Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation

From Clinical Gastroenterology and Hepatology

Evangelos Kalaitzakis; Axel Josefsson; Maria Castedal; Pia Henfridsson; Maria Bengtsson; Irene Hugosson; Bengt Andersson; Einar Björnsson

Posted: 02/10/2012; Clin Gastroenterol Hepatol. 2012;10(2):174-181. © 2012 AGA Institute

Abstract and Introduction

Abstract

Background & Aims: We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients.
Methods: A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T₃ and T₄, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year.
Results: Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05).
Conclusions: Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.

Introduction

Fatigue is considered to be common in chronic liver disease. Although there are reports on fatigue in patients with cholestatic liver disease,^[1–3] chronic hepatitis C,^[4,5] and nonalcoholic fatty liver disease,^[6] few of the patients in these studies had overt cirrhosis. Thus, published data on fatigue and its possible association with health-related quality of life (HRQL) in cirrhosis are scarce. Furthermore, fatigue is a troublesome and persistent symptom after liver transplantation.^[7–11] However, to our knowledge, there are no longitudinal studies specifically addressing the effect of transplantation on fatigue in cirrhosis.

The pathogenesis of fatigue in chronic diseases is usually multifactorial.^[12,13] Patients with cirrhosis often experience psychological distress^[14,15] and potentially debilitating complications such as hepatic encephalopathy, malnutrition, or hepatocellular carcinoma (HCC)^[16–19] that could lead to cognitive and physical weakness. However, it is unknown the extent to which these factors contribute to fatigue in cirrhosis.

Hormonal abnormalities and systemic inflammation are common in cirrhosis. In particular, diabetes,^[17] thyroid dysfunction,^[20] dysfunction of the hypothalamic-pituitary-adrenal axis,^[21] reduced dehydroepiandrosterone sulfate (DHEA-S),^[22] and reduced serum testosterone^[23] as well as increased interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)^[24] have been reported. These abnormalities are thought to be involved in the pathogenesis of fatigue in noncirrhotic patients,^{[12,13,25–28]} but it is unclear whether they contribute to fatigue in cirrhosis.

Our primary aim was to evaluate the severity of fatigue in patients with cirrhosis undergoing assessment for transplantation in comparison with the general population. We also aimed to identify determinants of fatigue in these patients and to study its potential relation to HRQL as well as to assess the effect of liver transplantation on fatigue.

Methods

Patients

A total of 108 consecutive patients with cirrhosis admitted in our institution for pretransplantation evaluation between May 2004 and April 2007 were prospectively enrolled. Inclusion criterion was cirrhosis of any cause. The diagnosis of cirrhosis was established histologically or based on the presence of at least 2 of the following: characteristic imaging features, varices, ascites, or increased international normalized ratio that could not be attributed to any other cause. Patients unable to understand Swedish as well as those unable to complete questionnaires owing to severe cirrhosis complications or comorbidities were excluded. Patient data, such as cirrhosis etiology, previous variceal bleeding, HCC, and comorbid illness, were collected from medical records. The glomerular filtration rate (GFR) was measured by means of 51 Cr-ethylenediaminetetraacetic acid (EDTA) clearance. Ascites was assessed by transabdominal ultrasound. The study was approved by the ethics committee of Västra Götalandsregionen, and written informed consent was obtained from all patients.

Assessment of Hepatic Encephalopathy

Encephalopathy was graded clinically from 0–4 (West Haven criteria) and by means of the number connection tests A and B.^[29] Fasting plasma ammonium ion levels were measured (CV% 2.1%; Roche Diagnostics, Scandinavia AB, Stockholm, Sweden). Hepatic encephalopathy was defined as overt according to West Haven criteria or as minimal if there was absence of overt encephalopathy and number connection test A and/or B score >3 standard deviations (SDs) of the general population.^[29,30]

Assessment of Nutritional Status

Nutritional status was assessed by an experienced dietitian as previously described.^[17] Body mass index (BMI) was calculated, and unintentional weight change (>1 kg) during the previous 3–6 months was noted. Body fat and lean mass was also determined by dual-energy x-ray absorptiometry (DEXA). Malnutrition was defined as triceps skin-fold thickness and/or mid-arm muscle circumference <5th percentile, according to standard tables for the Swedish population, and/or BMI <20 kg/m² and/or weight loss ≥5%–10% in the previous 3–6 months.^[31]

Questionnaires

The questionnaire booklet contained questions on work, marital status, and education as well as the following questionnaires.

Fatigue Impact Scale. This questionnaire was used to assess perceived fatigue during the last month on 3 subscales: physical (10 items), cognitive (10 items), and psychosocial functioning (20 items). Each item uses a 5-grade scale (0–4), yielding a maximum of 160. Higher scores indicate increased fatigue.^[32] The fatigue impact scale (FIS) has been used in chronic liver disease.^[1–3,5,6] To provide a control group, the FIS was mailed to a random sample (n = 2000) from the general population in Gothenburg. A total of 858 subjects (49% female) completed the questionnaire. From this group of subjects, 2 age- and gender-matched controls were provided for each patient with cirrhosis (n = 216). Patients were classified as fatigued if they had a FIS score >2 SDs compared with the general population cohort.

Hospital Anxiety and Depression Scale. The hospital anxiety and depression scale (HAD) was used to assess psychological distress. Each item uses a 4-grade scale (0–3) with subscales for anxiety (7 items) and depression (7 items). Higher scores indicate higher levels of anxiety and depression.^[33] There are published normative data from the Swedish population.^[34]

Short-form 36. Short-form 36 (SF-36) was used to assess HRQL (physical, emotional, and social functioning).^[35,36] It consists of 8 domains, scored from 0–100. Higher scores indicate better HRQL.

Measurement of Hormones and Cytokines

Fasting serum insulin was determined in all patients at about 7:00–8:00 AM on the day after enrollment in the study (CV 5.9%; Roche Diagnostics, Scandinavia). Fasting plasma glucose was measured on the same occasion. Patients were considered to have diabetes if they were receiving antidiabetic treatment or had fasting plasma glucose >7 mmol/L. Insulin resistance was expressed as the homeostasis model assessment index (HOMA-IR).^[37]

In a subset of patients (n = 80/108, 74%), additional blood samples were drawn on the same occasion. Plasma was immediately separated by centrifugation at 1000g (4°C) and stored at −80°C until subsequent analysis for thyroid-stimulating hormone (TSH) (CV 7%; Roche Diagnostics, Germany, Mannheim, Germany), free T₄ and T₃ (CV 10%; Roche Diagnostics, Germany), cortisol (CV 11%; Roche Diagnostics, Germany), DHEA-S (CV 12%; Diagnostic Products Corporation, Los Angeles, CA), estradiol (E₂) (CV 11%; DiaSorin s.r.l., Vercelli, Italy), and free testosterone (CV 10%; Diagnostic Products Corporation). The limits of normal of our institution for each of these hormones were used to identify patients with hormonal abnormalities.^[38] IL-6 and TNF-α were also measured (Siemens Medical Solutions Diagnostics, Tarrytown, NY). Serum IL-6 <5 pg/mL and TNF-α <20 pg/mL were considered normal on the basis of analysis from 50 healthy blood donors.

Follow-up One Year After Transplantation

Transplant recipients were followed up 1 year after transplantation and were asked to complete the same questionnaires. Patient data, such as rejection and immunosuppression, were collected from medical records.

Statistics

Data are expressed as mean (SD) or n (%) as appropriate. Analysis of variance or the Mann–Whitney test was performed to compare continuous variables. The Pearson or Spearman coefficient was calculated for correlation analysis. The χ² or Fisher exact test was used for comparisons between categorical variables as appropriate. The Wilcoxon test was used to assess changes in fatigue after transplantation. In an attempt to identify independent predictors of fatigue at baseline, all parameters univariately related to FIS domain and total scores were entered into multiple stepwise linear regression analyses. To avoid inflated type 1 error because of multiple tests, only variables univariately related at <.005 with fatigue scores were entered into regression analyses. We modeled the relationship between fatigue and patient features by using a staged approach. The first stage included clinical variables (available in all patients), whereas the second stage added hormone data (available in 74% of patients). All tests were two-tailed and conducted at a 5% significance level.

Results

Baseline characteristics of all patients (n = 108) are shown in Table 1. Patients with cirrhosis showed increased fatigue levels (Figure 1). The statistical power of all fatigue comparisons between controls and patients with cirrhosis before transplantation was >88%. All FIS domain scores were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). Patients working or studying had significantly lower fatigue levels (physical and cognitive domains) compared with those who were unemployed or on disability pension (P < .05 for both).

Figure 1. Severity of fatigue assessed as FIS domain and total scores in patients with liver cirrhosis before (n = 108, black bars) and after (n = 60, gray bars) liver transplantation in comparison with controls (n = 216, white bars). *P < .005. **P < .001.

Clinical Predictors of Fatigue at Baseline

Cirrhosis severity, ascites, and hepatic encephalopathy were related to fatigue (Table 2). Plasma ammonium ion levels were related to physical, cognitive, and total (r = 0.19–0.28, P < .05) but not to psychosocial FIS scores (P > .05). Neither indexes of malnutrition nor fat or lean mass as measured by DEXA were related to fatigue (P > .05 for all). Marital or educational status did not affect fatigue levels (P > .05).

Psychological Distress and Fatigue at Baseline

Before HAD testing, 11 patients had been diagnosed with depression, and 1 had been diagnosed with anxiety disorder. Compared with the general population,^[34] there were more patients with borderline or significant anxiety (12% vs 21% and 8% vs 16%, respectively; P = .034) and borderline or significant depression (9% vs 23% and 6% vs 14%, respectively; P = .001), as assessed by the HAD. Both anxiety and depression were related to fatigue (Table 2).

Fatigue at Baseline in Relation to Hormonal and Cytokine Levels

Two patients had known hypothyroidism (treated with thyroxine). None had any other known endocrine disease (except diabetes). A total of 80 patients (74%) consented to having blood samples drawn for hormonal and cytokine analyses. Patients who consented, when compared with those who did not consent to this part of the study, did not differ significantly in etiology or severity of liver cirrhosis or in total or domain scores of FIS, HAD, or SF-36 (data not shown). Five patients had increased TSH but were euthyroid (normal T₄). Two of 80 patients (2.5%) had T₄ levels and 27 of 80 (34%) had T₃ levels under the lower limit of normal. Cortisol, DHEA-S, free testosterone, and E₂ were under the lower limit of normal in 13 of 80 (16%), 61 of 80 (76%), 16 of 80 (15%), and 22 of 80 (28%), respectively. Also, 63 of 80 (79%) had increased IL-6, and 16 of 80 (20%) had increased TNF-α. Having low T₃, cortisol, or testosterone levels was significantly related to increased fatigue levels (Table 3). Patients with significant depression did not have low serum cortisol levels more often than patients without significant depression according to the HAD (data not shown).

Serum total cortisol assays are known to overstate adrenal insufficiency in the setting of hypoalbuminemia (<25 g/L).^[21] In our cohort only 1 patient with low serum cortisol had hypoalbuminemia, and exclusion of this patient from the analysis did not alter the relation of cortisol with fatigue (data not shown).

Regression Analyses

In linear regression analysis, anxiety and depression as well as cirrhosis severity and low cortisol were found to be major determinants of fatigue at baseline (Table 4). Anemia and impaired renal function were also independent predictors of physical fatigue (Table 4).

Effect of Liver Transplantation on Fatigue

Sixty-six of 108 patients (61%) underwent transplantation. Four patients died before follow-up at 1 year after transplantation, and 2 were lost to follow-up. Thus, follow-up data were available in 60 patients (Supplementary Table 1). FIS domain and total scores had improved 1 year after transplantation, but transplant recipients still had higher physical fatigue compared with controls (Figure 1). Thirty-seven of 60 patients (62%) had a pretransplant physical FIS score >2 SDs of controls and thus were classified as physically fatigued. Seventeen of 37 physically fatigued patients (46%) before transplant continued to be physically fatigued after transplant (P = .004). After transplant, 22 of 60 (37%) were classified as physically fatigued.

Clinical Predictors of Remaining Physically Fatigued After Transplant

Patients remaining physically fatigued (n = 17/37), compared with those whose fatigue levels dropped <2 SDs of the general population (n = 20/37) after transplant, had higher physical, psychosocial, and total FIS domain scores at baseline (30 [6] vs 25 [5] P = .022, 50 [13] vs 36 [15] P = .008, and 103 [26] vs 79 [29] P = .015, respectively) and had more frequent significant or borderline depression at baseline as assessed by the HAD (35% vs 15% and 41% vs 15%, respectively, P = .019). However, the 2 groups did not differ in any other baseline or transplant-related factor (data not shown, P > .05).

At 1 year after transplant, the proportions of patients with depression or anxiety as assessed by HAD did not differ significantly from the general population (data not shown).

Discussion

In the current study, we observed high fatigue levels in patients with cirrhosis undergoing pretransplant evaluation. Fatigue was related to impaired HRQL and to being unemployed or having disability pension. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of fatigue in these patients, whereas anemia and impaired renal function are of further importance in physical fatigue. Physical fatigue also appears to be of concern at 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant. Our findings are in line with previously published data showing increased fatigue levels in patients with decompensated cirrhosis compared with those with compensated cirrhosis or liver transplant recipients.^[39] Fatigue has also been shown to be common in patients with chronic liver disease, but only a fraction of the patients included in these studies had cirrhosis.^[1,2,4–6] Our study is a systematic evaluation of fatigue in cirrhosis, simultaneously assessing potential associations with psychological distress, hormone abnormalities, and HRQL, as well as the effect of transplantation.

Hypothalamic-pituitary-adrenal dysfunction resulting in hypocortisolism can be accompanied by weakness and fatigue. Hypocortisolism has been reported in patients with chronic fatigue syndrome and fatigued patients with other chronic conditions.^[12,13,25] In cirrhosis, dysfunction of the hypothalamic-pituitary-adrenal axis resulting in hypocortisolism has been previously described,^[21,40,41] and it has been shown to contribute to increased mortality in cirrhotic patients with sepsis.^[40,41] Our findings suggest that hypocortisolism might also contribute to fatigue and thus impaired HRQL in cirrhosis.

Psychological distress was found to be a major determinant of fatigue in cirrhosis. It was more closely related to fatigue domains than cirrhosis severity or peripheral factors, such as cirrhosis complications with an impact on patient survival, were. This is in accordance with studies in chronic (liver and nonliver) disease reporting that fatigue correlates strongly with anxiety and depression.^{[1,5,6,12,13]} In our cohort, 23% of patients had significant anxiety or depression as assessed by the HAD, and a dramatic improvement in both fatigue and psychological distress was seen after transplant. Previous studies have questioned the role of depression in the development of fatigue in cholestatic liver disease,^[3,42] and antidepressants do not improve cancer-related fatigue.^[43] Our findings, however, indicate that patients with cirrhosis and significant anxiety or depression confirmed by a psychiatrist might benefit from specific treatment for these disorders, which could lead to improvement in fatigue and HRQL. However, this would need to be formally tested in interventional trials.

Anemia, present in 60% of patients in our cohort, was a predictor of pretransplant physical fatigue. Previous studies have shown that anemia is common in cirrhotic patients and that hemoglobin levels are inversely related to the hepatic venous pressure gradient.^[44] Interestingly, 35% of patients were found to be anemic after transplant, but this did not affect fatigue. Although anemia in cirrhosis is probably multifactorial, it is conceivable that rigorous measures to treat known anemia causes, especially those related to portal hypertension, could potentially improve fatigue and HRQL.

Fatigue scores were found to be more closely related to Child–Pugh scores compared with the Model for End-Stage Liver Disease (MELD) score. This is in line with previously published data on the closer relationship of the Child–Pugh score with HRQL indexes compared with the MELD score.^[45] Ascites and hepatic encephalopathy are known to be important factors influencing HRQL in patients with cirrhosis^[46] and were also found to be associated with fatigue levels in the current study. The fact that the Child–Pugh score but not the MELD score includes ascites and encephalopathy might explain, at least in part, the better correlation with fatigue.

Renal function is often impaired in cirrhosis.^[16,18] Although fatigue is common in patients with renal failure and hemodialysis,^[47] the potential association of renal function impairment with fatigue in patients with cirrhosis has not been previously reported to our knowledge. Renal function has been tested as a potential determinant of HRQL in different cohorts of patients with cirrhosis, but no statistically significant results were obtained.^[8,19] However, serum creatinine was used as a measure of renal function in these studies, whereas the GFR assessed by 51 Cr-EDTA clearance was used in the current study.

Although fatigue domain scores improved after transplant, 37% of transplant recipients were physically fatigued 1 year after transplant. Previous studies have shown that physical fatigue is a major problem after liver transplantation,^[7,9–11] but our study specifically assessed fatigue in patients with cirrhosis before and after transplantation in a longitudinal fashion. A discussion about the expected benefit of transplantation on survival is part of the normal pretransplantation consent. Equally, with improving long-term transplantation results, being able to discuss the effect of transplantation on HRQL is central to an informed process. In the current study, almost half of fatigued patients before transplant remained fatigued at 1 year after transplant. However, no distinct potential cause of post-transplant fatigue could be identified. Further studies are clearly warranted on fatigue in transplant recipients.

The main strength of our study is its design, ie, it was a prospective longitudinal study in which validated HRQL instruments were used. Potential determinants of fatigue were carefully characterized, such as 51 Cr-EDTA clearance for GFR assessment, psychometric tests and serum ammonium ion measurements for hepatic encephalopathy, and anthropometry and DEXA measurements for nutritional status. One of the limitations of our study is potential selection bias because patients were recruited from a transplant program. Similarly, patients unable to fill in questionnaires were excluded, which might have underestimated the impact of more severe grades of hepatic encephalopathy on fatigue. Also, serum total cortisol measurements, used in the current study, are thought to overstate adrenal insufficiency in cirrhosis.^[21] However, hypoalbuminemia (<25 g/L) is the only reported risk factor for misdiagnosis of adrenal insufficiency by serum total cortisol assays.^[21] In the present study, only 1 patient with low serum cortisol had albumin <25 g/L, and exclusion of this patient from the analysis did not alter our results. Ideally, however, future studies investigating the role of glucocorticoids on fatigue in cirrhosis should use salivary cortisol measurements (not affected by hypoalbuminemia^[21]) and synachten testing to identify patients with altered cortisol response.^[40,41] Finally, controls were only asked to complete the FIS and not the questionnaire related to psychological distress (HAD), and they did not undergo any blood tests. In an attempt to improve the response rate of controls, published data on HAD results from the general Swedish population^[34] and established cutoff values of the laboratory of our institution^[38] were used.

In conclusion, patients with cirrhosis show increased fatigue, which impairs HRQL. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of most fatigue domains, whereas anemia and impaired renal function are of further importance in physical fatigue. Liver transplantation was associated with improvement in fatigue, but physical fatigue appeared to be of concern 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant.

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Drugmakers Seek Deals to Gain Share of Future Hepatitis C Combination Pill

By Ryan Flinn and Drew Armstrong - Feb 15, 2012 12:01 AM ET Wed Feb 15 05:01:00 GMT 2012

A developing medical theory that hepatitis C can be overcome with the same type of drug cocktails that tamed HIV may drive acquisition strategies as companies try to anticipate which products work best with other medicines.

Because only a few hepatitis C drugs are approved, and others in testing may not pan out, “we don’t know what the winning formula will be,” Ben Weintraub, an industry analyst at Wolters Kluwer InThought in New York, said during a Bloomberg Industries panel. To raise the odds, “companies are doing M&A and starting new trials on almost a daily basis.”

With more than two dozen drugs in development, doctors predict a new age of therapy for a bloodborne virus carried by 170 million people that now has few treatment options. The promise of a potential $20 billion market has already spurred three deals in the last year, the latest Bristol-Myers Squibb Co.’s $2.5 billion purchase this month of Inhibitex Inc. (INHX)

Next in line may be Idenix Pharmaceuticals Inc. (IDIX) andAchillion Pharmaceuticals Inc. (ACHN), said Raghuram Selvaraju, an analyst with Morgan Joseph TriArtisan in New York.

“I don’t think either of these companies will remain independent very long,” Selvaraju said in a telephone interview. “I think we’ll see both of them out of there by the end of the year.”

Blocking the Virus

Achillion, based in New Haven, Connecticut, is testing a so-called protease inhibitor, while Idenix, of Cambridge,Massachusetts, is developing a nucleotide polymerase inhibitor. The two medicines, which work differently to block the virus’s ability to replicate in the body, are in the second of three stages of testing normally required for U.S. approval.

By combining several classes of these new hepatitis C drugs, doctors may be able to limit the virus’ ability to infect, mimicking the strategy that a decade earlier helped turn HIV from a killer disease to a controlled one, said Charles Chui, an infectious disease doctor at the University ofCalifornia, San Francisco.

With the success of treatments that “work on the virus itself, there’s an increased urgency now to explore drugs in many different stages of the viral life cycle,” Chui said in a telephone interview.

Until last year’s introduction of Victrelis from Merck & Co. and Incivek by Vertex Pharmaceuticals Inc., both protease inhibitors, the standard treatment combined the antiviral drug ribavirin with interferon, an immune-boosting protein sold byWhitehouse Station, New Jersey-based Merck as PegIntron and by Basel, Switzerland-based Roche Holding AG (ROG) as Pegasys.

Interferon Shots

That treatment relied on interferon shots given weekly for a year and cured only about half of patients with the most common U.S. strain, called genotype 1. The drugs also caused side effects that include fatigue and flu-like symptoms.

The new protease inhibitors stop an enzyme that splits proteins and allows them to replicate. While they’ve been shown to cure more patients in less time than previous therapies, with fewer side effects, they still need to be combined with interferon shots.

Scientists see promise in the other class being developed, the nucleotide polymerase inhibitors, which bind to a different part of the virus than the protease inhibitors. These drugs are pan-genotypic -- meaning they are effective across the different types of hepatitis C. They could become the backbone for an interferon-free combination.

Mixing the classes together may be even more effective in beating the disease, which is blamed for more than 350,000 deaths a year worldwide.

‘Dramatic Change’

“We waited 15 years for protease inhibitors, and a year later we could have a new class of drugs, nucleotides, that surpass them,” said Steve Worland, former chief executive officer of Anadys Pharmaceuticals, an experimental hepatitis C drugmaker acquired by Roche in November for about $230 million.“That kind of dramatic change I have never seen before.”

Drugmakers want to own a piece of the eventual cocktail that will work best among patients worldwide, and have been working in the lab to create their own drugs as well as scouting other companies with an eye toward buying promising candidates.

Gilead Sciences Inc. (GILD) paid $10.8 billion for Pharmasset Inc. last month to use its experimental nucleotide drug, PSI-7977, as a cornerstone to a new hepatitis C combination -- one that it expects other drugmakers will want to use -- opening the door to added licensing revenue.

Pill’s ‘Driver’

“7977 is going to be the driver of an all oral regimens, and all of these other drugs are going to be layered on top of it,” said Selvaraju.

Rivals have the same idea as they hunt for potential targets. That’s why Achillion and Idenix are being closely watched as potential takeover targets, Selvaraju said. Abbott Laboratories and Roche are potential bidders, he said. Merck (MRK), Bristol-Myers and Johnson & Johnson are also in pursuit of the new regimens.

The potential market size for these therapies is at least $20 billion, according to Michael Kishbauch, chief executive officer of Achillion. The company is considering a licensing deal, selling itself or just its hepatitis C “asset,” the protease inhibitor, ACH-1625, Kishbauch said in a November interview.

Gilead increased its offer to acquire Pharmasset four times last year to $137 a share from $100 a share, after a clinical trial showed PSI-7977 cured all patients in a study and the company reached out to four other potential bidders.

‘Amazing Breakthroughs’

“The opportunity to be able to cure people with three months of therapy is one of the most amazing breakthroughs we can bring to health care -- and there’s a lot of competition,”Gilead CEO John Martin said in a Jan. 9 interview.

Idenix is in talks to find a partner to create a combination hepatitis C treatment, said Ron Renaud, the company’s CEO. While declining to comment on whether the company may be acquired, he said interest in hepatitis C drugs picked up last year during a liver disease conference.

“There is a tremendous market opportunity here, that people want to take advantage of, and there’s an intense race that’s under way to get to that point,” Renaud said in an interview on Jan. 11.

Inhibitex and Pharmasset parlayed multiple bids for their companies into record premiums. Inhibitex sold for a premium of 126 percent over the 20-day average of its share price in the 20 days prior, the second-largest on record for a drugmaker worth more than $500 million, according to data compiled by Bloomberg since 1999. Gilead’s purchase of Pharmasset, completed last month, featured an 89 percent premium.

Increasing Competition

At least one other buyer was willing to match Bristol-Myers’ $2.5 billion offer on Jan. 6 for Inhibitex, U.S. Securities and Exchange Commission filings reveal. Inhibitex began attracting bids last year, and had at least six suitors, including Bristol-Myers. (BMY)

“This market is giant,” said Mark Schoenebaum, an analyst with ISI Group in New York, who estimates sales of hepatitis C treatments may reach $100 billion over a decade.

Bristol-Myers and another, still unnamed, company both offered bids of $26 a share to buy Inhibitex. That’s raised questions as to whether another deal, led by the mystery bidder, is on the horizon, said ISI Group analyst Schoenebaum in a note to clients on Jan. 17.

“The revelation that there were six parties looking at Inhibitex could intensify investor speculation that consolidation in the HCV space could continue,” he said.

To contact the reporters on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net; Drew Armstrong in New York at darmstrong17@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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BioCryst Announces Promising Results from Preclinical Studies of BCX5191 for Hepatitis C

PRESS RELEASE

Feb. 15, 2012, 6:00 a.m. EST

BCX5191: Planning to file for first--in-human studies during the fourth quarter 2012

RESEARCH TRIANGLE PARK, N.C., Feb 15, 2012 (BUSINESS WIRE) -- --BioCryst to discuss study outcomes during its 2011 results call February 16 at 11:00 a.m. ET

BioCryst Pharmaceuticals, Inc. today announced favorable preclinical results for BCX5191, a novel adenine nucleoside analog targeting viral RNA polymerase for the potential treatment of hepatitis C.

BioCryst has successfully completed in vitro and in vivo studies in which BCX5191 exhibited potent and selective pan-genotypic antiviral activity against the hepatitis C polymerase enzyme. BCX5191 showed no inhibition of human RNA polymerase and no evidence of toxicity from standard in vitro screens.

Human liver cells rapidly and efficiently convert BCX5191 into its active triphosphate form. BCX5191 does not require prodrug technology to achieve bioavailability. BCX5191 inhibits the viral RNA polymerase enzyme across genotypes 1-4 at sub-micromolar concentrations (0.05-0.36 uM) and is active in replicon cell assays for genotypes 1a and 1b.

In preclinical models, BCX5191 demonstrates high oral bioavailability, and the drug is actively transported into the liver. Following a single oral dose in rats, liver BCX5191 triphosphate levels exceed the IC50 values for genotypes 1-4 through 24 hours. At Cmax, the drug triphosphate level is more than 100 times the IC50. This pharmacokinetic profile is expected to support once-daily dosing in clinical studies.

"BCX5191 has met stringent preclinical criteria to advance to IND-enabling studies. We expect this program to be ready to file for first-in-human studies during the fourth quarter of 2012," said Dr. William P. Sheridan, Senior Vice President & Chief Medical Officer of BioCryst Pharmaceuticals. "Based on our internal comparative preclinical studies of BCX5191 with the most advanced nucleotide analog in clinical development, GS-7977, we believe BCX5191 has the potential to be the backbone of best-in-class oral treatment regimens for hepatitis C patients."

Additional BCX5191 non-clinical experiments are ongoing or planned, including Good Laboratory Practices (GLP) non-clinical safety studies and in vitro evaluation of BCX5191 in combination with ribavirin.

Conference Call and Webcast

BioCryst's leadership team will host a conference call and webcast on Thursday, February 16, 2012 at 11:00 a.m. Eastern Time to discuss financial results and recent corporate developments, including results from the BCX5191 hepatitis C program. To participate in the conference call, please dial 1-877-303-8027 begin_of_the_skype_highlighting 1-877-303-8027 end_of_the_skype_highlighting (United States) or 1-760-536-5165 begin_of_the_skype_highlighting 1-760-536-5165 end_of_the_skype_highlighting (International). No passcode is needed for the call. The webcast and accompanying slides can be accessed by logging onto www.BioCryst.com . Accompanying slides will be available on the BioCryst website several hours prior to the call. Please connect to the website at least 15 minutes prior to the start of the conference call to ensure adequate time for any software download that may be necessary.

About Hepatitis C

Hepatitis C is a contagious liver disease that results from infection with the hepatitis C virus (HCV), which is the most common virus that infects the liver and can lead to life-threatening liver problems, such as liver damage, cirrhosis, liver failure or liver cancer. There are an estimated 170 million individuals worldwide who are chronically infected with HCV, and about 3 to 4 million people are infected annually. In the United States, there are approximately 4 million people who have chronic hepatitis C.

About BioCryst

BioCryst Pharmaceuticals designs, optimizes and develops novel small-molecule pharmaceuticals that block key enzymes involved in infectious diseases, inflammatory diseases and cancer. BioCryst currently has three novel late-stage compounds in development: peramivir, a neuraminidase inhibitor for the treatment of influenza, BCX4208, a purine nucleoside phosphorylase (PNP) inhibitor for the treatment of gout, and forodesine, an orally-available PNP inhibitor for cancer, which is being developed by Mundipharma under a global license agreement. Utilizing crystallography and structure-guided drug design, BioCryst continues to discover additional compounds and to progress others through preclinical and early development to address the unmet medical needs of patients and physicians. For more information, please visit the Company's website at www.BioCryst.com .

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performances or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Some of the factors that could affect the forward-looking statements contained herein include: that there can be no assurance that our compounds will prove effective in clinical studies; that development and commercialization of our compounds may not be successful; that we or our licensees may not be able to enroll the required number of subjects in planned clinical trials of our product candidates and that such clinical trials may not be successfully completed; that BioCryst or its licensees may not commence as expected human clinical trials with BCX5191; that ongoing and future preclinical and clinical development may not have positive results; that we or our licensees may not be able to continue future development of our current and future development programs; that our development programs may never result in future product, license or royalty payments being received by BioCryst; that BioCryst may not reach favorable agreements with potential pharmaceutical and biotechnology partners for further development of BCX5191; that our actual cash burn rate may not be consistent with our expectations; that BioCryst may not have sufficient cash to continue funding the development, manufacturing, marketing or distribution of its products and that additional funding, if necessary, may not be available at all or on terms acceptable to BioCryst. Please refer to the documents BioCryst files periodically with the Securities and Exchange Commission, specifically BioCryst's most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and current reports on Form 8-K, all of which identify important factors that could cause the actual results to differ materially from those contained in our projections and forward-looking statements.

BCRXW

SOURCE: BioCryst Pharmaceuticals, Inc.

        
        BioCryst Pharmaceuticals 
        Robert Bennett, 919-859-7910(investors) 
        or 
        WCG 
        Catherine Kyroulis, 212-301-7174(media)
        
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Different causes of liver disease may have the same outcome

Updated: 2012-02-13 17:03:02 CST

A number of different problems can afflict the liver, some infectious, others caused by environment. This means that many people should consider live panel testing, as large numbers of individuals may be at risk.

Hepatitis C infection is one of the leading causes of liver disease. This virus can be transmitted during sexual intercourse or by sharing needles. There is currently no cure for the infection, which primarily attacks the liver.

Other causes are the result of environmental factors. The number of people who experience non-alcoholic fatty liver disease has grown exponentially in recent years as the obesity epidemic has worsened.

According to the Mayo Clinic, this condition is the result of fatty deposits in the liver that can cause scarring, which diminishes the functioning of the liver. Overweight individuals face the greatest risk from this condition.

In many cases, these conditions can lead to cirrhosis, a very serious-stage liver condition that may eventually lead to total failure of the organ. This is why it is important for individuals who have risk factors for hepatitis infection or fatty liver disease to consider liver panel testing.

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Does Anesthesia Alter Tumor Recurrence?

By: Travis Giddings  Reviewed By: Joseph V. Madia, MD

Published: Feb 13, 2012 07:20 pm

Anesthetic choice changes liver cancer recurrence

(dailyRx) Occasionally, studies of medical data find unexpected trends. Recently, an analysis of anesthetic use during liver surgery found a surprising relationship for tumor recurrence.

A study of medical records over a nine-year period revealed that general anesthesia was associated with fewer recurrence of tumors in liver cancer.

But despite the difference, there was no significant difference in mortality between the two groups.

A group from China studied whether anesthetic technique made any difference in a specialized surgery known as radiofrequency ablation, where surgeons use radio waves rather than scalpels to destroy tumors. Radiofrequency ablation may be used for surgery in difficult areas to access, or when a minimally invasive technique is preferred.

Documented by Renchun Lai, M.D., of Sun Yat-Sen University Cancer Center in Guangzhou, the recurrence of liver tumors was lower in patients who had regional anesthesia instead of general anesthesia.

Dr. Lai examined the outcomes of 179 patients who underwent radio frequency ablation for small liver tumors, comparing general anesthesia in 117 patients to epidural anesthesia in 62.

The authors of the study called for randomized clinical trials to investigate further for the true cause of the relationship between anesthesia use and reduced tumor recurrence. Theories ranged from a direct effect of the anesthesia on the tumor cells or even the immune system itself, but the finding could reflect decisions by surgeons on which anesthesia to use on a case by case basis.

"Such retrospective studies are very difficult to interpret because it is impossible to understand what risk factors were not evenly distributed among the patients," commented Steven L. Shafer, M.D., of Columbia University, Editor-in-Chief of Anesthesia & Analgesia.

Other professionals believed that the anesthesia itself could be the cause. "There is overwhelming mechanistic support for regional analgesia protecting against cancer recurrence, along with strong animal data," commented Daniel I. Sessler, M.D., chair of Outcomes Research at The Cleveland Clinic.

"We and others have published both positive and negative retrospective studies. But all are small and suffer all the substantial limitations of observational analyses. Resolution of the question will have to await the results of randomized trials, including ours."

A separate study published in 2005 found that the costs of regional and general anesthesia were similar overall, with some variations of 10 percent in either direction depending on the characteristics of the individual surgery.

Results were published in the journal Anesthesia & Analgesia. Authors of the study declared no conflict of interest.

---

Liver Cancer (Hepatocellular Carcinoma)

The American Cancer Society estimates that there are over 26,000 new cases of primary liver cancer and bile duct cancer in the United States each year, and they are responsible for over 19,000 deaths. The average man has about a 1% chance of developing this cancer over his lifetime, while the average woman has about a half percent chance.

Primary liver cancer most commonly includes hepatocellular carcinoma (HCC) and can coexist with cholangiocarcinoma, a cancer of the bile ducts between the liver and gall bladder. It is important to note that most cases of cancer in the liver are metastases from other cancers, such as those from the colon, breast, or prostate. Primary liver cancers begin in the liver itself. Other less common forms of primary liver cancer include angiosarcomas and hemangiosarcomas (cancers that begin in the blood vessels of the liver), lymphoma of the liver, and hepatoblastoma (a rare pediatric cancer usually occurring in children under three years of age). There are also several variants of benign liver tumors. Hepatocellular adenomas (a benign liver tumor associated with oral contraceptive use and glycogen storage disease) must be watched closely, as they have a potential to turn cancerous.

Hepatocellular carcinoma, the most common form of liver cancer, is strongly associated with infection by chronic hepatitis B and C. These infections cause liver cancer more often in Asian and African countries where hepatitis viruses are endemic and people acquire the disease early in their life.

Cases of liver cancer in the United States have tripled over the past three decades. While the most common cause of liver cancer used to be from alcohol abuse and the resulting cirrhosis of the liver, hepatitis C infection is now a leading cause. Obesity, particularly fatty liver disease, is also implicated. Other causes include hemochromatosis (a disease that causes the body to store too much iron), high exposure to aflatoxins (a mold found in peanuts, rice, soybeans and corn; rare in developed countries), and Type 2 diabetes.

Symptoms of HCC usually present with classic signs of liver dysfunction such as jaundice (yellowing of the skin due to too much bilirubin), bruising and blood clotting problems (due to the liver making the clotting factors in our blood), and ascites (fluid buildup in the abdomen from liver dysfunction). Other general symptoms include nausea, fatigue, vomiting, and unintentional weight loss.

In patients who are at high risk for HCC, screening is usually done with ultrasound and CT scan, as well as MRI. While there is no reliable blood test for liver cancer screening, a high level of alpha-fetoprotein (AFP) should be considered suspicious for liver cancer. Liver biopsy is also done, although this is not necessary for diagnosis if imaging is definitive.

Treatment for HCC is difficult, as many patients with liver cancer also have damaged livers from cirrhosis. Treatment must be balanced between treating the cancer and also mitigating the risk of liver failure. Early stage cancer has the potential for surgical removal, however most cases of liver cancer are discovered when they are advanced, making surgery difficult. Other treatments are dependent on the size and location of the tumors, such as ethanol injection into the tumor (small tumors), radiofrequency ablation (using high-frequency radiowaves to destroy the tumor), transcatheter arterial chemoembolization (cuts off the blood supply to unresectable tumors), and cryosurgery (destroying cancerous tissue with subzero temperatures). Liver transplantation is a relatively successful option for patients without metastatic spread. Sorafenib (marketed as Nexavar) is a tyrosine kinase inhibitor that has shown efficacy in treating HCC.

Ultimately, HCC is a difficult cancer to treat and survival rates are low, with most cancers being unable to be completely removed. These patients usually succumb to the disease within three to six months. Across the board, patients with a solitary small tumor of less than three centimeters in size have a five-year survival rate of 20%. Patients with advanced disease have a one-year survival rate of 30%.

Prevention of liver cancer is extremely effective if vaccinated against hepatitis B. Avoidance of alcohol abuse is also effective. Other patients with different causes of cirrhosis or chronic liver inflammation will benefit from routine ultrasound screening and AFP measurements in the hope of detecting cancer early.

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Are You a Recovering Alcoholic?

By George Lundberg, MD, Editor-at-Large, MedPage Today, Editor-at-Large, MedPage Today

Published: February 13, 2012

Hello and welcome. I'm Dr. George Lundberg and this is At Large at MedPage Today.

Are you a recovering alcoholic?

Be honest.

How about a recovering nicotine addict, or recovering from an addiction to some illegal drug, or maybe addiction to gambling, or sex, or football, or even your computer screen, or Angry Birds?

I have worked in the addiction field most of my professional life. See here www.plndp.org. For me, addiction to a chemical includes physical and mental dependence, tolerance, withdrawal, and, of course, drug seeking behavior, despite recognized adverse consequences of use. This kind of chemical addiction is forever; it does not go away.

So, I was excited to see that the Substance Abuse and Mental Health Services Administration (SAMHSA), after many months of study, hearings, and input from thousands, on Dec. 22, 2011, issued a new working definition of "recovery" from mental disorders and substance use disorders.
SAMHSA defines "recovery" as a "process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential."

The new SAMHSA guiding principles state that recovery:

• Emerges from hope
• Is person-driven
• Occurs through many pathways
• Is holistic
• Is supported by peers and allies
• Is supported through relationships and social networks
• Is culturally based
• Is supported by addressing trauma
• Involves the individual, family, and community
• And is based on respect

Duh! Please forgive me for being underwhelmed.

Do you like apple pie? Is motherhood good? It seems to me that both this definition and the guiding principles simply describe how to live a successful human life.

How do these statements advance our knowledge about anything, clarify misunderstandings, chart a path for patients and professionals, or guide payers?

I guess the problem was their very process of writing a definition; too many cooks in the kitchen.

Suggestion for SAMHSA: acknowledge that you have nicely described how normal humans should try to live. Fine. Now try to deal with recovery from disorders of mental health, substance abuse, and addiction.

Maybe you need to divide the topics instead of creating an unhelpful, one-size-fits-all amorphous lump.

That's my opinion. I'm Dr. George Lundberg, At Large for MedPage Today.

George Lundberg, MD, helps shape the coverage of clinically relevant news at MedPage Today as Editor-at-Large. Dr. Lundberg also serves as president of the Lundberg Institute, and is a consulting professor of pathology and health research policy at Stanford University School of Medicine. He is a member of the Institute of Medicine (IOM) and serves on the Board of Directors of the Friends of the National Library of Medicine. Dr. Lundberg's editorial work is marked by his distinguished 17-year stint as Editor-in-Chief of the Journal of the American Medical Association (JAMA) and its Archives publications. Most recently he served as Editor-in-Chief of The Medscape Journal of Medicine, the original open-access general medical journal, and Editor-in-Chief of eMedicine at WebMD.

 

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Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study - Article in Press

Download the PDF here

Journal of Hepatology Feb 12 2012

Christophe Moreno, Thomas Berg, Tawesak Tanwandee, Satawat Thongsawat, Hans Van Vlierberghe, Stefan Zeuzem, Oliver Lenz, Monika Peeters, Vanitha Sekar, Goedele De Smedt

1Department of Gastroenterology and Hepatopancreatology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
2Department of Hepatology, Clinic of Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
3Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 4Chiang Mai University, Chiang Mai, Thailand
5Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
6Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany
7Tibotec, Beerse, Belgium

"Novel agents for the treatment of genotypes 4 to 6 would be advantageous as SVR rates are low [17,31], and together with genotype 1 these groups are considered 'difficult to treat'. Antiviral activity against genotypes 4 to 6 observed in this study suggests that TMC435 could provide a clinical benefit, particularly for patients infected with genotypes 4 and 6. For genotype 5, the mean decline in HCV RNA from baseline over the 7 day monotherapy period was slightly lower compared to genotypes 4 and 6, suggesting that the TMC435 activity was somewhat lower in this group. Due to SVR rates of ≥70% in genotype 2 and 3 patients following treatment with PegIFN/RBV, there is perhaps a less urgent need for novel agents to treat infection with these genotypes, though patients who do not respond to treatment could benefit from regimens including novel DAAs. TMC435 showed antiviral activity in 3/6 patients infected with genotype 2, and no activity against genotype 3. Of note, given the high sequence variability between the different genotypes and subtypes, further work is ongoing to investigate the role of naturally occurring baseline polymorphism in variation 1 in virologic response, and to fully characterise viral variants observed in patients with viral breakthrough."

"In spite of study limitations outlined above, the results of this phase IIa study in 37 treatment-naïve patients suggest that this investigational agent may be a future candidate for treatment of infection with HCV genotypes 4, 5 and 6, and potentially particular subtypes of genotype 2."

Abstract

Background & Aims

TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naïve patients infected with HCV genotypes 2 to 6.

Methods

The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from Day 8 with a follow-up period up to Days 37-42.

Results

Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary endpoint at Day 8, the mean (±standard error) change in plasma HCV ribonucleic acid (log10 IU/mL) from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43), followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.

Conclusions

The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.

Introduction

The hepatitis C virus (HCV) is a single-stranded RNA virus and one of the leading causes of chronic liver disease worldwide [1]. It is estimated that 130-170 million people are infected with HCV, constituting 2.2-3.0% of the global population [2]. HCV can be classified into six major genotypes based on sequence divergence of 30% [3]. Genotype 1 has a broad global distribution [4-10]. Genotype 2 is prevalent in North America, Europe and Japan (subtypes 2a and 2b), Northern Italy (2c) [11], and Western Africa [12]. Genotype 3 is noted for its wide distribution among intravenous drug users in a number of countries [13-15], and is also predominant in India and Pakistan [16]. Genotype 4 is responsible for >90% of HCV infections in Egypt, where it is associated with the re-use of needles during mass administration of parenteral antischistosomal therapy until the 1980s, and is also prevalent in other regions of the Middle East and sub-Saharan Africa [3,17-19]. In Europe, its prevalence has recently increased due to immigration and transmission between intravenous drug users [17]. Genotype 5 is found most commonly in South Africa, as well as in four regions in France, Spain, Syria and Belgium [3,17]. Genotype 6 is found in South East Asia and surrounding regions where overall HCV prevalence is high [3,20,21]. Recommended treatment for patients infected with non-genotype 1 HCV is pegylated interferon and ribavirin (PegIFN/RBV). Treatment for different genotypes differs slightly, with PegIFN alpha (α) plus weight-based RBV for 48 weeks recommended for genotypes 1, 4 and 6, and PegIFNα plus low-dose RBV (800 mg) for 24 weeks for genotypes 2 and 3 [22-27]. Of note, given the recent approval of the HCV NS3/4A protease inhibitors boceprevir and telaprevir [28,29] the standard of care for genotype 1 is expected to change [27,30].

Sustained virologic resp 1 onse (SVR, undetectable HCV RNA in patient plasma 24 weeks after treatment end) is achieved in approximately 75% of patients infected with genotypes 2 and 3 [31]. Rates with genotypes 4, 5 or 6 are 43-70% [17]. Furthermore, PegIFN/RBV therapy is poorly tolerated in some patients. In randomised trials of PegIFNα/RBV, influenza-like and neuropsychiatric symptoms occurred in up to 24-64% of patients [22,32], adverse events (AEs) led to study discontinuation in 14-32% and dose reduction in 11-42% [22,32], and anemia or neutropenia led to dose reduction in 9-22% and 18-20%, respectively [22,32].

It is, therefore, clear that novel direct-acting antivirals (DAAs) are required to address issues of sub-optimal efficacy, poor tolerability and compliance failures, and to reduce treatment duration.Boceprevir and telaprevir have demonstrated significantly improved virologic outcomes in both treatment-naïve and -experienced genotype 1 patients [28,29]. However, their thrice daily dosing schedule (with food) and increased rates of AEs including anemia and rash, in comparison to PegIFN/RBV, suggest that there is still room for improvement. Furthermore, activity in other genotypes has not been extensively investigated.

TMC435 is an investigational, once-daily oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily (q.d.) dosing, and demonstrates potent antiviral activity and efficacy [33-36]. Given sub-optimal responses to existing treatment options and the worldwide distribution of genotype 1, this genotype is the current focus of the TMC435 clinical development program. A phase IIa study (TMC435-C202; NCT00812331) was also performed in patients infected 1 with genotypes 2 to 6 to assess the antiviral activity of TMC435 against these genotypes. Data from biochemical protease assays available before the study start indicated that TMC435 is a potent NS3/4A protease inhibitor in genotypes 2, 4, 5 and 6, with a medium inhibitory concentration (IC50) of <13 nM for all HCV NS3/4A enzymes tested [37]. IC50 for genotype 3 was 37 nM [37]. This study assessed antiviral activity, safety, tolerability and pharmacokinetics of TMC435 (200 mg q.d. administered for 7 days as monotherapy) in treatment-naïve patients infected with HCV genotypes 2 to 6.

Results

Patient demographics and baseline characteristics

The trial was conducted from 3 March to 18 November 2009. A total of 37 patients were enrolled (Fig. 1) across Germany, Belgium and Thailand. No major differences in demographics and baseline disease characteristics were observed, except that all patients with genotype 6 were Asian, and median age of patients with genotype 5 was higher compared with other genotype cohorts (Supplementary Table 1). Overall, 11% of patients in the study had cirrhosis (Metavir score F4), including patients infected with genotype 2 (n=1), genotype 3 (n=1) and genotype 5 (n=2). Multiple subtypes were included in cohorts for genotype 2 (2b, 2c, 2i, 2k), genotype 4 (4, 4c, 4d) and genotype 6 (6a, 6c-l, 6j, 6n) (Table 1).

Following the 7-day TMC435 treatment period, all patients started PegIFN/RBV therapy. Thirty-one patients began PegIFN/RBV on Day 8 or 9, whereas one patient with genotype 3 and five with genotype 6 began PegIFN/RBV after Day 9.
Antiviral activity

Change in plasma HCV RNA from baseline

An initial rapid decline in HCV RNA from baseline at Day 3 of TMC435 monotherapy was evident for all patients infected with HCV genotypes 4 to 6, and for three out of six patients with genotype 2 (Figs 2 and 3). Of these three patients, those who responded were infected with subtypes 2b and 2c.

At Day 3, the mean (±standard error [SE]) change from baseline in plasma HCV RNA (log10 IU/mL) was greatest for genotypes 6 (-3.57±0.197) and 4 (-3.43±0.167), followed by genotypes 5 (2.71±0.335) and 2 (-2.02±0.625). For the primary endpoint at Day 8, the mean (±SE) change from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43) cohorts, followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39) (Figs 1 and 2). However, no clear antiviral activity was evident for patients with genotype 3 (change from baseline at day 3 and 8; Figs 2 and 3). At Day 8, four patients (two patients with genotype 4 and two with genotype 6) achieved HCV RNA levels of <25 IU/mL detectable. No patients achieved HCV RNA levels of <25 IU/mL undetectable at Day 8.

From Day 8 to the end of follow-up 2 (Days 37-42), when patients had been treated with PegIFN/RBV only for up to 35 days, mean HCV RNA declined in all genotypes, with the exception of genotype 4 where mean HCV RNA began to increase (Fig. 2). By the end of follow-up 2, HCV RNA change from baseline was -5.19±0.37 for genotype 2, -4.96±0.37 for genotype 3, -3.26±0.77 for genotype 4, -3.89±0.60 for genotype 5 and -5.46±0.32 for genotype 6. HCV RNA was <25 IU/mL detectable for 5/6 (83%), 6/8 (75%), 5/8 (63%), 2/7 (29%) and 7/8 (88%) of patients with genotypes 2, 3, 4, 5 and 6, respectively. HCV RNA <25 IU/mL undetectable was achieved by 5/6 (83%), 3/8 (38%), 5/8 (63%), 1/7 (14%) and 6/8 (75%) of patients with genotypes 2, 3, 4, 5 and 6, respectively.

Viral breakthrough

One patient infected with genotype 3, two with genotype 4 and three with genotype 5 experienced viral breakthrough during the TMC435 monotherapy period. In addition, another 6 patients experienced viral breakthrough during the follow-up period, whilst being treated with PegIFN/RBV only, suggesting lack of activity of PegIFN/RBV treatment in these patients: two infected with genotype 2, one with genotype 3, one with genotype 4, and two with genotype 6.

In genotype 2 and 3-infected patients with viral breakthrough, viral sequencing did not reveal emerging mutations. However, for most genotype 4, 5, and 6 patients with viral breakthrough, emerging mutations were detected. The most frequently observed emerging mutations in the NS3 protease domain were R155K, D168E and D168V (data not shown).

Safety and tolerability

The type and incidence of AEs (all Grade 1-2) during the 7-day TMC435 monotherapy period was similar across all cohorts in the study (Table 2) and the most common AEs were influenza-like illness and headache. There were no clinically relevant changes in laboratory parameters, and no clinically significant findings in terms of vital signs, physical examinations or ECG recordings. Mild elevations in bilirubin (total, direct and indirect) levels were observed in all cohorts. Mean change from baseline to Day 8 was 1.38 μmol/L (95% confidence interval [CI] 0.88, 1.87) for direct and 3.06 μmol/L (95% CI 1.51, 4.61) for indirect bilirubin. These returned to baseline value after completion of TMC435 dosing and were not associated with clinical symptoms or elevations in aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase (Supplementary Table 2). On Day 8 (after the 7-day dosing period with TMC435 was completed), one patient experienced an SAE of Grade 1 ileitis not considered related to TMC435 therapy. The patient 1 discontinued from the study and recovered after 4 days. No other discontinuations due to AEs occurred during the trial.

Pharmacokinetics

Steady-state TMC435 C0h, Cmin, Cmax and AUC24h were similar for the genotype 4, 5 and 6 cohorts, though lower values were observed for the genotype 2 and 3 cohorts with the lowest values in the genotype 3 cohort (Supplementary Table 3). Tmax 6 values were generally similar for all genotype cohorts (Supplementary Table 3). Exposure did not differ according to race or cirrhosis (data not shown).

Discussion

The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes, with the exception of genotype 3.

Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, potent activity was observed in three patients with genotype 2, with limited activity observed in the other three patients in this cohort. No antiviral activity was seen against genotype 3. Viral breakthrough (protocol defined: plasma HCV RNA increase >1 log10 IU/mL from the lowest reached, or >100 IU/mL in patients whose HCV RNA was previously <25 IU/mL undetectable or detectable) occurred in six patients during the monotherapy phase. Six additional patients had viral breakthrough during the PegIFN/RBV-only period, and could therefore be considered viral rebound after cessation of treatment with TMC435. In this study, TMC435 was generally safe and well tolerated. All AEs were mild to moderate and during the 7-day period of TMC435 monotherapy there were no discontinuations or untoward changes in biochemical parameters. This is the first study in which an HCV protease inhibitor has demonstrated antiviral activity in genotypes 5 and 6. Furthermore, data for genotypes 2, 3 and 4 are limited for other investigational agents. In a phase IIa study, telaprevir combined with PegIFN/RBV showed substantial activity against genotype 2, modest activity against genotype 4 [38] and limited activity against genotype 3 [39]. Of note, unlike nucleotide inhibitors, NS3 protease inhibitors are generally 1 considered to have limited activity in certain genotypes. However, results of this study suggest that the protease inhibitor TMC435 could be efficacious across multiple genotypes, though additional clinical data are required to provide further support.

A limitation of this study relates to the high subtype diversity in genotypes 2, 4 and 6 (such diversity is not observed in genotypes 3 and 5). Not all subtypes were included in this study and the number of patients per subtype was sometimes limited. Importantly, no difference in efficacy between included subtypes was observed in genotypes 4 or 6. The difference in antiviral activity between patients infected with genotype 2 may be caused by the different subtypes, as HCV RNA change from baseline at Day 3 in patients infected with 2b and 2c was -3.19 to -3.61- log10 IU/mL, compared with -0.26 to -0.99 in those infected with 2, 2k and 2i. In addition to this limitation, the sample size in each cohort was relatively small. It should also be noted that a TMC435 dose of 200 mg q.d. was administered in this trial, whereas a dose of 150 mg is currently in phase III development.

The lack of antiviral activity against genotype 3, compared with other genotypes, is consistent with the lower IC50 value of TMC435 against a genotype 3 isolate in an in vitro biochemical assay [37]. It is suggested that this may be due to the presence of a naturally occurring D168Q polymorphism at baseline, which is present in most genotype 3a isolates known to date and was observed in all genotype 3a patients included in this study (data not shown). A D168Q mutation alone has been shown to reduce TMC435 activity in a genotype 1b replicon assay by >700 fold [40]. TMC435 exposure (as indicated by C0h, Cmin, Cmax and AUC24h) was lower in genotypes 2 and 3 than in genotypes 4, 5 and 6, though it is suggested that this may be due to chance due to the small number of patients 1 in this study. Furthermore, as mean AUC values were <3 fold lower in the genotype 3 cohort compared to genotype 6 but in vitro susceptibility of genotype 3 isolates was >700 fold lower, the lower exposure observed in this cohort does not explain the lack of antiviral activity against genotype 3.

In patients infected with HCV genotype 4, mean change from baseline in HCV RNA began to increase after Day 5. Prior to Day 8, this was driven by two patients who experienced viral breakthrough under TMC435 monotherapy. The further increase in HCV RNA after Day 8 is thought to reflect a lack of response to PegIFN/RBV. Novel agents for the treatment of genotypes 4 to 6 would be advantageous as SVR rates are low [17,31], and together with genotype 1 these groups are considered 'difficult to treat'. Antiviral activity against genotypes 4 to 6 observed in this study suggests that TMC435 could provide a clinical benefit, particularly for patients infected with genotypes 4 and 6. For genotype 5, the mean decline in HCV RNA from baseline over the 7 day monotherapy period was slightly lower compared to genotypes 4 and 6, suggesting that the TMC435 activity was somewhat lower in this group. Due to SVR rates of ≥70% in genotype 2 and 3 patients following treatment with PegIFN/RBV, there is perhaps a less urgent need for novel agents to treat infection with these genotypes, though patients who do not respond to treatment could benefit from regimens including novel DAAs. TMC435 showed antiviral activity in 3/6 patients infected with genotype 2, and no activity against genotype 3. Of note, given the high sequence variability between the different genotypes and subtypes, further work is ongoing to investigate the role of naturally occurring baseline polymorphism in variation 1 in virologic response, and to fully characterise viral variants observed in patients with viral breakthrough.

In spite of study limitations outlined above, the results of this phase IIa study in 37 treatment-naïve patients suggest that this investigational agent may be a future candidate for treatment of infection with HCV genotypes 4, 5 and 6, and potentially particular subtypes of genotype 2.

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Vitamin E Tocotrienol Supplement Delays Progression of Advanced Liver Disease

By Staff Editor
Feb 13, 2012 - 2:00:01 PM

(HealthNewsDigest.com) - COLUMBUS, Ohio – New research conducted at The Ohio State University’s Wexner Medical Center suggests an alternate form of natural vitamin E delays the progression of disease in patients awaiting liver transplantation, the only definitive therapy that reduces a patient’s morbidity, mortality and improves their quality of life. The study shows, for the first time, successful delivery of the vitamin – administered orally – to vital human organs such as the brain, heart, liver, skin and fatty tissue.

Researchers at Ohio State’s Wexner Medical Center initially sought to measure levels of vitamin E tocopherol (TCP) and vitamin E tocotrienol (TE) in tissue and vital organs of patients with end stage liver disease. The data displayed a significant increase in TE levels in the bloodstream and tissue of study participants who received daily oral supplements of TE.

“This work is the first to show oral supplements of tocotrienol are being transported to the vital organs of patients,” says Chandan K. Sen, associate dean for translational and applied research in The Ohio State University College of Medicine. “This is exciting evidence for patients at high risk for stroke because our previous work identified low levels of TE to be protective against stroke-induced damage to the brain. Findings of this current research are equally excited for patients on the liver transplant list as it increases their chances of receiving a new liver, and therefore survival.”

Earlier research published by Dr. Sen and colleagues at Ohio State’s Medical Center proved tocotrienol a safe and neuroprotective nutrient, which minimizes stroke-related damage to the brain. “We also showed in previous studies that TE can be part of a regular diet and keeps the brain enriched and better prepared to defend itself,” added Sen, also vice chair for research in Ohio State's Department of Surgery.

For this recent study, published in the February issue of Journal of Nutrition, researchers studied blood and tissue samples from 80 participants. One cohort involved healthy patients who received oral TE or TCP supplements. Vitamin E levels found in tissue were measured in healthy participants after 12 weeks of receiving oral supplementation. Healthy adult participants were selected for this study because they could receive oral supplements for a designated period of time, whereas the other cohort was bound by surgery schedules.

In another cohort, adult surgical patients were randomized and received daily oral supplements of either TE or TCP. Concentration levels of both vitamin E sources were measured in vital organs, including: cardiac muscle from heart transplant patients with end stage heart failure; liver from transplant patients with end stage liver disease; abdominal fatty tissue from morbidly obese patients undergoing reconstructive plastic surgery; and brain tissue from epileptic patients.

The results showed oral supplementation of tocotrienol significantly increased the levels of the nutrient found in blood, skin, fatty tissue, the brain, cardiac muscle and the liver. Tocotrienol was delivered to the human brains of study participants at levels found to be neuroprotective in earlier stroke-related research.

Oral administration of tocotrienol also lowered the model for end stage liver disease (MELD) score in 50 percent of the patients who received TE supplements, while only 20 percent of patients who received TCP supplements experienced a reduction in their MELD score. MELD score refers to a clinical scoring system used to determine the severity of chronic liver disease and assess the priority and need for liver transplant allocation.

The tocotrienol form of vitamin E is available as a nutritional supplement in American supermarkets. One of the richest and healthiest food sources for TE is palm oil, which contains an abundance of the nutrient. It contains zero tans fat content and is also a popular component of a typical Southeast Asian diet. Other foods containing TE include rice, bran, oat, barley, and wheat germ.

Sen says he and colleagues are planning a much larger Phase II clinical trial testing the safety and effectiveness of tocotrienol against stroke and end stage liver disease in humans.

Along with Sen, other Ohio State researchers involved in the study were Viren Patel, Cameron Rink, Gayle M.Gordillo, Savita Khanna, Urmila Gnyawali, Sashwati Roy, Bassel Shneker, Kasturi Ganesh, Gary Phillips, J. Layne Moore, Atom Sarkar, Robert Kirkpatrick, Elmahdi A. Elkhammas, Emily Klatte, Michael Miller, Michael S. Firstenberg and E. Antonio Chiocca. Kalanithi Nesaretnam, from the Malaysian Palm Oil Board’s Food Technology and Nutrition Unit, also participated in the research.

The research was supported by a grant awarded by the National Institutes of Health. In addition, the Malaysian Palm Oil Board – an institution of Government of Malaysia – funded the study.

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