Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in HCV cell culture models

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

FDA Hepatitis Update -- Availability of draft Guidance: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment

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

A Multidisciplinary Therapeutic Approach for Reducing the Risk of Psychiatric Side Effects in Patients With Chronic Hepatitis C Treated With Pegylated Interferon α and Ribavirin

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

Kidney Grafts From HCV-Positive Donors: Advantages and Disadvantages

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

Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3

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

Pretreatment prediction of response to peginterferon plus ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis

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

Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C

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

Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C

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]

Source

Alcoholic liver disease-related mortality in the United States: 1980-2003

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

Free Author Manuscript

Source

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.

Source

Atorvastatin and Antioxidants for the Treatment of Nonalcoholic Fatty Liver Disease: The St Francis Heart Study Randomized Clinical Trial.

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]

Source

Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis

FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminalpropeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).

While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers.

Methods: In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively.

Results: Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC.

The accuracy (AUROC) for the diagnosis of significant fibrosis (F[greater than or equal to]2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.).

For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.).

Conclusion: FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.

Author: Mireen Friedrich-RustWilliam RosenbergJulie ParkesEva HerrmannStefan ZeuzemChristoph Sarrazin

Credits/Source: BMC Gastroenterology 2010, 10:103

Published on: 2010-09-09
 
Source

Bone Loss in HIV-Positive Men Tied to AIDS Diagnosis, Opiate Use and Hep C

September 9, 2010

Heroin and methadone users who’ve ever been diagnosed with AIDS are at dramatically higher risk of bone loss as they get older, according to a study published in the September 24 issue of AIDS.

Potent combination antiretroviral (ARV) therapy has significantly cut the death rate and led to longer life spans in people with HIV. This means that people are now living into older age, when additional health problems typically strike. In fact, experts project that by 2015 more than half of all people with HIV in the United States will be older than 50.

A growing concern is bone mineral loss—called osteopenia when it is mild and osteoporosis when it is more severe. Numerous studies have found higher rates of bone mineral loss among people with HIV than their HIV-negative counterparts. This is particularly true of HIV-positive men.

A further risk factor for decreased bone mineral density (BMD) is use of opiates, including heroin and methadone. Both drugs have been associated with osteopenia and osteoporosis. Since a significant number of people with HIV are current or former drug users, Anjali Sharma, MD, MS, and her colleagues from the State University of New York Downstate Medical Center in Brooklyn set out to measure bone health within this population.

Sharma’s team enrolled 389 men in the Bronx, New York, ages 49 and older who were HIV positive or at risk for infection. In total, 230 were HIV positive, and 159 were HIV negative. The men’s average age was 56, and most were of average height and weight. More than half of the HIV-positive men had been positive for at least 10 years, and 77 percent of them reported using protease inhibitors. More than half were African American, roughly one quarter were Latino, and the remainder were white or another race. The median CD4 count among the HIV-positive men was 398, and 42 percent had a history of an AIDS diagnosis.

All of the men underwent extensive interviews to determine their behavioral and medical histories. Each of them also underwent dual energy X-ray absorptiometry (DEXA) scans to measure their bone health in the thigh, hip and lower back, both at the time they entered the study and roughly three years later.

Risk factors associated with diminished BMD were common: 88 percent had a history of cocaine use, almost all had a history of smoking (64 percent were current smokers), 47 percent had evidence of alcoholism, and 47 percent had low serum testosterone.

At time of first DEXA, 46 percent of the men overall had normal BMD, while 42 percent had osteopenia, and 12 percent had osteoporosis. Of the men who initially had a normal BMD, 14 percent progressed to osteopenia, and 86 percent continued to have healthy bones. The risk for developing osteopenia among this group was nearly three times higher in the HIV-positive men. Of those who were initially diagnosed with osteopenia, roughly 12 percent progressed to osteoporosis. The rate of progression here was the same for HIV-positive men as for HIV-negative men.

Most of the typical factors for reduced BMD were associated with bone loss in this study, including, age, race, use of corticosteroids or testosterone, and hepatitis C virus (HCV) infection.

Sharma’s team, however, found a powerful interaction between use of heroin and a history of an AIDS diagnosis, such that the people with the greatest bone loss were heroin users who’d ever received an AIDS diagnosis. This held up after adjusting for all other risk factors. HCV status and current methadone use were also highly predictive. CD4 count and types of ARVs did not affect BMD.

Oddly, cigarette smoking was not significantly associated with bone loss. However, the authors comment that “the lack of an independent association of BMD loss with cigarette smoking might be due in part to the fact that nearly 90 percent of participants in the cohort were current or former smokers.”

“Taken together, these data suggest that HIV-infected opioid-using men may be at particular risk of bone loss as they age, as a result of comorbid disease such as hepatitis C infection, opioid substitution treatment with methadone, ongoing heroin use, progression to AIDS, or a combination of these factors,” the authors concluded.

“An improved understanding of factors associated with ongoing bone loss and fracture risk is needed,” they continued, “to help guide thresholds for assessment of BMD and for osteopenia treatment in HIV-infected persons and opioid users.”

Source

New HIV Cases High Among French MSM

By Michael Smith, North American Correspondent, MedPage Today

Published: September 08, 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

HIV appears to be out of control among French men who have sex with men, researchers reported.

Data for 2008 revealed that men who have sex with men (MSM) accounted for 48% of all new HIV infections in France, according to Stéphane Le Vu, PhD, of the French National Institute for Public Health, and colleagues.

The incidence rate in that population was 1% -- a rate of 1,006 new infections per 100,000 person-years in 2008 -- and 200 times higher than the rate estimated for French heterosexuals, Le Vu and colleagues reported online inThe Lancet Infectious Diseases.

"The HIV epidemic seems to be out of control in the MSM population," the researchers contended.

Over the six years from 2003 through 2008, HIV incidence among MSM was "comparatively high and stable," the researchers reported -- although the overall incidence of HIV in France fell by about 3.7% a year.

The new findings are no surprise to those involved in combating the HIV pandemic, said Robert Hogg, MD, of the British Columbia Centre for Excellence in HIV/AIDS in Vancouver.

"Rates in North America in terms of HIV incidence among MSM have been relatively stable and very high for the last little while," he told MedPage Today, although the reasons for that remain unclear.

Most analyses of HIV rates are based on new diagnoses, but the French study added a new wrinkle. Using an enzyme immunoassay, Le VU and colleagues were able to gauge the proportion of recent infections among the new diagnoses.

After accounting for under-reporting, Le Vu and colleagues estimated that 42,330 people were newly diagnosed with HIV over the study period and that overall HIV incidence decreased significantly from 8,930 new found infections in 2003 to 6,940 in 2008. The decline was significant at P=0.002.

The proportion of recent HIV infections, as determined by the immunoassay, remained stable at about 25% a year, they found.

Among those with recent infection during the study period, MSM led the way with 40%, compared with French-national heterosexual women and men (at 28% and 22%, respectively), heterosexual non-French-national women and men (at 16% and 12%), and injection drug users (at 15%), Le Vu's team reported.

In 2008, however, 48% of some 6,940 new infections were found among MSM, the researchers wrote, with only 1% of new infections seen in injection drug users.

Overall, HIV incidence in 2008 was 17 per 100,000 person-years, they reported, based on rates of:

• Nine per 100,000 person-years among heterosexuals
• 1,006 per 100,000 person-years among MSM
• 86 per 100,000 person-years among injection drug users

In a comment accompanying the French report in The Lancet, Hogg and colleagues at the BC Centre argued that one way to reduce those rates would be to employ a multifaceted approach including both individual and population-based prevention strategies.

As well, they argued, such an approach should take into account the increasing evidence that expanding antiretroviral therapy to all people who meet eligibility criteria would reduce the number of new cases.

"It's not treatment or prevention," Hogg told MedPage Today. "It's both."

Hogg added that any prevention strategy will also have to account for the way sexual transmission occurs among men who have sex with men. The pattern, he said, is "like a series of random forest fires," which can be difficult to extinguish.

That contrasts with injection drug users, where transmission usually occurs within a small circle of people involved in using drugs and prevention efforts can be closely targeted, Hogg said.

The study was supported by the French National Institute for Public Health Surveillance and the French National Agency for Research on AIDS and Viral Hepatitis. The authors declared they had no conflicts.

Hogg reported financial links with GlaxoSmithKline and Merck Frosst Laboratories.

Primary source: The Lancet Infectious Diseases

Source reference:

Le Vu S, et al "Population-based HIV-1 incidence in France, 2003-08: a modelling analysis" Lancet Infect Disease 2010; DOI: 10.1016/S1473-3099(10)70167-5.

Additional source: The Lancet Infections Diseases

Source reference:

Hogg RS, et al "Reduction of HIV incidence in men who have sex with men" Lancet Infect Disease 2010; DOI: 10.1016/S1473-3099(10)70200-0.

Source

ZymoGenetics Acquisition Highlights Competitive Hepatitis C Treatment Race

Bristol-Myers Squibb Company (BMS) announced Tuesday that it had signed an agreement to acquire biopharmaceutical company ZymoGenetics for $9.75 per share in cash, or approximately $885 million. Under the terms of the agreement, BMS will gain control of ZymoGenetics’ product development pipeline, which includes potential treatments for surgical bleeding, metastatic skin cancer, and atopic dermatitis.

However, perhaps the biggest prize BMS will acquire in the deal is pegylated-interferon lambda, a novel interferon drug candidate for the treatment of hepatitis C, an infectious disease that affects the liver. Approximately 3.2 million people in the U.S. are chronically infected with hepatitis C, according to the U.S. Centers for Disease Control, and ZymoGenetics’ drug candidate has the potential to improve upon the current standard of care, interferon combined with ribavirin. While this drug combination works for many patients, it has to be taken for months and has many potential side effects.

According to a report by market research firm Global Data, the global hepatitis C market was worth $4 billion in 2009 and is projected to grow at a compound annual growth rate of 9.8% to reach $8.5 billion by 2016. ZymoGenetics is competing with Vertex Pharmaceuticals, Merck, Anadys Pharmaceuticals, Idenix Pharmaceuticals, and a number of other companies to be the first to market a hepatitis C drug that outperforms the current standard of care.

Along with ZymoGenetics, Vertex has been drawing a lot of attention; the Cambridge, Mass.-based company released positive late-stage clinical data on Tuesday. In a study of 662 treatment-resistant hepatitis C patients, 65 percent of patients who took Vertex’s telaprevir were cured, compared to 17 percent of patients who were treated with the current standard of care. The news wasn’t as good for Idenix, which halted trials of two of its experimental hepatitis C drugs over safety concerns after liver abnormalities were discovered in three healthy study participants. Other news from the hepatitis C space: PSI-7977, developed by Pharmasset, recently received fast track designation from the FDA. The drug is currently in Phase 2b clinical trials. With such a significant need for effective hepatitis C treatments, and with so many competitors in the field, the race to commercialization continues to be an interesting one.

9 September 2010
 
Source

A Personal Plea for Better HIV & Hepatitis Prevention Policy

Christopher Kennedy Lawford
Actor, lecturer and author

Posted: September 9, 2010 12:32 PM

"I want to test you for hepatitis C and HIV," my doctor said to me during a routine physical in 2000. I'd been in recovery for 15 years, after battling drug addiction for fifteen years (a too public battle for me and my famed families). In the days before we knew about HIV and hepatitis C, I had shared needles -- it was something some of us did. The last time I had done that was in 1981, just as the first cases of AIDS were being identified in the United States.

I'd avoided getting tested for either HIV or Hep C out of fear that God had saved me from drowning in the disease of addiction only to kick me to death with AIDS or cirrhosis on the beach. It seemed the perfect irony, a final exclamation point on a life of great privilege and promise unappreciated and unfulfilled.

My doctor gave me the good news/bad news: I wasn't infected with HIV, but I was infected with hepatitis C.

I'd heard of hepatitis C -- folks trudging alongside me on the recovery road were getting diagnosed with hep C, and it didn't sound good. My doctor gave me the whole cold truth -- without treatment, I might face liver cancer, liver transplant. Maybe death.

A lot of things came together at that point in my life. I've died many, many times during my addiction, but I've never been confronted with the possibility of really dying in sobriety.

With the support of medical professionals, family and friends -- particularly those in recovery -- I survived hepatitis C and became an author and advocate for drug treatment, hepatitis C and HIV treatment, and better prevention policy.

In the ten years since I was cured, I've met thousands of persons confronting a diagnosis of HIV or hepatitis C, a cruel remnant of not only their past, but also a public policy environment in the United States that differs from the rest of the industrialized world. Most of the world responded to AIDS outbreaks among injection drug users by investing in addiction treatment and making sterile syringes available to those who would not, or could not, stop using drugs immediately. Those policies kept Western Europe from suffering a major outbreak of HIV among injection drug users, and a hepatitis C rate that is lower than the U.S.

There is absolutely no controversy among public health researchers and scientists on syringe access. Over 200 studies from around the world concur that allowing adults to legally access and possess syringes suppresses the spread of these diseases without contributing to any increase in drug use, crime or syringe litter.

It is time for California to catch up with the rest of the world. We have that option through two good bills that Governor Schwarzenegger should sign.

• SB 1029 by Senator Leland Yee would allow pharmacists the discretion to sell a limited number of syringes to adults without a prescription.

• AB 1858 by Assemblymember Bob Blumenfield would allow the state Department of Public Health to authorize syringe exchange programs wherever the conditions exist for the rapid spread of HIV or hep C through syringe sharing.

Neither bill costs much to implement, and will save taxpayers billions, literally billions, by averting costly infections.

In politics, there are always those who propose half-measures, like allowing legal syringe access to be a decision of local government. That makes no sense--communicable diseases don't respect the county line, and Californians deserve equal access to a proven disease prevention strategy, no matter where they live. Furthermore, all state taxpayers pay for the healthcare of a low-income person, no matter where he or she lives.

I trust the Governor will respect the scientific consensus that supports legal syringe access. Those of us strong enough to recover from addiction deserve a chance to get better--all the way better. And the taxpaying public deserves smart prevention policy. Governor, please sign SB 1029 (Yee) and AB 1858 (Blumenfield).

Source

Patient-to-patient transmission of hepatitis C virus (HCV) during colonoscopy diagnosis

No recognized risk factors can be identified in 10-40% of hepatitis C virus (HCV)-infected patients suggesting that the modes of transmission involved could be underestimated or unidentified. Invasive diagnostic procedures, such as endoscopy, have been considered as a potential HCV transmission route; although the actual extent of transmission in endoscopy procedures remains controversial.

Most reported HCV outbreaks related to nosocomial acquisition have been attributed to unsafe injection practices and use of multi-dose vials. Only a few cases of likely patient-to-patient HCV transmission via a contaminated colonoscope have been reported to date.

Nosocomial HCV infection may have important medical and legal implications and, therefore, possible transmission routes should be investigated. In this study, a case of nosocomial transmission of HCV from a common source to two patients who underwent colonoscopy in an endoscopy unit is reported.

Results: A retrospective epidemiological search after detection of index cases revealed several potentially infective procedures: sample blood collection, use of a peripheral catheter, anesthesia and colonoscopy procedures.

The epidemiological investigation showed breaches in colonoscope reprocessing and deficiencies in the recording of valuable tracing data. Direct sequences from the NS5B region were obtained to determine the extent of the outbreak and cloned sequences from the E1-E2 region were used to establish the relationships among intrapatient viral populations.

Phylogenetic analyses of individual sequences from viral populations infecting the three patients involved in the outbreak confirmed the patient pointed out by the epidemiological search as the source of the outbreak. Furthermore, the sequential order in which the patients underwent colonoscopy correlates with viral genetic variability estimates.

Conclusions: Patient-to-patient transmission of HCV could be demonstrated although the precise route of transmission remained unclear.

Viral genetic variability is proposed as a useful tool for tracing HCV transmission, especially in recent transmissions

Author: Fernando Gonzalez-CandelasSilvia GuiralRosa CarboAna ValeroHermelinda VanaclochaFrancisco GonzalezMaria Bracho

Credits/Source: Virology Journal 2010, 7:217

Published on: 2010-09-08

Source

Hepatitis C sufferers tell how 'manky' blood devastated their lives

Published Date: 09 September 2010
By Lyndsay Moss
Health Correspondent

SCOTTISH patients infected with hepatitis C or HIV through blood products have revealed the devastating impact on their lives as the first stage of a major inquiry ended.

The victims, who received the contaminated blood or blood products in the 1970s and 1980, told of long delays in getting their diagnosis, the stigma associated with their infection and the terrible symptoms.

Their testimonies came as the Penrose Inquiry into the blood scandal published its preliminary report, setting out the evidence it had gathered so far.

The 600-page report, produced after the inquiry team analysed over 80,000 documents and took more than 100 witness statements, also sets out the next stages of the investigation.

This includes looking at the use of commercial blood products in Scotland and the information given to patients after their diagnosis.

Lord Penrose and his team will also look at the introduction of heat treatment to inactivate hepatitis C in blood products in Scotland in 1987 - two years after it was implemented in England and Wales. But campaigners yesterday called for the inquiry to go even further, to include other possible illnesses spread in blood.

Hundreds of people in Scotland - many with haemophilia as well as other patients - were infected after receiving contaminated blood.

As part of the Penrose Inquiry, patients were asked to come forward to reveal their own experiences. Many patients with haemophilia - which means their blood does not clot - spoke of the positive effects treatment with new blood factor products had had on their lives, with one describing it as a "miracle cure".

But the majority of witnesses said they were not warned about the risks linked to the treatment at a time when less was known about hepatitis C and HIV and testing of products not possible. Elsewhere in the report, witnesses voiced concern that they were not being informed when they were being tested for hepatitis C and HIV.

One witness said he was invited for a hepatitis C test in 1996, but found his own medical records suggested he had been diagnosed in 1992. He claimed he had not been told then.

Patients reported "horrendous" side-effects from treatment for hepatitis C, as well as the stigma associated with their diagnosis.

One patient had to move villages for a "fresh start" after parents stopped inviting their children to play. Others reported problems getting insurance and financial problems caused by not being able to work.

Bruce Norval, a trustee of the Haemophilia Society and a victim of contaminated blood, said the inquiry should be widened to look at what other contaminants victims could have been exposed to through clotting products.

"There was all kinds of crap in that stuff.

This stuff was manky, it was filthy, it was dirty and they knew it, but they still stuck it in the arms of children," he said.

Solicitor Advocate Patrick McGuire, of Thompsons Solicitors, the recognised legal representative of families and sufferers, said the report was "a milestone" for families after their struggle for answers.

CASE STUDY

Philip Dolan is not sure when he was infected with hepatitis C during his treatment for haemophilia.

While he may have been diagnosed as early as 1978, he was not informed until 1991 when he asked a consultant.

The Haemophilia Society trustee from Glasgow said: "That is the same for a lot of people - they did not know until years later."

Mr Dolan said he had suffered fatigue due to his condition, while getting insurance was also a problem.
 
Source

Two Hepatitis C Drug Candidates on Hold Because of Adverse Events

Robert Lowes

September 8, 2010 — The US Food and Drug Administration (FDA) has ordered drug maker Idenix to suspend development of 2 candidate drugs to treat hepatitis C virus after 3 individuals treated with a combination of these drugs in a clinical trial experienced liver function abnormalities, the company announced yesterday.

The 2 investigational drugs are a nucleoside polymerase inhibitor called IDX184 and a protease inhibitor called IDX320.

The FDA verbally notified Idenix on September 3 that the agency had placed IDX184 and IDX320 programs on clinical hold, pending a review of all clinical and preclinical data for the programs, according to the company. An Idenix press release quoted Chief Executive Officer and Chairman Jean-Pierre Sommadossi, PhD, as saying that the company had not yet received a formal letter from the FDA.

A clinical hold means that a study sponsor must delay a proposed investigation or suspend an ongoing one. When an ongoing study is on clinical hold, no new participants may be recruited or given an investigational medication, and patients already enrolled should stop receiving the treatment unless the FDA specifically authorizes it.

Idenix has completed its planned studies of IDX184 and IDX320, and no healthy trial participants or patients are receiving either experimental drug, the company stated.

In a 2-week phase 1 randomized, double-blind, placebo-controlled trial, 16 of 20 healthy individuals were randomly assigned to receive a combination of IDX184 and IDX320. Half of them received IDX184 plus placebo for the 2 full weeks and IDX320 just for the last week, and the other half received IDX320 for 2 weeks and IDX184 for the last week.

Although the drug duo was generally safe and tolerated, elevated liver function tests (LFTs) in 3 participants were deemed serious adverse events, according to Idenix, which reported these findings to the FDA. During follow-up, LFTs in these 3 participants returned to nearly normal.

In a conference call with stock analysts yesterday, Idenix Chief Medical Officer Douglas Mayers, MD, said that the 3 participants with elevated LFTs were later evaluated by liver specialists and screened for hepatitis, drugs and alcohol, and any potentially confounding medications. The elevated LFT in 1 patient, he said, appeared to be related to gallstones. No explanation has yet emerged for the adverse events experienced by the other 2 participants.

Idenix will investigate the adverse events and provide the FDA with the information it needs, said Dr. Sommadossi. "We remain committed to the future potential of these drug candidates."

Source

Medivir Presenting at the National Swedish Hepatitis Meeting - Clinical Update on TMC435 HCV-Protease Inhibitor

Sept. 9, 2010, 3:41 a.m. EDT

STOCKHOLM, Sep 09, 2010 (BUSINESS WIRE) -- Medivir AB (STO:MVIRB), the biopharmaceutical company focused on infectious diseases caused by viruses, will today present a clinical update on its key drug, TMC435, a potential blockbuster therapy against Hepatitis C which is partnered with Tibotec, at the National Swedish Hepatitis Meeting.

Medivir's CSO, Prof Bertil Samuelsson, will give a presentation entitled 'Clinical update of TMC435 HCV-protease inhibitor' at 12:30 CEST on 9 September 2010 at the Nordic Sea Hotel in Stockholm. A copy of the presentation will be available on Medivir's website (http://www.medivir.se/) after the meeting.

About Medivir

Medivir is an established biopharmaceutical company focused on the development of high-value treatments mainly in infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product, an innovative treatment for cold sores.

Xerese(TM)/Xerclear(TM) is a treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GSK to be sold OTC in Europe and Russia and by Meda in North America. Medivir have retained the Rx rights for Xerclear(TM) in Sweden and Finland.

Medivir's key pipeline asset, TMC435, a protease inhibitor, is in Phase IIb clinical development for Hepatitis C and is partnered with Tibotec.

For more information on Medivir, please see the company website: http://www.medivir.se/

This information was brought to you by Cision http://www.cisionwire.com/

SOURCE: Medivir

Medivir
Rein Piir, CFO & VP Investor Relations
Office: +46 8 546 831 23
Mobile: +46 708 537 292

or

M:Communications
Mary-Jane Elliott / Emma Thompson
Medivir@mcomgroup.com
+44(0)20 7920 2345

Copyright Business Wire 2010

Source

Alcoholic Liver Disease More Aggressive

Tuesday September 7, 2010

Although many advances have been made in the detection and treatment of chronic liver disease in the past 40 years, the prognosis for patients with alcohol liver disease has not improved significantly. While advances have improved the outcomes for non-alcoholic liver disease patients, outcomes for alcohol liver disease patients remain bleak.

Researchers believe the prognosis for alcohol-related liver patients would improve if as much effort was placed in treating their alcohol dependence as is spent treating their liver disease.

Advances in treatment for hepatitis C and autoimmune hepatitis have improved outcomes for those patients in the past 40 years, and new diagnostic tools have increased early detection of the development of cirrhosis. These changes have been effective in improving outcomes for non-alcohol-related chronic liver disease patients.

Prognosis Unchanged for Alcohol Liver Patients

A new Swedish study of 36,462 patients hospitalized with alcoholic liver diseases and 95,842 patients hospitalized with non-alcoholic liver diseases found that the prognosis for alcohol-liver disease patients has remained basically unchanged.

The main difference is the alcohol dependence of the alcohol liver disease patients, said lead researcher Knut Stokkeland, of the Visby Hospital in Sweden. Since almost all alcohol liver disease patients are also alcohol dependent or alcoholics it affects their prognosis.

"Alcohol dependence increases the risks of social problems, being a smoker, and severe psychiatric diseases," Stokkeland said in a news release. "It also inhibits staying sober, which may stop disease progression."

Need Treatment for Alcoholism

The researchers believe that patients with alcohol liver disease should receive more attention, specifically they should be offered treatment for their alcohol problem as well as for their liver disease. The problem, they said, is that the lack of coordination between the hepatology and gastroenterology specialists who treat the liver and those who treat substance abuse.

Because drinking alcohol doubles the risk of developing a serious liver problem, any efforts to reduce alcohol consumption would improve the outcomes for those with alcohol-related liver disease, the researchers concluded.

In short, if you or someone you know develops liver disease, the best thing they can do to improve their chances of surviving is to stop drinking immediately.

Source

PolyTherics Moves Lead Candidate Into Development and Manufacturing With DSM BioSolutions

PR Newswire
DELFT, Netherlands, Sept. 7

DELFT, Netherlands, Sept. 7 /PRNewswire/ -- DSM BioSolutions ("DSM"), DSM's microbial fermentation CMO business unit and PolyTherics Limited ("PolyTherics"), an innovator in precision engineering of proteins, today announced that they have entered into an agreement for the process development and manufacture of PolyTherics' lead biobetter product, HiPEG™ IFN alpha-2a.

PolyTherics has applied its HiPEG™ site-specific PEGylation technology to interferon alpha to produce a product (HiPEG™ IFN alpha-2a) that has eight-fold higher activity than a marketed PEGylated interferon in vitro and a comparable half-life in a preclinical study.

HiPEG™ specifically attaches poly(ethylene) glycol (PEG) to a histidine tag at the end of the protein; histidine tags are commonly used to improve protein stability and to facilitate the purification of proteins. PolyTherics is seeking partners for the development of HiPEG™ IFN alpha-2a for hepatitis C.

DSM has successfully started development, scale-up and manufacture of the recombinant his-tagged IFN alpha-2a. PolyTherics will transfer its proprietary HiPEG PEGylation method to DSM so that the process can also be scaled-up. The companies intend to develop a robust process to produce sufficient material for preclinical development and then for cGMP production of HiPEG™ IFN alpha-2a for clinical development.

Keith Powell, CEO of PolyTherics, stated that, "The transfer of the production of our lead product to a contract manufacturer is a major milestone for PolyTherics and is the beginning of the development stage of its first biobetter drug."

Villaume Kal, Vice-President of DSM BioSolutions stated, "We are delighted to work with PolyTherics on this promising biobetter compound. Our technology, operational excellence, and outstanding cGMP and compliance record with the EMA and FDA allows us to serve this important customer and to develop, scale-up and manufacture their preclinical and clinical material".

No financial terms will be disclosed.

PolyTherics Limited

PolyTherics is a biopharmaceutical company that applies precision chemistry to develop improved protein and peptide-based drugs. It received investment of 2.3 million pounds Sterling from Imperial Innovations Group plc, Longbow Capital LLP and The Capital Fund in June 2007 and a further 3.0 million pounds Sterling investment from the same syndicate in February 2010.

PolyTherics has developed three proprietary technologies for attaching the polymer poly(ethylene glycol) (PEG) to any therapeutic peptide or protein in a targeted fashion. PEGylation slows elimination from the body, thereby improving half-life and potentially reducing drug treatment frequency, decreasing side effects and improving patient compliance.

PEGylated products derived from PolyTherics' technologies are more homogeneous than those derived from traditional methods, resulting in reduced complexity of downstream processing, more consistent product quality and cost-effective manufacture. PEGylation is an established method for improving drugs and nine PEGylated products are already approved for therapeutic use worldwide.

For more information, please visit: http://www.polytherics.co.uk/

DSM BioSolutions – Microbial Fermentation

DSM BioSolutions, part of the DSM Pharma cluster, offers a wide range of customer services ranging from process development to large scale production, all in the field of microbial fermentation. Expertise covers microbial strain construction and improvement, fermentation process development and product recovery and purification. DSM's production infrastructure for fermentation and associated product recovery and purification is based in a multipurpose facility in Capua, Italy, which currently produces pharmaceutical intermediates and APIs (with the exception of beta-lactams) and food/nutrition-related products. In the Pharma area, production lines are available for cGMP manufacturing of small molecules and pharmaceutical proteins. The facilities comply with all relevant regulations and are regularly inspected by the respective authorities (e.g. EMA and FDA).

For more information, please visit http://www.dsmbiosolutions.com/

DSM – the Life Sciences and Materials Sciences Company

Royal DSM N.V. creates solutions that nourish, protect and improve performance. Its end markets include human and animal nutrition and health, personal care, pharmaceuticals, automotive, coatings and paint, electrical and electronics, life protection and housing. DSM manages its business with a focus on the triple bottom line of economic performance, environmental quality and social responsibility, which it pursues simultaneously and in parallel. DSM has annual net sales of about euro 8 billion and employs some 22,700 people worldwide. The company is headquartered in the Netherlands, with locations on five continents. DSM is listed on Euronext Amsterdam.

For more information, please visit http://www.dsm.com/

Forward-looking statements

This press release may contain forward-looking statements with respect to DSM's future (financial) performance and position. Such statements are based on current expectations, estimates and projections of DSM and information currently available to the company. DSM cautions readers that such statements involve certain risks and uncertainties that are difficult to predict and therefore it should be understood that many factors can cause actual performance and position to differ materially from these statements. DSM has no obligation to update the statements contained in this press release, unless required by law.

For more information:

DSM BioSolutions:

Villaume Kal
Vice-President DSM BioSolutions
Tel: +31 15 279 2173
Email villaume.kal@dsm.com

Marco Oomen
Sr. Director Business Development Europe & Japan
Tel: +31 15 279 2251
Email marco.oomen@dsm.com

PolyTherics:

College Hill:
Tim Watson, Tony Stephenson
Tel: +44 (0)207 866 7861
Email: polytherics@collegehill.com

SOURCE DSM BioSolutions

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Teleflex Introduces The PICC WAND(TM)

Sept. 7, 2010, 9:00 a.m. EDT

All in One Vascular Access Device Provides Faster, Safer, Simpler Insertion for PICC or Midline Placements
 
LIMERICK, Pa., Sep 07, 2010 (BUSINESS WIRE) -- Teleflex has partnered with Access Scientific Incorporated, San Diego, California to become the U.S. distributor of The PICC WAND(TM) Safety Introducer with ARROW(R) peelable sheath. This new, all- in-one vascular access device provides clinicians a faster, safer, simpler way to insert a peel away sheath for PICC or Midline catheter placements.

Using the new Accelerated Seldinger Technique, The PICC WAND combines an echogenic needle, nitinol wire, sheath and dilator into an all in one safety introducer that eliminates the need to reach for separate components, improving sterile technique and reducing the risks associated with Modified Seldinger Technique (MST). These risks include accidental needle stick injury, loss of cannulation, vessel trauma, blood exposure, contamination of components and air and wire embolism. The PICC WAND actually reduces the risk of air emboli by 50% compared to MST.(1)

The passive needle safety mechanism of The PICC WAND automatically shields the contaminated needle during the procedure reducing the risk of accidental needle stick injury. This is important as there are 385,000 reported accidental sharps injuries occurring in hospitals annually, exposing healthcare workers to bloodborne pathogens that include Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV).(2)

Teleflex, a leader in providing innovative vascular access technologies, anticipates this device will become the new standard of care reducing risk to both patients and healthcare workers. "We are delighted to be partnering with Access Scientific to bring this truly innovative technology to market," said Cary Vance, Executive Vice President, Teleflex North America. "The PICC WAND provides significant benefits to both patients and caregivers and is an outstanding addition to our vascular access product portfolio."

Steve Bierman, M.D., CEO of Access Scientific said, "Having now seen The PICC WAND in operation, in some of the most challenging cases, I can assert without any doubt that the Accelerated Seldinger Technique establishes a new standard of care. Both patients and healthcare workers benefit significantly from the Wand's safety and efficiency features." He continued, "Access Scientific is proud to be introducing this game changing technology with our partner, Teleflex."

The PICC WAND will be available as a stand alone product and inside new ergonomically designed PICC kits from Teleflex. These new kits include a pressure injectable PICC line as well as maximal barrier and sharps safety components that reduce the risk of infection and accidental needle sticks.

About Teleflex Incorporated

Teleflex Incorporated /quotes/comstock/13*!tfx/quotes/nls/tfx (TFX 51.68, +0.48, +0.94%) is a global provider of medical technology products that enable healthcare providers to improve patient outcomes, protect against infections and support patient and provider safety. Teleflex, which employs approximately 12,600 people worldwide, also has niche businesses that serve segments of the aerospace and commercial markets with specialty engineered products. Additional information about Teleflex can be obtained from the company's website at http://www.teleflex.com/.

1 Data on File 2 NIOSH ALERT: Preventing Needlestick Injuries in Health Care Settings, Pub. 2000-108, Nov. 1999

The PICC WAND is a trademark of Access Scientific, Inc.

SOURCE: Teleflex Incorporated

Teleflex Incorporated
Jake Elguicze, 610-948-2836
Vice President, Investor Relations

Copyright Business Wire 2010

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Epidemiological study of phylogenetic transmission clusters in a local HIV-1 epidemic reveals distinct differences between subtype B and non-B infections

The number of HIV-1 infected individuals in the Western world continues to rise. More in-depth understanding of regional HIV-1 epidemics is necessary for the optimal design and adequate use of future prevention strategies.

The use of a combination of phylogenetic analysis of HIV sequences, with data on patients'demographics, infection route, clinical information and laboratory results, will allow a better characterization of individuals responsible for local transmission.

Methods: Baseline HIV-1 pol sequences, obtained through routine drug-resistance testing, from 506 patients, newly diagnosed between 2001 and 2009, were used to construct phylogenetic trees and identify transmission-clusters. Patients'demographics, laboratory and clinical data, were retrieved anonymously.

Statistical analysis was performed to identify subtype-specific and transmission-cluster-specific characteristics.

Results: Multivariate analysis showed significant differences between the 59.7% of individuals with subtype B infection and the 40.3% non-B infected individuals, with regard to route of transmission, origin, infection with Chlamydia (p=0.01) and infection with Hepatitis C virus (p=0.017). More and larger transmission-clusters were identified among the subtype B infections (p<0.001).

Overall, in multivariate analysis, clustering was significantly associated with Caucasian origin, infection through homosexual contact and younger age (all p<0.001). Bivariate analysis additionally showed a correlation between clustering and syphilis (p<0.001),higher CD4 counts (p=0.002), Chlamydia infection (p=0.013) and primary HIV (p=0.017).

Conclusions: Combination of phylogenetics with demographic information, laboratory and clinical data, revealed that HIV-1 subtype B infected Caucasian men-who-have-sex-with-men with high prevalence of sexually transmitted diseases, account for the majority of local HIV-transmissions.

This finding elucidates observed epidemiological trends through molecular analysis, and justifies sustained focus in prevention on this high risk group.

Author: Kristen ChalmetDelfien StaelensStijn BlotSylvie DinakisJolanda PelgromJean PlumDirk VogelaersLinos VandekerckhoveChris Verhofstede

Credits/Source: BMC Infectious Diseases 2010, 10:262

Published on: 2010-09-07
 
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FDA Puts Hold on Idenix Study Due to Safety Concerns

By Jennifer Booton
Published September 07, 2010
FOXBusiness

Idenix Pharmaceuticals (NASDAQ:IDIX) tumbled nearly 50% Tuesday on news that safety concerns led to the suspension by the US Food and Drug Administration of a drug interaction study involving a treatment for Hepatitis C.

The decision emerged after Idenix notified the FDA of three serious adverse events related to liver function that occurred during a drug-to-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers.

The liver function tests have since returned to normal, the company said, and no healthy volunteers or patients are currently receiving the treatment.

“We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events in the combination study of IDX184 and IDX320 and to provide the FDA with more information in order to expedite their review and resolve this matter as quickly as possible,” CEO Jean-Pierre Sommadossi, Ph.D. said.

Based on the studies, he said, the company remains committed to the “future potential” of the drugs.

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Vertex Cures Hard-to-Treat Hep C Patients

By Adam Feuerstein 09/07/10 - 04:02 PM EDT

CAMBRIDGE, Mass. (TheStreet) -- Vertex Pharmaceuticals (VRTX) released new late-stage clinical data Tuesday demonstrating that 65% of hepatitis C patients whose prior therapy was unsuccessful were able to later achieve a viral cure following treatment with the company's experimental drug telaprevir plus the current standard of care.

By comparison, only 17% of these hard-to-treat hepatitis C patients were cured after being treated again with the current standard of care -- long-acting interferon plus ribavirin. The results were statistically significant.

These results come from the last of three major phase III studies of telaprevir conducted by Vertex and partner Johnson & Johnson(JNJ). Previous, positive results from the other two late-stage telaprevir studies in newly treated hepatitis C patients were released in May and August. The companies intend to seek regulatory approval for telaprevir later this year.

This last phase III study, dubbed "Realize," was set up to confirm previous, earlier findings that showed telaprevir could cure a significant number of hepatitis C patients without treatment options because they failed to respond to the current standard of care.

The Realize study enrolled 662 so-called treatment resistant hepatitis C patients split into three different groups: Those who respond to treatment but then relapse during the follow-up period; patients who partially respond to treatment but whose virus never completely disappears; and patients who never respond well to treatment at all.

Since these patients have a form of the hepatitis C virus that is more stubborn or harder to treat, Vertex extended the total treatment duration in the Realize study to 48 weeks, compared to just 24 weeks in the previous studies of newly treated patients. [Like in other studies, telaprevir was still dosed for only 12 weeks.]

The overall results showed that 65% of patients treated with telaprevir plus the standard of care achieved a cure, or sustained viral response, compared to 17% of patients in the control arm who were re-treated with just the standard of care.

Breaking the results down into the different groups, 86% of relapsers were cured after telaprevir treatment compared to 24% in the control arm.

Among partial responders, the cure rate for the telaprevir-treated patients was 57% compared to 15% for the control arm.

Finally, in the null responder patients, the most difficult to treat patients, telaprevir achieved a 31% cure rate compared to 5% for the control arm.

Results across all three patients types were statistically significant in favor of telaprevir over standard of care.

Wall Street has been waiting for the data from the Realize study, generally expecting overall cure rates for telaprevir in the 60-70% range. The data are important because the competitive race towards approval of the first new hepatitis C drug that acts directly against the virus is heating up.

Merck (MRK) is developing its own hepatitis C drug boceprevir and is the closest competitor to Vertex. In August, Merck announced results from phase III studies showing that treatment with boceprevir led to a 66% cure rate in treatment-resistant patients.

Optically, it would appear that boceprevir and telaprevir are equally effective in curing treatment-resistant patients, which would be a letdown for Vertex and its investors given that expectations have clearly favored Vertex's drug over Merck's.

However, Vertex allowed truly non-, or null, responders into the Realize study of telaprevir, which made it more difficult for the drug to prove efficacy. Merck, on the other hand, used a less stringent definition of null response that essentially helped boceprevir achieve a higher cure rate.

If null responders are removed from analysis of the Realize study, the cure rate for partial responders and relapsers to telaprevir was 78%, which is a more accurate comparison to the 66% cure rate seen in the Merck study of boceprevir.

This doesn't mean that all went swimmingly for Vertex in the Realize results. The 31% cure rate in the null responders group treated with telaprevir was lower than what Wall Street was expecting given prior results from earlier studies.

Some analysts, including Bank of America's biotech analyst (and hepatitis C axe) Rachel McMinn, were expecting to see null responder cure rates for telaprevir in the 50% range.

Vertex said that the null responders enrolled in the Realize study had higher rates of cirrhosis and high hepatitis C viral load than the other patients in the study, which could help explain why the cure rate among these patients was lower. Despite that, telaprevir still cured five times more null responders than re-treatment with the standard of care.

Likewise, the 57% cure rate for telaprevir in partial responder patients was also a bit lower than Wall Street expectations, which means the overall, high response rate to Vertex's drug was driven largely by relapsers, considered to be the easiest of the treatment-resistant patients to respond to follow-on therapy.

On the safety side of the ledger, the new telaprevir data appear to be little changed from what's been released from the previous phase III studies. Adverse events leading to patients dropping out of the study were 4% in the telaprevir arm compared to 3% in the control arm. The most common adverse events attributed to telaprevir were fatigue and rash.

Vertex intends to make a full presentation of the Realize study data at a future medical meeting or by publication in a medical journal. Both Vertex and Merck will be among the companies presenting hepatitis C drug data at the American Association for the Study of Liver Disease annual meeting at the end of October.

--Written by Adam Feuerstein in Boston

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Vertex Nails Third Big Trial With Hepatitis C Drug, In Toughest Patients to Treat

Luke Timmerman 9/7/10

Vertex Pharmaceuticals stepped up to the plate this year with three big swings for the fence, and it can now say it has gone 3-for-3.

The Cambridge, MA-based biotech company (NASDAQ: VRTX), which has significant operations in San Diego, is announcing today that a combination of standard treatment and its novel drug for hepatitis C was able to cure two-thirds of patients who had failed to respond to a prior round of the standard drugs alone. That response rate for patients on Vertex’s telaprevir (65 percent) far exceeded that of the comparison group, in which just 17 percent of patients were cured after getting the usual combination of pegylated interferon alpha and ribavirin. Vertex is making the announcement today, based on findings from more than 660 patients who enrolled in a study called “Realize.”

“The Realize data represent a major milestone in the development of new treatments for hepatitis C,” Stefan Zeuzem, a professor of medicine at the JW Goethe University Hospital in Frankfurt, Germany and principal investigator of the trial, said in a Vertex statement. “These results may provide hope to people who have not been cured and who are in need of new treatment options.”

This is the third major batch of study results from Vertex this year, and part of its quest to shake up the standard of care for patients with hepatitis C, a chronic liver disease. The company showed back in May, in a study of more than 1,000 patients, that about three-fourths of people getting their first round of treatment were considered cured after getting telaprevir in combination with the standard meds. A second study, released last month, showed that the drug could cut the treatment time in half, which is important because it means patients don’t have to endure the flu-like symptoms caused by the other drugs in the regimen for nearly as long. And today’s announcement reinforces findings from small trials that says the telaprevir-based regimen has far greater ability to kill the virus in the toughest patients to treat.

The business opportunity, which we’ve written about a lot in these pages, is huge. An estimated 6 million people in the U.S. and Europe have chronic hepatitis C infections, and an estimated 650,000 of them have failed a prior round of the standard treatment. If the FDA clears the drug for sale based on the latest clinical trials, telaprevir could generate more than $2.6 billion in U.S. sales by 2013, according to analyst Rachel McMinn of Cowen & Co.
Based on the results of the three pivotal trials, Vertex plans to file an application for FDA approval by the end of this year.

The drug’s side effect profile appeared to be similar to what researchers have already seen from telaprevir. Patients in the trial reported cases of  fatigue, itching, headache, rash, flu-like symptoms and nausea. About 4 percent of patients in the telaprevir group dropped out of the study because of adverse events, while about 3 percent discontinued in the control group, Vertex said.

The latest results from the Realize study are not just important to patients, but also to Vertex from a competitive standpoint. The company is preparing to face off against Merck’s boceprevir, another drug from the class of anti-viral drugs known as protease inhibitors. Merck released results from a pair of Phase III clinical trials last month, one in which patients were getting their first round of therapy, and another in which patients were getting re-treatment. The re-treated patients had a clinical cure rate of 59 percent to 66 percent, according to this recap from TheStreet.com.

Of course, the Merck and Vertex trials were designed differently, and didn’t test the drugs head to head, so it’s really an apples to oranges comparison. But Vertex offered some insight in this feature back in September 2008 about how it designed the Realize trial to hopefully provide a little extra advantage for its product in the minds of physicians.

Now that Vertex has cleared all three major trials that it needed to run to fill out its FDA application, the question of how telaprevir stacks up against the Merck drug and how it will be received by physicians and patients will take on even greater significance than before. You can be sure that patients are going to be hounding the company and the FDA about exactly when this drug might become commercially available in the U.S.

Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman

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