Interferon May Be Harmful in Retreatment of Hepatitis C

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C

Some patients with chronic hepatitis C progress from a relatively benign condition to a life-threatening illness. Interferon has been used to try to prevent this but researchers have struggled to investigate its effects reliably. Ron Koretz from Granada Hills in the USA, tells us about the January 2013 update of the relevant Cochrane Review, outlining what the authors did to try to solve this and what they found.

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Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C Updated

Koretz RL, Pleguezuelo M, Arvaniti V, Barrera Baena P, Ciria R, Gurusamy KS, Davidson BR, Burroughs AK

 

Published Online:

January 31, 2013

 

Antiviral treatment for chronic hepatitis C infections is currently judged as being successful if, at least six months after therapy, blood tests for hepatitis C viral RNA are negative; this has been called a sustained viral response. In the past, other outcomes for treatment have included improvements in biochemical tests (especially liver enzyme tests such as the serum alanine aminotransferase) or evidence of reduced inflammation and/or fibrosis on subsequent liver biopsies. All of these outcomes are tests, and it has been assumed that if the test gets better the patient will as well. However, there is no direct evidence that has proven that these outcomes are valid because there have been no long-term trials that have shown that an improvement in these tests translates into reduced mortality or morbidity. Patients who fail to have sustained viral responses after an initial course of therapy do become potential candidates for retreatment; some of them may be intolerant to ribavirin, and possibly even the newer protease inhibitors, so retreatment would have to be with interferon alone. It has also been speculated that long-term treatment (namely treatment for several years) might be beneficial; such long-term therapy would be further complicated if multiple drugs were used because of the additional drug toxicities and costs, so interferon alone could be considered.....

 

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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.

http://www.eurekalert.org/pub_releases/2013-01/w-chc012813.php

Interferon May Be Harmful in Retreatment of Hepatitis C

Medscape

When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse
To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.
Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.
Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?
Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2013:1:CD003617.

 

Detection of Hepatocellular Carcinoma at Advanced Stages Among Patients in the HALT-C Trial: Where Did Surveillance Fail?

This week in an analysis of HALT-C data, investigating the surveillance of liver cancer in academic centers published by the American Journal of Gastroenterology, reported only 20% of hepatocellular carcinoma (HCC), was found at a very early stage.

The primary goal of the HALT-C Trial was to determine if ongoing therapy with pegylated interferon monotherapy could suppress the Hepatitis C virus and slow disease progression, including the development of liver cancer in patients who were not able to achieve SVR using pegylated interferon and ribavirin.

Detection of Hepatocellular Carcinoma at Advanced Stages Among Patients in the HALT-C Trial: Where Did Surveillance Fail?

DISCUSSION Only

Full text available @ Nature
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In this retrospective analysis of HALT-C data, we found that even among patients closely followed by expert hepatologists in academic centers, nearly one-third of patients had inconsistent HCC surveillance. Only 20% of patients who developed HCC were found at a very early stage (TNM stage T1) and over one-fourth of tumors were found beyond Milan criteria. This study is the first that describes the contribution of surveillance process failures to the occurrence of more advanced HCC stage. We found that patients with tumors beyond stage T1 were significantly more likely to have experienced an absence of screening or follow-up, and these surveillance process failures potentially contributed to more advanced tumors in one-third of patients.

 

The strongest predictor for receipt of consistent surveillance was study site, after adjusting for differences in patient characteristics. Although consistent surveillance was associated with patient-level factors including platelet count and clinic visit adherence, these factors explained a smaller proportion of the variance in surveillance rates. This implies that variations in physician- and system-level factors are more important than patient-level factors in determining surveillance rates, as suggested from prior studies ((14,23)). We examined several potential system-level factors, including general clinical research center support and the number of enrolled patients, but could not identify any factor correlated with consistent surveillance rates. Site-level variation in visit adherence did not explain inter-site difference in consistent surveillance rates. However, we were unable to fully analyze why study site was an important predictor of consistent surveillance given limited data on physician- and system-level factors. We did not have data regarding which study sites covered screening costs or the timing and location of ultrasonography (e.g., on-site on the day of the visit vs. performing locally on a different day). Finally, potentially relevant factors, such as number of study coordinators and study team commitment toward HCC screening, are difficult to measure and may vary during the study.

 

In clinical practice, inconsistent surveillance could be related to physician-level factors, including under-recognition of at-risk individuals or lack of provider knowledge, clinic time constraints, or physicians forgetting to order surveillance given competing clinical concerns. Several potential barriers, such as under-recognition of the at-risk population, were not present in this setting given that all patients had known advanced fibrosis related to HCV and were followed by hepatologists in academic centers with the aid of a clinical protocol. Furthermore, surveillance rates were similar among patients with and without cirrhosis, so inconsistent surveillance was not related to lower surveillance rates among those without cirrhosis. If physicians forgetting to order surveillance is an important determinant of surveillance underuse, intervention such as reminder systems may be a more effective means to increase HCC surveillance rates than physician education.

 

Although studies have suggested breakdowns in follow-up may contribute to advanced breast, cervical, and colon cancer, ((9,10)) our study is the first to examine this issue in HCC surveillance. The effectiveness of HCC surveillance is dependent on timely follow-up with cross-sectional imaging among patients with an abnormal surveillance test. We found that follow-up was not completed within 6 months of positive surveillance testing, and therefore may have contributed to more advanced tumor stage, in 25% of patients diagnosed with HCC. Follow-up rates for positive surveillance testing may be even lower in clinical practice, given other potential barriers such as lack of provider knowledge about appropriate follow-up testing, financial barriers, and limited access to CT/MRI imaging. Further studies are necessary to determine specific barriers to follow-up in clinical practice and if there are subgroups of patients at higher risk for not receiving timely follow-up testing.

 

Although an absence of screening or follow-up was present in one-third of patients with HCC, the most common reason for detecting HCC at a late stage was an absence of detection. Surveillance failure was attributed to an absence of detection in nearly 70% of patients with tumors beyond Milan criteria despite use of both ultrasound and AFP. Ultrasound and AFP had a complementary role in surveillance, as there were several patients whose HCC diagnosis was triggered by AFP without a suspicious mass on ultrasound (19). An effectiveness study recently demonstrated that ultrasound only had a sensitivity of 32% for early stage tumors, which was significantly increased to 63% when used in combination with AFP (24). The variable effectiveness of ultrasound may be related to differences in operator experience and technique, with many patients in the United States receiving their ultrasounds in local community centers instead of tertiary care centers. Furthermore, the ability of ultrasound to accurately visualize the liver in patients with morbid obesity or a very nodular liver may be impaired (25). Although we did not find a difference in detection rates according to BMI, we could not assess the impact of truncal obesity, which might be more important than BMI. Similarly, we did not find a difference in detection rates according to cirrhosis; however, some patients without cirrhosis on baseline biopsies might have had cirrhosis at the time of HCC related to progression of fibrosis or the initial liver biopsy being understaged because of sampling error. It is clear that better surveillance tools, including more accurate biomarkers or more cost-effective advanced imaging with lower radiation risk, are necessary to help improve the sensitivity of finding tumors at an early stage. Until that time, removal of AFP from the AASLD guidelines may decrease the sensitivity of surveillance to find HCC at an early stage.

 

Our study has several limitations. We used data from the HALT-C Trial, which followed highly compliant patients in a near optimal setting, so our findings may not be generalizable to other clinical settings. However, surveillance process failures are likely to be more prevalent in conventional clinical practice where additional barriers to care are present. Second, it is possible that some patients had imaging performed, for surveillance or follow-up purposes, without being recorded in the HALT-C database. Although HCC surveillance was not the primary focus of HALT-C, the development of HCC was an important study outcome and the protocol included a standardized HCC surveillance algorithm. Given the prospective nature of HALT-C and that HCC outcomes were a secondary aim, we believe this would account for a minority of surveillance process failures. Finally, our analysis was limited by missing data given that this was a secondary analysis of the HALT-C Trial. We were only able to determine follow-up rates for positive surveillance testing among patients with HCC given that data regarding CT or MRI imaging was not routinely collected on all patients. Our ability to examine why study site was an important predictor of consistent surveillance was restricted by limited data on physician- and system-level factors. The study's strengths include its large well-characterized cohort and prospective data collection system, providing near optimal conditions for a surveillance study.

 

Although optimal surveillance protocols, including novel effective biomarkers, are still evolving, these data provide insights into the contribution of surveillance process failures to the occurrence of advanced HCC. The most common reason for finding HCC at a late stage was an absence of detection by ultrasound and AFP. However, patients with tumors beyond stage T1 were also significantly more likely to have experienced an absence of screening or follow-up, and these surveillance process failures potentially contributed to more advanced tumors in over one-third of patients under near-optimal conditions. Further studies are needed to determine the prevalence and impact of surveillance process failures in clinical practice.

 

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New developments in liver disease

New developments in liver disease

YOUR DOSE OF MEDICINE By Charles C. Chante, MD
(The Philippine Star) Updated October 28, 2012 12:00 AM

The liver disease session featured four highly regarded experts in the field who provided an outstanding overview.

They discussed what to do with a no responder to antiviral therapy for chronic hepatitis C. The current treatment that includes pegylated interferon with ribavirin leads to a sustained virologic response rate of close to 30%; thus a significant number of patients will not respond.

One of the options considered for these patients was long-term pegylated interferon to reduce inflammation and thereby reduce the progression toward cirrhosis, and also to prevent the complications of portal hypertension in those who already have cirrhosis.

But several prospective studies, including the HALT-C trial (Hepatitis C antiviral Long-term Treatment against Cirrhosis), showed that long-term interferon did not halt the progression of chronic HCV infection. The exciting aspect is that new antiviral is being developed and is currently in clinical trials. These antiviral include NS3/4A protease inhibitors, NS5B polymerase (RdRp) inhibitors, and NS5A inhibitors.

The next topic was chronic hepatitis B. They described which patients benefit from antiviral therapies, namely those with active disease defined as elevated ALT levels and/or inflammation on liver biopsy, with elevated HBV DNA levels (>20,000 IU/mL antigen-positive, and >2,000 IU/mL for the antigen-negative patients).

The benefits of therapy are to reduce progression, reduce hepatocellular carcinoma (HCC), and improve overall survival. The goal of therapy is to reduce inflammation, but unfortunately, it is not to cure the disease. At this time there are excellent antiviral that can lead to viral suppression.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease due to the obesity epidemic. Interestingly, the severity of NAFLD correlates with the severity of the metabolic syndrome, which is more commonly seen in obese patients.

Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD, which may ultimately lead to complications such as cirrhosis and HCC. The treatment of NASH centers on diet and exercise. However, in a study that they led showed that vitamin E improved the laboratory data and liver biopsy results in NASH. Therefore, lifestyle, medication, and vitamin E are the best treatments for NASH.

HCC is one of the fastest growing types of cancer in the United States and one of the leading causes of cancer-related deaths worldwide. Since HCV and HBV are the major etiologic agents that lead to HCC, surveillance of these patients has been shown to improve outcomes.
One of the most important aspects of HCC is that the diagnosis is determined by radiologic imaging using CT or MRI. An enhancing mass in the arterial phase followed by no enhancement (or washout) in the portal venous phase is diagnostic of HCC. Liver transplantation, surgical resection, and radio-frequency ablation are considered curative interventions, while transarterial chemoembolization and sorafenib improve overall survival but are considered palliative.

http://www.philstar.com/Article.aspx?articleId=864198&publicationSubCategoryId=64

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes


August 4, 2011

Download: PDF To View Figures, Supporting Information and Materials/Methods

Joel M. O'Bryan1, James A. Potts1, Herbert L. Bonkovsky2,3, Anuja Mathew1*, Alan L. Rothman1,4, for the HALT-C Trial Group

1 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 2 Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, United States of America, 3 Carolinas Medical Center, Charlotte, North Carolina, United States of America, 4 Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island, United States of America

Abstract

Background

Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.

Methods/Principal Findings

Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNα group for an additional 3.5 years. Significant telomere loss in naïve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8+CD45RA+CD57+ memory T cells and an inverse correlation of alanine aminotransferase levels with naïve CD8+ T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.

Conclusions/Significance

Sustained interferon-alpha treatment increased telomere loss in naïve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.

Introduction

Telomeres are repetitive DNA sequences, consisting of hundreds to thousands of double-stranded repeats, found at both ends of every chromosome [1]. A normal cell's replicative potential has been linked to a combination of its telomere length (TL) and the ability to express telomerase. Telomerase assists in TL maintenance and slows telomere erosion during activation-induced proliferation of T lymphocytes [2], [3].

Type I interferons (IFN), in addition to anti-viral and anti-proliferative effects, inhibit expression and activity of telomerase [4]. IFN also commonly causes lymphopenia [5], which is a stimulus for homeostatic proliferation [6]. How these competing IFN responses combine to modulate TL in peripheral naïve and memory T cells is currently unclear. Combination pegylated-IFNα (peg-IFNα) with ribavirin is the standard therapy for subjects with chronic hepatitis C virus (cHCV) infection. Unfortunately, therapy results in a sustained virologic response (SVR) in less than 50% of HCV subjects [7]. After decades of cHCV, many patients progress to liver cirrhosis and subsequent hepatic failure, and are at risk for developing hepatocellular carcinoma [8].

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial was a clinical trial designed to assess whether sustained peg-IFNα reduced the progression of liver disease in subjects who did not achieve SVR [9]. All study subjects initially received peg-IFNα plus ribavirin for 24 weeks. Subjects failing to achieve SVR were then randomly assigned either to a control, monitor-only group or to a continued peg-IFNα-treated group at a maintenance dose for an additional 3.5 years [10].

Multiple clinical measures, such as patient age, duration of infection, viral load, obesity, and liver enzyme levels have been noted to correlate to varying degrees with the IFNα treatment virologic response rate in cHCV infection [11], [12], [13], [14], [15], [16]. The role of liver hepatocyte destruction, seen as elevated blood serum levels of alanine aminotransferase (ALT), may reflect cytotoxic killing of virus infected cells by the on-going immune response. Thus serum ALT levels are used in monitoring the progression of liver damage [17]. Additionally, increasing obesity, commonly measured as body mass index (BMI), has been observed to affect telomere length in peripheral blood leukocyte subsets in otherwise healthy adults [18], [19], [20]. The availability of these clinical measures for the HALT-C cohort allowed for additional analyses in this study of their interactions with the measured peripheral blood T cell telomere lengths and telomere length changes from screening to study month 45. In this study the primary aim was to examine the effects of long-term peg-IFNα therapy on TL in peripheral blood T lymphocytes using a flowFISH (flow cytometric fluorescence in situ hybridization) telomere length assay. Here we report significant associations between changes in TL and treatment group, patient age, serum HCV RNA level, body mass index (BMI) and alanine aminotransferase (ALT) levels.

Discussion

In subjects with cHCV infection, sustained peg-IFNα therapy (90 μg/week) was associated with an increased rate of TL loss in both CD4+ and CD8+ T cell subsets. Additionally, based on a single intermediate time-point, this IFNα therapy-enhanced TL loss was fully concentrated in the initial 21 months. The delineation of TL changes in T cell CD45RA+/-/CD57- subsets shows that declines in the T cell TL are not shifts in naïve (long TL) versus memory (shortened TL) T cell proportions, but true decreases in TL with the greatest impact on the naïve T cell subsets. The lack of an accelerated TL loss effect in naïve T cells in the second interval in the peg-IFNα group suggests that a new homeostasis is reached. Our findings are consistent with the telomere erosion effects of increased lymphocyte turn-over in response to a sustained lymphopenic signal as predicted from the mathematical models of de Boer and Noest [29]. Increased T cell turn-over would also account for our observation that sustained peg-IFNα treatment inhibited the expansion of CD8+ CD45RA+ CD57+ TEMRA cells, a phenomenon observed in the control group.

By HALT-C trial design, subjects in both groups received combination therapy with peg-IFNα (180 μg/week) plus ribavirin for the initial 24 weeks of the study. PBMC were not available from other intermediate time points. Therefore, it is possible that accelerated TL loss occurred in both groups during the initial phase of lead-in therapy. Average TL could then have rebounded in the control group between the end of therapy at week 24 and month 21 whereas ongoing, lower-dose peg-IFNα therapy maintained the lower average TL (or suppressed a TL recovery) in the therapy group. Consistent with this interpretation, the decline in TL was slower during the second interval than in the earlier interval in the therapy group. If this interpretation is correct, it is impossible to determine whether the effect of the initial therapy on TL is attributable to the higher dose of peg-IFNα or to ribavirin. Nevertheless, sustained peg-IFNα was clearly associated with accelerated TL loss during the subsequent 31/2 years in comparison with the control group.

An important finding from our study is the correlation of baseline T cell TL in these cHCV subjects with viremia and BMI. It should be noted that subjects in the randomization phase of the trial had endured HCV viremia for decades (range: 14-51 years) and failed to achieve SVR during combination peg-IFNα-ribavirin therapy. The absence of a negative correlation of baseline T cell TL with age in this cohort may therefore reflect stronger impacts of long-term viremia and the generally high levels of obesity in these subjects.

We speculate that the negative association between serum viral RNA levels and baseline TL reflects chronic elevated T cell activation, cell death, and proliferation due to persistent presentation of HCV antigens in a dose-dependent manner. Alternatively, higher circulating viral RNA levels may also drive greater endogenous type I IFN production. A negative correlation of BMI with baseline TL in naïve T cells could also reflect chronic inflammation in obesity [30]. Chronic inflammation as a result of obesity may lead to decreased thymic output [31], inducing increased homeostatic proliferation of naïve T lymphocytes and thus a decrease in TL through replicative erosion. Another possible explanation for the lack of an age-dependent TL association in this cohort relates to evidence that short telomeres play a causal role in a variety of age-related diseases [32], [33], [34], [35]. Thus it is plausible that study inclusion criteria biased the enrolled study population away from subjects with very short telomeres.

Elevated ALT levels in cHCV are indicative of hepatocellular inflammation and necrosis [12]. Our finding of a correlation of serum ALT levels with naïve T cell TL loss in the control group likely reflects T cell responses to infected HCV-infected hepatocytes and the extended time frame over which telomere lengths were analyzed. This relationship was possibly obscured in the peg-IFNα group by the effects of continuous therapy. The correlation between TL changes and ALT, which could be due to T cell clonal exhaustion, immunosenescence, or a combination of these and/or other immunological factors, suggests that normalization of liver enzymes levels in the blood may coincide with a reduction in T cell turn-over and thus reduced telomere erosion.

We hypothesized that maintenance peg-IFNα therapy would cause increased TL loss in T cells as a result of inhibition of telomerase activity [4], [36]. However, we did not find a significant difference between the peg-IFNα and control groups in telomerase activity in PBMC stimulated in vitro. It is quite possible that using in vitro-stimulated PBMC the telomerase assay fails to detect an inhibitory effect of peg-IFNα therapy that existed in vivo. In any case, a telomerase inhibition mechanism falls short in explaining the predominance of an accelerated TL loss on naïve T cells in these older adults where thymic output of new, longer telomere naïve T cells is thought to be neglible.

We further found a decline in the peg-IFNα effect on TL loss with increasing age. Increasing age is associated with increased failure rates of IFN therapy for cHCV [14]. This may suggest that elevated TL erosion caused by peg-IFNα is counteracted by replicative senescence deferentially within T cell compartments. The delineation of TL loss effect by CD4+ and CD8+ T cell subset by age group results suggest a hierarchy of age-dependent T cell senescence in chronic HCV patients. Thus senescence may occur in the order: memory CD4+>memory CD8+>naïve CD4+>naïve CD8+ in this cHCV setting. Further, this result of the memory CD4+ T cell compartment becoming refractory to IFN-induced TL decreases as a marker of immunosenescence onset is consistent with the finding by Hoare, et al. where they found TL in CD4+ CD45RO+ memory T cells was a stronger predictor of SVR with IFN therapy than TL in any other T cell subset [37].

Enhanced T cell TL loss in subjects who received long-term peg-IFNα therapy suggests that T cells in these subjects have reduced proliferative reserve. Subjects receiving type I IFN therapy are known to be more susceptible to bacterial infections; this has been attributed to neutropenia, but several studies have shown no temporal correlation between neutrophil count and infections [38], [39]. Diminished memory T cells and proliferative reserve related to naïve T cell TL loss, as shown in this study, could contribute to the increased susceptibility to infection and disease while on interferon therapy. Importantly, diminished naive T cell proliferative TL reserve incurred under sustained IFN therapy may persist well beyond the end of therapy. Indeed, as age-related thymic involution severely limits production of new, long telomere, naïve T cells [37], a sustained accelerated TL erosion thus may leave a permanently degraded naïve T cell compartment. Support for this possibility comes from a recent analysis of a subset of patients from the HALT-C cohort prospectively followed for more than 5 years after the trial. That study showed rates of non-liver-related death were significantly higher (p = 0.01) among patients with liver fibrosis who received the 31/2 year peg-IFNα therapy compared to similar patients in the control arm [40].

Although extended type I interferon therapy beyond 48 weeks in the cHCV settings is not typically warranted, there are additional clinical settings where extended interferon therapy is utilized. Some examples include relapsing-remitting multiple sclerosis and melanoma [41], [42]. Accordingly, as extended type I interferon is clinically practiced, our findings suggest that additional studies of the effects of peg-IFNα therapy on age-related T cell senescence are warranted.

Abstract
Introduction
Results
Discussion
Materials and Methods
Supporting Information
Acknowledgments
Author Contributions
References

Peginterferon Maintenance Therapy in Patients with Advanced Hepatitis C to Prevent Hepatocellular Carcinoma: The Plot Thickens

Source: J Hepatol

Peginterferon Maintenance Therapy in Patients with Advanced Hepatitis C to Prevent Hepatocellular Carcinoma: The Plot Thickens

Aghemo A, Colombo M; Journal of Hepatology (Jul 2011)

BACKGROUND&AIMS:
Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression.

We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period.

METHODS:
The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years.

RESULTS:
Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03).

CONCLUSIONS:
Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.

Hepatitis C Follow-Up of HALT-C Some Benefit of Interferon

From Medscape Medical News
Extended Follow-Up of HALT-C Study Shows Some Benefit of Interferon
Bob Roehr
Authors and Disclosures

November 7, 2010 (Boston, Massachusetts) — The utility of maintenance pegylated interferon (PegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis has been a contentious matter for some time.

The pendulum has swung from support for the idea to early evidence of a lack of efficacy. Now, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, longer-term data suggest marginal, limited support for its use. Most surprisingly, data opposing its use — and now for its support — have come from the same study, the ongoing Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial.

Anna S. Lok, MD, from the University of Michigan Medical Center in Ann Arbor, presented the latest iteration of data on extended follow-up. "In an earlier report, which included a median follow-up of up to 4.6 years, with a total of 53 HCC cases, we found no difference between the treated and the control groups. The 2 lines basically were identical."

The newer analysis was based on a median of 6.1 years of follow-up. There were "almost double the number of HCC cases, with a total of 88," Dr. Lok reported. The cumulative incidence of HCC at 3, 5, and 7 years for the treated group was 2.3%, 6%, and 8.1%, respectively. Incidence in the control group was 2.5%, 6.2%, and 13.8% at 3, 5, and 7 years, respectively.

"The 2 lines of the Kaplan-Meier Curve completely overlap until the end of year 6, when there is a divergence in the 2 lines, and the P value was not significant," Dr. Lok said.

"However, when we analyzed the data separately, for the fibrosis substratum and the cirrhosis substratum, we saw that the treated group had a significantly lower incidence of HCC compared with the untreated group, with a hazard ratio of 0.45 and a P value of .01."

Subsequent analysis showed that incidence of HCC was significantly lower in patients who had completed at least 2 years of treatment. "They had less advanced liver disease, more normal platelet counts, and normal [aspartate aminotransferase] levels."

Dr. Lok concluded, "Extended follow-up of the HALT-C cohort showed a modest effect of long-term low-dose PegIFN in reducing the incidence of HCC in patients with hepatitis C and cirrhosis, but not in those with advanced fibrosis.

"Given the marginal benefit on HCC, the lack of overall benefit on disease progression, and the side effects of PegIFN, the utility of maintenance PegIFN to prevent HCC in patients with HCV-related cirrhosis who failed to achieve SVR is limited," she acknowledged.

Arun J. Sanyal, MD, American Association for the Study of Liver Diseases president and head of the division of gastroenterology at Virginia Commonwealth University, in Richmond, said, "This, potentially, could be very important."

During the question session, treatment activist Jules Levin said 4 years ago the initial analysis and strong recommendations not to treat "did a lot of damage to patients and to the field. I took issue with the investigators over that" at the time, Mr. Levin said.

Subsequent research and analysis of this trial have shown that they were wrong. "It has done irreparable damage to patients. It is important to take note of this." Mr. Levin said. "Patients and their own clinicians should be able to make their own decision for what benefits them based on a clear understanding of the data."

The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases is funding the HALT-C trial. The speakers have disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Abstract 214. Presented November 2, 2010.
Authors and Disclosures
Journalist
Bob Roehr
Bob Roehr is a freelance writer for Medscape.

http://www.medscape.com/viewarticle/732079

Liver Biopsies With Advanced Liver Disease, Are They Safe?

Are Biopsies Safe for Patients with Advanced Liver Disease?

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On AGA Journals Blog today Kristine Novak, PhD, Science Editor writes:

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"In the October issue of Clinical Gastroenterology and Hepatology, Leonard Seeff et al. analyzed case reports from 2740 liver biopsies of patients with hepatitis C-related bridging fibrosis or cirrhosis who were enrolled in the HALT-C trial at 10 different centers. The rate of serious adverse events in this cohort was 1.2%—no higher than that of other patients, but bleeding was the most common event, occurring in 0.6% of cases. Low levels of albumin, platelet counts of 60,000 mm3 or less, an international normalized ratio (INR) of 1.3 or greater, and esophageal varices all associated significantly with serious adverse events. Seeff et al. calculated that if liver biopsies had been avoided when platelet counts were 60,000 mm3 or less, the incidence of bleeding would have been reduced by 25%."

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"Bleeding risk should therefore be assessed before patients receive percutaneous liver biopsies. The authors also observed that patients with histologically proven cirrhosis were no more likely than those with bridging fibrosis to develop a serious adverse event or bleeding.
In an accompanying editorial, Stephen Caldwell and Patrick Northup suggest considering platelet counts, as well as conditions such as hyperfibrinolysis, before performing biopsies. They add that it will be important to identify better measures of the hemostatic system balance in patients with cirrhosis and investigate the roles of pro-coagulants in this important diagnostic procedure".

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The study found :Liver biopsies are relatively safe and well tolerated among patients with advanced chronic hepatitis C, based on data from the HALT-C trial.

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Read The Full Article Here

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Read the article online.

This article has an accompanying podcast.

Seeff LB, Everson GT, Morgan TR et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol and Hepatol 2010;8:877–883.

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Read the accompanying editorial:Caldwell Sand Northup PG. Bleeding complication with liver biopsy: is it predictable? Clin Gastroenterol and Hepatol 2010;8:826–829.
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Read the complementary Gastroenterology article:

West J and Card TR. Reduced mortality rates following elective percutaneous liver biopsies. Gastroenterology 2010;139:1230–1237.

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Varices progression/In HCV and advanced fibrosis

It was very interesting what the study found, one finding was that people with bridging fibrosis should be checked for Varices.

Click To Listen To The Podcast From Gastroenterolgy

This study was a substudy of the

Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial

June 2010

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Development and progression of gastroesophageal varices in patients with chronic hepatitis C.

A study in the June 2010 issue of Gastroenterology sought to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. Dr. Kuemmerle speaks with the author of this article, Dr. Robert J. Fontana of the Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School.
Fontana RJ, Sanyal AJ, Ghany MG, et al. Factors that Determine the Development and Progression of Gastroesophageal Varices in Patients with Chronic Hepatitis C. Gastroenterology 2010; June; 138(7): 2321-2331.

http://www.gastro.org/