Peginterferon Alfa-2b Research Articles

Safety and Efficacy of Combined Treatment with Pegylated Interferon Alpha-2b and Ribavirin for HCV Genotype 4 in Children.

Combined treatment with pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV) is the only currently approved treatment for hepatitis C virus (HCV) infection in children. The aim of this study was to assess the safety and efficacy of combined treatment with PEG-IFN-α2b and RBV in Egyptian children and adolescents with genotype 4 (GT4) HCV infection. The study included 66 patients (3-17 years of age), of both sexes, infected with HCV GT4, treated with PEG-IFN-α2b (60 μg/m(2)), subcutaneously once weekly plus RBV (15 mg/kg/day) in 2 divided oral doses. Efficacy was assessed by achievement of sustained virological response (SVR). Safety was assessed by questionnaires directed to the patients at specific intervals, growth assessment and laboratory tests. SVR was achieved in 28 patients (42.4%). Nonresponders had significantly commoner history of treated malignancies (P = 0.03), baseline lower absolute neutrophil count (ANC; P = 0.009), higher gamma glutamyl transpeptidase (GGT; P = 0.003), and higher viral load (P = 0.03). Fever was the most frequently reported side effect occurring in 98.5% of the patients followed by musculoskeletal symptoms. Neutropenia was observed in 36 patients (54.6%) and necessitated treatment discontinuation in 1 patient. Decline in both weight and height percentiles was observed in 70% of children who received the combined therapy for a total of 48 weeks. In conclusion, the currently available treatment for HCV GT4 in pediatric patients has modest SVR with numerous adverse events necessitating meticulous monitoring to optimize care of the patients. Side effects could be managed with dose modifications and specific treatment when necessary.

A randomized clinical trial of peginterferon alpha‐2b with or without entecavir in patients with HBeAg‐negative chronic hepatitis B: Role of host and viral factors associated with treatment response

Combining peginterferon (PEG-IFN) and a potent nucleoside/nucleotide analogue might improve treatment response in patients with chronic hepatitis B (CHB). The aims of this study were to compare the efficacy of PEG-IFN alpha-2b with or without entecavir in HBeAg-negative CHB and to investigate predictors of response. A total of 126 treatment-naïve patients were randomly assigned to receive monotherapy (n = 63) or combination therapy (n = 63) for 48 weeks. Virological response (VR) was defined as HBV DNA level <2000 IU/mL at week 96. Baseline factors including polymorphisms in the IFNL3 (rs12979860) and HLA-DPA1 (rs3077) genes and on-treatment viral kinetics were determined. At week 48, rates of undetectable HBV DNA were lower in the monotherapy than combination groups, but rates of HBsAg clearance and decline were comparable. At week 96, there was no difference between the corresponding groups regarding virological response (41.3% vs 38.1%, P = 0.856), HBsAg clearance (9.5% vs 4.8%, P = 0.491) and HBsAg decline. Baseline HBsAg level [odds ratio (OR): 3.14 (1.34-7.69), P = 0.012] and rs3077 polymorphism [OR: 2.78 (1.27-6.11), P = 0.011] were independent predictors of response. Patients carried GG genotype of rs3077 with low baseline HBV (<1000 IU/mL) had high probability of achieving VR (76.5%) and HBsAg clearance (29.4%). None of the patients without decrease in HBsAg combined with <2 log10 HBV DNA decline at week 12 achieved a virological response. In conclusion, the combination therapy lead to greater on-treatment HBV DNA suppression but did not improve virological response and HBsAg clearance/decline over monotherapy. Host and viral factors could help optimize decision-making at baseline and during PEG-IFN-based therapy.

Simeprevir and sofosbuvir for treatment of hepatitis C infection.

The pharmacology, pharmacokinetics, efficacy, safety, costs, and place in therapy of simeprevir and sofosbuvir in the management of hepatitis C virus (HCV) infection are reviewed. Sofosbuvir and simeprevir are classified as direct-acting agents because they target specific proteins essential to the replication of HCV. Phase III trials demonstrated that simeprevir in combination with peginterferon alfa and ribavirin was superior to placebo combined with peginterferon alfa and ribavirin in achieving a sustained virological response in both treatment-naive patients and patients who relapsed after treatment with peginterferon alfa-2a or alfa-2b and ribavirin. Q80K polymorphism substantially decreases the efficacy of simeprevir. Clinical trials revealed that sofosbuvir in combination with ribavirin was superior to peginterferon plus ribavirin against HCV genotype 2 infection and as effective as peginterferon plus ribavirin against HCV genotype 3 infection. These findings were significant because they demonstrated the effectiveness of an anti-HCV regimen that did not include peginterferon alfa. Sofosbuvir has much better adverse-effect and drug interaction profiles than previous hepatitis C antiviral agents. Both simeprevir and sofosbuvir are approved for the treatment of chronic hepatitis C in combination with other antiviral medications. Simeprevir has been approved specifically for patients infected with HCV genotype 1 with compensated liver disease (including cirrhosis) in combination with peginterferon alfa-2a or alfa-2b and ribavirin. Sofosbuvir has shown efficacy in HCV genotypes 1-4. Simeprevir and sofasbuvir have advantages in response rates and convenient dosage forms and frequency compared with other HCV treatments; however, they are more expensive than previous HCV therapies.

Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis

We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm3 or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm3) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.

Polymorphisms at IL28B gene as predictors of viral relapse in genotype 4 Egyptian hepatitis C patients.

Chronic HCV is one of the commonest causes of chronic liver disease worldwide with about 15% of population infected in Egypt. Certain single nucleotide polymorphisms (SNPs) lying near the IL28B gene were found to affect the spontaneous clearance as well as treatment outcome of HCV. To examine the association between different IL28B variants and the relapse of HCV infection after combined therapy with ribavirin and pegylated interferon (pegIFN). Hundered HCV genotype four patients received 1.5 mg/kg/week peginterferon alfa-2b plus 800-1400 mg/d ribavirin (weight-adjusted) for 48 weeks. IL28B polymorphisms (rs12980275, rs12979860, and 1 rs8099917) were studied in responders and relapsers at week 72. Out of 69 patients receiving treatment, 13 (18.8%) were relapsers. By stratifying patients on the basis of the IL-28/60 genotype (CC vs. CT/TT), CC patients showed lower relapse rates (2.3%) compared with CT/TT patients (46.2%) (P < 0.001). On the basis of the IL-28/75 genotype (GG vs. GA/AA), the GG patients achieved higher relapse rates (62.5%) compared with GA/AA patients (13.1%) (P = 0.004). Moreover, no statistical significant difference was observed between the TT patients compared with GG/GT patients on the basis of the IL-28/17 genotype. SNPs at IL-28/60 and IL-28/75 are possible predictors of relapse in patients receiving dual treatment.

Perspectives on dual hepatitis B and C infection in Taiwan.

Dual hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is not rare in HBV or HCV endemic areas, and can be found in populations at risk of parenteral viral transmission. Clinical observatory studies suggest a higher risk of liver disease progression in patients with dual HCV/HBV infection than in HBV or HCV monoinfected patients. Recent trials confirmed that combination therapy of peginterferon alfa-2a or alfa-2b and ribavirin was effective and safe in dually infected patients with positive HCV RNA. Moreover, about 30% of the dually infected patients cleared hepatitis B surface antigen within 5 years after the start of peginterferon-based therapy. The optimal treatment strategies for dually infected patients with active hepatitis B, with decompensated cirrhosis, or in other clinical situations should be explored in further studies. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may lead to the development of strategies for the treatment of dually infected patients with active hepatitis C, particularly for those not tolerating or not eligible for peginterferon-based therapy. Notably, direct-acting antivirals would not have any activity against HBV infection; simultaneous or on-demand nucleos(t)ide analogs would be needed if clinically indicated.

Potential genetic markers for prediction of treatment response in Egyptian children infected with HCV genotype 4

Background: Egypt has a high prevalence of hepatitis C virus (HCV) infection. Limitations of the current HCV treatment in children are low rate of sustained virological response, significant side effects and high expenses, making prediction of treatment response crucial. Aim: This study aimed to investigate association of single nucleotide polymorphisms (SNPs) in interleukins (IL) 10, 28 and 29 genes in predicting the response to therapy in HCV infected children. Methods: Sixty-six Egyptian children infected with HCV genotype 4, receiving pegylated interferon alpha 2b and ribavirin, were included. Genotyping of six SNPs in interleukin 10, 28B and 29 gene as well as HCV genotype were analyzed by real-time polymerase chain reaction. Results: The CC genotype in IL28B; rs12979860 had 8.547 folds higher chance to develop sustained virological response than CT and TT genotypes (P=0.014). Genotype distribution of rs8099917 in IL28B gene (TG and GG genotypes) was found to be 3.348 more likely not to respond to treatment than the TT genotype (P=0.018). In multivariate analysis, interleukin 28 gene single nucleotide polymorphisms rs 12979860, interleukin 10 single nucleotide polymorphisms −592A > C and basal viral load were independent variables that significantly improved prediction of response to HCV therapy. Conclusion: This association can be translated into clinical decision making for HCV treatment.

Effect of peginterferon alfa-2b and ribavirin on hepatocellular carcinoma prevention in older patients with chronic hepatitis C.

The population of patients chronically infected with hepatitis C virus (HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma (HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C (CH-C). We compared the sustained virological response (SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH-C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan-Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non-SVR in all patients: higher gamma-glutamyltranspeptidase, and non-SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/L. The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH-C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR.

Anti-C1q Antibody as a Predictor of Chronic HCV Genotype 4 Response to Treatment in Egyptian Children

Background: Hepatitis C virus (HCV) infection has been reported to be the most common blood born pathogen all over the world. The prevalence of HCV in children in developed countries ranges between 0.1 and 0.4 %, and is generally lower than in adults. Combinedpegylated interferon and ribavirin is still the only standard of care treatment in spite of its side effects, high costs and low sustained virological response (SVR) rates. Hence, this provides a compelling reason for the identification of biomarker predictors of disease response to treatment. Objective: To evaluate anti-C1q antibody as a predictor of chronic HCV response to treatment with combined pegylated interferon alpha-2b and ribavirin in Egyptian children. Methodology: This study was conducted on forty-four chronic HCV-infected children (Male/Female: 30/14; aged 12.02±3.1 years) from the outpatient clinic, Pediatric Hepatology Department, National Liver Institute, Menoufiya University. They were given combined pegylated interferon alpha-2b (Peg-IFN-α-2b) and ribavirin (RBV) for 48 weeks and a quantitative polymerase chain reaction (PCR) for hepatitis C virus Ribonucleic acid was performed at 12, 24, 48 weeks during treatment and after another 24 weeks post-treatment. Anti-HCV antibody and Real-time PCR for HCV-RNA was performed (the detection limit was 15 IU/mL). Anti-C1q antibodies were performed by enzyme-linked immunosorbent assay (ELISA). Results: Serum levels of Anti-C1q antibodies were significantly higher (P = 0.001) in the Non-responders group (mean = 14.61± 6.749ng/ml) compared to the SVR one (mean = 2.27 ± 3.77ng/ml). No statistically significant difference (P > 0.05) had been found between SVR and Non-responders regarding the age, ALT, viral load, or hepatic necroinflammatory activity and liver fibrosis. Anti-C1q at a cutoff value of9.05ng/ml, had sensitivity and specificity of 84.6% and 75% respectively and 92% positive predictive value. No significant correlation between the serum level of anti-C1q antibodies and the age, sex or HCV viral load, liver enzymes, and the degree of fibrosis and necroinflammatory activity was found (P> 0.05) for all parameters. Conclusion: Anti-C1q could be a good predictor for HCV treatment and should be included in pretreatment laboratory assessment for proper choice of chronic HCV children patients who will benefit from combination therapy.

Retinopathy from Interferon Therapy for Cutaneous Melanoma in a Patient with Hypertension and Diabetes—A Case Report

High-dose pegylated interferon alpha-2b (IFN 〈2b) is an antineoplastic agent and biological response modulator used as first-line adjuvant therapy in cases of melanoma. Development of IFN-associated retinopathy is a rare but known complication of treatment. In the setting of additional co-morbidities, such as diabetes or hypertension, the etiology of retinopathy may be difficult to assess given the shared findings of nerve fiber layer infarcts and variably affected visual acuity. Thus, it is recommended to conduct a baseline ophthalmologic examination for patients with other comorbidities prior to initiating high-dose IFN therapy to help guide appropriate intervention should retinopathy develop. Once detected, the distribution of nerve fiber layer infarcts should be noted on exam, as well as duration and severity of diabetes, hypertension, and IFN therapy to help narrow the differential. We report a case of a 55-year-old female who developed retinopathy after initiating high-dose IFN therapy for cutaneous melanoma in the setting of a history of diabetes and systemic hypertension. The retinopathy resolved with discontinuation of the adjuvant therapy.

The Combination of Simeprevir and Sofosbuvir Is More Effective Than That of Peginterferon, Ribavirin, and Sofosbuvir for Patients With Hepatitis C–Related Child's Class A Cirrhosis

The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615.

Study of pruritus in chronic hepatitis C patients

To investigate the occurrence and severity of pruritus in chronic hepatitis C patients treated with or without interferon (IFN) therapy. A total of 89 patients with chronic hepatitis C and 55 control (non-hepatitis) patients were asked to rate their experience of diurnal and nocturnal pruritus in the preceding week using a visual analogue scale (VAS) and a five-point scale, respectively. Blood samples were taken and serum thymus and activation-regulated chemokine (TARC) levels were measured by enzyme-linked immunosorbent assay. A significantly greater proportion of chronic hepatitis C patients experienced nocturnal pruritus compared with control (58.4% vs 5.5%, P < 0.0001). Chronic hepatitis C patients also had more severe pruritus compared with control patients, indicated by the higher mean VAS scores in both the IFN-treated and non-IFN-treated groups. In particular, patients who received combined peginterferon alfa-2b and ribavirin had significantly higher mean VAS scores than those receiving peginterferon alfa-2a or no IFN treatment. Serum TARC levels did not correlate with pruritus scores, and no significant differences in TARC levels were observed between the IFN-treated and non-IFN-treated groups. Patients with chronic hepatitis C experience pruritus more than those without. Serum TARC levels do not correlate with pruritus severity in chronic hepatitis C patients.

Pityriasis rosea in chronic hepatitis C.

Dear Editor, The report on “Pityriasis rosea (PR) in chronic hepatitis C” is very interesting (1). Guner et al. (1) noted that this is “the first case of PR found in a patient with chronic hepatitis C while receiving Pegylated interferon (PEG-IFN) alpha 2b and ribavirin.” In fact, the cause of the existence of PR in hepatitis C is an interesting issue. Recurrence of hepatitis C following existence of PR is possible (2). The PR is mentioned because of its association with reactivation of human herpesvirus-6 (3) and human herpesvirus-6 can increase the severity of clinical features of hepatitis C infection (4). In the present case, whether PR previously existed or not is still inconclusive. Finally, it should be noted that there is at least one previous report on PR in a chronic hepatitis C patient receiving PEG-IFN alpha 2b and ribavirin (2).

Telaprevir or boceprevir in HIV/HCV-1 co-infected patients in a real-life setting. Interim analysis (24 weeks). COINFECOVA-SEICV study.

IntroductionIn general, HIV co-infected patients included in clinical trials evaluating the hepatitis C virus (HCV) therapy with telaprevir (TVR) or boceprevir (BOC) with advanced fibrosis, are scarce. We analyze data concerning the use of these drugs in a real-life clinical setting with patients affected by a more advanced degree of fibrosis in a Spanish cohort.MethodsWe evaluated safety and efficacy in an interim analysis encompassing the first 24 weeks of triple therapy with peginterferon (alfa-2a or alfa-2b), ribavirin and TVR or BOC in an observational, multicentre study. HIV/HCV genotype 1 co-infected patients beginning therapy from January 2012 to July 2013 were included.ResultsEnrolled patients were 155 (144 patients on TVR and 11 on BOC), average age was 47 years, 83% were male. With respect to HCV treatment, 44% were naïve, 13% relapsers, 17% partial responders, 21% null responders, and in seven patients, the previous response was unknown. All but three (98%) were under antiretroviral therapy (ART) (other than reverse transcriptase inhibitors, the backbone was raltegravir 43%, atazanavir 35%, and etravirine 28%). Median HCV-RNA at baseline was 6.1 log10, 54% were cirrhotic and 38% F3. At week 4, 93% of patients continued on therapy, 81% at w12, and 73% at w24. Virological failure was observed more frequently in: cirrhotic patients (19% [95% CI, 11–27]) vs F3 (12% [CI, 4–20]); patients with TT allele of the IL28B polymorphism (40% [CI, 18–61]) vs CT (21% [CI, 12–31]), or CC (2,2% [CI, −2–6]); previous null responders (37.5% [CI, 21–54]) vs partial responders (15.4% [CI, 1–29]), naïve (13% [CI, 5–21]) or relapsers (0% [CI, 0–0]); and in patients with a genotype subtype 1a (23.6% [CI, 57–76]) vs 1b (8.1% [CI, −1–17]). Overall, 17% had virological failure and in 8% treatment was discontinued due to adverse events. Severe adverse events occurred in 30 patients (19%). Haematologic disorders were the most common type including severe anaemia in 12 (7.7%) patients. Erythropoietin was employed in 41 patients (26.4%) and 11 (7.1%) received blood transfusions. Nineteen patients (12.2%) were treated with G-CSF, and 17 (11%) with thrombopoietin-receptor agonists. Five patients died (3.2%), three due to hepatic decompensation, one due to pneumonia and one due to pulmonary hypertension.ConclusionsIn a real-life setting, therapy against HCV in co-infected patients with advanced liver fibrosis shows high virologic success at 24 weeks. However, frequent haematologic disorders are observed and a close monitoring and an intensive therapy are needed to optimize the results.

Features and role of lipid peroxidation in patients with chronic hepatitis C (genotype 1b) before and after antiviral therapy

Aim. To estimate the levels of lipid peroxidation products in erythrocytes of patients with chronic hepatitis C (genotype 1b) before the initiation of antiviral therapy and after its completion. Methods. The study included 195 patients with chronic hepatitis C (genotype 1b). The levels of conjugated dienes, triene ketones, Schiff bases and oxidation index were measured after extraction of erythrocyte membranes with chloroform/isopropanol (2:1) mixture according to I.D. Stal’naya method modified by I.A. Volchegorskiy. All patients were allocated to four groups depending on the alanine transaminase activity prior to antiviral therapy: the first group (n=52) - with normal levels of the enzyme, the second (n=74) - with elevation not exceeding 3 normal ranges, the third group (n=42) - 3 to 5 normal ranges, the fourth group (n=27) - exceeding 5 normal ranges. Antiviral treatment included pegylated interferon alfa-2b and ribavirin for 48 weeks. Results. Level of conjugated dienes, triene ketones, Schiff bases and oxidation index were ranged from 0.71±0.04 to 1.02±0.03, from 0.45±0.08 to 0.94±0.02, 0.17±0.04 to 0.41±0.04 and from 0.91±0.13 to 1.91±0.03 units respectively, which was significantly higher than normal ranges and was directly dependent on the alanine transaminase activity. In addition, in patients who did not respond to antiviral treatment, these parameters were significantly higher compared to patients with immediate virologic response (p 0.01). Conclusion. Patients with chronic hepatitis C had increased levels of lipid peroxidation products in erythrocytes; their high content in patients who did not respond to antiviral treatment may be a predictive factor for antiviral treatment effectiveness.

The clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C in children and young people: a systematic review and economic evaluation.

Optimal therapy for children with chronic hepatitis C is unclear. Two treatment regimens are currently licensed in children. To assess the clinical effectiveness and cost-effectiveness of peginterferon alfa-2a (Pegasys®, Roche) and peginterferon alfa-2b [ViraferonPeg®, Merck Sharp & Dohme (MSD)] in combination with ribavirin (RBV), within their licensed indications, for the treatment of chronic hepatitis C virus (HCV) in children and young people aged 3-17 years. Twelve electronic bibliographic databases, including The Cochrane Library, MEDLINE and EMBASE, were searched from inception to November 2012. Bibliographies of retrieved papers, key hepatitis C websites and symposia and manufacturers' submissions to the National Institute for Health and Care Excellence were also searched, and clinical experts were contacted. Systematic reviews of clinical effectiveness and cost-effectiveness were conducted, including studies of health-related quality of life (HRQoL), following standard guidelines to ensure methodological rigour. Clinical effectiveness studies were included if they were in children and young people aged 3-17 years with chronic compensated HCV of any severity, including those with human immunodeficiency virus co-infection and those who were treatment naive or had been previously treated. Eligible interventions were peginterferon alfa-2a or peginterferon alfa-2b, each in combination with RBV, compared against best supportive care (BSC) or against each other, and study designs were randomised controlled trials (RCTs) or non-RCTs, or uncontrolled cohort studies. Outcomes included sustained virological response (SVR) and adverse events. Previously published Markov state-transition economic models of chronic HCV in adults were adapted to estimate the cost-effectiveness of peginterferon alfa-2a and -2b (in combination with RBV), compared with BSC and with one another in children. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs. Uncertainty was explored through probabilistic and deterministic sensitivity analyses. Seven studies [two peginterferon alfa-2a and RBV (Copegus®, Roche), and five peginterferon alfa-2b and RBV (Rebetol®, MSD)] were included in the review of clinical effectiveness. Six were single-arm cohort studies and one was a RCT for which only those data for a single arm met the inclusion criteria. Overall, the studies were relatively small and of generally poor quality. SVR rates ranged from 53% to 66% (peginterferon alfa-2a) and 29% to 75% (peginterferon alfa-2b) (49% to 65% if excluding two studies with very small sample sizes). Rates of non-response and relapse were variable and adverse events were generally mild. No studies of cost-effectiveness or HRQoL in children and young people met the inclusion criteria. HRQoL, utilities and costs of treatment were therefore taken from studies of adults with chronic HCV. From this model, peginterferon alfa (-2a or -2b) in combination with RBV was more effective and had lower lifetime costs than BSC. Peginterferon alfa-2a had slightly lower lifetime costs and higher quality-adjusted life-years than peginterferon alfa-2b; therefore, peginterferon alfa-2b was dominated by peginterferon alfa-2a. Results were robust to changes in the sensitivity analyses. There were few good quality studies and parameter data had to be taken from adult studies, which is a limitation of the work. Treatment of children and young people with peginterferon (alfa-2a or -2b) and RBV may be an effective therapy. Results from the independent Markov model suggest that peginterferon (alfa-2a or -2b) in combination with RBV is cost-effective compared with BSC. However, the available evidence is of poor quality. Future research into the impact of these treatments on growth and quality of life in children and young people is recommended. This study is registered as PROSPERO CRD42012002743. The National Institute for Health Research Health Technology Assessment programme.

PO-0147a Efficiency Of The Combined Antiviral Therapy Of Chronic Hepatitis C In Children

<h3>Aim</h3> The purpose of this work was to study efficiency of the combined antiviral therapy in children with chronic hepatitis C in Republic of Moldova. <h3>Methods</h3> In compliance with the National Program (2007–2016) in paediatric hepatology department 35 children, aged 4–17 years, were treated with pegylated interferon alpha 2b (60 mcg/m²/week) plus ribavirin in a dose of 15 mg/kg/day; therapy length of 24 weeks for genotype 2 and 3 or 48 weeks for genotype 1b. The diagnosis was confirmed by clinical, biochemical, immunological modification, including degree of viremia (ARN VHC PCR Real Time ROTOR Gene6000 CORBETT RESEARCH) and transient elastometry (Fibroscan) for detecting liver fibrosis. <h3>Results</h3> Chronic hepatitis C (genotype 1b – 31, genotype 2–1, genotype 3a in 3 children) was characterised by the minimal clinical signs, low biochemical activity in 60% of cases. Low virus loading ( &lt;600000 ui/ml) and a minimum degree of fibrosis of F0-F2 was identified in 29 of 35 children. 33 patients finished treatment. 2 children discontinued treatment because of the expressed headaches and in connexion with immigration. In the course of treatment by pegylated interferon and ribavirin most common of the side effects were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema and vomiting. <h3>Conclusions</h3> Combined antiviral therapy of chronic hepatitis C in children was safe. This treatment program needs an individual approach and it was effective SRV in 73% cases, inclusive in genotype 1b – 69%, in genotypes 2 and 3a – in 100%.

Keynote-029: Phase 1/2 Study of Mk-3475 in Combination with Pegylated Interferon Alfa-2B (Peg-Ifn) or Ipilimumab (Ipi) in Patients (Pts) with Advanced Melanoma (Mel) or Renal Cell Carcinoma (Rcc)

ABSTRACT Background: The interaction between programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 permits evasion of antitumor immune responses. PD-l inhibition has been shown to possess significant antitumor activity in patients with advanced MEL and RCC. Preclinical data suggest that adding PEG-IFN or IPI may increase the antitumor activity of PD-1 inhibitors. Clinically, IPI + the PD-1 antibody nivolumab has shown a greater response rate than nivolumab alone in pts with MEL. MK-3475 is a potent, highly selective, humanized IgG4/kappa, anti-PD-1 monoclonal antibody designed to block the interaction between PD-1 and its ligands. Trial design: This is an open-label, multicenter, phase 1/2 study of MK-3475 in combination with PEG-IFN or IPI for pts with advanced MEL or RCC. Phase 1 is a dose escalation study designed to determine the maximum tolerated/administered dose and/or recommended phase 2 dose of MK-3475 + PEG-IFN and MK-3475 + IPI. Using a modified 3 + 3 design followed by a toxicity probability interval for dose confirmation, 3-14 pts per dose level will be enrolled sequentially at escalating/de-escalating MK-3475 doses (2 mg/kg intravenously [IV] 3 times/wk [Q3W] or 10 mg/kg Q2W) in combination with PEG-IFN (subcutaneous 1, 2, or 3 µg/kg/wk) or IPI (4 IV doses of 1 mg/kg Q3W). If dose levels are open for both PEG-IFN and IPI, pts will be randomized between the combinations. Pending phase 1 results, a randomized phase 2 study designed to evaluate the efficacy of combination therapy will be initiated. Up to 150 pts with MEL will be randomized 1:1:1 to MK-3475 + PEG-IFN, MK-3475 + IPI, or MK-3475 alone. Treatment will continue until progression, intolerable toxicity, or 24 mo of MK-3475. Primary endpoint is progression-free survival. Secondary endpoints include objective response rate, overall survival, and safety. Response will be evaluated by investigator by RECIST v1.1 at wk 12, every 6 wk thereafter until wk 30, and then every 12 wk. Adverse events will be monitored and graded according to NCI CTCAE v4.0. Phase 1 pt enrollment is ongoing. Disclosure: T.K. Choueiri: Advisory board for Pfizer, GSK, Novartis, Aveo. Research funding from Pfizer (institutional) A. Ribas: Advisory board for Merck; F.S. Hodi: Nonpaid role on advisory board for Merck. Research support to institution from Merck; W. Hwu: Advisory board member, Merck. Corporate-sponsored research, Merck; A. Tosolini: Full-time employee of Merck Sharp & Dohme with stock ownership; R. Iannone: Full-time employee of Merck & Co., Inc., with stock ownership; Z. Yang: Full-time employee of Merck & Co., Inc., with stock ownership; C. Gause: Full-time employee of Merck Sharp & Dohme with stock ownership; R. Perini: Full-time employee of Merck & Co., Inc., with stock ownership; M.B. Atkins: Advisory board for BMS, Merck, Genentech. All other authors have declared no conflicts of interest.

Peginterferon alfa-2b in the treatment of Chinese patients with HBeAg-positive chronic hepatitis B: A randomized trial

BackgroundIn mainland China, peginterferon (PEG-IFN) alfa-2b 1.0μg/kg/wk for 24 weeks is the approved treatment for HBeAg-positive chronic hepatitis B. ObjectiveThis multicenter, randomized trial evaluated the safety and efficacy of regimens utilizing increased dose or treatment duration in treatment-naive Chinese patients with chronic hepatitis B. Study design670 HBeAg-positive patients from China, Malaysia, Taiwan area, Singapore, and Thailand were enrolled. Patients received PEG-IFN alfa-2b 1.0μg/kg/wk (arm A) or 1.5μg/kg/wk (arm B) for 24 weeks, or 1.5μg/kg/wk for 48 weeks (arm C). The primary end point was loss of HBeAg 24 weeks after end of treatment. ResultsAt the end of follow-up, HBeAg loss was significantly greater in arm C compared with arm A (31.3% vs. 17.3%; P=0.001) and arm B (31.3% vs. 18.1%; P=0.001). No significant difference in the rate of HBeAg loss was observed between arms A and B. The proportions of patients with HBe seroconversion, HBV DNA levels <20,000IU/mL, and ALT normalization at the end of follow-up were significantly higher in arm C compared with arm A and arm B. In arms A, B, and C, rates of early treatment discontinuation were 6.3%, 4.9%, and 8.9%; of discontinuation due to an AE, 2%, 3%, and 3%; and of AEs requiring dose modification, 3%, 6%, and 10%, respectively. ConclusionsIn Chinese patients with HBeAg-positive chronic hepatitis B, PEG-IFN alfa-2b 1.5μg/kg/wk for 48 weeks is more efficacious compared with 1.0 and 1.5μg/kg/wk for 24 weeks.

Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin.

The current standard of care therapy (SOC) for chronic HCV is pegylated interferon/ribavirin (Peg-IFN/RBV). Many reports showed the possible role of vitamin D supplementation in augmenting the response to SOC. The aim of this study was to assess the role of vitamin D supplementation on the response to treatment in chronic HCV genotype 4 patients. One hundred and one chronic HCV patients were classified into two groups (Group 1): 51 patients received the SOC therapy consisting of Peg-interferon alfa-2b plus ribavirin, (Group 2): 50 patients received the SOC therapy+vitamin D3 (Cholecalciferol) in a dose of 15,000 IU/week during the treatment course. Vitamin D deficiency was found in 95% of patients. No correlation was found between vitamin D levels and stage of fibrosis in the whole population. Vitamin D supplementation had no positive impact on treatment outcome where sustained virological response (SVR) was achieved in 51.2% in group 2 and 71.4% in group 1 by per-protocol analysis and in 44% in group 2 and in 68.6% in group 1 by intention to treat analysis (P value 0.22 and 0.220 respectively). Despite its role in other genotypes, vitamin D supplementation has no significant impact on SVR in HCV Genotype 4 patient. No correlation was found between vitamin D levels and stage of liver fibrosis.