment of chronic hepatitis C patients who failed to respond to interferon-alpha monotherapy in Taiwan.

With the favorable result of interferon (IFN)-ribavirin combination therapy for 24 weeks among naive Taiwanese chronic hepatitis C (CHC) patients, the optimal regimens of re-treatment for CHC patients who failed initial IFN monotherapy is not well-established. The study evaluated the effectiveness of re-treatment for 24 weeks with 3 different regimens and predictors for sustained virological response (SVR). METHODS: Total 120 Taiwanese CHC patients (81 males, 70 relapsers, mean age: 48.6 years) who failed initial IFN monotherapy were enrolled. They were assigned randomly (with a ratio of 1:1:2) to receive one of the three regimens for re-treatment for 24 weeks; group A: IFN 6 million units (MU) monotherapy (N=30), group B: combination therapy with ribavirin and IFN 3 MU (N=30) or group C: combination therapy with ribavirin and IFN 6 MU (N=60). The intention-to-treat rate of sustained virological response (SVR) was 38.3%. The SVR rate in group C (53.3%) was significantly higher than group A (16.7%, P<0.005) and group B (30%, P<0.05). Drop-out rates were similar between the three groups. Patients achieving SVR had significant improvement histologically. Hepatitis C virus (HCV) genotype non-1b infection, lower pretreatment HCV RNA levels, combined with ribavirin and with higher IFN dose, and relapsers were independent predictors for SVR. CONCLUSION: We concluded that more than one-third Taiwanese CHC patients achieved SVR after 24 weeks re-treatment and combination therapy, especially with higher dose of IFN, yielded higher efficacy.     

Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

INTRODUCTION The goal of therapy for chronic hepatitis C (CHC) is the eradication of the hepatitis C virus (HCV)[1]. In the recent decade, anti-viral therapy against HCV has been markedly improved, especially treatment with ribavirin and peg- interferon (…     

Natural Interferon α Treatment and Interferon α Receptor 2 Levels in Acute Hepatitis C

Efficacy of interferon (IFN) therapy during the acute phase of hepatitis C infection is promising, although the optimal regimen has yet to be determined. It is not known whether the known prognostic factors for chronic hepatitis C (CHC) influence the effect of IFN in acute hepatitis C (AHC). Seventeen patients with AHC were analyzed for hepatic IFN alpha receptor 2 (IFNAR2) prior to IFN treatment. All patients were subsequently treated with either 168 million units (MU) or 336 MU of natural IFN alpha. Seventeen age-matched samples of CHC were provided as controls. The overall sustained response rate was 64.7% (11/17). In patients who received a total dose of 168 MU IFN, the sustained response rate was 28.6% (2/7), and in those who received 336 MU of IFN, the sustained response rate was 90.0% (9/10). The peaks of ALT and HCV-RNA quantity were not associated with the response to IFN. The hepatic IFNAR2 levels were 1.52 +/- 0.34 densitometry units and 0.92 +/- 0.16 in AHC and CHC, respectively (P = 0.042). There was no difference in hepatic IFNAR2 levels between sustained virological responders (SVR) and nonsustained virological responders (NR). The hepatic receptor levels were higher in AHC than in CHC patients. The levels of hepatic IFNAR2 did not differ in SVR and NR, indicating that high-dose natural IFN alpha treatment is effective for AHC, irrespective of the levels of hepatic IFNAR2.     

Hepatitis C virus clearance is prominent in women in an endemic area

BACKGROUND: The clinical and virological backgrounds of cases with previous hepatitis C virus (HCV) infection (positive for HCV antibody (anti-HCV) and HCV-RNA negative) in an HCV endemic area were examined to identify factors related to the clearance of HCV. METHODS: The study population comprised 3117 inhabitants, 1037 male and 2080 female, from an HCV endemic area. Hepatitis C virus antibody was detected by a passive haemagglutination test. The HCV-RNA and the HCV genotype were detected by using the polymerase chain reaction method. The HCV serotype was determined by enzyme immunoassay by using the peptides of the core region. RESULTS: Twenty-two per cent of the inhabitants were positive for anti-HCV, with males and the elderly having a significantly higher antibody titre (P < 0.01) than youths and females. Hepatitis C virus-RNA was detected in 78% of the HCV antibody-positive cases. The rate of HCV-RNA positivity was significantly higher in males than in females (P < 0.01). No relationship was found between HCV-RNA positivity and age. The HCV genotype 1b was the predominant genotype among the HCV-RNA-positive cases. Mixed genotypes (1b + 2a) were observed in 12% of cases, primarily in elderly males and females. In cases with previous HCV infection, serotype 1 was the most common serotype, and there appeared to be no relationship between the distribution of HCV serotypes and age and gender. There was a female predominance with regard to previous HCV infection, but not to being HCV carriers (P < 0.01). CONCLUSIONS: Gender, not HCV genotype, is the primary factor influencing HCV clearance.