Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C

Interstitial pneumonitis(IP) is an uncommon pulmonary complication associated with interferon(IFN) therapy for chronic hepatitis C virus(HCV) infection.Pneumonitis can occur at any stage of HCV treatment,ranging from 2 to 48 wk,usually in the first 12 wk.Its most common symptoms are dyspnoea,dry cough,fever,fatigue,arthralgia or myalgia,and anorexia,which are reversible in most cases after cessation of IFN therapy with a mean subsequent recovery time of 7.5 wk.Bronchoalveolar lavage in combination with chest high resolution computed tomography has a high diagnostic value.Prompt discontinuation of medication is the cornerstone,and corticosteroid therapy may not be essential for patients with mild-moderate pulmonary functional impairment.The severity of pulmonary injury is associated with the rapid development of IP.We suggest that methylprednisolone pulse therapy followed by low dose prednisolone for a short term is necessary to minimize the risk of fatal pulmonary damage if signs of significant pulmonary toxicity occur in earlier stage.Clinicians should be aware of the potential pulmonary complication related to the drug,so that an early and opportune diagnosis can be made.

Immediate virological response predicts the success of shortterm peg-interferon monotherapy for chronic hepatitis C

AIM:To investigate the efficacy of short-term peginterferon(PEG-IFN)monotherapy for chronic hepatitis C patients who achieved an immediate virological response.METHODS:Defining an"immediate virological response(IVR)"as the loss of serum hepatitis C virus(HCV) RNA 7 d after the first administration of PEG-IFNα,we conducted a 12-wk course of PEG-IFNα2a monotherapy without the addition of ribavirin for 38 patients who had low pretreatment HCV RNA load and exhibited IVR.The patients included 21 men and 17 women,whose ages ranged from 22 to 77 years(mean±SD:52.0±17.8 years).There were 4 patients with HCV genotype 1b,23 patients with genotype 2a and 4 patients with genotype 2b.HCV genotype was not determined for the remaining 7 patients.Patients were categorized into a sustained virological response(SVR)group,if serum HCV RNA remained negative for 24 wk after the end of treatment,or into a relapse group.RESULTS:Based on the intention-to-treat analysis,35 patients(92.1%)achieved SVR.One patient(2.6%)relapsed with serum HCV RNA 12 wk after the end of treatment.Two patients(5.3%)withdrew from the study during the 24-wk follow-up period.With regard to the HCV RNA genotype,the SVR rates were 100%(4/4) for genotype 1b,95.7%(22/23)for genotype 2a and 100%(4/4)for genotype 2b.The SVR rate in 7 patients,whose HCV RNA genotypes were not determined,was 71.4%(5/7).CONCLUSION:Short-term PEG-IFNα2a monotherapy is highly effective for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR.

Factors influencing the failure of interferon-free therapy for chronic hepatitis C:Data from the Polish EpiTer-2 cohort study

BACKGROUND The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C,making it highly effective and safe for patients.However,few researchers have analyzed the factors causing therapy failure in some patients.AIM To analyze factors influencing the failure of direct antiviral drugs in the large,multicenter EpiTer-2 cohort in a real-world setting.METHODS The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020.Data collected from the online EpiTer-2 database included the following:hepatitis C virus(HCV)genotype,stage of fibrosis,hematology and liver function parameters,Child-Turcotte-Pugh and Model for End-stage Liver Disease scores,prior antiviral therapy,concomitant diseases,and drugs used in relation to hepatitis B virus(HBV)and/or human immunodeficiency virus(HIV)coinfections.Adverse events observed during the treatment and follow-up period were reported.Both standard and machine learning methods were used for statistical analysis.RESULTS During analysis,12614 patients with chronic hepatitis C were registered,of which 11938(mean age:52 years)had available sustained virologic response(SVR)data[11629(97%)achieved SVR and 309(3%)did not].Most patients(78.1%)were infected with HCV genotype 1b.Liver cirrhosis was diagnosed in 2974 patients,while advanced fibrosis(F3)was diagnosed in 1717 patients.We included patients with features of hepatic failure at baseline[ascites in 142(1.2%)and encephalopathy in 68(0.6%)patients].The most important host factors negatively influencing treatment efficacy were liver cirrhosis,clinical and laboratory features of liver failure,history of hepatocellular carcinoma,and higher body mass index.Among viral factors,genotype 3 and viral load also exerted an influence on treatment efficacy.Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex,which was not confirmed by the multivariate analysis using the machine learning algorithm(random forest).Coinfection with HBV(including patients with on-treatment reactivation of HBV infection)or HIV,extrahepatic manifestations,and renal failure did not significantly affect the treatment efficacy.CONCLUSION In patients with advanced liver disease,individualized therapy(testing for resistance-associated variants and response-guided treatment)should be considered to maximize the chance of achieving SVR.

Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C

AIM: To elucidate risk factors contributing to the development of hepatocellular carcinoma (HCC) among patients with sustained viral response (SVR) after interferon (IFN) treatment and to examine whether HCV-RNA still remained in the liver of SVR patients who developed HCC. METHODS: Two-hundred and sixty-six patients, who achieved SVR, were enrolled in this study. We retrospectively reviewed clinical, viral and histological features of the patients, and examined whether the development of HCC depends on several clinical variables using Kaplan-Meier Method. RT-PCR was used to seek HCV-RNA in 3 out of 7 patients in whom liver tissue was available for molecular analysis. RESULTS: Among the enrolled 266 patients with SVR, HCC developed in 7 patients (7/266; 2.6%). We failed to detect HCV-RNA both in cancer and non-cancerous liver tissue in all three patients. The cumulative incidence for HCC was significantly different depending on hepatic fibrosis (F3-4) (P = 0.0028), hepatic steatosis (Grade 2-3) (P = 0.0002) and age (≥ 55) (P = 0.021) at the pre-interferon treatment. CONCLUSION: The current study demonstrated that age, hepatic fibrosis, and hepatic steatosis at pre- interferon treatment might be risk factors for developing HCC after SVR.

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, 128histologically 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 1a,1b, 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 vs46.6±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-1b, 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.

Impact of cigarette smoking on response to interferon therapy in chronic hepatitis C Egyptian patients

AIM: Smoking may affect adversely the response rate to interferon-α. Our objective was to verify this issue among chronic hepatitis C patients. METHODS: Over the year 1998, 138 chronic hepatitis C male Egyptian patients presenting to Cairo Liver Center, were divided on the basis of smoking habit into: group I which comprised 38 smoker patients (>30 cigarettes/d) and group II which included 84 non-smoker patients. Irregular and mild smokers (16 patients) were excluded. Non eligible patients for interferon-~ therapy were excluded from the study and comprised 3/38 (normal ALT) in group I and 22/84 in group II (normal ALT, advanced cirrhosis and thrombocytopenia). Group I was randomly allocated into 2 sub-groups: group Ia comprised 18 patients who were subjected to therapeutic phlebotomy while sub-group Ib consisted of 17 patients who had no phlebotomy. In sub-group Ia, 3 patients with normal ALT after repeated phlebotomies were excluded from the study. Interferon-α2b 3 MU/TIW was given for 6 mo to 15 patients in group Ia, 17 patients in group Ib and 62 patients in group II. Biochemical, virological end-of- treatment and sustained responses were evaluated.RESULTS: At the end of interferon-α treatment, ALT was normalized in 3/15 patients (20%) in group Ia and 2/17 patients (11.8%) in group Ib compared to17/62 patients (27.4%) in group II (P=0.1). Whereas 2/15 patients (13.3%) in group Ia. and 2/17 patients (11.8%) in group Ib lost viraemia compared to 13/62 patients (26%) in group II(P=0.3). Six months later, ALT was persistently normal in 2/15 patients (13.3%) in group la and 1/17 patients (5.9%) in group Ib compared to 9/62 patients (14.5%) in group Ⅱ (P= 0.47). Viraemia was eliminated in 1/15 patients (6.7%) in group Ia and 1/17 patients (5.9%) in group Ib compared to 7/62 patients (11.3%) in group Ⅱ, but the results did not mount to statistical significance (P = 0.4). CONCLUSION: Smokers suffering from chronic hepatitis C tend to have a lower response rate to interferon-α compared to non-smokers. Therapeutic phlebotomy improves the response rate to interferon-α therapy among this group.

Anti-hepatitis C virus therapy in chronic kidney disease patients improves long-term renal and patient survivals

BACKGROUND Hepatitis C virus (HCV) infection is a documented risk factor for chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD). However, to date there are no reports on the long-term hard endpoints (ESRD and death) of anti-HCV therapy [interferon-based therapy (IBT) or new direct-acting antivirals] in CKD patients. Direct-acting antivirals are not available in Taiwan’s singlepayer national health insurance database currently released for research. Therefore, we hypothesized that a retrospective analysis of the long-term outcomes of IBT in CKD patients will serve as a proxy for direct-acting antivirals to increase our understanding of progression to ESRD following HCV infection. AIM To evaluate the long-term outcomes (ESRD and death) of anti-HCV therapy, especially IBT, in HCV-infected patients with stage 1-5 CKD. METHODS We analyzed 93894 Taiwan Residents adults diagnosed with CKD and without HBV infection. Of these, 4.9% were infected with HCV. Of the 4582 HCV-infected CKD patients, 482 (10.5%) received IBT (treated cohort). They were matched 1:4 with 1928 untreated HCV-infected CKD patients (untreated cohort) by propensity scores and year, which further matched 1:2 by propensity scores with 3856 CKD patients without HCV infection (uninfected cohort). All participants were followed until the occurrence of ESRD, death, or the end of 2012. The association between HCV infection, IBT use, and risks of ESRD and death was analyzed using competing risk analysis. RESULTS Taking the uninfected cohort as a reference, the adjusted hazard ratios for ESRD, after adjusting for competing mortality, were 0.34 (0.14-0.84, P = 0.019) and 1.28 (1.03-1.60, P = 0.029) in the treated and untreated cohorts, respectively. The treated cohort had a 29%(0.54-0.92, P = 0.011) decrease in mortality compared to the untreated cohort, in which the mortality was 31%(1.18-1.45, P < 0.001) higher than in the uninfected cohort. The reduced risks of ESRD (0.14, 0.03–0.58, P = 0.007) and death (0.57, 0.41-0.79, P = 0.001) were greatest in HCV-infected CKD patients who received at least 4 mo of IBT, which accounted for 74% of the treated cohort.CONCLUSION Adequate anti-HCV therapy in CKD patients improves long-term renal and patient survival.

High-dose interferon-α2b induction therapy in combination with ribavirin for treatment of chronic hepatitis C in patients with non-response or relapse after interferon-a monotherapy

AIM: To evaluate the daily high-dose induction therapy with interferon-α2b (IFN-α2b) in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on the assumption that the viral burden would decline faster, thus increasing the likelihood of higher response rates in this diffficult-to-treat patient group.METHODS: Seventy patients were enrolled in this study.Treatment was started with 10 MU IFN-α2b daily for 3 wk,followed by IFN-α2b 5 MU/TIW in combination with ribavirin (1 000-1 200 mg/d) for 21 wk. In case of a negative HCV RNA PCR, treatment was continued until wk 48 (IFN-α2b 3 MU/TIW+1 000-1 200 mg ribavirin/daily).RESULTS: The dose of IFN-α2b or ribavirin was reduced in 16% of patients because of hematologic side effects,and treatment was discontinued in 7% of patients. An early viral response (EVR) was achieved in 60% of patients. Fifty percent of all patients achieved an end-of-treatment response (EOT) and 40% obtained a sustained viral response (SVR). Patients with no response had a significantly lower response rate than those with a former relapse (SVR 30% vs 53%; P = 0.049). Furthermore,lower response rates were observed in patients infected with genotype 1a/b than in patients with non-1-genotype (SVR 28% vs74%; P= 0.001). As a significant predictive factor for a sustained response, a rapid initial decline of HCV RNA could be identified. No patient achieving a negative HCV-RNA PCR at wk 18 or later eventually eliminated the virus.CONCLUSION: Daily high-dose induction therapy with interferon-α2b is well tolerated and effective for the treatment of non-responders and relapsers, when interferon monotherapy fails. A fast decline of viral load during the first 12 wk is strongly associated with a sustained viral response.

Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C

AIM:To investigate the efficacy of Viusid,a nutritional supplement,as an antioxidant and an immunomodulator in patients with chronic hepatitis C.METHODS:Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid(3 sachets daily,n=30) or placebo(n=30) for 24 wk.The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals(lipid peroxidation products).Secondary outcomes were changes in serum tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ) and interleukin-10(IL-10).RESULTS:Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values,but the patients who received Viusid showed a more marked reduction as compared with the control group(P=0.001).TNF-α levels significantly increased from 6.9 to 16.2 pg/mL(P< 0.01) in the patients who received placebo in comparison with almost unchanged levels,from 6.6 to 7.1 pg/mL(P=0.26),in the patients treated with Viusid(P=0.001).In addition,IL-10 levels were markedly increased in the patients treated with Viusid(from 2.6 to 8.3 pg/mL,P=0.04) in contrast to the patients assigned to placebo(from 2.8 to 4.1 pg/mL,P=0.09)(P=0.01).Likewise,the administration of Viusid markedly increased mean IFN-γ levels from 1.92 to 2.89 pg/mL(P< 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL(P=0.70) in the placebo group(P< 0.0001).Viusid administration was well tolerated.CONCLUSION:Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.

Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis C patients

BACKGROUND Liver fibrosis is a common pathway of liver injury and is a feature of most chronic liver diseases.Fibrosis progression varies markedly in patients with hepatitis C virus(HCV).Liver stiffness has been recommended as a parameter of fibrosis progression/regression in patients with HCV.AIM To investigate changes in liver stiffness measured by transient elastography(TE)in a large,racially diverse cohort of United States patients with chronic hepatitis C(CHC).METHODS We evaluated the differences in liver stiffness between patients treated with direct-acting antiviral(DAA)therapy and untreated patients.Patients had≥2 TE measurements and no prior DAA exposure.We used linear regression to measure the change in liver stiffness between first and last TE in response to treatment,controlling for age,sex,race,diabetes,smoking status,human immunodeficiency virus status,baseline alanine aminotransferase,and baseline liver stiffness.Separate regression models analyzed the change in liver stiffness as measured by kPa,stratified by cirrhosis status.RESULTS Of 813 patients,419(52%)initiated DAA treatment.Baseline liver stiffness was 12 kPa in 127(16%).Median time between first and last TE was 11.7 and 12.7 mo among treated and untreated patients,respectively.There was no significant change in liver stiffness observed over time in either the group initiating DAA treatment(0.016 kPa/month;CI:-0.051,0.084)or in the untreated group(0.001 kPa/mo;CI:-0.090,0.092),controlling for covariates.A higher baseline kPa score was independently associated with decreased liver stiffness.CONCLUSION DAA treatment was not associated with a differential change in liver stiffness over time in patients with CHC compared to untreated patients.

Ribavirin induced hemolysis:A novel mechanism of action against chronic hepatitis C virus infection

Hepatitis C virus(HCV)is not usually cleared by our immune system,leading to the development of chronic hepatitis C infection.Chronic HCV induces the production of various cytokines,predominantly by Kupffer cells(KCs),and creates a pro-inflammatory state in the liver.The chronic dysregulated production of interferon(IFN)and other cytokines by KCs also promotes innate immune tolerance.Ribavirin(RBV)monotherapy has been shown to decrease inflammation in liver of patients with chronic hepatitis C.Sustained virological response(SVR)is significantly higher when IFN is combined with RBV in chronic HCV(c HCV)infection.However,the mechanism of their synergy remains unclear.Previous theories have attempted to explain the anti-HCV effect based on direct action of RBV alone on the virus or on the immune system;however,these theories have serious shortcomings.We propose that hemolysis,which universally occurs with RBV therapy and which is considered a limiting side effect,is precisely the mechanism by which the anti-HCV effect is exerted.Passive hemolysis results in anti-inflammatory/antiviral actions within the liver that disrupt the innate immune tolerance,leading to the synergy ofRBV with IFN-α.Ribavirin-induced hemolysis floods the hepatocytes and KCs with heme,which is metabolized and detoxified by heme oxygenase-1(HMOX1)to carbon monoxide(CO),biliverdin and free iron(which induces ferritin).These metabolites of heme possess anti-inflammatory and antioxidant properties.Thus,HMOX1 plays an extremely important anti-oxidant,anti-inflammatory and cytoprotective role,particularly in KCs and hepatocytes.HMOX1 has been noted to have anti-viral effects in hepatitis C infected cell lines.Additionally,it has been shown to enhance the response to IFN-αby restoring interferon-stimulated genes(ISGs).This mechanism can be clinically corroborated by the following observations that have been found in patients undergoing RBV/IFN combination therapy for c HCV:(1)SVR rates are higher in patients who develop anemia;(2)once anemia(due to hemolysis)occurs,the SVR rate does not depend on the treatment utilized to manage anemia;and(3)ribavirin analogs,such as taribavirin and levovirin,which increase intrahepatic ribavirin levels and which produce lesser hemolysis,are inferior to ribavirin for treating c HCV.This mechanism can also explain the observed RBV synergy with direct antiviral agents.This hypothesis is testable and may lead to newer and safer medications for treating c HCV infection.

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.

Hepatitis C comorbidities affecting the course and response to therapy

Several studies have demonstrated that the outcome of chronic hepatitis C (CHC) infection is profoundly influenced by a variety of comorbidities. Many of these comorbidities have a significant influence on the response to antiviral therapy. These comorbidities negatively affect the course and outcome of liver disease, often reducing the chance of achieving a sustained virological response with PEGylated interferon and ribavirin treatments. Comorbidities affecting response to antiviral therapy reduce compliance and adherence to inadequate doses of therapy. The most important comorbidities affecting the course of CHC include hepatitis B virus coinfection, metabolic syndrome, and intestinal bacterial overgrowth. Comorbidities affecting the course and response to therapy include schistosomiasis, iron overload, alcohol abuse, and excessive smoking. Comorbidities affecting response to antiviral therapy include depression, anemia, cardiovascular disease, and renal failure.

Hepatitis C Virus Experimental Model Systems and Antiviral drug Research

An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics.

Effect of in vitro interferon-beta administration on hepatitis C virus in peripheral blood mononuclear cells as a predictive marker of clinical response to interferon treatment for chronic hepatitis C

AIM:To test whether in vitro incubation of peripheral blood mononuclear cells (PBMC) with interferon (IFN) could efficiently decrease hepatitis C virus-RNA (HCV-RNA) amount and to analyze whether this effect was associated with clinical response to IFN.METHODS:Twenty-seven patients with histologically proven chronic hepatitis C were given intravenous administration of 6 million units (MU) IFN-β daily for 6 weeks followed by three times weekly for 20 weeks. PBMC collected before IFN therapy were incubated with IFN-β and HCV-RNA in PMBC was semi-quantitatively determined.RESULTS: Twenty-five patients completed IFN therapy.Eight patients (32%) had sustained loss of serum HCV-RNA with normal serum ALT levels after IFN therapy (complete responders).HCV-RNA in PBMC was detected in all patients,whereas it was not detected in PBMC from healthy subjects.In vitro administration of IFN-β decreased the amount of HCV-RNA in PMBC in 18 patients (72%). Eight of these patients obtained complete response. On the other hand,none of the patients whose HCV-RNA in PBMC did not decrease by IFN-β was complete responders. Multiple logistic regression analysis revealed that the decrease of HCV-RNA amount in PBMC by IFN-β was the only independent predictor for complete response (P<0.05).CONCLUSION:The effect of in vitro IFN-β on HCV in PBMC reflects clinical response and would be taken into account as a predictive marker of IFN therapy for chronic hepatitis C.

Ketoprofen,peginterferon 2a and ribavirin for genotype 1 chronic hepatitis C:A phaseⅡ study

AIM:To evaluate the safety of adding ketoprofen to pegylated-interferon(PEG-IFN)with or without ribavirin and the effect on viral kinetics,STAT1 activity and expression of 2'-5'-oligoadenylate synthetase (2'-5'OAS)in genotype 1 chronic hepatitis C in a phaseⅡstudy. METHODS:Forty-five patients were studied:fifteen were randomized to PEG-IFN plus ribavirin(PR),16 to PEGIFN plus ketoprofen and 14 to PR and ketoprofen.Themolecular study of IFN-dependent signal transduction was conducted in 9 patients from each group. RESULTS:The combination of ketoprofen and PEG- IFN with or without ribavirin was safe and well tolerated.An early activation of STAT1 was observed in ke-toprofen-treated patients,but this activation was less sustained over time.Conversely,ketoprofen plus PEG- IFN and ribavirin induced an early and sustained increase of 2'-5'OAS transcription starting 24 h after the first dose until the 36th wk.These data are consistent with the clinical results,showing a better sustained virological response and a lower relapse rate in patients receiving ketoprofen plus PEG-IFN and ribavirin. CONCLUSION:The addition of ketoprofen to the standard therapy of chronic hepatitis C should be explored in larger randomized clinical studies.

A randomized trial of a 4- vs 12-week daily interferon dose regimen combined with ribavirin in treatment of patients with chronic hepatitis C

BACKGROUND: Standard combination-therapy of ribavi- rin with alternate day interferon (IFN) in patients with chronic hepatitis C ( CHC) has been reported to achieve 30%-55% sustained viral response. Early reduction of viral load by daily dosage of IFN could enhance viral clearance. However, the duration of daily dosage protocol and the likely side-effects have not been well studied. We compared the efficacy and safety of a 4- vs 12-week daily IFN dosage in patients with CHC. METHODS: Fifty-nine, histologically proven CHC patients having ALT levels >1.5 ×ULN were divided randomly into 2 groups, group I was given IFN 3 MIU daily for 4 weeks, followed by tiw up to 12 months and group was given IFN 3 MIU daily for 12 weeks, followed by tiw up to 12 months. Ribavirin was given in a dose of 800-1200 mg/d for 12 months. RESULTS: Fifty-two of the 59 patients (group group completed the study. The pretreatment vari- ables and the prevalence of HCV genotype 1 were compara- ble between the groups. Nine patients (29%) in group and 6 (25%) in group had stage 3, 4 fibrosis. At the end of 4, 12, 24 and 52 weeks, HCV RNA negativity was ob- served in 27%, 54%, 65% and 71% in group I and 38%, 54%, 71% and 75% in group respectively (P =ns). Four of the eight (50%) patients with genotype 1 and 30 (69.8%) of 43 patients with genotype non-1 responded to therapy (P =ns). Sustained viral response was achieved in 61% and 71% in groups respectively. None of the variables predicted non-response precisely. No serious adverse effects were observed and they were comparable between the two groups. CONCLUSION: Daily IFN dosage with ribavirin is safe and can achieve response in up to 65% patients. Since the effica- cy of a 4-week daily dosage of IFN is comparable to a 12- week schedule, we recommend the former regimen.

Addicts with chronic hepatitis C:Difficult to reach,manage or treat?

AIM:To assess the acceptance,safety and efficacy of care and treatment for chronic hepatitis C(CHC)in drug addicts.METHODS:We designed a multidisciplinary,phase IV prospective cohort study.All illicit drug users(IDUs)visited a Territorial Addiction Service(SerT)in the District of Brescia,and hepatitis C antibody(HCVAb)testing positive were offered as part of a standardised hepatologic visit in our Gastroenterology Unit.Patients with confirmed CHC and without medical contraindications were administered peginterferon alfa-2b 1.5μg/kg per week plus ribavirin(800-1400 mg/d)for 16-48wk.All IDUs were unselected because of ongoing addiction and read and signed an informed consent form.Virologic responses at weeks 4 and 12 of therapy,at the end of treatment and 24 wk after the end of treatment were the main measures of efficacy.Adherence was estimated according to the 80/80/80 criteria.RESULTS:From November 2007 to December 2009,162 HCVAb+IDUs were identified.Sixty-seven patients(41%of the initial cohort)completed the diagnostic procedure,and CHC was diagnosed in 54(33%of the total).Forty-nine patients were offered therapy,and 39agreed(80%of acceptance rate).The prevalent HCV genotype was type 1,and the HCV RNA baseline level was over 5.6 log/mL in 61%of cases.Five patients dropped out,two because of severe adverse events(SAEs)and three without medical need.Twenty-three and 14 patients achieved end of treatment responses(ETRs;59%)and sustained virologic responses(SVRs;36%),respectively.Thirty-one patients were fully compliant with the study protocol(80%adherence).The prevalence of host and viral characteristics negatively affecting the treatment response was high:age over40 years(54%),male gender(85%),overweight body type(36%),previous unsuccessful antiviral therapy(21%),HCV genotype and viral load(60%and 62%,respectively),earlier contact with HBV(40%)and steatosis and fibrosis(44%and 17%,respectively).In a univariate analysis,alcohol intake was associated with a non-response(P=0.0018,95%CI:0.0058-0.4565).CONCLUSION:Drug addicts with CHC can be successfully treated in a multidisciplinary setting using standard antiviral combination therapy,despite several"difficult to reach,manage and treat"characteristics.

Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy:A prospective pilot study

AIM:To evaluate the association between liver stiffness(LS) prior to the initiation of dual/triple therapy and viral response.METHODS:LS was measured in all patients before treatment was administered.The therapeutic approach was based on hepatic,virological,and immunological evaluations and considered the fact that patients with severe fibrosis(F3)or compensated cirrhosis(F4)in Child-Pugh class A are the primary candidates for triple therapy.In total,65 hepatitis C virus(HCV)patients were treated with Peg-interferon/ribavirin(Peg-IFN/RBV);24patients were classified as genotypes 1/4(36.92%),and41 patients were classified as genotypes 2/3(63.08%)(dual therapy).In addition,20 HCV treatment-experienced genotype 1 patients were treated with Peg IFN-RBV and boceprevir(triple therapy).Wilcoxon rank-sum tests were used to compare the groups.RESULTS:LS significantly differed between dual therapy and triple therapy(P=0.002).The mean LS value before dual therapy treatment was 8.61±5.79k Pa and was significantly different between patients achieving a sustained virologic response(SVR)24weeks after therapy and those who did not(7.23±5.18 k Pa vs 11.72±5.99 k Pa,respectively,P=0.0003).The relative risk of non-response to therapy was 4.45(95%CI:2.32-8.55).The attributable risk of non-response to therapy was 49%.The mean LSvalue before triple therapy treatment was 13.29±8.57k Pa and was significantly different between patients achieving and not achieving SVR24(9.41±5.05 vs19.11±9.74,respectively;P=0.008).The relative risk of non-response to therapy was 5.57%(95%CI:1.50-20.65).The attributable risk of non-response to therapy(70%)was increased compared with dual therapy patients.Pre-treatment stiffness>12 k Pa was significantly associated with non-SVR(P<0.025)in both groups.CONCLUSION:Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.

Response of TT virus to IFN plus ribavirin treatment in patients with chronic hepatitis C

AIM: TT virus (TTV) is a newly described DNA virus related to postransfusion hepatitis that produces persistent viremia in the absence of clinical manifestations. PEG-IFN plus ribavirin have been useful in the treatment of chronic hepatitis C infection. This study investigated the responses ofTT virus(TTV) and hepatitis C virus (HCV) to PEG-IFN plus ribavirin therapy. METHODS: Fifteen patients infected with HCV were treated with PEG-IFN(0.5 μg/body weight/week) and ribavirin(1 000 mg-1 200 mg/daily) for 48 weeks. Blood samples were drawn at the beginning and the end of the therapy. Serum TTV DNA and HCV RNA were quantified by real time PCR. RESULTS: At the beginning of treatment, TIV infection was detected in 10/15 (66.6%) of HCV-infected patients. Loss of serum Trv DNA at the end of therapy occurred in 6/10(60%) patients. Out of these 6 patients, 4 (67%) became positive for TTV DNA after 6 months of therapy. Regarding HCV viremia, 11/15 (73%) patients were negative for serum HCV RNA after 48 weeks of therapy, 7/11 (64%) of these cases also became negative for TTV DNA following the combined treatment. In the 3/4 (75%) patients who were positive for HCV RNA at the end of therapy, TTV DNA was detected as well. Sustained HCV response at 6 months after treatment was 53% (8/15). CONCLUSION: No TTV sustained response can be achieved in any patient after PEG-IFN plus ribavirin administration.