Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment.

OBJECTIVES: To evaluate the alterations of serum procalcitonin (PCT) levels in patients with chronic hepatitis C during pegylated interferon-alpha (PEG-IFNa) plus ribavirin (RIB) treatment and to correlate them with clinical and virological outcomes. STUDY DESIGN: Fifty-two consecutive patients (29 males, age=41.2+/-14.7 years) with chronic HCV-related liver disease (six cirrhotics) were evaluated for PCT levels at baseline and during the treatment course (at week 12, 24, 48 and 72) with PEG-IFNa plus RIB. Sustained virological response (SVR) was confirmed by undetectable serum HCV-RNA at the end of treatment and again 6 months after completion of treatment. RESULTS: Two patients exhibited culture-proved bacterial infections during the treatment course. Thirty-six patients (69.2%) exhibit SVR and 16 (30.8%) were non-responders. Serum PCT levels remained within normal limits (0.1-0.5 ng/mL) in all treated patients throughout the follow-up period except those two who exhibited bacterial infections during the treatment course. Virological responders exhibited significant decline of serum PCT levels over time compared to non-responders (p<0.001), even when adjusted for multiple baseline parameters (p=0.037). CONCLUSION: Serum PCT levels decline in chronic hepatitis C patients during PEG-IFNa plus RIB treatment, especially in the sustained virological responder group, while they elevate only when bacterial infections complicate the treatment course.     

Proapoptotic IL-18 in patients with chronic hepatitis C treated with pegylated interferon-alpha

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. In mainland of China, It was estimated the population of 1.3 billion infected with HCV. HCV is not cytopathic. Immune response that is essentially conducted by cytokines may play an important role in the pathogenesis of HCV infection. Interleukin (IL)-18, mainly produced by monocytes/macrophages, plays an important role in the immune system by enhancing T cell responses, regulating interferon-gamma (IFN-γ) production and promoting the development of T helper cell Th1 immune responses. Raised serum levels of IL-18 have recently been reported in patients with chronic hepatitis C before antiviral therapy. Herein we report the IL-18 sequential changes in patients with hepatitis C during the period of pegylated interferon (PEG-IFN) alpha treatment for 48 weeks. We established the correlation of plasma IL-18 level and alanine aminotransferase (r = 0.77, P < 0.05). Hepatic inflammatory activity in chronic hepatitis C was shown to be closely associated with an increased amount of IL-18. HCV-infected patients had raised IL-18 levels (93.67 ± 23.58 pg/ml versus 59.73 ± 24.06 pg/ml; P < 0.001) comparing donor negativity for HCV. PEG-IFN alpha-2a treatment induces a marked decline in IL-18 and remission of hepatic inflammatory in responders at week 24 and week 48 follow-up time point, while increased levels persist in those in whom the HCV infection was not eliminated by the therapy. We proposed declined IL-18 levels favor for virus solution, while persistent raised IL-18 associated with PEG-IFN treatment failure.     

Treatment with ribavirin and interferon-alpha reduces interferon-gamma expression in patients with chronic hepatitis C

Recent studies in vitro and in animals have suggested that ribavirin may potentiate the antihepatitis C virus (HCV) activity of interferon-alpha (IFN-alpha) by up-modulating the production of T cell-derived cytokines, such as interleukin (IL)-2 and IFN-gamma, which play a key role in the cellular immune response against HCV. To study the immune-modulatory mechanisms of ribavirin further, cytokine production by activated T cells and circulating cytokine levels were studied by FACS analysis and ELISA testing in 25 patients with chronic hepatitis C unresponsive to IFN-alpha, before and after treatment with either ribavirin plus IFN-alpha or IFN-alpha alone. After 16 weeks of treatment, both the expression of IFN-gamma by activated T cells and the blood levels of IFN-gamma, were significantly reduced with respect to pretreatment values in patients treated with ribavirin and IFN-alpha but not in those undergoing treatment with IFN-alpha alone. The expression of IFN-gamma was significantly lower in patients that gained normal ALT levels with respect to those that did not. No modification of the expression of IL-2, IL-4 and IL-10 was found before and after treatment in either group of patients. In conclusion, the results of this study do not support up-modulation of IFN-gamma and IL-2 production as the mechanism by which ribavirin potentiates IFN-alpha anti HCV activity. In addition, our findings suggest that ribavirin may exert an anti-inflammatory effect and may help reducing IFN-gamma-driven T cell activation and liver damage.     

Efficacy of chronic hepatitis C therapy with pegylated interferon and ribavirin in patients on methadone maintenance treatment

A considerable number of patients undergoing methadone maintenance treatment (MMT) are not considered for treatment against hepatitis C virus (HCV) infection due to a possible lower adherence and efficacy in this population. We aimed to compare the response rates to HCV treatment in patients with or without MMT. HCV-infected patients who initiated pegylated interferon plus ribavirin were included in this prospective cohort study. The relation between sustained virologic response (SVR) and MMT was analyzed. A total of 214 patients were included in the study [81 (37.9%) with and 133 (62.1%) without MMT]. No differences in HCV and interleukin 28B (rs12979860) genotype distribution were observed between the two groups. Of these patients, 103 (48.1%) achieved SVR. Among the patients who received MMT, 39 (48.1%) reached SVR compared to 64 (48.1%) subjects without MMT (p = 0.99). The frequency of voluntary drop-out and treatment discontinuations due to adverse events was comparable between the patients with and without MMT [10 (12.3%) versus 14 (10.5%), p = 0.68, and 4 (4.9%) versus 9 (6.8%), p = 0.59, respectively]. The efficacy of HCV therapy in MMT patients is similar to that found in subjects not taking methadone. MMT patients should be equally considered for treatment with pegylated interferon plus ribavirin in HCV-infected patients.     

Durability of a sustained virological response in chronic hepatitis C patients treated with pegylated interferon alfa and ribavirin

Background/Aims

The reappearance rates of hepatitis C virus (HCV) RNA after a sustained virological response (SVR) have been reported to be 1-2%. We investigated the reappearance rate of HCV RNA after SVR in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN) and ribavirin.

Methods

In total, 292 CHC patients who achieved an SVR after PEG-IFN and ribavirin treatment were included. They were treated with subcutaneous injections of either PEG-IFN-α 2a or 2b plus ribavirin orally. Liver function tests and qualitative HCV RNA assays were performed every 6 months during the follow-up period after an SVR.

Results

Among the 292 patients, 224 (genotype 1, 92; genotype non-1, 132) were followed up for more than 6 months after SVR. These 224 patients were aged 48.1±11.5 years (mean±SD), and 129 of them were male. The median follow-up duration was 18 months (range 6-60 months). The reappearance rate of HCV RNA during follow-up was 0%. Two patients who achieved an SVR developed hepatocellular carcinoma during the follow-up period.

Conclusions

An SVR was maintained in all CHC patients treated with PEG-IFN plus ribavirin during a median follow-up of 18 months. However, a screening test for hepatocellular carcinoma is needed for patients with an SVR.     

Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin

BACKGROUND: No safe and effective therapy exists for chronic hepatitis C in dialysis patients. Available data on the antiviral treatment of hepatitis C in dialysis population is mostly based on standard interferon monotherapy. OBJECTIVES: We conducted a prospective, cohort trial with combined therapy (pegylated-interferonalpha-2a (135 mcg/week) plus low dose ribavirin (200 mg/day)) for chronic hepatitis C in 15 patients undergoing long-term dialysis. Twelve patients had HCV genotype 1a/1b, three were co-infected with human immunodeficiency virus (HIV), and two had compensated cirrhosis. End-points were sustained viral response and adverse effects. RESULTS: Sustained virological response was obtained in four patients (including two with HCV genotype 1); the SVR rate was 28.6% (4/14), on an intention-to-treat analysis. One subject with SVR had compensated cirrhosis. All HIV co-infected patients had well controlled HIV and one of them (33%) reached SVR. Seven (50%) of the 14 patients were non-responders, two of which relapsed after discontinuation of therapy. Drop-out rate was 71.4% (10/14). The most frequent side-effect was anemia, which required ribavirin discontinuation in three patients; seven (47%) patients received blood transfusions. Two patients died (week 4 and 14) of causes related to cardiovascular disease, which was frequent in our cohort. Two subjects were hospitalized and discontinued therapy (week 1, and 27). CONCLUSIONS: Results from this study showed that about one-third of HD patients achieved sustained virological response with pegylated-interferon-alpha-2a plus low-dose ribavirin; however, tolerance to antiviral treatment was unsatisfactory. Well- controlled HIV infection should not be a contraindication to HCV therapy in dialysis patients. Prospective, controlled clinical trials of combined antiviral therapy targeted at HCV in chronic kidney disease population are indicated.     

Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients

A combination of pegylated interferon alpha (PEG-IFNalpha) and ribavirin has been used widely. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. The aim of the study was to elucidate whether the frequency or function of immunocompetent blood cells is related to the outcome of the therapy. Twenty-five chronic hepatitis C patients with high viral load of HCV genotype 1 who underwent 48 weeks of PEG-IFNalpha2b and ribavirin therapy were examined. During the treatment, frequencies of dendritic cell subsets, helper T cell subsets, and NK cells were phenotypically determined. In some patients, the ability of dendritic cells to stimulate allogeneic CD4(+)T cells was examined at the end and after the therapy. Among the 25 patients, 11 showed a sustained virological response, 11 a transient response, and 3 no response. In comparison with sustained virological responders, non-sustained virological responders showed impaired dendritic cell function at the end and after the treatment. The transient responders showed a decline of plasmacytoid dendritic cell frequency from Weeks 1-12 and impaired dendritic cell function as well. Even in patients who attained negative serum HCV RNA at Week 12, the transient responders showed a significant decrease of plasmacytoid dendritic cell frequency and impaired dendritic cell function. In conclusion, in PEG-IFNalpha and ribavirin combination therapy for chronic hepatitis C patients, the early-phase plasmacytoid dendritic cell frequency and/or end-of-treatment dendritic cell function are related to the virological outcome of the therapy.     

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype‐4 chronic hepatitis C patients

The therapeutic effect of pegylated interferon (peg‐IFN) alfa‐2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa‐2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa‐2a (160 μg) subcutaneous once weekly and oral weight‐based ribavirin (1000–1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170–2178, 2016. © 2016 Wiley Periodicals, Inc.

     

Association of HLA alleles with response (especially biochemical response) to interferon therapy in Japanese patients with chronic hepatitis C.

The response of chronic hepatitis C to interferon (IFN) treatment is classified as complete response (CR), biochemical response (BR), or no response (NR). Several studies have found no difference in prevention of hepatocellular carcinoma by IFN therapy between patients with CR and those with BR. We investigated whether specific human leukocyte antigen (HLA) alleles were associated with response to IFN, especially BR, in 138 patients with chronic hepatitis C. Comparing patients with and without CR, male, a low viral titer, genotype 2a or 2b, HLA-B55, and HLA-DRB1-0803 were more common in the group with CR. Multivariate analysis showed that age (adjusted odds ratio [OR], 0.95 by every year [95% confidence interval [CI] 0.90 - 0.99], p = 0.028), genotype 2a or 2b (5.21 [95% CI 1.63 - 16.6], p = 0.005), and low viral titer (8.58 (2.66 - 27.7), p < 0.001) were associated with CR. Comparing patients with BR and NR, the pretreatment alanine aminotransferase (ALT) level was lower in the BR group (p < 0.001). Both HLA-B7 and HLA-DRB1-0101 were more common in this group (p = 0.002). As the alleles HLA-B7 and HLA-DRB1-0101 were in linkage disequilibrium, the HLA-B7-DRB1-0101 haplotype may be associated with BR. Multivariate analysis indicated that a low ALT level (0.98 by every 1 IU/L [95% CI 0.98 - 0.99], p = 0.001) and HLA-B7-DRB1-0101 haplotype (32.3 [95% CI 1.50 - 693.1], p = 0.026) contributed significantly to BR. This study suggested that host HLA expression, but not viral factors, can influence BR.     

Prevalence and impact of occult hepatitis B infection in chronic hepatitis C patients treated with pegylated interferon and ribavirin

The prevalence of occult hepatitis B, defined by absence of HBsAg and HBV DNA, ranges widely in patients with hepatitis C. This may influence the treatment of hepatitis C and the severity of liver disease. Sensitive and specific real‐time PCR techniques are available commercially and can detect more reliably low HBV DNA levels. The aim of this study was to determine the prevalence of occult hepatitis B virus infection using the COBAS Taqman assay (Roche Diagnostics, Meylan, France) in the serum and liver of HBsAg negative patients with chronic hepatitis C and to evaluate its clinical consequences on liver pathology and its impact on the response to treatment with peg‐IFNα and Ribavirin. HBV DNA detection was assessed retrospectively on 140 sera and 113 liver biopsies of HCV positive/HBsAg negative patients before treatment. A 4.4% (5/113) prevalence of occult hepatitis B was recorded in liver samples and in none of the sera. Anti‐HBc was not detected in one, three of whom were sustained virological responders to treatment, one was relapsed responder and one was non‐responder. Furthermore, in this cohort composed of 12% anti‐HBs negative/anti‐HBc positive and 20% anti‐HBs positive/anti‐HBc positive patients, anti‐HBc was not associated with pre‐therapeutic viral load, ALT serum levels, and histological activity or fibrosis. Using a commercial real‐time PCR assay, we observed a low prevalence of occult B hepatitis. This, just as anti‐HBC status, had no clinical impact in a large cohort of hepatitis C patients. It therefore does not appear useful to screen for occult hepatitis B in these patients with this test before beginning HCV treatment. J. Med. Virol. 82: 000–000, 2010. © 2010 Wiley‐Liss, Inc. J. Med. Virol. 82: 747–754, 2010. © 2010 Wiley‐Liss, Inc.     

The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients

Background/Aims

Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment.

Methods

In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of β cells (HOMA-β) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx).

Results

A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0±11.2 years, mean±SD; non-SVR, 56.6±9.9 years; P<0.01), there were no significant differences in the baseline characteristics between the SVR and non-SVR groups. In the SVR group, low density lipoprotein-cholesterol (LDL-C) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-β were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group.

Conclusions

LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).     

nTreg与基因1型CHC患者抗病毒疗效的关系

目的研究基因1型慢性丙型肝炎（CHC）患者治疗过程中外周血自然调节性T细胞（nTreg）的动态变化及其与抗病毒疗效的关系。方法32例初治的CHC患者,均为基因1型,治疗方案为干扰素联合利巴韦林治疗48周。分别在治疗前、治疗过程中2、4、8、12、24、48周以及治疗结束后12或24周采集外周血标本。用流式的方法检测外周血单个核细胞（PBMC）中nTreg的比率。COBASAmpliprep／COBAS TaqmanHCV试剂盒检测HCV—RNA定量。结果24例患者治疗12周时HCV—RNA转阴,并且随访至治疗结束后24周仍阴性,达到持续病毒学应答（SVR）;8例患者治疗12周时病毒量未转阴,无应答（NVR）,24周时终止治疗。应答组和无应答组治疗前外周血中nTreg的比率差异无统计学意义（P〉0．05）。应答组治疗过程中2、4、12、24、48周及治疗结束后各个时间点PBMC中nTreg水平分别为（0．91±0．22）％、（1．31±0．29）％、（1．78±0．43）％、（1．92±0．44）％、（1．90±0．37）％、（1．14±0．35）％;在治疗2周（P〈0．001）及治疗结束后（P〈0．001）下降明显。无应答组治疗过程中2、4、12、24周及治疗结束后各时间点PBMC中nTreg水平分别为（1．21±0．15）％、（1．24±0．18）％、（1．42±0．11）％、（1．45±0．11）％、（1．14±0．10）％;Treg水平在治疗4周时缓慢上升（P=O．005）,在治疗结束后显著下降,与治疗24周比较差异有统计学意义（P〈0．001）。结论CHC患者外周血nTreg水平与干扰素／N巴韦林抗病毒治疗的疗效密切相关,抗病毒治疗2周时nTreg水平的下降可以预测其疗效。提示nTreg可能在机体清除病毒的早期过程中起着重要作用。     

HLA class II alleles and chronic hepatitis C virus infection

The aim of this study was to investigate association of human leucocyte antigens (HLA)-DRB1 and DQB1 polymorphisms with hepatitis C virus (HCV) infection and with the occurrence of severe liver fibrosis/cirrhosis in chronically infected patients. Ninety-nine white patients, from southeast Brazil, with confirmed HCV chronic infection were included in the study. Severe fibrosis/cirrhosis (METAVIR scores F3-F4) was present in 49 patients. HLA-DRB1 specificities and DRB1*11 and DQB1* alleles were determined by PCR-SSP, and their frequencies were compared between patients and a control group of 103 healthy white Brazilian individuals. The results confirmed previous reports of the association of DRB1*11 and DQB1*03 with protection from chronic HCV infection, but did not confirm their association with protection from severe fibrosis/cirrhosis. Furthermore, the results suggested that the polymorphic sites on HLA molecules responsible for protection from chronic HCV infection are encoded not only by the DRB1*1101 and DQB1*0301, as suggested in the literature, but also by other DRB1*11 and DQB1*03 alleles. Thus, we hypothesized that the common polymorphic residues shared by different DRB1*11 and/or DQB1*03 alleles might be responsible for selection of viral epitopes for presentation to CD4(+) T cells, leading to an efficient immune response against the virus.