September 20, 2010

J Clin Gastroenterol. 2010 Sep 2. [Epub ahead of print]

Cheung O, Sterling RK, Salvatori J, Williams K, Hubbard S, Luketic VA, Stravitz TR, Sanyal AJ, Contos MJ, Mills S, Shiffman ML.

* Hepatology Section daggerDepartment of Pathology, Virginia Commonwealth University Medical Center, Richmond double daggerLiver Institute of Virginia, Bon Secours Health System, Newport News, VA.

Abstract

BACKGROUND: Excessive alcohol consumption is associated with an increased risk for fibrosis progression and cirrhosis in patients with chronic hepatitis C virus (HCV) infection. However, the impact of mild-moderate alcohol use on the severity of liver fibrosis is unclear.

GOALS: The objective of this retrospective study was to assess the impact of mild alcohol consumption on liver fibrosis in patients with chronic HCV.

STUDY: 857 patients with well-characterized chronic HCV were enrolled. All underwent liver biopsy to assess hepatic fibrosis. The duration of HCV infection was determined by detailed questionnaires and personal interviews. Alcohol use history was estimated by the Skinner Alcohol Examination Questionnaire. Mild alcohol use was defined as 1 to 3 alcoholic beverages/day (<30 grams/d). Participants were divided into 4 groups based on their average lifetime daily alcohol consumption (essentially none, <1, 1 to 3 or >3 drinks/d) and into quartiles based on their presumed duration of HCV infection (<23, 23 to 31, 31 to 38, or >38 y).

RESULTS: Mean alcohol consumption was 2.7 drinks/d; mean duration of HCV infection was 29 years. Daily alcohol consumption was not significantly higher among participants with advanced fibrosis (bridging fibrosis or cirrhosis) when compared with those with none or portal fibrosis (3.2 vs. 2.2 drinks/d, respectively, P=NS). The degree of fibrosis increased significantly with the duration of HCV infection (P<0.0001) and was independent of mild-moderate alcohol consumption.

CONCLUSIONS: Mild alcohol use does not seem to adversely affect the severity of fibrosis in patients with chronic HCV.

PMID: 20818236 [PubMed - as supplied by publisher]

Source

Androgen Receptor May Explain Male Dominance in Liver Cancer

ScienceDaily (Sep. 14, 2010) — A University of Rochester study helps to explain why men get liver cancer more often than women and opens the door for a new treatment pathway, by showing a direct link between the androgen receptor, which is more active in men, and the hepatitis B virus as it relates to the deadly cancer.

The study is published May 19, 2010, in Science Translational Medicine.

Primary liver cancer is the fifth most common cancer in men. It often arises after infection from the hepatitis B virus (HBV), which is widespread across the globe and growing in the United States. Other studies of liver cancer have focused on risk factors such as age, family history, and use of alcohol and cigarettes, but those epidemiology studies have not explained the mechanisms driving hepatocellular carcinoma and why men are more susceptible.

Now, corresponding author Chawnshang Chang, Ph.D., the George Hoyt Whipple Distinguished Professor of Pathology at the University of Rochester Medical Center, and colleagues, showed that the androgen receptor (AR), a protein that mediates male sex hormones, promotes liver cancer when hepatitis B is present by altering DNA replication of the virus. Chang's laboratory created a mouse model for HBV-induced liver cancer and reported that knocking out AR suppressed the HBV-induced cancer.

According to an accompanying editorial in the journal, the identification of the AR pathway is a potential new treatment target that could translate to the clinic.

"Our study is the first in vivo evidence to demonstrate a direct connection between HBV-induced liver cancer and the AR," Chang said. "This is important because so far most work has focused on eliminating total serum androgen levels, a type of therapy that has shown little success."

"This important paper offers insight into something we have long observed but not entirely understood, namely that men with HBV are much more likely to develop cancer than women with the same infection," said Aram Hezel, M.D., a gastrointestinal oncologist at the James P. Wilmot Cancer Center at University of Rochester Medical Center. "This is great use of the tools of genetics and mouse modeling to explain a clinical finding and most importantly turn our attention to potentially more promising treatment approaches for patients with hepatocellular carcinoma."

"This study also raises the possibility of prevention among men with HBV infection through inhibition of the androgen receptor," Hezel added. "The potential impact on clinical care is great."

For decades Chang has focused on the particular role of the AR in human health. In 1988 he successfully cloned AR, which led to breakthroughs in several AR-related diseases such as prostate and bladder cancer, and Kennedy's neuron disease, a rare and progressive motor disorder similar to Lou Gehrig's disease, and that affects only men.

The AR is central to the action of testosterone and has a profound effect on many organs. In previous experiments, Chang has shown that mice without AR have dramatically lower rates of bladder cancer, a cancer that strikes men three times more often than women.

Male dominance in liver cancer suggested that the AR would be a key factor, as well. (About 74 percent of liver cancer cases occur in men.) Chang's objective was to locate a new pathway for treatment that would not require depletion of androgen levels in the entire body, which amounts to castration and causes severe side effects for patients.

His study took the first step toward demonstrating this could be done, at least for early stage liver cancer. Researchers showed that an experimental drug, ASC-J9, attacked and degraded the faulty AR, and suppressed liver tumors in mice.

Chang developed ASC-J9 earlier this decade and first reported on its clinical potential in March 2007 in the journal Nature Medicine. The drug is a synthetic compound loosely based on the compounds found in curcumin, the polyphenol that gives the spice tumeric its yellow color. It has been used for centuries as a folk medicine in Asia and India. In this case, however, scientists significantly altered the natural substance to be more powerful, and are carefully screening it for safety and effectiveness.

AndroScience Corp., a biotech company founded by Chang and others in 2000, is evaluating ASC-J9 in several clinical settings, although not yet in the treatment of liver cancer, Chang said. The URMC owns a stake in AndroScience, and has licensed several of Chang's research findings.

In the current study, researchers found that AR cooperates with the hepatitis B virus to trigger the expression of several oncogenes, resulting in normal liver cells transforming into cancer cells. Furthermore, they showed that liver tumors without the AR had fewer proliferating cancer cells, which helps to explain the gender disparity in the disease.

Some of the findings are in agreement with earlier studies by Chang's lab on the role of AR in prostate cancer. Just as in prostate cancer, the liver tumor microenvironment is rich in various cell types, each of which has a distinct role in promoting the cancer.

"It will be interesting to see if targeting AR at different stages or in different liver cancer cell types may also lead to differential effects during the progression of cancer," the paper concluded.

The hepatitis B and C viruses account for approximately 80 percent of primary liver cancer cases worldwide. Newborn vaccines and screenings for HBV and HCV, particularly in Asian and African countries, have reduced the incidence of liver cancer in later years. Still, an estimated 560,000 new cases are diagnosed annually. In high-risk areas such as China, Japan and sub-Saharan Africa the male-to-female ratio of liver cancer can be as high as 8 to 1. The current best treatment is surgery; median survival is generally six months.

The National Institutes of Health and the George Whipple Professorship Endowment funded the research. Co-authors from the Whipple Lab and the URMC James P. Wilmot Cancer Center are: Ming-Heng Wu, Wen-Lung Ma, Cheng-Lung Hsu, Yuh-Ling Chen, Charlotte Kathryn Ryan and Shuyuan Yeh. Additional co-authors include Jing-Hsiung James Ou, of the Department of Molecular Microbiology and Immunology at the University of Southern California, Los Angeles; Yao-Ching Hung and Wen-Lung Ma, of the Sex Hormone Research Center at China Medical University/Hospital in Taiwan. Ming-Heng Wu is also associated with Cheng Gung University in Taiwan; and Cheng-Lung Hsu, with Chang Gong University in Taiwan.

Source
Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)

Emmanuel Thomas 1, Jordan J. Feld 1,2, Qisheng Li 1, Zongyi Hu 1, Michael W. Fried 3, T. Jake Liang 1,*
DOI: 10.1002/hep.23985
Copyright © 2010 American Association for the Study of Liver Diseases

Author Information
1 Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
2 Toronto Western Hospital Liver Centre, Department of Medicine, Division of Gastroenterology, 6B Fell Pavillion Room 160, 399 Bathurst St, Toronto, ON M5T 2S8, Canada
3 Division of Gastroenterology and Hepatology, University of North Carolina, CB 7584, Room 8015 Burnett Womack Building, Chapel Hill, NC, 27514, USA

Email: T. Jake Liang (JakeL@bdg10.niddk.nih.gov)

* Correspondence: T. Jake Liang, Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA

Publication History
Accepted manuscript online: 14 SEP 2010 08:04AM EST
Manuscript Accepted: 4 SEP 2010
Manuscript Revised: 2 SEP 2010
Manuscript Received: 25 MAR 2010

Funded by
  • The Intramural Research Program
  • The National Institute of Diabetes and Digestive and Kidney Diseases
  • NIH
  • NIH K24 mentoring award. Grant Number: DK066144
Abstract

The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. (HEPATOLOGY 2010.)

Source
Below is an email message that I received from the FDA:

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

The Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry entitled “Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment.” At present, there are a large number of drugs for the treatment of chronic hepatitis C (CHC) in active development. The purpose of this guidance is to assist sponsors in all phases of development of direct-acting antiviral agents (DAAs), defined as agents that interfere with specific steps in the hepatitis C virus (HCV) replication cycle. The guidance outlines the types of nonclinical studies and clinical trials recommended throughout the drug development process, such as early phases of clinical development, phase 3 protocol designs, and endpoints for the treatment of CHC to support approval of treatments for CHC, including patients with compensated and decompensated cirrhosis and those co-infected with HIV. The guidance also addresses pre-approval access in the form of treatment investigational new drug applications (INDs) and intermediate-sized safety protocols (collectively known as expanded access).

Important issues addressed in this guidance include: drug development methods to reduce the emergence of drug resistance, types of trial designs to assess optimal dose and treatment duration, combination therapy with multiple investigational drugs, recommendations on development of drugs to meet unmet medical needs, and use of treatment INDs or other smaller safety protocols to provide early access of multiple DAAs for patients at risk of imminent progression of liver disease.

The draft guidance, when finalized, will represent the agency’s current thinking on developing DAAs for treatment of CHC virus infection. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

The draft guidance is available on the FDA web site at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf

Although comments are accepted for any guidance at any time, to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance, please submit written or electronic comments on the draft guidance by November 15, 2010, and include the docket number, FDA-2010-D-0462, in any comment you submit.

You may submit written comments on the draft guidance to the

Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061,
Rockville, MD 20852

You may also submit electronic comments at http://www.regulations.gov/search/Regs/home.html#submitComment?R=0900006480b4e9b3.

FOR FURTHER INFORMATION CONTACT:

Jeffrey Murray,
Center for Drug Evaluation and Research,
Food and Drug Administration,
10903 New Hampshire Ave.,
Bldg. 22, rm. 6360,
Silver Spring, MD 20993-0002,
301-796-1500.

The complete Federal Register Notice announcing availability of this draft guidance is available at http://edocket.access.gpo.gov/2010/pdf/2010-22806.pdf

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Source: Received via email

TV Show Delivers Hope for Hepatitis C

September 8, 2010

A recent television news piece helped boost awareness of Hepatitis C - but it also may have created false hope by alluding to the speedy arrival of a Hep C cure.

by Nicole Cutler, L.Ac.

As the number of people receiving a Hepatitis C diagnosis grows, media attention focusing on this virus has intensified. Education about the prevalence and potential severity of Hepatitis C is badly needed to raise awareness of this highly communicable and often asymptomatic (until it's too late) disease. A television program broadcast in June of 2010 is to be commended for spearheading such an awareness campaign; but it also has some people expecting a cure for Hepatitis C to arrive unrealistically soon.

As described in a recent TV presentation, scientists around the world are fervently working to find effective, safe drugs for treating and preventing Hepatitis C. However, those who are not familiar with the process of drug development could easily misinterpret the progress described on television with the notion that a vaccine for Hepatitis C will hit the market any day now.

Believed to currently infect between four and five million Americans, those infected with Hepatitis C far outnumber those with HIV, the virus that causes AIDS. A leading cause of chronic liver disease that has no vaccine or reliable cure, Hepatitis C presents many challenges to the medical community. Among those challenges are:

· The current treatment in effect is only successful in about half of all cases.
· The virus demonstrates an ability to develop drug resistance.
· Chronic Hepatitis C can progress to severe or even fatal liver disease.

According to their website, KQED Public Television 9 is one of the nation's most-watched public television stations during primetime with more than 1.5 million households viewing per month. A KQED weekly program, This Week in Northern California with host Belva Davis follows a magazine format and is committed to news and public affairs. The June 25, 2010 episode of This Week in Northern California featured an informative piece entitled "Hepatitis C: The Silent Epidemic." Summing up this segment, KQED reports:

"A San Francisco Task Force on Hepatitis C is helping to find a cure for the disease, which is four times more prevalent in the Bay Area as AIDS. ...Dr. Jeffrey Glenn and his team of researchers at the Stanford University School Of Medicine are looking for compounds that will prevent the Hepatitis C virus from replicating. And at the Gladstone Institutes at UCSF, Dr. Melanie Ott and her staff are doing groundbreaking research on the relationship between the virus and fat droplets in the liver that could soon lead to a cure."

Watching the video segment delivers hope to those waiting for a reliable solution for Hepatitis C. The researcher interviewed appears excited to be a part of a Hepatitis C-soon-to-be-cure. While it is hard not to get caught up in the excitement, the research from Stanford and UCSF's Gladstone Institutes are still in the beginning stages of making progress against this virus.

A scientific discovery that further unravels the mystery behind Hepatitis C is definitely reason for celebration, but it is far from delivering a cure. After realizing the clinical impact of the discovery, scientists begin the process of identifying potential substances that could inhibit or fight the virus. Once a promising medication is apparent, the testing of that drug is a long process. Typically taking about 12 years to come to fruition, a new drug must persevere through pre-clinical testing, clinical trials and U.S. Food and Drug Association (FDA) approval before it finally reaches the marketplace. For more detailed information about this process, read "An Overview of the HCV Drug Development Process."

The research described in the KQED segment is encouraging. Scientists at the Gladstone Institute of Virology and Immunology found that an important viral protein, called the "core" protein, localizes to the mitochondria. Through examining liver fat droplets in the mitochondria, new mechanisms for treating Hepatitis C could follow. While drugs capitalizing on this information could be in the future, there are others that are closer to actualization. This television program focused solely on San Francisco Bay area developments. However, there are other medications, such as telaprevir, that have already endured years of development. Shown to drastically boost the Hepatitis C cure rate, telaprevir could be available to the public as early as 2011.

Good job to KQED for bringing the lack of Hepatitis C awareness and education to the forefront. The research focusing on fat droplets in the liver is invaluable to the eventual conquering of the Hepatitis C virus, but it has not yet produced a cure. As we see more education campaigns exposing the gravity of Hepatitis C infection, a greater level of comprehension will also be needed to understand the drug development process. In the meantime, rest assured that progress is being made - and even if it doesn't end the Hepatitis C epidemic this year - the scientific community is certainly headed in that direction.

References:

http://news.ucsf.edu/fyi/daily/2010/06/28/, UCSF Television Coverage, Retrieved August 26, 2010, The Regents of the University of California, 2010.

http://www.gladstone.ucsf.edu/wp/2010/02/hepcviralprotein/, Hepatitis C Viral Protein Associates with the Mitochondria, Retrieved August 25, 2010, J. David Gladstone Institutes, 2010.

http://www.hepatitis-central.com/mt/archives/general_hepatitis_c_newsupdates/, An Overview of the HCV Drug Development Process, Nicole Cutler, L.Ac., Retrieved August 28, 2010, Natural Wellness, 2010.

http://www.kqed.org/tv/programs/thisweek/watch/archive/226569/b, Hepatitis C: The Silent Epidemic, Retrieved August 26, 2010, KQED, 2010.

http://www.mdpi.com/1999-4915/2/5/1195/, Lipid Metabolism and HCV Infection, Paul Targett-Adams, et al, Retrieved August 25, 2010, Viruses, May 2010.

Sourcehttp://www.hepatitis-central.com/mt/archives/2010/09/tv_show_deliver.html?eml=hepcen115

Partial Hep C Treatment Response Offers Health Benefits

September 17, 2010

Even a partial response to hepatitis C virus (HCV) therapy confers significant health benefits to people coinfected with both HIV and HCV, though not as much as a full response. These data were presented September 14 at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Boston.

The goal of HCV therapy is total eradication of the virus. This outcome, called a sustained virological response (SVR), means that a person achieves and maintains undetectable HCV levels for at least six months after completing a course of pegylated interferon and ribavirin treatment, which is the standard of care for hepatitis C. People who achieve an SVR are generally considered to be “cured” of their HCV infection.

Unfortunately, standard treatment is not particularly effective for people infected with HCV genotype 1, the most common and difficult to treat strain in the United States. SVR rates in people coinfected with both HIV and HCV genotype 1 are generally no higher than 25 percent. There is, however, a segment of people who have undetectable HCV levels at the end of treatment, but who see their virus come back in subsequent months. These people are considered to have an end of treatment response (ETR). What remains unknown is whether and to what degree these individuals have benefited from taking HCV treatment.

To explore this question, Juan Berenguer, MD, from the Hospital Universitario Gregorio Maranon in Madrid, and his colleagues, analyzed data from the GESIDA 3603 cohort, which follows HIV and HCV coinfected people from 19 clinics across Spain. Out of the 1,428 people in the analysis, 697 did not respond to HCV treatment (non-responders), 211 had an ETR, and 520 had an SVR.

The analysis looked at the rate of developing a variety of liver problems over a four-year period after completing HCV treatment. The presentation did not report on the participants’ average age, CD4 counts, distribution of HCV genotypes or other demographic factors, but those factors were included in the analysis.

Berenguer’s team found that although people with an ETR had poorer outcomes than people who achieved an SVR, they still did far better than non-responders. People with an ETR were 60 percent less likely to have liver damage (decompensation) than non-responders. People with an SVR were 92 percent less likely. People with ETRs and SVRs were both about 95 percent less likely to die from liver disease than non-responders.

The best treatment outcomes were achieved with an SVR, the authors concluded. They added, however, that ETR was associated with less liver-related mortality and liver decompensation than a non-response to treatment.

Search: Hepatitis C, HCV, genotype 1, ICAAC, SVR, ETR, liver, liver decompensation, Juan Berenguer

Source
J Clin Gastroenterol. 2010 Oct;44(9):e210-e217.

Neri S, Bertino G, Petralia A, Giancarlo C, Rizzotto A, Calvagno GS, Mauceri B, Abate G, Boemi P, Di Pino A, Ignaccolo L, Vadalà G, Misseri M, Maiorca D, Mastrosimone G, Judica A, Palermo F.

Departments of *Internal Medicine †Psychiatry ∥Internal and Specialty Medicine, Center of Statistics, University of Catania §Research Doctorate in Hepatology, University of Catania ‡School of Psychology, Kore University, Enna, Italy.

Abstract

GOALS: To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-α and ribavirin among study participants compared with standard clinical monitoring alone.

BACKGROUND: Interferon-α is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy.

STUDY: Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test).

RESULTS: At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05).

CONCLUSIONS: Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment.

PMID: 20838237 [PubMed - as supplied by publisher

Source
Transplant Proc. 2010 Sep;42(7):2436-46.

Maluf DG, Archer KJ, Mas VR.

Division of Transplantation Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.

Abstract

The Organ Procurement and Transplantation Network database (2001-2006) was reviewed for kidney transplant (KT) recipients, to evaluate the effects of use of grafts from donors positive for hepatitis C virus (HCV) on recipient outcome. Data for 76,787 de novo adult KT recipients were included in the analysis. Serologic tests revealed HCV positivity in 6.25% of cadaver kidneys and 2.97% of living-donor kidneys. Median follow-up in patients still alive was 36 months. At multivariable Cox regression analysis in recipients of cadaver kidney, HCV serostatus was significantly associated with overall and graft survival (both P < .001), with a hazard ratio for HCV-positive patients of 1.43 for overall survival and 1.48 for graft survival. Similar results were obtained for living-donor kidney recipients. Recipients of HCV-positive organs tended to be male and African American and to have a shorter waiting time. Infection was the most commonly reported cause of death in recipients of organs from HCV-positive donors. In patients willing to accept HCV-positive grafts (929 [25.6%]), waiting time was significantly shortened (P < .001). However, this benefit was offset by decreased patient survival (P < .001) and graft survival (P = .007).

PMID: 20832522 [PubMed - in process]

Source
J Hepatol. 2010 Aug 4. [Epub ahead of print]

Mangia A, Bandiera F, Montalto G, Mottola L, Piazzolla V, Minerva N, Pellicelli A, Ricci GL, Cela M, Carretta V, Scotto G, Bacca D, Annicchiarico B, Romano M, Russello M, Barbarini G, Agostinacchio E, Andriulli A.

Liver Unit, IRCCS, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.

Abstract

BACKGROUND & AIMS: The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established.

METHODS: Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200mg of ribavirin daily according with body weight > or <75kg. Patients were randomized to standard 24weeks (Std24) or to a 12 or 36weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36weeks duration.

RESULTS: At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25).

CONCLUSIONS: HCV genotype 3 patients with week4-R may be treated safely with 12weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36weeks of treatment than after the currently recommended 24weeks.
PMID: 20843575 [PubMed - as supplied by publisher]

Source
J Gastroenterol. 2010 Sep 10. [Epub ahead of print]

Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Hiramatsu N, Sugauchi F, Yatsuhashi H, Izumi N.

Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo, 180-8610, Japan, kurosaki@musashino.jrc.or.jp.

Abstract

BACKGROUND: This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C.

METHODS: Data from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis.

RESULTS: Age (<50 years), alpha-fetoprotein (AFP) (<8 ng/mL), platelet count (≥120 × 10(9)/l), gamma-glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group.

CONCLUSIONS: A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.

PMID: 20830599 [PubMed - as supplied by publisher]

Source
Hepatology. 2010 Jul 29. [Epub ahead of print]

Roomer R, Hansen BE, Janssen HL, de Knegt RJ.

Departments of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Abstract

Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC <375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Conclusion: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (HEPATOLOGY 2010).

PMID: 20830784 [PubMed - as supplied by publisher]

Source
Gastroenterology. 2010 Sep 9. [Epub ahead of print]

Rao GA, Pandya PK.

Kansas City Veterans Affairs Medical Center, 4801 E. Linwood Blvd, Kansas City, MO 64128; Arnold School of Public Health, University of South Carolina, 800 Sumter St, Columbia, SC 29208.

Abstract

BACKGROUND & AIMS: Patients with chronic hepatitis C infection are 2-3-fold more likely to develop type-2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of national Veterans Affairs (VA) administrative database.

METHODS: We analyzed data from VA Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetics (n=1704) and non-diabetics (n=6589). Significant predictors of SVR were identified by logistic regression analysis.

RESULTS: Diabetics had a lower SVR compared to non-diabetics (21% vs. 27%, p < 0.001). Diabetics had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetics for SVR, the positive predictors were higher low density lipoprotein (OR=1.45, p=0.0129), use of statin (OR = 1.52, p = 0.0124) and lower baseline viral load (OR = 2.31, p < 0.001), while insulin therapy (0.7, p = 0.0278) was a negative predictor. Diabetics on statins had a higher pre-treatment viral loads (log 6.2vs.6.4, p= 0.006) but better early virologic response. There was a graded inverse relationship between HbA1c and SVR rate (p=0.0482). This relationship was highest among insulin users (p=0.0154) and lost among metformin users (p=0.5853).

CONCLUSIONS: Statin use was associated with an improved SVR among both diabetics and non-diabetics receiving combination antiviral therapy. Diabetics who received insulin achieved lower SVR compared to those not receiving insulin. Poor diabetes control was associated with lower SVR rates.

PMID: 20833169 [PubMed - as supplied by publisher]

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Am J Gastroenterol. 2010 Aug;105(8):1782-7. Epub 2010 Feb 23.

Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Abstract

OBJECTIVES: Data on temporal changes in alcoholic liver disease (ALD)-related mortality in the United States are lacking. This longitudinal assessment is important, given the divergent data on trends in worldwide ALD-related mortality, concerns for underestimation of mortality attributed to ALD in previous investigations, and shifting attention to hepatitis C virus (HCV)-related mortality.

METHODS: We analyzed mortality data compiled in the multiple cause-of-death public-use data file from the National Vital Statistics System from 1980 to 2003 using categorization by both International Classification of Diseases (ICD)-9 and ICD-10 systems. The main outcome measure was age- and sex-adjusted death rates attributable to ALD, HCV, or both (ALD/HCV) listed as immediate or underlying cause of death.

RESULTS: A total of 287,365 deaths were observed over the 24-year period. Age- and sex- adjusted incidence rates of ALD-related deaths decreased from 6.9/100,000 persons in 1980 to 4.4/100,000 persons by 2003. After introduction of HCV diagnostic testing, HCV-related liver mortality increased to 2.9/100,000 persons by 2003. Death rates for subjects with concomitant ALD/HCV rose to 0.2/100,000 persons by 1999 and then remained unchanged through 2003. Age-specific mortality related to ALD was highest in the ages of 45-64 years. Between 1980 and 2003, the age- and sex-adjusted ALD-related mortality (per 100,000 persons) decreased from 6.3 to 4.5 among Caucasians, 11.6 to 4.1 among African Americans, and 8.0 to 3.7 among the "other" race group.

CONCLUSIONS: Despite a decline in ALD-related mortality, the proportion of alcohol-related liver deaths is still considerably large and comparable in scope to that of HCV.

PMID: 20179691 [PubMed - indexed for MEDLINE] PMCID: PMC2916935

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Study Spells End of the Road for One Anti-HIV Gel

By Michael Smith, North American Correspondent, MedPage Today
Published: September 19, 2010
Reviewed by Barry S. Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY
and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

A microbicide gel -- PRO2000 -- aimed at preventing HIV infection in women was ineffective, despite promising early clinical trials, researchers reported.

In a large randomized phase III trial, the PRO2000 microbicide was safe, but did nothing to prevent women from acquiring HIV, according to Sheena McCormack, MD, of the MRC Clinical Trials Unit in London, and colleagues.

The report, online in The Lancet, comes only a few weeks after researchers studying another microbicide gel combined with an antiretroviral drug reported partial success -- a significant 39% reduction in the risk of HIV infection. Further studies of microbicides that include antiretroviral drugs are underway.

The PRO2000 compound is a synthetic naphthalene sulphonate polymer that -- in animals and the lab -- had shown anti-HIV activity, McCormack and colleagues noted. A phase II/IIb trial, reported in 2009, also found a nonsignificant but promising trend toward protection in humans.

But only a few days after that report, the data monitoring committee of this study called a halt to one of the arms -- testing a 2% solution of PRO2000 -- on the grounds that there was little likelihood of benefit. The other arm, testing a 0.5% solution, was allowed to continue to completion, McCormack and colleagues reported.

The study, conducted in 13 clinics in South Africa, Tanzania, Uganda, and Zambia, randomly assigned sexually active, HIV-negative women to get one of three gels -- a hydroxyethylcellulose placebo, 0.5% PRO2000, or 2% PRO2000.

The researchers reported two efficacy analyses -- all three arms compared at the time of the 2% PRO2000 discontinuation and the placebo and 0.5% PRO2000 arms compared at the planned end of the study.

Overall, McCormack and colleagues found, adherence was high, with an average reported gel use at the last sex act of 89%.

Despite that, the incidence of HIV was much the same in both analyses:

• At the discontinuation of the 2% PRO2000 arm, the incidence per 100 woman-years was 4.7 for 2% PRO2000, 3.9 for 0.5% PRO2000, and 3.9 for placebo. Neither treatment was significantly better than placebo.

• At study's end, the incidence per 100 woman-years was 4.5 for 0.5% PRO2000 and 4.3 for placebo. The 1.05 hazard ratio had a 95% confidence interval from 0.82 to 1.34 and was nonsignificant at P=0.71.

The primary safety endpoint was an adverse event of grade 3 or worse, and again there was little difference -- 4.6 per 100 woman-years in the 0.5% PRO2000 group and 3.9 in the placebo group at study's end. It was 4.5 in the 2% PRO2000 group at discontinuation, the researchers reported.

The findings are "disappointing," especially in view of the earlier trial that showed a nearly significant result, according to Sandra McCoy, PhD, of the University of California Berkeley, and colleagues.

Writing in an accompanying commentary, McCoy and colleagues said the report "will certainly indicate the end of the road for PRO2000 as a potential HIV-prevention tool for women."

But, they noted, the positive results of the latest microbicide study, combined with other interventions that are showing promise in reducing HIV incidence among women, "have the potential to greatly expand prevention options for women in sub-Saharan Africa."

The study was supported by the Microbicides Development Programme, the U.K. Department for International Development, the European and Developing Countries Clinical Trials Partnership, and the U.K. Medical Research Council. Study gels were provided by Endo Pharmaceutical Solutions. McCormack reported no conflicts.

Commentary author Charlotte Watts, of the London School of Hygiene and Tropical Medicine, is supported by the Sigrid Rausing Trust and the Microbicides Development Programme.

All authors said they had no conflicts.

Primary source: The Lancet
Source reference:
McCormack S, et al "PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)61086-0.

Additional source: The Lancet
Source reference:
McCoy SI, et al "Preventing HIV infection: Turning the tide for young women" Lancet 2010; DOI: 10.1016/S0140-6736(10)61309-8.

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Am J Gastroenterol. 2010 Sep 14. [Epub ahead of print]

Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD.

Department of Medicine, University of California, Los Angeles, California, USA.

Abstract

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD.

METHODS: In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years.

RESULTS: There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001).

CONCLUSIONS: In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy.Am J Gastroenterol advance online publication, 14 September 2010; doi:10.1038/ajg.2010.299.

PMID: 20842109 [PubMed - as supplied by publisher]

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