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Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.

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 (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) 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 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (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 180 μg 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., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Interferon-based treatment of chronic hepatitis C virus (HCV) infection can negatively affect patient-reported outcomes (PROs) and work productivity (WP). We assessed these factors in patients with chronic hepatitis C treated with sofosbuvir and ribavirin, with or without pegylated interferon., Methods: The HCV-specific Quality of Life (Chronic Liver Disease Questionnaire-HCV version [CLDQ-HCV]), Functional Assessment of Chronic Illness Therapy-Fatigue, and Work Productivity and Activity Index: Specific Health Problem questionnaires were completed before, during, and after treatment of patients infected with HCV genotypes 2 or 3 who received sofosbuvir and ribavirin for 16 or 12 weeks (the FUSION study, n = 201) or patients infected with HCV genotype 1 who received pegylated interferon, sofosbuvir, and ribavirin for 12 weeks (the NEUTRINO study, n = 327)., Results: Patients in each group of the FUSION study had similar PRO and WP scores at each time point (all comparisons, P > .05). Compared with baseline, patients had modest reductions in fatigue, HCV-specific quality of life, and WP and Activity Index scores during treatment (P = .02 to <.0001). However, by 4 weeks after treatment, all scores returned to baseline levels or higher. Subjects in the NEUTRINO study had greater reductions in these scores during treatment; most remained significant through 4 weeks after treatment (P < .05). Significant improvements in PROs were observed among patients with sustained virologic responses 12 weeks after treatment in the FUSION and NEUTRINO studies (all P < .05). In multivariate analyses after adjustment for confounders, interferon therapy was independently associated with worse PROs after 12 weeks of treatment., Conclusions: On the basis of an analysis of 2 large clinical trials (FUSION and NEUTRINO), patient outcome and productivity are more negatively affected by the inclusion of pegylated interferon in treatment than by interferon-free regimens. Patients with sustained virologic responses 12 weeks after treatment had significant improvements in PROs in both studies., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Hepatitis C virus (HCV) is prevalent in patients with end stage renal disease who are on dialysis. Liver disease from HCV is a cause of substantial morbidity and mortality after kidney transplantation in infected recipients. Effective treatment of chronic HCV is needed in this group of patients. We aimed to determine from the literature the efficacy and safety of interferon monotherapy in dialysis patients with chronic HCV., Methods: We reviewed the literature from 1986 to 2001 on the efficacy of interferon monotherapy in patients with HCV and end stage renal disease who were on dialysis. The outcomes measured were sustained viral response (SVR) and drop-out rate., Results: We reviewed 17 studies, of which 11 studies with a total of 213 patients met criteria for our analysis. Eight studies evaluated 3 million units (MU) three times/wk (t.i.w.), and three studies evaluated higher doses. The pooled SVR for 3 MU was 33% (95% CI = 21-51%). The pooled SVR for genotype 1 patients was 26% (95% CI = 15-37%). Of 152 patients in eight studies treated with 3 MU t.i.w. of interferon monotherapy, 45 patients (29.6%) discontinued therapy because of side effects., Conclusions: Our analysis suggests that interferon monotherapy is more effective in patients on dialysis than in patients with normal renal function. Interferon monotherapy is associated with more adverse events in dialysis patients. The optimal dose and duration of interferon monotherapy and selection criteria of dialysis patients need to be studied further in clinical trials.

Objective: The aim of this study was to analyze the clinical presentation and outcomes of significant pulmonary toxicity associated with interferon and ribavirin., Methods: We conducted a retrospective review of patients enrolled in four clinical trials at three sites, two academic medical centers and one community practice, and reviewed the literature., Results: Four patients, while on therapy with interferon a and ribavirin for chronic hepatitis C, developed significant pulmonary signs and symptoms. Further workup, which included lung biopsy in three, revealed bronchiolitis obliterans organizing pneumonia in two, and interstitial pneumonitis in two other cases. There were no other predisposing factors for lung disease identified. Resolution of symptoms occurred in all patients upon discontinuation of interferon and ribavirin, with or without corticosteroid therapy. One of the patients developed pulmonary complications while on a clinical trial of pegylated interferon and represents the first reported case associated with the use of long-acting interferon in chronic hepatitis C infection., Conclusions: A spectrum of significant pulmonary toxicity, including bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis, can occur with interferon or pegylated interferon in combination with ribavirin. Though pulmonary toxicity of interferon is well known, these cases represent the first cases reported in the literature with combination therapy. It is likely that pulmonary toxicity may not be investigated in patients on combination therapy because of the frequent pulmonary symptoms with ribavirin. Though usually reversible, at least one case has required long-term steroids with inadequate resolution. Though pulmonary toxicity is rare, symptoms which are more than mild or progressive in nature should likely be investigated.

Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus ( HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals ( DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups. [ABSTRACT FROM AUTHOR]

Background: Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies.Methods: Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing.Results: Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin.Conclusions: Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF. [ABSTRACT FROM AUTHOR]

Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-α/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12–88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5′-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment. [ABSTRACT FROM AUTHOR]

Based on meta-analysis, the higher the proportion of addiction-treated patients, the higher the treatment completion rate. The rate of sustained virologic response rate in drug users is very similar to that in the general population.Background. Hepatitis C virus (HCV)–infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics.Methods. Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects).Results. Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%–88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%–60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001).Conclusions. Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals. [ABSTRACT FROM PUBLISHER]

Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus ( HCV) that works through inhibition of the NS3/4A serine protease inhibitor.Phase 2b and 3 studies have shown marked increase in sustained virological response rates in both treatment- naïve and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (PEG- IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anaemia to a greater degree than that observed with PEG- IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort. [ABSTRACT FROM AUTHOR]

Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon- plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens. [ABSTRACT FROM AUTHOR]

Telaprevir is a potent HCV NS3/4A protease inhibitor. A completed development program has demonstrated the superior efficacy of a regimen of telaprevir combined with pegylated interferon alfa and ribavirin (PR) over PR alone in patients with HCV genotype 1. In the ADVANCE trial in treatment-naïve patients, 12 weeks of telaprevir, peginterferon alfa-2a and ribavirin followed by either 12 or 36 weeks of PR alone (depending upon extended rapid virologic response, or eRVR, i.e. HCV RNA undetectability at weeks 4 and 12), was associated with sustained virological response (SVR) in 75% of patients compared with 46% receiving PR for 48 weeks. The ILLUMINATE trial established the foundation for response-guided therapy in patients with eRVR. The REALIZE trial in treatment-experienced patients showed a gradient of SVR from prior relapsers (86%) to partial responders (57%) to null responders (31%), with rates of virologic failure and emergent resistance highest in the latter group. Incremental adverse effects of telaprevir include rash, anemia, pruritus, diarrhea, and nausea. Treatment naïve patients and relapsers are eligible for response-guided therapy. Stopping rules of telaprevir-based treatment include HCV RNA > 1000 IU/ml at weeks 4 and 12. [ABSTRACT FROM AUTHOR]

Purpose: To inform nurse practitioners (NPs) of the vital role they play in recognizing patients who may have hepatitis C. Data sources: Selected review of scientific literature. Conclusions: NPs involved in the management of patients with chronic hepatitis C are well positioned to provide supportive care and contribute to the development of effective treatment strategies that maximize the opportunity for successful treatment outcomes. Although peginterferon alfa plus ribavirin therapy is associated with a well-described series of side effects, effective measures are available for the management of these events that permit the continuation of treatment and enhance the likelihood of attaining sustained virologic response. NPs can play a pivotal role in ensuring that these measures are in place in a preemptive manner. For example, growth factor supplementation represents an alternative to dose reduction or treatment discontinuation in selected patients with neutropenia or anemia and may help to improve treatment adherence. Implications for practice: Hepatitis C is a widespread problem; approximately 3% of the global population is chronically infected with the virus. Awareness of risk factors for hepatitis C will help the NP to recognize at-risk patients, who should then be screened for the virus and referred for treatment based on specific criteria. [ABSTRACT FROM AUTHOR]

Background: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. Methods: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon–ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon–ribavirin for 8 weeks and placebo with peginterferon–ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon–ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Results: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon–ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Conclusions: Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.) [ABSTRACT FROM PUBLISHER]

Prospective, randomized, controlled, phase 3 clinical trials establish pegylated interferon (PEG-IFN) alfa plus ribavirin as the standard of care for patients with chronic hepatitis C. Such clinical trials are conducted in a highly regimented manner; patients must meet strict inclusion/exclusion criteria, and treatment is administered under rigid protocols with close monitoring by study personnel. Whether the results of phase 3 trials can be generalized or achieved in everyday clinical practice is questioned in several therapeutic areas. The efficacy of PEG-IFN alfa plus ribavirin therapy observed in pivotal phase 3 trials has been confirmed in several community-based trials conducted in North America and Europe, demonstrating consistent overall rates of sustained virologic response across a wide range of patient populations. Sustained virologic response rates stratified by genotype, viral load, fibrosis score, age, and ethnicity, factors known to impact treatment outcome, are consistent between these trials and comparable to those reported in clinical trials. The United States–based WIN-R trial confirmed the value of combining weight-based ribavirin dosing with weight-based PEG-IFN alfa-2b dosing across a spectrum of patient body weights. Large Canadian trials (POWeR and EAP), a German trial (AWB), a French study (Hepatys), and an Italian study demonstrated that PEG-IFN alfa plus ribavirin produces excellent efficacy in difficult-to-treat patient populations. Collectively, these results confirm the efficacy of current standard treatment regimens in a wide range of community-based settings, affording clinicians confidence that they can attain results similar to those of rigidly controlled randomized trials. [Copyright &y& Elsevier]

Pegylated interferon alfa-2a or alfa-2b plus ribavirin for 24 or 48 weeks, depending on genotype, is the standard of care for patients with chronic hepatitis C. However, up to 50% of patients are nonresponsive or experience relapse after treatment ends. Consequently, effective retreatment approaches for this population are urgently needed. Retreatment strategies aimed at viral eradication have included retreatment with the same or higher doses of the first pegylated interferon alfa used plus the same or higher doses of ribavirin, switching from one pegylated interferon alfa to the other, increasing the duration of therapy, or using other interferon formulations. Recent studies have demonstrated that sustained virologic response can be attained in 10% to 20% of patients retreated with pegylated interferon alfa plus ribavirin after previous nonresponse to standard interferon plus ribavirin and in 6% to 8% of prior nonresponders to pegylated interferon plus ribavirin retreated for 48 weeks. Extending the duration of retreatment to 72 weeks increases sustained virologic response rates. Prior relapsers to interferon-based therapy have higher rates of sustained virologic response with retreatment than prior nonresponders. Three large multicenter studies evaluating the capacity of long-term, low-dose, maintenance interferon-based therapy to delay or halt disease progression have been conducted, demonstrating no significant impact on overall clinical outcomes in the intent-to-treat analyses. Finally, specifically targeted antiviral therapies for hepatitis C have shown promising results in preclinical and early-stage clinical trials when combined with pegylated interferon alfa plus ribavirin. Novel approaches, including combinations of direct antiviral agents, are needed to achieve major improvements in the treatment of nonresponders. [Copyright &y& Elsevier]

Five agents are currently approved for the treatment of chronic hepatitis B infection. This article will discuss the three agents for which the most extensive data are available; interferon (IFN), lamivudine, and adefovir, while the following article by Dr. Jules Dienstag will discuss the recently marketed agents, entecavir and peginterferon alfa-2a. The advantages of IFN are its finite duration of therapy (4–6 months), lack of emergence of resistance, and durability of response. On the negative side, response to IFN is less durable in patients with HBeAg-negative chronic hepatitis B virus (HBV). Also, use of IFN is limited by adverse effects and the mode of administration (daily to thrice-weekly subcutaneous injection). Lamivudine and adefovir are orally administered and have good tolerability and safety. Even in patients who experience a marked decrease in serum HBV DNA and loss of HBeAg, oral therapy needs to be continued for at least 6 months, to avoid the risk of reappearance of HBeAg and viremia. Rates of HBeAg seroconversion to anti-HBe-positivity increase with duration of lamivudine or adefovir therapy. The likelihood of development of resistance to lamivudine and associated viral breakthrough limits its long-term use. In patients with HBeAg-negative chronic hepatitis B, long-term therapy is usually required, as off-treatment relapse is common. The emergence of resistance to adefovir is delayed and infrequent, hence adefovir may be preferred in patients requiring long-term therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The efficacy of combination therapy with pegylated interferon (PEG IFN) α plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established. METHODS: Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN α-2b 1.5 μg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN α-2b 1.0 μg/kg per wk plus RBV 1,000–1,200 mg per day (Regimen B, n = 161) for 48 wks. RESULTS: Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18% vs 13%, p= 0.21), in 8% of the combination therapy nonresponders (10% vs 6%, p= 0.35), in 21% of the IFN monotherapy nonresponders (16% vs 27%, p= 0.35), and in 42% of the combination therapy relapsers (50% vs 32%, p= 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels ≥100,000 copies/mL (21% vs 5%, p= 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14% vs 33%, p= 0.01), and African Americans had lower SVR than Caucasians (4% vs 18%, p= 0.01). CONCLUSION: Combination therapy with PEG IFN α-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/orde novoALT elevations. We sought to evaluate the efficacy of two doses of interferon alpha-2b (IFN) with ribavirin (RBV) in patients with normal ALT.METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000–1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy.RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%,p= 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs10%, p= 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted.CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients.De novoALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.(Am J Gastroenterol 2004;99:1700-1705) [ABSTRACT FROM AUTHOR]

OBJECTIVE:The aim of this study was to analyze the clinical presentation and outcomes of significant pulmonary toxicity associated with interferon and ribavirin.METHODS:We conducted a retrospective review of patients enrolled in four clinical trials at three sites, two academic medical centers and one community practice, and reviewed the literature.RESULTS:Four patients, while on therapy with interferon α and ribavirin for chronic hepatitis C, developed significant pulmonary signs and symptoms. Further workup, which included lung biopsy in three, revealed bronchiolitis obliterans organizing pneumonia in two, and interstitial pneumonitis in two other cases. There were no other predisposing factors for lung disease identified. Resolution of symptoms occurred in all patients upon discontinuation of interferon and ribavirin, with or without corticosteroid therapy. One of the patients developed pulmonary complications while on a clinical trial of pegylated interferon and represents the first reported case associated with the use of long-acting interferon in chronic hepatitis C infection.CONCLUSIONS:A spectrum of significant pulmonary toxicity, including bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis, can occur with interferon or pegylated interferon in combination with ribavirin. Though pulmonary toxicity of interferon is well known, these cases represent the first cases reported in the literature with combination therapy. It is likely that pulmonary toxicity may not be investigated in patients on combination therapy because of the frequent pulmonary symptoms with ribavirin. Though usually reversible, at least one case has required long-term steroids with inadequate resolution. Though pulmonary toxicity is rare, symptoms which are more than mild or progressive in nature should likely be investigated. [Copyright &y& Elsevier]

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon α-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon mono-therapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21(14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon α-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon a-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable. [ABSTRACT FROM AUTHOR]

Relapse in patients who have evidenced an initial response to a course of interferon monotherapy for chronic hepatitis C virus (HCV) infection has been a major frustration. At least 70% of responders will relapse after a 6-month course of treatment and more than 50% will relapse after a 12-month course of treatment, usually within the first 3 to 6 months after treatment discontinuation. At most, half of patients relapsing after an initial 6-month course will have a sustained response to a second, 12-month course of interferon monotherapy. A more promising second-line regimen is the combination of interferon plus ribavirin. A recent multicenter international trial has shown that this regimen results in a sustained virologic response rate of nearly 50%, fully 10-fold higher than the sustained response rate observed with a second 6-month course of interferon alone (49% vs 5%, respectively). In patients with non-1 genotype and viral levels no greater than 2 million copies/mL, the likelihood of sustained response to the second course of combination therapy was 100%. Biochemical and virologic responses (normalization of liver enzymes and disappearance of HCV RNA from the serum) were frequently accompanied by histologic improvement. HCV-RNA levels < or = 2 million copies/mL and non-1 viral genotype predicted treatment response, whereas age, gender, body weight, source of infection, type of interferon used for the first round of treatment, and elapsed time since first treatment had no effect. Based on these data, combination therapy with interferon and ribavirin is now considered the treatment of choice for relapsers. It is not clear whether 12 months of combination therapy might have produced even better rates of viral eradication in relapsed patients. [ABSTRACT FROM AUTHOR]

Therapy for hepatitis C virus (HCV) is a rapidly evolving field wherein traditional treatment with the nonspecific antiviral agents pegylated interferon (IFN)-alfa and ribavirin has been and will continue to be supplanted by combinations of targeted therapies against HCV with and without concomitant pegylated IFN and/or ribavirin, resulting in markedly superior rates of viral clearance. Exhaustive study of HCV structure and replication through the development of in vitro systems has enabled the development of numerous novel direct acting antiviral agents that currently are undergoing clinical trials. As our understanding of the HCV virus and its antiviral targets increases, the future of HCV therapy holds the promise of high rates of viral eradication in all patient populations, many or all of whom will be treatable with IFN-free combinations of all-oral agents. [Copyright &y& Elsevier]

Background & Aims: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a–ribavirin (PEG2a/R) in patients with identical study entry criteria. Methods: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended. Results: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log10 decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log10 decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log10 decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm3). Conclusions: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065. [Copyright &y& Elsevier]

Background & Aims: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism''s clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. Methods: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). Results: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1–6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). Conclusions: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome. [Copyright &y& Elsevier]

Background The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. Methods For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. Results We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0.94), or in cohort C (p=0.78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. Interpretation Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Funding Gilead Sciences. [ABSTRACT FROM AUTHOR]

Background & Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×109/L and an absolute neutrophil count (ANC) ⩾1500/mm3. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). Results: 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p =10−10). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p =10−12, p =10−7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p =10−17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified. [ABSTRACT FROM AUTHOR]

Background: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies. Methods: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 μg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy). Results: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation. Conclusions: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.) N Engl J Med 2009;360:1827-38. [ABSTRACT FROM AUTHOR]

Interferon (IFN)-α plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-α/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-α-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10–19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase (χ2=7.6, df=2, p<0.05). In addition, a 20-point or greater increase in SDS Index score during IFN-α/ribavirin therapy significantly predicted failure to clear virus when considered alone [crude odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3–8.0; p<0.01] or when controlling for other factors that affected IFN-α treatment response (adjusted OR, 3.6; 95% CI, 1.3–9.5; p=0.01). These preliminary findings suggest that individuals who experience significant increases in depressive symptoms during IFN-α/ribavirin therapy may be less likely to clear virus, highlighting the importance of identifying and treating depressive symptoms in this patient population. [Copyright &y& Elsevier]