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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 versus active chronic infection. Interferon alfa may convert 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: HBs 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 hepatitis B e antigen (HBeAg) seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders versus nonresponders at all time points (P0.70). CONCLUSIONS: HBs proteins 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.

Brouwer, Willem Pieter/0000-0001-8713-1481; van Campenhout, Margo J.H./0000-0003-0460-4920 WOS:000478827400001 PubMed ID: 31135084 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. Foundation for Liver and Gastrointestinal Research, Rotterdam, the NetherlandsNetherlands Government; Fujirebio Europe, Ghent, Belgium; Dutch government (Health Holland- TKI-LSH) [LSHM15032]; Dutch government [FES0908]; F. HoffmannLa Roche Ltd., Basel, SwitzerlandHoffmann-La Roche This work was supported, initiated and sponsored by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. Financial support was provided by Fujirebio Europe, Ghent, Belgium and the Dutch government (Health Holland- TKI-LSH, [project number LSHM15032]). The studies are part of the Virgo consortium, funded by the Dutch government [project number FES0908]. For the original study, financial support, study medication and drug supply were provided by F. HoffmannLa Roche Ltd., Basel, Switzerland. The funding sources did not have any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication.

Objective Treatment guidelines for chronic hepatitis B (CHB) do not recommend antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB. Methods Fifty-nine children aged 3 to 20,000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was hepatitis B surface antigen loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group. Results Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events. Conclusions The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.

Background/Purpose: Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and outcomes of PegIFN for CHB. Methods: 57 HBeAg-negative CHB patients receiving 48 weeks of PegIFN therapy were prospectively followed for a median period of 5.3 years after the end of treatment (EOT). Serum CXCL9 and IP-10 levels were measured. Flow cytometry analysis for T cell subsets was performed in 23 patients. Factors associated with long-term outcomes were analyzed. Results: The cumulative incidences of virological relapse, clinical relapse and HBsAg loss at year 7 were 18.1%, 0%, 31.6%, respectively, in patients with sustained off-treatment virological response (SVR), and 100%, 67.4%, 6.7%, respectively, in patients without SVR. By multivariate analysis, baseline CXCL9 > 80 pg/mL (hazard ratio (HR) = 0.418, p = 0.018) and on-treatment HBsAg declines were associated with a lower risk of virological relapse. Non-SVR was the only predictor of clinical relapse. CXCL9 >200 pg/mL (HR = 8.154, p = 0.038) and HBsAg 1 log at EOT (HR = 23.296, p = 0.005) was the on-treatment predictor of HBsAg loss. In subgroup patients with available PBMC, populations of T cell subsets correlated with virological and clinical relapses in univariate analysis. Conclusion: Baseline serum CXCL9 and HBsAg levels could predict HBsAg loss after PegIFN therapy for HBeAg-negative CHB. Combining virological and immunological biomarkers could predict long-term outcomes of PegIFN therapy for HBeAg-negative CHB.

BACKGROUND: Chronic hepatitis B virus infection remains a major global public health problem. Peginterferon-alpha-2a (PEG-IFN) has direct antiviral and immunoregulatory effects, and it has become one of the first choice drugs for the treatment of chronic hepatitis B (CHB). Cytokines play an important role in immunity, and they directly inhibit viral replication and indirectly determine the predominant pattern of the host immune response. AIM: To determine the correlation between cytokine/chemokine expression levels and response to PEG-IFN treatment in patients with CHB. METHODS: Forty-six kinds of cytokines were analyzed before PEG-IFN therapy and at 24 wk during therapy in 26 CHB patients. RESULTS: The monokine induced by INF-γ (CXCL9) and serum interferon-inducible protein 10 ( IP-10) levels at baseline were higher in virological responders than in non-virological responders (NRs) and decreased during treatment, whereas the NRs did not exhibit significant changes. The macrophage inflammatory protein 1d (MIP-1d) levels at baseline and during treatment were significantly higher in the virological responders than in the NRs, while thymus and activation-regulated chemokine (TARC) levels at baseline and during treatment were significantly lower in the virological responders than in the NRs. The CXCL9, IP-10, MIP-1d, and TARC baseline levels exhibited the expected effects for interferon treatment. The area under the receiver operating characteristic curve values of CXCL9, IP-10, MIP-1d, and TARC for predicting virological responses were 0.787, 0.799, 0.787, and 0.77 (P = 0.01, 0.013, 0.01, and 0.021), respectively. CONCLUSION: We found that cytokine levels before and during treatment may represent potential biomarkers to select CHB patients who can respond to PEG-IFN. Therefore, cytokines can be used as an indicator of antiviral drug selection before CHB treatment.

Background and Aims Hepatitis B surface antigen (HBsAg) loss is the ideal clinical endpoint but is achieved rarely during oral antiviral treatment. A current unmet need in CHB management is achievement of HBsAg loss with a finite course of oral antiviral therapy, thereby allowing discontinuation of treatment. Significantly higher rates of HBsAg loss at 72 weeks post-treatment have been demonstrated when tenofovir disoproxil fumarate (TDF) was combined with pegylated interferon (PEG-IFN) for 48 weeks compared with either monotherapy. This analysis provides follow-up data at week 120. Methods In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus PEG-IFN for 48 weeks (group A), TDF plus PEG-IFN for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or PEG-IFN for 48 weeks (group D). Efficacy and safety at week 120 were assessed. Results Rates of HBsAg loss at week 120 were significantly higher in group A (10.4%) than in group B (3.5%), group C (0%), and group D (3.5%). Rates of HBsAg loss and HBsAg seroconversion in group A were significantly higher than rates in group C (P

Background Peginterferon alfa-2a induces durable responses in some hepatitis B e antigen-negative patients, but robust pretreatment predictors are not available to identify likely responders. In this study we aimed to develop genotype-specific baseline scoring systems to predict response. Methods Data from 323 hepatitis B e antigen-negative peginterferon alfa-2a recipients from three studies were analyzed. Scoring systems were developed using generalized additive models and multiple logistic regression analysis. Response was defined as hepatitis B virus DNA

BACKGROUND Peginterferon induces off-treatment responses in approximately one-third of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. AIM To develop an easy-to-use baseline prediction score to identify hepatitis B virus (HBV) genotype B-/C-infected HBeAg-positive Asian patients likely to respond to peginterferon alfa-2a. METHODS Generalised additive models, multiple logistic regression (MLR) analysis and internal validation methods were applied to data from 647 HBeAg-positive patients from China, Hong Kong and Taiwan to develop a scoring system to predict response 24 weeks after completing a 48-week course of peginterferon alfa-2a. RESULTS Five baseline factors (age, sex, alanine aminotransferase ratio, hepatitis B surface antigen (HBsAg) level and HBV DNA level) were retained in the final MLR for HBeAg seroconversion and used to develop a scoring system from 0 to 7. Among patients with scores of 0-1, 2-3, 4 or ≥5, HBeAg seroconversion was achieved in 6.4% (6/94), 23.0% (61/265), 36.4% (67/184) and 54.8% (57/104), respectively, and a combined response (HBeAg seroconversion plus HBV DNA

Trotz effektiver Impfungen und Therapiemoglichkeiten ist die chronische Hepatitis-B-Virus(HBV)-Infektion weltweit eine der 30 haufigsten Todesursachen. Eine Koinfektion mit dem Hepatitis-D-Virus (HDV; chronische Hepatitis delta) fuhrt zu einem besonders raschen Progress. Anhand einer Analyse aktueller internationaler Leitlinien und Studien soll ein Uberblick zur aktuellen und zukunftigen Therapie der chronischen Hepatitis B und delta gegeben werden. Durch die Therapie mit Nukleosid- bzw. Nukleotidanaloga ist eine fast vollstandige HBV-DNA-Suppression bei Patienten mit chronischer Hepatitis B zu erreichen, die mit einer Fibroseregression und einem geringeren Risiko fur die Entwicklung eines hepatozellularen Karzinoms assoziiert ist. Eine Heilung bzw. funktionelle Heilung ist jedoch selten. Die Therapie der chronischen Hepatitis delta mit pegyliertem Interferon alfa zeigt nur geringe Ansprechraten mit hohen Ruckfallquoten. In praklinischen und klinischen Studien werden derzeit verschiedene Therapieansatze untersucht, die zu einem deutlichen Abfall des Hepatitis-B-Oberflachenantigens (HBsAg) und der HDV-RNA fuhren. Aktuelle Therapien der chronischen Hepatitis B konnen effektiv Folgekomplikationen reduzieren. Neue Therapieansatze versprechen zukunftig eine funktionelle Heilung der HBV-Infektion sowie effektive Behandlungsmoglichkeiten fur Patienten mit chronischer Hepatitis delta.

Background Peginterferon alfa-2a (PEG-IFN) treatment stopping rules in chronic hepatitis B (CHB) are clinically desirable. Previous studies exploring this topic contained important limitations resulting in inconsistent recommendations within the current treatment guidelines. We undertook a systematic review and individual patient data meta-analysis to identify the most appropriate PEG-IFN treatment stopping rules. Methods Roche's internal database, PubMed and conference abstracts were searched for studies that enrolled >50 treatment-naive patients with CHB who received PEG-IFN treatment for 48 weeks. Stopping rules were identified using receiver-operating characteristic curve analyses and pre-specified biomarker cutoff target performance characteristics (sensitivity >95%, specificity >10%, negative predictive value >90%). Robustness of proposed stopping rules was assessed using internal/external validation analyses. Results Eight study datasets were included in the meta-analysis ( n=1,423; 765 hepatitis B e antigen [HBeAg]-positive, 658 HBeAg-negative patients). In general, performance of hepatitis B surface antigen (HBsAg) and HBV DNA cutoffs at weeks 12 and 24 was similar, and common biomarker cutoffs that met target performance criteria were identified across multiple patient subgroups. For HBeAg-positive genotype B/C and HBeAg-negative genotype D patients the proposed stopping rule is HBsAg >20,000 IU/ml at week 12. Alternatively, HBV DNA level cutoffs of >8 log10 and >6.5 log10 IU/ml, respectively, can be used instead. The proposed stopping rules accurately identify up to 26% of non-responders. Conclusions The meta-analysis demonstrates that early PEG-IFN discontinuation should be considered in HBeAg-positive genotype B/C and HBeAg-negative genotype D patients at week 12 of treatment based on HBsAg or HBV DNA levels.

In this study, we aim to identify patient characteristics that predict severe thrombocytopenia induced by peginterferon alfa-2a in hepatitis C virus-infected patients. Demographic, clinical, and genetic data collected from patients with chronic hepatitis C virus infection (n = 232; age ≥18 years) who received peginterferon alfa-2a following eltrombopag treatment. Predictors of severe thrombocytopenia (platelet count below 50 GI/L) were identified using a 2-step approach: First, univariate analysis, using χ test for categorical variables and t test for continuous variables, was performed to identify possible predictors of severe thrombocytopenia (P < 0.05). Second, a logistic regression with backward stepwise selection was then performed using predictors identified in univariate analysis step to produce final model containing independent predictors at P < 0.05. Logistic model identified several predictors of severe thrombocytopenia. Increased spleen length and increased alkaline phosphatase levels increases the likelihood of severe thrombocytopenia. However, being Central/South Asian, increased neutrophils count and increased platelet baseline count decreases the probability of developing severe thrombocytopenia. In summary, we identified several patient characteristics that predict severe thrombocytopenia induced by peginterferon alfa-2a. Early selection of individuals with high risk of developing interferon-associated severe thrombocytopenia allows early intervention (such as eltrombopag treatment). Early intervention in turn minimizes the odds of developing severe thrombocytopenia and allows the continual of antiviral therapy before patient progress into liver decompensation.

Background and Aims We assessed the feasibility of field-based directly observed therapy (DOT) with minimal monitoring to deliver HCV treatment to people with a history of drug use in Chennai, India. Methods 50 participants were randomized 1:1 to sofosbuvir + peginterferon alfa 2a + ribavirin (SOF+PR) for 12 weeks (Arm 1) vs. sofosbuvir + ribavirin (SOF+R) for 24 weeks (Arm 2). SOF+R was delivered daily at participant chosen venues and weekly peginterferon injections at the study clinic. HCV RNA testing was done to confirm active HCV infection and sustained virologic response 12 weeks after treatment completion (SVR12). No baseline genotyping or on-treatment viral loads were performed. Results Median age was 46 years. All were male and 10% had significant fibrosis/cirrhosis. All self-reported history of injection drug use, 18% recent non-injection drug use and 38% alcohol dependence. Six discontinued treatment (88% completed treatment in each arm). Of 22 who completed SOF+PR, all achieved SVR12 (22/25 = 88%); 15 of 22 who completed SOF+R achieved SVR12 (15/25 = 60%; p=0.05). Among those completing SOF+R, SVR12 was significantly less common among reporting ongoing substance use (36% vs. 100%) and missed doses. Active substance use and missed doses did not impact SVR with SOF+PR. Conclusions Field-based DOT of HCV therapy without real-time HCV RNA monitoring was feasible; however achieving 100% adherence was challenging. SOF+PR appeared superior to SOF+R in achieving SVR12, even when doses were missed with no discontinuations due to side effects. Further exploration of short duration treatment with peginterferon plus direct acting antivirals is warranted. This article is protected by copyright. All rights reserved.

Summary Background Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. Methods We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659 . Findings Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Interpretation Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. Funding The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.

Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D-infected patients. We conducted an open-label study of peginterferon alfa-2a 180 μg/week added to ongoing NA therapy in hepatitis B e antigen (HBeAg)-negative, genotype D-infected patients with HBV DNA

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 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.

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.

Background & Aims: Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection. Methods: Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 lug) or peginterferon alfa-2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%. Results: Baseline characteristics were balanced across groups (lambda N = 80; alfa N = 83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA

Background and aims Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. Methods A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. Results The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/ 394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels 20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a

Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment. Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis. Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA

An alternative approach in the treatment of chronic hepatitis B (CHB) with pegylated (PEG)-interferon (IFN) is the prolonged course to 96 weeks of therapy, with higher sustained response (SR) than patients treated for 48 weeks. This result was confirmed in patients with CHB and D genotype, while no data are currently available about the prolonged course of PEG-IFN in E genotype. This retrospective analysis reported the role of different treatment duration of PEG-IFN on the SR in patients affected by CHB and E genotype. A total of 86 subjects with CHB and E genotype were considered in this analysis; different treatment durations were: 48 weeks (control group, 41 patients), 72 weeks (25 patients), and 96 weeks (19 patients). Treatment effectiveness was evaluated with sustained response (SR) and serological response. SR was significantly higher in patients who underwent PEG-IFN for 96 weeks in comparison to 48 weeks: 14.6% versus 26.3% (P = 0.016). HBsAg loss rate was 5.3% in patients treated for 96 weeks and 2.4% in the control group. In the multivariate analysis only the 72 and 96 weeks of therapy (OR 2.335, 95% CI 1.550-4.578; P = 0.020 and (OR 3.890, 95% CI 1.991-10.961; P = 0003) were predictive of SR. The extended duration of PEG-IFN course in patients with CHB and genotype E is a promising approach to increase the SR and HBsAg clearance.

Background & aims It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. Methods Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA < 2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA < 2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. Results The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. Conclusions This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.

Background In the large randomised NEPTUNE study, peginterferon alfa-2a 180 μg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 μg/wk) and/or shorter duration (24 weeks) (range 14%-26%). Aim To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. Methods HBeAg-positive patients who completed 24 weeks' follow-up in NEPTUNE (with peginterferon alfa-2a 90 μg/wk × 24 weeks [group 1]; 180 μg/wk × 24 weeks [2]; 90 μg/wk × 48 weeks [3] or 180 μg/wk × 48 weeks [4]) were followed up. Results Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. Conclusion Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 μg × 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration.

Background: Hepatitis B virus (HBV) RNA is a novel serum biomarker that has the potential to predict treatment response in patients with chronic hepatitis B. We explored whether HBV RNA serum levels can predict hepatitis B e antigen (HBeAg) seroconversion in patients treated with peginterferon alfa-2a. Methods: Serum samples from HBeAg-positive patients previously treated with peginterferon alfa-2a in 2 large randomized controlled trials were retrospectively analyzed. HBV RNA levels were measured using a real-time polymerase chain reaction assay. Ability of individual biomarkers to predict HBeAg seroconversion at 24 weeks posttreatment was evaluated using receiver operating characteristics (ROC) analyses. Results: The study included 131 subjects (70% male, 96% Asians, 35% HBV genotypes B, and 61% C), 76 treated with peginterferon alfa-2a alone and 55 in combination with lamivudine. Median HBV RNA levels were significantly lower, at all timepoints, in patients achieving HBeAg seroconversion. Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (area under ROC scores >0.75, P < .001). A HBV RNA cutoff of >5.5 log10 copies/mL identified 30% of nonresponders at week 12 (negative predictive value >90%). Conclusion: Serum HBV RNA is an early predictor of HBeAg seroconversion in patients treated with peginterferon alfa-2a. Clinical Trials Registration: NCT01705704.

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.

Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1–4. Treatment-naive patients received Lambda (120/180/240μg) or peginterferon alfa-2a (alfa; 180μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37–46% Lambda; 37% alfa) and GT2,3 (60–76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180μg dose reduction was therefore implemented. Serious adverse events were comparable (3–13% Lambda; 3–7% alfa). Grade 3–4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16–28% vs. 47–63%) and influenza-like events (8–23% vs. 40–46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

Background: Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. Methods: This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. Results: No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (−0.56 IU/mL, −0.60 IU/mL, and −0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. Conclusion: Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. Clinical trial ID: NCT: 00922207. Keywords: Chronic hepatitis B, Hepatitis B e antigen, Peginterferon alfa-2a, Adefovir, Entecavir

Children with chronic hepatitis B (CHB) represent an area of unmet medical need, attributed to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to

Background and Aims: The use of additional nucleos(t)ide analogues (NAs) without cross-resistance to previously used NAs as a rescue therapy is recommended by most international guidelines for chronic hepatitis B patients with NA-resistance. We aimed to investigate the efficacy and safety of combination therapy of peg-interferon (PegIFN) alfa-2a and NA in these patients, comparing to those who switch to an alternative NA therapy without cross-resistance. Methods: In this prospective, comparative and cohort study, data were collected from the patients’ hospital records. Eligible patients were those with hepatitis B e antigen (HBeAg) positivity and resistance to one or more NAs. All patients were treated with alternative NA alone or in combination with PegIFN alfa-2a for 52 weeks or 72 weeks, respectively. HBeAg seroconversion was measured at the end of follow-up (EOF; more than 104 weeks after the end of treatment). Results: Sixty-three patients were recruited to the cohort study (NA-therapy group = 31 patients; combination therapy group of NA and PegIFN alfa-2a = 32 patients). At the EOF, significantly more patients in the combination therapy group (13/27, 48.2%) achieved primary outcome of HBeAg seroconversion than those in the NA therapy group (4/32, 12.5%) (p = 0.003). Four patients (14.8%) in the combination therapy group achieved hepatitis B surface antigen (HBsAg) loss and HBsAg seroconversion, but none in the NA therapy group did (p = 0.039). In the combination therapy group, 16 patients (51.6%) achieved HBeAg seroconversion at the end of treatment, of which, 11 patients (68.8%) maintained the response until EOF. Conclusions: Adding on PegIFN alfa-2a in combination with NA therapy might be an appropriate rescue treatment option for patients who have prior NA resistance. In addition, combination therapy induced sustained off-treatment biochemical responses in these patients.

Background and aim: Precore (PC) and basal core promoter (BCP) mutations are associated with responses to interferon-based treatment in HBeAg-positive chronic hepatitis B (CHB) patients. Here, we identify viral minority variants in these regions and assess association with response to peginterferon-alfa (Peg-IFN) and adefovir combination therapy. Patients and methods: Ultra-deep pyrosequencing analysis of the BCP and PC region was performed for 89 CHB patients (42 HBeAg-positive; 47 HBeAg-negative), at baseline and during treatment. Specifically, associations of individual positions with the HBeAg-negative phenotype were studied, as well as the association of the most prevalent mutations with combined response in HBeAg-positive and negative patients at week 72 (HBeAg negativity, HBV-DNA

Background The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. Methods PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naive and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). Results SVR12 rates in treatment-naive genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naive patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. Conclusion The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies. Keywords Boceprevir, peginterferon, ribavirin, telaprevir, virological response Ann Gastroenterol 2017; 30 (3): 327-343

Background/purpose Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in patients with hemophilia. However, the efficacy and safety of pegylated interferon (PEG-IFN) plus ribavirin (RBV) for hemophilic patients with chronic HCV infection in Taiwan are still unknown. The aim of this study is to report the efficacy and safety of PEG-IFN plus RBV in a single center in Taiwan. Methods In an open-label single-treatment one-arm cohort study, 12 hemophilic patients with elevated alanine aminotransferase level more than two times the upper limit of normal for more than 3 months received 180 μg/week of PEG-IFN-α-2a plus RBV 1000–1200 mg/day at a cut-off value of 75 kg. The duration of treatment was 48 weeks for patients with HCV Genotype 1/4 infection and 24 weeks for patients with HCV Genotype 2/3 infection. Efficacy of therapy was expressed as sustained virological response (SVR). Results Eight patients achieved SVR (66.7%). The SVR rates were 57%, 100%, 100%, and 0% for patients with HCV Genotypes 1, 2, 3, and 4 infection, respectively. Adverse events (AEs) developed in 10 patients (83.3%). Severe thrombocytopenia developed in one patient. However, the patient did not suffer from severe bleeding. Conclusion Our study shows that the SVR rates are similar in hemophilic and nonhemophilic patients with chronic HCV infection who receive PEG-IFN-α-2a plus RBV in Taiwan. The rate of AEs also resembled other studies in nonhemophilic patients in Taiwan. No patient suffered from severe bleeding. However, large-scale, well-conducted studies are still needed to verify the treatment efficacy and safety.

Durable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a.Hepatitis B e antigen (HBeAg)-positive CHB patients who had received ETV for 9-36 months, with HBeAg100 PEIU/ml and HBV DNA ⩽1000 copies/ml, were randomised 1:1 to receive peginterferon alfa-2a 180 μg/week or ETV 0.5mg/day for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48 (ClinicalTrials.gov: NCT00940485).200 patients were randomised; 197 received ⩾1 study drug dose. Five patients who were anti-HBe-positive at baseline were excluded from the modified intention-to-treat population (peginterferon alfa-2a, n = 94; ETV, n = 98). Patients who switched to peginterferon alfa-2a achieved higher week 48 HBeAg seroconversion rates vs. those who continued ETV (14.9% vs. 6.1%; p = 0.0467). Only patients receiving peginterferon alfa-2a achieved HBsAg loss (8.5%). Among peginterferon alfa-2a-treated patients with HBeAg loss and HBsAg1500 IU/ml at randomisation, 33.3% and 22.2% achieved HBeAg seroconversion and HBsAg loss, respectively. Early on-treatment HBsAg decline predicted response at week 48; highest rates were observed in patients with week 12 HBsAg200 IU/ml (HBeAg seroconversion, 66.7%; HBsAg loss, 77.8%). Alanine aminotransferase elevations were not associated with viral rebound (n = 38). Peginterferon alfa-2a was well-tolerated.For patients who achieve virological suppression with ETV, switching to a finite course of peginterferon alfa-2a significantly increases rates of HBeAg seroconversion and HBsAg loss. A response-guided approach may identify patients with the greatest chance of success.

Background Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B "e" antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. Methods In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 µg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. Results Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log10 Paul Ehrlich international units [PEIU]/mL): monotherapy: -1.4 (SD, 1.8); ETV add-on: -1.6 (SD, 1.8); ETV pretreatment: -1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 [31%]; ETV add-on: 18 [25%]; ETV pretreatment: 19 [26%]). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. Conclusions Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined. Clinical Trials Registration. NCT00614471.

Background Published clinical trials of the treatment of HCV are largely multicentre prospective pharmaceutical trials. Patients in clinical trials tend to have more favorable outcomes than patients in the ‘real-world’, due to strict patient selection and differences in treatment conditions and available resources. Objectives To assess the outcomes of Hepatitis C infected patients treated at the Barwon Health Liver Clinic with combination Pegylated interferon (PEG-IFN) and Ribavirin (RBV) therapy and to determine factors associated with a treatment response. Methods Retrospective review of patients who received treatment for Hepatitis C at our institution's Liver Clinic from January 2001–September 2011. Patient demographics, comorbidities, treatment-related parameters and side effects were extracted from medical records and analyzed. Results A total of 190 patients (120 male, 70 female) with a mean age of 42.8 years (range 20–68 years) commenced treatment. The most common genotype was genotype 3 (48.9%), followed by genotype 1 (42.6%). 150 of 190 patients (78.9%) completed treatment and had end of treatment data available. 107 of 182 patients, (58.8%) for whom sustained virologic response (SVR) rate data was available achieved an SVR. Overall response rates were; 46.9%, 68.8% and 62.4% in genotypes 1, 2 and 3 respectively. The response rate was significantly lower in 29 patients with documented cirrhosis (20.7%). Age, diabetes and alcohol abuse did not predict treatment response in our cohort. Side effects reported in 81.6% of patients included general malaise, hematological disturbance and psychiatric issues, and necessitated cessation of therapy in 16 patients (8.4%) and dose reduction in 26 patients (13.7%). Conclusions Response rates to combination PEG-IFN and RBV therapy at our institution are comparable to other ‘real-world’ and pharmaceutical registration trials. Side effects of combination therapy were prominent but resulted in fewer discontinuations of therapy compared to pharmaceutical trials.

Peginterferon I±-2a (20 kDa) derived from Hansenula Polymorpha is a distinct variety of peginterferons (PEG-IFN). A pilot study of this drug was conducted on healthy human subjects to evaluate its safety and pharmacokinetic behavior in local population. With due approval of the IEC operating under ICH-GCP guidelines; ten healthy male subjects were selected randomly from the Pakistani population after thorough screening and signing of the Informed consent for an open label, single dose study. Each subject received a subcutaneous injection of the drug (180 µg) in abdominal skin and blood samples were collected at 0 and 1, 2, 3, 6, 12, 24, 36, 60, 84, 108, 132 and 156 hours, and analyzed by a validated ELISA method for peginterferon I±-2a (20kDa), Unipeg ® . The Mean ± SEM (standard error of mean) PK parameters were found to be: Cmax: 18.67±2.92 ng/ml (7.05-34.51); AUC0-∞: 1440±113 h.µg/l] (969-2101); Absorption Half-Life: 17.02±2.06 h (10.37-29.26), elimination half life: 41.437±6.21 h (18.51-78.97 h); volume of distribution 8.933±1.72 L (4.81-18.34), clearance: 112.6±8.21 ml/h (71.96–155.96). The safety of the drug was evaluated by observation of adverse effects and evaluating the change in general health parameters, hematological and biochemical test results during and after the study. No Sever Adverse Effect was observed however the most common adverse event (AE) was the fever; observed in all volunteers (n=10), headache (6), Fatigue (5), Vomiting (4) and diarrhea, loss of appetite, body ache was observed in 3 volunteers. Three out of ten volunteers demonstrated decrease in WBC and platelets count. Changes observed in hematology returned to normal values within 16 days. The safety profile of UNIPEG ® was found to be very similar to those of reported in literature for unmodified IFNs and other pegylated interferons generally used in therapy. Future clinical trials are recommended to further establish the safety profile and pharmacokinetics.

Polyethylene glycol-interferon α (PEG-IFNα), used in the treatment of chronic hepatitis C, has the potential risk for serious side effects. Among the most frequent side effects are symptoms similar to flu, depression, nervousness, and bone marrow suppression. Serious neurological side effects that have an influence on the peripheral nerves are rarely reported. In this article, a 58-year-old woman with the clinical findings of Guillain-Barre syndrome in the sixth week of PEG-IFa-2a treatment is analyzed and discussed.

Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a–ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a–ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a–ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log 10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a–ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a–ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.)

Background & Aims Pretreatment identification of patients likely to achieve a sustained virological response (SVR) with peginterferon alfa-2a/ribavirin would be useful for individualizing treatment choices. The aim of this analysis was to devise a simple scoring system to identify patients with high probability of achieving an SVR with peginterferon alfa-2a/ribavirin. Methods Using data from 2109 Caucasian treatment-naive hepatitis C virus (HCV) genotype 1 mono-infected patients from the PROPHESYS cohorts, the relationship between favourable baseline characteristics and SVR was explored using generalized additive model analysis, and a scoring system was devised to predict SVR. Results Points were assigned for: age (years) (≤35: 2; >35, ≤45: 1; >45: 0); body mass index (kg/m2) (≤20: 2; >20, ≤22: 1; >22: 0); HCV RNA (IU/ml) (≤100 000: 3; >100 000–400 000: 2; >400 000–800 000: 1; >800 000: 0); platelets (>150 ×109/l: 1; ≤150 ×109/l: 0); alanine aminotransferase [×upper limit of normal (ULN)] (>3: 1; ≤3: 0); serum aspartate aminotransferase (×ULN) (≤1: 1; >1: 0). 1029, 698 and 382 patients had scores of 0–2, 3–4 and ≥5, respectively, among whom SVR rates were 35.0, 54.9 and 76.7%. SVR in patients with scores ≥5 and undetectable HCV RNA by week 4 was 86.7%. The score was tested against two databases of patients who received peginterferon alfa-2a/ribavirin in other clinical trials; similar high SVR rates in patients with scores ≥5 were reported. Conclusions The scoring system can reliably identify treatment-naive HCV genotype 1 mono-infected Caucasian patients who have a high probability of achieving an SVR with peginterferon alfa-2a/ribavirin and will be particularly useful where protease inhibitors are not readily available.

Introduction Hepatitis C is an infection caused by the hepatitis C virus that attacks the liver and leads to inflammation. The current standard-of-care regimens include a protease inhibitor—telaprevir or boceprevir—in combination with pegylated interferon and ribavirin. Hepatitis C treatment options on the horizon hold promise for better viral clearance with less toxicity than current regimens. There are new data about new drugs, both direct-acting antivirals while minimizing intolerable side effects or adverse events. Developed new data from 4 phase 3 trials with the hepatitis C drug sofosbuvir and ribavirin show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. In the Annual Scientific Meeting and Postgraduate Course of the American College of Gastroenterology, different research was presented that was drawn from 4 phase 3 studies: NEUTRINO, FISSION, POSITRON and FUSION which enrolled different types of patients, who received Sofosbuvir with Peginterferon Alfa 2a and Ribavirin for 12 or 24 weeks in treatment; for all studies, the primary end point was sustained virologic response at 12 and 24 weeks posttreatment. In all studies, sofosbuvir was well tolerated, with a low incidence of adverse events. In conjunction with the suggested brief duration of this regimen, this indicates that drug combinations should improve treatment adherence compared with IFN-based treatment. In conclusion, 2 novel direct-acting antiviral agents—sofosbuvir and simeprevir—target various components of the HCV genome. Advantages of these drugs include a high barrier to viral resistance, a shorter duration of treatment, once-daily dosing, absence of food restrictions, few clinically significant drug interactions, and similar efficacy in all genotypes.

Hepatitis B surface antigen (HBsAg) loss is the ideal clinical endpoint but is achieved rarely during oral antiviral treatment. A current unmet need in CHB management is achievement of HBsAg loss with a finite course of oral antiviral therapy, thereby allowing discontinuation of treatment. Significantly higher rates of HBsAg loss at 72 weeks post-treatment have been demonstrated when tenofovir disoproxil fumarate (TDF) was combined with pegylated interferon (PEG-IFN) for 48 weeks compared with either monotherapy. This analysis provides follow-up data at week 120.In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus PEG-IFN for 48 weeks (group A), TDF plus PEG-IFN for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or PEG-IFN for 48 weeks (group D). Efficacy and safety at week 120 were assessed.Rates of HBsAg loss at week 120 were significantly higher in group A (10.4%) than in group B (3.5%), group C (0%), and group D (3.5%). Rates of HBsAg loss and HBsAg seroconversion in group A were significantly higher than rates in group C (P 0.001 for both) or group D (HBsAg loss: P = 0.002; HBsAg seroconversion: P 0.001).The results of this analysis confirm the results from earlier time points which demonstrate the increased rate of HBsAg loss in patients treated with a finite course of PEG-IFN plus TDF compared with the rates in patients receiving either monotherapy.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

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.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.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) RNA50 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(-30)) was stronger than that between METAVIR (p = 3.86 × 10(-13)) or APRI (p = 5.48 × 10(-6)) 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.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.

Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12979860CC genotype (r = 0.65, p0.0001) but not in CT/TT (r = 0.13, p = 0.53) and patients with CC genotype had a higher DTmax (1.4 ± 0.8 C vs. 0.8 ± 0.6 +C, p = 0.001). DTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12979860CC [corrected].ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49-0.88).Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.

Background. This partially blinded, randomized, phase 2a C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 4 infection. Methods. Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa-2a and ribavirin (Peg-IFN/RBV) for 15 days (TPR; n = 8), or Peg-IFN/ RBV plus placebo for 15 days (PR; n = 8), followed by Peg-IFN/RBV for 46 or 48 weeks. The primary objective was to assess the effect of telaprevir on HCV RNA levels. Results. HCV RNA levels decreased slightly with T and PR; TPR produced substantial, rapid declines. On day 15, median reductions in the HCV RNA load from baseline were −0.77, −4.32, and −1.58 log10 IU/mL for T, TPR, and PR, respectively, and 0 patients in the T group, 1 in the TPR group, and 0 in the PR group had undetectable HCV RNA. Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with the incidences from previous clinical trials. One patient (in T group) had a serious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation. Conclusions. Telaprevir with Peg-IFN/RBV had greater activity than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in patients with HCV genotype 4 infection is warranted. Clinical Trials Registration. NCT00580801.