Boceprevir plus peginterferon/ribavirin for treatment ofchronic hepatitis C in Russia

AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebocontrolled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. t N patients randomized to triple therapy received boceprevir(800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8(t W8) HCV RNA levels. t E patients received boceprevir plus PR for 32 wk and then further therapy according to t W8 HCV RNA levels. treatment was discontinued for t N patients with detectable HCV RNA at t W24 and t E patients with detectable HCV RNA at t W12 because of futility. the primary efficacy end point was sustained virologic response(SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2%(95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both t N and t E patient groups(t N 78.4% vs 56.3%; t E 69.4% vs 30.0%). Within t E patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type(null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both t N(86%) and t E(71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone(47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia(< 10 g/d L) and those without anemia(71.2% vs 77.4%).CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

Brain endothelial cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway in aging and neurodegeneration

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial cells,emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature,particularly in brain endothelial cells.Therefore,studying the role 7of inflammation caused by the cGAS-STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions.Here,we review the multifaceted role of global cGAS-STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS-STING in brain endothelial cells.

Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.

Expression level of interferon-stimulated genes PKR,OAS1,MX1,and ISG15 in peripheral blood mononuclear cells of COVID-19 patients:A retrospective study

Objective:To explore expression level of interferon-stimulated genes PKR,OAS1,MX1,and ISG15 in peripheral blood mononuclear cells of COVID-19 patients.Methods:In this study,changes in the expression of four interferon-stimulated genes(ISGs),including PKR,OAS1,MX1,and ISG15,in peripheral blood mononuclear cells of 45 COVID-19 patients with different severities were evaluated by real-time PCR method.Results:OAS1,MX1,PKR,and ISG15 were differently expressed in COVID-19 patients with different severity.The results showed that the expression of OAS1,MX1,PKR,and ISG15 genes was significantly(P=0.001)lower in severe patients.Conclusions:Weak and defective IFN response and subsequent disruption of ISGs may be associated with COVID-19 severity.

Relationship between Phenotypic Changes of Dendritic Cell Subsets and the Onset of Plateau Phase during Intermittent Interferon Therapy in Patients with CHB

Objective This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40,CD80,CD83,and CD86.Method This was a cross-sectional study in which patients were divided into a natural history group(namely NH group),a long-term oral nucleoside analogs treatment group(namely NA group),and a plateau-arriving group(namely P group).The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer.Results In total,143 patients were enrolled(NH group,n=49;NA group,n=47;P group,n=47).The results demonstrated that CD141/CD1c double negative myeloid dendritic cell(DNmDC)/lymphocytes and monocytes(%)in P group(0.041[0.024,0.069])was significantly lower than that in NH group(0.270[0.135,0.407])and NA group(0.273[0.150,0.443]),and CD86 mean fluorescence intensity of DNmDCs in P group(1832.0[1484.0,2793.0])was significantly lower than that in NH group(4316.0[2958.0,5169.0])and NA group(3299.0[2534.0,4371.0]),Adjusted P all<0.001.Conclusion Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

Evaluation of Interferon-Gamma Release Assay Testing and Tuberculin Skin Test for Early Diagnosis of Tuberculosis in Children and Adolescents

Background: This study aimed to evaluate the diagnostic value of interferon-γ release assay (IGRA), a sensitive microbiological diagnostic method, in children and adolescents with suspected tuberculosis in a country with a high burden of tuberculosis. Method: This study included 581 children and adolescents aged 4 - 19 years who were suspected of having tuberculosis, were latently infected with Mycobacterium tuberculosis, and had received at least one dose of BCG vaccine between April 17, 2019, and February 24, 2021. The study evaluated the TST results of 106 patients who had a positive Quantiferon test and were suspected of having tuberculosis. Results: The study included 581 patients aged between 4 and 19 years. Of these, 106 patients tested positive for the Quantiferon test, while 19 were indeterminate and 456 were negative. The Quantiferon test positivity rate was 18.24%. Among the 106 QFT-Plus-positive cases, 23 patients also tested positive for TST. The difference in distribution was found to be statistically significant. Conclusion: The QFT-Plus test is considered an alternative to TST and other microbiological diagnostic methods for early tuberculosis diagnosis, particularly in children and adolescents.

Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.

Combination of "low-dose" ribavirin and interferon alfa-2a therapy followed by interferon alfa-2a monotherapy in chronic HCV-infected nonresponders and relapsers after interferon alfa-2a monotherapy

AIM To report on the efficacy, safety and tolerability of interferon alfa-2a combined with a "low dose" of ribavirin for relapsers and non responders to alpha interferon monotherapy.METHODS Thirty-four chronic hepatitis C virus-infected non-responders to interferon alfa2a monotherapy (a course of at least 3 months treatment) and 13 relapsers to interferon alfa 2a monotherapy (a dose of 3 to 6 million units three times per week for at least 20 weeks but not more than 18 months) were treated with the same dose of interferon alfa-2a used before (3 to 6 million units three times per week) and ribavirin (10 mg/ kg daily) for 6 months. In complete responders, interferon alfa-2a was administered for further 6 months at the same dose used before as monotherapy.RESULTS Seven (20.6%) of 34 non-responders stopped the combined therapy due to adverse events, including two patients with histological and clinical Child A cirrhosis. In 17/27 (63%)non-responders, the combined therapy was stopped after three months because of non-response. Ten of the 27 non-responders completed the 1;2-month treatment course. At a mean follow up of 28 months (16- 37 months)after the treatment, 4/10 (15%) previous non-responders still remained complete responders,All 13 previous relapsers completed the 12-month treatment course. At a mean follow up of 22months (9 - 36 months) after treatment, 6/13(46%) the previous relapsers were stillsustained complete responders.CONCLUSION Our treatment schedule of the combined therapy for 6 months of interferon alfa2a with a low dose of ribavirin (10 mg/kg/day)followed by 6 months of interferon alfa-2amonotherapy is able to induce a sustainedcomplete response rate in 15% of non-responders and 46% of relapsers with chronic hepatitis C virus-related liver diseases comparable to those obtained with the standarddoses of ribavirin 1000 - 1200 mg/day.Randomized prospective controlled trials using lower total amounts of ribavirin in combination with interferon should be performed.

Anti-rods/rings autoantibody generation in hepatitis Cpatients during interferon-α/ribavirin therapy

Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.

Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2:A project of the Kyushu University Liver Disease Study Group

AIM： To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus （HCV） of genotype 2, a multi-center study was retrospectively analyzed. METHODS： In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600-800 mg of ribavirin daily for 24 wk. RESULTS： The overall sustained virological response （SVR）, defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4%, （146/173） by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin （46.9% vs 92.9 %）, but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment （34.8 % vs 92.0 %）. CONCLUSION： The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16

Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-β1,vascular endothelial growth factor,and basic fibroblast growth factor in patients with chronic hepatitis C

AIM： To assess the role of transforming growth factor-β1 （TGF-β1）, vascular endothelial growth factor （VEGF） and basic fibroblast growth factor （bFGF） in the pathogenesis of fibrosis associated with chronic hepatitis C （CHC） and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results （complete response or no response）. METHODS： Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed （Scheuer fibrosis score： 1-4 points）. Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis （Scheuer fibrosis score： 0 points）. Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin. RESULTS： TGF-β1 levels were significantly higher in the study group compared to the control group （35.89 vs 32.37 ng/mL; P= 0.023）. Such differences were not found in VEGF and bFGF levels. In patients showing complete response （negative HCV RNA and normal ALT level）, significant increase in VEGF （112.8 vs 315.03 pg/mL; P〈 0.05） and bFGF （2.51 vs 15.79 pg/mL; P=0.04） levels were found. Significant decrease in TGF-β1 level was observed both in responders （37.44 vs 30.02 ng/mL; P=0.05）, and in non-responders （38.22 vs 30.43 ng/mL; P=0.043）. bFGF levels before the treatment were significantly lower （2.51 vs 5.94 pg/mL; P=0.04）, and after the treatment significantly higher （15.79 vs 4.35 pg/mL; P=0.01） in patients with complete response response. CONCLUSION： Among the analyzed parameters TGF-β1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-β1, VEGF, and bFGF levels, bFGF seems to have the highest usefulness in the prognosis of treatment efficacy.

Peginterferon and ribavirin treatment for hepatitis C virus infection

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

AIM:To evaluate the efficacy of pegylated interferon α-2b(peg-IFNα-2b) plus ribavirin(RBV) therapy in Japanese patients with chronic hepatitis C(CHC) genotype Ib and a high viral load.METHODS:One hundred and twenty CHC patients(58.3% male) who received peg-IFNα-2b plus RBV therapy for 48 wk were enrolled.Sustained virological response(SVR) and clinical parameters were evaluated.RESULTS:One hundred(83.3%) of 120 patients completed 48 wk of treatment.53 patients(44.3%) achieved SVR.Early virological response(EVR) and end of treatment response(ETR) rates were 50% and 73.3%,respectively.The clinical parameters(SVR vs non-SVR) associated with SVR,ALT(108.4 IU/L vs 74.5 IU/L,P = 0.063),EVR(76.4% vs 16.4%,P < 0.0001),adherence to peg-IFN(≥ 80% of planned dose) at week 12(48.1% vs 13.6%,P = 0.00036),adherence to peg-IFN at week 48(54.7% vs 16.2%,P < 0.0001) and adherence to RBV at week 48(56.1% vs 32.1%,P = 0.0102) were determined using univariate analysis,and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis.In the older patient group(> 56 years),SVR in females was significantly lower than that in males(17% vs 50%,P = 0.0262).EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR.CONCLUSION:Peg-IFNα-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%.Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFNα-2b is important in improving the SVR rate.

Hepatitis C virus genotypes, HLA-DRB alleles and their response to interferon-α and ribavirin in patients with chronic hepatitis C

BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-α) therapy have been identified, but the conclusions differ in various counties and areas. The aim of this study was to study the associa- tions between HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin in Chinese patients with chronic hepatitis C in Northeast China. METHODS: HCV genotypes of 113 patients with HCV were investigated. Gene chips were used to analyze the fre- quency of HLA-DRB in 25 of these patients and their re- sponse to IFN-α and ribavirin. The associations of HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin were also studied. RESULTS: The response rates differed in several types of HCV, with HCV 2b being the highest (57.78% ), HCV 1a and 2a lower (46.15% and 47.62% ) and HCV 1b the low- est (11.76% ). The response rates to IFN-α and ribavirin in patients with DRB1 07 were higher than those with DRB1 04. Sex, HCV type and HLA-DRB were all related to the response. Most female patients with HCV 2b and HLA- DRB1 07 presented complete response, whereas male pa- tients with HCV 1b and HLA-DRB1 04 usually demon- strated no response. DRB1 07 allele and HCV 2b were the factors closely related to the response. CONCLUSIONS: The response rate of HCV 1b may be the lowest even IFN-α and ribavirin are combined in treat- ment. Not only virus but also the host plays an important role in anti-virus therapy. Thus, it is necessary to adjust the host's immune status to accelerate the clearance of HCV.

Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment

A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN-alpha 2b and ribavirin,and her HCV-RNA became negative at wk 12,but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH.

Risk factors for retinopathy associated with interferonα-2b and ribavirin combination therapy in patients with chronic hepatitis C

AIM： To elucidate the frequency and risk factors for retinopathy in patients with chronic hepatitis C who are treated by interferon-ribavirin combination therapy. METHODS： We prospectively analyzed 73 patients with histologically confirmed chronic hepatitis C, who underwent combination therapy for 24 wk. Optic fundi were examined before, and 2, 4, 12 and 24 wk alter the start of combination therapy. RESULTS： Fourteen patients （19%） developed retinopathy, which was initially diagnosed by the appearance of a cotton wool spot in 12 patients. Retinal hemorrhage was observed in 5 patients. No patient complained of visual disturbance. Retinopathy disappeared in 9 patients （64%） despite the continuation of combination therapy. However, retinopathy persisted in 5 patients with retinal hemorrhage. A comparison of the clinical background between the groups with and without retinopathy showed no significant differences in age, gender, viral genotype, RNA level, white blood cell count, platelet count, prothrombin time, complications by diabetes mellitus or hypertension, or pretreatment arteriosclerotic changes in the optic fundi. However, multiple logistic regression analysis revealed that complication by hypertension was observed with a high frequency in the group with retinopathy （P = 0.004, OR = 245.918, 95% CI = 5.6-10786.2）.CONCLUSION： Retinopathy associated with combination therapy of interferon α-2b and ribavirin tends to develop in patients with hypertension.

Sudden hearing loss associated with peginterferon and ribavirin combination therapy during hepatitis C treatment

Adverse effects associated with peginterferon and ribavirin during hepatitis C treatment are well known. Sudden hearing loss has rarely been reported. Possible mechanisms involved include direct ototoxicity of interferon, autoimmunity, and hematological changes. Hearing loss is frequently fully resolved after discontinuation of antiviral therapy. We report a 47-year- old man with chronic hepatitis C, genotype 2 ac who developed sudden hearing loss 22 wk after starting therapy with peginterferon alpha 2a at a dose of 180 ~g per week and ribavirin 800 mg per day. Since symptoms did not worsen, antiviral therapy was continued for 2 wk, according to the patient＇s wish. Hearing loss resolved within 2 wk after the end of treatment. Serum liver alanine aminotransferase remained normal during and after the end of antiviral therapy. HCV RNA was undetectable at the end of therapy and remained negative 24 wk later. Thus, patients should be aware that hearing loss may occur with peginterferon therapy, but the decision whether to continue or to stop the treatment is based on the clinical judgment of the physician and the wishes of the patient.

Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin

AIM： The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C （CHC） and response of both viruses to combination therapy with high-dose interferon-alfa （IFN） plus ribavirin remain uncertain and are being investigated.METHODS： Total 164 （97 males and 67 females, the mean age 48.1＋11.4 years, range： 20-73 years, 128 histologically proved） naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method.Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay （COBAS AMPLICOR HCV Test, version 2.0）. HCV genotypes la,lb, 2a, 2b, and 3a were determined by using genotypespecific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay （Quantiplex HCV RNA 3.0）. There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined.RESULTS： Sixty-one （37.2%） patients were positive for SENV-D DNA and had higher mean age than those who were negative （50.7＋ 10.6 years vs 46.6＋ 11.6 years,P = 0.026）. The rate of sustained viral response （SVR） for HCV and SENV-D were 67.3% （105/156） and 56.3% （27/48）, respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b （P〈0.001）, younger ages （P = 0.014）, lower pretreatment levels of HCV RNA （P = 0.019） and higher histological activity index （HAI） score for intralobular regeneration and focal necrosis （P= 0.037）. By multivariate analyses, HCV genotype non-lb, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR （odds ratio （OR）/95% confidence interval （CI）： 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively）. The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy （P = 0.04）.CONCLUSION： Coexistent SENV-D infection, apparently associated with higher ages, is found in more than onethird Taiwan Residents CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.

Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C

AIM:To investigate the possibility of shortening the duration of peginterferon(Peg-IFN)plus ribavirin(RBV) combination therapy by incorporating interferon-β (IFN-β)induction therapy. METHODS:A one treatment arm,cohort prospective study was conducted on seventy one patients.The patients were Japanese adults with genotype 1b chronic hepatitis C,HCV-RNA levels of≥5.0 Log IU/mL or 100 KIU/mL,and platelet counts of≥90 000/μL.The treatment regimen consisted of a 2 wk course of twicedaily administration of IFN-βfollowed by 24 wk PegIFN plus RBV combination therapy.We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it. RESULTS:The patients,including 44%males,were characterized by an median age of 63 years(range: 32-78 years),an median platelet count of 13.9(range: 9.1-30.6)×10 4 /μL,62%IFN-na?ve,and median HCV- RNA of 6.1(range:5.1-7.2)Log IU/mL.The sustained virologic response(SVR)rates were 34%(Peg-IFN:1-24 wk,n=61,95%confidence interval(CI): 24%-47%)and 55%(Peg-IFN:20-24 wk,n=31,95% CI:38%-71%,P<0.001;vs Peg-IFN:1-19 wk).TheSVR rate when the administration was discontinued early was 13%(Peg-IFN:1-19 wk,n=30,95%CI: 5%-30%),and that when the administration was prolonged was 50%(Peg-IFN:25-48 wk,n=10,95% CI:24%-76%,P<0.05;vs Peg-IFN:1-19 wk).In the patients who received 20-24 wk of Peg-IFN plus RBV,only the higher platelet count(≥130 000/μL) was significantly correlated with the SVR(odds ratio: 11.680,95%CI:2.3064-79.474,P=0.0024).In 45% (14/31)of the patients with a higher platelet count (≥130000/μL)before therapy,the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-β,and their SVR rate was 93%(13/14)after 20-24 wk administration of Peg-IFN plus RBV. CONCLUSION:These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-βinduction regimen.