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.

 

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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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32. Hsieh MC, Yu ML, Chuang WL, Shin SJ, Dai CY, et al. (2000) Virologic factors related to interferon alpha induced thyroid dysfunction in patients with chronic hepatitis C. Eur J Endocrinol. 142: 431–437. Find this article online
33. Floreani A, Chiaramonte M, Greggio NA, Fabris P, De Lazzari F, et al. (1998) Organ-specific autoimmunity and genetic predisposition in interferon-treated HCV-related chronic hepatitis patients. Ital J Gastroenterol Hepatol 30: 71–76. Find this article online
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37. Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, et al. (1995) Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon α-2a. Eur J Endocrinol 132: 587–593. Find this article online
38. Loviselli A, Oppo A, Velluzzi F, Atzeni F, Mastinu GL, et al. (1999) Independent expression of serological markers of thyroid autoimmunity and hepatitis virus C infection in the general population: results of a community-based study in northwestern Sardinia. J Endocrinol Invest 22: 660–665. Find this article online
39. Rose NR, Rasooly L, Saboori AM, Burek L (1999) Linking iodine with autoimmune thyroiditis. Environ Hlth Perspect 107: 749–752. Find this article online
40. Minelli R, Braverman LE, Valli MA, Schianchi C, Pedrazzoni M, et al. (1999) Recombinant interferon α (rIFN-α) does not potentiate the effect of iodine excess on the development of thyroid abnormalities in patients with HCV chronic active hepatitis. Clin Endocrinol (Oxf) 50: 95–100. Find this article online
41. Bini EJ, Mehandru S (2004) Incidence of thyroid dysfunction during interferon alfa-2b and ribavirin therapy in men with chronic hepatitis C: a prospective cohort study. Arch Intern Med 164(21): 2371–2376. Find this article online
42. Imagawa A, Itoh N, Hanafusa T, Oda Y, Waguri M, et al. (1995) Autoimmune endocrine disease induced by recombinant interferon α therapy for chronic active type C hepatitis. J Clin Endocrinol Metab 80: 922–926. Find this article online
43. Ramos-Casals M, Trejo O, García-Carrasco M, Font F (2003) Therapeutic management of extrahepatic manifestations in patients with chronic hepatitis C virus infection. Rheumatol 42: 818–28. Find this article online
44. Gupta VK, Kotwar NK, Jha A, Menon AS, Shukla R (2011) A case of Interferon induced Hypothyroidism. MJAFI 67: 1. Find this article online
45. Nagayama Y, Kazuhiroo HTA, Suruta MT, Akeshita A, Kimura H, et al. (1994) Exacerbation of thyroid autoimmunity by interferon α treatment in patients with chronic viral hepatitis: Our studies and review of the literature. Endocr Jl 41 (5): 562–572. Find this article online
46. Mandac JC, Chaudhry S, Sherman KE, Tomer Y (2006) The Clinical and Physiological Spectrum of Interferon - Alpha Induced Thyroiditis: Toward a New Classification. Hepatol 43: 661–672. Find this article online
47. Testa P, Castaldi V, Fant GF, Fiore V, Grieco A, et al. (2006) Prevalence of HCV antibodies in autoimmune thyroid disease. Eur Rev Med Pharmacol Sci 10: 183–186. Find this article online
48. Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, et al. (2004) Thyroid disorders in chronic hepatitis C. Am J Med. 117(1): 10–3. Find this article online
49. Dalgard O, Bjoro K, Hellum K, Myrvang B, Bjoro T, et al. (2002) Thyroid dysfunction during treatment of chronic hepatitis C with interferon α: no association with either interferon dosage or efficacy of therapy. J Intern Med 251: 400–406. Find this article online
50. Nadeem A, Aslami M, Khan DA, Hussain T, Khan SA (2009) Effects of combined interferon alpha and ribavirin therapy on thyroid functions in patients with chronic hepatitis C. J Coll Physic Surg Pak 19. (2): 86–90. Find this article online
51. Yan Z, Fan K, Fan Y, Wang X, Mao Q, et al. (2012) Thyroid dysfunction in Chinese patients with chronic hepatitis C treated with interferon alpha: Incidence, long term outcomes and predictive factors. Hepat Mon 12 (9): e6390 DOI:10.5812/hepatmon.6390. .
52. European Association for the Study of the Liver (2011) EASL Clinical Practice Guidelines: Management of hepatitis C. J Hepatol. 55: 245–264. Find this article online
53. Ghany MG, Strader DB, Thomas DL, Seeff B (2009) American Association for the study of liver diseases practice guidelines-Diagnosis, management and treatment of Hepatitis C: An update. Hepatology 49(4): 1335–1374. Find this article online
54. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, et al. (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358: 958–965. Find this article online
55. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, et al. (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347: 975–982. Find this article online
56. Hadziyannis SJ, SetteHJr, Morgan TR, Balan V, Diago M, et al. (2004) Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140: 346–355. Find this article online
57. Barut S, Gunal O, Erkorkmaz U, Yildiz F (2012) Thyroid dysfunction in Turkish patients with chronic hepatitis C receiving peginterferon plus ribavirin in the period of 2005–2010. Braz J Infect Dis 16(5): 448–51. Find this article online
58. Kim BK, Choi YS, Park YH, Lee SU (2011) Interferon-alpha-induced destructive thyroiditis followed by Graves’ disease in a patient with chronic hepatitis C: a case report. J Korean Med Sci 26(12): 1638–41. Find this article online
59. Vasiliadis T, Anagnostis P, Nalmpantidis G, Soufleris K, Patsiaoura K, et al. (2011) Thyroid dysfunction and long-term outcome during and after interferon-alpha therapy in patients with chronic hepatitis C. Ann Acad Med Singapore. 40(9): 394–400. Find this article online
60. Andrade LJ, Atta AM, Atta ML, Mangabeira CN, Paraná R (2011) Thyroid disorders in patients with chronic hepatitis C using interferon-alpha and ribavirin therapy. Braz J Infect Dis 15(4): 377–81. Find this article online
61. Dabrowska MM, Panasiuk A, Flisiak R (2010) Thyroid dysfunction in antiviral therapy of chronic hepatitis C. Hepatogastroenterol. 57(101): 826–31. Find this article online
62. Costelloe SJ, Wassef N, Schulz J, Vaghijiani T, Morris C, et al. (2010) Thyroid dysfunction in a UK hepatitis C population treated with interferon-alpha and ribavirin combination therapy. Clin Endocrinol (Oxf) 73(2): 249–56. Find this article online
63. Tran HA, Reeves GE (2009) The Spectrum of Autoimmune Thyroid Disease in the Short to Medium Term Following Interferon-alpha Therapy for Chronic Hepatitis C. Int J Endocrinol. 2009: 241786 Doi:10.1155/2009/241786. .
64. Vezali E, Elefsiniotis I, Mihas C, Konstantinou E, Saroglou G (2009) Thyroid dysfunction in patients with chronic hepatitis C: virus- or therapy-related? J Gastroenterol Hepatol 24(6): 1024–9. Find this article online
65. Jamil KM, Leedman PJ, Kontorinis N, Tarquinio L, Nazareth S, et al. (2009) Interferon-induced thyroid dysfunction in chronic hepatitis C. J Gastroenterol Hepatol. 24(6): 1017–23. Find this article online
66. Masood N, Ghori R, Memon A, Memon S, Memon KI, et al. (2008) Frequency of thyroid disorders during interferon and ribavirin therapy in chronic hepatitis C infection. J Coll Physicians Surg Pak 18(6): 347–51. Find this article online
67. Tran HA, Jones TL, Batey RG (2005) The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-alpha2beta and Ribavirin.BMC Endocr Disord 12. 5: 8. Find this article online
68. Parana R, Cruz M, Santos-Jesus R, Ferreira K, Codes L, et al. (2000) Thyroid disease in HCV carriers undergoing antiviral therapy with interferon plus ribavirin. Braz J Infect4: 284–290. Find this article online
69. Wirth S, Pieper-Boustani H, Lang T, Ballauff A, Kullmer U, et al. (2005) Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatol. 41: 1013–1018. Find this article online
70. Kee KM, Lee CM, Wang JH, Tung HD, Changchien CS, et al. (2006) Thyroid dysfunction in patients with chronic hepatitis C receiving a combined therapy of interferon and ribavirin: incidence, associated factors and prognosis. J Gastroenterol Hepatol 21: 319–26. Find this article online
71. Gehring S, Kullmer U, Koeppelmann S, Gerner P, Wintermeyer P, et al. (2006) Prevalence of autoantibodies and the risk of autoimmune thyroid disease in children with chronic hepatitis C virus infection treated with interferon-alpha. World J Gastroenterol 28 12(36): 5787–92. Find this article online
72. Kowala-Piaskowska A, Mozer-Lisewska I, Figlerowicz M, Słuzewski W (2007) Adverse effects during the treatment with pegylated interferon and ribavirin in children with chronic hepatitis C. Pharmacoepidemiol drug saf. 16: 1095–1103. Find this article online
73. Plockinger U, Kruger D, Bergk A, Weich V, Wiedenmann B, et al. (2007) Hepatitis-C patients have reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-alpha. Amer J Gastroenterol 102: 2724–2731. Find this article online
74. Tran HA, Reeves GE, Jones TL (2009) The natural history of interferon-alpha2b-induced thyroiditis and its exclusivity in a cohort of patients with chronic hepatitis C infection. QJM 102: 117–122. Find this article online
75. Tran HA, Jones TL, Ianna EA, Reeves GE (2011) The natural history of interferon-a induced thyroiditis in chronic hepatitis c patients: a long term study. Thyroid Res 8 4(1): 2 Doi:10.1186/1756-6614-4-2. .
76. Moncoucy X, Leymavie F, Delemer B, Levy S, Bernard-Chabert B, et al. (2005) Risk factors and long term course of thyroid dysfunction during antiviral treatments in 221 patients with chronic hepatitis C. Gastroenterol Clin Biol. 29: 339–345. Find this article online
77. Gowans EJ. Distribution of markers of hepatitis C virus infection throughout the body. Semin Liver Dis 20: 85–102. Find this article online
78. Lloyd AR, Jagger E, Post JJ, Crooks LA, Rawlinson WD, et al. (2007) Host and viral factors in the immuno pathogenesis of primary hepatitis C virus infection. Immuno Cell Biol 85: 24–32. Find this article online
79. Huang JF, Chuang WL, Dai CY, Chen SC, Lin ZY, et al. (2006) The role of thyroid autoantibodies in the development of thyroid dysfunction in Taiwanese chronic hepatitis C patients with interferon-alpha and ribavirin combination therapy. J Viral Hepat 13(6): 396–401. Find this article online
80. Murakami M, Kakizaki S, Takayama H, Takagi H, Mori M (1999) Autoimmune thyroid disease induced by interferon therapy. Nippon Rinsho 57: 1779–83. Find this article online
81. Carella C, Amato G, Biondi B, Rotondi M, Morisco F, et al. (1995) Longitudinal study of antibodies against thyroid in patients undergoing interferon-alpha therapy for HCV chronic hepatitis. Horm Res 44: 110–14. Find this article online
82. Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, García-Monzón C, Arranz A, et al. (1996) Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy. Clin Endocrinol (Oxf) 44: 635–42. Find this article online
83. Wong V, Fu AX, George J, Cheung NW (2002) Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis. Clin Endocrinol (Oxf) 56(6): 793–8. Find this article online
84. Morisco F, Mazziotti G, Rotondi M, Tuccillo C, Iasevoli P, et al. (2001) Interferon-related thyroid autoimmunity and long-term clinical outcome of chronic hepatitis C. Dig Liver Dis. 33(3): 247–53. Find this article online
85. Rocco A, Gargano S, Provenzano A, Nardone M, De Sanctis GM, et al. (2001) Incidence of autoimmune thyroiditis in interferon-alpha treated and untreated patients with chronic hepatitis C virus infection. Neuro Endocrinol Lett 22(1): 39–44. Find this article online
86. Gelu-Simeon M, Burlaud A, Young J, Pelletier G, Buffet C (2009) Evolution and predictive factors of thyroid disorder due to interferon alpha in the treatment of hepatitis C. World J Gastroenterol. 15(3): 328–33. Find this article online
87. Doi F, Kakizaki S, Takagi H, Murakami M, Sohara N, et al. (2005) Long-term outcome of interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C. Liver Int. 25(2): 242–6. Find this article online
88. Berris B, Feinman SV (1991) Thyroid dysfunction and liver injury following interferon treatment of chronic viral hepatitis. Dig Dis Sci 36: 1657–1660. Find this article online
89. Pateron D, Hartmann DJ, Duclos-Vallee JC, Jouanolle H, Beaugrand M (1993) Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 17(3): 417–419. Find this article online
90. Kodama T, Katabami S, Kamijo K, Katanuma A, Yamashita K, et al. (1994) Development of transient thyroid disease and reaction during treatment of chronic hepatitis C with interferon. J Gastroenterol 29(3): 289–92. Find this article online
91. Friedrich-Rust M, Theobald J, Zeuzem S, Bojunga J (2009) Thyroid function and changes in ultrasound morphology during antiviral therapy with pegylated interferon and ribavirin in patients with chronic hepatitis C. J Viral Hepat. 16(3): 168–77. Find this article online
92. Krupinska J, Wawrzynowicz-Syczewska M, Urbanowicz W, Poblock J, Syrenicz A (2011) The influence of interferon alpha on the induction of autoimmune thyroiditis patients treated for chronic viral hepatitis type C. Endokrynol Pol. 62(6): 517–22. Find this article online

TGIF-HCV Rewind:Liver Cancer, Interferon Free Regimens and Noninvasive Methods To Diagnose Liver Fibrosis

 

Hello folks,

Welcome to HCV rewind, a weekly digest of news, research and a look at today's headlines. Grab a cup of jamoke, sit back and catch up on what you missed.


Liver Cancer

A Few Facts;

The World Health Organization has predicted that by 2020 liver cancer will surpass lung as the No. 1 cancer worldwide.

At present, it is estimated that about 170 million people, roughly 3% of the world population, are chronically infected with HCV.

Source - Medscape : Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).

A study is published in the December issue of Liver Transplantation reported; HCV is the most common blood-borne infection and cause of liver disease requiring transplantation in the U.S., chronically infecting more than one percent of Americans. Previous studies show that among patients living with chronic HCV, 10% to 20% will develop cirrhosis and up to 5% will progress to liver cancer (hepatocellular carcinoma; HCC). Further evidence implicates HCV as the primary risk factor for developing HCC in up to 47% of cases of patients with HCC.

Journal Update

Over at Clinical Liver Disease, an issue devoted to Hepatocellular Carcinoma headed up by Jorge A. Marrero, MD, MS, and a team of leading experts in the field hepatology address current issues in HCC. Topics include; natural history, staging, risk factors, and new treatment options. Visitors are able to view videos, full data, and download files in either HTML or PDF formats.
Click here to view this issue of CLD.

Failure - HEAT Study

Celsion announced yesterday their Phase III HEAT Study of ThermoDox® in combination with radio frequency ablation (RFA) for hepatocellular carcinoma (HCC) or primary liver cancer failed to meet the company's goal.

(Reuters) - Celsion Corp shares plunged by more than 80 percent after a late-stage study of the company's experimental liver cancer treatment ThermoDox failed to meet the main goal of increasing patients' survival without worsening their cancer.

In the HEAT Study, ThermoDox® is administered intravenously in combination with RFA. ThermoDox® is a proprietary heat-activated liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers.
Read more here...

Research

Scientists Discover Process That Turns Normal Liver Cells to Cancer Cells

A team of scientists from the Cancer Science Institute of Singapore (CSI) at the National University of Singapore (NUS) has identified a genetic process in which normal liver cells transform into cancerous ones.
Continue reading....

Statins May Lower Death Risk in Liver Cancer

SAN FRANCISCO -- Statin use seemed to reduce the risk of death in patients with hepatocellular cancer, researchers reported here.
Continue reading @ MedPage Today

Noninvasive Methods To Diagnose Liver Fibrosis

Noninvasive Estimation of Fibrosis Progression Overtime Using the FIB-4 Index in Chronic Hepatitis C

Discussion Only
Full Text Available @ Medscape

Recently, noninvasive markers of liver fibrosis have been used as a predictive factor of liver-related outcome such as mortality^[22–24] or HCC development^[24–26] in patients with chronic liver disease. There have been few studies that investigated the association between changes of noninvasive markers and liver-related outcome.^[27–29] However, it is still unclear whether there is a relation between the time-course changes in the value of noninvasive markers and progression of liver fibrosis.

The aim of the study was to evaluate the utility of the real-time assessment of the FIB-4 index for the prediction of time-course progression in liver fibrosis. We have shown that the FIB-4 index reduced along the regression of the fibrosis stage, while the FIB-4 index increased along the progression of the fibrosis stage. These results indicate that the measurement of the time-course changes in the FIB-4 index may be useful for the noninvasive and real-time estimation of the progression in liver fibrosis overtime.

Although the gold standard for diagnosis of liver fibrosis is liver biopsy, there are a variety of problems including invasiveness and sampling errors.^[6] Diagnostic methods of liver fibrosis by measurement of elasticity of the liver by ultrasonography^[10–14] have been developed, but these modalities are not widely available.

The FIB-4 index has an advantage among these noninvasive liver fibrosis diagnostic methods. Firstly, it is quite easily calculated. The parameters required for calculation are only age, AST, ALT and platelet counts, which are measured at the routine examination of patients with liver disease.

Therefore, additional blood collection is unnecessary, and the index can be calculated at no cost. Secondly, because of its simple calculation, it is possible to evaluate the clinical conditions in a real-time manner. Repeated measurements of the FIB-4 index make it possible to predict deterioration in liver fibrosis continuously over time. Because no special equipment or system is necessary, and objective data on the clinical conditions are provided in a real-time manner, the FIB-4 index is simple and convenient compared with other noninvasive liver fibrosis diagnostic methods.

It is widely known that a decrease in platelet counts is useful for the prediction of the progression of fibrosis stage.^[30] We have reported that elevated AST or ALT is also associated with the progression of liver fibrosis.^[31] However, the results of this study showed that a change in the FIB-4 index over time was a more useful factor for the prediction of the progression of fibrosis stage than AST, ALT and changes in platelet counts.

Liver biopsy is still an important examination as the gold standard for diagnosis of liver fibrosis, but time-course changes cannot be readily observed by repeated biopsies because of its invasiveness. On the other hand, it is possible to estimate the progression of liver fibrosis by repeated measurement of the FIB-4 index. Therefore, two examinations should be combined: liver biopsy may be utilized to determine the baseline of fibrosis stage, and the serial measurement of the FIB-4 index may be utilized to predict changes of fibrosis stages overtime in a real-time manner.

In conclusion, we believe that measurement of the time-course changes in the FIB-4 index is useful for the noninvasive and real-time estimation of the progression in liver fibrosis.
Continue reading @ Medscape

Retreatment of Hepatitis C - Monotherapy

Update Cochrane Review

This review addressed the ability of interferon monotherapy to favorably alter the clinical course of chronic hepatitis C when it is used to retreat patients who failed at least one previous course of therapy

Chronic hepatitis C: Interferon may be harmful in re-treatment

People with hepatitis C and chronic liver disease who relapsed or failed to respond to initial treatment are unlikely to improve on interferon retreatment. In fact, they may face an increased risk of dying sooner, and are likely to experience a variety of adverse effects, according to an updated systematic review published in The Cochrane Library.

Hepatitis C affects around 170 million people worldwide. In some cases, infection leads to chronic liver disease, liver failure or liver cancer, eventually resulting in death. Treatment is based on antiviral drugs.

Interferon monotherapy, meaning using interferon alone, is not the first choice of therapy for most clinicians, but it is used in some patients when other drugs cannot be used. Despite costing thousands of dollars to treat one patient for a year, there is currently little evidence that it works. Treatment is considered to have been successful if the virus cannot be detected in a patient's blood six months after treatment. This outcome is known as sustained viral response (SVR). However, it has never been confirmed that SVR leads to an improvement in the patient's disease state or their chances of survival.

The authors of the review analysed data from seven trials involving a total of 1,976 patients with chronic hepatitis C liver disease who were being retreated with interferon monotherapy having previously been treated unsuccessfully. When they included all trials in their analysis, the risk of death was no higher for interferon than for placebo or no treatment. However, the researchers also performed a further analysis, leaving out studies that had a high risk of bias and gave less reliable estimates of effect. For example, one of these trials was not blinded, was stopped before the planned number of patients had been enrolled, and did not have all of those who had been enrolled counted in the final analysis. This left the two largest trials, together incorporating 1,676 patients. Focusing only on these trials, the risk of death was significantly higher at 9.4% for interferon retreatment compared to 6.7% for placebo or no treatment.

"It was troubling to see that in those trials providing the most reliable estimates of treatment effects, interferon seemed to increase the risk of death," said lead researcher Ronald Koretz of Granada Hills in California, US. "Based on these results, interferon monotherapy cannot be recommended for chronic hepatitis C patients who have already failed one course of treatment and are being retreated. Furthermore, patients who are receiving interferon as part of a combination therapy should be informed about this potential adverse effect."

Interferon treatment did seem to reduce levels of hepatitis C virus in the blood compared to controls, resulting in what would be considered successful treatment or SVR. However, since this response was not associated with an improvement in disease or risk of death, the review suggests that SVR may be inadequate as an indicator of a successful treatment outcome. "Sustained viral response did not suggest that a patient who was destined to develop symptoms or death from hepatitis C was cured, at least in this setting. This tells us that as a treatment outcome it is not universally reliable and needs to be validated before it can be viewed as the goal of any therapy in other clinical scenarios," said Koretz.

Patients in the treatment group were also more likely to suffer adverse effects. Although the drug did appear to reduce the incidence of nonfatal internal bleeding, the researchers conclude that it is so expensive that it may be hard to justify based on this one small benefit.

Listen to the podcast here, continue to updated material @ Cochrane, additional summary is available at Medscape.

Pegasys Or PegIntron ?

*pegylated interferon alfa-2a (Pegasys) and alfa-2b (PegIntron)

Pegylated interferon alfa-2a, 2b similarly effective for chronic HCV genotype 1

Coppola N. BMC Infect Dis. 2012;doi:10.1186/1471-2334-12-357.

January 29, 2013

Standard doses of pegylated interferon alfa-2a and alfa-2b, administered with ribavirin, were similarly effective in patients with chronic hepatitis C genotype 1 in a recent study.

Researchers performed meta-analysis of seven studies evaluating the efficacy of peginterferon-alfa-2a (Peg-IFN a-2a) and 2b (Peg-IFN a-2b) in 3,026 patients with chronic hepatitis C genotype 1. Five prospective randomized trials and one prospective and one retrospective nonrandomized trial were included. All participants were treatment-naive and anti-HIV-negative.

Study quality was measured according to the Chalmers and Jadad scales. Scores on the Chalmers scale ranged from 0.2 to 0.6 (mean of 0.43) overall, from 0.11 to 0.58 (mean 0.36) for the protocol, and from 0.23 to 0.67 (mean 0.53) for data analysis and presentation. On the six-point (0-5) Jadad scale, two studies scored 0, two scored 1 and three scored 3.

Rapid virological response (RVR) was evaluated in four studies in 2,729 patients, and occurred at similar rates among patients taking alfa-2a and 2b (RR=1.05; 95% CI, 0.87-1.27). Sustained virological response (SVR) rates, measured in 2,646 patients across six studies, also were similar for the treatments (RR=1.08; 95% CI, 0.99-1.18).

Early complete virological response (EVR) and end-of-treatment response (ETR) were assessed in five studies each, in 2,766 and 2,460 patients, respectively. EVR and ETR were more common among alfa-2a recipients (RR=1.12, 1.03-1.22 for EVR; RR=1.22, 1.14-1.31 for ETR).
Sensitivity analysis excluding nonrandomized and poor-quality studies did not significantly impact results.

“The data show that there is no difference between the two treatments in the achievement of RVR and SVR; the higher rates of EVR and ETR in the patients treated with Peg-IFN a-2a are clearly of lesser clinical impact,” the researchers wrote. “The datum on SVR may be considered the most important result from this meta-analysis. … Peg-IFN a-2a and Peg-IFN a-2b, both in combination with ribavirin … can be used indifferently for patients with genotype 1 chronic hepatitis C who are anti-HIV-negative and naïve to antiviral treatment.”
Source

Peginterferon/ribavirin effective for children, adolescents with chronic HCV

Druyts E. Clin Infect Dis. 2012;doi:10.1093/cid/cis1031.
February 1, 2013

Treatment of chronic hepatitis C with pegylated interferon and ribavirin is effective and relatively safe for children and adolescents, according to recent results.

Researchers performed a systematic review and meta-analysis of eight trials assessing the use of pegylated interferon (PEG-IFN) alfa-2a or 2b with ribavirin (RBV) in patients aged 3 to 18 years with chronic HCV. Complete early virologic response (EVR) was defined as undetectable HCV RNA after 12 weeks of treatment, and sustained virologic response (SVR) was defined as undetectable RNA after 24 weeks of post-treatment follow-up.

Across all cohorts, EVR occurred in 70% of patients and SVR occurred in 58%, with higher response rates among participants with genotypes 2 (87% of cases) or 3 (89%) than those with genotypes 1 (61%) or 4 (52%). Relapse occurred in 7% of cases.

Lack of response in 15% of participants resulted in discontinuation of treatment, while 4% required discontinuation because of adverse events and 4% discontinued as a result of virologic breakthrough. Common adverse events included leukopenia (52%), neutropenia (32%), erythema at the injection site (27%), alopecia (13%) and anemia (11%).

Investigators noted that, across five studies with evaluable data, some growth inhibition was observed during treatment, and it returned to normal upon treatment cessation. In one randomized controlled trial, some participants who had experienced growth inhibition had not returned to baseline height-for-age after 2 years of follow-up.

Edward J. Mills
“In the rare instance where a child is identified to be progressing toward advanced liver disease from HCV … our work demonstrates that PEG-IFN and RBV can be used relatively safely and with a reasonable hope of cure,” researcher Edward J. Mills, PhD, department of clinical epidemiology and biostatistics at McMaster University in Hamilton, Canada, told Healio.com. He also noted that combination direct-acting antiviral regimens may provide better therapeutic options in the future. “[IFN-based] medications do cause multiple side effects and adverse events, which is not ideal in any population; in particular, a population of children.”

Disclosure: See the study for a full list of relevant disclosures.
Source - Healio

Hepatitis C -Frequency of Thyroid Dysfunctions during Interferon Alpha Treatment

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.
Continue reading....

Boceprevir and Telaprevir

Boceprevir and Telaprevir Improve Hepatitis C Treatment, Literature Reviews Find

 

Triple therapy with a direct-acting antiviral drug was more effective than pegylated interferon and ribavirin alone for people with chronic hepatitis C, but there is not yet enough data to determine many differences between boceprevir and telaprevir , or to see effects on long-term clinical outcomes, according to 2 recent medical literature ...
Continue reading....

Interferon Free Regimens

Is The HCV Pipeline Heading in the Right Direction? - Commentary
24 January 2013

Andrew Aronsohn, Andrew J. Muir, Donald Jensen

 

Will All Patients Be Able to Be Treated Without Interferon?

Interferon-free HCV therapy will represent a breakthrough in HCV treatment. Trials to date are encouraging, but have begun to reveal important interactions between drug, host, and virus that need to be better understood before interferon-free therapy becomes a mainstay of treatment. Previously unidentified host and viral characteristics may create a requirement for interferon-based therapy for some, raising the possibility that all oral regimens may not be appropriate for all patients. In addition, the cost of newly developed interferon-free regimens may be prohibitive, especially in many resource-limited regions of the world. Enthusiasm over the possibility of an "all-oral" cure for HCV must be balanced with realization that cost of therapy will create a disparity among those who can receive interferon-free therapy and those who do not have access. HCV will carry an extensive global burden of disease, even in an interferon-free era, if efforts are not made to diminish this disparity....
Read More.....

 

Hepatitis C progress in pipeline

New drugs to treat virus expected be available in 2014-15

By Bonnie Miller Rubin, Chicago Tribune reporter

January 30, 2013

For more on this rapidly changing landscape, we turned to Dr. Donald M. Jensen, director of the Center for Liver Diseases at University of Chicago Medicine and a noted hepatitis C researcher, with more than 100 peer-reviewed articles .

Q: Tell me about the new drugs and what they mean for patients.

A: In May 2011, two new drugs were approved — telaprevir and boceprevir — and were added to the backbone of interferon, which has been around since the early 1990s, and ribavirin (since 1998), and have always been the standard of care. The old therapy had a lot of side effects — such as aches, severe fatigue and depression. Even then, the cure rate was only about 40 percent.

Q: Did the new drugs eliminate the nasty side effects?

A: No. Sometimes, it aggravated them ... with anemia and a skin rash. It wasn't pleasant, but the success rate jumped to 70 percent, which was nothing to scoff at. But now there are even better drugs in the pipeline, such as Sofosbuvir, Daclatasvir, Simeprevir, Faldaprevir, ABT450, Danoprevir, Apeline, which should be available in the 2014-15 time frame. The treatment is shorter — 12 to 24 weeks vs. 24 to 48 weeks — and has fewer side effects and even better success rates (90 to100 percent cure rates). Many patients with mild cases are deciding to wait.

Read more.........

Editorial
Interferon free regimens for the “difficult to treat”: are we there?

Journal of Hepatology

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

In this editorial response rates using interferon free combinations and standard therapy in difficult to treat patients are discussed.

Within the next few years, we will certainly witness more progress. When choosing a combination of antiviral agents, we will need to take into consideration a certain number of variables: potency, genetic barrier to resistance, range of activity (pangenotypic or not), potential drug-drug interactions. Importantly, safety and simplicity of the regimen will also be very relevant. Up to now, most of the oral compounds appear to be safe and well tolerated by most patients, but until large phase 3 studies are finished, safety needs to be closely monitored. Most of our current knowledge on interferon-free regimes is based on phase 2 trials including small numbers of patients. Added to which, we still have very little information on the safety and efficacy of these regimens in difficult to treat subjects, particularly in null responders with advanced fibrosis or cirrhosis, or in special populations such as transplant patients with hepatitis C recurrence....

Download PDF, or view the editorial here on the blog.

Clinical Trials

New Interferon-free Development Program
Alan Franciscus
Editor-in-Chief, HCV Advocate
January 28 2013 - Medivir announced a collaboration between Medivir/Janssen and Idenix for the clinical development of multiple HCV inhibitors with and without ribavirin—all the studies will be interferon-free.
Continue reading....

Press Release...
Simeprevir, TMC647055 and IDX719 Phase II all-oral combination Hepatitis C studies to be initiated shortly

More @ NATAP includes four articles:
Phase II all-oral combination studies of Simeprevir (TMC435), TMC647055 (non nuc polymerase inhibitor) and IDX719 (NS5A) for the treatment of Hepatitis C

HCV Awareness

The U.S. Centers for Disease Control recently issued its recommendation that all adults born between 1945 and 1965 should have a one-time hepatitis C test. The Canadian Liver Foundation (CLF has extended the recommendation for testing beyond the boomer generation to those born between 1945 and 1975, taking into account immigration from countries where hepatitis C is more common.



National Hepatitis C Survey Prompts Call for All Canadian Boomers to Get Tested

TORONTO, Jan. 29, 2013 /CNW/ - Current realities of chronic hepatitis C in Canada and results of a new national survey of physicians and Canadians on awareness of the liver disease, have prompted the Canadian Liver Foundation (CLF) to urge general practitioners (GPs) to immediately begin recommending a one-time blood test for all adults born between 1945 and 1975.

"We know that risk-based testing has not been effective in identifying all infected adults, and most physicians surveyed agree they do not screen enough patients for hepatitis C," said Dr. Morris Sherman, Chairman of the CLF and hepatologist at Toronto General Hospital. "Given that today's treatments can cure a majority of those infected, it's time to be proactive at identifying chronic hepatitis C in the age group with the highest prevalence. The hepatitis C antibody test is inexpensive and is covered by all provincial health care plans."

According to the survey, conducted by Ipsos Reid, 83 per cent of GPs agree that patients would benefit from more routine screening. GPs also admit to having a limited understanding of the disease and its treatment. Only 35 per cent feel they know a lot about symptoms and nearly four in 10 (38 per cent) feel they know nothing at all or not much about available treatments. More than half (57 per cent) are unaware that hepatitis C can be cured.

Focus on Boomers
While anyone can be exposed to hepatitis C, Canadian data show that chronic hepatitis C is most pervasive among those born between 1945 and 1975.1 Baby boomers are up to five times more likely to be infected by hepatitis C than other adults.2 Yet Canadian boomers are less likely than younger generations to have been tested, according to the survey. Additionally, boomers claim to be the most knowledgeable generation about hepatitis C, but scores from the survey show they know the least.
"Hepatitis C is a silent disease, meaning often symptoms don't appear for many years until the liver is severely damaged," said Dr. Marc Bilodeau, hepatologist and Associate Professor of Medicine at Université de Montréal. "The large number of people infected, the asymptomatic nature of the disease and the serious consequences associated with it justify broader testing. The good news is nearly all Canadians would accept being tested if suggested by their doctor."

The CLF extended the recommendation for testing beyond the boomer generation, taking into account immigration from countries where hepatitis C is more widespread and common.
While nine in 10 Canadians believe that someone can have hepatitis C and not know it, this is not leading to testing. In fact, while over 300,000 Canadians are living with chronic hepatitis C and an estimated 71,000 Canadians are living with HIV,3 more are being tested for HIV/AIDS (32 per cent) than hepatitis C (23 per cent) according to the survey.

Survey Design and Methodology

The results of the survey, completed in September 2012, are based on 1,000 online interviews conducted nationally with adults over the age of 18 and 300 online interviews with GPs. The sample was generated by Ipsos Reid's Canadian Online Panel to reflect the Census data for Canadian adults and the national distribution of Canadian GPs.4

With the given sample size, the poll is accurate within +/- 3.5 percentage points for all Canadians and +/- 6.5 percentage points for all GPs, 19 times out of 20 had the entire adult population and all GPs been polled.5

The survey was conducted by Ipsos Reid on behalf of the Canadian Liver Foundation. The Canadian Liver Foundation acknowledges Merck Canada for its support of the Canadian Liver Foundation's campaign to raise awareness of hepatitis C as a serious liver disease and promote liver health.

About Hepatitis
Hepatitis C is a serious and potentially fatal liver disease. More than 300,000 people in Canada are living with chronic hepatitis C but many are unaware of it.6 It can take decades after individuals are infected for symptoms to appear.7 Undiagnosed and untreated chronic hepatitis C can lead to cirrhosis, liver cancer, liver failure or the need for a liver transplant.8

People can contract hepatitis C through any blood-to-blood contact including injection drug use (even a single episode), blood transfusions prior to 1990, participation in medical procedures or immunization in countries where hepatitis C is common, sharing personal care items (razors/nail clippers), and tattoos and piercings with improperly sterilized equipment.9

The CLF is encouraging GPs to learn more about screening and testing for hepatitis C. Tools to help physicians screen, diagnose and treat hepatitis C are available at http://www.liver.ca/liver-education-liver-research/resources-health-professionals/. Canadians looking for more information on hepatitis C can also visit the CLF website at www.liver.ca/hepatitis.

Silent killer may lurk in baby boomers' blood

He picked up hepatitis C sometime in his 62 years, possibly after a motorcycle accident that led to a blood transfusion as far back as the 1960s. If that was the source, it didn't turn up until almost a half-century later, in 2011.

That discovery led to a costly drug treatment with miserable side effects, but Hays looks back now as a man who is happy, cured and in disbelief
Read more.........

Transmission

Spread of hepatitis C pinpointed

 

Scientists say they have, for the first time, worked out the pattern of spread of hepatitis C, showing early diagnosis is key to preventing epidemics.

A study in injecting drug users in Greece indicated that each infected person spread the disease to 20 others - 10 of these in the first two years.

The researchers said their results would help tackle the disease's spread.

Globally up to 180 million people live with the virus, most are unaware that they have it.

Those infected do not develop symptoms for up to 20 years and spread it to others without realising.

Study leader Dr Gkikas Magiorkinis, from Oxford University, said when people were infected with something such as flu it was very easy to work out where it had come from, because people knew they were infected within days.

But with hepatitis C, no-one has been able to pin down how the virus spreads, because cases occur months or years apart.

Genetic signature

To overcome this problem, the researchers looked at four hepatitis C epidemics in Greece, using data from 943 patients collected between 1995 and 2000.

But to provide more detail on how it spreads, they also included genetic information on the virus taken from 100 samples.

Plugging the details into a computer model, they calculated that injecting drug users were "super-spreaders", each transmitting the virus to 20 other people.

Most importantly they discovered that most of the transmissions occurred in the first couple of years, they report in PLoS Computational Biology.

The researchers said that people were more infectious at in the early days of catching hepatitis C because they had higher levels of virus.

The evidence they have produced suggests programmes targeting the diagnosis and treatment of hepatitis C in high-risk groups as early as possible would prevent many new infections and associated health care costs many years down the line.

About 20% of those infected will develop cancer or liver scarring after 20 years of infection, at which point the only treatment is liver transplantation, which costs about £100,000 ($160,000).

Dr Magiorkinis, who did the work in collaboration with the University of Athens and Imperial College London, said the model had helped build a "solid argument" to improve early diagnosis and antiviral treatment in drug users.

"Working out how many people are likely to be infected by each super-spreader of Hepatitis C, as well as how soon they will be infected, has been a puzzle for over 20 years," he said.

"Our research has resolved this issue and paves the way for a modelling study to show what kind of public health interventions could really make a difference."

He added the approach could be useful in other infections such as HIV.
Source

Related - Drug Users Are 'Super-Spreaders' of Hepatitis C, Study Finds

 In Case You Missed It

Hepatitis Connect Presents An Interview With Alan Franciscus

There is a very good argument to be made that Alan Franciscus is the most significant trailblazer in his work for the hepatitis C awareness and advocacy movement in the United States. In 1997, Alan founded the Hepatitis C Support Project (HCSP) to help support and advocate for people affected by hepatitis C, hepatitis B, and HIV and hepatitis coinfections. HCSP has generated several essential support services and informational resources that have become an invaluable part of the current HCV landscape in America.
Continue reading...

Hepatitis C infection and presence of advanced fibrosis:Wait or treat? Why wait? There is no time to lose, is there?

All too frequent we physicians ignore “primum non nocere” (first do not harm), and believe all too frequently treatment is always the answer. Once we have treatments available, we frequently believe that the worst which can happen is the failure of treatment, ignoring that side effects might be more than a mere nuisance. Even a supposedly safe treatment such as lamivudine was demonstrated to be lethal in very special individuals with certain viral resistance mutations, when lamivudine was not stopped in time. In contrast to lamivudine and other oral antivirals for hepatitis B, which extremely rarely cause adverse events and seem to have a safety profile similar to placebo the current therapy of hepatitis C is both less safe and not effective in everyone.
Read more here...

Healthy You

Mindfulness-Based Meditation May Help Reduce Inflammation

Mindfulness meditation techniques designed to reduce emotional reactivity also reduce poststress inflammatory responses and might be useful in chronic inflammatory conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and asthma, according to a study by Melissa A. Rosenkranz, PhD, and colleagues at the University of Wisconsin-Madison.
Read more @ Medscape

Infectious flu particles reach as far as 6 feet

Bischoff W. J Infect Dis. 2013;doi:10.1093/infdis/jis773.

 

Patients in the hospital with influenza could potentially spread influenza virus particles as far as 6 feet by air, researchers from Wake Forest University have found, potentially exposing health care workers to small infectious particles.The CDC [and others] have expressed lack of knowledge and the urgent need for research in influenza virus transmission routes,” the researchers wrote in the Journal of Infectious Diseases. “CDC and WHO state that influenza virus transmission primarily occurs by large-particle respiratory droplets traveling within a short distance of the source and that such particles are blocked during encounters between patients and health care professionals.”
 

The researchers evaluated 94 patients with influenza-like illness who were admitted to the ED or inpatient care. The patients provided nasopharyngeal swab specimens, and the researchers evaluated air samples at distances of 1 foot, 3 feet and 6 feet from the patient’s head.

Sixty-one patients tested positive for influenza, and 26 of these patients released influenza virus into the room air. At all sample locations, the airborne 50% human infectious dose of influenza virus was surpassed. Health care workers were mainly exposed to small influenza virus particles, and the concentrations decreased as they went farther from the patient.

The release of influenza virus into the air was associated with higher nasopharyngeal viral load. Among patients with a higher viral load, coughing and sneezing were associated with increased influenza virus release. Five of the virus emitters released 32 times more influenza virus into the air, and these patients had more severe illness.

“We found that patients produced mostly small influenza virus-carrying particles during routine, non-aerosol-generating care activities,” the researchers wrote. “Health care professionals could be exposed to infectious doses of influenza virus at a distance of 6 feet from patients, with small particles potentially exceeding the suggested exposure zones. This raises concerns regarding the adequacy of protection afforded to health care professionals by the current recommendations during routine care.”

In an accompanying editorial, Caroline Breese Hall, MD, of the University of Rochester School of Medicine and Dentistry in New York, wrote that it is important to better understand influenza transmission, especially because global travel presents the risk for a worldwide influenza outbreak.
“A tenable conclusion from these findings is that infection control procedures should be commensurate with the concern generated by the clinical observations of the intensity and severity of the community outbreak,” she wrote.

Disclosure: The researchers report no relevant financial disclosures. Breese Hall has consulted for GlaxoSmithKline and MedImmune.
Read more @ Healio

Newsletters

February 2013 HCV Advocate

 

In This Issue:

HCV in Water, Containers and Filters
Alan Franciscus, Editor-in-Chief

HCV Snapshots
Lucinda K. Porter, RN

HealthWise: - The Happy Hepper
Lucinda K. Porter, RN

Liver Cancer in People with Hepatitis C: Part 1—Benefits of Antiviral Therapy
Liz Highleyman

New Phase III Interferon-Free Studies
Alan Franciscus, Editor-in-Chief

Personal Experiences

New @ Hepatitis C News

This week, we’ve been taking a closer look at I Help C, a moving and personal blog and resource from Karen Hoyt.
Read more.........

New @ Life Beyond Hepatitis C

Hep C Triple Therapy Experience from Hep C Warrior K: Part 3

Today we continue our interview with Hep C Warrior K and her Hep C Triple Therapy Experience

Connie: What has your blood work been like while on treatment?

Hep C Warrior K: I’ve been showing “Undetected” (virus count) since week 4. My white and red blood counts are getting better but not normal yet. I’ve had some changes with my thyroid and changed my thyroid medication.

Connie: How long is the course of your treatment with receiving Non-Detected virus count?

Hep C Warrior K: I started treatment August 19^th 2012 and will finish February 2, 2013^. The course of my treatment will be 6 months.
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New @ Lucinda Porter.Com

Twenty-Five Years of Living with Hepatitis C

On this date, twenty-five years ago, I received a life-saving blood transfusion, along with an unintended extra ingredient—hepatitis C. For twenty-five years, hepatitis C has been replicating in my liver every day. The miracle is that I am as healthy as I am.
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New @  Hep B Blog

Preventable Loss of an Older Brother From Hepatitis B Related Liver Cancer

A frantic call from my sister-in-law shattered what would have otherwise been an enjoyable Labor Day weekend in 2010. She anxiously told me that my brother, Dan, would be undergoing an emergency procedure on his liver.
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Off The Cuff

Supramap, a recently developed Web application, tracks the global movement of epidemics, offering a visual record of the evolution and spread of deadly diseases around the world.