February 15, 2012

Alberta researchers develop vaccine to fight hep C

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A University of Alberta researcher said his research team has made a “significant discovery” in the search for a vaccine against hepatitis C. (Shutterstock)

Angelique Rodrigues, QMI Agency

First posted: Wednesday, February 15, 2012 07:18 PM EST | Updated: Wednesday, February 15, 2012 07:25 PM EST

EDMONTON — A University of Alberta researcher has discovered a vaccine he believes may one day cure hepatitis C -- a virus that kills more people in Canada than HIV.

Canada Excellence Research Chairman (CERC) in Virology Michael Houghton said his research team has made a “significant discovery” in the search for a vaccine against hepatitis C.

Houghton presented his findings Wednesday in Vancouver at the Canada Excellence Research Chairs Summit.

The summit is held in conjunction with the American Association for the Advancement of Science’s annual meeting and offers some of Canada’s most renowned researchers a chance to share their latest discoveries with their peers.

Officials said Houghton and fellow U of A research partner John Law have already tested their vaccine on human subjects.

They reportedly found the drug was capable of fighting all major strains of hepatitis C -- which can cause liver cancer and has a high rate of mortality.

The CERC program supports universities across Canada in furthering the nation’s leadership in research and innovation.

The program awards world-renowned researchers and their teams up to $10 million over seven years to establish ambitious research programs.

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Product for liver disease now commercialized in Europe

PR-Logo-Businesswire

PRESS RELEASE

Feb. 15, 2012, 9:15 a.m. EST

Corgenix Automated Hyaluronic Acid (HA) Test Kit Now CE Marked

DENVER, Feb 15, 2012 (BUSINESS WIRE) -- Corgenix Medical Corporation , a worldwide developer and marketer of diagnostic test kits, announced today its second generation Hyaluronic Acid (HA) Immmunoturbidimetric Test Kit for use on automated chemistry analyzers has received CE marking for commercialization in Europe. The new product is the second Corgenix product for measuring blood levels of hyaluronic acid to assess the degree of liver fibrosis and cirrhosis in chronic liver disease. The first Corgenix product is configured as an ELISA microplate and has been commercialized worldwide since 1998.

"The CE marking of our automated HA product reaffirms our market leadership position in non-invasive biomarkers for assessing chronic liver disease and allows us to commercialize the product in Europe through our distribution partner ELITech," said Corgenix President and CEO Douglass Simpson. "We have a very active development program with ELITech and over the next few years will be bringing additional new and exciting products to the world markets."

In 2010 Corgenix and ELITech entered into the Joint Product Development Agreement, a strategic alliance to co-develop new diagnostic tests. The automated HA product was the first product released as a result of that collaboration. It is now available worldwide, including Europe, through ELITech; in the U.S. it will be available for research purposes only through Corgenix.

In all countries where the use of this product has not been cleared by local regulating agencies, the product shall not be used for diagnostic purposes. None of the Corgenix Hyaluronic Acid products are FDA cleared for diagnostic use in the U.S.

About Corgenix Medical Corporation

Corgenix is a leader in the development and manufacturing of specialized diagnostic kits for immunology disorders, vascular diseases and bone and joint disorders, including the world's only non-blood-based test for aspirin effect. Corgenix diagnostic products are commercialized for use in clinical laboratories throughout the world. The company currently sells over 50 diagnostic products through a global distribution network. More information is available at www.corgenix.com .

About the ELITech Group

The ELITech Group is a privately held group of worldwide manufacturers and distributors of in vitro diagnostic equipment and reagents. By bringing together IVD specialty companies that offer innovative products and solutions, ELITech Group has become a major contributor in advancing clinical diagnostics to laboratories in the proximity market, those operating closer to the patient. The ELITech Group manufactures and distributes diagnostic products for clinical chemistry, microbiology, immunology, and molecular biology though direct sales and a distribution network encompassing more than 100 countries. More information is available at www.elitechgroup.com .

Statements in this press release that are not strictly historical facts are "forward-looking" statements (identified by the words "believe", "estimate", "project", "expect" or similar expressions) within the meaning of the Private Securities Litigation Reform Act of 1995. These statements inherently involve risks and uncertainties that could cause actual results to differ materially from the forward-looking statements. Factors that would cause or contribute to such differences include, but are not limited to, continued acceptance of the Company's products and services in the marketplace, competitive factors, changes in the regulatory environment, and other risks detailed in the Company's periodic report filings with the Securities and Exchange Commission. The statements in this press release are made as of today, based upon information currently known to management, and the Company does not undertake any obligation to publicly update or revise any forward-looking statements.

SOURCE: Corgenix Medical Corporation

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PR-Logo-Newswire

PRESS RELEASE

Feb. 15, 2012, 2:52 p.m. EST

IEO Press Conference Highlights Benefits of New Treatment Advance in Europe

NEW YORK, Feb. 15, 2012 /PRNewswire via COMTEX/ -- Delcath Systems, Inc. and the European Institute of Oncology (Instituto Europeo di Oncologia - IEO) introduced the Delcath Hepatic CHEMOSAT® Delivery System to media at a Feb. 15 press conference and discussed the status of the first European patients treated with the technology. CHEMOSAT is a critical new treatment option for patients who suffer from inoperable liver-dominant metastases.

During the press conference, the IEO, a premier European cancer treatment and research center located in Milan, also inaugurated a specialized task force for melanoma diagnosis and skin cancer treatment, underscoring their commitment to broadening availability of treatment options in Europe.

The IEO initiated CHEMOSAT treatments on January 31, 2012, and has thus far treated three patients-- two with liver metastasis stemming from ocular melanoma and one from gastric cancer. Patients responded well to treatment, and after observation physicians reported that their condition is good and expected to improve in the coming weeks.

"CHEMOSAT is a unique option for those suffering from cancers in the liver, which have significantly lower survival rates when compared to other cancers," said Dr. Alessandro Testori, a surgical oncologist and director of the Division of Melanoma and Skin-Muscle Sarcoma. "The IEO is pleased to be the first center in Europe to perform these procedures in an institutional setting. For the first time, patients now have access to a new technology which will ultimately create options for those in need."

Dr. Umberto Veronesi, Scientific Director at the IEO and speaker at the press conference, also discussed the importance of CHEMOSAT and its potential reach across Europe. Other physicians and members of the specialized task force, including Dr. Franco Orsi, Dr. Pier Francesco Ferrucci, Dr. Luisa Lanfrancone, Dr. Maria Rescigno, Dr. Giuseppe Spadola and Dr. Giulio Tosti, participated in the historic press conference.

"The preliminary results from these procedures reaffirm our confidence of CHEMOSAT's ability to help patients suffering from cancers in the liver," said Eamonn P. Hobbs, president and CEO of Delcath. "We are delighted with the status of our partnership with the IEO, a prestigious leader in cancer treatment. Furthermore, we are extremely encouraged by the IEO's support in helping to advance the progress of CHEMOSAT treatment in Europe."

About the IEO

The European Institute of Oncology was established in 1994 to implement an innovative model for health and advanced research in the international oncology field. The IEO's mission is focused on state-of-the-art cancer research and treatment, from basic laboratory research that grapples with the genetic roots of cancer, to advanced clinical research such as testing new drugs, all with the unifying goal of finding ways to treat patients more effectively.

About Delcath Systems

Delcath Systems, Inc. is a development stage specialty pharmaceutical and medical device company focused on oncology. Delcath's proprietary system for chemosaturation is designed to administer high dose chemotherapy and other therapeutic agents to diseased organs or regions of the body, while controlling the systemic exposure of those agents. The Company's initial focus is on the treatment of primary and metastatic liver cancers. In 2010, Delcath concluded a Phase III metastatic melanoma study, and the Company recently completed a multi-arm Phase II trial to treat other liver cancers. The Company obtained authorization to affix a CE Mark for the Hepatic CHEMOSAT delivery system in April 2011. The Company has not yet received FDA approval for commercial sale of its system in the United States. For more information, please visit the Company's website at http://www.delcath.com/ .

The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by the Company or on its behalf. This news release contains forward-looking statements, which are subject to certain risks and uncertainties that can cause actual results to differ materially from those described. Factors that may cause such differences include, but are not limited to, uncertainties relating to the future use and adoption of the CHEMOSAT system by the European Institute of Oncology, uncertainties relating to future initial launch and training agreements with other cancer centers in Europe, CE Marking for the Generation Two system and the timing of our commercial launch in Europe, the time required to build inventory and establish commercial operations in Europe, adoption, use and resulting sales, if any, for the Hepatic CHEMOSAT delivery system in the EEA, our ability to successfully commercialize the chemosaturation system and the potential of the chemosaturation system as a treatment for patients with terminal metastatic disease in the liver, acceptability of the Phase III clinical trial data by the FDA, our ability to address the issues raised in the Refusal to File letter received from the FDA and the timing of our re-submission of our NDA, re-submission and acceptance of the Company's NDA by the FDA, approval of the Company's NDA for the treatment of metastatic melanoma to the liver, adoption, use and resulting sales, if any, in the United States, approval of the current or future chemosaturation system for other indications, actions by the FDA or other foreign regulatory agencies, our ability to obtain reimbursement for the CHEMOSAT system, our ability to successfully enter into distribution and strategic partnership agreements in foreign markets and the corresponding revenue associated with such foreign markets, uncertainties relating to the results of research and development projects and future clinical trials, and uncertainties regarding our ability to obtain financial and other resources for any research, development and commercialization activities. These factors, and others, are discussed from time to time in our filings with the Securities and Exchange Commission. You should not place undue reliance on these forward-looking statements, which speak only as of the date they are made. We undertake no obligation to publicly update or revise these forward-looking statements to reflect events or circumstances after the date they are made.

Only the English version of this press release is legally valid. The versions in other languages only represent a translation of the original English version.

SOURCE Delcath Systems, Inc.

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From Journal of Viral Hepatitis

C. V. Almario; M. Vega; S. B. Trooskin; V. J. Navarro

Posted: 02/14/2012; J Viral Hepat. 2012;19(2):e163-e169. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Prior studies found that hepatitis C virus (HCV) risk assessment and testing in primary care clinics were suboptimal. We aimed to determine the actual HCV testing rate among patients with HCV risk factors and to identify variables predictive of testing. In order to do so, we performed a prospective cohort study among patients seen in four urban primary care clinics. At the initial visit, patients were given a questionnaire that listed HCV risk factors and they were instructed to check 'yes' or 'no' if they did or did not have a risk factor, respectively. Patients then handed this questionnaire to their physician during their initial visit. Among those who acknowledged having a HCV risk factor via the questionnaire, we determined the subsequent HCV testing rate and calculated adjusted odds ratios (aOR) with 95% confidence intervals (CI) to identify variables predictive of testing. Of the 578 individuals who acknowledged having a HCV risk factor via the questionnaire, only 8% (46/578) were tested for HCV within 2 months of their initial visit. Among those tested, 11% (5/46) had a positive HCV antibody test result. The only variable predictive of HCV testing after adjusting for confounders was having a specific HCV risk factor identified and documented in the chart by physicians [16% (26/159) vs 5% (20/419); aOR 4.5, 95% CI 2.1–9.5]. In summary, 92% of patients with a HCV risk factor were not tested for HCV in the primary care setting, and efforts to improve such rates are clearly warranted.

Introduction

Hepatitis C virus (HCV) is the most common bloodborne infection in the United States, as 3.2 million individuals are chronically infected nationwide.[1] Furthermore, 40% of chronic liver disease is related to HCV, and HCV-associated end-stage liver disease is the most frequent indication for liver transplantation.[2] Given the significant morbidity and mortality associated with HCV, the Centers for Disease Control and Prevention (CDC),[2] National Institutes of Health (NIH),[3] and American Association for the Study of Liver Diseases (AASLD)[4] all recommend HCV testing for persons at high risk. However, previous studies, most of which were survey based, showed that HCV risk assessment and testing in primary care settings were suboptimal.[5–11] Shehab et al.[5] noted that among primary care physicians (PCPs) surveyed nationwide, only 59% asked all patients about HCV risk factors. A retrospective chart review by Trooskin et al.[11] revealed that PCPs documented a history (positive or negative) of intravenous drug use and blood transfusion prior to 1992 for 12% and 2% of patients, respectively. Furthermore, they also found that of those who admitted intravenous drug use, only 55% were subsequently tested for HCV.[11]

Patient care in primary care settings has become increasingly complex. While the time physicians spent with patients has increased over the years,[12,13] the number of clinical items addressed per visit also increased.[13] Yet, the increase in the number of addressed clinical diagnoses outpaced the increase in visit duration, thereby leading to a decrease in the amount of time devoted to each clinical item.[13] Given the increased demands placed on PCPs along with the fact that most prior studies that examined HCV testing practices were survey based, we aimed to perform a prospective cohort study to determine the actual rate of HCV testing among primary care patients with a HCV risk factor and to identify factors predictive of testing.

Materials and Methods

We performed a prospective cohort study among patients seen at four urban primary care clinics in Philadelphia, Pennsylvania, from October 2004 to June 2005. Two clinics were university-based primary care practices (an internal medicine practice and a family medicine practice) at Thomas Jefferson University Hospital, while the other two clinics were federally qualified community health clinics. Each of the four primary care clinics served a unique population. The internal medicine university-based practice provided care for a population of which 45% were African American. A majority of the internal medicine patients had private insurance. For the family medicine university-based practice, 60% of the patients were African American and approximately 50% had private insurance. Regarding the community clinics, one served a predominantly Latino population (85%), of which approximately 25% were undocumented immigrants. The second community clinic served a predominantly African American population (70%). The majority of patients receiving care at the two community health clinics were either uninsured or covered by a Medicaid Health Maintenance Organization.

Our group previously performed a retrospective chart review among patients seen in the four clinics described previously. The aim of the prior study was to examine HCV risk factor ascertainment, testing and referral for treatment, with particular attention to the role of race and ethnicity.[11] For our current prospective study, we focused on examining HCV testing practices and determining factors predictive of testing. Participants in our current study included patients, 18 years of age or older, who had not been seen in the clinic for 5 years or more. Individuals were asked to participate in the study while they were in the waiting room, and those who agreed to participate were given a HCV risk factor questionnaire that listed risk factors for HCV. The questionnaire asked patients whether they ever had any of the following: a blood transfusion before 1992, an organ transplant before 1992, long-term dialysis, a spouse or significant other who was diagnosed with HCV, been in prison or jail for more than 24 h, worked as a healthcare worker and accidentally been stuck with a needle, injected recreational drugs even if it was just one time or a tattoo or body piercing (ear piercing not included). At the bottom of the questionnaire, participants were instructed to check 'yes' or 'no' if they did or did not have any of the above HCV risk factors, respectively. Those who had a HCV risk factor were told to simply check 'yes' and to not identify their specific HCV risk factor on the questionnaire. The questionnaire was made in duplicate with one copy given to the study's personnel. Patients were instructed to hand the other copy of the questionnaire to their PCP during their initial visit. Of note, the HCV risk factor questionnaire did not include any language prompting the PCP to order HCV testing if the patient acknowledged having a HCV risk factor via the questionnaire.

The charts of all patients who identified themselves as having a HCV risk factor on the questionnaire were reviewed 2 months after their initial visit by a team of trained chart reviewers. Demographics collected included age, sex, race/ethnicity, primary care clinic setting (university-based vs community), total number of clinic visits within a 2-month period after the initial visit, insurance status, highest level of education and annual income. All pre-existing medical comorbidities documented in the chart were recorded. Anyone with a known prior diagnosis of HCV was excluded from the study. We checked to see whether the HCV risk factor questionnaire was present in the chart and determined whether physicians identified and documented in the chart the specific HCV risk factor that each patient possessed. We also determined whether a HCV antibody test was subsequently performed by searching the chart for a HCV antibody test result or documentation from the physician clearly stating that the patient was referred for HCV antibody testing.

Statistical tests were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). Student's t-test and the chi-square test were used to analyse continuous and categorical variables, respectively. When sample sizes for categorical variables were small, the Fisher's exact test was used in place of the chi-square test. A P value <0.05 was considered statistically significant. A binary logistic regression model was used to calculate adjusted odds ratios (aOR) with 95% confidence intervals (CI) to find variables predictive of HCV testing. Variables from univariate analysis with a P < 0.20 were included as covariates in the regression model. This cut-off value was chosen so that we could liberally include variables in the model and therefore assess confounding by more variables. This study was approved by the Institutional Review Board of Thomas Jefferson University Hospital

Results

Overall, 1848 individuals from four urban primary care clinics agreed to complete the HCV risk factor questionnaire during their initial primary care visit. Of the 1848 individuals who participated, 658 (36%) acknowledged on the questionnaire that they had a risk factor for HCV. On the subsequent chart review 2 months after their initial visit, 58 individuals either had charts with incomplete data or charts that could not be located. We excluded 22 individuals because they had a known prior diagnosis of HCV. Therefore, our study population included 578 patients with a HCV risk factor.

Demographic characteristics of the study population are presented in Table 1. Only 46 of 578 (8%) individuals with a HCV risk factor were tested for HCV within 2 months after their initial visit. Among those tested, five of 46 (11%) had a positive HCV antibody test result, 39 of 46 (85%) were negative, and two of 46 (4%) had pending results at the time of chart review.

When comparing those who were tested for HCV vs those who were not, we found that those tested had a higher proportion of Latinos, were more often seen in the community primary care clinic setting, had more clinic visits during the 2 months after their initial visit and were less educated. They were also more likely to have the HCV risk factor questionnaire present in their chart and to have a physician who identified and documented a specific HCV risk factor in the chart. No statistically significant differences were found in regard to age, sex, insurance status, annual income and number of comorbidities.

Of the 578 individuals who acknowledged having a HCV risk factor via the questionnaire, only 159 of 578 (28%) had physicians who identified and documented a specific HCV risk factor in the chart. Twenty-one of 159 (13%) patients had two documented risk factors while 138 of 159 (87%) only had one. Table 2 lists the specific risk factors documented in the chart by physicians and their associated rates of HCV testing. No association was found between HCV testing and the number of identified HCV risk factors, as one of 21 (5%) individuals with two risk factors were tested vs 25 of 138 (18%) of those with one risk factor (P = 0.20).

Table 3 presents the rate of HCV testing associated with each medical comorbidity. The only comorbidity with a statistically significant association with HCV testing was hyperlipidemia. All other medical comorbidities were not predictive of HCV testing. Among individuals with 0, 1, 2 or ≥3 medical comorbidities, the rate of HCV testing was 22 of 343 (6%), 12 of 135 (9%), six of 64 (9%) and six of 36 (17%), respectively (P = 0.16).

Table 4 shows the unadjusted and aOR for variables predictive of HCV testing. In our unadjusted analysis, we noted that patients with ≥3 medical comorbidities were more likely to undergo HCV testing when compared to those without medical comorbidities. However, after adjusting for confounders with a binary logistic regression, no statistically significant difference was seen in HCV testing rates between patients with 0, 1, 2 or ≥3 medical comorbidities. The only variable that remained predictive of HCV testing after adjusting for confounders was having a physician who identified and documented a specific HCV risk factor in the chart.

Discussion

The rate of HCV testing among primary care patients with a HCV risk factor was very low, as only 8% underwent HCV testing. We found that having a specific HCV risk factor identified and documented in the chart by physicians predicted HCV testing.

Our study has a number of unique features that differentiate it from prior studies examining HCV testing in primary care settings. Most notable was the prospective design of our study and our focus on actual PCP practices, as we examined individual medical charts. Prior investigators primarily used surveys to study how PCPs identified and managed HCV,[5–10] but surveys are prone to bias and may not reflect true practices. In fact, our HCV testing rate of 8% is in stark contrast to the 70% of surveyed PCPs who stated that they test all patients with risk factors.[5] This strongly suggests that actual practices differ markedly from surveyed responses. The low rate of HCV testing among our study population was especially surprising given that all PCPs were handed a questionnaire from each patient at the initial visit identifying themselves as having a HCV risk factor. This strongly suggests that HCV testing was not a high priority for PCPs at the initial visit. The low rate may also reflect PCPs' unfamiliarity with HCV testing guidelines from national organizations. This is supported by our finding that only 47% and 7% of patients with a history of intravenous drug use and blood transfusion before 1992 were tested for HCV, respectively. These two risk factors are arguably the most important ones for HCV acquisition, and the CDC,[2] NIH,[3] and AASLD[4] all recommend testing these two cohorts for HCV. Further supporting the idea that PCPs are unfamiliar with HCV testing guidelines was a prior survey that found that 42% of PCPs were unaware of the national guidelines regarding HCV testing.[8] Other surveys administered among primary care residents[9] and family physicians[10] revealed their insufficient knowledge about HCV testing guidelines and that they often tested for HCV in inappropriate clinical situations.

Another unique aspect of our study was our examination of the impact of medical comorbidities on HCV testing rates. Originally, we hypothesized that patients with comorbidities would be less likely to undergo testing for HCV. Given the increasing demands placed on PCPs,[12,13] we theorized that PCPs would prioritize the management of comorbidities they perceived as having a more immediate impact on the patient's health and be less concerned with testing for HCV, which is often asymptomatic for years. We also thought that PCPs would be more likely to manage or screen for medical conditions for which effective therapies are available. At the time of our study, the standard HCV treatment of peginterferon-α and ribavirin led to sustained virological response in only 41–52% of those with HCV genotype 1.[14–16] However, our results showed that the presence of comorbidities did not negatively impact the HCV testing rate, thus disproving our original hypothesis. In fact, we found a trend, albeit not statistically significant, towards increased testing with increasing number of medical comorbidities. There are several possible explanations for this finding. PCPs may have given more attention to sicker patients in regard to assessing risk factors for other disease processes, including HCV. Also, patients with multiple medical conditions often receive frequent laboratory tests, and PCPs may have been more likely to order HCV serological testing for a patient already going for blood work.

Other interesting findings from our study included our examination of the rates of HCV testing associated with specific HCV risk factors. Notably, only 47% of patients with a history of intravenous drug use were tested for HCV. This rate is comparable to our prior retrospective study that discovered that 55% of intravenous drug users were tested.[11] These findings are surprising given that 98% of surveyed family physicians stated that they offer HCV testing to this group.[7] Such a low rate of testing among intravenous drug users is troubling because prior studies found that 35% to 57% were HCV antibody positive.[17,18]

A limitation of our study included our data being limited to what was documented in the chart. We may have missed specific HCV risk factors and medical comorbidities that went undocumented. We also may have missed patient refusals for HCV testing that were not documented by the PCP. Another limitation relates to the fact that our study population only included patients new to each primary care clinic and that we only looked for HCV antibody test results within the 2 months after their initial visit. It is possible that HCV testing could have occurred at later visits. However, the initial visit is often the most comprehensive visit, and we would expect that most referrals for HCV testing would occur during the first visit. Our study was also limited by the fact that we were unable to determine why PCPs did not offer HCV testing to most individuals who admitted to having a HCV risk factor. Lastly, our study did not examine a realistic clinical situation, as patients were 'prelabelled' as being high risk for HCV via the HCV risk factor questionnaire. Yet, we should point out that despite 'prelabelling' patients as high risk for HCV, only 8% were tested and the true HCV testing rate is likely much lower.

In summary, we found that 92% of patients with a HCV risk factor were not tested for HCV. Testing those at high risk for HCV is critical, as it can lead to early identification of infection and find those who will benefit from antiviral therapy.[19] This is especially important given the new and effective protease inhibitors that are now available.[20,21] Aside from referring for antiviral treatment, PCPs can also immunize patients with the hepatitis A and B virus vaccines, recommend abstinence from alcohol and provide education regarding behaviours that transmit HCV to others.[22–24] Given these benefits, PCPs should make every effort in increasing HCV testing rates among patients with a HCV risk factor. Future studies that further define the barriers associated with HCV testing in primary care settings as well as the development of novel strategies to improve HCV testing rates are clearly needed.

References

  1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705–714.
  2. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related
  3. chronic disease. Centers for Disease Control and Prevention. MMWRRecomm Rep 1998; 47: 1–39.
  4. NIH consensus statement on management of hepatitis C. 2002. NIHConsens State Sci Statements 2002; 19: 1–46.
  5. Strader DB, Wright T, Thomas DL et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39: 1147–1171.
  6. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the
  7. USA: results of a national survey. JViral Hepat 2001; 8: 377–383.
  8. Navarro VJ, St Louis TE, Bell BP. Identification of patients with hepatitis C virus infection in New Haven County primary care practices. J Clin Gastroenterol 2003; 36: 431–435.
  9. Clark EC, Yawn BP, Galliher JM, Temte JL, Hickner J. Hepatitis C identification and management by family physicians. Fam Med 2005; 37: 644–649.
  10. Kallman JB, Arsalla A, Park V et al. Screening for hepatitis B, C and nonalcoholic fatty liver disease: a survey of community-based physicians. AlimentPharmacol Ther 2009; 29: 1019–1024.
  11. Coppola AG, Karakousis PC, Metz DC et al. Hepatitis C knowledge among primary care residents: is our teaching adequate for the times? Am JGastroenterol 2004; 99: 1720–1725.
  12. Ferrante JM, Winston DG, Chen PH, de la Torre AN. Family physicians' knowledge and screening of chronic hepatitis and liver cancer. Fam Med 2008; 40: 345–351.
  13. Trooskin SB, Navarro VJ, Winn RJ et al. Hepatitis C risk assessment, testing and referral for treatment in urban primary care: role of race and ethnicity. World J Gastroenterol 2007; 13: 1074–1078.
  14. Mechanic D, McAlpine DD, Rosenthal M. Are patients' office visits with physicians getting shorter? N Engl JMed 2001; 344: 198–204.
  15. Abbo ED, Zhang Q, Zelder M, Huang ES. The increasing number of clinical items addressed during the time of adult primary care visits. J Gen Intern Med 2008; 23: 2058–2065.
  16. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–965.
  17. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982.
  18. Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–355.
  19. Judd A, Hutchinson S, Wadd S et al. Prevalence of, and risk factors for, hepatitis C virus infection among recent initiates to injecting in London and Glasgow: cross sectional analysis. J Viral Hepat 2005; 12: 655–662.
  20. Miller CL, Johnston C, Spittal PM et al. Opportunities for prevention: hepatitis C prevalence and incidence in a cohort of young injection drug users. Hepatology 2002; 36: 737–742.
  21. Mallette C, Flynn MA, Promrat K. Outcome of screening for hepatitis C virus infection based on risk factors. Am J Gastroenterol 2008; 103: 131–137.
  22. McHutchison JG, Everson GT, Gordon SC et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl JMed 2009; 360: 1827–1838.
  23. McHutchison JG, Manns MP, Muir AJ et al. Telaprevir for previously treated chronic HCV infection. NEngl J Med 2010; 362: 1292–1303.
  24. Peters MG, Terrault NA. Alcohol use and hepatitis C. Hepatology 2002; 36: S220–S225.
  25. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998; 28: 805–809.
  26. Shehab TM, Orrego M, Chunduri R, Lok AS. Identification and management of hepatitis C patients in primary care clinics. Am J Gastroenterol 2003; 98: 639–644.

Source

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).

757995-fig1

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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Source

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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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)
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