Showing posts with label Peginterferon. Show all posts
Showing posts with label Peginterferon. Show all posts

Tuesday, February 11, 2014

Hepatitis C-Antidepressants for prevention of Interferon-associated depression

International Journal of Clinical Practice

Prevention of Interferon-Alpha-Associated Depression With Antidepressant Medications in Patients With Hepatitis C Virus

A Systematic Review and Meta-analysis
M. Ehret, D. M. Sobieraj
Int J Clin Pract. 2014;68(2):255-261.

Abstract and Discussion Only
Objective: To conduct a systematic review and meta-analysis evaluating the efficacy and safety of antidepressant medications for the prevention of interferon-alpha (INF-α)-associated depression in patients with chronic hepatitis C virus (HCV).
Data sources: Medline, Cochrane Central and PsycInfo from inception to September 2012, without limitations using terms describing hepatitis C and the individual drug names.
Study selection: We reviewed 132 citations for inclusion using the following criteria: randomised controlled trials in patients with chronic HCV initiating INF-α comparing prophylactic use of an antidepressant vs. placebo and reporting at least one outcome of interest [depression, completion of antiviral therapy, sustained virologic response (SVR), and serious adverse events and bleeding].
Data extraction: Trial characteristics, assessment of risk of bias and data needed for analyses were extracted by two independent investigators using a standard extraction form. Disagreements were reviewed by a third investigator.
Results: A DerSimonian and Laird random-effects model was used for analysis. Heterogeneity and publication bias were evaluated where applicable. Of the seven included trials, the risk of bias was low in four and unclear in the remaining three. All trials evaluated selective serotonin reuptake inhibitors (SSRIs). Prophylactic use of a SSRI significantly reduced the risk of depression by 41% compared with placebo [RR, relative risk 0.59 (0.37–0.93)]. The impact of SSRIs on completion of antiviral therapy, SVR and serious adverse events was not found to be significant.
Conclusions: SSRIs prevent depression in patients with HCV treated with INF-α therapy. The impact of SSRIs on completion of antiviral therapy or on the development of adverse events is less clear.

Discussion Only
To our knowledge, this is the first systematic review and meta-analysis analysing the use of SSRIs for the prevention of INF-α-associated depression in patients with chronic HCV. The trials which have previously evaluated this clinical practice have had differing results. The trials were all very similar in terms of interventions, outcomes assessment and follow up. Although the sample sizes varied and most were small, two of the smallest trials concluded SSRIs were not effective as did two of the larger trials. By using methods of systematic review and meta-analysis, we were able to pool the results of these trials to discern an overall effect of SSRIs in this population. In our analysis, the prophylactic use of a SSRI during INF-α-based therapy in patients with HCV reduced the risk of depression during antiviral treatment. However, the severity of depressive symptoms as measured by the MADRS score did not differ. SSRI therapy was initiated at least 2 weeks prior to antiviral therapy and was continued throughout the duration of antiviral therapy. Although SSRI therapy was successful in reducing depression risk, this did not translate into differences in completion rates of antiviral therapy or achievement of SVR. Safety outcomes were not frequently reported and therefore the overall safety of this practice is unclear.

Selective serotonin reuptake inhibitors work by inhibiting 5-HT reuptake and thus increasing serotoninergic transmission. This is opposite to the proposed mechanism by which INF-α is thought to cause depression (decreasing tryptophan and 5-HT levels, increasing 5-HT reuptake and thus decreasing synaptic availability of 5-HT and 5-HT transmission). [21,22] SSRIs have high rates of success in treating IFN-α-induced depression, beyond that typically observed in RCTs in major depression. [23] Although SSRIs have considerably less adverse effects compared with other antidepressant classes, several major concerns should be considered prior to use, including an increased risk of bleeding and development of manic episodes. [24–26] Other mild and transient adverse effects include sexual dysfunction, gastrointestinal distress, anxiety, sweating, and headache. [27] Despite these limitations, SSRIs should be considered the first choice for the prevention of IFN-α-induced depression because of their excellent efficacy, favourable adverse effect profile, minimal hepatic toxicity and few drug–drug interactions. [23]
Although the use of SSRIs did decrease the risk of depression by 41%, there was no significant difference in the change of MADRS scores from baseline to follow up in those treated with SSRIs vs. placebo. It would be expected that a reduction in the diagnosis of depression would equate to a decrease in the change score for those treated with SSRIs. There was a higher level of statistical heterogeneity seen between the studies in this analysis, with disagreement in both magnitude and direction of effect, which may be related to the small number of participants in the studies and type II error. Additionally, the MADRS was developed to measure the overall severity of depressive symptoms in patients with a diagnosis of major depressive disorder. [28] It does not focus on the somatic symptoms of depression, which are included in the DSM-IV criteria used to diagnose depression in six of the seven included studies. The neurovegetative and somatic symptoms of depression, such as anorexia, fatigue and altered sleep and pain, typically develop with the first few weeks of treatment with IFN-α and are less responsive to antidepressants. While, depressed mood, anxiety and cognitive dysfunction typically develop later (i.e. 12 weeks) during IFN-α treatment and are more responsive to antidepressants. [29]
There are several limitations to the analysis and literature base that are worth noting. The patient population evaluated in the included trials represented four HCV genotypes (1–4) although slightly more than half of the population had genotype 1. In 2011, two protease inhibitors were approved in the United States for the treatment of HCV, genotype 1, in combination with pegylated INF-α and ribavirin: boceprevir (Victrelis®) and telaprevir (Incivek®). Most recent guidelines from the American Association for the Study of Liver Disease recommend this triple therapy for patients with genotype 1. [30] Although our current analysis does not reflect the use of triple therapy to treat HCV, we do not anticipate a difference in SSRI treatment effect since the protease inhibitors are not known to cause depression as a side effect. [31,32] However, it is noteworthy that the package insert for both protease inhibitors does warn of a potential drug interaction with escitalopram and that 'SSRIs such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined'. [31,32] The populations of the included trials may in fact have been diverse. Although the studies excluded patients with a current depressive episode, previous depressive episodes were not used as an exclusion criterion which could have diversified the population of subjects. Previous studies have demonstrated rates of neuropsychiatric symptoms of 12–41% in those that excluded patients with psychiatric histories while those studies without this exclusion criteria report an incidence of 17–58%. [33] This diverse population could account for different rates of changes in MADRS scores and the heterogeneity seen within the studies. Additional research should focus on each population, those with and those without psychiatric histories, separately in determining the use of antidepressants in preventing depressive symptoms. Although we sought to identify trials evaluating other antidepressant, none was found in the peer reviewed literature. Therefore, little is known about whether or not other types of antidepressants, which have varying types of adverse effects, such as the serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, may decrease the development of depression in this population. There is also a lack of reported information on adverse effects from the use of the SSRIs in this population. Bleeding is a potential issue with the use of SSRIs because of the ability to decrease intraplatelet 5-HT content and inhibit platelet function. [24] This is a significant concern in those with liver dysfunction who are at an increased risk of gastrointestinal bleeding. Included trials did not routinely report liver function tests or markers of liver function to know the severity of liver dysfunction. Although the true risk vs. benefit is unclear, a retrospective analysis recently found an overall rate of 0.3% of bleeding in those with hepatitis C treated with SSRIs, suggesting a low risk. [34]
Patients receiving SSRIs had a lower risk of developing depression vs. placebo in those with HCV treated with INF-α-plus ribavirin. Future research should focus on the evaluation of other antidepressants and the safety of antidepressant use in this patient population.


Wednesday, January 22, 2014

Neutropenia-Lymphocyte count associated with infection risk during HCV interferon treatment

Lymphocyte count associated with infection risk during interferon treatment
Melia M. Clin Infect Dis. 2014;doi:10.1093/cid/ciu009.

Adults with hepatitis C who were treated with pegylated interferon and ribavirin for up to 48 weeks commonly experienced moderate, severe or life-threatening infections, according to a report in Clinical Infectious Diseases.

The nadir lymphocyte count, but not the nadir neutrophil count, was associated with the increased risk for infections in the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study.

“While the risk of infection associated with severe neutropenia due to chemotherapy among cancer patients and recipients of hematopoietic cell transplants is well-established, most studies have not demonstrated any increased risk among patients who develop neutropenia while receiving [pegylated interferon],” the researchers wrote. “Nevertheless, up to 23% of patients develop acute infections during HCV treatment.”

Patients in the IDEAL study were randomly assigned to varying doses of pegylated interferon with ribavirin for chronic HCV treatment. In this study, the investigators from evaluated the risk for infection among patients with myelosuppression, a common adverse effect of pegylated interferon treatment.

The IDEAL study included 3,070 treatment-naïve patients. Among those, 581 (19%) patients experienced moderate, severe or life-threatening infections, determined by the investigator. In a logistic regression model, female gender, history of depression and nadir on-treatment absolute lymphocyte count were associated with moderate, severe or life-threatening infections. After adjustment, pegylated interferon type (alfa-2a vs. alfa-2b) and nadir absolute neutrophil count were not associated with moderate, severe or life-threatening infections.

“This observation has important implications for the management of patients treated with [pegylated interferon/ribavirin] alone or in combination with other agents,” the researchers wrote. “While further research is needed to confirm this observation, clinicians should carefully monitor the [absolute lymphocyte count] in addition to the [absolute neutrophil count] for patients receiving HCV therapy with [pegylated interferon and/or ribavirin].”

Disclosure: See study manuscript for disclosure information.

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Monday, November 11, 2013

Gender-Oriented Analysis: Who Is More Likely to Respond To Dual Therapy W-PEG-IFN/RBV For Hepatitis C?

Who Is More Likely to Respond to Dual Treatment With Pegylated-Interferon and Ribavirin for Chronic Hepatitis C?

A Gender-Oriented Analysis

V. Di Marco, L. Covolo, V. Calvaruso, M. Levrero, M. Puoti, F. Suter, G. B. Gaeta, C. Ferrari, G. Raimondo, G. Fattovich, T. Santantonio, A. Alberti, R. Bruno, C. Mussini, M. Mondelli, F. Donato, A. Craxì

J Viral Hepat. 2013;20(11):790-800.

Discussion Only
Full Text Available @ Medscape

In this real-life study, we simultaneously assessed the actually known viral and host-related factors that can influence the effectiveness of combined PEG-IFN and RBV therapy. Patients were enrolled in tertiary centres with consolidated experience in the management of hepatitis C infection.

Only roughly one in 10 patients stopped treatment, the majority of whom in the first 12 weeks, because of subjective adverse effects. This low rate of adverse events is similar to that reported by registered trials (5–7), confirming that combination therapy with PEG-IFN and RBV is substantially well tolerated.

Analysis of the entire cohort showed that SVR was independently associated with host factors, such as female gender, younger age and C/C genotype of the rs8099860 SNP, and virologic factors such as virus genotype and low levels of serum HCV-RNA. Therefore, we separately analysed patients according to virus genotype and gender. We further divided females into those under the age of 50, and those 50 or older, in the light of a recent study that suggested that menopause influences SVR and that the average age of spontaneous menopause in Italy is 50.[26]

The characteristics observed in genotype 1 females over the age of 50 were similar to those identified by Villa et al.[26] in menopausal females included in their study. In fact, at baseline, females over 50 years included in our cohort had frequently high BMI and visceral obesity, metabolic alterations and severe histological liver damage, like those observed in the menopausal females in the study by Villa et al. These data confirmed that genotype 1 females over 50 years, especially during menopause, had several factors that reduce the efficacy of interferon-based therapy.[25]

Another host factor analysed in our cohort was the IL28B polymorphism. As reported in other studies, patients who carried the C/C genotype of the rs12979860 SNP had a higher likelihood of responding to dual therapy (12–15). This factor was independent of gender, virus genotype, degree of fibrosis and presence of metabolic cofactors. Age under 50 years and C/C genotype of the rs12979860 SNP were the only two independent favourable factors associated with RVR and SVR in females. Combining the two factors, the rate of RVR in females increased from 15.5% to 73.3%, and the rate of SVR increased from 27.6% to 84.6%. Using these variables, it is possible to identify three groups of naïve females infected with genotype 1. Females with no favourable factors have a very low baseline likelihood of achieving an SVR with dual combination therapy, and this likelihood remains about 50% even in patients who achieve an RVR. Therefore, these patients should be treated with the new therapeutic approach including PEG-IFN, RBV and telaprevir or boceprevir. On the other hand, females with both favourable factors have a very high baseline likelihood of achieving an SVR, and so do not need to be treated with triple therapy as first choice. Finally, in females who have only one of the two favourable factors, RVR predicts patients who have a close to 90% likelihood of achieving an SVR.

In males infected with HCV genotype 1, absence of visceral obesity was an independent host factor associated with SVR, in addition to serum HCV-RNA levels < 400 000 IU/mL and C/C genotype of the rs8099860 SNP. We found no association between age and SVR in genotype 1 males. A possible explanation is that the males, unlike the females, did not experience an increase in inflammation and rapid progression of fibrosis related to menopause. As in the females, in genotype 1 males, we also found an independent association between RVR and SVR. The likelihood of achieving an RVR and an SVR in males with C/C genotype of the rs8099860 SNP, without visceral obesity, and with baseline serum HCV-RNA levels < 400 000 IU/mL, was more than 64% and more than 85%, respectively. These males could be successfully treated with dual therapy. Even males who have 2 or 3 favourable factors have a relatively high likelihood of achieving RVR and SVR, and the presence of RVR predicts patients with a more than 85% likelihood of achieving an SVR. On the contrary, males with no or only one favourable factor have a less than 30% likelihood of achieving SVR, which increases to 57% in those with RVR, a figure lower than that obtained with the triple therapy in all patients with genotype 1. The discriminatory ability of our prediction rule was quite high, with the AUC of the model for predicting SVR in males being near 0.75 and 0.7 in females.

In genotype 2 and genotype 3 patients, we found a very high rate of SVR, and also that host-related factors do not affect the success of therapy. As reported in other studies, RVR was associated with a significantly higher rate of SVR both in females and males infected with genotype 2.[36] We observed a significant difference in SVR among females and males infected with genotype 3. Genotype 3 males who did not achieve an RVR had a rate of SVR of less than 30%. This observation could strengthen the hypothesis that at least males infected with genotype 3 who do not have an RVR should be treated for longer than 24 weeks.[37]

Triple therapy with boceprevir and telaprevir in naive patients infected with HCV genotype 1 obtains an SVR of more than 60%, but the pivotal trials on higher efficacy have also reported a greater number of adverse events and a risk of developing viral resistance.[9,10] AASLD practice guidelines[11] recommend as the optimal therapy for genotype 1 chronic HCV infection the use of boceprevir or telaprevir in combination with PEG-IFN and RBV, but alternative strategies for reducing costs and improving effectiveness using favourable factors associated with the success of dual or triple therapy have also been proposed.[38,39]

Our study suggests that simultaneous analysis of the demographic, genetic and metabolic characteristics of the host that can influence the efficacy of antiviral therapy, and viral factors that may affect the possibility of eradication, may indicate groups of genotype 1 patients with very different likelihoods of achieving an SVR through dual therapy with PEG-IFN and RBV. In males and females, the factors associated with SVR were substantially different, and should, in any event, be combined with the viral variables. In patients who have only a few favourable factors, RVR can significantly predict a successful cure.

This study suggests that factors associated with the efficacy of dual therapy may be different in males and females. However, some possible drawbacks of the research should be mentioned.

First, although the total number of patients included in the cohort was relatively large, we examined many factors possibly associated with response, which reduced considerably the number of subjects according to the combination of some variables and, consequently, the power of statistical tests. For this reason, these results need to be confirmed in a larger data set of patients. Second, several published studies analysed genetic,[12–15] metabolic[19–23] and viral factors,[27,28] which are possibly associated with sustained virologic response, but, to our knowledge, there are not studies that analysed all together the factors assessed in our research so far.

In conclusion, our study suggests that some factors associated with the success of dual antiviral therapy may be different in males and females and that dual therapy with PEG-IFN and RBV can still be used for genotype 1 patients who have favourable clinical, genetic and viral profiles.

  • Abstract and Introduction
  • Patients and Methods
  • Methods
  • Results
  • Discussion

  • Saturday, July 27, 2013

    Fever after interferon injection for HCV predicts treatment success

    Fever after interferon injection for HCV predicts treatment success

    Last Updated: 2013-07-25 15:20:15 -0400 (Reuters Health)

    By Will Boggs, MD

    NEW YORK (Reuters Health) - Patients with chronic hepatitis C virus (HCV) who become febrile after peginterferon alfa-2a (PEG-IFN) injection are more likely to have a virological response than those who don't, a retrospective study suggests.

    "Many patients find it difficult to complete interferon-based regimens because of the side-effects," Dr. Yaron Rotman from National Institutes of Health, Bethesda, Maryland told Reuters Health by email. "Clinicians can use our findings as a tool to encourage patients who suffer from side effects, to let them know that these actually suggest they are responding, and to help convince them to persist and maintain their compliance and adherence to treatment."

    Fever commonly follows PEG-IFN injection, but the factors that predict the magnitude of this febrile response and its association with the antiviral efficacy of PEG-IFN are unknown.

    To explore this issue, Dr. Rotman and colleagues reviewed data from a prospective trial of 60 treatment-na�ve adults with chronic HCV.

    Most (57%) were infected with genotype 1, and their average age was 52 years.

    As reported online July 11th in the Journal of Hepatology, oral temperature rose above 38.0 C in 20 patients (33%) at a median of 12.5 hours after injection.

    The maximum temperature increase correlated strongly with the first phase virological decline, with a 0.49 C increase for each 1 log10 decline in viral levels.

    Temperature increases did not differ significantly by gender. The link between temperature increase and virological decline also didn't differ by gender, nor by the presence or absence of cirrhosis or the viral genotype.

    The maximum temperature change was higher for patients with the IL28B-related SNP rs12979860 CC genotype, and the correlation of maximum temperature increase with virological decline was limited to patients with the CC genotype.

    Despite the link of temperature change with virological response, maximum temperature change did not predict either rapid or sustained virological response very well, and it was only a weak predictor of early virological response.

    "Since the spike of fever is independent of virological predictors of response, it could potentially serve in the research setting as a tool to tease out host interferon-responsiveness from viral- and liver-related factors," the researchers say.

    "The clinical importance of the study is in the novel appreciation that medication side-effects are closely linked to its efficacy," Dr. Rotman said.

    "Of course," he continued, "the interferon-induced fever is not causing viral clearance, and we are not claiming that, but its occurrence early on (in the first 24 hours) can give patients and their doctors an inclination that the drug is actually doing its job."

    Dr. Hans Van Vlierberghe from Ghent University Hospital in Belgium, who has published work on chronic HCV treatment, told Reuters Health by email, "This is a very nice and elegant study, monitoring temperature after peginterferon administration and linking the rise in temperature to response. However, treatment of hepatitis C is evolving more and more to an interferon-free combination schedule, making the observation by the authors less and less relevant."

    Dr. Rotman added, "I would have to credit the first author, Hwalih Han, BSN, BS, the research nurse specialist, who has done a significant amount of the work on this study under my mentorship. Research nurses are not typically involved in the analysis and writing of clinical trial manuscripts; our work shows how physicians and nurses can work in synergy not only in clinical care, but also in research, especially in areas that straddle both disciplines."


    J Hepatol 2013.

    Wednesday, June 12, 2013

    Noncompliance with guidelines 'stop rules' for the treatment of hepatitis C is frequent in daily practice.

    Eur J Gastroenterol Hepatol. 2013 Jun 6. [Epub ahead of print]

    Noncompliance with guidelines for the treatment of hepatitis C is frequent in daily practice.

    Niederau C, Mauss S, Böker K, Lutz T, Heyne R, Moog G, John C, Witthöft T, Alshuth U, Hüppe D.


    Department of Medicine, Katholische Kliniken Oberhausen, St Josef Hospital, Oberhausen bCenter for HIV and Hepatogastroenterology, Düsseldorf cCenter for Hepatology, Hannover dInfektiologikum Frankfurt, Frankfurt eLiver and Study Center Checkpoint fCenter of Gastroenterology, Berlin gMedical Office for Gastroenterology and Hepatology, Kassel hMedical Office for Gastroenterology and Hepatology, Stade iRoche Pharma AG, Virology, Grenzach-Wyhlen jCenter for Gastroenterology and Hepatology, Herne, Germany.



    In trials of pegylated interferons (PEG-IFNs), the lack of an early virological response (EVR) was associated with sustained virological response (SVR) rates of only 0-3%. The rates were similarly low when hepatitis C virus (HCV)-RNA was positive at week 24. Treatment guidelines therefore recommend 'stop rules' on the basis of HCV-RNA levels at weeks 12 and 24 of treatment. We analyzed the use of these rules under 'real-life' conditions.


    This was a prospective, community-based cohort study involving 467 physicians from institutions throughout Germany, including 4727 treatment-naive genotype-1 patients who received a full course of treatment with PEG-IFN α-2a plus ribavirin between 2003 and 2009.


    The overall SVR rate was 43.1%. Failure to determine EVR decreased from 20% in 2003-2004 to 10% in 2006-2007. Unexpectedly, treatment was continued in 86.1% of patients without an EVR and in those who had an EVR but were HCV-RNA positive at week 24 (67.5%), resulting in SVR rates of 15.7 and 40.9%, respectively. Between 77.5 and 95.3% of physicians did not follow prescribed recommendations to reduce PEG-IFN or ribavirin in cases of hematological abnormalities.


    Although recommendations to assess EVR and HCV-RNA at week 24 were increasingly observed in daily practice, the corresponding 'stop rules' in nonresponders were neglected. The subsequent SVR was 5-10 times higher than that reported in controlled trials. This may partly be because of the fact that reductions in PEG-IFN or ribavirin dose were not performed despite recommendations. The issue of stop rules will gain even more interest since the first HCV protease inhibitors have been approved. Prolongation of treatment beyond the new stop rules is associated with risks of resistant HCV variants. Thus, the new stop rules are to be observed more strictly when compared with previous therapy with interferons and ribavirin.

    Tuesday, May 7, 2013

    Early HCV Response More Likely With Peg-Interferon Alpha-2a Than -2b

    Pegasys (Peginterferon alfa-2a )..Peg-Intron (Peginterferon alfa-2b)
    Reuters Health Information
    Early HCV Response More Likely With Peg-Interferon Alpha-2a Than -2b
    May 03, 2013
    By Will Boggs, MD

    NEW YORK (Reuters Health) May 03 - Patients with hepatitis C virus (HCV) are more likely to have an early response to pegylated interferon alpha-2a than alpha-2b, a new meta-analysis has found.

    "The Cochrane meta-analysis about sustained virological response and our meta-analysis taking into account rapid virological response and early virological response (show that) the efficacy of peg-a-2a is superior to peg-a-2b and thus it is the first choice in the management of hepatitis C," Dr. Manuel Romero-Gomez from Valme University Hospital in Seville, Spain, told Reuters Health by email.

    Dr. Romero-Gomez and colleagues pooled data from eight randomized trials that compared peginterferon alpha-2a and alpha-2b in 4,566 patients.

    A complete early virological response (EVR) was achieved by 53.3% of patients treated with peginterferon alpha-2a and 43.8% of those treated with alpha-2b (p=0.0028), the authors reported April 14 online in Alimentary Pharmacology & Therapeutics.

    Results were similar in a sub-analysis of patients infected with HCV genotypes 1 and 4, but the difference fell short of statistical significance.

    Crude rates of rapid virological response (RVR) were higher for peginterferon alpha-2a than alpha 2-b (25.0% vs 16.8%; p=0.0056), and results were also significantly better for alpha-2a in a sub-analysis of patients infected with HCV genotypes 1 and 4 (p=0.0048).

    "RVR and EVR are crucial in the management of therapy in hepatitis C because they allow us to make decision about futility rules, saving cost and adverse events," Dr. Romero-Gomez said. "Using peg-a-2a we can treat more patients with double therapy if they reach RVR or add boceprevir/telaprevir in patients without RVR."

    "We need more data to define which patients have to be treated with peg-a-2a or peg-a-2b," Dr. Romero-Gomez cautioned. "According to baseline characteristics, pega-a-2a seems to be better in very difficult-to-cure patients (genotype 1 with advanced fibrosis and metabolic derangements), but this point needs to be confirmed in further studies."


    Aliment Pharmacol Ther 2013

    Monday, April 1, 2013

    Type 1 Diabetes Mellitus with Dual Autoimmune Mechanism Related to Pegylated Interferon and Ribavirin Treatment for Chronic HCV Hepatitis

    Type 1 Diabetes Mellitus with Dual Autoimmune Mechanism Related to Pegylated Interferon and Ribavirin Treatment for Chronic HCV Hepatitis

    Cristina Popescu1, 2, Gabriel-Adrian Popescu1, 2, Victoria Arama1, 2

    1) "Prof. dr. Matei Bals" National Institute of Infectious Diseases
    2) "Carol Davila" University of Medicine and Pharmacy Bucharest Romania


    We report a case of type 1 diabetes mellitus during pegylated interferon and ribavirin treatment for chronic
    hepatitis C, in a young man previously diagnosed with Hashimoto's thyroiditis and vitiligo. The diabetes
    mellitus occurred during the 12th month of therapy and the cessation of interferon was necessary. Besides
    anti-islet autoantibodies our patient had also anti-insulin receptor autoantibodies, which explains the type
    B insulin resistance. One year after interferon discontinuation the patient continues insulin treatment and
    all the pancreatic autoantibodies are still positive. Patients with autoimmune disorders should be closely
    monitored and periodically tested for pancreatic autoantibodies during interferon treatment, even in the
    absence of hyperglycemia.

    Key words:
    type 1 diabetes mellitus - interferon-alpha side effects - insulin resistance - hepatitis.

    AIRA - anti-insulin receptor autoantibodies; APS - autoimmune polyglandular syndrome; cANCA - classical antineutrophil cytoplasmic antibodies; DM - diabetes mellitus; DNA - deoxyribonucleic acid ; FT4 - free thyroxin; GAD Ab - glutamic acid decarboxylase antibodies; HbA1c - glycated haemoglobin; HCV - hepatitis C virus; HLA - human leukocyte antigen; IA-2 Ab- insulinoma associated antigen 2 antibodies; IAA - insulin autoantibodies; ICA - islet cell autoantibodies; NK - natural killer; PAA - pancreatic associated autoantibodies; pANCA- protoplasmic-staining antineutrophil cytoplasmic antibodies; T1DM - type 1 diabetes mellitus; TNF - tumor necrosis factor; TSH - thyroid-stimulating hormone; VL - viral load; ZnT8 Ab - zinc transporter-8 autoantibodies; IL2 - interleukin 2; IL10 - interleukin 10.

    Thursday, March 7, 2013

    Peg-Interferon Plus Ribavirin Safe, Modestly Effective for HCV in Kidney Recipients

    By Will Boggs, MD

    NEW YORK (Reuters Health) Mar 05 - In kidney transplant recipients with chronic hepatitis C, pegylated interferon plus ribavirin does not increase rejection rates and is modestly effective, researchers from Saudi Arabia report.

    "Our primary concern in approaching hepatitis C-infected renal transplant patients in our clinical practice was that the evidence citing the poor outcome of interferon-based therapy was, unfortunately, of a poor grade and yet had found its way into guideline recommendations," Dr. Faisal M. Sanai from King Saud University, Riyadh, Saudi Arabia told Reuters Health.

    "We believe that in an era of evidence-based practice, clinicians should be willing to challenge established dogmas if the evidence in favor of (or against) a practice is poorly supported by evidence."

    Dr. Sanai and colleagues did just that, testing pegylated interferon and ribavirin in a prospective study of 32 kidney recipients with treatment-na�ve chronic HCV. They compared that group with 31 untreated controls who either declined study participation or were considered unsuitable candidates.

    Treated patients received pegylated interferon alfa-2a 135-180 mcg/week, plus ribavirin 200-1200 mg/day for 48 weeks. Actual doses were adjusted for glomerular filtration rate.

    Twelve patients (37.5%) had a sustained virologic response (SVR) after at least 12 weeks of treatment. Four patients (12.5%) had a rapid virologic response (i.e., within 4 weeks), and 18 (56.3%) had early virologic responses (i.e., within 12 weeks).

    Among the 13 patients with end-of-treatment responses, three suffered virologic relapse during follow-up. In addition, two of five patients who stopped treatment due to nonhematological effects also relapsed.

    No one developed acute rejection, but four treated patients (12.5%) and eight controls (25.8%) had allograft dysfunction with sustained increases in creatinine at week 96.

    The authors say these results compare favorably with those of a recent meta-analysis in which 18% of 102 patients achieved SVR and 30% developed chronic allograft nephropathy.

    Two patients had serious nonrenal adverse events, and three patients discontinued treatment - two for grade 3/4 hematological effects and one after withdrawing consent.

    All hematological adverse events were transient and returned to baseline levels by week 72, according to the authors' February 19 report online in the Journal of Hepatology.

    In binary logistic regression analysis, early virologic response was the only independent predictor of SVR.

    "A pegylated peginterferon alpha-2a dose of 135 mcg/week and ribavirin dose of 400 mg/day may be an appropriate dosing strategy in order to improve treatment tolerance without necessarily compromising SVR rates," the researchers conclude. "The results of this study provide an impetus for conducting a larger, randomized controlled trial aiming to define the optimal dosage of peginterferon alpha-2a and ribavirin and identify predictors of graft dysfunction."

    "We believe that physicians should be generally heartened to use interferon-based therapy in carefully selected patients with intense monitoring of potential side effects," Dr. Sanai concluded. "Of course, this is true only as long as there is an adequate rationale for the use of this kind of therapy."

    He added, "We are now treating qualified HCV patients post renal transplantation under the stringent monitoring criteria we adopted in our study protocol. We will report the post study, real life experience in due course. We would like to see our study as an impetus and encouragement to other groups for conducting larger clinical trials in this area."


    J Hepatol 2013.

    Thursday, February 21, 2013

    Peg-Interferon and Ribavirin in HCV Compensated Cirrhosis

    Role of IL-28B and Inosine Triphosphatase Polymorphisms in Efficacy and Safety of Peg-Interferon and Ribavirin in Chronic Hepatitis C Compensated Cirrhosis With and Without Oesophageal Varices


    Genetic factors can influence the outcome of antiviral therapy in chronic hepatitis C (HCV). We evaluated the role of interleukin-28B single nucleotide polymorphisms (SNPs) and inosine triphosphatase (ITPA) gene variants in HCV cirrhosis treated with Peg-Interferon and ribavirin. A prospective cohort of 233 patients with compensated cirrhosis received 1–1.5 μg/kg/week of Peg-Interferon alpha-2b plus 1000–1200 mg/day of RBV for 48 weeks. A sustained virologic response (SVR) was achieved in 27% of patients. On multivariate logistic analysis, the absence of oesophageal varices (OR 3.64 CI 95% 1.27–10.44 P = 0.016), infection with genotype 2 or 3 (OR 4.06, CI 95% 1.08–15.26, P = 0.038), C/C alleles of rs12979860 SNP (OR 7.04, CI 95% 2.40–20.72, P < 0.001) and rapid virologic response (RVR) (OR 78.29, CI 95% 16.07–381.29, P < 0.001) were independently associated with SVR. Patients who experienced post-treatment relapse received lower total doses of Peg-Interferon (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and lower total dose of RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) than patients who achieved an SVR. ITPA variants predictive of high ITPase activity were associated with reduction of haemoglobin ≥3 g/dL in the first 4 weeks (P < 0.001), and with reduction of haemoglobin <10 g/dL (P = 0.03) on treatment. In conclusion, combination therapy with Peg-Interferon and RBV in patients with HCV cirrhosis must be guided by virus genotype, severity of portal hypertension, favourable IL-28B polymorphisms and ITPA variants, and RVR on treatment.

    The prevalence of hepatitis C virus (HCV) cirrhosis and the incidence of its complications have increased recently in several countries because of the long-term persistence of HCV infection.[1,2] Identification and treatment of patients with HCV cirrhosis can reduce the number of cases of decompensation and hepatocellular carcinoma (HCC).[3–6] There are few data on the efficacy and safety of combination therapy with Peg-Interferon (Peg-IFN) and ribavirin (RBV), in cirrhosis with portal hypertension, because these patients have been excluded from randomized controlled trials. Host factors such as age, gender, staging of liver fibrosis and steatosis, HCV genotypes, baseline HCV RNA levels and rapid disappearance of serum HCV RNA can influence the rate of sustained virologic response (SVR).[7,8]

    Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) located in and near the interleukin-28B (IL-28B) locus, which encodes for IFN-λ3 and is associated with a higher rate of SVR.[9–11] Two genetic variants of rs1127354 and rs7270101 SNPs in the inosine triphosphatase (ITPA) gene, which encode a protein that hydrolyses inosine triphosphate (ITP), have been found to be associated with anaemia in patients treated with Peg-IFN and RBV.[12–14]
    As patients with cirrhosis have a low SVR rate and frequently have adverse events,[15] it may be relevant to identify factors associated with higher probability of viral clearance, and to assess a patient's likelihood of SVR.

    We studied a large prospective cohort of patients with compensated HCV cirrhosis to assess the safety and the efficacy of Peg-IFN and RBV, and to evaluate the association between virus-, genetic- and disease-related factors and SVR and the incidence of adverse events.

    Patients Selection
    In this independent, investigator-driven, prospective cohort study, we included all consecutive anti-HCV positive patients with METAVIR stage 4 at liver biopsy and/or presence of oesophageal varices (OV) observed at our Liver Unit between June 2003 and June 2007. Other inclusion criteria were age below 70 years, ultrasound scan (US) negative for focal lesions, values of alpha-1-fetoprotein levels (AFP) ≤20 ng/dL, bilirubin ≤2 mg/dL, albumin ≥2.8 g/dL, prothrombin time ≥60%, alanine-aminotransferase (ALT) upper normal limit, HCV RNA positive by polymerase chain reaction (PCR), naïve to antiviral treatment, or previously treated with interferon alone.
    Exclusion criteria were previous decompensation of cirrhosis, HBsAg and/or anti-HIV positivity, history of alcohol abuse or IV drugs, platelet count ≤40 × 103/dL, leucocyte count ≤2.0 × 103/dL or absolute neutrophil count ≤1.0 × 103/dL, haemoglobin values ≤11 g/dL, creatinine ≥1.5 mg/dL, previous combination therapy with interferon or Peg-IFN plus RBV. The study protocol was approved by our hospital's Ethics Committee, and written consent was obtained from all patients.

    Baseline Evaluation
    At baseline, a quantitative HCV RNA was performed by Cobas Monitor HCV v 2.0 (Roche Diagnostics, Basel, Switzerland), and HCV genotyping by Innolipa (Innogenetics, Belgium). All patients underwent clinical assessment including haematologic control, liver function tests, renal function tests, AFP serum levels, abdominal US and upper gastro-intestinal endoscopy to evaluate the presence and degree of OV.

    Genetic Tests
    Patients were genotyped for rs12979860 SNP of the IL-28B locus and for rs1127354 and rs7270101 SNPs of ITPA variants using serum samples collected at baseline and frozen at −80 °C. DNA was purified using the QIAmp Circulating Nucleic Acid Kit (Qiagen, Mainz, Germany), and DNA samples were quantified using spectrophotometric determination. To genotype the rs12979860 SNP, we used a custom assay, while commercial genotyping assays were available for the rs1127354 SNP (cat. C_27465000_10) and the rs7270101 SNP (C_29168507_10). The ABI TaqMan allelic discrimination method commercialized by Applied Biosystems was used, and the genotyping call was made with SDS software v.1.3.0 (ABI Prism 7500, Foster City, CA, USA). In accordance with previous reports,[12,13] the severity of the ITPase deficiency variable was defined according to the allele combination of rs1127354 and rs7270101 SNPs. The combination of two wild-type alleles (C/C for rs1127354 SNP and A/A for rs7270101) was predictive of absence of ITPase deficiency, while the combination with at least the presence of a minor allele (A for rs1127354 SNP and C for rs7270101) in heterozygosis or homozygosis form was predictive of mild, moderate or severe ITPase deficiency.

    Treatment Schedules
    Patients included in the cohort between June 2003 and March 2005 received 1 μg per kilogram per body weight weekly of Peg-IFN α2b (PEG-Intron; Schering Plough, Merck & Co. Inc., (formerly Shering-Plough) Whitehouse Station, NJ, USA.) plus 1000 mg/daily (patients with body weight <70 kg) or 1200 mg/day (patients with body weight ≥70 kg) of oral RBV (Rebetol; Schering Plough) for 48 weeks. Patients included after March 2005 received 1.5 μg per kilogram per body weight weekly of Peg-IFN α2b plus oral RBV at the same doses for 48 weeks. Granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) was used after March 2005, when Italian medical regulations allowed these drugs to be used for cirrhotic patients on combination antiviral therapy.

    Clinical and Virologic Evaluation of Therapy
    All patients underwent haematologic, liver and renal function tests every 4 weeks on therapy and every 24 weeks during post-therapy follow-up. Abdominal US control and AFP were performed every 6 months to assess the HCC screening and surveillance. All patients were observed for at least 24 months. The study ended at the end of December 2009.

    The primary virologic outcome was SVR, defined as undetectable HCV RNA by sensitive qualitative PCR assay with a cut-off <50 IU/mL (Amplicor HCV v 2.0 Roche Diagnostics) 24 weeks after cessation of therapy. Virologic outcomes of therapy, in accordance with European Association of the Study of the Liver Clinical Practice Guidelines (8), were rapid virologic response (RVR), defined as undetectable HCV RNA by PCR at 4 weeks of therapy; early virologic response (EVR), defined as undetectable HCV RNA by PCR at 12 weeks of therapy; late virologic response (LVR), defined as undetectable HCV RNA by PCR at 24 weeks of therapy; end-of-treatment virologic response (ETR), defined as undetectable HCV RNA by PCR at 48 weeks of therapy for patients who completed entire treatment schedule, or at the last clinical control in patients who were withdrawn from therapy because of adverse events. Treatment was withdrawn after 24 weeks if HCV RNA was still positive.

    Assessment of Safety
    Safety was assessed by haematologic control and liver function tests, evaluation of subjective adverse events and evidence of liver- and nonliver-related clinical events every month during treatment. Treatment was lowered or discontinued if severe adverse events occurred. Before March 2005, RBV was lowered to 600 mg/day if haemoglobin levels were lower than 10 g/dL, and was discontinued if the values fell below 8.5 g/dL. The dose of Peg-IFN was decreased by 50% if the total leucocyte count was <1.5 × 103/dL or if the absolute neutrophil count was <1.0 × 103/dL. Peg-IFN was discontinued if the total leucocyte count dropped to <1.0 × 103/dL or the absolute neutrophil count dropped to <0.75 × 103/dL and/or if the platelet count fell below 25 × 103/dL. When the drugs were stopped, they were not reintroduced.

    After March 2005, when Italian medical regulations allowed G-CSF and EPO for HCV cirrhotic patients on antiviral combination therapy, patients with haemoglobin levels lower than 10 g/dL were treated with alpha erythropoietin at a dose of 10 000 IU three times a week or 40 000 times a week. Patients with an absolute neutrophil count <0.75 × 103/dL were treated with G-CSF at the dose of 30 MU/week. RBV was lowered to 600 mg/day if haemoglobin levels were still lower than 10 g/dL after 4 weeks of erythropoietin therapy, and was discontinued if the values fell below 8.5 g/dL on erythropoietin therapy. Antiviral therapy was also withdrawn if ALT values exceeded 10 times upper normal limit and/or bilirubin rose beyond 4 mg/dL or if liver decompensation or HCC appeared.
    To evaluate the association between the ITPase deficiency variants and incidence of anaemia during combination therapy, we analysed the rate of patients who experienced a reduction of haemoglobin levels ≥3 g/dL in the first 4 weeks of therapy or over the full course of 48 weeks, and the rate of patients who experienced a decrease in haemoglobin to <10 g/dL.

    Statistical Analysis
    All data were entered into a database and analysed using SPSS 13.0 for Windows software (SPSS Inc., Chicago, IL, USA) on an intention-to-treat (ITT) basis. Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as absolute and relative frequencies. The differences between continuous data were analysed by t-test, and corrected chi-square analysis was used for dichotomous or categorical variables. Fisher's exact test was used to examine the association between baseline features and SVR. Multiple logistic regression analysis was used to identify baseline variables (age, gender, previous treatment with interferon monotherapy, diagnosis of diabetes, presence of OV, haemoglobin values, leucocyte and platelet counts, AST/ALT, gamma-glutamyl transferase (GGT), bilirubin, albumin values, prothrombin time, viral genotypes, serum HCV RNA levels, genotypes of rs12979860 SNP, variants of ITPA deficiency, Peg-Interferon doses and RBV doses) and on treatment variables (RVR) associated with SVR. Variables with a threshold value of P = 0.05 at univariate analysis were included in the model, and variables with a threshold value of P = 0.05 were considered significant in the final model. The results were expressed as odds ratio (OR) and their 95% confidence intervals (CI). Cumulative incidence curves of haemoglobin reduction ≥3 g/L in relation to ITPase deficiency variants were estimated with the Kaplan–Meier method, and the differences between groups were assessed using logrank tests.

    Baseline Clinical Features
    The baseline clinical features of the 233 patients included in the cohort are shown inTable 1. One hundred and four patients (44.6%) had OV, and 22 of them (9.4%) were on primary prophylaxis with beta-blockers at the start of antiviral therapy because they had F2 OV. Sixty-five patients (27.9%) had a previous diagnosis of diabetes, and 75 patients (32.2%) had hypertension. Forty-eight patients (20.6%) had values <75 × 103. The majority of patients (85%) were infected with HCV 1b genotype, and 73.4% of patients were naïve to antiviral therapy. The prevalence of C/C genotype of rs12979860 SNP was 29%, while the distribution of ITPA variants was the same as that described by Thompson et al.[14,15] One hundred and fourteen patients received 1 μg/kg/week of Peg-IFN α2b plus 1000/1200 mg/daily of RBV for 48 weeks, and 119 patients received 1.5 μg/kg/week of Peg-IFN α2b plus RBV at the same doses for 48 weeks.

    Virologic Response
    On ITT analysis, 44 patients (18.9%) achieved an RVR, 52 patients (22.3%) achieved an EVR and 19 patients (8.1%) an LVR, with a total number of 115 patients (49.3%) who achieved an ETR. After 24 weeks of observation from the end of therapy, 63 patients (27.0%) achieved an SVR, while 52 patients (22.3%) showed a virologic relapse.

    Logistic Regression Modelling for Sustained Virologic Response
    We analysed baseline and on-therapy variables that were associated with SVR. On univariate analysis, absence of OV (P = 0.016), higher albumin (P = 0.042) and ALT values (P = 0.009), lower GGT values (P = 0.035), infection by genotype 2 or 3 (P < 0.001), C/C genotypes of rs12979860 SNP (P < 0.001) and RVR (P < 0.001) were associated with SVR (Table 2). On multivariate logistic analysis, absence of OV (OR 3.64 CI 95% 1.27–10.44 P = 0.016), viral genotype 2 or 3 (OR 4.06, CI 95% 1.08–15.26, P = 0.038), C/C genotype of rs12979860 SNP (OR 7.04, CI 95% 2.40–20.72, P < 0.001) and RVR (OR 78.29, CI 95% 16.07–381.29, P < 0.001) were independently associated with SVR.

    Viral Genotypes and Virologic Response
    Only 25 (12.5%) of 199 genotype, 1 patient achieved an RVR vs 19 (55.9%) of 34 patients with genotype 2 or 3 (P < 0.001; Fig. 1). Rates of EVR and LVR were comparable for different genotypes (22.1% and 8.5% for genotype 1 and 23.5% and 5.9% for genotype 2 or 3, respectively). ETR was achieved in 86 patients (43.2%) with genotype 1, and in 29 patients (85.3%) with genotype 2 or 3 (P < 0.001). After the end of therapy, we observed a virologic relapse in 46 of 86 genotype 1 patients (53.5%) with ETR, but in only 6 of 29 genotype 2 or 3 patients (20.1%). Overall, 40 of 199 genotype 1 patients (20.1%) and 23 of 34 patients (67.6%) with genotype 2 or 3 achieved an SVR (P < 0.001).

    Figure 1
    Virologic response according to viral genotypes RVR, rapid virologic response; EVR, early virologic response; LVR, late virologic response; ETR, end-of-treatment virologic response; SVR, sustained virologic response.

    Oesophageal Varices and Virologic Response
    Patients with and without OV achieved a comparable rate of virologic response on therapy. Patients with OV had a higher rate of relapse and, finally, the rate of SVR was significantly higher in patients without OV than in patients with OV (33.3%vs 19.2%, P = 0.01).

    Time of Virologic Response on Therapy and Sustained Virologic Response
    An RVR occurred in 25 of 199 genotype 1 patients, and in 19 of 34 genotype 2 or 3 patients (12.5%vs 55.9%, P < 0.001), while an EVR occurred in 44 of 199 genotype 1 patients, and in 8 of 34 genotype 2 or 3 patients (22.1%vs 23.5%, P = 0.6; Fig. 2). The rate of SVR was very high regardless of genotype in patients who achieved an RVR (92% in 25 genotype 1 patients and 84.2% in 19 genotype 2 or 3 patients), while it was correlated with genotype in patients who achieved an EVR (34.1% in 44 genotype 1 patients and 87.5% in 8 genotype 2 or 3 patients, P = 0.007).

    Figure 2.
    Rates of sustained virologic response (SVR) according to time of virologic response on treatment, and viral genotypes RVR, rapid virologic response; EVR, early virologic response; LVR, late virologic response.
    IL-28B Polymorphisms and Virologic Response
    Polymorphism in the interleukin-28B was available in 206 patients (88.4%; Fig. 3). In the entire cohort, the C/C genotype of rs12979860 SNP was significantly associated with the rate of SVR (51.6% in C/C patients vs 19.2% in C/T or T/T patients, P < 0 .001). The rs12979860 SNP was not a determinant of SVR in genotype 1 patients who achieved RVR (100% in 14 patients with C/C genotype and 87.5% in 8 patients with C/T or T/T genotype) but was a determinant in patients who achieved EVR (59% in 17 patients with C/C genotype and 19.2% in 26 patients with C/T or T/T genotype, P = 0.01).

    Figure 3.
    Sustained virologic response (SVR) according to time of response on therapy and IL-28B single nucleotide polymorphisms in genotype 1 patients RVR, rapid virologic response; EVR, early virologic response; LVR, late virologic response.
    Drugs Doses and Sustained Virologic Response
    We evaluated Peg-IFN and RBV doses received by 115 patients who achieved an ETR. Higher total doses of Peg-IFN and RBV reduced the rate of post-treatment relapse. In fact, patients who experienced post-treatment relapse received lower total doses of Peg-IFN (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and lower total dose of RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) than patients who achieved an SVR. When we evaluated only genotype 1 patients with ETR, the total dose of Peg-IFN (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) remained significantly lower in patients who experienced relapse than in patients who achieved an SVR.

    Adverse Events on Therapy
    Fifty-six patients (24%) were withdrawn from treatment because of adverse events (Table S1). Twenty-one patients (9.1%) stopped treatment because of specific events, with the most common event being severe fatigue. Eight patients (3.5%) discontinued treatment because of psychiatric or neurologic disorders, two patients (0.8%) because of vascular disorders and three patients (1.3%) contracted serious infection. Eight patients (3.4%) discontinued treatment because of liver-related complications: four developed ascites, on developed encephalopathy and one portal thrombosis. All of them had OV. One patient showed HCC at US control after 6 months of therapy, and another patient developed an ALT flare after 4 months of therapy. The laboratory abnormalities that caused treatment discontinuation were severe anaemia in seven patients (3%) and severe leukopenia in five patients (2.2%), while only two patients (0.8%) had severe thrombocytopenia.

    Variants in the Inosine Triphosphatase Gene and Haemolytic Anaemia
    On treatment, 105 of 133 patients (78.9%) who carried variants predictive of high ITPase activity, 24 of 41 patients (58%) who carried polymorphisms associated with mild reduction in ITPase activity, and 16 of 32 patients (50%) who carried polymorphisms associated with moderate or severe reduction in ITPase activity experienced a reduction of haemoglobin levels ≥3 g/dL (P < 0.001 by logrank test; Fig. 4). Thirty of 133 of patients (22.5%) with high ITPase activity, but none of 41 patients with mild reduction in ITPase activity, and only one of 32 patients (3.1%) with a moderate or severe reduction in ITPase activity experienced a reduction of haemoglobin levels ≥3 g/dL in the first 4 weeks of treatment (P < 0.001). Finally, patients with high ITPase activity had a significantly higher risk of reduction of haemoglobin values to <10 g/dL than patients with mild, moderate or severe reduction in ITPase activity (51/133 vs 17/73, P = 0.03).

    Figure 4.
    Incidence of haemoglobin reduction ≥3 g/L during treatment according to ITPase deficiency variants identified by Kaplan–Meier method (P < 0.001 by logrank test).
    Among 71 patients who experienced a reduction of haemoglobin values to <10 g/dL, 44 patients used EPO as support therapy and 27 adjusted RBV doses. Eighteen of 44 patients (41%) who used EPO achieved an SVR, while five of 27 patients (18.5%) who reduced RBV doses achieved an SVR (P = 0.06).
    The efficacy of antiviral therapy with Peg-IFN and RBV is evidence based in patients with cirrhosis, as the eradication of HCV significantly reduces the incidence of disease complications and increases survival.[4–6] In this setting of patients, the overall rate of SVR is <30%, with a clear difference between genotype 1 or 4 patients who achieved an SVR in <20% of cases, and genotype 2 or 3 patients who achieved an SVR in more than 50% of cases.[16–18] In addition, the rate of therapy withdrawal because of adverse events was higher in patients with cirrhosis than in those with chronic hepatitis.[15]

    This is the first study to evaluate viral factors, genetic variants, disease features, drugs doses and kinetics of virologic responses that are associated with antiviral therapy outcomes in patients with advanced, but not decompensated, cirrhosis.

    About half of the patients included in our cohort had OV and 20% had platelet counts <75 × 103. As reported by the studies of the HALT-C Trial Group, patients with these characteristics have a low probability of achieving an SVR[19] and a high probability of developing or increasing OV[20] and of developing HCC[21] during the follow-up. In this setting of 'difficult to treat patients', it is crucial to identify predictors of SVR and host factors associated with the development of severe adverse events on therapy and to understand the kinetics of virologic response to apply a response-guided strategy.[8]
    The overall rate of SVR in our study was 27%, with no significant differences among the patients in terms of age, gender and BMI. SVR was similar in naïve patients and patients previously treated with interferon alone. By contrast, absence of OV, 'easy' viral genotypes, 'favourable' IL-28B polymorphisms and RVR on therapy were all independently associated with SVR. Patients with OV achieved the same rate of virologic response on therapy as patients without OV, but they had a higher rate of relapse, and therefore, the rate of SVR was significantly higher in patients without OV. It is difficult to explain the mechanisms underlying these data, but it is likely that the progression of fibrosis simultaneously increases the portal pressure and reduces the possibility of HCV clearance.[22]
    The rate of SVR was 68% in genotype 2 patients, and 66% in genotype 3 patients. In this subset of patients, the success of therapy was not related to IL-28B polymorphisms and not conditioned by RVR. It is unclear whether these patients require 48 weeks of therapy or could be treated with a cycle of 24 weeks. A recent study[18] suggests that treatment failure was the consequence of higher rates of post-treatment relapse in genotype 2 or 3 cirrhotic patients than in patients with chronic hepatitis treated for 24 weeks and reported a rate of 29% and 61% in genotype 2 and genotype 3 cirrhotic patients, respectively. In our study, all patients were treated for 48 weeks, and the rate of post-treatment relapse was 19% in genotype 2 patients, and 25% in genotype 3 patients. These data reinforce the indication for PEG-IFN and RBV in genotype 2 and 3 patients with compensated cirrhosis and confirm the suggestion that this group of patients may benefit from extended duration of treatment.[23]

    Only 20.1% of genotype 1 patients achieved an SVR, and this low rate of success was related to IL-28B polymorphisms and the time of virologic response during treatment. First, the low rate of SVR may be related to low prevalence of C/C genotype of rs12979860 SNP among genotype 1 cirrhotics, and to the low rate of RVR. Second, we observed a high post-treatment relapse rate in patients who carried a C/T or TT of rs12979860 SNP and who achieved EVR or LVR. This suggests that genotype 1 patients who carry C/C genotypes of rs12979860 SNP and achieve an RVR have a very high likelihood of achieving an SVR with 48 weeks of combination therapy, but patients with C/T or TT genotypes of rs12979860 SNP who do not achieve an RVR have a very low likelihood of obtaining clearance of HCV and should be considered for new therapies with direct-acting antivirals.[24,25]
    Finally, we observed that the rate of SVR in the 115 patients who achieved an ETR was related to higher doses of Peg-IFN and RBV. Analysis of the SVR rate in patients with a virologic response showed that patients who experienced post-treatment relapse received lower doses of Peg-IFN and Ribavirin than patients who achieved an SVR. This observation strengthens the hypothesis that the intensification of treatment is a possible approach to reducing the incidence of relapse.[26]

    Regarding the safety of therapy, we observed that types and frequencies of adverse events were different from those reported in a larger randomized trial.[26] Twenty-four per cent of our patients stopped therapy because of severe adverse events, and we observed some events that were related to cirrhosis. All patients who experienced serious infection and liver decompensation had OV, a low platelet count and increased bilirubin levels. As these clinical features predict liver decompensation,[27] and infections in patients with cirrhosis increase mortality,[28] the choice of antiviral therapy in these patients must be carefully evaluated and weighed. The rate of patients whose haemoglobin values had reduced to <10 g/dL was similar to that reported in a previous study,[26] and the use of EPO seems to influence the efficacy of therapy because it allows maintenance of the standard regimen of RBV.

    In conclusion, our study confirms that combination therapy with Peg-Interferon and RBV is effective and safe in patients with cirrhosis and portal hypertension, but that before applying it, one must consider the clinical and genetic characteristics of patients, the viral genotypes and the kinetics of viral response. In genotype 2 or 3 patients, the administration of combination therapy for 48 weeks can achieve results similar to those obtained in patients with chronic hepatitis. In genotype 1 patients, the therapy must be guided by the presence of OV, genetic variants and by RVR. It is also worth noting that patients with severe portal hypertension may have an increased risk of developing complications related to liver disease during treatment.

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    13. Thompson AJ, Fellay J, Patel K et al. Variants in the ITPA gene protect against Ribavirin-induced hemolytic anemia and decrease the need for Ribavirin dose reduction. Gastroenterology 2010; 139: 1181–1189.
    14. Thompson AJ, Santoro R, Piazzolla V et al. Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR. Hepatology 2011; 53: 389–395.
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    Friday, February 15, 2013

    Incident anemia improved response to peginterferon, ribavirin, boceprevir in HCV patients

    Incident anemia improved response to peginterferon, ribavirin, boceprevir in HCV patients

    Sulkowski MS. Hepatology. 2013;doi:10.1002/hep.26096.

    February 15, 2013

    Patients with chronic hepatitis C who developed anemia during treatment with pegylated interferon alfa-2b, ribavirin and boceprevir were more likely to experience sustained virologic response in a recent study.

    As part of the Serine Protease Inhibitor Therapy 2 (SPRINT-2) Trial, 1,097 patients with chronic HCV genotype 1 randomly were assigned either peginterferon and ribavirin (PegIFN/RBV) with placebo or 800 mg boceprevir (BOC) three times a day for 44 weeks or response-guided PegIFN/RBV with BOC, following 4 weeks of lead-in therapy with PegIFN/RBV. Nearly all patients (n=1,080) had hemoglobin (Hb) levels measured during the study. Anemia (Hb below 10 g/dL) was managed with erythropoietin and/or RBV dose reduction.

    Half of BOC recipients developed anemia during the study, compared with 31% of placebo recipients (P<.001). Severe anemia (Hb below 8.5 g/dL) occurred in 4% of placebo recipients and 7% BOC patients (P=.04). Patients who developed anemia had significantly lower Hb levels at baseline and estimated creatinine clearance and were more likely to use statins. Multivariate analysis indicated that baseline Hb was predictive of incident anemia (OR=0.58, 95% CI, 0.51-0.67) while low creatinine levels approached statistical significance (P=.0524).

    Rates of SVR (72% vs. 58%) and response at end-of-treatment (81% vs. 67%) were higher among anemic patients than in nonanemic patients. SVR rates did not vary significantly based on anemia management method (range 70%-74%). Investigators noted that SVR rates were higher among anemic patients who experienced a maximum decline of more than 3 g/dL during treatment.

    “The addition of BOC to PegIFN/RBV therapy is associated with greater risk of anemia compared with PegIFN/RBV alone,” the researchers wrote. “However, the SVR rate was higher in patients with incident anemia compared with those without anemia irrespective of the anemia management strategy. Additional studies are under way to further evaluate these strategies to management treatment-emergent anemia. Until such data is available, RBV dose reduction should remain the primary approach to anemia management during BOC [with PegIFN/RBV] therapy for treatment-naive patients.”

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

    Thursday, February 14, 2013

    Vitamin A deficiency reduced response to therapy for chronic HCV

    Vitamin A deficiency reduced response to therapy for chronic HCV

    Bitetto D. Hepatology. 2013;doi:10.1002/hep.26186.

    February 14, 2013

    Vitamin A deficiency is common among patients with chronic hepatitis C, and is associated with nonresponse to interferon-based treatment, according to recent results.

    Researchers measured vitamin A and 25-OH vitamin D levels in 199 treatment-naive patients with chronic HCV before receiving interferon (INF)-based treatment, and compared them with 119 healthy controls. Participants also underwent genotyping for the IL-28B rs12979860 C>T polymorphism.

    Patients with HCV had lower vitamin A serum levels than controls (256 ng/mL vs. 742 ng/mL; P<.0001). Vitamin A deficiency (200 ng/mL or less) was observed in 42.2% of patients, while 19.6% had severe vitamin A deficiency (100 ng/mL or less). Vitamin D deficiency (20 ng/mL or less) was present in 45.8% of evaluable patients; 9% were vitamin D deficient and severely vitamin A deficient.

    Sustained viral response (SVR) occurred in 84.4% of genotype 2 or 3 patients and 42.2% of those with genotypes 1, 4 or 5. Nonresponse occurred in 21.6% of evaluable patients, including 2.3% of those with genotypes 2 or 3 and 37.5% of those with the more difficult-to-treat HCV genotypes. More people with severe vitamin A deficiency experienced nonresponse to treatment, overall (36.1% of cases vs. 18.2%; P=.019) and particularly among those with difficult-to-treat genotypes (61.9% vs. 31% of nondeficient participants; P=.015).

    Multivariate analysis indicated associations between treatment nonresponse and vitamin A levels of 100 ng/mL or less (OR=3.68, 1.03-13.2); HCV RNA above 600,000 IU/mL (OR=4.87, 1.48-16.0); IL-28B T/* genotype (OR=22.8, 3.92-13.3); baseline gamma-glutamyltranspeptidase levels above 60 IU/mL (6.33, 1.92-20.8), and a cumulative ribavirin dose of 80% or lower (3.89, 1.05-14.4) for difficult-to-treat patients (95% CI for all).

    “The real novelty and probably the most important finding … is the association between serum vitamin A deficiency and the condition of nonresponse to antiviral therapy, suggesting that vitamin A could be an important and modifiable factor interfering with IFN sensitivity in patients with chronic hepatitis C,” the researchers wrote. “ … vitamin A supplementation and normalization of its serum levels, before antiviral treatment, could enhance the responsiveness to IFN-based antiviral therapy.”

    Tuesday, January 29, 2013

    Pegylated interferon- Pegasys, PegIntron similarly effective for chronic HCV genotype 1

    *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.”

    Thursday, January 24, 2013

    One in Six Chronic Hepatitis C Patients May Have a Contraindication to Standard Treatment

    One in Six Chronic Hepatitis C Patients May Have a Contraindication to Standard Treatment

    By Will Boggs, MD
    NEW YORK (Reuters Health) Jan 21 - About one in six of the estimated 5 million U.S. patients with chronic hepatitis C (HCV) has a contraindication to standard treatment with pegylated interferon and ribavirin, researchers say.

    "When we designed the study, we expected that the rate of these contraindications would be higher than we discovered," Dr. Andrew H. Talal from the State University of New York, Buffalo, told Reuters Health by email. "The fact that the majority of the contraindications are reversible or readily treatable was another surprising aspect."

    The study, published online January 7 in Alimentary Pharmacology & Therapeutics, was funded in part by Genentech Inc. and F. Hoffmann-La Roche Ltd; some of the authors are employees of Genentech.

    Dr. Talal and colleagues used data from the General Electric Centricity electronic medical record dataset to determine how many people with HCV in the general population would be ineligible for therapy with pegylated interferon plus ribavirin because of medical and psychiatric problems.
    Previous research from VA Medical Centers suggested that just over two-thirds (67.8%) of veterans referred for HCV treatment were ineligible according to standardized HCV treatment criteria; only 11.8% of those diagnosed with HCV between 1999 and 2003 received a prescription for antiviral therapy.

    In this study, which included 45,690 patients diagnosed with HCV between 2004 and 2009, 7,903 (17.3%) had contraindications to therapy. Most (6,928, 87.6%) had only one contraindication.
    Patients with contraindications were more likely to be younger, female, white, not currently married, and receiving Medicaid or Medicare health coverage than those without contraindications to treatment.

    The most common contraindications were bipolar disorders (6.5%), anemia (5.9%), and pregnancy (1.9%).

    "As such," the researchers note, "many contraindications observed in the current analysis are relative (and/or modifiable) or transient and therefore many patients could potentially benefit from current pegylated interferon-containing triple therapies or future pegylated interferon- or ribavirin-free regimens."

    In contrast, conditions common in the general population (myocardial infarction, acute coronary syndromes, and depression) were usually not identified as contraindications.

    "I think that the main message is that the vast majority of contraindications to pegylated interferon/ribavirin are reversible or potentially modifiable before treatment," Dr. Talal said. "Therefore, physicians need to very carefully assess the severity of contraindications and their potential treatment prior to deeming an individual ineligible for HCV treatment."

    "The fact that the contraindications are higher in special populations, such as that found in the VA, is another important aspect of the work," Dr. Talal said. "I think that these findings should encourage physicians to search, especially for those contraindications that are the most prevalent, and to seek to modify them if the physician believes that they might interfere with a patient's ability to tolerate treatment."
    "These findings should encourage further research to determine why patients have been reluctant to pursue HCV therapy," Dr. Talal added. "We know that a large percentage of those who know that they are HCV infected have elected not to proceed with HCV therapy for various reasons and we now know, as a result of this research, that contraindications to therapy are not as important an obstacle as we might have expected previously."

    "Therefore," Dr. Talal concluded, "I think that additional interventions will need to be pursued to educate patients and providers on the importance of HCV treatment and to determine the additional reasons why a large percentage of those who are infected have not yet been treated."


    Aliment Pharmacol Ther 2013.

    Thursday, December 27, 2012

    Retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3

    Research article
    The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil
    Simara Artico, Karine Medeiros Amaral, Candice Beatriz Gonçalves and Paulo Dornelles Picon
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    BMC Infectious Diseases 2012, 12:377 doi:10.1186/1471-2334-12-377
    Published: 27 December 2012

    Astract (provisional)
    More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR).

    From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight <= 75 Kg and 1,250 mg if >= 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN.

    The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely.

    This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored.
    The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.