August 28, 2013

Provided by NATAP

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(from jules: this was an initial small study with only GS7977+Rbv - 83% African-American/70-80% genotype 1a/23% advanced liver disease/96% undetectable in rbv wt-based group at the end of 24 weeks treatment with 7 relapsers after that)

JAMA August 28, 2013

Anuoluwapo Osinusi, MD, MPH1,2; Eric G. Meissner, MD, PhD1; Yu-Jin Lee1; Dimitra Bon, MS3; Laura Heytens, RN4; Amy Nelson, RN1; Michael Sneller, MD1; Anita Kohli, MD1; Lisa Barrett, MD, PhD1; Michael Proschan, PhD5; Eva Herrmann, PhD3; Bhavana Shivakumar, MS1; Wenjuan Gu, PhD6; Richard Kwan, PAC4; Geb Teferi, MD7; Rohit Talwani, MD8; Rachel Silk, RN2; Colleen Kotb, RN2; Susan Wroblewski, RN1; Dawn Fishbein, MD9; Robin Dewar, PhD6; Helene Highbarger, MS6; Xiao Zhang, MS1; David Kleiner, MD10; Brad J. Wood, MD11; Jose Chavez, MD7; William T. Symonds, PharmD12; Mani Subramanian, MD, PhD12; John McHutchison, MD12; Michael A. Polis, MD, MPH1; Anthony S. Fauci, MD1; Henry Masur, MD4; Shyamasundaran Kottilil, MD, PhD1

Gilead HCV Program, GS-7977 - (08/19/13)

"Participants were enrolled in this single-center, 2-part, randomized controlled trial conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from October 2011 through April 2012. Eligible participants were infected with HCV genotype 1, had liver biopsy-proven chronic disease, and were naive to HCV treatment..........Eighty-three percent of the participants were black; 66%, men; and 48%, body mass index greater than 30 (calculated as weight in kilograms divided by height in meters squared); 81% had the IL28 CT or TT genotype; 70%, GT-1a genotype; 23%, advanced liver disease; and 62%, baseline HCV RNA levels greater than 800 000...........

In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events....... Bivariable analysis of baseline factors showed that in all randomized participants who completed treatment, the odds of relapse was significantly higher in participants who were male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54), and baseline HCV RNA greater than 800 000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38; Table 4). Given the small number of events and the exploratory nature of the stepwise analysis that determined variables used in the model, only the bivariable model results are reported herein........ Deep sequencing of all baseline samples showed no S282T resistant mutant......Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement"

"........Twenty-four participants (96%) in each group achieved viral suppression by week 4. Four participants discontinued the study drug by week 8 due to nonadherence (1 in the weight-based group; 3 in the low-dose; Figure). One patient declined to continue study drug past week 12, but his viral load remained undetectable 24 weeks after stopping treatment. He is included in the final analysis. A total of 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group (Table 2). A within-cohort comparison of baseline factors related to SVR was performed and is shown in eTable 3 in the Supplement. Deep sequencing of all baseline samples showed no S282T resistant mutant......."

"........All participants experienced a rapid decline in plasma HCV RNA. A viral kinetic model over the first 50 days of treatment of all randomized participants showed no differences in viral decay based on ribavirin dose or baseline characteristics (eFigure 1 and eFigure 2 in the Supplement). However, a fully fitted pharmacokinetics-viral kinetics model of a subset of 20 participants (10 in the low-dose group and 10 in the weight-based group) showed a significantly slower loss rate of free virus (clearance) in relapsers than participants who achieved SVR (clearance, 3.57 vs 5.60 per day; P = .009). There were no observable differences in viral decay, drug efficiency, loss rate of infected cells, or loss rate of infectious virus based on baseline characteristics (eTable 4 in the Supplement).......Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement)."

HCV1

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ABSTRACT

Importance The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.

Objective To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.

Design, Setting, and Patients Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).

Interventions In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. Main Outcomes and Measures The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).

Results In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.

Conclusion and Relevance In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively.

Chronic infection with hepatitis C virus (HCV) is a major cause of chronic liver disease, end-stage liver disease, hepatocellular cancer and remains the leading indication for liver transplants in western countries.1- 2 The HCV epidemic in the United States is centered in large urban areas among populations with a high prevalence of unfavorable traditional predictors of treatment response.1,3- 4 The addition of the recently approved directly acting antiviral agents telaprevir or boceprevir to pegylated interferon-alfa and ribavirin has resulted in improved sustained virologic response (SVR) rates; however, adverse reactions, high pill burdens, and drug interactions continue to make treatment challenging.5- 7 Furthermore, certain host and viral factors including black race, advanced liver fibrosis, IL28B CT or TT genotypes, high baseline HCV viral loads, and prior treatment experience appear to remain associated with poorer treatment outcomes.5,7- 9

Recent studies show that interferon-free, directly acting antiviral agent-only regimens can successfully achieve SVR; however, populations traditionally associated with poorer treatment outcomes have been underrepresented.10- 12 Many studies also use ribavirin, currently a standard component of interferon-based HCV therapy, which is associated with significant adverse events including hemolytic anemia, nausea, and teratogenicity.13 Although ribavirin clearly improves SVR rates with interferon-based therapies,14- 15 the role and requirement for ribavirin in emerging directly acting antiviral agent regimens, including optimal dosing, have not been established.

In this study, we evaluated the safety and efficacy of sofosbuvir administered in combination with weight-based or low-dose once daily ribavirin for 24 weeks in a treatment-naive population with unfavorable characteristics of treatment success. We report the efficacy of this regimen as defined by SVR rates 24 weeks after completion of treatment as well as the host and viral factors associated with treatment relapse.

METHODS

Participants

Participants were enrolled in this single-center, 2-part, randomized controlled trial conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from October 2011 through April 2012. Eligible participants were infected with HCV genotype 1, had liver biopsy-proven chronic disease, and were naive to HCV treatment. Additional eligibility criteria included seronegativity for human immunodeficiency virus (HIV) and hepatitis B; absolute neutrophil count of 750 cells/μLor more; platelet count of 50 000 cells/μL or more; and hemoglobin of 11 g/dL or more for women and 12 g/dL or more for men. Race/ethnicity was classified as white, black, or Hispanic using patient self-reported data. Written consent was obtained from all participants except for 2 patients with limited literacy who gave oral consent after the entire constent form had been read and explained to them.

Study Design

The study was performed in 2 parts. In the first part (proof of concept), participants with early to moderate liver fibrosis (Knodell histology activity index [HAI] fibrosis score, 0-1) were treated for 24 weeks with 400 mg/d of sofosbuvir and weight-based ribavirin (400 mg in the morning, 600 mg in the evening if <75 kg or 600 mg twice a day if >75 kg). In the second part, eligible participants with all stages of fibrosis (including compensated cirrhosis) were randomized in a balanced fashion to receive 400 mg/d of sofosbuvir in combination with either weight-based ribavirin or low-dose (600 mg/d) of ribavirin for 24 weeks. The randomization used a set of 60 random numbers, in which blocks of 4 numbers were selected. Within a block, the highest numbers were assigned to the weight-based protocol, and the lower numbers were assigned to the low-dose group. Once enrollment occurred, participants received a study number in sequential fashion. Participants who experienced treatment failure were offered the current standard of care.

Study Oversight

The study was approved by the institutional review board of the National Institute of Allergy and Infectious Diseases (NIAID) and was conducted in compliance with the Good Clinical Practice guidelines, the Declaration of Helsinki, and regulatory requirements. An independent safety monitor participated in the interim safety and efficacy analysis.

Efficacy Assessments

Plasma HCV RNA levels were measured using the real-time HCV assay (Abbott Molecular), with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL. The Abbott assay was used to measure HCV RNA levels in all participants at all time points. Plasma HCV RNA levels were also measured using the COBAS TaqMan HCV RNA assay, version 1.0 (Roche), with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 12 IU/mL at specified clinical time points.

Safety Assessments

Adverse events and clinical laboratory results were recorded throughout the study. Adverse events were graded from 1 (mild) to 4 (severe) by a standardized scale using the Division of AfIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Division of AIDS toxicity table version 1.0). Patient adherence was determined by pill counts at each visit and during patient interviews. A missed dose was defined as any component of the medication regimen not taken on a given day.

Viral Kinetics, Pharmacokinetics, and Pharmacodynamics

Early viral kinetics, pharmacokinetics, and pharmacodynamics of sofosbuvir and its metabolite GS-331007 were obtained and calculated. Levels of sofosbuvir and its metabolite GS-331007 in serum were measured at 0, 1, 2, 4, 8, 12, 24, and 36 hours after administration of sofosbuvir and ribavirin using a high-performance liquid chromatography-mass spectrometry bioanalytical technique (QPS LLC).

IL28B Genotyping

Genotyping of the IL28B single-nucleotide polymorphism rs12979860 has been previously shown to be associated with treatment outcome.16- 17Whole blood was collected using PAXgene Blood DNA tubes (Qiagen) and stored at -80°C until DNA extraction. DNA was extracted using the Paxgene Blood DNA Kit (PreAnalytiX, a Qiagen/BD Company). The IL28B genotype was conducted in a blinded fashion on DNA specimens using the 5' nuclease assay with IL28B-allele-specific TaqMan probes (ABI TaqMan allelic discrimination kit) and the ABI7500 Real-Time PCR system (Applied Biosystems). The IL28B genotyping was classified as either favorable (CC genotype) or unfavorable (CT or TT genotypes).18

454 Deep Sequencing for the Detection of S282T NS5B Mutation

The major mutation shown to confer resistance to NS5B drugs including sofosbuvir is an S282T mutation.19 The HCV viral RNA was extracted from baseline plasma using QIAamp Viral RNA Mini (Qiagen) followed by reverse transcription-polymerase chain reaction to amplify complementary DNA. Using the Genome Sequencer FLX system, 454 Deep sequencing was then performed in the NS5B region to determine the presence of putative resistance-associated variants to sofosbuvir, including S282T.

Liver Biopsy

All participants had undergone a liver biopsy within 3 years of enrollment, and an optional research biopsy was offered after treatment completion (within 2 weeks of drug cessation). Histopathological assessments were performed by a single pathologist in a nonblinded fashion at the time of biopsy and staged according to the Knodell-HAI scoring system.20

Clinical End Points

The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (SVR24). Secondary efficacy end points included the proportion of participants with undetectable HCV viral load at specified time points during and after treatment. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes.

Modeling Viral Kinetics, Pharmacokinetics, and Pharmacodynamics

Pharmacokinetics, pharmacodynamics, and viral kinetic modeling of sofosbuvir in the 20 randomized participants in the substudy were calculated using previously described techniques.21- 23 An estimation of mean and maximum drug efficacy, infected cell loss rate, and loss rate of free virus was generated with this model.

Statistical Analysis

Although the primary interest was the per-protocol analysis, we also present the intention-to-treat analysis of all randomized participants because these results are more readily generalizable. The per-protocol analysis included all participants who received at least 8 weeks of the study drug. For efficacy analysis, missing data points were deemed a success if the immediately preceding and subsequent time points were successful; otherwise, data points were termed as failures. Participants who had missing data due to premature discontinuations were considered failures from the point of discontinuation. Comparisons were analyzed using the nonparametric Wilcoxon rank sum test for continuous outcomes and Fisher exact test for binary outcomes. A bivariable logistic regression model of baseline characteristics was used to identify factors associated with relapse. All P values were 2-tailed and were considered significant only when lower than .05. Analysis was performed using PRIZM 8.0 (GraphPad Software), SAS (SAS Institute Inc), STAT-CRUNCH, and S-Plus 8.0 (Statistical Sciences Inc). Sample size was calculated using an assumed early response rate of 90% for the weight-based group vs 85% for the low-dose group. With 50 participants, the study would be able to estimate the difference in early virologic response proportions to within plus or minus 0.18. There was a substantial gain in precision (from an accuracy of ± 0.24 to ± 0.18) from increasing the sample size from 15 to 25 per group but diminishing returns after a sample size of 25.

RESULTS

Seventy-nine participants were screened and 60 were enrolled in this study (10 participants in part 1 [proof of concept] and 50 participants in part 2 [randomized portion]; Figure). All results including treatment response and safety in the 10 nonrandomized participants are shown in eTable 1 and eTable 2 in the Supplement.

Figure.

Study Flow Diagram

The first 10 were sequentially enrolled from eligible participants in an open-label exploratory group. Relapse is determined at any time after end of treatment response but brior to sustained virologic response at 24 weeks.The patient who discontinued at week 12 was still included in both analyses as having reached sustained virologic response at 24 weeks.

HCV2

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Baseline Characteristics of Participants

Baseline characteristics were similar among treatment groups (Table 1). Eighty-three percent of the participants were black; 66%, men; and 48%, body mass index greater than 30 (calculated as weight in kilograms divided by height in meters squared); 81% had the IL28 CT or TT genotype; 70%, GT-1a genotype; 23%, advanced liver disease; and 62%, baseline HCV RNA levels greater than 800 000.

HCV3

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Virologic Response

Twenty-four participants (96%) in each group achieved viral suppression by week 4. Four participants discontinued the study drug by week 8 due to nonadherence (1 in the weight-based group; 3 in the low-dose; Figure). One patient declined to continue study drug past week 12, but his viral load remained undetectable 24 weeks after stopping treatment. He is included in the final analysis. A total of 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group (Table 2). A within-cohort comparison of baseline factors related to SVR was performed and is shown in eTable 3 in the Supplement. Deep sequencing of all baseline samples showed no S282T resistant mutant.

Viral Kinetic, Pharmacokinetic, and Pharmacodynamic Modeling

All participants experienced a rapid decline in plasma HCV RNA. A viral kinetic model over the first 50 days of treatment of all randomized participants showed no differences in viral decay based on ribavirin dose or baseline characteristics (eFigure 1 and eFigure 2 in the Supplement). However, a fully fitted pharmacokinetics-viral kinetics model of a subset of 20 participants (10 in the low-dose group and 10 in the weight-based group) showed a significantly slower loss rate of free virus (clearance) in relapsers than participants who achieved SVR (clearance, 3.57 vs 5.60 per day; P = .009). There were no observable differences in viral decay, drug efficiency, loss rate of infected cells, or loss rate of infectious virus based on baseline characteristics (eTable 4 in the Supplement).

Histologic Response

Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement).

Safety

The combination of sofosbuvir and ribavirin was safe and well tolerated with no death or discontinuation of treatment due to adverse events. The most frequent adverse events were headache, anemia, fatigue, and nausea, the severity of which ranged from mild to moderate (Table 3). There were 7 grade 3 events.

Participants in the weight-based group experienced a higher incidence of hemoglobin decline, which was maintained through week 12, than did participants in the low-dose group (week 4, 37% vs 4%; P = .005; week 12, 39% vs 4%; P = .01; eFigure 4B, in the Supplement). Eight participants (5 in the weight-based group) underwent ribavirin dose reduction for decreased hemoglobin including 3 with a history of coronary artery disease with ribavirin reduction instituted at a hemoglobin level of less than 12 g/dL. There was no use of erythropoietin-stimulating agents in this study. No major biopsy-related complications were observed.

Characteristics Associated With Relapse

Bivariable analysis of baseline factors showed that in all randomized participants who completed treatment, the odds of relapse was significantly higher in participants who were male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54), and baseline HCV RNA greater than 800 000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38; Table 4). Given the small number of events and the exploratory nature of the stepwise analysis that determined variables used in the model, only the bivariable model results are reported herein.

HCV4

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DISCUSSION

Although the treatment of HCV is rapidly evolving, several questions remain unanswered. This study demonstrates the efficacy of an interferon-free regimen in a traditionally difficult-to-treat population while exploring the reasons for treatment relapse. In this study, treatment of chronic HCV infection with a single directly acting antiviral agent (sofosbuvir) and weight-based ribavirin resulted in a high SVR rate in a population with unfavorable traditional predictors of treatment response compared with reported rates with currently used interferon-based therapy in similar populations.7- 8Compared with previous trials testing boceprevir and telaprevir, this population had a higher prevalence of unfavorable traditional predictors of treatment response including black race (80% vs 7%-15%); genotype 1a (70% vs 60%-64%); advanced fibrosis (24% vs 9%-20%); and body mass index greater than 30 (49% vs 22%).7- 8 The overall SVR rate achieved by participants who received sofosbuvir in combination with weight-based ribavirin in our study was 68% compared with the 84% reported in a recent New Zealand study of sofosbuvir and weight-based ribavirin in a predominantly white, treatment-naive population.11 Because treatment of HCV is evolving from an interferon-based combination therapy to an all-oral, interferon-free directly acting antiviral agent regimen, these results are encouraging and provide important information regarding the expected treatment responses in a population representative of the US epidemic.

In an exploratory bivariable model, we found that the baseline factors of male sex, advanced liver disease, and high baseline HCV RNA were associated with relapse. The association of advanced liver disease with higher odds of relapse is similar to that described with direct-acting antiviral agent interferon-based regimens.6- 8 In this regard, 7 of the 13 participants (54%) with advanced liver fibrosis treated in this study relapsed including all 4 participants with cirrhosis. Future studies are warranted to evaluate the efficacy of sofosbuvir and ribavirin regimens in participants with advanced fibrosis.

There were no cases of viral breakthrough while receiving therapy in participants treated with sofosbuvir and ribavirin similar to what has been reported in prior studies.11 Comprehensive analysis of baseline plasma HCV quasi-species by 454 deep sequencing failed to detect the characteristic S282T mutants previously associated with resistance to sofosbuvir.

The kinetics of HCV decline during interferon and ribavirin therapy has been previously described as a predictor of SVR.21- 22 Because interferon-free directly acting antiviral agent therapy is entirely based on achieving maximum suppression of HCV replication, we sought to explore the effect of early HCV viral kinetics, pharmacokinetics, and pharmacodynamics on therapeutic response. Although there were no significant differences in viral kinetics or pharmacokinetics between the weight-based ribavirin and low-dose ribavirin groups, the viral kinetics-pharmacodynamics model demonstrated a significantly slower loss rate of infectious virus in participants who subsequently relapsed. The mechanism of viral relapse in these participants remains elusive and future research will be focused on identifying the biological basis for incomplete clearance of HCV in these participants.

Limitations of this study include the relatively small sample size in each group and a higher, though small, increase in the number of discontinuations with low-dose ribavirin. Due to the small size, associations described are preliminary in nature and require further evaluation in larger studies.

Ribavirin is associated with significant adverse events13,23 but appears to be essential for optimal response to interferon-based and certain directly acting antiviral agent therapies.11,14- 15 Although our study did not show a significant association between treatment response and ribavirin dosing, it remains important to determine the optimal dose and role of ribavirin in the treatment of chronic HCV infection in larger interferon-free studies. In conclusion, treatment with a 24-week regimen of sofosbuvir and ribavirin resulted in an SVR rate of 68% in the weight-based ribavirin regimen and 48% in the low-dose ribavirin regimen among patients with chronic HCV and unfavorable traditional predictors of treatment response who are representative of the demographics of the US HCV epidemic. The delineation of the host and viral factors associated with treatment relapse with different directly acting antiviral agent interferon-free regimens needs to be further assessed. As new direct-acting antivial agent regimens are being evaluated, it is important that these studies involve populations most affected by the disease.

Source

Journal of Viral Hepatitis

A Systematic Review

A. Raza, S. Mittal, G. K. Sood

J Viral Hepat. 2013;20(9):593-599.

Abstract and Introduction

Abstract

The incidence of retinopathy in patients with chronic hepatitis C treated with interferon-based regimens has been variably reported in the literature. There is no consensus regarding ophthalmologic screening before and during treatment with interferon-based therapy. To assess the incidence of retinopathy in patients with chronic hepatitis C being treated with interferon-based regimens and estimate the rate of resolution. A systematic literature search was performed to locate all relevant publications. Pooled incidence of retinopathy was calculated in patients treated with interferon or pegylated interferon. We also estimated the rate of discontinuation of treatment and resolution after the treatment was stopped. A total of 21 studies fulfilled the inclusion criteria. The overall incidence of retinopathy using random effect model was 27.7% (95% confidence interval [CI] 20.9–34.5%). The pooled incidence of retinopathy in 10 studies that only used pegylated interferon was 20.9% (95% CI: 11.6–29.8). The incidence of retinopathy with pegylated interferon in diabetic and hypertensive patients (high-risk group) was 65.32% and 50.7%, respectively. This was significantly higher compared with the incidence of retinopathy (11.7%) in patients without these risk factors. Overall pooled estimate for the resolution of retinopathy was 87% (95% CI 75.7–98.4%). The rate of discontinuation of treatment was 6.3%. The incidence of retinopathy with pegylated interferon in patients without hypertension and diabetes is low, but the risk is higher in patients with diabetes and hypertension. Routine pretreatment fundoscopic screening may not be warranted in all patients and can be limited to the patients with these risk factors.

Introduction

In recent years, there have been significant advances in the treatment of chronic hepatitis C virus (HCV) infection. There are many new agents on horizon, and the novel interferon (IFN)-free regimens are being explored. But IFN-based regimens along with the new direct acting antiviral agents are likely to stay as part of hepatitis C treatment for the next few years.[1–3] Currently, pegylated interferon alpha (PegIFNα) is a part of all the standard regimens for the treatment of HCV. The development of retinopathy is a well-known side effect of the PegIFNα therapy.[4] However, the data report discordant results about the frequency and clinical significance of retinopathy seen during PegIFNα-based therapy. Retinopathy has been reported in 18–86% of patients with chronic HCV who received IFN-based treatment regimens, and the risk is even higher in diabetic and hypertensive patients.[4–6] The wide range of frequency reported in the literature reflects the limitations of small studies, which are heterogeneous in selection of the patients and screening protocols for retinopathy. Given the inconvenience and cost associated with the ophthalmological screening, significance of IFN-associated retinopathy during HCV treatment and lack of screening or surveillance protocols, we conducted a systematic review to estimate the incidence of retinopathy in patients with chronic HCV being treated with PegIFNα or IFNα and its outcomes. We specifically reviewed incidence in various high-risk groups, pertinently in patients with associated diabetes mellitus (DM) and hypertension (HTN). We also studied the rate of discontinuation of the treatment due to the development of severe retinopathy and the outcomes of retinopathy after the treatment was completed or discontinued.

Methods

Electronic databases (PubMed and Scopus EMBASE, ISI Web of Science) were searched for the studies between January 1991 and December 2012 by two independent investigators (AR and SM). The search terms used were hepatitis C, HCV, Interferon, interferon alpha, pegylated interferon, pegylated interferon alpha and retinopathy and their Boolean combination. The search was limited to the studies published in English. Related abstracts presented at meetings were also reviewed. In addition, a manual search was performed for cross-references from publications.

Study Selection

We selected the studies reporting the incidence of retinopathy in patients with chronic HCV, who were treated with IFNα or PegIFNα with or without ribavirin. We included both retrospective and prospective observational studies.

Following inclusion criteria were used:

  1. Retinal examination performed at baseline, which is prior to the initiation of treatment or within 1 week of the initiation of treatment.

  2. Retinal examination performed at least once during treatment and at least once after the discontinuation or finishing the treatment.

Studies were excluded if:

  1. The patient population had co-infection with hepatitis B (HBV) or human immunodeficiency virus (HIV).

  2. History of liver transplantation.

  3. Studies that did not meet the inclusion criteria for ophthalmological examination.

Outcome Measures

Following outcome measures were assessed

  1. The pooled incidence of retinopathy in patients with chronic HCV treated with PegIFNα or IFNα.

  2. The pooled Incidence of retinopathy in high-risk (patients with DM or HTN) and low-risk (patients without HTN or DM) groups treated with PegIFNα for chronic HCV.

  3. The rate of resolution of retinopathy in patients treated with PegIFNα and IFNα.

  4. The rate of discontinuation of PegIFNα and IFNα treatment.

Data Extraction

The data were systematically extracted and entered into the tables. The data included study type, year of publication, type of interferon used, retinopathy prior to the treatment, incidence of retinopathy on active treatment and the rate of resolution of retinopathy after discontinuation of the treatment. Retinopathy was defined as the presence of cotton wool spots, retinal haemorrhages or microaneurysm. Resolution of retinopathy was defined as disappearance of cotton wool spots, retinal haemorrhages or microaneurysms on the surveillance fundoscopic examination.

Data Synthesis and Statistical Analysis

The incidence of retinopathy for each study was calculated using the number of patients who developed retinopathy and the total number of patients treated with IFN. Data analysis was performed in Microsoft Excel using methodology described in details by Neyeloff et al.[7] Proportions were compared using chi-squared test, and a P-value <0.05 was considered significant. Summary pooled incidence with 95% confidence interval (CI) was obtained. Heterogeneity was evaluated using Q statistic and I 2 index. To take the effect of heterogeneity into consideration, random effects model was used for analysis.

Results

After careful review of the literature and applying the inclusion and exclusion criteria, only 21 studies were selected (see Table 1 for all the citations). There was wide geographical spread; seven studies from Asia, six from Europe, five from USA, two from Africa and one study from Canada. Ten studies used PegIFNα, eight studies used IFNα, and three studies used a combination of PegIFNα and IFNα to treat the patients with chronic HCV (Table 1). Overall incidence of retinopathy was calculated in studies that used PegIFNα or IFNα either alone or in combination with ribavirin. Incidence of retinopathy was calculated in diabetic and hypertensive patients[4, 10, 11, 18, 25] as well as nonhypertensive and nondiabetic patients[4, 10, 18, 25] in the PegIFNα treatment studies that provided pertinent clinical information.

Overall Incidence of Retinopathy

There were a total of 1382 patients in 21 studies that received either IFNα or PegIFNα. The incidence of retinopathy ranged from 2.6% to 61.1% among studies using random effect model (heterogeneity I 2 = 17.9%). The overall incidence of retinopathy using random effect model was 27.7% (95% confidence interval [CI] 20.9–34.5%).

PegIFNα vs IFNα

The pooled incidence of retinopathy in 10 studies (Fig. 1, 608 patients) that exclusively used PegIFNα was 20.7% (95% CI: 19.8–21.6). The pooled incidence of retinopathy in eight studies that exclusively used IFNα was 41.6% (95% CI: 28.8%–54.5%), which was significantly higher than PegIFNα-treated group (P < 0.0001).

809465-fig1

Figure 1. The incidence of retinopathy in PegIFNα treated patients.

Incidence of Retinopathy in High-risk and Low-Risk Groups With PegIFNα Treatment

Only five of the ten studies[4, 10, 11, 18, 25] looked at the incidence of retinopathy in diabetic and hypertensive patients (Table 2). Among these patients, 84 had HTN and 38 had DM. Some of these high-risk patients had overlap of both diseases, but the information about this was not provided in all studies. The incidence of retinopathy in diabetic and hypertensive patients was 65.32% (95% CI: 39.6–91) and 50.7% (95% CI: 39.6–61.8), respectively (Table 3). Four of these five studies looked at the incidence of retinopathy in patients without HTN or DM.[4, 10, 18, 25] The incidence of retinopathy in this low-risk group was 11.7% (95% CI: 6.4–17). The incidence of retinopathy in diabetic and hypertensive patients (high-risk group) was significantly higher compared with the patients without these risk factors (P < 0.0001 and P < 0.0001, respectively).

Resolution of Retinopathy in Patients Treated With IFNα/PegIFNα

Estimates of resolution of retinopathy were reported in 17 studies (Table 1). Pooled data from these studies included 260 patients that developed retinopathy, of which retinopathy resolved in 233 patients. Pooled estimate for resolution of retinopathy was 87% (95% CI 75.7–98.4%). Data on resolution of retinopathy were reported in eight studies that used PegIFNα. Among 92 patients that developed retinopathy with PegIFNα, retinopathy resolved in 77 patients after completion or discontinuation of treatment. The pooled estimate of resolution was 81.9% (95% CI 63.4–100%). Resolution rate in subgroups (high-risk vs low-risk) was not performed due to small sample size.

The Rate of Treatment Discontinuation

Overall, 6.3% (n = 8) and 1.9% (n = 3) of the patients discontinued treatment in PegIFNα and non-PegIFNα groups, respectively. Reasons to discontinue the PegIFNα treatment included patient request (n = 4), retinal vein occlusion (n = 2), transient visual loss (n= 1) and per study protocol (n = 1). The reason to discontinued IFNα treatment was related with worsening retinopathy.

Discussion

Interferons belong to a large group of glycoproteins with antiviral, anti-tumour and immune modulatory effects. Upon contact with a virus, innate immune system activates and produces cytokines, chemokines and IFNs. IFNs turn on hundreds of interferon-stimulating genes (ISGs) through JAK-STAT pathway. The products of ISGs act on multiple steps of viral life cycle to counter replication. Side effects of IFNs include influenza-like syndrome, haematological, psychiatric, cardiovascular, endocrine and ophthalmological abnormalities. The exact mechanism of IFN-associated retinopathy is not known. Ikebe and colleagues reported the first case of IFN-associated retinopathy in a 39-year-old woman who developed cotton wool spots and retinal haemorrhages after intravenous administration of IFN in 1990.[26] In 1993, Miller et al.[27] showed that systemic administration of IFNα successfully inhibited angiogenesis in an experimental model of iris neovascularization. For its antiangiogenic effects, IFNα has been used to stop the subretinal neovascularization in the treatment of age-related macular degeneration.[28] Later, Guyer et al.[29] used fluorescein angiography in patients who developed retinopathy after IFN administration for reasons other than HCV and showed areas of retinal ischaemia and poor perfusion. Nishiwaki et al.[30] showed increased trapping of leucocytes in the retinal microcirculation of rats after the administration of IFNα. The trapping of leucocytes was dose dependent; the authors postulated that this might be related to impairment of the retinal microcirculation. Nagaoka et al.[13] studied the effects of IFN on retinal microcirculation in patients with chronic HCV receiving treatment. They showed that wall shear stress increased significantly within 2 weeks of treatment initiation. Their findings suggested endothelial dysfunction as a cause of IFN-associated retinopathy. IFN-associated retinopathy was more frequent in patients with DM or HTN in the previously reported studies.

Abe et al.[31] demonstrated that patients with chronic HCV infection had a higher incidence of retinopathy compared with the age- and sex-matched controls, independent of the IFN treatment. Similarly, Purtscher-like retinopathy was reported in a chronic HCV patient with cryoglobulinemia who was not on IFN treatment. Authors of the above two studies suggested an immune complex mediated ischaemic injury to the retina. HCV has been isolated from the lacrimal secretions and tears of the patients with chronic HCV infection,[32] but we do not know of any study demonstrating active replication of HCV in the retinal epithelial cells causing retinopathy.

The incidence of retinopathy related to IFNα or PegIFNα has been variably reported in the literature, and there is no consensus on screening and surveillance protocols in such patients.[4, 8, 9] A recent study by Vujosevic et al.[4] reported a very high incidence (30%) of retinopathy in 97 patients with chronic HCV during PegIFNα and ribavirin treatment. The frequency of the development of retinopathy was even higher among hypertensive patients (68%) during serial ophthalmological examination. Based on these findings, the authors not only recommended baseline ophthalmological examination in all patients with HTN but also serial fundoscopic examinations at 3-month intervals during the treatment period. They further suggested continuing the fundoscopic examination 3 months after the end of treatment if the patient developed any retinopathy during the treatment period, regardless of any visual symptoms. On the contrary, Panetta et al.[9] reported a very low incidence (3.8%) of retinopathy among 183 patients with chronic HCV treated with PegIFNα and ribavirin. Moreover, patients with HTN and DM were not at higher risk of IFN-associated retinopathy. The authors concluded that pretreatment and during treatment, fundoscopic examinations were not necessary in asymptomatic patients, even in the presence of HTN and DM. The study by Vujosvic et al. was prospective and evaluated both symptomatic and asymptomatic patients, while the study by Panetta et al. was retrospective and ophthalmological examinations were only carried out in symptomatic patients. This wide variation in the frequency of retinopathy is due to the differences in study designs, patient population and protocols for evaluation of retinopathy.[4, 9]

The result of this systematic review highlights some important points (i) The overall incidence of retinopathy during IFN (IFNα and PegIFNα) treatment and ribavirin is around 27%. The risk is higher in patients treated with standard IFNα but much lower in patients treated with the current standard of care, PegIFNα. The precise mechanism by which IFN causes retinopathy is unknown, but it is thought to be related to microvascular changes in the retinal circulation.[4] The difference between the incidence of retinopathy between PegIFNα and IFNα may be explained by their pharmacokinetics. PegIFNα is a once a week subcutaneous injection with a steady release, and IFNα is administered at least three times a week with a shorter half-life and higher peak concentration. (ii) The risk of development of retinopathy in patients without DM and HTN is low, and the frequency of retinopathy increases with coexisting DM and HTN. (iii) The IFN-related retinopathy is not a progressive disease, and most of the patients had spontaneous resolution of retinopathy after finishing the treatment. (iv) A significant number of patients developed retinopathy on treatment with IFN, but only a few patients discontinued treatment. In our literature review, only three patients in the PegIFNα group had to discontinue treatment due to worsening retinopathy, and all three of them developed visual symptoms during the treatment. The other five patients in the PegIFNα group discontinued treatment due to nonmedical reasons (patient preference and per study protocol). Even in the study of Vujosevic et al., despite a very high incidence of the retinopathy, only one patient had to stop treatment. This patient came to medical attention because he developed significant visual symptoms. It appears that the development of visual symptoms is a key finding during the treatment and necessitates a complete fundoscopic examination regardless of co-morbidities or pre-existing retinopathy.

The current study has limitations. Studies included had variable design and patient population giving rise to incidence rates with wide dispersion. We used random effects model for all our analysis to account for this heterogeneity. All the studies did not provide information about the presence of risk factors such as HTN and DM. Most of the studies also did not provide information regarding which patients had both HTN and DM.

In conclusion, pooled analysis of studies suggests that incidence of retinopathy with PegIFNα is low, especially among patients without underlying DM or HTN. Results also highlight that retinopathy is mostly a temporary and asymptomatic complication, if it is not associated with visual symptoms. Based on these findings, we recommend that baseline screening for retinopathy should only be performed in high-risk group (with HTN and DM) prior to the initiation of the treatment. Low-risk group does not need any baseline screening evaluation. Also, we recommend against the serial fundoscopic examinations in both high-risk and low-risk groups during the treatment. We recommend complete ophthalmological evaluation in any patient who develops visual symptoms during treatment.

References

  1. Lewis H, Cunningham M, Foster G. Second generation direct antivirals and the way to interferon-free regimens in chronic HCV. Best Pract ResClin Gastroenterol 2012; 26: 471–485.

  2. Martel-Laferriere V, Dieterich DT. Update on combinations of DAAs with and without pegylated-interferon and ribavirin: triple and quadruple therapy more than doubles SVR. Clin Liver Dis 2013; 17: 93–103.

  3. Gane E. Future perspectives: towards interferon-free regimens for HCV. Antivir Ther 2012; 17: 1201–1210.

  4. Vujosevic S, Tempesta D, Noventa F, Midena E, Sebastiani G. Pegylated interferon-associated retinopathy is frequent in hepatitis C virus patients with hypertension and justifies ophthalmologic screening. Hepatology 2012; 56: 455–463.

  5. Narkewicz MR, Rosenthal P, Schwarz KB et al. Ophthalmologic complications in children with chronic hepatitis C treated with pegylated interferon. J Pediatr GastroenterolNutr 2010; 51: 183–186.

  6. d'Alteroche L, Majzoub S, Lecuyer AI, Delplace MP, Bacq Y. Ophthalmologic side effects during alphainterferon therapy for viral hepatitis. J Hepatol 2006; 44: 56–61.

  7. Neyeloff JL, Fuchs SC, Moreira LB. Meta-analyses and forest plots using a microsoft excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5: 52.

  8. Abd El-Badie Mohamed M, Abd-El Azeem Eed K. Retinopathy associated with interferon therapy in patients with hepatitis C virus. ClinOphthalmol 2012; 6: 1341–1345.

  9. Panetta JD, Gilani N. Interferon-induced retinopathy and its risk in patients with diabetes and hypertension undergoing treatment for chronic hepatitis C virus infection. Aliment Pharmacol Ther 2009;30: 597–602.

  10. Fouad YM, Khalaf H, Ibraheem H, Rady H, Helmy AK. Incidence and risk factors of retinopathy in Egyptian patients with chronic hepatitis C virus treated with pegylated interferon plus ribavirin. Int J Infect Dis 2012; 16: e67–e71.

  11. Mehta N, Murthy UK, Kaul V, Alpert S, Abruzzese G, Teitelbaum C. Outcome of retinopathy in chronic hepatitis C patients treated with peginterferon and ribavirin. Dig DisSci 2010; 55: 452–457.

  12. Malik NN, Sheth HG, Ackerman N, Davies N, Mitchell SM. A prospective study of change in visual function in patients treated with pegylated interferon alpha for hepatitis C in the UK. Br J Ophthalmol 2008; 92: 256–258.

  13. Nagaoka T, Sato E, Takahashi A, Yokohama S, Yoshida A. Retinal circulatory changes associated with interferon-induced retinopathy in patients with hepatitis C. Invest OphthalmolVis Sci 2007; 48: 368–375.

  14. Andrade RJ, Gonzalez FJ, Vazquez L et al. Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels. Antivir Ther 2006; 11: 491–498.

  15. Okuse C, Yotsuyanagi H, Nagase Y et al. Risk factors for retinopathy associated with interferon alpha-2b and ribavirin combination therapy in patients with chronic hepatitis C. World J Gastroenterol 2006; 12:3756–3759.

  16. Ogata H, Suzuki H, Shimizu K, Ishikawa H, Izumi N, Kurosaki M. Pegylated interferon-associated retinopathy in chronic hepatitis C patients. Jpn J Ophthalmol 2006; 50:293–295.

  17. Chisholm JA, Williams G, Spence E et al. Retinal toxicity during pegylated alpha-interferon therapy for chronic hepatitis C: a multifocal electroretinogram investigation. AlimentPharmacol Ther 2005; 21:723–732.

  18. Cuthbertson FM, Davies M, McKibbin M. Is screening for interferon retinopathy in hepatitis C justified? Br J Ophthalmol 2004; 88: 1518–1520.

  19. Schulman JA, Liang C, Kooragayala LM, King J. Posterior segment complications in patients with hepatitis C treated with interferon and ribavirin. Ophthalmology 2003; 110:437–442.

  20. Jain K, Lam WC, Waheeb S, Thai Q, Heathcote J. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001; 85: 1171–1173.

  21. Saito H, Ebinuma H, Nagata H et al. Interferon-associated retinopathy in a uniform regimen of natural interferon-alpha therapy for chronic hepatitis C. Liver 2001; 21: 192–197.

  22. Sugano S, Suzuki T, Watanabe M, Ohe K, Ishii K, Okajima T. Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C. AmJ Gastroenterol 1998; 93: 2441–2444.

  23. Kawano T, Shigehira M, Uto H et al. Retinal complications during interferon therapy for chronic hepatitis C. Am J Gastroenterol 1996; 91: 309–313.

  24. Hayasaka S, Fujii M, Yamamoto Y, Noda S, Kurome H, Sasaki M. Retinopathy and subconjunctival haemorrhage in patients with chronic viral hepatitis receiving interferon alfa. Br J Ophthalmol 1995; 79: 150–152.

  25. Kim ET, Kim LH, Lee JI, Chin HS. Retinopathy in hepatitis C patients due to combination therapy with pegylated interferon and ribavirin. Jpn J Opthalmol 2009; 53: 598–602.

  26. Ikebe T, Nakatsuka K, Goto M, Sakai Y, Kageyama S. A case of retinopathy induced by intravenous administration of interferon. FoliaOpthalmol Jpn 1990; 41: 2291–2296.

  27. Miller JW, Stinson WG, Folkman J. Regression of experimental iris neovascularization with systemic alfainterferon. Opthalmology 1993; 100: 9–14.

  28. Fung WE. Interferon alfa 2a for treatment of age-related macular degeneration. Am J Opthalmol 1991; 112: 349–350.

  29. Guyer DR, Tiedeman J, Yannuzzi LA et al. Iterferon-associated retinopathy. Arch Opthalmol 1993; 111: 350–356.

  30. Nishiwaki H, Ogura Y, Miyamoto K, Matsuda N, Honda Y. Interferon alpha induces leukocytecapillary trapping in rat retinal microcirculation. Arch Opthalmol 1996; 114: 726–730.

  31. Abe T, Nakajima A, Satoh N et al. Clinical characteristics of hepatitis C virus-associated retinopathy. Jpn JOpthalmol 1995; 39: 411–419.

  32. Jacobi C, Wenkel H, Jacobi A, Korn K, Cursiefen C, Kruse FE. Hepatitis C and ocular surface disease. Am J Opthalmol 2007; 144: 705–711.

Source

ICAAC to Feature Higher Cure Rate Options for Hepatitis C

Medscape Medical News > Conference News

Jim Kling

Aug 28, 2013

DENVER, Colorado — New therapeutic regimens are in the works to permanently curb many hepatitis C infections. Delegates attending the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) will be privy to the latest, cutting-edge information.

"There will be a symposium on what every infectious disease physician should know about treating hepatitis C," Robin Patel, MD, vice chair of the ICAAC program committee, told Medscape Medical News.

Current hepatitis C therapy consists of a protease inhibitor, pegylated interferon, and ribavirin, but the adverse effects of flu-like symptoms and anemia are poorly tolerated by some patients and disqualify others because of comorbidities. "Response rates are very good, but we are limited in who we can treat because of side effects and required length of therapy," explained session comoderator Kimberly Brown, MD, chief of gastroenterology and hepatology at the Henry Ford Hospital in Detroit, Michigan.

New therapies are shorter in duration and eliminate interferon but still lead to high cure rates. New therapies will be administered orally and target hepatitis C genotypes 2 and 3; genotype 1 will be treated with an oral agent, interferon, and ribavirin, but for a shorter period of time. The new regimens should have a higher cure rate than the current regimen, and be applicable to a wider patient population, according to Dr. Brown.

More Cures

The developments are good news for patients. "Cures have been associated with improved liver histology, better liver function, reduced rates of liver cancer, and overall improved survival," said Dr. Brown. "Patients who have previously not been candidates for treatment because of their other medical conditions are looking forward to access to therapies they can tolerate."

The new drugs and regimens have been in development for years, but they are coming to the market more rapidly now because the shorter treatment duration makes it possible to test them more quickly for safety and efficacy.

“This is really a huge change in clinical practice.”

"This is really a huge change in clinical practice," said Dr. Patel.

The ICAAC, which runs from September 9 to 13, will host delegates from 80 different countries. Of the 5000 people expected to attend, about 3000 will be from outside the United States.

"Over the years, the ICAAC has become a very international meeting," said Dr. Patel. "There are people literally from everywhere around the globe. I always learn so much from all the attendees, but especially the international attendees. I think our big international presence is a bit different from other meetings."

Because infections spread from country to country and continent to continent, it is important to stay up to date on current research, pointed out Dr. Patel, who is professor of medicine and microbiology at the Mayo Clinic in Rochester, Minnesota. A microbial agent that is currently absent in the United States could arrive any time, she cautioned.

The meeting will feature plenaries, oral sessions, and posters. In all, more than 1500 abstracts will be presented. Studies will outline which treatment regimens have been modified so that existing drugs can be applied to novel infectious agents.

Pharmacology will have a big presence at the meeting. "You can come up with new ways of giving an old drug that will make it work better or will work against organisms that we didn't traditionally think it would work against, " said Dr. Patel. "This can include a novel way of administering the drug — for instance, using prolonged infusion."

Updates on novel vaccines and vaccine trials will cover various disease organisms, including some with no current vaccines, such as tuberculosis.

There will be a keynote lecture on the future of antimicrobial therapies by Fernando Baquero, MD, from Ramón y Cajal Institute for Health Research in Madrid, Spain. There will also be a lecture on the importance of innovation in the treatment of infectious diseases in developing countries by Trevor Mundel, MD, president of global health at the Bill and Melinda Gates Foundation.

In a special session on Escherichia coli, James Johnson, MD, professor of medicine at the University of Minnesota in Minneapolis, will describe 3 pathotypes of E coli and changes in E coli populations that can lead to increased virulence and antimicrobial resistance.

The ICAAC will have an extensive online presence. Six sessions will be streamed live and, after the meeting, more than 125 sessions will be available online.

For entertainment, conference organizers will host a game show. Infectious disease experts from around the world will be pitted against one another to answer trivia questions. In addition to fun, the show will provide "interesting and educational pieces about infectious diseases," Dr. Patel noted.

Dr. Patel has disclosed no relevant financial relationships. Dr. Brown reports being a consultant for Janssen, Merck, Vertex, Gilead, Salix, and Genentech; being on the speakers' bureau for Gilead; and receiving research support from Merck, Gilead, Mass Biologics, Vertex, and Eisai.

Source

New protease inhibitors showing promise for HIV/HCV coinfection

Provided by Healio

August 28, 2013

This is an exciting time in the treatment of chronic hepatitis C virus infections. As opposed to the antibiotic pipeline, there are a number of new antiviral agents for treatment of hepatitis C in development that may transform the way these patients are treated.

Chronic infection with HCV has emerged as a major cause of morbidity and mortality in those living with HIV infection. Approximately 15% to 30% of patients with HIV in the United States are estimated to be coinfected with HIV and HCV. All patients with HIV/HCV coinfection should be evaluated for HCV therapy because of the more rapid progression of liver disease in those with HCV alone, and because the successful treatment of HCV may also reduce the risk for hepatotoxicity from the use of HAART in these patients.

The treatment for HCV has become increasingly successful, but it is complex, particularly in the HIV coinfected patient who is often on multiple medications and has other barriers to care. Treatment of both HIV and HCV is feasible, although it can be complicated because of the high pill burden, drug interactions and overlapping adverse effects that require careful monitoring.

Available treatment options

The currently available treatment regimens for HCV leave much to be desired. They have poor safety profiles, tolerability issues and low success rates, particularly in the HIV/HCV coinfected patients. While the treatment of HIV has led to reduced mortality during the past 15 years, the treatment of HCV has essentially remained unchanged with pegylated interferon alfa plus ribavirin (PegIFN/RBV).

PegIFN/RBV is recommended for those HIV/HCV coinfected patients who are at the greatest risk for developing liver disease. Pegylated interferon has covalently bound molecules of polyethylene glycol that slow the metabolism of interferon, which permits a weekly dosing schedule, increased serum levels, and improved activity against HCV. The primary goal in HCV treatment is to achieve a sustained viral response, which is defined as an undetectable HCV RNA 24 weeks after the end of therapy. HCV treatment in HIV/HCV coinfected patients is complicated by low rates of treatment initiation, higher rates of contraindications to the medications and a low sustained virologic response in those who are treated for HCV.

The two newest agents available are boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals), which are protease inhibitors specific for HCV. They were approved in the United States and Europe in 2011 for use in combination with PegIFN/RBV among HIV-negative patients with HCV genotype-1 infection only. The approval was based on randomized trials demonstrating that patients achieved a greater sustained viral response with triple therapy compared with standard dual therapy in those who were either treatment-naive or were treated previously, but were nonresponders. Despite not being FDA-approved for treatment of HIV/HCV coinfected patients, use of these agents in this patient population is evolving because of the disappointing success with standard treatment.

J861_2608_12.indd

Evolving therapies for HIV/HCV

A newly published controlled trial conducted by Sulkowski and colleagues randomly assigned 60 patients with HIV and HCV genotype-1 infection to 12 weeks of pegylated interferon alfa-2a and ribavirin, plus either placebo or telaprevir, followed by 36 weeks of peginterferon with ribavirin. After 4 weeks of therapy, 68% of the patients in the telaprevir group had undetectable HCV RNA, whereas 0% of those in the control arm had this response. The sustained viral response was achieved in 74% of patients in the telaprevir treatment group vs. 45% of those in the control group. Reported adverse effects were more common with telaprevir-treated patients, specifically pruritus, dizziness, headache, nausea, rash and anemia. Telaprevir is a substrate and an inhibitor of CYP3A4 and p-glycoprotein enzymes, so interactions with antiretrovirals metabolized by these pathways may occur.

Drug interactions possible

To date, there is less published data available for treatment of HIV/HCV coinfected patients with boceprevir. A phase 2a study was presented at the 19th CROI meeting comparing boceprevir or placebo combined with PegIFN/RBV for the treatment of chronic HCV genotype-1 infection in adults. Ninety-eight patients were given 4 weeks of lead-in treatment with PegIFN/RBV, followed by 44 weeks of combination therapy of boceprevir 800 mg every 8 hours, plus PegIFN/RBV. Patients assigned efavirenz (Sustiva, Bristol-Myers Squibb) or other non-nucleoside reverse transcriptase inhibitors were not enrolled based on previous drug interaction studies.

The sustained viral response at week 12 was higher in the boceprevir treatment group (67.7%) compared with PegIFN/RBV alone (26.5%). Reported adverse effects were common among patients who received boceprevir, with a greater frequency of anemia, neutropenia, pyrexia, decreased appetite, diarrhea, vomiting, and taste disturbances. Boceprevir is metabolized by aldo-keto reductase, but it is also a substrate and inhibitor of CYP3A4/5 and p-glycoprotein enzymes, so drug-drug interactions may occur. When boceprevir is administered with efavirenz, and ritonavir-boosted regimens of atazanavir, darunavir (Prezista, Janssen Therapeutics), lopinavir and raltegravir (Isentress, Merck), bidirectional interactions occur, so concomitant use is not recommended. If patients are taking an HIV protease inhibitor along with boceprevir, then consideration should be given to changing the HIV protease inhibitor or efavirenz to raltegravir.

Telaprevir and boceprevir are the first generation of direct-acting antiviral agents that have improved the sustained viral response for HCV genotype-1 infections. However, PegIFN/RBV treatment is still required. Although use of telaprevir or boceprevir in the HIV/HCV coinfected patient would be considered off-label, consideration should be given to utilizing these agents when HCV treatment is desired because the current evidence shows a substantial improvement in treatment success.

However, use of these medications along with PegIFN/RBV presents several challenges such as substantial side effects, drug-drug interactions and increased costs. There are several direct-acting antiviral agents in the pipeline that will likely yield higher sustained viral response, shorter treatment durations, lower pill burden and improved safety profiles. Until they are available, careful selection of patients who may benefit from a HCV-specific protease inhibitor may help improve the outcomes of the HIV/HCV infected patient.

- By Jeff Brock, PharmD

References:

Ghany MG. Hepatology. 2011;54:1433-1444.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
Sulkowski MS. Ann Intern Med. 2013;159:86-96.
Sulkowski MS. J Infect Dis. 2013;207(suppl 1):s26-s32.

Disclosure: Brock reports no relevant financial disclosures.

Source

Here's Why Mosquitoes Can't Transmit HIV

By Christina Sterbenz | Business Insider – Thu, Aug 22, 2013 11:45 AM EDT

mosquito-on-skin

Getty Images/Tom Ervin

HIV/AIDS kills about 1.6 million people every year, according to the most recent World Health Organization data. Hopefully, high school health classes taught us all how to avoid contraction: Don't have random, unprotected sex or use dirty needles.

Mosquitoes function the same way as hypodermic needles though — They can both inject chemicals and extract blood. And if mosquitoes carry West Nile Virus and other blood-borne diseases, shouldn't they logically be able to transmit HIV, too?

Thankfully, we were reassured that that's not the case. Mosquitoes can not transmit HIV.

"It's definitely not a stupid question," Joe Conlon, former Navy entomologist and current technical advisor for the American Mosquito Control Association, told Business Insider.

Conlon explained that first of all, when a mosquito bites you, it draws your blood into its gut. Acids there kill the HIV virus. Plain and simple.

Even if the mosquito's stomach acids didn't render the virus harmless, it wouldn't be able to get back out of the insect.

That's because mosquitoes use two different tubes to suck up blood and to inject you with saliva that stops your blood from clotting up while it's drinking. Even if a mosquito had virus-containing blood from another human inside it, the blood would never exit the bug through its salivary glands and into your blood stream.

"For a mosquito to transmit a disease, it's gotta pick up the virus. The virus has to survive in the gut and then get outside the gut into the body cavity and then eventually into the salivary glands to be injected into something else. It's a very complicated process, and with HIV, it just doesn't happen," Conlon said.

Malaria parasites, on the other hand, are able to grow in the mosquito gut, then migrate specifically to the salivary glands to continue their lifecycle in another human.

Thank goodness HIV doesn't have that ability. If mosquitoes spread HIV the way they spread Malaria, we'd have a million more deaths every year on our hands.

Source

Japan conducts first operation of liver cells transplant to baby

English.news.cn   2013-08-23 21:18:06

TOKYO, Aug. 23 (Xinhua) -- Japan's National Center for Child Health and Development (NCCHD) said here Friday that it has successfully transplanted liver cells to a baby boy for the first time in Japan.

Akira Matsui, the NCCHD hospital chief, said they have safely conducted the operation that could develop into regenerative medicine using embryo-stem or induce pluripotent stem cells, according to Japan's Kyodo News Agency.

The center used some surplus liver cells left frozen after 14 living liver transplantations it conducted in and after May 2011 in the globally rare case.

The baby, whose liver failed to function properly, received the transplantation on Aug. 10, when he was 11 days old, and on Aug. 13.

The baby could be discharged from the hospital in a month and a half.

Editor: Yang Yi

Source

Janssen’s Simeprevir: Hep C Patients Hope It Is Worth the Wait

Randi Hernandez, MS, Associate Editor/Online

Published Online: Monday, July 8, 2013

Recent actions by the FDA to accelerate simeprevir’s journey to market may be instrumental in helping close the treatment gap for genotype 1 hepatitis C patients in need.



The hepatitis C (HCV) patient population is incredibly complex and diverse. Patients with genotype 1 chronic HCV—especially patients who have relapsed after prior interferon-based treatment—can be particularly difficult to cure.

The current standard of care for genotype 1 chronic HCV involves treatment with pegylated interferon and ribavirin plus a protease inhibitor, but a number of new agents in the pipeline have been creating a great deal of buzz in the HCV community. In fact, many physicians are encouraging their HCV patients to defer treatment (a practice known as “warehousing”) until these new, potentially more effective drugs are approved by the FDA.

These investigational agents reportedly have fewer side effects than the interferon-based therapies and appear to produce significantly higher sustained virologic response (SVR) rates in clinical trials. In addition, most of the new therapies can be taken orally. Before 2011, all HCV treatments required weekly injections.

If these new interferon-free medications are approved, their impact could be widespread. Indeed, uptake of the new therapies is expected to quadruple spending on HCV over the next 3 years, according to a recent drug trend forecast from Express Scripts.

Simeprevir, a protease inhibitor developed by Janssen and Medivir, is 1 of the prospective agents that has been creating a stir in the HCV community The FDA recently granted the drug priority review, which may accelerate its journey to market and help close the treatment gap for patients in need. Janssen is seeking approval for simeprevir administered once daily along with pegylated interferon and ribavirin to treat adult patients with genotype 1 chronic HCV with compensated liver disease.

Janssen’s HCV clinical development program has investigated simeprevir’s potential use in a number of different treatment combinations and HCV patient populations. Specialty Pharmacy Times recently corresponded with Gaston Picchio, hepatitis disease area leader at Janssen, to learn more about the development of simeprevir.

———————————————————-

SPT: What is novel about simeprevir?

GP: Currently available protease inhibitors are administered 3 times daily in the United States and 2 or 3 times daily in the European Union. If simeprevir is approved by the FDA, it would offer the option of a protease inhibitor–based regimen that includes simeprevir taken once daily for 12 weeks in combination with 24 or 48 weeks of pegylated interferon and ribavirin.

SPT: How does simeprevir compare with other protease inhibitors already on the market in terms of sustained virologic response?

GP: Simeprevir has not been investigated in a head-to-head study with other PIs already on the market.

In the QUEST-1 and QUEST-2 Phase 3 trials, the use of simeprevir led to sustained virologic response 12 weeks after the end of treatment (SVR12) in 80% and 81%, respectively, of treatment-naïve genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis, when administered once daily with pegylated interferon and ribavirin. In the PROMISE Phase 3 trial, the use of simeprevir led to SVR12 in 79% of treatment-experienced genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis, when administered once daily with pegylated interferon and ribavirin.

SPT: What is the anticipated FDA approval date for simeprevir? Will the drug’s Priority Review status affect this date?

GP: On March 28, 2013, Janssen announced it had submitted a New Drug Application (NDA) to FDA seeking approval for simeprevir with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients. In May, the FDA granted Priority Review to the NDA for simeprevir. 

Under the Prescription Drug User Fee Act, FDA review will begin approximately 60 days after receipt of the application and will aim to be complete within 6 months from when the review period begins, which for simeprevir is expected to be in late November.

SPT: Tell us something about the drug that may not have been included in the press releases from Janssen that you think is important to note.

GP: Simeprevir is being studied in combination with several direct-acting antiviral agents with different mechanisms of action, with and without ribavirin, as part of multiple interferon-free regimens. These include:

  1. The Phase 2 COSMOS study of simeprevir and Gilead’s nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naïve and previous null-responder genotype 1 HCV patients, including patients with cirrhosis;
  2. A Phase 2 study of simeprevir and Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naïve and previous null-responder genotype 1 HCV patients; and
  3. A Phase 2a trial of simeprevir and TMC647055, Janssen R&D Ireland’s non-nucleoside polymerase inhibitor, with and without ribavirin in treatment-naïve genotype 1a and 1b HCV patients.

SPT: Were pegylated interferon and ribavirin added to therapy in both of the QUEST trials and the PROMISE trial?

GP: In QUEST-1, QUEST-2, and PROMISE, patients were randomized to receive one 150 mg capsule of simeprevir or placebo once daily plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin alone for either 12 or 36 weeks based on response-guided therapy. 

SPT: NDAs were submitted in both United States and Japan for simeprevir. What factors went into filing in these 2 areas in particular?

GP: In February, Janssen submitted a regulatory application to Japanese authorities for approval of simeprevir administered with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C patients who are treatment-naïve, prior non-responders, or relapsed following treatment with pegylated interferon with or without ribavirin. This was the first worldwide regulatory application for simeprevir.

In March, Janssen submitted a New Drug Application to the FDA seeking approval of simeprevir administered once daily with pegylated interferon and ribavirin for the treatment of adult patients with genotype 1 chronic HCV with compensated liver disease.

Additionally, in April, Janssen submitted a Marketing Authorisation Application to the European Medicines Agency seeking approval for simeprevir administered as 1 capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 or genotype 4 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis), with or without HIV-1 co-infection, who are treatment-naïve or who have failed previous interferon-based therapy.

SPT: It has been said that simeprevir treatment will be part of an “interferon-free regimen.” Could you please explain what this means and the benefit of not using an interferon regimen to treat HCV?

GP: As a result of the complexity and diversity of the patient population, a proportion of patients with HCV do not tolerate interferon-containing regimens. Therefore, physicians need multiple treatment options, including interferon-free ones, in order to provide their patients the best possible chance at successful therapy.

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Press Release 28 August 2013

Medivir announces interim results from Cohort 2 of the COSMOS study evaluating Simeprevir and Sofosbuvir in HCV patients with METAVIR scores F3-F4
  • In Hepatitis C patients with advanced liver fibrosis or cirrhosis (METAVIR  F3 or F4) 12 weeks all oral treatment with simeprevir and sofosbuvir with or without ribavirin led to SVR4 rates of 96% and 100%, respectively
  • Once-daily simeprevir and sofosbuvir with or without ribavirin was generally safe and well tolerated

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announced interim results from the second Cohort in the ongoing COSMOS study evaluating a once daily combination of simeprevir and sofosbuvir in hard to cure hepatitis C (HCV) patients.

SVR4 results from the 12 week arms of Cohort 2, including treatment naïve or previous null responder HCV patients all with METAVIR score F3-F4 were reported. Treatment for 12 weeks with simeprevir and sofosbuvir, with or without ribavirin, led to SVR4 rates of 96% and 100%, respectively.

Interim results from Cohort 1 of the COSMOS study, which include only prior null responder HCV patients (METAVIR F0-F2) have been reported earlier and demonstrated SVR8 rates of 96% and 93% after 12 weeks treatment simeprevir and sofosbuvir with and without ribavirin, respectively.

“The high SVR rates seen in genotype 1 prior null responders and treatment-naïve patients with advanced liver disease, in the COSMOS study and the safety profile of the combination are highly encouraging. We look forward to the final results of this study in difficult to cure patients.” says Charlotte Edenius, EVP Development, Medivir AB.

COSMOS - Study Design

COSMOS is a randomized, open label, phase IIa clinical trial evaluating a once-daily combination of the HCV protease inhibitor simeprevir and the nucleotide sofosbuvir with and without ribavirin (RBV) for 12 and 24 weeks. Cohort 1 (n=80) evaluates prior null responder genotype 1 hepatitis C (HCV) patients with METAVIR scores F0-F2 and Cohort 2 (n=87) evaluates prior null responder and treatment-naïve genotype 1 hepatitis C patients with METAVIR scores F3-F4. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver. Liver fibrosis is scored on a four-point scale.

At the time of the interim analysis, SVR4 results were available for all patients (n=41) in the 12 week arms of Cohort 2. In this Cohort, 78.2% of patients had GT1a subtype with 40% of those having a Q80K baseline polymorphism, 79.3% had IL28B CT or TT genotype, 47.1% had Metavir score F4 (cirrhosis) and 54.0% were prior null responders.

In the previously reported Cohort 1, 77.5% of the patients had GT1a subtype with 50% of those having a Q80K baseline polymorphism, 93.7%, had IL28B CT or TT genotype and 58.8% had METAVIR score F2.

COSMOS - Summary Interim Results: Efficacy

Efficacy results with 150 mg simeprevir (SMV) and 400 mg sofosbuvir (SOF) once daily for 12 weeks with or without ribavirin (RBV). Intent-to-treat (ITT) population.

Cohort 1*
Prior null responder HCV patients (METAVIR score F0-F2)

Cohort 2
Prior null responder and treatment naïve HCV patients (METAVIR scores F3 or F4)

 

SMV / SOF+ RBV (n=27)

SMV / SOF (n=14)

SMV / SOF + RBV (n=27)

SMV / SOF(n=14)

SVR4

26/27(96%)

13/14(93%)

26/27(96%)

14/14(100%)

SVR8

26/27(96%)

13/14(93%)

-

-

* Data reported at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in March 2013 in Atlanta, USA. SVR: Sustained Virologic Response 4 or 8 weeks (SVR4 or SVR8) after end of treatment.

There were no viral breakthroughs in either Cohort. At the time of respective cut-off there was 1 relapse in Cohort 2, which was detected 4 weeks after end of treatment. As previously reported there were 2 relapses detected in Cohort 1 both at the 4 week time point after end of treatment.

COSMOS - Summary Interim Results: Safety
Once-daily simeprevir and sofosbuvir with or without ribavirin for 12 weeks was generally considered safe and well tolerated. Among events defined in the protocol as being of special interest, increased bilirubin was observed in 9.3% of the patients in the ribavirin containing arms, compared with 0%, for the non-ribavirin containing arms. Anemia was observed in 13.0% of the patients in the ribavirin containing arms, compared with 0% for the non-ribavirin containing arms.   

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR Mobile: +46 708 537 292.

About Simeprevir
Simeprevir is a new generation NS3/4A protease inhibitor jointly developed by Medivir and Janssen R&D Ireland, part of the Janssen Pharmaceutical Companies for the treatment of chronic hepatitis C in adult patients with compensated liver disease.

For additional information about simeprevir clinical trials, please visit www.clinicaltrials.gov.

About Sofosbuvir
Sofosbuvir (formerly referred to as GS-7977) is a once-daily nucleotide analog polymerase inhibitor for the treatment of HCV infection being developed by Gilead Sciences, Inc. Sofosbuvir is being evaluated as part of multiple therapeutic regimens, including programs with RBV alone and in combination with peg-IFN and RBV.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease and liver transplants, is a rapidly evolving treatment area with a clear need for innovative treatments. Approximately 150 million people are infected with hepatitis C worldwide, and 350,000 people per year die from the disease.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases.

Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

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