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Background: Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity. Methods: A retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI. Results: Patients' age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage. Conclusions: Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Protein higher order structure (HOS) including the oligomer distribution can be critical for efficacy, safety and stability of drug products (DP). Oligomerization is particularly relevant to chemically modified protein therapeutics that have an extended pharmacokinetics profile. Therefore, the direct assessment of protein oligomerization in drug formulation is desired for quality assurance and control. Methods: Here, two non-invasive methods, dynamic light scattering (DLS) and diffusion ordered spectroscopy (DOSY) NMR, were applied to measure translational diffusion coefficients (Ddls and Dnmr) of proteins in formulated drug products. The hydrodynamic molecular weights (MWhd), similar to hydrodynamic size, of protein therapeutics were derived based on a log(Ddls) vs log(MWhd) correlation model established using protein standards. Results: An exponent value of -0.40 ± 0.01 was established for DLS measured log(D) vs. log(MWhd) using protein standards and a theoretical exponent value of -0.6 was used for unstructured polyethylene glycol (PEG) chains. The analysis of DLS derived MWhd of the primary species showed the fatty acid linked glucagon-like peptide 1 (GLP-1) was in different oligomer states, but the fatty acid linked insulin and PEG linked proteins were in monomer states. Nevertheless, equilibrium and exchange between oligomers in formulations were universal and clearly evidenced from DOSY-NMR for all drugs except peginterferon alfa-2a. Conclusion: The correlation models of log(D) vs. log(MWhd) could be a quick and efficient way to predict MWhd of protein, which directly informs on the state of protein folding and oligomerization in formulation. [ABSTRACT FROM AUTHOR]

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Selecting the best medications for ALT and HBV-DNA control in HBeAg negative chronic hepatitis patients is necessary as they are vulnerable to developing cirrhosis and hepatocellular carcinoma. The present study was aimed to evaluate the response rate of treatment by Peginterferon alfa-2a. In this systematic review and meta-analysis, a review of articles evaluating response rate to Peginterferon alfa-2a was done through the databases of Scopus, Google Scholar, Pubmed (inception - 2019). Fourteen studies reporting the response rate of HBeAg negative chronic patients' response to Peginterferon alfa- 2a were included in the study. Cochran test was used to determine the homogeneity of the samples (based on Q test and I² index). The prevalence was estimated based on the Random Effect size model in Revman software (version 3.5). The main result of this study showed that, in the 14 studies that PEG interferon was prescribed for patients with Hbe Ag negative chronic hepatitis B, the pooled incidence of treatment responders in comparison to non-responders was significantly lower (OR = 0.78, CI (0.7-0.87), p <0.0001). High heterogeneity was observed in this analysis (I2 = 95%, p <0.0001). to investigate factors affecting heterogeneity, a subgroup analysis was done based on the HBV genotype. 5 Studies in which most patients (>90%) had C genotype were compared with 3 studies with D genotype dominant study population. Again a high heterogeneity was observed in both genotype C and D dominant (I2=92% and 95%, respectively). However, higher pooled responders to non-responders rate were seen in C dominant populations versus D genotype (OR=0.72, CI (0.69-0.75), p<0.0001). Using Peginterferon alfa-2a alone is not the best choice of treatment due to the low rate of response to treatment; while considering the patient's HBV genotype is important in response rate. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive vs active chronic infection. Interferon alfa may convert hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. Methods: Hepatitis B surface proteins were measured before and during peginterferon alfa‐2a therapy in serum from 127 Asian patients with HBeAg‐positive CHB. Sustained response was defined as HBeAg seroconversion 24 weeks post‐treatment. Results: Mean total HBs levels were significantly lower in responders vs nonresponders at all time points (P <.05) and decreased steadily during the initial 24 weeks treatment (by 1.16 vs 0.86 ng/mL in responders/nonresponders respectively) with unchanged relative proportions. Genotype B had a two‐fold higher proportion of LHBs than genotype C (13% vs 6%). HBV DNA, HBeAg, HBsAg and HBs protein levels predicted response equally well but not optimally (area under the receiver operating characteristic curve values >0.70). Conclusions: Hepatitis B surface protein levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa‐2a therapy in HBeAg‐positive patients. [ABSTRACT FROM AUTHOR]

Serum Hepatitis B core‐related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG‐IFN) therapy for HBeAg‐negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg‐negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG‐IFN alfa‐2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was −3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (−2.4 vs −1.0 log U/mL, P = 0.001), but no cut‐off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg −2.5 log U/mL; HBV DNA: −4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI‐95% [0.0.629‐0.855], P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI‐95% [0.629‐0.855] P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI‐95% [0.641‐0.867], P < 0.001). In conclusion, in Caucasian patients with HBeAg‐negative CHB, decline of HBcrAg during PEG‐IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG‐IFN treatment. [ABSTRACT FROM AUTHOR]

In a multicentre, genome‐wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa‐2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post‐treatment, using serological and/or virological endpoints. Thirty‐six single‐marker analyses and a gene‐by‐gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome‐wide significance (P < 5 × 10−8) in single‐marker analyses, but suggestive associations (P < 1 × 10−5) were identified for 116 SNPs. In gene‐by‐gene analyses, one gene, FCER1A (rs7549785), reached genome‐wide significance (P = 2.65 × 10−8) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10−7). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa‐2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997). [ABSTRACT FROM AUTHOR]

Summary: HBV surface antigen (HBsAg) reduction is well observed in chronic hepatitis B (CHB) patients treated with pegylated interferon alpha‐2a (PegIFNα). However, the mechanism of HBsAg suppression has not been fully elucidated. Twenty‐seven of 55 entecavir‐treated CHB e antigen positive patients were switched to PegIFNα treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD56bright/CD56dimNK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co‐cultured with HepAD38 cells for measurement of HBsAg, apoptosis and covalently closed circular DNA (cccDNA). In association with a reduction of HBsAg, the percentage and absolute number of CD56brightNK cells was significantly elevated in patients in group A, especially in Virologic Responders (VRs, HBsAg decreased). Furthermore, the percentage of NKp30+, NKp46+, TRAIL+, TNF‐α+ and IFNγ+CD56brightNK cells were significantly expanded in Group A, which were positively correlated with the decline of HBsAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HBsAg in comparison with NK cells from Group B which was significantly inhibited by anti‐TRAIL, anti‐TNF‐α and anti‐IFNγ antibodies. Furthermore, apoptosis of HepAD38 cells and levels of cccDNA, were significantly reduced by TRAIL+ and TNF‐α+/IFNγ+NK cells from Group A, respectively. A functional restoration of CD56brightNK cells in entecavir‐treated patients who were switched to PegIFNα contributes to HBsAg and cccDNA clearance through TRAIL‐induced cytolysis and TNF‐α/IFNγ‐mediated noncytolytic pathways. [ABSTRACT FROM AUTHOR]

Copyright of Der Internist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Aim Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection. Methods Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 105 IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12). Results Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14. Conclusions Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates. [ABSTRACT FROM AUTHOR]

Background and purpose: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. Methods: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Results: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. Conclusion: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV. [ABSTRACT FROM AUTHOR]

Introduction: Boceprevir was not previously studied with peginterferon alfa-2a/ribavirin in phase III trials in treatment-naïve chronic hepatitis C patients. The international phase IIIb/IV TriCo study was, therefore, designed to evaluate boceprevir in combination with peginterferon alfa-2a/ribavirin in treatment-naïve genotype 1 patients. Methods: A total of 165 treatment-naïve genotype 1 patients were assigned to boceprevir plus peginterferon alfa-2a/ribavirin therapy according to the label. All patients received a 4-week lead-in with peginterferon alfa-2a/ribavirin, after which boceprevir (2400 mg/day) was introduced. The total duration of treatment ranged from 28 to 48 weeks depending on the virological response at Weeks 4, 8, and 24, and on fibrosis status. The primary efficacy outcome was sustained virological response (SVR) [undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) 12 weeks after actual end of treatment, SVR12]. Results: The overall SVR12 rate was 81% (133/165, 95% confidence interval 74-86%). After 8 weeks of treatment, 61% of patients had undetectable HCV RNA, and 78 patients (47%) had an early response (undetectable HCV RNA at Weeks 8 and 24) and were eligible to stop all therapy at Week 28. Among early responders the SVR12 rate was 95% (74/78), and among patients with cirrhosis assigned to 48 weeks' treatment, the SVR12 rate was 67% (14/21). The overall relapse rate was 7% (10/143), and was 4% (3/77) among early responders. The most common adverse events were anemia (41%), neutropenia (32%), and dysgeusia (31%). Conclusion: High SVR12 rates can be achieved with boceprevir plus peginterferon alfa-2a/ribavirin in treatment-naïve HCV genotype 1 patients, including patients with well-compensated cirrhosis. Treatment is well tolerated when label restrictions are taken into account. Trial Registration Number: ClinicalTrials.gov Identifier: NCT01591460. Funding: F. Hoffmann-La Roche Ltd. [ABSTRACT FROM AUTHOR]

Peginterferon alfa-2a ( PEG- IFN alfa-2a) is commonly used to treat hepatitis C virus infection and is also being used increasingly to treat myeloproliferative neoplasms including polycythemia vera. Sarcoidosis associated with IFN therapy for treatment of hepatitis C is well described, with hypercalcemia occurring as a rare manifestation. We describe a 25-year-old man with polycythemia vera who became resistant to hydroxyurea after 6 years of treatment, requiring therapeutic phlebotomy procedures with increasing frequency for elevated hemoglobin and hematocrit levels. PEG- IFN alfa-2a was then initiated at 90 μg subcutaneously once/week and was progressively increased to 180 μg/week over the next 11 months, with normalization of his hemoglobin and hematocrit. The patient then developed hypercalcemia with low parathyroid hormone, parathyroid hormone-related protein, and 25-hydroxyvitamin D levels, and high 1,25-dihydroxyvitamin D and angiotensin-converting enzyme levels, without other evidence of sarcoidosis. PEG- IFN alfa-2a was discontinued, treatment with intravenous fluids and zoledronic acid was initiated, and the hypercalcemia resolved 10 weeks later. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 7) between the patient's development of hypercalcemia and PEG- IFN alfa-2a therapy; the relationship could not be considered as definite because the patient was not rechallenged with the drug. To our knowledge, this is the first case report of IFN-induced hypercalcemia without other manifestations of sarcoidosis. Practitioners should be aware of hypercalcemia as a potential complication of PEG- IFN alfa-2a therapy, as well as its protracted time course, in patients with myeloproliferative neoplasms. [ABSTRACT FROM AUTHOR]

Background: Despite changes in the treatment paradigm towards non-interferon-based therapies, interferon-based treatments are still used in some geographical regions for treating patients with hepatitis C virus (HCV) infection. Use of eltrombopag with interferon-based treatment for patients with thrombocytopenia and HCV was assessed in two similarly designed phase 3 trials (Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects With Hepatitis C-Related Liver Disease [ENABLE-1 and ENABLE-2]). These trials also aimed to determine whether response to antiviral therapy (e.g., sustained virologic response [SVR]) is associated with changes in health-related quality of life (HRQoL). This pooled, post-hoc analysis aimed to (1) determine whether or not specific aspects of clinical response to treatment (i.e., achieving SVR) are associated with a significant change in HRQoL, and (2) to determine the magnitude and direction of the association between important changes in HRQoL, clinical response to interferon-based therapy (e.g., SVR) and treatment (eltrombopag or placebo), and patient and disease attributes.Methods: The Short-Form 36 Health Survey version 2 and Chronic Liver Disease Questionnaire-Hepatitis C Virus version were administered at various time points during the studies. Results from both trials were pooled for the analyses. Logistic regression analysis was used to assess the influence of 5 clinical factors (SVR, early virologic response [EVR], genotype [2/3 vs. non-2/3], treatment [eltrombopag or placebo], and cumulative interferon dose), plus other factors including ethnicity, model of end-stage liver disease score, and platelets as predictors of meaningful changes in HRQoL.Results: Between antiviral therapy baseline and the end of the 24-week post-treatment follow-up, declines in HRQoL were smaller in eltrombopag-treated patients than in placebo-treated patients, but the differences were not statistically significant. Mean changes among patients achieving SVR and EVR were small in comparison to thresholds of minimally important changes. Logistic models did not confirm the strength of the 5 clinical factors as predictors of meaningful changes in HRQoL during antiviral therapy, with the exception of the interaction between SVR and EVR (P = 0.0009). Asian ethnicity had a consistent effect on HRQoL, with East Asian patients being more likely to experience deterioration in HRQoL compared with white and/or other non-East Asian patients.Conclusions: While on active antiviral therapy, declines in HRQoL were not statistically different for eltrombopag-treated patients versus placebo-treated patients, suggesting that eltrombopag neither worsened HRQoL nor mitigated the effects of antiviral therapy on HRQoL. [ABSTRACT FROM AUTHOR]

Background: There is no information on the long-term effects of peginterferon (PEG-IFN) alfa-2a therapy for chronic hepatitis B (CHB) in Japan. This double-blind, randomized trial investigated the efficacy of PEG-IFN therapy. Methods: We analyzed 22 Japanese patients with CHB (hepatitis B e antigen [HBeAg]-positive: 17, HBeAg-negative: 5) treated with PEG-IFN alfa-2a and followed-up posttreatment for 5 years. Responders represented patients who showed persistent normalization of alanine transferase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels (HBeAg-positive patient; <5 log copies/mL, HBeAg-negative patient; <4.3 log copies/mL) at end of treatment, and at 1, 2, 3, 4 and 5 years posttreatment. In addition, baseline HBeAg-positive patients who showed sustained normalization of ALT level, HBeAg clearance, and low HBV DNA level for more than 6 months until at 1, 2, 3, 4, and 5 years after completion of PEG-IFN were also classified as "triple responders" and the proportion of triple responders relative to all patients was termed the "triple response rate". Results: The response rates among HBeAg-positive patients were 13 %, 25 %, 14 %, 21 % and 21 % at end of treatment, and at 1, 2, 3, 4, and 5 years, respectively. The response rate tended to be higher in patients treated for 48 than 24 weeks. The respective response rates among HBeAg-negative patients were 0 %, 20 %, 20 %, 20 % and 25 %. During the treatment period, hepatitis B surface antigen (HBsAg) clearance at 3.5 years was noted in one patient, who was 37-year-old, male, had genotype C and received PEG-IFN alfa-2a at 90 μg for 48 weeks. Conclusion: At 5 years after completion of PEG-IFN, the triple response rate in HBeAg-positive patients and combined response rate in HBeAg-negative patients were 21 % (3/14) and 25 % (1/4), respectively. The triple response was seen in three patients who had all been treated with PEG-IFN for 48 weeks. [ABSTRACT FROM AUTHOR]

Background & Aims Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B ( CHB) patients. Methods We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders ( HBeAg loss, HBV- DNA <2000 IU/ml, alanine aminotransferase normalization after 1 year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT- qPCR. Results Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non-responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for eight selected genes. A 2-gene subset ( HLA- DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype and baseline HBsAg level correctly classified 90% of all patients, in which HLA- DPB1 and SERPIN-E1 were independent predictors of response. Conclusion We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment. [ABSTRACT FROM AUTHOR]

The aim of this post hoc analysis from four prospective clinical trials was to determine if the association between anemia and increased SVR occurs in patients with cirrhosis treated with peginterferon alfa-2a/ribavirin. The results suggest that rates of anemia were similar in patients with and without cirrhosis (hemoglobin ≤10 g/dL 17.9 vs 18.5 %; ≥3 g/dL decrease in hemoglobin 74.3 vs 70.6 %, respectively). SVR rates were consistently higher in noncirrhotic patients with and without anemia; however, within each cohort, SVR rates were considerably higher in patients who experienced a ≥3.0 g/dL drop in hemoglobin level. Among patients with cirrhosis, SVR rates with and without a ≥3.0 g/dL drop in hemoglobin were 30.6 and 17.7 %. SVR rates were similar in cirrhotic patients with or without hemoglobin levels dropping to ≤10.0 g/dL (29.9 vs 26.7 %). This analysis confirmed that SVR rates are higher in patients who experience a >3.0 g/dL drop in hemoglobin during treatment with peginterferon alfa-2a/ribavirin and, for the first time, showed that this phenomenon occurs in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatitis C virus ( HCV) genotype 3 (G3) is common among HIV/ HCV co-infected individuals and associated with moderate sustained virological response ( SVR) rates with pegylated interferon ( PEG- IFN) plus ribavirin ( RBV) therapy, while G2 is less frequent and associated with higher SVR. To determine SVR and other response rates, identify SVR predictors and analyse differences between G2 and G3 with PEG- IFN/ RBV in a large HIV/ HCV G2/3 patient population. Methods This subgroup analysis of the prospective, observational OPERA (Optimized Pegylated interferon Efficacy and anti-Retroviral Approach) study was conducted between 2005 and 2011 in Italy in PEG-IFN/RBV-naïve HIV/HCV patients. The primary efficacy endpoint was SVR rate (HCV RNA <50 IU/ml or undetectable 24 weeks after end-of-treatment). Results Five hundred and fifty-six HCV G2/3 patients (G2 n = 60; G3 n = 496) were treated with PEG- IFN alfa-2a 180 μg/week or PEG- IFN alfa-2b 1.5 μg/kg, + RBV 13.6 ± 2.3 (mean ± SD) mg/kg/day for median 47 (26-54) weeks. SVR rates were 57.7%, 68.3% and 56.5% for G2/3, G2 and G3 respectively) and RVR rates were 53.2%, 57.1% and 45.8% respectively. Independent SVR predictors were undetectable baseline HIV RNA [adjusted odds ratio ( AOR), 2.64; 95% CI: 1.523-4.565, P = 0.0005], age ( AOR 0.95 per year; 95% CI: 0.908-0.994, P = 0.0258) and anti- HCV treatment duration ( AOR 1.034 per week; 95% CI: 1.013-1.057, P = 0.0019). Conclusions Undetectable HIV RNA, longer anti- HCV treatment adherence and younger age were independent SVR predictors in treatment-naïve HIV/ HCV G2/3 patients receiving PEG- IFN/ RBV. Suppressing HIV RNA replication before anti- HCV therapy and increasing adherence to PEG- IFN/ RBV treatment SVR rates may improve SVR. [ABSTRACT FROM AUTHOR]

Background & Aims GSK2336805 is a HCV NS5A inhibitor for chronic hepatitis C ( CHC). In a prior Phase I study, GSK2336805 was well tolerated and had an antiviral and pharmacokinetic profile suitable for once-daily administration. This 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60 mg alone or in combination with peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) ( PEG/ RIBA) in treatment-naive genotype 1 CHC subjects. Methods Five centres enrolled 16 subjects in the USA and Puerto Rico who received GSK2336805 + PEG/ RIBA or placebo + PEG/ RIBA. Results Following a single monotherapy dose of GSK2336805 on day 1, median reduction from baseline in HCV RNA was −2.96 log10 ( N = 11) vs. −0.13 log10 ( N = 4) for placebo. With the addition of PEG/ RIBA on day 2, subjects receiving GSK2336805 exhibited greater decreases in viral load over the 28-day treatment period as compared with placebo. At day 28, median reduction from baseline was −4.86 log10 ( N = 9) in the GSK2336805 + PEG/ RIBA group as compared with −1.98 log10 ( N = 4) in the placebo + PEG/ RIBA group. At day 28, rapid virological response ( RVR) occurred in 8/11 (73%) of the GSK2336805 + PEG/ RIBA subjects as compared with 1/4 (25%) of the placebo + PEG/ RIBA subjects. Adverse events were consistent with those reported in clinical trials of peginterferon and ribavirin, and no unique adverse events appeared to be associated with GSK2336805. Conclusions GSK2336805 is a potent NS5A inhibitor that showed a substantial antiviral effect as a monotherapy and in combination with peginterferon and ribavirin. Identifier: NCT01439373. [ABSTRACT FROM AUTHOR]

Background: We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). Methods: The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F). Results: Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. Conclusion: In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy. [ABSTRACT FROM AUTHOR]

Purpose: Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. Methods: Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. Results: CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40 KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores ( N = 1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50 IU/mL] by week 4 of treatment (rapid virologic response) and 24 weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR ( p < 0.1 × 10) was stronger than that between METAVIR ( p = 3.86 × 10) or APRI ( p = 5.48 × 10) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. Conclusion: The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40 KD)/ribavirin. [ABSTRACT FROM AUTHOR]

Objective The study aimed to investigate the efficacy and safety of peginterferon α-2a ( PEG IFNα-2a) in combination with lamivudine or adefovir in the treatment of hepatitis B e antigen ( HBeAg)-positive chronic hepatitis B ( CHB). Methods In total, 47 patients with HBeAg-positive CHB received either PEG IFNα-2a (135 μg once weekly) plus lamivudine (100 mg daily) or adefovir (10 mg daily). All patients completed 96 weeks of therapy and were followed up for a further 24 weeks. Results Baseline characteristics and treatment efficacy of the two groups were similar. All patients achieved hepatitis B virus ( HBV) DNA <500 copies/mL at 96 weeks, and none had a virological rebound after stopping the therapy. The rate of HBeAg seroconversion was 46.8% at 48 weeks, increased to 74.5% at 96 weeks, and kept at 72.3% at 120 weeks. Hepatitis B surface antigen ( HBsAg) seroconversion rate was 6.4% at 48 weeks, increased to 21.3% at 96 weeks, and kept at 27.7% at 120 weeks. Conclusions Extended treatment with PEG IFNα-2a with lamivudine or adefovir for 96 weeks is a promising strategy to achieve high rates of sustainable HBeAg and HBsAg seroconversion and HBV DNA suppression in patients with HBeAg-positive CHB. [ABSTRACT FROM AUTHOR]

Study C209 evaluated the activity of telaprevir in treatment-naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22-24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy. [ABSTRACT FROM AUTHOR]

Background: The safety and efficacy of weight-based ribavirin (RBV) dosing regimens in patients with HIV-HCV coinfection has not been demonstrated in randomized clinical trials. Objective: This randomized, double-blind, international, parallel-group study in specialist outpatient clinics in the United States, Spain, and Portugal compares the efficacy and safety of 2 RBV dose regimens (800 mg/day and 1000/1200 mg/day) combined with peginterferon alfa-2a (40KD) in patients with HIV-HCV (genotype 1) coinfection. Methods: Patients with HIV-HCV coinfec-tion, quantifiable HCV RNA in serum, HCV genotype-1 infection, compensated liver disease, and stable HIV disease (CD4+ count &nvge;100 cells/µL) with or without ongoing antiretroviral therapy were randomized to 48 weeks' treatment with RBV at standard dose (800 mg/day) or weight-based dose (1000 mg/day for patients weighing <75 kg; 1200 mg/day for patients weighing &nvge;75 kg) in combination with peginterferon alfa-2a (40KD) 180 µg once a week. Planned enrollment was 400 patients with &nvge;100 non-Latino African Americans. The primary endpoint was sustained virological response (SVR) (undetectable HCV RNA [<20 IU/mL] at the end of a 24-week untreated follow-up period [week 72]). Results: SVR rates were 19% (26/135) and 22% (60/275) in patients randomized to RBV 800 mg/day and 1000/1200 mg/day, respectively (odds ratio, 1.15; 95% CI, 0.68-1.93; P = .6119). In the 1000/1200 mg/day RBV dose group, the incidence of hemoglobin reductions <100 g/L and anaemia reported as an adverse event were higher versus the standard 800 mg/day RBV dose group. Conclusions: Compared with the standard RBV dose (800 mg/day), weight-based RBV dosing (1000/1200 mg/day) did not significantly increase SVR rates, but did increase the incidence of anemia in HIV-HCV (genotype 1) coinfected patients. [ABSTRACT FROM AUTHOR]

Purpose: The relationship between peginterferon/ribavirin exposure and the probability of achieving a sustained virologic response (SVR) in HIV-HCV coinfected patients is not well described. We conducted a retrospective analysis of HIV-HCV coinfected patients randomized to 48 weeks of treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 800 mg/day in the multinational APRICOT study to define optimal exposure thresholds. Method: Actual drug exposure was estimated in 287 patients, taking into consideration dose reductions for adverse events or laboratory abnormalities. Results: SVR overall and SVR in those completing treatment was, respectively, 29% and 37% among HCV genotype-1 patients and 59% and 68% among genotype non-1 patients. No patients with ≤40% exposure to ribavirin achieved an SVR. Receiver operating characteristic analysis identified that threshold exposures to both drugs of &nvgt;75% (genotype-1) and &nvgt;60% (genotype non-1) are associated with SVR. An existing generalized additive model populated with data from HCV monoinfected patients was updated to predict an overall SVR of 37% if genotype-1 patients received ribavirin 1000 or 1200 mg/day but at the cost of a higher incidence of anemia (23%). Conclusion: Completion of scheduled treatment and exceeding certain thresholds for exposure to peginterferon alfa 2a (40 kD) and ribavirin is associated with higher SVR rates. [ABSTRACT FROM AUTHOR]

There are a number of antiviral treatments for chronic hepatitis B currently available, and these include both interferon and a variety of nucleoside and nucleotide analogues. Interferon has been shown in numerous trials to be superior to the nucleoside analogues in inducing virologic, biochemical, histologic, and serologic responses. However, this response is not universal among patients and the side effects of interferon can be dose limiting. It is thus important to consider interferon in select populations, who are most likely to respond. In this review, we aim to identify the patient population in which interferon therapy will yield the most benefit while minimizing its use in those who may be better served using the nucleoside or nucleotide analogues. [ABSTRACT FROM AUTHOR]

Hepatitis C virus affects more than 180 million people worldwide and as many as 4 million people in the United States. Given that most patients are asymptomatic until late in the disease progression, diagnostic screening and evaluation should be performed in patients who display high-risk behaviors associated with acquisition of hepatitis C. Chronic hepatitis C is associated with cirrhosis, hepatic failure, and death; therefore, treatment is aimed at reducing these complications, as well as improving quality of life and minimizing adverse effects. The American Association for the Study of Liver Diseases Practice Guidelines on the Diagnosis, Management, and Treatment of Hepatitis C represent the gold standard for guidance on the management of hepatitis C. Standard treatment for hepatitis C is peginterferon alfa in combination with ribavirin. Currently, two pegylated interferon products are approved by the U.S. Food and Drug Administration for the treatment of hepatitis C. The duration of therapy with peginterferon and ribavirin is dictated by viral genotype and virologic response. Additional therapies are under investigation for treatment of chronic hepatitis C and show early promise of comparative efficacy and fewer adverse effects. Special considerations in certain populations, including patients coinfected with human immunodeficiency virus, those with end-stage renal disease, injection drug users, pregnant women, and pediatric patients, should guide treatment decisions. [ABSTRACT FROM AUTHOR]

The 2 reported trials investigated the effectiveness of treatment with peginterferon alfa-2a in Asian patients with chronic hepatitis B (CHB). Patients with HBeAg-positive ( n = 708) or HBeAg-negative ( n = 332) CHB were enrolled in 2 randomized, double blind, placebo-controlled studies. Patients received peginterferon alfa-2a 180 μg once weekly, peginterferon plus lamivudine 100 mg per day, or lamivudine alone for 48 weeks. Patients were followed up at 6 and 12 months posttreatment. Peginterferon alfa-2a provided significantly higher rates of HBeAg seroconversion (31%) in HBeAg-positive patients than did lamivudine (19%, P = 0.005) 6 months posttreatment, irrespective of genotype. Of these, 83% achieving seroconversion during treatment or early posttreatment sustained their response at 12 months posttreatment. In patients who seroconverted, 69% maintained HBV DNA suppression at <10,000 copies/ml and alanine aminotrasferase (ALT) normalization. In HBeAg-negative patients, peginterferon produced a significantly higher combined response of HBV DNA at <20,000 copies/ml and ALT normalization (45%) than lamivudine (31%, P = 0.032), irrespective of genotype. Almost 80% of these patients sustained their response at 12 months posttreatment. In conclusion, a finite course of peginterferon alfa-2a provides significant and sustained treatment benefit in Asian CHB patients, who have traditionally been regarded as difficult to treat. [ABSTRACT FROM AUTHOR]

Background: Peginterferon alfa-2a (40KD), a new treatment option for patients with chronic hepatitis B (CHB), offers improved efficacy with a defined treatment duration compared with lamivudine, but at a higher cost. We undertook an economic evaluation of peginterferon alfa-2a from the perspective of the Taiwan Bureau of National Health Insurance to assess the clinical outcomes and costs of 48 weeks of peginterferon alfa-2a for the treatment of patients with hepatitis B e antigen (HBeAg)-positive CHB, compared to lamivudine treatment for 48 weeks. Methods: We performed a cost-effectiveness analysis using a state-transition Markov model simulating the natural history of HBeAg-positive CHB. Efficacy data were obtained from a randomized clinical trial of 820 patients (87% were Asian) comparing peginterferon alfa-2a to lamivudine. We modeled a hypothetical cohort of 32-year-old patients with HBeAg-positive CHB. Life expectancy, quality-adjusted life expectancy, lifetime costs ($NTD) and incremental cost-effectiveness ratios (ICER) were estimated. One-way sensitivity analyses were performed on all parameters in the model to evaluate uncertainty. Results: Treatment with peginterferon alfa-2a compared to lamivudine resulted in higher total costs, but longer quality-adjusted life expectancy, yielding an ICER of $NTD 381 000 ($US 12 000) per quality-adjusted life year (QALY) gained. Although there is uncertainty associated with the prognosis of HBeAg-positive CHB, the ICER did not exceed $NTD 485 000 ($US 15 000) per QALY gained despite variation in the parameters used in the analysis. Conclusions: Our analysis suggests that 48-week treatment with peginterferon alfa-2a compared to 48-week treatment with lamivudine in HBeAg-positive patients offers life expectancy and quality of life benefits at a favorable cost-effectiveness ratio. [ABSTRACT FROM AUTHOR]

Objective. Patient- and virus-related factors influence the response of patients with chronic hepatitis C to interferon-based therapy. The purpose of this study was to model the probability of achieving a sustained virological response in individual patients, taking into consideration various predictive factors. Material and methods. We combined data from two randomized, multinational trials in which patients received peginterferon alfa-2a (40KD) plus ribavirin. The logistic regression model for patients infected with hepatitis C virus genotype 1 included age, viral load, histology, alanine aminotransferase quotient, body mass index, treatment duration, ribavirin dose and adherence. Results. In the genotype 1 model, varying baseline factors had a striking effect on the probability of sustained virological response. A dramatic difference in the probability of sustained virological response was seen in a series of hypothetical patients in whom five factors were varied to represent best and worst case scenarios. The best case scenario (age 20 years; no cirrhosis/bridging fibrosis; alanine aminotransferase quotient =7; body mass index 20 kg/m2; viral load 40,000 IU/mL) was associated with a 97% probability of sustained virological response, compared with 7% in the worst case scenario (age 60 years; cirrhosis/bridging fibrosis; alanine aminotransferase quotient =1; body mass index 30 kg/m2; viral load 9,000,000 IU/mL). Both adherence to treatment and achieving an early virological response increased the probability of sustained virological response. Conclusions. In treatment-naïve patients with chronic hepatitis C, host factors play a major role in determining treatment outcome and the logistic regression model is useful for predicting the probability of sustained virological response in individual patients. [ABSTRACT FROM AUTHOR]

HCV infections are two-times more prevalent in black Americans than in whites. We previously reported that treatment with peginterferon alfa-2a plus ribavirin produced a sustained virologic response (SVR) rate of 26% in blacks, a lower efficacy compared with the SVR in whites. Here we detail the safety profile of peginterferon alfa-2a plus ribavirin and the relationship between treatment adherence, defined by cumulative drug exposure, and SVR in 78 black patients infected with HCV genotype 1. Sixty-two (79%) patients completed 48 weeks of combination treatment. Peginterferon alfa-2a dose was modified for neutropenia in 36 patients (46%), whereas ribavirin dose was modified due to anemia in 31 patients (40%). The SVR rate was related to medication exposure, based on the percentage of the planned doses of peginterferon and ribavirin that the patients received. The SVR rates were 33, 25 and 0% in patients who received >80, 61–80 and ≤60% of the planned peginterferon, respectively. The SVR rates were 28, 33 and 18% in patients who received >80, 61–80 and ≤60% of the planned ribavirin. The SVR rate was 29% (11 of 38) in patients who received >80% of the total planned doses of both peginterferon and ribavirin and 7% (1 of 14) in patients who received ≤80% of both medicines. The SVR was 30% in patients who received >60% exposure to both, and 0% in patients with ≤60% exposure. In conclusion, peginterferon alfa-2a plus ribavirin demonstrated good safety and tolerability profiles in blacks infected with HCV genotype 1. Adherence to at least >60% of the planned peginterferon alfa-2a and ribavirin doses for 48 weeks was associated with a greater SVR in black patients with HCV genotype 1 infections. [ABSTRACT FROM AUTHOR]

In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma. [ABSTRACT FROM AUTHOR]