IDX184 and IDX19368 - Idenix drops development of hepatitis C drugs

Idenix drops development of 2 hepatitis C drugs

NEW YORK -- Idenix Pharmaceuticals Inc. said Monday that it is ending development of two hepatitis C drugs after regulators told the biopharmaceutical company the drugs would remain on clinical hold.

Shares of the Cambridge, Mass.-based company fell in after-hours trading.

The two Idenix drugs, IDX184 and IDX19368, as well as another drug from Bristol-Myers Squibb Co. called BMS-986094, work in similar ways. All three products are nucleotide inhibitors, meaning they are designed to prevent the hepatitis C virus from making copies of itself.

In August Bristol-Myers halted testing of BMS-986094 after one patient in the clinical trial died of heart failure following treatment. The drugmaker eventually abandoned development of the product.
Idenix has said there are important differences between the drugs, but the Food and Drug Administration placed IDX184 on clinical hold Aug. 16. At the time, it was Idenix's most advanced experimental drug. The FDA also had placed a hold on IDX19368, which hadn't begun patient dosing.

The company submitted cardiac safety data on IDX184 to the FDA in December, but said Monday it received word from the FDA this month that the programs for both IDX184 and IDX19368 would remain on hold.

Shares of the company slipped nearly 6 percent to $4.45 in after-hours trading, after giving up 13 cents, or 2.7 percent, to close at $4.73, during the regular session. The stock is down 42 percent in the past six months.

"Although we are choosing not to continue our IDX184 and IDX19368 programs, we intend to maintain our strong presence in developing nucleotide polymerase inhibitors for HCV (hepatitis C virus) based on our broad discovery platform," said Ron Renaud, Idenix's president and chief executive.

Hepatitis C is a virus that can lead to life-threatening liver damage and is the main cause of liver transplants in the U.S. The disease is spread through the blood, which can happen through sharing intravenous drug needles or having sex with an infected person. There are around 3 million Americans with the disease, which can go undetected for many years until the liver is severely damaged. More people are expected to be diagnosed as the baby boomer generation ages.

That group account for about two-thirds of the 3.2 million Americans thought to be infected.
http://www.cnbc.com/id/100433177

February 4, 2013

 

Idenix Pharmaceuticals Provides Update on IDX184 and IDX19368 Development Programs

 

Management to Host a Conference Call and Webcast Today at 4:30 pm ET

 

CAMBRIDGE, Mass., Feb. 4, 2013 (GLOBE NEWSWIRE) -- Idenix Pharmaceuticals, Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced the Company has elected not to continue its clinical development program for IDX184, a nucleotide polymerase inhibitor in phase IIb testing for the treatment of hepatitis C virus (HCV) infection, or to continue its development of IDX19368, an HCV nucleotide polymerase inhibitor for which the Company had previously filed an IND but had not initiated patient dosing. In August 2012, the U.S. Food and Drug Administration (FDA) placed IDX184 on partial clinical hold and IDX19368 on clinical hold due to cardiac adverse events seen in a competitor's phase II clinical trial of BMS-986094. All three drug candidates are 2′-methyl guanosine nucleotide prodrugs. In December, Idenix completed the submission of requested cardiac safety data for IDX184 to the FDA. Idenix has found no evidence of severe cardiac findings to date. In February, the FDA communicated that the IDX184 and IDX19368 programs would remain on clinical hold, and, as a result, the Company has determined it will not continue the development of these programs.

 

"Although we are choosing not to continue our IDX184 and IDX19368 programs, we intend to maintain our strong presence in developing nucleotide polymerase inhibitors for HCV based on our broad discovery platform," said Ron Renaud, Idenix's President and Chief Executive Officer. "We are completing IND-enabling studies for a uridine nucleotide analog, which is in a sub-class of nucleotide polymerase inhibitors distinct from IDX184, IDX19368 and BMS-986094. We anticipate filing an IND for this next-generation compound during the first half of 2013, and we also plan to continue to advance other preclinical nucleotide prodrugs in earlier-stage development."

Mr. Renaud continued, "Further, we are pleased with the progress of IDX719, our potent, pan-genotypic NS5A inhibitor for HCV. In January 2013, we entered into a non-exclusive collaboration with Janssen Pharmaceuticals, Inc. for the development of all-oral direct-acting antiviral (DAA) HCV combination therapies incorporating IDX719. Following an initial drug-drug interaction study to begin in the first quarter of 2013 and pending approval from regulatory authorities, we expect to begin the first phase II study under this program of a two-DAA regimen, including IDX719."

ABOUT IDENIX
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical Company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.

CONFERENCE CALL AND WEBCAST INFORMATION
Idenix will hold a conference call today at 4:30 p.m. ET. To access the call please dial (877) 640-9809 U.S./Canada or (914) 495-8528 International and enter passcode 97346472 or to listen to a live webcast go to "Events & Presentations" in the Idenix Investor Center at www.idenix.com. A replay of the call will also be available from February 4, 2013, at 7:30 p.m. ET until February 10, 2013, at 11:59 p.m. ET. To access the replay, please dial (855) 859-2056 U.S./Canada or (404) 537-3406 International and enter passcode 97346472. An archived webcast will also be available for two weeks after the call on the Idenix website.

FORWARD-LOOKING STATEMENTS
This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are any expressed or implied statements with respect to: the Company's plans to continue to developing nucleotide polymerase inhibitors for HCV; its clinical development plans for its uridine nucleotide analog drug candidate and IDX719; its plans to advance other preclinical nucleotides; and statements regarding the efficacy and safety of its clinical compounds. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization due to numerous risks inherent in pharmaceutical research and development; management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, preclinical and clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the Company's ability to obtain additional funding required to conduct its research, development and commercialization activities; competition; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other important factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's annual report on Form 10-K for the year ended December 31, 2011 and the quarterly report on Form 10-Q for the quarter ended September 30, 2012, each as filed with the Securities and Exchange Commission (SEC) and in any subsequent periodic or current report that the Company files with the SEC.

All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change.

CONTACT: Idenix Pharmaceuticals Contacts: Teri Dahlman (617) 995-9807 or dahlman.teresa@idenix.com

Source: Idenix Pharmaceuticals

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Gilead Announces SVR Rates from Two Phase 3 Studies of Sofosbuvir (GS-7977) for Hepatitis C

Investment Commentary,  press release from Gilead Sciences below.

Gilead passes two Phase III tests with key hep C pill

Three down, one to go. Gilead Sciences ($GILD) met the main goals of two Phase III studies with its blockbuster hopeful sofosbuvir in patients with hepatitis C virus. The biopharma giant aims to use the results from the late-stage studies as part of a larger data package, which will go to the FDA later this year in the company's bid to advance the first all-oral attack on the liver-damaging disease

Read more: Fierce Biotech

Feb 4 (Reuters)

Gilead Sciences on Monday said two late-stage hepatitis studies have met their goals.

The studies, dubbed Fission and Neutrino, evaluated a 12-week course of once-daily nucleotide sofosbuvir in combination with ribavirin for the Fission study, and in combination with ribavirin and pegylated interferon for the Neutrino study.

The drugs were tested in patients who have chronic hepatitis C virus (HCV) infection and have never been treated for it.

In the Fission study, patients with HCV infection were selected at random to receive either a 12-week course of sofosbuvir plus ribavirin (RBV), or standard of care with 24 weeks of pegylated interferon alfa-2a (peg-IFN) plus RBV.

The study met its primary goal showing that the treatment was just as good as sofosbuvir plus RBV to peg-IFN plus RBV. In the study, 67 percent of patients achieved a sustained virologic response in the sofosbuvir plus RBV treatment group, versus 67 percent in the peg-IFN plus RBV treatment group.

Common adverse events - fatigue, headache, nausea, insomnia and dizziness - occurred more frequently in patients receiving peg-IFN and RBV compared with sofosbuvir and RBV.

In the Neutrino study, patients were given a 12-week course of sofosbuvir, RBV and peg-IFN. This study met its primary goal of achieving superiority, with 90 percent of patients in the study group showing a sustain response versus 60 percent in the control group.

The most common adverse events that occurred in bout 20 percent of patients in the Neutrino study were fatigue, headache, nausea, insomnia and anemia.

http://www.reuters.com/article/2013/02/04/gilead-hepatitis-idUSL1N0B42QN20130204

Gilead Announces Sustained Virologic Response Rates from Two Phase 3 Studies of Sofosbuvir for Hepatitis C

-- FISSION and NEUTRINO Studies Both Meet Primary Endpoints and Will Support Regulatory Filing for Sofosbuvir --

 

FOSTER CITY, Calif.--(BUSINESS WIRE)--Feb. 4, 2013-- Gilead Sciences (Nasdaq:GILD) today announced topline results from two Phase 3 studies, FISSION and NEUTRINO, evaluating a 12-week course of the once-daily nucleotide sofosbuvir in combination with ribavirin (FISSION) and in combination with ribavirin and pegylated interferon (NEUTRINO) among treatment-naïve patients with chronic hepatitis C virus (HCV) infection.
  
In the FISSION study, patients with genotype 2 or 3 HCV infection were randomized to receive either a 12-week course of sofosbuvir plus ribavirin (RBV) or standard of care with 24 weeks of pegylated interferon alfa-2a (peg-IFN) plus RBV. The study met its primary efficacy endpoint of non-inferiority of sofosbuvir plus RBV to peg-IFN plus RBV, with 67 percent (170/253) of patients achieving a sustained virologic response (SVR) in the sofosbuvir plus RBV treatment group versus 67 percent (162/243) in the peg-IFN plus RBV treatment group (95 percent CI for the difference: -7.5 to +8.0 percent for sofosbuvir plus RBV versus peg-IFN plus RBV; predefined criterion for non-inferiority was a lower bound of a two sided 95 percent CI of -15 percent).

All common adverse events (≥10 percent in any group) occurred more frequently in subjects receiving peg-IFN and RBV as compared to sofosbuvir and RBV. The most common adverse events in the sofosbuvir plus RBV arm occurring in ≥10 percent of the patients were fatigue, headache, nausea, insomnia and dizziness.

In the NEUTRINO study, patients with genotype 1, 4, 5 or 6 HCV infection were treated with a 12-week course of sofosbuvir, RBV and peg-IFN. This study met its primary efficacy endpoint of superiority compared to a predefined historic control SVR rate of 60 percent with 90 percent (295/327) of patients achieving SVR12 after completing therapy (P<0.001).

In the NEUTRINO study the most common adverse events that occurred in ≥20 percent of patients were fatigue, headache, nausea, insomnia and anemia.
  
“These data support the favorable clinical profile of sofosbuvir as the backbone of a potent, safe and well-tolerated treatment regimen that is effective across a broad range of HCV patient genotypes,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “The sofosbuvir regimens in these trials allowed us to shorten the duration of effective hepatitis C therapy to just 12 weeks for treatment-naïve patients with genotypes 1 through 6.” 

About FISSION
In FISSION, treatment-naïve HCV genotype 2 and 3 patients were randomized (1:1) to receive either 12 weeks of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day) (n=256) or 24 weeks of peg-IFN (180 μg/week) plus RBV (800 mg/day) (n=243). Overall, 20 percent of patients had compensated cirrhosis (advanced liver disease) and 72 percent had genotype 3 infection. The SVR12 rates in patients receiving sofosbuvir plus RBV were 97 percent for genotype 2 patients and 56 percent for genotype 3 patients. The SVR12 rates in patients receiving peg-IFN plus RBV in this study were 78 percent for genotype 2 patients and 63 percent for genotype 3 patients. Among patients with cirrhosis at baseline who received sofosbuvir/RBV, 47 percent achieved SVR12; 38 percent of cirrhotics who received peg-IFN plus RBV achieved SVR12.
  
With the exception of one patient who was non-compliant, all patients in the sofosbuvir/RBV arm became HCV negative on treatment and relapse accounted for the virologic failures.
Three patients (1 percent) receiving sofosbuvir discontinued treatment due to adverse events compared to 26 patients (11 percent) receiving peg-IFN/RBV.
  
About NEUTRINO
In NEUTRINO, 327 treatment-naïve HCV genotype 1, 4, 5 and 6 patients were treated for 12 weeks with sofosbuvir 400 mg once daily in combination with RBV (1,000 or 1,200 mg/day) and peg-IFN (180 μg/week). Seventeen percent of patients had compensated cirrhosis and 89 percent were infected with genotype 1. Among genotype 1 patients, 89 percent achieved SVR12. Of the 35 patients with genotypes 4, 5 or 6, 97 percent achieved SVR12. Among patients with cirrhosis at baseline, 80 percent achieved SVR12. All patients in this study became HCV RNA negative on treatment and relapse accounted for all virologic failures.

Five patients (2 percent) receiving sofosbuvir in combination with peg-IFN and RBV discontinued treatment due to adverse events.
  
FISSION, NEUTRINO, POSITRON and FUSION are the pivotal Phase 3 studies designed to support an initial regulatory filing for sofosbuvir as part of all-oral therapy with RBV for genotype 2 and 3 treatment-naïve, treatment-experienced and interferon-intolerant HCV patients, and for sofosbuvir in combination with RBV and peg-IFN for genotype 1, 4, 5 and 6 treatment-naïve patients. Topline results from the POSITRON study were announced in November 2012, and topline results from the last Phase 3 study, FUSION, are anticipated later this quarter. Full results from all four studies will be presented at a future scientific conference.

Additional information about these and other ongoing clinical studies can be found at www.clinicaltrials.gov. Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.
  
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
  
Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility that the proportion of patients in the FISSION and NEUTRINO trials will not maintain SVR with longer follow up as favorable as the SVR12 rates reported in this press release. In addition, there is the possibility of unfavorable results from additional clinical trials involving sofosbuvir, including the FUSION trial. Further, we may not release topline results from the FUSION study or file for regulatory approval of sofosbuvir in the timelines currently contemplated. As a result, sofosbuvir may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of the compound if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
  

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Eligibility and Safety of Triple Therapy for Hepatitis C

Research Article Eligibility and Safety of Triple Therapy for Hepatitis C: Lessons Learned from the First Experience in a Real World Setting

Benjamin Maasoumy, Kerstin Port, Antoaneta Angelova Markova, Beatriz Calle Serrano, Magdalena Rogalska-Taranta, Lisa Sollik, Carola Mix, Janina Kirschner, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg mail

Source PLOS ONE

Abstract
Background

HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center.

Methods

All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12.

Results

208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12.

Conclusions

P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.
 

Citation: Maasoumy B, Port K, Markova AA, Serrano BC, Rogalska-Taranta M, et al. (2013) Eligibility and Safety of Triple Therapy for Hepatitis C: Lessons Learned from the First Experience in a Real World Setting. PLoS ONE 8(2): e55285. doi:10.1371/journal.pone.0055285
Editor: John E. Tavis, Saint Louis University, United States of America
   
Received: October 29, 2012; Accepted: December 21, 2012; Published: February 1, 2013

Copyright: © 2013 Maasoumy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: BM was supported by the Integrated Research and Treatment Center Transplantation (IFB-Tx) funded by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF). Publication costs were covered by the DFG (Deutsche Forschungsgemeinschaft)-Project “Open Access Publizieren”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have read the journal’s policy and declare the following conflicts concerning Peg-Interferon alpha-2a (Roche), Peg-Interferon alpha-2b (Merck), Ribavirin (Roche, Merck), Boceprevir (Merck), Telaprevir (Janssen-Cilag): BM received travel grants from Merck and Janssen-Cilag, KP received lecture fees from Roche and Janssen-Cilag, AM declares no conflict, BCS received lecture fees from Merck, MRT declares no conflict, LS declares no conflict, JK declares no conflict, CM declares no conflict, MPM received grants, lectural fees and/or consult fees from Roche, Merck and Janssen-Cilag, HW received grants, lectural fees and/or consult fees from Roche, Merck and Janssen-Cilag. HW is also Academic Editor of PLOS ONE. MC received grants, lectural fees and/or consult fees from Roche, Merck and Janssen-Cilag. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Introduction

Hepatitis C virus (HCV) infection remains a global health burden with approximately 160 million chronically infected individuals worldwide [1] including 8–11 million patients in Europe [2]. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma [3], [4]. An effective antiviral treatment with sustained virological response (SVR) is associated with a significant improvement of the overall clinical outcome in particular at more advanced stages of the disease with severe liver fibrosis [5].

Combination therapy of pegylated interferon alfa and ribavirin (P/R) has been the standard of care since more than 10 years [6]. Recently the approval of the protease inhibitors (PI) boceprevir (BOC) and telaprevir (TLV) as first generation of new direct acting antivirals (DAA) has been a milestone in the therapy of chronic HCV genotype 1 infection. In phase III studies 67–75% of the therapy-naïve patients achieved SVR after a triple therapy consisting of P/R and PI [7], [8]. Even higher SVR rates of up to 80% were observed in those, who experienced a relapse after a previous therapy with P/R [9], [10]. In addition, the overall safety profile appeared to be moderate in these trials [7]–[10]. Despite these encouraging results there still remain some challenges ahead. SVR rates with PI-based triple therapies were much lower in patients with a previous null-response to P/R, especially in those individuals who also had advanced liver fibrosis and cirrhosis [11]. Furthermore, phase III trials do not necessarily reflect real world setting since the study population was highly selective. For example, patients with liver cirrhosis were underrepresented in these studies and those with advanced cirrhosis, low platelets or with additional risk factors like higher age or comorbidities were entirely excluded. Preliminary week 16 results of the French early access program (CUPIC) investigating the new triple therapy only in those with advanced liver fibrosis revealed a totally different safety profile with alarming rates of severe adverse effects (SAE) of up to 49% and a mortality rate of up to 2% [12]. In addition, it has to be considered that a certain part of the infected population is not eligible for the new therapies at the first place. Since current therapy concepts are still based on interferon alfa, several contraindications may prevent antiviral therapy. Various DAAs are currently in preclinical and clinical development and encouraging results have been published recently suggesting the introduction of interferon-free regimens in the near future [13]. Thus, it might well be a preferable alternative to wait for more efficient and safer treatment options in patients with only mild liver disease. In addition, limited resources may prevent treatment of all eligible patients.

The aim of our study was to analyze the eligibility and safety of new triple therapy concepts for the treatment of chronic HCV genotype 1 infection in a real world setting of a German tertiary referral center.

Patients and Methods
Patient Selection

All consecutive patients with chronic HCV genotype 1 infection who were referred to our hepatitis outpatient clinic between June 1^st and November 30^th 2011 were included. Excluded were patients with antiviral treatment at the time of their initial presentation during this time period. All patients were evaluated for a triple therapy concept. Figure 1 gives a schematic overview of the selection algorithm of our study. We recorded all reasons that influenced whether treatment was initiated or not until May 31^st 2012. Patient data were analyzed anonymously.

 

Click To Enlarge

 



               

 

Figure 1. Selection of the study cohort.

doi:10.1371/journal.pone.0055285.g001

This study has been conducted according to the principles expressed in the Declaration of Helsinki. The ethical committee of Hannover Medical School approved this research project and waived the need for written informed consent because of the anonymous evaluation of patient data from patient records. For routinely assessment of IL28B genotype written informed consent was obtained.

Assessment of Baseline Parameters

Routine laboratory parameters like hemoglobin level, platelet counts, ALT, AST and INR were measured by standard procedures. HCV RNA levels were detected using Roche COBAS TaqMan, Version 1. Extraction of the RNA was done automatically by COBAS AmpliPrep (Roche) according to the manufactures instructions. In those patients who gave written informed consent, assessment of the IL28B genotype (rs12979860) was performed as described previously using the Light Mix Kit rs12979860 TIB MOLBIOL [14]. The stage of liver fibrosis is described according to the METAVIR-Score. The majority of patients were classified using transient elastography/Fibroscan (84%). For classification the following cut off values were used: F0/F1:<7.1 kPa; F1/F2: ≥ 7.1 kPa; F2 ≥ 8.7 kPa; F3: ≥ 9.5 kPa; F3/F4: ≥ 12.5 kPa; Definite cirrhosis: ≥ 14.5 kPa [15], [16]. In the remaining cases the stage of fibrosis was determined based on a liver biopsy or obvious clinical parameters indicating liver cirrhosis.

Triple Therapy Concepts

Different triple therapy concepts were considered. Some patients were treated with an individualized lead-in phase followed by the treatment protocol according to the approved label. These individualized concepts were planned for cases of uncertain treatment tolerability or low chances for SVR. In a few patients individualized lead-in phases included episodes with RBV mono-therapy prior to the standard BOC or TLV treatment protocol i.e. in cases of uncertain RBV tolerance or in some patients with thrombocytopenia with the purpose to increase or stabilize platelet count. Davis et al. have shown that IFN-induced decrease of platelet count was less pronounced if RBV is co-administered [17]. In addition we also used a P/R lead-in prior to the TLV label regimen with or without previous RBV mono-therapy. For patients who were started on a triple therapy concept at our hepatitis outpatient clinic until May 31^st 2012 safety and efficacy data were analyzed until treatment week 12 of the standard treatment regimen according to label. In those patients treated with an individualized lead-in concept week 0 of therapy was defined as the start of the approved standard treatment (4 weeks P/R, 24–44 weeks P/R/BOC or 12 weeks P/R/TLV).

Definition of Treatment Failure

Treatment failure was defined as either virological failure or a permanent discontinuation of all antiviral medication due treatment intolerance i.e. in cases of AEs. Virological failure was defined along with the futility rules according to the respective labels: A) HCV RNA level ≥ 1,000 IU/ml at week 4 and/or week 12 of triple therapy including TLV. B) HCV RNA ≥100 IU/ml at treatment week 12 of a BOC protocol. C) Virological breakthrough was defined as an increase of HCV RNA level of>1 log.

In addition, patients with liver cirrhosis and previous null-response to P/R were also classified as virological failure, if they achieved<1 log decline of HCV RNA after a four-week lead-in phase with P/R. According to previously published studies chances for SVR have to be estimated as very low in these cases [18]. Thus we decided not to continue treatment due to an inadequate risk/benefit ratio.

Statistical Analysis

All data are either presented as absolute numbers or as mean ± SD unless otherwise stated. Continuous data we analyzed with t-test and categorical data with χ2 tests.

 

Results

Patients and Evaluation Process

Baseline characteristics of the study cohort are shown in Table 1. 55% of the patients were male. Mean age was 52.9 years. The majority of patients were infected with HCV genotype 1b (62%) and the predominant IL28B genotype was CT (44%), whereas IL28B CC was present in only 18% of the individuals. Only 40% of the patients were treatment-naïve. Platelet counts below 150/nl were detected in 84 (40%) patients and 35 patients (17%) had platelets of<90/nl. The mean hemoglobin concentration was 14.3 g/dl including 21 individuals with hemoglobin levels<13 g/dl (men) or 12 g/dl (women). Baseline serum ALT levels were elevated in the majority of patients but only 15 patients had ALT levels of more than five times the upper limit of normal (ULN). Advanced liver fibrosis (F3/F4 according to METAVIR) was present in 133 (64%) individuals including 88 (42%) patients with definite cirrhosis. Only nine patients (4.3%) had a Child-Pugh Score of B indicating pre-selection of patients referred for antiviral therapy to our hepatitis treatment unit. Patients with decompensated cirrhosis are being referred to our liver transplant outpatient clinic.

 

Click To Enlarge

 



 

               

Table 1. Baseline characteristics of the study cohort.

doi:10.1371/journal.pone.0055285.t001

Of the 208 patients, eleven were included into clinical phase II or III trials and were therefore not further considered for this analysis. Treatment was not initiated in 103 patients. The remaining 94 patients were considered for a triple therapy concept, of which eight preferred treatment at other centers. Thus, treatment was started in 86 patients at our hepatitis outpatient clinic. Patients who received antiviral therapy at our center were more likely to be male, to be infected with HCV genotype 1b, to have higher ALT levels and to show a more advanced stage of liver fibrosis than patients who were not treated. Treated patients were more often patients with previous treatment failure, which explains the lower prevalence of IL28B CC in the treated population (Table 1).

 

Factors that Influenced the Decision not to Start P/R/PI

Four key factors were considered to calculate the risk/benefit ratio during evaluation process: (i) Therapy-associated safety concerns, (ii) chances for SVR, (iii) treatment urgency and (iv) nonmedical patient related reasons. Sometimes one of these factors completely dominated final decision i.e. in some patients with obvious interferon intolerance. Still, in many patients two or more of these factors significantly influenced the final decision indicating the complexity of the evaluation process.

1. In 66 (64%) patients risk of SAEs during P/R/PI treatment was considerable. This was majorly related to comorbidities affecting 48 (47%) patients, most frequently the risk of exacerbation of an autoimmune reaction during treatment with interferon alfa since 18 patients were either recipients of organ transplants or had a history of an autoimmune disease. Severe psychological instability and disorders like severe depression i.e. with a history of a suicidal attempt or psychosis were relevant in 15 cases. Cardiovascular diseases i.e. a history of heart attacks, bypass or present congestive heart failure were important in eight and a low level of hemoglobin in seven individuals. Other comorbidities as impaired renal function, thyroidal dysfunction or severe diabetes were only relevant in a few patients. Besides comorbidities liver related morbidity played an essential role as well. Overall, in 10 patients with an advanced stage of liver disease risk of hepatic decompensation during antiviral treatment was estimated as to high. Thrombocytopenia had a significant impact on the negative evaluation in 12 subjects. In addition, advanced age (> 70 years) linked to a limited physical capacity was a reason that prevented treatment in eight patients. Six individuals reported poor tolerability of the previous treatment. Two patients were pregnant at the time of presentation.(ii) In seven (6.8%) patients mainly with advanced fibrosis, a history of treatment failures and further negative predictors, the chance to achieve SVR was considered to be too low to reach an acceptable risk/benefit ratio.
2. Thirty-one (30%) patients were considered to have no urgent treatment indication in our view, as the stage of liver fibrosis was not advanced limiting the benefit of an immediate treatment.
3. Finally, nonmedical patient related reasons played an important role in thirty-two patients (31%). All patients were widely informed about their liver related prognosis, risks, benefits and conditions of current triple therapy concepts as well as the chances for alternative treatment options that may be accessible in the future. Eighteen patients decided to wait for future treatment options. Twelve patients were either completely lost to follow up or missed appointments and were considered as incompliant. In seven cases a triple therapy concept was not possible due to social or work related reasons i.e. two subjects were professional drivers. In Table 2 we have listed the factors that influenced treatment decision.

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Table 2. Factors that influenced the decision not to treat with P/R/PI.
doi:10.1371/journal.pone.0055285.t002

 

 

Safety and Effort of Triple Therapy

Overall, 406 visits during 1022 treatment weeks (one visit every 2.5 weeks) were documented. During the investigated time period several cases of cytopenia occurred that required dose modifications of the antiviral therapy. Thirty-two patients (37%) experienced at least one episode of significant anemia (Hb<10 g/dl). In 12 (14%) of these patients, hemoglobin level dropped to a concentration of less than 8.5 g/dl. In 12 patients anemia was countered by blood transfusions. Less commonly thrombocytopenia (20%) and neutropenia (12%) reached a stage where dose modifications are recommended. Ribavirin dose reduction was required in 31 patients (36%) predominantly due to anemia. In 11 patients (13%) a temporary discontinuation became necessary. The dosage of pegylated interferon alfa was reduced in 20 (23%) patients and six (7%) required a temporary discontinuation.

Twenty-one hospitalizations related to antiviral therapy have been documented in 16 patients (19%). Most frequent reason was a severe or symptomatic anemia (62%), followed by infections (14%) and hepatic decompensations (14%). Overall, the rate of treatment-associated hospitalization was estimated as 0.99/patient treatment year. The 16 patients who were referred to hospital were at a similar age as the remaining patients (53.9 vs. 53.4 years) but more likely to have a more advanced liver disease at baseline indicated by a significantly higher MELD-Score (9.6 vs. 7.3) and a lower platelet count (107.5/nl vs. 169.9/nl). Platelets<110/nl (48% hospitalized patients) and>five points in the Child-Pugh Score (45% hospitalized patients) were associated with a high risk of hospitalization. In contrast, only four out of 60 patients (6.7%) who had none of the above-mentioned risk factors required hospitalization (Table 3).

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Table 3. Baseline characteristics of patients who were hospitalized until week 12.
doi:10.1371/journal.pone.0055285.t003

 

Treatment Failure at Week 12

Of the 86 patients that were started on a triple therapy concept 20 (23%) dropped out before week 12 of the approved treatment regimen. In 10 of these patients treatment was stopped due to a virological failure, while seven had to discontinue because of AEs and one patient died after a gastrointestinal infection. In two patients, both poor tolerability as well as poor virological response contributed equally. Of those, who maintained on therapy, four patients had to stop at week 12 because they met futility criteria. In addition, one patient experienced a SAE at week 12 of therapy that resulted in a permanent discontinuation. As a result, 25 out of 86 patients (29%) had to be classified as a treatment failure at week 12 (Figure 2).
 

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Figure 2. Treatment failures during the observed time period.

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Patients that discontinued had a significantly lower platelet count at baseline (123/nl vs. 172/nl, p<0.001). More than half of the patients with a baseline platelet count of less than 110/nl had to be classified as a treatment failure at week 12 of therapy. Patients infected with HCV genotype 1a were more likely to experience a treatment failure (p<0.05). IL28B CC genotype was associated with a superior treatment outcome. None of the 10 patients with the IL28B CC genotype that started a triple therapy experienced a virological failure until week 12 of treatment. However, one patient experienced a lethal AE. No significant difference could be observed between TLV and BOC in those receiving at least one dose of PI (p = 0.73) (Table 4).

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Table 4. Baseline characteristics of patients with and without treatment failure until week 12.
doi:10.1371/journal.pone.0055285.t004

Overall, 128 patients (65%) were either not eligible or experienced a treatment failure at week 12 (Figure 3).

 

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Figure 3. Overall outcome of the evaluation process and treatment period.
doi:10.1371/journal.pone.0055285.g003

 

Discussion

Pivotal phase III trials investigating the efficacy and safety of triple therapy including boceprevir or telaprevir showed excellent response rates with a reasonable safety profile. However, considerable concerns have been raised to what extend the new treatment concepts can be translated into clinical practice as only highly selected patients qualified for registration trials [11]. At this stage it remains unclear what proportion of the total HCV genotype 1-infected population is eligible for treatment and which patients will subsequently benefit from the novel therapeutic options. Here we describe our initial experience in selecting patients for and treating with PI-based antiviral treatment regimens. Selection of patients for treatment was based on four main factors, which were treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. It has to be considered that the here studied patient population has already been preselected by the referral approach. Patients with decompensated cirrhosis and other obvious contraindications for therapy are managed by other clinics at our center, i.e. by the liver transplant unit (Figure 1). Still, so-called difficult-to-treat patients including those with advanced liver disease, previous treatment failures and individuals with comorbidities were overrepresented in this cohort. Subsequently, safety concerns for P/R/PI played a major role for not selecting patients for therapy. On the other side, mild liver disease and patient’s wish were also frequent reasons for not initiating therapy at this stage with more convenient interferon free regimens on the horizon (11, 13). Interestingly, poor chance to achieve SVR played a minor role not to start therapy mainly due to high expectations in efficacy and the opportunity of the lead-in phase. In the end, treatment was not initiated in half of the patients, including several patients with the most urgent medical need as well as individuals likely being the easiest to treat. Considering the referral approach to our hepatitis treatment unit, we suggest that the proportion of HCV-infected patients not qualifying for current treatment options can be estimated to be even higher than 50% if the here used evaluation criteria are applied.

Management of adverse events was an enormous effort in this cohort. Patients were seen almost every two weeks at our outpatient clinic and the overall frequency of consultations was certainly considerably higher since we did not assess visits at the general practitioner, local hospitals and telephone calls. Although we only analyzed the first treatment period, hospitalization became already necessary in nearly one out of five patients. Anemia was the most prevalent side effect requiring frequent hemoglobin monitoring and blood transfusions.

Infections represent the most serious complication of interferon alfa-based treatment of hepatitis C. Death of one patient during the first 12-week treatment period and an additional death of a patient at week 14 was related to gastrointestinal infection with sepsis.

In contrast to the registration trials a much larger proportion of patients had to stop therapy early during therapy. Both virological treatment failure and adverse events accounted for these early treatment discontinuations. An obvious explanation for virological failure might be the large number of patients with F3/F4 fibrosis and previous treatment failure [19]. In addition, advanced liver fibrosis has been shown to be linked to a higher incidence of adverse events [12]. In our cohort HCV genotype 1a infection and low platelet counts were associated with early treatment failure. The impact of platelet counts suggests that the negative predictive value of liver cirrhosis increases with more advanced stages of cirrhosis.

Platelet counts also predicted the need for hospitalizations during therapy further highlighting the value of this specific marker in the context of new antiviral therapies. Of note only six out of 14 patients with platelet counts of less than 90/nl, which is the recommended cut-off level for treatment eligibility with P/R [20], managed to pass week 12 futility rules. Our data indicate that even higher platelet levels have to be considered as a predictive marker for poor treatment outcome since six out of seven patients with a baseline platelet count between 90 and 110/nl either needed to be referred to hospital and/or experienced a virological failure. Platelets<110/nl were also significantly associated with treatment failure at week 12. By further follow-up, 70% of patients with platelets<110/nl required hospitalization at some point and 2 of these patients died (data not shown). We therefore suggest that low platelet count of<110/nl is a marker for advanced liver disease with a high risk for serious adverse events during P/R/PI treatment. In addition, more than 5 points in the Child-Pugh score was another valuable predictive marker for adverse events and hospitalization.

Our study was not designed to directly compare the two available PIs. Many of the observed adverse events are certainly related to P/R since some patients discontinued treatment even before taking a single dose of a PI. It was not the aim of this study to attribute treatment-associated risk and effort to a single component of the antiviral therapy regimen. We could already demonstrate that, in contrast to pivotal registration trials, safety and efficacy of currently available antiviral regimens are limited in a real world cohort. In addition treatment required enormous recourses both in terms of time and monitoring visits as well as by the management of side effects. On the other side HCV RNA became undetectable in most of the patients who reached week 12 of therapy. Thus it is crucial to identify reliable markers for the prediction of both safety and efficacy. In our opinion a lead-in phase regardless of the later used PI can be a valuable tool in patients with uncertain treatment tolerability and offer additional information on chances for SVR. Early discontinuation may prevent SAEs and even some lethal complications. According to our data platelet count and Child-Pugh Score, markers for advanced liver disease, seem to be valuable tools to identify patients with a high therapy associated risk and a poor treatment outcome. However, specific cut-offs to determine ineligibility for triple therapy (i.e. platelet count <110/nl, Child-Pugh Score >5) warrants further validation in larger cohorts. Still, the risk/benefit ratio should be well calculated in patients with advanced cirrhosis indicated by such risk factors. If treatment will be initiated in such patients a very close monitoring and early management of adverse events is essential.

We here presented our first experiences with new triple therapies, rising considerable safety concerns at least in certain populations. However, overall safety of these new treatments will certainly improve with more “real world” data and more experience gained regarding the optimal management of adverse events in particular anemia. According to recently published data RBV dose reduction as first line strategy is done much more rapidly in our center, which seemed to decrease the number of hospitalizations in following cohorts [21]. More effective strategies to meet severe infections need to be developed. High efficacy of PI-based therapies raises high ambitions to treat a huge amount of patients. This may lead to an underestimation of risk factors. Our data suggest, that patients need to be selected very carefully since a sensible patient selection is the first and may be the most important step to ensure a reasonable safety profile and a high efficacy. From a retrospective point of view we might slightly shift our patient selection to a cohort with less advanced liver disease. In our opinion ideal candidates for current PI based therapies are those with middle stage fibrosis (F2–F3) and well-compensated cirrhosis as well as prevalence of some positive predictors for SVR. Including some more easier-to-treat patients would certainly reduce the huge effort that is required for therapy management. A more balanced patient cohort may also permit to treat a higher number of HCV-infected individuals even more cost-effectively. Conclusions of our study are supported by a recently published, huge epidemiologic study comparing different approaches to the initiation of antiviral treatment. Here it has been demonstrated that starting treatment as soon as liver fibrosis has reached F2 might be a more effective strategy than delaying treatment until higher stages of fibrosis have been established [22]. We here identified valuable pretreatment markers to predict both safety and efficacy, which may help to select the appropriate patients in the future. However, further studies will certainly be necessary to develop a valuable scoring system for this selection process. According to the poor outcome of patients with advanced disease and the small benefit for those at very early stages of the disease, it has to be concluded that despite the improvements that have been achieved during the last year safer and more efficient treatment options are still urgently needed.

Acknowledgments

The authors thank Janet Cornberg for her help with the data assessment.

Author Contributions
Assesment of data: BM KP AM BCS MRT LS CM JK. Conceived and designed the experiments: BM MPM HW MC. Analyzed the data: BM HW MC. Wrote the paper: BM MPM HW MC.

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8. Poordad F, McCone JJ, Bacon BR, Bruno S, Manns MP, et al. (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364: 1195–1206. doi: 10.1056/NEJMoa1010494. Find this article online
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Hepatitis C -Frequency of Thyroid Dysfunctions during Interferon Alpha Treatment

Frequency of Thyroid Dysfunctions during Interferon Alpha Treatment of Single and Combination Therapy in Hepatitis C Virus-Infected Patients: A Systematic Review Based Analysis

Source - PLOS ONE

Abstract

Background

Thyroid dysfunction is the commonest endocrinopathy associated with HCV infection due to interferon-based treatment. This comprehensive and systematic review presents the available evidence for newly developed thyroid antibodies and dysfunctions during interferon treatment (both single and combination) in HCV patients.

Methodology/Principal Findings
This systematic review was conducted in accordance with the PRISMA guidelines. The data generated were used to analyze the risk for thyroid dysfunctions during interferon (IFN) treatment in HCV patients. There was a wide range in the incidence of newly developed thyroid dysfunctions and thyroid antibodies in HCV patients during IFN treatment (both single and combination). The wide range of incidence also denoted the possibility of factors other than IFN treatment for thyroid-related abnormalities in HCV patients. These other factors include HCV viral factors, genetic predisposition, environmental factors, and patho-physiological factors. Variations in IFN dosage, treatment duration of IFN, definition/criteria followed in each study for thyroid dysfunction and irregular thyroid function testing during treatment in different studies influence the outcome of the single studies and jeopardise the validity of a pooled risk estimate of side effects of thyroid dysfunction. Importantly, reports differ as to whether the thyroid-related side effects disappear totally after withdrawal of the IFN treatment.

Conclusions/Significance
The present review shows that there is a wide range in the incidence of newly developed thyroid dysfunctions and thyroid antibodies in IFN treated HCV patients. This is a comprehensive attempt to collate relevant data from 56 publications across several nations about IFN (both mono and combination therapy) related thyroid dysfunction among HCV patients. The role of each factor in causing thyroid dysfunctions in HCV patients treated with IFN should be analyzed in detail in future studies, for a better understanding of the problem and sounder clinical management of the disease.
 

Citation: Nair Kesavachandran C, Haamann F, Nienhaus A (2013) Frequency of Thyroid
Dysfunctions during Interferon Alpha Treatment of Single and Combination Therapy in Hepatitis C Virus-Infected Patients: A Systematic Review Based Analysis. PLoS ONE 8(2): e55364. doi:10.1371/journal.pone.0055364

Editor: Valli De Re, Centro di Riferimento Oncologico, IRCCS National Cancer Institute, Italy

Received: September 7, 2012; Accepted: December 21, 2012; Published: February 1, 2013

Copyright: © 2013 Nair Kesavachandran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This research project was funded by the German Accident Insurance Institution for the Health and Welfare Services (BGW), Hamburg, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

As per the World Health Organization (WHO), nearly 3% of the global population suffers from Hepatitis C Virus (HCV) infection, prevalence of the same ranging from 0.1–5% is reported for different European countries [1], [2]. Interferon alpha (IFN α) - singly and in combination with other drugs - has been popularly used to treat the HCV infection [3], [4]. However, despite its success, this treatment causes several side effects in the HCV patients, including influenza-like symptoms, hematological effects, neuropsychiatric symptoms and, significantly, various thyroid-associated diseases [5]. Severe and even life-threatening side effects of IFN reportedly occur in 0.1 to 1% of patients treated; these include thyroid, visual, auditory, renal and cardiac impairment and pulmonary interstitial fibrosis [6], [7].

A higher prevalence of thyroid disorders has been reported in HCV-infected patients than in the general population [8]. Indeed, thyroid dysfunction is the most common endocrinopathy associated with the IFN-based treatment of HCV infection [7]. Interferon-induced thyroiditis (IIT) is a major clinical problem for patients who receive IFN therapy, with complications like thyrotoxicosis being especially severe [9], [10], [11], [12]. Thyroid diseases have been reported due to treatment based on IFN α as well as IFN ß [4].

IFN has important immunomodulatory properties due to which it can induce autoimmune phenomena like autoimmune thyroiditis with hypo - or hyperthyroidism [8]. Autoimmune thyroiditis has been reported in up to 20% of the patients during IFN-based therapies in a review article [13]. Thyroid dysfunction may also manifest as destructive thyrotoxicosis, Graves’ thyrotoxicosis and hypothyroidism. These pathological conditions may occur in the same patient as a result of different immunological effects of IFNα therapy on the thyroid gland [14]. IFN treatment may also induce a subtle defect in the thyroidal organification of iodide, thus further impairing hormone synthesis [9].
A common drug used with IFN α in HCV treatment is Ribavirin (RIBA) [15]. RIBA is a synthetic analog of guanoside that induces the Th1 cytokines in the immune response against HCV infection [15].When undergoing treatment, IFN and ribavirin synergize to stimulate the immune system in order to eradicate the virus [7]. One innocent bystander in this accentuated response is the thyroid [7].
Such is the correlation between the therapy and the gland malfunction that clinicians have often reduced the dose or sometimes even discontinued IFN α treatment in patients who develop thyroid dysfunction, thus possibly compromising the therapeutic response [16]. The current state of art treatment for HCV patients is a combination of pegylated IFN alpha (2a or 2b) and Ribavirin.
This background, a comprehensive and systematic review presenting the available evidence for the newly developed thyroid antibodies (Tab) and dysfunctions during interferon treatment (both single and combination) in HCV patients was conceived. We have included herein 19591 case studies/patient histories (16149 from mono-therapy and 3442 from combination therapy) from 56 publications (31 mono and 25 combination treatments) to understand the frequency of risk associated with thyroid dysfunctions during IFN treatment (single and combination) among HCV patients.
To the best of our knowledge, this systematic review has included the highest number of case studies and publications to analyze the risk of thyroid dysfunction in patients during both single and combination IFN α treatment compared to earlier studies that were based either on single or combination therapy of IFN α or dealt with limited numbers of patients and publications in earlier narrative and systematic reviews with meta-analysis [7], [17], [18], [19], [20]. The study also analyzes the pre-disposing factors that may cause thyroid dysfunctions in HCV patients.

Methods

Search Strategy and Screening

A systematic literature search was performed using PubMed, EMBASE and Google. The keywords used were ‘interferon treatment’ combined with ‘thyroid’, ‘hepatitis C’, ‘antibodies’, ‘autoimmunity’, ‘dysfunctions’, ‘pegylated’, ‘meta-analysis’, ‘pathogenesis’, ‘molecular mimicry’, ‘genetic predisposition’, ‘Levovirin’, ‘consensus Interferon’, ‘diagnosis’, ‘management’ and ‘ribavirin’ for the period between January 1990 to November 2012. Identification, screening, eligibility and inclusion of database for the study have been depicted in a flow chart (Fig. 1). The flow chart was developed on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for reporting databases in systematic reviews [21]. The systematic review protocol for PRISMA was based on the information available at http://www.prisma-statement.org/statemen​t.htm.

 

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Figure 1. Identification, screening, eligibility and inclusion of data sources for the study.

 

doi:10.1371/journal.pone.0055364.g001

The inclusion of publications for the present study was based on the following criteria:

1. Design of study: Case-control, prospective, retrospective
2. Availability of data on thyroid disease ie., newly developed thyroid dysfunctions (hyper and hypothyroidism),newly developed thyroid antibody (Tab’s) during IFN treatment
3. Treatment must include at least one of the following therapy regimes:

1. IFN α
2. IFN α+RIBA
3. IFN in combination with RIBA [IFNα 2b+RIBA]
4. Consensus Interferon-1 (IFN α Con-1)+RIBA
5. Pegylated IFN (PEG-IFN) α+RIBA
6. Pegylated IFN (PEG-IFN) α+Levovirin
7. Consensus Interferon (CIFN) α

German and English Language articles were screened for the study.

Study Quality
The methodological quality of the literature was assessed as “moderate” or “good”. A study was deemed to be of “moderate” quality if it did not include any of the key words given for search and did not follow the inclusion criteria of publication mentioned above. A study was rated as “good” if publications were relevant to the topic, any two of the above keywords were mentioned in the publication, and it followed the inclusion criteria discussed previously. Only the “good” quality publications were selected for the study.

Results

Frequency of Occurrence of Thyroid-related Side Effects among HCV Patients Undergoing IFNα Treatment (Mono and Combination Therapy)

The study found 168 publications from PUBMED and EMBASE and 114 documents from other sources like Google during the systematic database search. Of these, 56 publications were synthesized on the basis of the inclusion criteria and PRISMA guidelines (Fig 1). Table 1 reports the frequency of newly developed thyroid antibodies and thyroid dysfunctions in HCV patients from 31 previous studies, with single and 25 studies pertaining to combination IFN therapy (Table 2). 16149 patients (mono-therapy) and 3442 patients (combination therapy) from different case studies and patient histories were included in the risk analysis from 31and 25 studies from mono-therapy and combination therapy respectively.

 

 

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Table 1. Frequency of newly developed thyroid antibodies and clinical thyroid Disease (Including Autoimmune IIT and Non-Autoimmune IIT) in Patients with Hepatitis C Infection treated with mono therapy (IFN α, Ribavirin) treatment.

doi:10.1371/journal.pone.0055364.t001

 

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Table 2. Frequency of newly developed thyroid antibodies and clinical thyroid Disease (Including Autoimmune IIT and Non-Autoimmune IIT) in Patients with Hepatitis C Infection treated with combination therapy (IFN α (pegylated or non-pegylated+Ribavirin or Levovirin) treatment.

doi:10.1371/journal.pone.0055364.t002

 

Mono-therapy of IFN

The frequency of newly developed Tab during IFN mono-treatment was in the range between 1.9–47% in 16 studies whereas the newly developed thyroid dysfunction ranged from 0.6–34.6% in 30 studies (Table 1). From 31 studies and out of a total of 16149 patients, the overall frequency of newly developed thyroid dysfunction during IFN treatment (mono-therapy) was 2.7% (Table 1). In one study, the frequency was not reported. From 16 studies and 1656 patients, the overall frequency of occurrence of newly developed Tab during IFN therapy was 20.6% (Table 1). In 15 studies, the frequency of thyroid antibodies was not reported.

 

Combination Therapy for IFN

The frequency of newly developed Tab during IFN treatment in combination therapy was in the range between 0–33.3% in 13 studies whereas the newly developed thyroid dysfunction ranged from 0–100% in 25 studies (Table 2). From 25 studies and out of a total of 3442 patients, the overall frequency of newly developed thyroid dysfunction during IFN treatment (combination therapy) was 12.8% (Table 2). From 13 studies and 1292 patients, the overall frequency of occurrence of newly developed Tab during IFN therapy was 5% (Table 2). There are 3 studies with no newly developed thyroid dysfunction and 2 studies with no Tabs during combination treatment. In 12 studies, the frequency of thyroid antibodies was not reported.

 

Country Wide Publications on Mono-therapy

The 31 publications (mono-therapy) included studies from Japan (8 studies), USA (1 studies), France (3 studies), Italy (12 studies), Spain (2 studies), Norway (1 study), China (1 study), Australia (1 study), Germany (1 study), Pakistan (1 study) and Canada (1 study). 13 studies from Italy showed frequency of the newly developed Tab and thyroid dysfunctions in the range of 9.3–47% and 4–34.6%, respectively. Eight studies from Japan showed the frequency in the range of 1.9–32.8% for newly developed thyroid antibody and 2.7–14.3% for thyroid dysfunctions. Studies from other countries (with 1–3 studies) also demonstrated similar wide variations in the frequency of newly developed thyroid antibody and thyroid dysfunctions (Table 1).

 

Country Wide Publications on Combination Therapy

The 25 publications (combination therapy) included studies from USA (1 study), Italy (1 study), Brazil (2 studies),UK (1 study), China (1 study), Australia (5 studies), Taiwan (2 study), Germany (4 studies), Pakistan (2 studies), Poland (2 studies), Greece (2 studies), Korea (1 study) and Turkey (1 study). 5 studies from Australia showed frequency of the newly developed Tab and thyroid dysfunctions in the range of 0–5% and 0–33.4%, respectively. Four studies from Germany showed the frequency in the range of 5–11.5% for newly developed thyroid antibody and 7.5–18.6% for thyroid dysfunctions. Studies from other countries (with 1–3 studies) also demonstrated similar wide variations in the frequency of newly developed thyroid antibody and thyroid dysfunctions (Table 2).

 

Treatment-specific Thyroid-related Side Effects in HCV Patients Undergoing Single or Combination IFN α Treatment

 

Single IFN α treatment.

Intriguingly, neither the IFN α dosage nor the virological treatment response was found to be related to the incidence of thyroid dysfunction as per one report [21]. The prevalence of thyrotoxicosis in HCV patients treated with IFN α was reported by another study to be 2–3% of the treated patients [14]. Another study concluded that though positive thyroid antibodies with normal thyroid function tests were the most common findings in patients treated with IFN α, thyroid dysfunction was usually described in no more than 15% of all the treated patients [18]. An earlier study [22] conducted on patients undergoing IFN alpha therapy for chronic HCV and with no evidence of pre-existing thyroid disease did not report any thyroid autoantibodies after IFN treatment. As per one report, 15% of the patients treated with IFN α showed thyroid dysfunctions [10].

 

In contrast, the long-acting pegylated IFNα (PIFN) treatment had a lower incidence of thyroid-related side effects compared to non-pegylated IFNα [23], [5]. In patients treated with IFNα, hypothyroidism occurred in 2.4–19% of the patients, especially in those with pre-existing thyroid autoimmunity [24], [4]. The duration of IFN treatment was found to be related to the occurrence of thyroid dysfunction [25]. Another study reported that IFNα could induce both autoimmune and non-autoimmune thyroiditis [26]. Treatment of CIFN α alone showed 6.5% patients with newly developed thyroid antibodies and 11.9% patients with thyroid dysfunctions in a single study (Table 1). In HCV patients, therapy with IFN α and Consensus Interferon (CIFN), namely IFN α con-1 had higher cytotoxic effects on thyroid cells and a higher incidence of destructive thyroiditis than therapy with IFN α [10]. RIBA treatment alone resulted in 23.6% patients with new thyroid antibodies and 15.3% patients with thyroid dysfunctions (Table 1).

 

Combination treatment of IFN α (Pegylated or non-pegylated+RIBA or Levovirin.

Patients treated with IFN α+RIBA have a relative risk of 4.3 for developing thyroid dysfunction [27]. Hypothyroidism was found to be more frequent in patients undergoing this treatment. The risk of developing thyroid autoimmunity after treatment of IFN+RIBA can be a consequence of enhancement of the Th1 immune response, which induces cell-mediated cytotoxicity [27].

 

Our study further brings to front the following findings observed in an earlier study:(i) the addition of RIBA to IFN α therapy for Chronic Hepatitis C (CHC) was associated with a higher risk of hypothyroidism, (ii) Patients without thyroid autoantibodies after treatment with IFN α alone were protected from the development of thyroid autoimmunity and/or dysfunction in a second course of antiviral treatment with IFN α+RIBA, (iii) the development of hypothyroidism in patients with thyroid autoantibodies undergoing treatment with IFN α+RIBA was significantly associated with the long-term remission of CHC [27].The result of the meta-analysis with only four studies and 1231 subjects showed high risk of thyroid dysfunction using Pegylated IFN (PIFN) compared to ribavirin in combination with IFN [17].This study further suggested that the pegylation of IFN, in combination with RBV, had no aggravating effect on thyroid diseases in the hepatitis C-afflicted population [17].

 

Pre-Disposing Factors Causing Thyroid-related Side Effects in HCV Patients

As discussed earlier, a wide range in the prevalence of thyroid-related side effects was observed in the same study locations - for instance, in Italy and Japan (Table 1).This shows that there is the possibility of factors other than IFN playing a role. The other factors like pathophysiological factors, gender and ethnicity, genetic predisposition, HCV viral factors and environmental factors can also lead to thyroid dysfunctions during IFN treatment, which was explained in detail below.

 

Pathophysiological factors.

Pre-existing thyroid autoimmunity can emerge as an important risk factor for developing thyroid dysfunction during IFN therapy. The presence of thyroid peroxidase antibodies (TPO-Ab) before treatment was identified as a risk factor for the incidence of thyroid disease in 60% of HCV patients receiving IFN α [28]. The relative risk of developing thyroid dysfunction, mainly hypothyroidism, was reported to betwo to 14 fold higher in patients with pre-existing positive TPO-Ab, as compared to patients with negative antibodies [9], [29].

 

Gender and ethnicity.

Women were found to be more susceptible than men to develop IFN-related thyroid disease in some studies [3], [18], [30], [31], [32], [51]. These reports show a relative risk of three to seven folds higher for female compared to male. There are other reports which don’t claim any gender based relationship for IFN-related thyroid disease [24], [25], [33], [34], [35]. A higher prevalence of positive antithyroid antibodies (12.7%) and hypothyroidism (8.3%) were observed in female HCV patients undergoing IFN therapy, compared to only 1% positive antithyroid antibodies and no thyroid disease, after IFN treatment [49]. In a multivariate analysis, female gender and being of Asian origin were independent predictors of the development of biochemical thyroid dysfunction during IFNα treatment [49].

 

Genetic predisposition.

A genetic predisposition to thyroid autoimmune disease is probably necessary for the development of thyroid disease in patients treated with IFN [33], [49]. The remarkable variation in the prevalence of IFN-related thyroid disease may also reflect variability in individual predisposition and genetic susceptibility to the disease [8].

 

HCV infection or viral factors itself as a pre-disposing factor.

HCV infection in a patient can lead to development of thyroid autoimmune disease [30], [32], [35], [37]. Among patients infected with HCV, 20–42% show positive thyroid antibodies [30], [37]. In support of this hypothesis, some viral features like mixed HCV genotype infection and low HCV RNA levels are reportedly related to increased risk of developing thyroid disease [32]. HCV proteins show amino acid sequence homology with those of thyroid antigens [28], [35]. The presence of HCV particle within the thyroid cells may additionally contribute further damage to the thyroid gland (77). Therefore, HCV patients may carry a predisposition to autoimmune reactions through the mechanism of molecular mimicry [28].

 

However, a population-based study excluded a specific role of HCV infection in determining the development of thyroid disease [38]. In the absence of interferon treatment, the link between antithyroid autoantibodies, thyroid dysfunction and HCV infection is still debated [8].

 

Excess or deficiency of iodine.

Epidemiological and clinical evidence suggest that iodine supplementation in an iodine-deficient population may precipitate the onset of thyroid autoimmunity [39]. The concomitant administration of pharmacological quantities of iodine to euthyroid patients treated with IFN α did not increase the frequency of thyroid dysfunction, especially hypothyroidism [40]. Destructive thyrotoxicosis was also correlated to low radioiodine uptake [14].

 

Aftermath of IFN Withdrawal

Several studies have put forth contradictory results regarding the reversibility of the effect of IFN therapy on thyroid function after withdrawal of the treatment. As per one study, IFN alpha-related thyroid autoimmunity was not a completely reversible phenomenon because some patients developed chronic thyroiditis [22]. Another relevant observation of the study [22] was the coexistence of thyroglobulin antibodies (Tg-Ab) and TPO-Ab at the end of the treatment. This is a predictive factor for the presence of thyroid dysfunction, even if subclinical, many years after IFN withdrawal.

Autoimmune thyroiditis may not be reversible after IFN therapy [13], but a complete recovery of thyroid function within a few months of IFN withdrawal was also reported in earlier studies [34], [41]. Another report suggested that the treatment of HCV with IFN was safe in patients, since thyroid diseases are mostly reversible after treatment [41]. However, others have reported only a partial reversal of the thyroid dysfunction [29], [30], [42].

 

These contrasting results may be due to either the variable length of follow-up after IFN withdrawal or differences in the criteria used to define the recovery from thyroid disease [16]. Thyroid autoantibodies remain indefinitely positive in about 50% of patients with IFN-induced thyroid disease, whereas in others, circulating antibodies disappear after IFN withdrawal [41].

The uncertainty in the clinical management of patients developing IFN-induced thyroid disease may also be due to the variable expressions and different long-term outcomes of this side effect [16].

 

Managing IFN-induced Thyroid Dysfunction in HCV Patients

Perhaps the true prevalence of thyrotoxicosis or hypothyroidism is much higher than that reported in literature [14], [24], [29], because it is often transient and has mild clinical manifestations [14]. Moreover, the symptoms of thyroid diseases (i.e., fatigue, myalgia, anxiety, depression, weight loss) may be easily mistaken for the side effects of IFN therapy per se [28].

 

Hence, the systematic screening of thyroid gland function and TPO-Ab titers in all patients with HCV - before, during and after IFN alpha therapy - should be recommended. Also, patients should be informed of the associated risk of thyroid dysfunction [30], [43], [44], [45]. To minimize the side effects of IFN treatment like hypothyroidism in the HCV patients it is required to screen the patient for thyroid-related diseases before the onset of the therapy [5], [46].

 

Considering the significant association between HCV infection and autoimmune thyroid diseases (AITD), the detection of TPO-Ab and TG-Ab in all HCV patients, independent of IFN therapy, is suggested [47]. Controlled studies on a large scale are needed to evaluate the role of HCV per se, and that of PEG-IFN and RIBA in the development of autoimmune thyroid diseases [48].

IFN therapy has shown to have direct toxic effect on thyroid cells, resulting in thyrocyte apoptosis, rupture of follicles and release of thyroid hormones [79]. These pathophysiologic events manifest themselves in the form of the bi-phasic thyroid response (0–18 months of treatment: testing will falsely reassure with normal thyroid tests, 18–25 months treatment: testing will detect hyperthyroidism and 25–42 weeks will indicate hyperthyroidism) that is so classical of this type of thyroiditis [74]. Hence the study [74] suggest the need for regular monthly thyroid testing to fully document and diagnose this prevalent and exclusive thyroid dysfunction in HCV patients.

 

Clinical Practice Guidelines for HCV

The current standard approach of European Association for the Study of Liver (EASL) and well accepted standard of care for chronic hepatitis C is treatment with a combination of pegylated INF alpha plus ribavirin [52]. Two pegylated IFN-α molecules can be used in combination with ribavirin. They are pegylated IFN-α 2a and pegylated IFN-α2b [52]. The American Association for the Study of Liver Diseases (AASLD) also proposes the recommended therapy of chronic HCV infection as the combination of a pegylated interferon alpha and ribavirin [53]. The choice of the regimen for pegylated interferon alpha and ribavirin was based upon the results of three pivotal, randomized, clinical trials that demonstrated the superiority of this combination treatment over standard interferon alpha and ribavirin [54]–[56]. Even though the clinical practice guidelines are mostly followed, the mono-therapy is still continued as treatment regimen for HCV patient as per the available literature in the present systematic review. There are recent studies with single therapy of IFN due to country specific treatment modalities following other than EASL and AASLD criteria.

 

Constraints in Pooled Analysis of Studies

The wide variation among the frequency of side effects was observed in both single and combination therapy studies. The different dosage and treatment schedule and measurements of thyroid parameters at different time intervals viz., 3 months [49], [70], 2–3 months [76], 24 weeks [32] in the publications result in constraints for the outcome of the pooled analysis. Variations in definition/criteria for thyroid dysfunction followed in each study [Table 3] influence the outcome of the pooled risk estimate of side effects of thyroid dysfunction. Hence the overall frequency of thyroid dysfunctions and newly developed Tabs reported as side effects of mono and combination therapy of IFN in HCV patients from different studies in this systematic review analysis may have limitations of factors mentioned above.

 

Click To Enlarge

 

 

 

Table 3. Differences in definition of thyroid dysfunction/positive for thyroid autoantibody given in method section of some of the publications.

 

doi:10.1371/journal.pone.0055364.t003

 

Conclusion

To conclude, the present review shows that there is a wide range in the incidence of newly developed thyroid dysfunctions and thyroid antibodies in IFN-treated HCV patients. IFN α therapy alone or in combination with other drugs has different effects on the incidence of thyroid dysfunctions. Several factors that pre-dispose an HCV patient to acquire thyroid related abnormalities during IFN treatment have been discussed. These may include gender and ethnicity, HCV viral factors, genetic predisposition, and environmental and patho-physiological factors among others. Variations in IFN dosage, treatment duration of IFN, definition/criteria followed in each study for thyroid dysfunction and irregular thyroid function testing during treatment in different studies influence the outcome of each study and render the pooled risk analysis of side effects of thyroid dysfunction difficult. Another aspect highlighted by this systematic review is the variability that occurs among reports discussing the reversibility of thyroid dysfunction after IFN withdrawal. This is a comprehensive attempt to collate relevant data from 56 publications across several nations about IFN (both mono and combination therapy) related thyroid dysfunction among HCV patients. The role of each factor in causing thyroid dysfunctions in HCV patients treated with IFN should be analyzed in detail in future studies, for a better understanding of the problem and sounder clinical management of the disease.

 

Acknowledgments

We wish to thank Dana Wendeler, Documentation Officer of the German Accident Insurance Institution for the Health and Welfare Services (BGW), Hamburg, Germany, for her support with the management of the literature.

Author Contributions

Conceived and designed the experiments: CNK FH AN. Performed the experiments: CNK FH. Analyzed the data: CNK. Contributed reagents/materials/analysis tools: CNK. Wrote the paper: CNK FH AN.

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