Hepatitis C Caring Ambassadors Program Newsletter
In The News....................................................................................................1-13
Clinical Trials, Cohort Studies, Pilot Studies.................................... 13-20
Basic and Applied Science, Pre-Clinical Studies..................................20-23
Complementary & Alternative Therapies.............................................26
Miscellaneous Works................................................. ...............................26-27
New Data from Largest U.S. Hepatitis C Trial Provide Insights Into Optimizing Treatment for Patient Populations Traditionally Considered Difficult to Treat
BOSTON, Oct. 30 -- New data from the WIN-R trial, the largest hepatitis C study ever conducted in U.S. patients, provide important insights into optimizing treatment with peginterferon alfa-2b (PEG-INTRON(R), Schering-Plough) and ribavirin (REBETOL(R), Schering-Plough) combination therapy in patient populations traditionally considered difficult to treat. Researchers evaluated results in specific patient groups to determine if characteristics such as age, ethnicity, body weight, hepatitis C genotype and viral load were independent predictors of response or medication tolerability. The findings were reported in four separate presentations here at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
… New WIN-R Data at AASLD 2006
Patient weight (Dr. Ira Jacobson and colleagues). Historically, studies have shown that heavier patients with hepatitis C virus (HCV) infection are less likely to achieve an SVR with antiviral therapy. Results of the WIN-R study, however, showed that patients treated with peginterferon alfa-2b and weight-based ribavirin achieved consistent rates of SVR regardless of body weight. Even obese patients (those weighing 125 kg [275 lbs] or more) achieved SVR rates similar to all other patients in the study (45% vs. 44%). The heavier patients in WIN-R were much more likely to achieve an SVR with weight-based ribavirin than with flat-dosed ribavirin (64% vs. 25%). Obese patients also showed low rates of anemia, neutropenia and dose reductions, probably reflecting lower levels of ribavirin exposure with their larger body size. The authors concluded that obesity alone should not preclude consideration for hepatitis C treatment with peginterferon alfa-2b plus weight-based ribavirin.
Elderly patients (Dr. Steven Flamm and colleagues). Little data are available on how age affects the response to interferon-based therapies for hepatitis C because patients older than age 65 are ineligible for most clinical trials. This study showed that, while young adults age 18-25 years (n=69) were more likely than any other age group to achieve an SVR (57%), patients older than 65 (n=55) had a similar rate of SVR compared to all other age groups (46% vs. 44%, respectively). Although there were more adverse events among the older patients, the rate of serious adverse events and treatment drop-outs were the same or less than in the younger age groups. The authors concluded that older patients should not be denied access to hepatitis C therapy with peginterferon alfa-2b plus ribavirin based upon age alone.
Patient ethnicity (Dr. Bradley Freilich and colleagues). Past studies with standard interferon plus ribavirin therapy suggest that ethnic origin may be an important predictor of response, with SVR rates highest in Asian patients (61%), followed by Caucasian (39%), Hispanic (23%), and African-American (14%) patients.(7) The WIN-R study included the largest dataset in Hispanic patients reported to date, and the results confirm that hepatitis C is challenging to treat in this population. Rates of SVR were significantly lower in Hispanic patients compared to Asian patients and Caucasian patients: 34% vs. 52% (p=0.0002) and 46% (p=0.0057), respectively. Among Hispanic patients, the best results were seen in those with hepatitis C genotype 2 or 3 and low baseline viral load who were treated with peginterferon alfa-2b plus weight-based ribavirin. Additional studies are required to identify factors that will improve SVR rates in this ethnic group. -- Patients with HCV genotype 3 high viral load (Dr. Robert Brown and colleagues).(8) Patients with HCV genotype 2 or 3 (G2 or G3) generally respond better to treatment than patients with genotype 1,(9) and most studies have reported treatment responses in G2 and G3 patients as a single group. In WIN-R, these responses were examined separately, and showed that G2 patients achieved higher SVR rates (66% vs. 55%, p<0.0001) and lower relapse rates compared to G3 patients. G3 patients with high baseline viral load were more likely to relapse. While these findings suggest higher doses of ribavirin may benefit patients with hepatitis C genotype 3, additional research is needed to define the optimal strategy for lowering relapse rate in these patients.
New Drug May Expand Treatment for Hepatitic C
TUESDAY, Oct. 31 -- A new drug called eltrombopag may enable certain hepatitis C patients to take antiviral medications they previously could not use to fight the disease, researchers say. Hepatitis C patients with cirrhosis and abnormally low platelet levels -- a disorder called thrombocytopenia -- can't take two standard medications, ribavirin and pegylated interferon. These drugs, which are commonly used to fight hepatitis C infection, cause platelet levels to decrease even further.
However, eltrombopag works by stimulating cells in the bone marrow to produce more platelets, said the study's principal investigator Dr. John McHutchison, a liver specialist and professor of medicine at Duke University.
"Eltrombopag increases platelet levels to the point where patients with thrombocytopenia can be effectively treated with the antiviral therapies. If the promising results we've seen so far in these early clinical trials are borne out in future larger scale registration trials, we will be able to potentially treat many more patients for whom there are currently no options," McHutchison said in a prepared statement. The study was supported by GlaxoSmithKline, which developed eltrombopag. McHutchison has also received research support from the drug company.
The Phase II trial included 74 hepatitis C patients with thrombocytopenia who were placed in one of four groups: three groups received eltrombopag at doses of 30 milligrams, 50 milligrams or 75 milligrams. Patients in the fourth group received a placebo. "We found that 95 percent of the patients who received the highest dose of the new drug responded with increased levels of platelets, and 91 percent of those patients were then able to start antiviral therapy with pegylated interferon and ribavirin," McHutchison said. "After 12 weeks, 61 percent of these patients were still able to maintain antiviral therapy."
The study also found that platelet levels in 75 percent of the patients taking the lower doses of eltrombopag increased enough to allow them to begin antiviral therapy. Of those, 53 percent of the patients taking the 50 milligram dose and 36 percent of those taking the 30 milligram dose were able to complete 12 weeks of antiviral treatment. The patients who took the placebo showed no improvement in platelet levels.
WASHINGTON, Oct 31 - U.S. antitrust authorities have cleared a tie-up of Roche Holding AG and InterMune Inc. to develop and commercialize hepatitis C treatments, the Federal Trade Commission said on Tuesday.
The authorities closed their review without taking any action to block the collaboration, according to a notice issued by the agency.
InterMune will receive an upfront payment of $60 million and up to $470 million in milestone payments. The agreement also includes a 50-50 split of any U.S. profits from products that come from the collaboration.
An estimated 3.9 million Americans have been infected with the hepatitis C virus, of whom 2.7 million are chronically infected, according to the Centers for Disease Control and Prevention.
CHICAGO, Oct 31 - Human Genome Sciences Inc. said on Tuesday Albuferon, its long-acting drug for chronic hepatitis C, may be as safe and effective as the current standard of care, based on interim results from midstage clinical trials. The biotechnology company said it plans to start late-stage clinical trials of its treatment in patients who have received no prior therapy by the end of 2006.
Human Genome studied its antiviral drug Albuferon, or albumin-interferon alpha 2b, in combination with ribavirin, for patients with the chronic liver-wasting disease hepatitis C… In a mid-stage trial of Albuferon combined with ribavirin in patients who had failed prior therapies, the treatment proved to be safe, well-tolerated and effective at high doses. The study results, combined with safety data from lower-dose treatment groups, suggest that Albuferon could be used as a first-time treatment at higher doses every four weeks, said Dr. Mani Subramanian, director of clinical research in infectious diseases for Human Genome Sciences.
Human Genome in June cut a $507 million deal with Swiss drugmaker Novartis AG to market Albuferon together in the United States and share U.S. commercialization costs and U.S. profits equally.
New Data for Investigational Hepatitis C Drug
Telaprevir (VX-950) to be Presented at AASLD Meeting
BOSTON, Oct. 27 -- Researchers will present new data this week suggesting that both wild-type hepatitis C virus and resistant variants were suppressed in patients when pegylated interferon (peginterferon alfa-2a; peg-IFN) was added to telaprevir (VX-950), Vertex's investigational hepatitis C virus (HCV) protease inhibitor, in a Phase 1b clinical study. In addition, clinical investigators will report that 24 of 26 patients who received telaprevir (VX-950) in two early-stage clinical trials had undetectable HCV RNA after receiving follow-on combination therapy with peg-IFN and ribavirin (RBV) through 24 weeks of treatment, a therapeutic regimen following the conclusion of the clinical trials. Clinical investigators will also report that some of these patients have stopped therapy, and that a proportion of them continued to have undetectable HCV RNA after stopping therapy.
… Telaprevir (VX-950) is an investigational drug candidate being developed as part of a global Phase 2b clinical development program by Vertex Pharmaceuticals Incorporated…
Tara Kieffer, Ph.D., of Vertex will present data in a Presidential Plenary session on Monday, October 30, analyzing viral sequences isolated from patients receiving telaprevir (VX-950) as a single agent or in combination with peg-IFN in a Phase 1b 14-day clinical study. In this study, viral variants were suppressed when peg-IFN was combined with telaprevir, or when peg-IFN and RBV were administered subsequent to telaprevir dosing. In one arm of the trial, resistant viral variants were isolated from six of eight patients who had detectable HCV RNA while receiving telaprevir as a single agent over a period of 14 days. Subsequently, clinical investigators reported that all patients who received follow-on therapy with peg-IFN and RBV had undetectable HCV RNA at 24 weeks. In a second arm of the study, resistant viral variants were isolated from two of eight patients who received a combination of telaprevir and peg-IFN for 14 days. Both patients subsequently had undetectable HCV RNA at week 12 of follow-on therapy.
On Tuesday, October 31, Dr. Nicole Forestier of Saarland University Hospital in Homburg, Germany will review the current status of 20 patients from a Phase 1b study who received 14 days of telaprevir therapy either alone or in combination with peg-IFN, or peg-IFN alone, in a poster presentation titled "Current status of subjects receiving peg-interferon alfa-2a (peg-IFN) and ribavirin (RBV) after a 14-day study of the hepatitis C protease inhibitor telaprevir (VX-950), with peg-IFN." Clinical investigators previously reported that at the end of 14 days of dosing, one of eight patients receiving telaprevir as a single agent and four of eight patients receiving telaprevir in combination with peg-IFN had undetectable HCV RNA (less than 10 IU/mL, Roche Taqman®). All patients who did not discontinue therapy at week 24 are expected to continue to receive peg-IFN+RBV for a total of 48 weeks of treatment. The current status of patients, as reported by the poster authors, is described in the following table:
HCV RNA results for patients receiving follow-on peg-IFN+RBV therapy following
14-day Phase 1b study of telaprevir (VX-950)
Initial Patients Patients Patients Patients who Patients
14-day with with with stopped continuing
regimen undetectable undetectable undetectable therapy at to receive
(number HCV RNA at HCV RNA at HCV RNA at week 24 who peg-
of end of 14 end of 12 end of 24 had IFN+RBV
patients) days of weeks of weeks of undetectable through 48
dosing follow-on follow-on HCV RNA 12 weeks of
treatment treatment weeks post- follow-on
with peg- with peg- treatment therapy
alone 1 of 8 5 of 7* 7 of 7 2 of 4** 3
peg-IFN 4 of 8 8 of 8 8 of 8 5 of 6** 2
alone 0 of 4 1 of 4 3 of 4 - 4
* 1 patient in the VX-950 alone group refused follow-on therapy after the
initial 14-day dosing period.
** At the 24 week timepoint, four of the seven patients originally
randomized to the telaprevir monotherapy arm, and six of the eight
patients originally randomized to the telaprevir+peg-IFN arm, were
determined to be eligible by their physicians to stop treatment at week
24, and following discussions, were willing to stop treatment at that
timepoint in order to assess whether they would maintain undetectable
HCV RNA status. Two of four patients from the telaprevir monotherapy
arm, and one of the six patients from the telaprevir+peg-IFN arm, had
detectable HCV RNA within 12 weeks after stopping treatment.
On Monday, October 30, Dr. Maribel Rodriguez-Torres of Fundacion de Investigacion de Diego, Puerto Rico will review the current status of 12 patients originally enrolled in a 28-day Phase 2a study of telaprevir in a poster presentation titled "Current status of subjects receiving peg-interferon alfa-2a (peg-IFN) and ribavirin (RBV) follow-on therapy after 28-day treatment of the hepatitis C protease inhibitor telaprevir (VX-950), peg-IFN and RBV." Clinical investigators previously reported that at the end of 28 days of dosing with telaprevir in combination with peg-IFN and RBV, 12 of 12 patients had HCV RNA below the limit of detection of a highly sensitive assay (less than 10 IU/mL Roche Taqman®)…
At the end of 24 weeks of follow-on peg-IFN+RBV therapy, eight patients who were still receiving peg-IFN+RBV had undetectable HCV RNA. These patients continue to receive peg-IFN+RBV at week 36 of follow-on therapy. Additionally, one patient stopped treatment at week 18 and remained HCV RNA undetectable 6 weeks after stopping therapy (week 24). Two patients had detectable HCV RNA and stopped treatment at week 24 of follow-on therapy. In these two patients, viral sequencing analyses at week 24 showed predominantly wild-type virus, with a minority population of R155K variants also detected. One patient, after having undetectable HCV RNA at week 12, was lost to follow-up at week 18 of follow-on therapy.
The results reported above represent clinical treatment of comparatively small numbers of patients who were initially dosed in clinical trials of telaprevir for 14 or 28 days. These results may not be predictive of patient outcomes in large clinical trials evaluating telaprevir. In clinical studies reported to date, telaprevir has been administered as a single agent, in combination with peg-IFN only, and in combination with peg-IFN and RBV for 28 days or less. In subjects who received telaprevir alone, commonly reported adverse events were headache, diarrhea, urinary frequency, sleepiness, and skin disorders (dry skin, rash and itching). In subjects who received telaprevir in combination with peg-IFN and with or without RBV, the commonly reported adverse events were flu-like symptoms, fatigue, headache, nausea, anemia, depression, insomnia, and skin disorders (dry skin, rash and itching). Except for one headache in one patient receiving telaprevir in combination with peg-IFN and RBV that was judged to be severe, adverse events across all studies reported to date were mild to moderate.
Haemophilia sufferers infected with Hepatitis C by contaminated blood will receive up to $63,000 each in a move expected to cost the Government $11 million, it was reported today.
Health Minister Pete Hodgson has not yet announced the payments but The Press newspaper today reported 180 people infected with contaminated blood products in the 1980s and 1990s would be paid out as well as receiving improved treatment. Prime Minister Helen Clark, health minister during part of the period in question, would also give them an apology.
Up to 700 people who received the products, but were not haemophiliacs, could also be in line for a payment. The Press reported that could cost about $44 million if they were paid on the same basis. The payments would be calculated on what the patients would have received from ACC before the end of lump-sum payments in 1992, with interest added.
Haemophilia Foundation president Dave McCone said he was relieved the payments were going to happen. " I know people outside the foundation who have received hepatitis C through blood transfusions. Many of them have been out there, absolutely lost, not knowing what to do or who to get in touch with."
China to Prevent Hepatitis C
Beijing, Oct 27 (Prensa Latina) China declared near 40 million nationals carriers of hepatitis C a significant threat to national public health. Zhuang Hui, director of the Society of Hepatic Diseases, called to raise public awareness to prevent further contagion. The malady spreads via sexual intercourse, infected needles, blood transfusion, organ transplant and intravenous injection.
The National Center for Disease Control and Prevention registered 60,000 new carriers in 2005, adding that 50 to 85 percent of them will ultimately develop the disease. Laboratories do not make a routine analysis to check for hepatitis C and it is sometimes very difficult to detect in an infected patient because the symptoms are much less acute than in other types of hepatitis, however Zhuan Hui warned this does not mean it is less dangerous as it can evolve to chronic cases of cirrhosis or liver cancer.
The official called for control measures for risk groups such as health workers, drug users, promiscuous people and blood donation recipients, and for the population in general to become more careful.
Idenix Pharma Teams With Metabasis To Enhance Hepatitis C Pipeline - Quick Facts
Idenix Pharmaceuticals, Inc. announced a two-year research collaboration agreement with Metabasis Therapeutics, Inc. Under the terms of the agreement, Metabasis' HepDirect liver-targeted technology will be applied to proprietary Idenix compounds to develop second-generation nucleoside analog drug candidates for the treatment of hepatitis C. Under the agreement, Idenix will provide $2.0 million in an upfront payment to Metabasis. If a lead is identified, Idenix will assume development responsibility and Metabasis will be eligible to receive payments upon achievement of predetermined preclinical and clinical development and regulatory milestones.
at the University of Pennsylvania's School of Medicine have found that heart
transplant patients who receive a donor heart from a person with hepatitis C
(HCV) have a lower rate of survival. Corresponding Author Leanne Gasink, MD,
MSCE, of the University of Pennsylvania's Division of Infectious Disease and
colleagues report their findings in the October 17th issue of The Journal of
the American Medical Association.
Each year between 10% and 20 % of patients awaiting heart transplants expire due to the critical shortage of available cardiac organs. One potential solution formed by the American Heart Association in 2001to narrow this gap stated HCV-positive donors "may be appropriate in selected higher-risk recipients." Despite the substantial risk of HCV transmission to the patient and subsequent liver enzyme damage, the effects on patient survival have previously been unclear.
"Some medical experts have advocated the use of HCV-positive cardiac organs because of shortages in suitable donor hearts," Gasink said. "This approach should be used cautiously as use of HCV-positive donors is associated with decreased survival, even in older recipients." Dr. Gasink's study used data from the Scientific Registry of Transplant Recipients. All adult heart transplant recipients from April 1994 to July 2003 were eligible for inclusion. Out of 10,915 patients documented, 261 received an HCV-positive heart.
Using Kaplan-Meier methods, the study found the survival rates lower among HCV-positive recipients compared with HCV-negative recipients at 1 year (83% vs. 92%), 5 years (53% vs. 77%), and 10 years (25% vs. 53%). The rate of death was also higher among recipients of HCV-positive hearts compared to HCV-negative hearts. At 1, 5, and 10 years, death rates for HCV-positive organs were 16.9 %, 41.8%, and 50.6% versus 8.2%, 18.5%, and 24.3 % for HCV-negative cardiac organs. These numbers appear to be independent of recipient age and HCV status. Furthermore, recipients of HCV-positive donor hearts were more likely to die from liver disease and coronary artery disease.
College Students Unaware of Hepatitis C Risks
WEDNESDAY, Oct. 25 -- About 75 percent of U.S. college students have behaviors such as sharing body jewelry and getting tattoos that put them at risk for hepatitis C, according to a survey of 610 undergraduates at a large Midwestern university. The study also found that many of the students didn't know about the risk factors for hepatitis C. For example, 27 percent of the students didn't know that hepatitis C could be spread through intravenous drug use, while 77 percent didn't know it could be spread by intranasal cocaine use.
The researchers also found that 53 percent of the students said they had shared pierced jewelry, which is another risk factor for hepatitis C. "We were surprised at the proportion of undergraduates who were inadvertently putting themselves at risk for hepatitis C," Dr. Thomas Shehab, of St. Joseph Mercy Health System, said in a prepared statement. "In addition to well documented traditional risk factors, we are concerned about students who may be putting themselves at risk for this serious disease with even something as simple as sharing pierced body jewelry," Shehab said.
He and his colleagues were also alarmed that few of the students' doctors had talked to them about viral hepatitis/HIV risk factors. "The majority of the group had been to the physician for a health care maintenance examination in the last three years, but during that visit, most had never been asked about behaviors that put them at risk for serious infection," Shehab said.
One Drug Vial Infects 16 Heart Patients With Hepatitis C
ATLANTA, Oct. 24 -- Sixteen patients in three unrelated clinics were infected with hepatitis C virus (HCV) when they were injected with a radiotracer prepared at a single nuclear pharmacy in Maryland, reported CDC researchers here. The source of the outbreak appears to have been a patient with HIV, HCV, and hepatitis B co-infection whose blood was processed at the pharmacy for a radiolabeled white-blood-cell study 12 hours before the contaminated vial was prepared, found Priti R. Patel, M.D., M.P.H., of the National Center for Infectious Diseases, and colleagues. The authors noted that this is the first known report of HCV transmission from contaminated nuclear medicine products.
"The findings from this and other recent investigations demonstrate that blood-borne pathogens can be transmitted in any setting where blood exposures occur and aseptic technique is compromised," the investigators wrote in the Oct. 25 issue of Journal of the American Medical Association. "Health care-related exposures should be considered in the evaluation of patients with acute HCV infection, and clinicians should report these cases to facilitate prompt identification and control of potential outbreaks."
None of the 16 patients who tested positive for HCV infection was found to be HIV-positive, the authors noted.
Their investigation traced the possible source of contamination of the radiopharmaceutical to pharmacy practices such as reuse of needles and syringes during dilutions, resulting in possible cross-contamination of vials, and the use of common flow hoods for some steps in the preparation of sterile and blood-derived products.
The authors, including staffers from the CDC, Maryland Department of Health and Mental Hygiene in Baltimore, and Anne Arundel Department of Health in Annapolis, investigated the outbreak of acute HCV infection that occurred among patients who underwent myocardial perfusion studies with an injected radiopharmaceutical on Oct, 15, 2004.
The cases, which occurred in three clinics, occurred among 90 patients who received injections drawn from select radiopharmaceutical vials prepared on Oct. 14 and 15 at a single nuclear pharmacy. The investigators took a close look at pharmacy practices, and performed HCV RNA genotyping to help narrow the search for a source of infection. They found that 16 patients in three clinics had received injections of Tc99m sestamibi for myocardial perfusion studies; these patients were the only ones who received injections from the vials. Of an additional 59 patients who received doses from six other vials prepared at the same pharmacy, none were found to have acute HCV infection. None of the pharmacy workers tested positive for HCV.
Fifteen of the patients with HCV were symptomatic, and 11 had jaundice. The median time from exposure to symptom onset was 24 days (range 15-41). One of the infected patients developed liver failure and died of sepsis 10 weeks after being infected. A second patient died from a cerebrovascular event nine months after exposure to HCV.
Twelve of the 16 patients had sufficient HCV RNA for genotyping. The analysis determined that the RNA sequences of the HCV quasispecies from the cases were 97.8% to 98.5% similar to that of a patient whose blood was prepared at the same laboratory the day before the 16 patients were injected.
"Blood from a patient with chronic HCV and HIV infections was the source of HCV transmission, probably through contamination of supplies (syringes or a multidose saline vial) during the preparation of Indium 111-labeled white blood cells on Oct. 14," Dr. Patel and colleagues wrote.
Although they did not identify the specific point of contamination, possible sources included overlap between areas of the pharmacy where the radiotracer was prepared and blood products were processed, problems distinguishing between used and unused syringes, no prohibition on re-using syringes, and sharing the use of saline vials between different sterile preparations, which could have allowed the saline vial to serve as a reservoir of contamination.
"All compounding pharmacies should comply with US Pharmacopeia standards and establish policies to ensure sterile equipment and environments, standardized compounding procedures, and training of employees on aseptic technique," the investigators wrote. "Nuclear pharmacies that handle blood products should additionally recognize the risks for blood contamination of radiopharmaceuticals and implement appropriate precautionary measures to prevent such contamination."
Peregrine Finalizes Patient Enrollment In Phase Ib Bavituximab Hepatitis C Trial - Quick Facts
(RTTNews) - Peregrine Pharmaceuticals Inc. revealed the completion of patient enrollment for its Phase Ib repeat dose, dose escalation study of bavituximab in patients with chronic HCV infection. According to the company, the main aim of the study is to determine the safety, distribution and pharmacokinetic properties of bavituximab as a multiple dose monotherapy in HCV patients. The company expects initial data from the trial to be available during the first quarter of 2007.
InterMune to Present Research on ITMN-191 in Hepatitis C at Two Liver Disease Conferences
InterMune scientists will make the following presentation at Virology Education:
Wednesday, October 25, 2006 -- 3:00 p.m. Eastern Session: Resistance and New Compounds -- Slide Presentation: Sequence variation of NS3 and NS4A in hepatitis C virus (HCV) replicons following exposure to ITMN-191 concentrations likely to encompass those achieved in human liver following clinical dosing InterMune scientists will make the following presentations at AASLD: Monday, October 30, 2006 -- 8:00 a.m. Eastern Session: HCV Therapy: Pre-clinical and Early Clinical Development -- Poster Presentation (#933): In Vitro Synergistic Antiviral Activity of ITMN-191, an Orally Active Inhibitor of the Hepatitis C Virus (HCV) NS3/4A Protease, in Combination with PEG-Interferon Alfa-2a Tuesday, October 31, 2006 -- 8:00 a.m. Eastern Session: Clinical Trials and Therapeutic Developments -- Poster Presentation (#1134): Final Results of pilot study evaluating safety, viral clearance and antifibrotic efficay of treatment with Interferon Gamma-1b plus an Interferon alpha plus Ribavirin in HCV patients who failed prior Pegylated Interferon Plus Ribavirin therapy.
InterMune has successfully completed preclinical toxicology and pharmacokinetic studies in multiple species in support of initiating Phase I clinical studies of ITMN-191 for the treatment of chronic HCV. The European Clinical Trial Authorization (CTA) application, which InterMune filed in the third quarter of 2006, includes results of 28-day preclinical toxicology studies utilizing doses many-fold higher than those expected to be given to humans. These studies demonstrate that ITMN-191 has a favorable toxicology profile, allowing the compound to be studied in clinical trials over a range of doses predicted to have antiviral efficacy. ITMN-191 has also demonstrated high in vitro potency and specificity in biochemical assays and in assays utilizing the HCV replicon system. Moreover, ITMN-191 displays a favorable cross-resistance profile, including significant potency against variants of the NS3/4A protease that are resistant to other HCV protease inhibitors currently in development. The preclinical pharmacokinetic results support the exploration of twice-daily oral dosing in HCV patients. On October 16, 2006, InterMune signed a collaboration agreement with Roche for the research, development and commercialization of ITMN-191 and potential second-generation HCV protease inhibitor compounds.
Culturing Hepatitis C
Hepatitis C virus (HCV) has been difficult to study since its discovery in 1989; its unculturable status left researchers with a narrow view of the viral life cycle. But the discovery a few years ago of a highly infectious HCV strain (JFH-1) by Takaji Wakita's lab, then at Tokyo Metropolitan Institute of Neuroscience, raised the possibility of developing a robust cell culture system. JFH-1 was a huge find, says Frank Chisari, from Scripps Research Institute, and Wakita gladly shared it.
The race to develop an efficient cell culture system with JFH-1 was a short one, and in the Hot Papers featured here, several labs showed that JFH-1 could produce high levels of infectious particles in vitro. Chisari's lab demonstrated that JFH-1 could be cultured in human hepatoma Huh-7-dervied cell lines. In a different approach, Charles Rice's group at Rockefeller University cultured chimeras of JFH-1 to high levels, showing that the resulting virus particles could be neutralized with HCV antibody. In a third paper, Ralf Bartenschlager's group at University of Heidelberg, in collaboration with Wakita, now at the National Institute of Infectious Diseases in Tokyo, replicated large amounts of JFH-1, and for the first time viewed the virions by immunoelectron microscopy.
With HCV persistently infecting 170 million people worldwide and causing liver disease in many, the cell culture systems promised to speed HCV research. "It was like going from virtually nothing to a workable system for genetics, cell biology, and drug screening," says Rice. In the time since, the systems have spread through the field, as researchers hurry to experiment with viral entry, assembly, and release.
Wide Open Possibilities
Thomas Baumert, an HCV researcher at the University of Freiburg, says the entire field was "waiting for this long sought after cell culture system, since we could now do functional genomics, test new vaccine approaches, and analyze the whole life cycle." Such wide open possibilities spurred Baumert to set up a JFH-1-based system in his own lab, where infection rates were found to be about "100-fold higher than all previous systems."
One of the first things Bartenschlager's lab did with such high infection rates was to create luciferase reporter viruses. This allowed them to quantify early steps of the HCV life cycle with authentic viral particles and to show that different chimeric viruses seem to use a conserved mode of entry. 4 An explosion of such work is just on the horizon, says Chisari, whose lab is now working to modify the HCV culture system to produce persistent infections. "Most infections are chronic in the vast majority of patients," says Chisari, "so we want to maintain infections continuously in tissue culture to study how the virus adapts."
Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson Scientific, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.
Rice says his lab is also using the system "24/7," in particular looking into its biological relevance. Before the discovery of JFH-1, HCV researchers could infect chimpanzees with various HCV strains, but they either didn't replicate in cell culture or they replicated but without producing infectious virus. Rice's lab recently showed that virus produced in cell culture can establish long-term infections in chimpanzees and that re-isolated virus was still highly infectious when returned to cell culture. "This underpins the exceptional properties of this [JFH-1] isolate," says Bartenschlager, "since normally when isolates from patients are put into cell culture, it's hard to measure anything."
Yet the unique properties of JFH-1 leave room for criticisms of the culture systems, says Stanley Lemon at the University of Texas Medical Branch. JFH-1 was isolated from a patient with fulminant hepatitis C - a rare form of the disease with rapid onset - and its unusual infectivity does raise questions about whether findings can be applied to other HCV isolates. Moreover, "JFH-1 is genotype 2a, and the real medical problem is with genotype 1 viruses which are more prevalent," says Lemon. Chisari, Rice, and Bartenschlager all agree. While chimeras between JFH-1 and genotype 1 viruses can help solve this problem, "ideally we still want to work with natural isolates of any type at some point," says Rice.
Despite the caveats, these culture systems do open the search for new therapeutics. An HCV replicon system, created in 1999, allowed for the study of RNA replication. "Most of the HCV drugs currently in clinical or preclinical phase are polymerase or protease inhibitors tested with the replicon system," says Chao Lin from Vertex Pharmaceuticals, whose own drug, VX-950, an inhibitor of HCV NS3-4A protease, was tested in this way. "But with the new systems you can start to test for HCV entry, fusion, or assembly inhibitors," says Lin.
Nevertheless, all the developments in HCV cell culture systems point to one crucial question: Why is JFH-1 so infectious? Answers are only speculative at this point, but "there is a big race on to find out what is special about this 2a isolate," says Rice. The answer could reveal a good deal about why some HCV strains remain uncultured.
GlobeImmune Announces GI-5005 Tarmogen Data for Chronic Hepatitis C Infection to be Presented at the American Association for the Study of Liver Diseases (AASLD)
LOUISVILLE, CO – Oct. 17, 2006 – GlobeImmune, Inc. announced today that the interim results from a placebo-controlled Phase 1b study of GI-5005 in patients chronically infected with hepatitis C virus will be presented at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) on Monday, October 30 in the Late Breaking Poster session. Full abstracts can now be viewed at the AASLD website at
Poster number: LB17
Location: Exhibit Hall C (Hynes Convention Center)
Time: 8:00 am – 5:30 pm
Title: "Interim Results from a Randomized, Double-blind, Placebo-controlled Phase 1b Study in Subjects with Chronic HCV after Treatment with GI-5005, a Yeast-Based HCV Immunotherapy Targeting NS3 and Core Proteins." G.T. Everson; M.J. Tong; I.M. Jacobson; D.M. Jensen; A.A. Haller; G.M. Lauer; J. Parker; J. Ferraro; S.E. Cruickshank; R.C. Duke; D. Apelian; T.C. Rodell; E.R. Schiff
TarmogensTM (Targeted Molecular Immunogens) are a proprietary, immunotherapeutic platform utilizing whole, heat-killed recombinant Saccharomyces cerevisiae yeast genetically modified to express disease-specific protein targets. The GI-5005 Tarmogen expresses a NS3-Core fusion protein. These HCV-specific proteins are expressed in infected cells, believed to be essential for viral replication and are highly conserved among HCV genotypes 1a and 1b, the HCV strains most prevalent in the U.S.
GI-5005 is designed to elicit a cellular immune response against cells infected with the HCV virus. The yeast vector is designed to not only stimulate an innate immune response mediated by Toll-like receptors (TLRs), but also to deliver target protein directly to antigen presenting cells, eliciting an antigen-specific helper T cell (CD4) and killer T cells (CD8) cellular immune response to eliminate diseased cells.
About GlobeImmune, Inc.
associated with fewer missed work days and better patient-reported
quality-of-life scores than pegylated interferon through week 12 -
MD -- October 16, 2006 -- Human Genome Sciences, Inc. today reported 12-week
interim quality-of-life results from a phase 2b clinical trial to evaluate the
efficacy, safety and impact on health-related quality of life of Albuferon(TM)
in combination with ribavirin in patients with genotype 1 chronic hepatitis C
(HCV) who are naive to interferon alpha-based treatment regimens.
The interim results demonstrate that all Albuferon treatment groups consistently performed favorably through week 12 compared to the pegylated interferon alpha treatment group, based on patient-reported disability days and health-related quality of life as measured by the SF-36 health survey. The data were presented over this past weekend at the annual Australian Gastroenterology Week in Adelaide.
"Health-related quality-of-life issues, including lost days of work and normal activity, pose a significant challenge for patients undergoing treatment for chronic hepatitis C," said Stephen Pianko, MD, FRACP, PhD, Associate Professor of Medicine, Monash University (Melbourne, Australia). "Interim results of the current study suggest that Albuferon may have the potential to offer a therapeutic alternative with less impairment of health-related quality of life, and fewer disability days, compared with the current standard of care, with at least comparable safety and efficacy. We look forward to continuing the evaluation of Albuferon to determine its appropriate role in the treatment of hepatitis C."
"Through week 12 of the phase 2b study, patients in the Albuferon treatment groups recorded fewer missed work days and, based on the SF-36 health assessment, reported better quality of life than patients in the pegylated interferon treatment group," said David C. Stump, MD, Executive Vice President, Drug Development, HGS. "This result was observed in both the physical and mental component summary measures, as well as in the 8 individual domain scores. The SF-36 results in mental health suggest significantly less impairment of psychological well-being across the Albuferon treatment groups."
About the Albuferon Phase 2B 12-Week Quality-of-Life Results
Albuferon treatment groups recorded fewer disability days and reported less impairment of health-related quality of life through week 12 of the phase 2b study than patients in the pegylated interferon treatment group. The 900- mcg Albuferon dose administered at 2-week intervals was associated with 75% fewer disability days, and the 1200-mcg Albuferon doses administered at 2-week and 4-week intervals were associated with 25% fewer disability days.
Through week 12, based on the SF-36 health assessment, patient-reported outcomes showed that the Albuferon treatment groups consistently performed favorably compared to Pegasys in both the physical and mental component summary measures and in the 8 individual domain scores. SF-36 results in the mental health domain demonstrated significantly less impairment of psychological well-being across the Albuferon treatment groups (P =.002 vs. Pegasys).
Of the four treatment arms in the phase 2b study, the 900-mcg Albuferon dose administered once every 2 weeks was significantly associated with the least negative impact on mental and physical function, bodily pain, vitality, social functioning, and mental health domains, while maintaining efficacy and safety at least comparable to pegylated interferon alpha. Less worsening of health-related quality of life also was observed in the treatment arms receiving 1200-mcg Albuferon doses administered at 2-week and 4-week intervals, respectively, compared to the pegylated interferon alpha treatment group, with clinically meaningful differences observed in bodily pain, mental health and social functioning.
Health-related quality of life was assessed using the Short Form 36 (SF-36) health survey. SF-36 is a patient-reported outcomes instrument, consisting of 36 questions used to measure the health status of patients with chronic hepatitis C. The 36 questions result in an 8-scale health profile including: physical function, physical role limitations, vitality, general health perceptions, pain, social function, emotional role limitations, and mental health. Summaries of the combined physical and mental component measures were also used in the assessment.
About the Albuferon Phase 2B Trial Design
Data are available through week 12 on 458 patients enrolled in the randomized, open-label, multi-center, active-controlled, dose-ranging study, which is being conducted in Australia, Canada, Czech Republic, France, Germany, Israel, Poland and Romania. Patients were enrolled and randomized into four treatment groups, three of which receive subcutaneously administered Albuferon (900 mcg at 2-week intervals, 1200 mcg at 2-week intervals, and 1200 mcg at 4-week intervals). The fourth treatment group serves as the active control group and receives 180-mcg doses of subcutaneously administered peginterferon alfa-2a (Pegasys) once every week. All patients receive oral daily ribavirin. The primary efficacy endpoint of the phase 2b study is sustained virologic response (SVR), defined as undetectable virus 24 weeks after completion of 48 weeks of treatment. The secondary endpoints include early virologic response at week 12 (EVR12), and safety and health-related quality of life at Weeks 12, 24 and 48.
AVI BioPharma has reported results from the second phase of its study in patients with hepatitis C virus, that suggest the drug is ineffective at the dosage levels used in the trial.
The second phase of this exploratory trial was designed to assess the safety, tolerability, pharmacokinetics, and response to treatment with AVI's proprietary compound, AVI-4065, developed from the company's NeuGene technology. AVI said that the therapeutic threshold required for efficacy of the drug was not achieved at the treatment dose used, which was consistent with preliminary results. The company added that there was a direct pharmacodynamic response to hepatitis C infection. AVI-4065 also exhibited favorable safety and tolerability profiles.
"It is encouraging that we observed a significant pharmacodynamic effect that we believe can be fine-tuned to provide a clinical benefit," said Denis Burger, AVI CEO. AVI has said they will continue to research NeuGene technology and are planning to increase treatment duration and dosage in order to exceed the therapeutic threshold predicted from preclinical models. Hepatitis C is a single-stranded RNA virus. Because the hepatitis C virus has a relatively simple genetic structure, it is an attractive target for AVI's NeuGene antisense, which is designed to target conserved portions of the viral genetic code that are not likely to mutate over time.
Mark "Chopper" Read has Hepatitis C, the underworld figure turned novelist has revealed. Read has cancelled his road show with football identity Mark "Jacko" Jackson because of the debilitating illness, which he attributes to sharing razors while behind bars.
New Idea magazine, which goes on sale on Monday, says doctors have told the 51-year-old he faces a major health challenge over the next eight years. Read has also considered suing the Victorian government for breaching its duty of care to prison inmates. We've traced it back to the `70s when I was at (Melbourne's) Pentridge Prison," says Read - who gained notoriety for cutting his ears off while in jail. "Virtually everyone contracted Hepatitis C as they made us all use the same shaver. "The blades were only changed once per week and if you cut yourself, you were exposed to blood-borne diseases."
The Hepatitis C virus causes inflammation of the liver and, eventually, it can lead to liver failure and other serious complications. Read told New Idea he has had to adopt a healthier lifestyle after the illness, and his workload, took him to the brink. "I can't take it anymore. The workload was killing me. I'd be vomiting minutes before jumping on stage," Read says. "I've also had to give up alcohol, which I haven't enjoyed because I'm a devout alcoholic."
The magazine notes other celebrities to have contracted the virus include actor Pamela Anderson and Steven Tyler, from rock band Aerosmith.
Tacere Therapeutics, Inc., an innovative biotechnology
company specializing in the development of both traditional and novel
therapeutics to treat serious infectious diseases, announced today that the
company has secured an undisclosed amount of seed financing from Hokkaido
Venture Capital, and has thus established operations and resumed preclinical
development of TT-033i, its lead candidate for the treatment of Hepatitis C
Sara Cunningham Hall, President and Chief Executive Officer of Tacere, stated, "As pioneers in RNA interference (RNAi) we are pleased to resume development of TT-033i, a drug that we have taken from concept to preclinical studies over the last several years. Initiated at Avocel, Inc. and furthered at Benitec Ltd., our expertise in Hepatitis C and RNAi allows Tacere to begin corporate life with a great deal of experience and a competitively staged clinical program.
"The company will also capitalize on its extensive knowledge of HCV to advance a number of novel small molecule compounds for the treatment of this viral disease. Broader market acceptance and lower regulatory hurdles continue to drive the development of small molecule antivirals. However, the emergence of RNAi as a legitimate therapeutic modality offers a powerful new approach to treating HCV. We look forward to returning to the forefront of this exciting technology."
Mike Catelani, Chairman, Senior Vice President, and Chief Financial Officer of Tacere, remarked, "It's not often that one has the opportunity to take the best of a technology and implement it anew in a sound and well-supported corporate structure. Tacere recently exclusively in-licensed from Benitec Ltd. the RNAi drug development program that this team has been advancing toward the clinic over the past four years. Tacere staff and management, with the support of a strong group of directors and scientific advisors, are well-positioned to move this program forward and meet the challenges of developing both traditional and novel therapeutics."
Tacere was founded by Mike Catelani, Sara Cunningham Hall, Dr. John Monahan, founder and former CEO of Avigen, Inc., and Dr. Amit Kumar, CEO of CombiMatrix Corporation. Scientific advisors of Tacere include notable scientists and clinicians, Dr. Paul Pockros, Director of the Liver Disease Center and Scripps Clinic Research Consortium, Dr. Robert Lanford, Scientist at the Southwest Foundation for Biomedical Research and the Southwest National Primate Research Center, and Dr. Jonathan Coates, Founder and Chief Scientific Offer of Avexa Ltd.
'Hep C Aware' Telethon Expands Television Broadcast to 8 Hours
With the support from KVMD TV and Roche Pharmaceuticals as well as sponsors, friends and volunteers, The 3rd Annual Hepatitis C Awareness Telethon, airing Live on the Internet on October 21st will expand the televised portion of the event from 2 to 8 hours. It will now air on KVMD from 12-8pm PST. Check KVMDTV.com for local listings.
October 13, 2006 -- With the support from KVMD TV and Roche Pharmaceuticals
as well as sponsors, friends and volunteers, The 3rd Annual Hepatitis C
Telethon, airing Live on the Internet on October 21st will expand the televised
portion of the event from 2 to 8 hours, from 12-8pm PST. Originally an Internet-only Telethon, the need for Hepatitis C awareness in Southern CA prompted
Kelly Zirbes, founder of HepCAware.org, to make the event available on
television. Local Listings for the television broadcast can be found at
KVMDTV.com. Log on to www.HepCAware.org for
The telethon will feature musical performances, comedians and medical experts as well as special guests, Hep C advocates and featured spots. Sponsors and partners like Alternative.nu and the Hepatitis C Caring Ambassadors Program have helped the telethon to become a voice for those affected by Hep C. “I believe more support is on the way” says Zirbes, “finally the call for help is being heard.” Other sponsors include KJLA, EarCandy, iHost.nu, Valeant, KVMD, The Hepatitis C Support Project, The City Of Los Angeles Aids Coordinator's Office, Maximum Milk Thistle, YellowSpot Design, Go Girls Music and Take 12 Radio.
Broadcasting on television in Southern California is an important component to this campaign. “Not everyone is Internet savvy and we want to reach everyone here,” says Zirbes. KJLA is also a key part of this whole picture. Last year, Francis Wilkinson, general manager of KJLA, gave the okay for HepCAware.org to come in and shoot their telethon. “Frances came through for us”, says Zirbes. “He understood that we needed help and he gave it!” On board again this year is Michael Mascarelli as Director, Technical Director Eliza Espinosa, Producer James Dozer and the group of volunteers from KJLA and LATV. Volunteers and advocates are flying in from all over the country to be a part of this event.
Alternative.nu, which originates the Internet broadcast, has been a key supporter of HepCAware.org. George Seymour, owner and operated of the Web site and employee at KJLA, is the link that started it all. Every year he donates time, equipment and even broadband to bring this event to the widest audience possible. Back in 2004, Kelly and her volunteers filmed the 1st Telethon in George’s garage in Panorama City, CA. “Sure it was low budget”, laughs Seymour, “but we reached hundreds of thousands of people across the world with that first telethon”. Now on television for 8 hours, it’s easy to say, ‘They’ve come a long way baby.’”
Zirbes stresses that the Internet broadcast is still key to the awareness campaign. “Broadcasting on the Internet is still the most important medium for our organization, says Kelly. “It’s the only way to reach everyone, everywhere.” Groups, volunteers, friends and friends of friends all over the country are helping to promote the telethon, including the Hepatitis C Advocacy Council, a group of organizations dedicated to raising awareness of Hepatitis C.
That there is no vaccine for Hepatitis C is just one of the important messages the telethon will make clear. The call to “Get Tested” will be mentioned throughout the telethon and a link will be provided with a list of resources across the country. Hep C is a systemic blood borne virus that primarily attacks the liver. One in 50 Americans have Hep C, yet two out of three of them do not know it. "There is no vaccine for Hepatitis C (HCV) and people need to know if they are at risk", Zirbes points out. "HCV is a silent virus."
You may have been exposed to Hep C and should get tested if you have: received blood, blood products, or an organ transplant prior to 1992, ever shared drug, paraphernalia, either by injecting or snorting, ever been stuck by a used blood needle, been on kidney dialysis, had a tattoo or body piercing, had sexual activity that involves contact with blood, shared personal care items(razors, toothbrushes, etc.) with other people, been incarcerated or are a war veteran (especially Vietnam).
This major event will be hosted by Kelly Zirbes, Alfie Martin, Mary White M.D. and special guests and will feature performances by some of the industry’s most celebrated artists. Already on board are legendary MC5 founder and guitarist Wayne Kramer, international blues artist Teresa James, comedians Courtney Cronin, Steve Mazan and Lisa Sundstedt and national touring artist Keaton Simons. Other musical artists include Orange County’s Mystery Hangup, Orange County's Buck Wildstar, Blues Guitarist/Songstress Peach, Female fronted rockers Kanary, Malibu’s Big Dume, Eden Automatic from Dallas, Internet Stars Dig Jelly, Boston’s own Deb Pasternak, Percussion Guru Homero Chavez, Scott Detweiler from New Orleans, Rockers Hard Luck Story and JKB, Dean Chamberlain, formerly of the Motels, national touring artist Shauna Burns, Hep C Advocate and Pop/Rocker Lauren Adams, Bi-Coastal artist Malea McGuinness and Hep C Spokesband Kelly's Lot with special guest musicians Carl Esrasen M.D. and Michael Davis, MC5 Bassist.
Epidemiology of hepatitis C virus among long-term dialysis patients: a 9-year study in an Italian region.
BACKGROUND: Monitoring hepatitis C virus (HCV) antibodies (anti-HCV) in long-term dialysis patients is an important issue of public health. The aim of the study is to analyze the prevalence, seroconversion rate, and impact of HCV-positive serological test results on survival. METHODS: We studied 6,412 patients starting long-term dialysis therapy reported to Lazio Dialysis Registry (Italy) between 1995 and 2003. HCV serological status was assessed by using second- or third-generation assays. Patients who were seronegative at the beginning of a period who became seropositive at the end of the same period are defined as seroconverters. RESULTS: In 1995 to 2003, the overall prevalence of anti-HCV among long-term dialysis patients decreased from 30.6% to 15.1%; we did not observe a decrease in prevalence of anti-HCV in those starting dialysis treatment. After a decrease in the first year, HCV seroconversion rates remained stable at approximately 2 cases/100 person-years. Survival at 9 years was lower for both HCV seroconverters and those already anti-HCV positive at dialysis therapy initiation compared with HCV-negative subjects (log-rank test, P < 0.001). Results of a multiple Cox model showed that subjects who were or became anti-HCV positive had a hazard ratio of 1.29 (95% confidence interval, 1.15 to 1.44) compared with HCV-negative patients. CONCLUSION: We did not observe a significant decrease in HCV seroconversion rates in 1995 to 2003. The overall decrease in anti-HCV prevalence could be related to the lower survival probability for both HCV seroconverters and those already HCV positive at long-term dialysis therapy initiation compared with HCV-negative subjects. Our findings confirm that additional efforts should be made to minimize the risk for HCV infection before and during long-term dialysis treatment.
-1082 GG polymorphism influences the occurrence and the clinical
characteristics of hepatitis C virus infection. Persico M, et al. J Hepatol. 2006 Sep
22; [Epub ahead of print]
BACKGROUND/AIMS: In this study, we determined the genotypic and allelic frequencies of the Interleukin (IL)-10(-1082G/A) IL-10(-592A/C), and IL-10(-819C/T) polymorphisms, and their association with the risk to develop B cell Non Hodgkin Lymphoma (NHL) in hepatitis virus C (HCV) carriers. RESULTS: Genetic polymorphisms in the IL-10 gene promoter were studied in 250 consecutive patients with B-cell NHL with no clinical and/or laboratory findings of cryoglobulinemia, 142 NHL/HCV- and 108 NHL/HCV+ with chronic hepatitis (CH), 120 consecutive subjects with HCV-related CH, and 110 age, sex-matched healthy blood donors. The frequency IL-10(-1082GG) genotype vs remaining genotypes (IL-10(-1082GA/AA)) was higher in NHL/HCV+ patients than HCV-related CH patients (P=0.0002, OR=2.89, CI: 1.62-5.15) and in NHL/HCV+ than NHL/HCV- patients (P=0.0001, OR=2.99, CI: 1.72-5.19). Moreover, the IL-10(-1082GG) genotype was more prevalent in indolent NHL/HCV+ cases than aggressive NHL/HCV+ (P=0.0004, OR=4.97, CI: 2.10-11.79). Finally, we confirmed that IL-10(-1082GG) genotype is associated with higher IL-10 production compared to AA homozygous (P=0.037). CONCLUSIONS: The high IL-10 production, due to IL-10(-1082GG) genotype, influences the clinical expression of the HCV infection by increasing susceptibility to develop NHL and might contribute to the indolent form of the disease.
Treatment rates in
patients with chronic hepatitis C after liver biopsy. Narasimhan G, et al. J Viral Hepat. 2006
Hepatitis C virus (HCV) infection is a major health problem in the United States. Only about 30% of patients infected with HCV are being treated despite the development of increasingly effective therapies. The aims of this study were to determine the rate of treatment for patients with HCV after undergoing liver biopsy, to assess any change in their treatment rates over recent years and to delineate the reasons for nontreatment. We retrospectively reviewed the charts of all HCV patients who had liver biopsies at Beth Israel Medical Center, New York between 1998 and 2002. The data gathered included patient demographics, stage of liver fibrosis, insurance information, treatment history and reasons for nontreatment. There were 433 liver biopsies done for chronic hepatitis C between 1998 and 2002. Of those, 267 (61%) were men. The mean age was 47 years (range, 18-72). Only 159 (37%) patients were treated after liver biopsy. Overall there were no significant differences in the treatment rates from 1999 to 2002. The common reasons for nontreatment included minimal/mild disease (stage 0-1 fibrosis, 38%), lost to follow-up or noncompliance (31%) and patient refusal (22%). Older patients more frequently had co-morbid conditions (P = 0.009). Younger age and female gender correlated with minimal disease on biopsy (P = 0.004 and 0.01, respectively). Men were lost to follow-up more frequently than women (37%vs 22%, P = 0.01). Multivariate analysis showed that age and gender were both independent predictors of minimal disease. Patients having Medicaid with or without Medicare were significantly more likely to be treated than patients with private or commercial insurance or patients with Medicare alone. A minority of HCV infected patients were treated even after having undergone liver biopsy. The proportion of HCV patients being treated after liver biopsy has been relatively stable despite advances in therapeutic success. Liver histology frequently identified patients with mild disease in whom antiviral therapy was deemed not urgent.
study of risk factors for hepatitis C infection in patients with unexplained
routes of infection*.
Karmochkine M, et al. J Viral Hepat. 2006 Nov;13(11):775-82.
Twenty to 40% of hepatitis C virus (HCV)-infected patients do not have a recognized parenteral risk factor suggesting that still-unidentified modes of transmission exist. In order to investigate potential routes of HCV transmission for patients with no recognized parenteral risk factor, we conducted a multicentre case-control study. A total of 450 HCV-seropositive patients with no history of transfusion or intravenous drug use and 757 controls were recruited from the general population and matched for sex, age, geographical residence and number of chronic diseases. All subjects answered an interviewer-administered questionnaire on potential risk factors for HCV. Eighty per cent of cases had chronic hepatitis or cirrhosis. Respective percentages of genotypes 1, 2, 3, 4 and 5 were 65, 14, 11, 5 and 4. Among the 66 items considered, multivariate analysis identified 15 independent risk factors for HCV infection: nosocomial [admission to medical (odds ratio, OR = 2.1) or surgical ward (OR = 1.7), digestive endoscopy (OR = 1.9), abortion (OR = 1.7)], outpatient treatments [cutaneous ulcer and wound care (OR = 10.1), diathermy (OR = 3.0), gamma globulin (OR = 1.7), intravenous (OR = 1.7) or intramuscular (OR = 1.4) injections, varicose vein sclerotherapy (OR = 1.6), acupuncture (OR = 1.5)] and lifestyle-associated [intranasal cocaine use (OR = 4.5), practice of contact sports (OR = 2.3), beauty treatments (OR = 2.0), professional pedicure/manicure (OR = 1.7)]. These factors could explain 73% of community-acquired hepatitis C. In conclusion, for patients with unexplained routes of HCV infection, our data incriminate previously unidentified risk factors (abortions, some dermatological procedures, outpatient injections, contact sports, beauty treatments, professional pedicure/manicure) and confirm those already recognized (hospitalization, digestive endoscopy, acupuncture and intranasal cocaine use).
HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin. Helbling B, et al. J Viral Hepat. 2006 Nov;13(11):762-9.
In patients with hepatitis C virus (HCV)-related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon alpha-2a (PEG-IFN) alone, but the efficacy and tolerability of the PEG-IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment-naive patients with biopsy proved HCV-related advanced fibrosis/cirrhosis (Ishak score F4-F6, Child-Pugh score </=7) were randomized to 48 weeks of PEG-IFN (180 mug sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG-IFN (180 mug sc weekly) and low-dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG-IFN/STD RBV (52%) were higher - albeit not significantly - than that with PEG-IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count >/=150 x 10(9)/L were independently associated with SVR. The likelihood of SVR was <7% if viraemia had not declined by >/=2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV-cirrhotics with STD PEG-IFN/RBV is favourable.
BACKGROUND: Data on essential mixed cryoglobulinemia (MC) are scarce, and most date back to studies before 1989 (ie, before the discovery of hepatitis C virus [HCV] infection). Our objective was to describe the spectrum of MC in the era of HCV infection. METHODS: Retrospective study from a single university hospital's database of 1434 patients who tested positive for MC between January 1989 and December 2003. RESULTS: One hundred thirty-three patients (9%) with persistent MC without HCV were included in the study. Sixty-five of 133 patients who fulfilled the criteria for MC vasculitis were compared with 118 patients with HCV-related MC vasculitis. The patients without HCV had increased frequencies of renal involvement and B-cell non-Hodgkin lymphoma (NHL), lower gammaglobulin levels, and higher death rates. Twenty-three of the patients had B-cell NHL (primarily of the lymphoplasmocytic and marginal zone types), and 8 patients had Sjogren syndrome. In multivariate analysis, a cryoglobulin level higher than 0.6 g/L (odds ratio [OR], 1.44) and the presence of MC vasculitis (OR, 4.3) and hypogammaglobulinemia (OR, 6.7) were independently associated with B-cell NHL. After a mean follow-up of 49.4 months, 18 (14%) of 133 patients had died, primarily of sepsis. In multivariate analysis, age at diagnosis older than 60 years (OR, 1.06) and renal involvement (OR, 5.20) were independently associated with death. CONCLUSION: Patients with non-HCV-related MC vasculitis have a poor outcome and have a 4-fold increased risk of developing B-cell NHL.
BACKGROUND: There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin. AIM: To evaluate efficacy and safety of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in such patients. METHODS: 161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily and amantadine 200 mg/daily for 12 months. RESULTS: At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure. CONCLUSIONS: The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).
Noninvasive indexes have been developed to predict fibrosis staging. The aim of this study was to assess the diagnostic accuracy of these indexes in comparison with liver histology in hepatitis C virus (HCV)-infected patients. A total of 235 consecutive patients with HCV infection from the Fibropaca multicentre independent study were included in this paper. FibroTest (FT), aspartate aminotransferase to platelet ratio index (APRI) and Forns score were assessed in the cohort and compared with liver histology performed on the same day. The main end point was the area under characteristic curves (AUCs) for the diagnosis of significant fibrosis (F2-F4) and cirrhosis (F4) by the METAVIR classification. Mean age was 46 (+/-11) years, 55% were males, 42% (n = 99) had significant fibrosis (F2-F4) and 7% (n = 16) had cirrhosis (F4). For the diagnosis of significant fibrosis, respective AUCs of FT, APRI and Forns score were 0.81 (95% confidence interval: 0.76-0.86), 0.71 (0.67-0.79) and 0.76 (0.70-0.82); for cirrhosis prognosis, AUCs of FT and APRI were 0.82 (0.77-0.87) and 0.81 (0.76-0.86) (AUCs not significantly different). Using each index independently, all patients were classified by FT, 214 (91%) patients were classified by APRI and 129 (55%) by Forns score. There were significantly more cases of discordances between APRI and liver biopsy than between FT or Forns score and liver biopsy (P < 0.05). Performing all scores (FT, Forns and APRI) without liver biopsy allowed fibrosis to be well evaluated in 191 patients (81.3%), including patients with FT failure. Liver biopsy remained mandatory to evaluate fibrosis in 44 patients (18.7%). Our study shows that performing all the tests and liver biopsy improves the diagnostic accuracy for liver fibrosis in chronic hepatitis C patients without patent comorbidities. The combination of all tests with liver biopsy allowed 225/235 (96%) patients to be correctly classified. The combination of all tests without liver biopsy allowed 191/235 (81.3%) patients to be correctly classified; liver biopsy remained mandatory in some patients (18.7%).
BACKGROUND: We investigated associations between interferon (IFN)-gamma-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4. METHODS: Plasma IP-10 was monitored before, during, and after treatment with pegylated IFN- alpha 2a and ribavirin in 265 HCV-infected patients. RESULTS: In univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively. CONCLUSION: Baseline IP-10 levels are predictive of the response to HCV treatment.
(HCV) treatment-related side-effects is often incomplete, and many patients turn to cannabis for symptom relief. Unfortunately, there are few data about cannabis use on treatment outcomes, leaving clinicians without the data needed to inform recommendations. METHODS: To define the impact of cannabis use during HCV treatment, we conducted a prospective observational study of standard interferon and ribavirin treatment in 71 recovering substance users, of whom 22 (31%) used cannabis and 49 (69%) did not. RESULTS: Seventeen of the 71 study patients (24%) discontinued therapy early, one cannabis user (5%) and 16 non-users (33%) (P=0.01). Overall, 37 patients (52%) were end-of-treatment responders, 14 (64%) cannabis users and 23 (47%) non-users (P=0.21). A total of 21 out of 71 (30%) had a sustained virological response: 12 of the 22 cannabis users (54%) and nine of the 49 non-users (18%) (P=0.009), corresponding to a post-treatment virological relapse rate of 14% in the cannabis users and 61% in the non-users (P=0.009). Overall, 48 (68%) were adherent, 29 (59%) non-users and 19 (86%) cannabis users (P=0.03). Although cannabis users were no more likely than non-users to take at least 80% of the prescribed interferon or ribavirin, they were significantly more likely to remain on HCV treatment for at least 80% of the projected treatment duration, 95 versus 67% (P=0.01). CONCLUSIONS: Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen.
A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C.
BACKGROUND: FibroTest, a noninvasive method of measuring biomarkers of liver fibrosis, is an alternative to liver biopsy for determining the severity of chronic hepatitis C virus (HCV) infection. We compared the 5-year prognostic value of the FibroTest with biopsy staging for predicting cirrhosis decompensation and survival in patients with chronic HCV infection. METHODS: Fibrosis stage was assessed on the same day by FibroTest and biopsy in a prospective cohort of 537 patients. Disease classification at baseline was 157 patients with severe fibrosis (FibroTest >0.58), 137 with moderate fibrosis (FibroTest 0.32-0.58), and 243 with no or minimal fibrosis (FibroTest <0.32). RESULTS: In 64 untreated patients with severe fibrosis, survival without HCV complications was 73% [95% confidence interval (CI), 59%-086%; 13 complications], and survival without HCV-related death was 85% (95% CI, 73%-96%; 7 HCV deaths). Survival rates were higher in patients with moderate fibrosis, [99% (95% CI, 97%-100%; 1 complication; P <0.001) and 100% (no HCV death; P <0.001) for patients with and without HCV-related complications, respectively], and in patients with minimal fibrosis [100% (no complication; P <0.001 vs severe) and 100% (no HCV death; P <0.001 vs severe), respectively]. FibroTest was a better predictor than biopsy staging for HCV complications, with area under the ROC curves (AUROC) = 0.96 (95% CI, 0.93%-0.97%) vs 0.91 (95% CI, 0.85%-0.94%; P = 0.01), respectively; it was also a better predictor for HCV deaths: AUROC = 0.96 (95% CI, 0.93%-0.98%) vs 0.87 (95% CI, 0.70%-0.94%; P = 0.046), respectively. The prognostic value of FibroTest was still significant (P <0.001) in multivariate analyses after taking into account histology, treatment, alcohol consumption, and HIV coinfection. CONCLUSION: The FibroTest measurement of HCV biomarkers has a 5-year prognostic value similar to that of liver biopsy.
Hepatitis C virus
reinfection in injection drug users. Grebely J, Conway B, Raffa JD, Lai C, Krajden M, Tyndall MW. Hepatology. 2006 Nov;44(5):1139-45.
Spontaneous clearance of hepatitis C (HCV) may provide protection against reinfection. In a large community-based cohort study of 3,553 inner-city residents (mainly injection drug users), we identified HCV-infected individuals in whom virological clearance had occurred and compared the rate of reinfection in this group with that observed in previously uninfected members of the same cohort. We identified 926 HCV-uninfected and 658 HCV-infected viremic subjects at baseline, with 152 of 658 (23.1%) spontaneously clearing viremia over a median follow-up of 5.2 years (IQR, 2.8-7.4). At baseline, individuals with HCV clearance were more likely to be HIV coinfected (P < .001) and to be engaged in frequent illicit drug use (P = .004) and injection drug use (P < .001). The occurrence of HCV infection was lower in individuals with previous infection (14/152, 9.2%) compared with that in those without previous infection (172/926, 18.6%), with incidence rates of 1.8 (95% CI, 0.9-3.0 cases/100 person-years) and 8.1 (95% CI, 6.9-9.4 cases/100 person-years) cases/100 person-years, respectively, after accounting for follow-up. In a logistic regression analysis, with previous HCV infection assessed as a covariate with other potential confounding variables (age, sex, ethnicity, HIV infection, housing status, and illicit and injection drug use), individuals with previous HCV infection and viral clearance were 4 times less likely to develop infection than those infected for the first time (adjusted odds ratio, 0.23; 95% CI, 0.10-0.51, P < .001). In conclusion, individuals with clearance of HCV infection may have a lower risk of acquiring HCV than individuals who have never been infected, despite ongoing exposure to HCV.
BACKGROUND: Though regular blood transfusion improves the overall survival of patients with beta-thalassemia, it carries a definite risk of infection with blood-borne viruses. We carried out this multicenter study to provide epidemiologic data on hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection among Iranian beta-thalassemic patients. Moreover, HCV infection-associated risk factors were investigated in this population. METHODS: Seven hundred and thirty-two patients with beta-thalassemia major or beta-thalassemia intermedia, selected from five provinces of Iran including Tehran (n = 410), Kerman (n = 100), Qazvin (n = 95), Semnan (n = 81), and Zanjan (n = 46), were enrolled in this study. Using ELISA, their sera were tested for HBsAg, HBcAb, HBsAb, HCVAb, and HIVAb. The positive HCVAb results were confirmed by RIBA-2nd generation. RESULTS: The study sample consisted of 413 males and 319 females, with a mean +/- SD age of 17.9 +/- 9.0 years. One hundred forty-one (19.3%) patients were HCVAb positive; 11 (1.5%) were HBsAg positive. No one was HIVAb positive. Univariate analysis showed that beta-thalassemia major (P = 0.01), older age (P = 0.001), longer transfusion duration (P = 0.000), HBsAg seropositivity (P = 0.03), and higher serum ferritin level (P = 0.002) were significantly associated with a higher prevalence of HCV. Furthermore, the prevalence of HCV infection dropped significantly after the implementation of blood donors screening (22.8% vs. 2.6%; P = 0.000). Using multivariate analysis, beta-thalassemia major (P = 0.002), age (P < 0.001), serum ferritin level (P < 0.001), as well as consumption of unscreened blood (P = 0.003), were independent factors associated with HCV infection. CONCLUSION: The prevalence of HCV infection is much higher among Iranian beta-thalassemic patients as compared with HBV and HIV infections. Routine screening of donated blood for HCV is highly recommended.
quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected
patients with hemophilia. Shire NJ, et al. Hepatology. 2006 Nov;44(5):1146-57.
Hepatitis C virus (HCV) treatment response rates remain low in HCV/HIV-1-coinfected individuals compared with those with HCV alone. Persons with inherited coagulation disorders have high rates of HCV and HIV-1 infection, but HCV treatment trials in this patient population are scarce. We hypothesized that differences by infection status in HCV viral kinetics would be associated with differences in HCV quasispecies complexity over time and with treatment response disparities. Coinfected and monoinfected patients were enrolled in a treatment trial for pegylated-interferon alpha-2a (peg-IFN) + ribavirin. Patients were treated for 48 weeks and followed for an additional 24. Quantitative HCV RNA was tested at multiple times during and after treatment. Viral kinetic parameters associated with response were estimated with a mathematical model. Quasispecies emergence was determined via heteroduplex complexity assay. Twenty-two patients were HCV RNA-positive at baseline, with no significant demographic or virological differences by infection status. Five of eleven (45%) of monoinfected and 3 of 11 (27%) of coinfected patients achieved sustained viral response (SVR). Peg-IFN efficacy (epsilon) of 90% or greater was associated with probability of end-of-treatment response (ETR) (P = .001) and SVR (P = .06). Patients with SVR had lower baseline quasispecies complexity than those without SVR (P = .07). Those with epsilon of 90% or greater also had lower baseline complexity (P = .07). Coinfection status mediated changes in complexity over time (P = .04). In conclusion, low pretreatment quasispecies complexity may predict peg-IFN response; early peg-IFN response is critical for sustained HCV clearance and is altered in coinfection. Further studies are warranted.
Chronic hepatitis C virus (HCV) infection in children is a problem affecting thousands of children worldwide. Although standard interferon (INF) has better efficacy in pediatric patients than in adults, results in children with genotype 1 are poor; response rates to combination treatment with standard INF and ribavirin are better but the treatment requires thrice-weekly injections. The improved antiviral efficacy of weekly pegylated interferons relative to standard interferons in adults with chronic HCV infection suggests that pegylated interferons may also improve antiviral efficacy in children. We therefore investigated the pharmacokinetics, efficacy and safety of peginterferon alpha2a (pegINF-alpha2a) (40 kd) in 14 children ages 2 to 8 years with chronic hepatitis C (13 genotype 1, 1 non-1 genotype). Drug dose was calculated from each patient's body surface area (BSA) according to the formula BSA (m2)/(1.73 m2) x 180 microg, and patients were administered once-weekly subcutaneous injections for 48 weeks. Viral load and pharmacokinetic parameters were determined from blood drawn throughout the study and during follow-up. At week 24, the mean trough concentration was about 20% below values obtained from adults treated with pegINF-alpha2a, and the area under the curve from 0 to 168 hours was about 20% above adult values, suggesting that drug doses calculated from BSA achieved therapeutically adequate concentrations. Six of 14 patients (43%), all infected with genotype 1, achieved a sustained virological response. Adverse events were those commonly associated with INF-based treatment, and none was deemed serious. In conclusion, our findings provide a basis for larger studies evaluating the efficacy and safety of pegINF-alpha2a as monotherapy as well as in combination with ribavirin in pediatric patients with chronic hepatitis C.
Diagnostic accuracy of a fibrosis serum pane (FIBROSpect II) compared with Knodell and Ishak liver biopsy scores in chronic hepatitis C patients. Christensen C, et al. J Viral Hepat. 2006 Oct;13(10):652-8.
Liver biopsy is the primary method of assessing liver injury in hepatitis C patients. FIBROSpect II (FS), a diagnostic panel of three extracellular matrix remodelling markers, may be useful as a noninvasive alternative to this procedure. The purpose of this study was to correlate FS results with liver fibrosis scores to determine if this test is sufficiently accurate to be a viable alternative to liver biopsy. A total of 142 serum specimens were evaluated for fibrosis with FS and were compared with Knodell and Ishak fibrosis scores. FS reports an index score ranging from 0.1 to 1.0, which corresponds to the probability of progressive liver fibrosis. Using a FS index cut-off of 0.42, 50 of 54 patients with Ishak 3-6 were classified as having advanced fibrosis (METAVIR F2-F4) and 58 of 88 patients with Ishak 0-2 as having no/mild fibrosis (METAVIR F0-F1), resulting in a sensitivity of 93%, specificity of 66%, and an overall test accuracy of 76%. With a 38% prevalence of advanced fibrosis, the negative predictive value was 94% and positive predictive value was 63%. A biopsy length of > or = 2 cm was associated with higher concordance between FS results and liver fibrosis scores (P = 0.01). FS was clinically useful in ruling out advanced fibrosis in hepatitis C by identifying patients with mild disease in whom treatment could be deferred. The limitation of this test is its decreased sensitivity and specificity in the middle of the test's reporting range between scores of 0.42 and 0.80.
CONTEXT: Nuclear pharmacies prepare radiopharmaceutical products for use in common diagnostic procedures, including myocardial perfusion studies. Hepatitis C virus (HCV) transmission has not been reported previously in the setting of nuclear imaging studies. OBJECTIVE: To investigate an outbreak of acute HCV infection identified among patients who underwent myocardial perfusion studies on October 15, 2004, using an injected radiopharmaceutical. DESIGN, SETTING, AND PATIENTS: Outbreak investigation including molecular epidemiology and pharmacy site investigation at outpatient cardiology clinics and a nuclear pharmacy in Maryland. Ninety patients who received injections drawn from select radiopharmaceutical vials prepared on October 14-15, 2004, at a single nuclear pharmacy were offered testing for bloodborne pathogens. Pharmacy procedures were reviewed and HCV quasi species analysis was performed. MAIN OUTCOME MEASURES: Hepatitis C virus infection and quasispecies sequence similarity. RESULTS: Sixteen patients with acute HCV infection were identified from 3 separate clinics. All patients received radiopharmaceutical injections drawn from a single pharmacy vial (vial 1). None of the 59 tested patients who received doses from 6 other vials had acute HCV infection. Blood from a potential source patient with HCV and human immunodeficiency virus (HIV) infection was processed for a radiolabeled white blood cell study in the pharmacy 12 hours before vial 1 was prepared. The HCV quasispecies sequences from this potential source patient were nearly identical to those from cases (97.8%-98.5% similarity). No acute HIV infections were identified. Pharmacy practices that could have led to blood cross-contamination included reuse of needles and syringes during dilutions and use of common flow hoods for some steps in the preparation of sterile and blood-derived products. CONCLUSIONS: Sixteen persons acquired HCV infection from a blood-contaminated radiopharmaceutical. The source and practices that could have facilitated breaks in aseptic technique were identified at the pharmacy. Nuclear pharmacies that handle biological products should follow appropriate aseptic technique to prevent contamination of sterile radiopharmaceuticals.
2'-,5'-Oligoadenylate synthetase response ratio predicting virological response to PEG-interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C. Kim KI, et al. J Clin Pharm Ther. 2006 Oct;31(5):441-6.
OBJECTIVE: Although all the mechanisms of elimination of hepatitis C virus (HCV) by Interferon (IFN) have not been fully elucidated, the 2'-5'-oligoadenylate (2-5A) system is one of the mechanisms of the antiviral effect of IFN. Consequently, the measurement of 2'-5'-oligoadenylate synthetase (2-5AS) activity could be useful for the evaluation of IFN treatment. This retrospective study was aimed at assessing whether 2-5AS activity functions as a clinical marker of virological response to PEG-interferon-alpha2b (PEG-IFN) plus ribavirin therapy of chronic hepatitis C. METHODS: The 32 patients included in this study had high viral loads of serum HCV-RNA of genotype 1b with chronic hepatitis C. All the patients received a regimen of PEG-IFN plus ribavirin for 48 weeks, and were then divided into two groups: one group (effective group) with undetectable serum HCV-RNA levels at 24 weeks (n = 22) of therapy, the other group (ineffective group) with persistent presence of HCV-RNA in serum at 24 weeks (n = 10). The 2-5AS activity in serum was measured 2, 8 and 12 weeks before initial administration. RESULTS: The 2-5AS response ratio (measured value/measured value of baseline 2-5AS) at 2, 8 and 12 weeks after the administration in the effective group was significantly higher than that in the ineffective group. CONCLUSIONS: These results suggest that the ratio of 2-5AS is closely related to the antiviral effect, and that the measurement of 2-5AS response ratio may be a useful clinical parameter of virological response to PEG-IFN plus ribavirin therapy of chronic hepatitis C.
The aim of the study was to assess the role of selected elements of innate immunity in the pathogenesis of chronic hepatitis C in children. The study comprised 20 children with chronic hepatitis C (group 1), nine healthy hepatitis C virus (HCV) seropositive children (group 2) and 18 healthy children (control group). We evaluated the expression of Toll-like receptor (TLR)2 and TLR4 on peripheral blood neutrophils, and generation of interleukin (IL)-8, IL-10, IL-12 and reactive oxygen species (ROS) by neutrophils. The performed tests demonstrated higher expression of TLR2 and TLR4 on stimulated neutrophils and of TLR4 on non-stimulated neutrophils in group 1 in comparison to HCV seropositive children and controls. In group 1, the expression of TLR2 after granulocyte colony-stimulating factor (GCSF) stimulation showed positive correlation with alanine aminotransferase and asparate aminotransferase activities, while the expression of TLR2 without stimulation and of TLR4 after GCSF stimulation also correlated with necrosis. IL-12 generation by lipopolysachcharide-stimulated neutrophils was higher in group 1 versus controls. In group 1, maximum chemiluminescence (CL) without pre-activation, both spontaneous and after formyl-methionyl-leucyl-phenylanine and phorbol-myristate-acetate (PMA) stimulation, was significantly lower than in the controls. CL after tumour necrosis factor-alpha pre-activation and PMA stimulation was still lower than in the controls, however, after opsonized zymosane stimulation it was significantly higher than in the controls. Our studies suggest the involvement of neutrophils in the pathogenesis of chronic hepatitis C in children. Neutrophils demonstrate increased expression of TLR2 and TLR4 (correlating with the features of hepatocytic damage and intensification of necrosis), inhibition of oxygen metabolism, and after TNF-alpha pre-activation higher ability to produce ROS.
RNA interference (RNAi) has been extremely effective against hepatitis C viral (HCV) gene expression in short-term cell culture. Our aim was to determine whether long-term RNAi might result in HCV-resistant mutants. Huh7 HCV subgenomic replicon cells were transfected with short interfering RNAs (siRNAs). HCV-RNA was quantified by real-time RT-PCR, and HCV NS5A levels were assayed by Western blots using specific antibody. Treatment with HCV-siRNA resulted in a 50% inhibition of HCV-RNA levels compared with pretreatment levels after 4 weeks (P < 0.05). HCV-RNA returned to 85% of pretreatment levels after cessation of HCV-siRNA treatment. Sequencing of the HCV-siRNA target and upstream region was performed on 10 colonies from subcloning using PCR products, each before, during and after siRNA treatment. All colonies except one from HCV-siRNA-treated cells during and after treatment had mutations. There were no mutations in the HCV-siRNA target region following control HBV-siRNA treatment. Subcloned replicon cells containing the point mutations in the target region were found to be resistant to HCV-siRNA inhibitory effects. In conclusion, even after 4 weeks of treatment of replicon cells with HCV-siRNA, HCV-RNA and HCV-NS5A protein expression could not be completely eliminated. HCV replicons isolated during or after treatment were associated with mutations in the siRNA target region, while controls were not.
Detection of a
5' end subgenome of hepatitis C virus terminating at nucleotide 384 in
patients' plasma and liver tissues. Shimizu YK, et al. J Viral Hepat. 2006
Quadri and Negro [Dig Liver Dis 2001; 33: 480] reported greater distribution of 5' end genomic RNA of hepatitis C virus (HCV) over its 3' end in the liver of patients with recurrent hepatitis C after liver transplantation. We not only confirmed their results by quantifying the 5' end subgenomes in various specimens by using dilution and real-time polymerase chain reaction methods, but also discovered that such subgenomes terminated at nucleotide (nt) 384 of the viral genome or in its immediate upstream. The subgenomes in the plasma uniformly, with a few exceptions, ended at this position, while those in the liver more heterogeneously at various points upstream of nt 384. Subgenome populations ending some points in the downstream of nt 384 were not detected. The amount of the 5' end subgenome, while fluctuating during the clinical course of the patients, exceeded that of the longer sized HCV genomes which included the intact genome, and, when the relative ratio of the 5' end subgenome increased, the amount of longer sized HCV RNA tended to decrease, suggesting a suppressive effect of the 5' end subgenome on viral replication.
of tumour necrosis factor alpha promoter polymorphisms at position -308 and
-238 with clinical characteristics of chronic hepatitis C. Dai CY, et al. J Viral Hepat. 2006 Nov;13(11):770-4..
The aim of this study was to investigate the association between G vs A transitions in the promoter region of the tumour necrosis factor (TNF) alpha at positions -308 (TNF308.2) and -238 (TNF238.2) and clinical features of chronic hepatitis C (CHC). These two promoter TNF-alpha variants were determined in 250 biopsy-proven CHC patients by polymerase chain reaction amplification, followed by the Restriction Fragment Length Polymorphism (RFLP) method. The distribution of -308 and -238 TNF-alpha promoter genotypes were TNF308.1/TNF308.1: 187 (74.8%), TNF308.1/TNF308.2: 57 (22.8%) and TNF308.2/TNF308.2: 6 (2.4%), respectively, and TNF238.1/TNF238.1: 247 (98.8%) and TNF238.1/TNF238.2: 3 (1.2%). The frequencies of the TNF308.2 and TNF238.2 promoter alleles were 13.8% and 0.6%. Increased TNF308.2 allele copy numbers were significantly associated with increased frequency of lower pretreatment hepatitis C virus (HCV) RNA levels (<800 000 IU/mL; P = 0.031) and severe fibrosis stage (F3-F4; P = 0.006) and higher mean fibrosis score (P = 0.007). The higher cytokine production (with one or two TNF308.2 alleles) was correlated significantly with lower pretreatment HCV RNA levels with a lower mean HCV RNA level (P = 0.024) and increased frequency of lower pretreatment HCV RNA levels (<800 000 IU/mL; P = 0.017). Stepwise logistic regression showed that higher fibrosis score and low HCV RNA levels were independently related to the TNF308.2 allele [odds ratio (95% CI): 1.385 (1.127-1.702) and 0.698 (0.488-0.990)]. We conclude that inheritance of the TNF-alpha promoter genotype at the position -308 appears to be associated with variability in severity of fibrosis and viral load in chronic HCV infection.
Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence. Golden-Mason L, et al. Hepatology. 2006 Nov;44(5):1098-109.
Interleukin-7 (IL-7) is required for the establishment and maintenance of memory CD4(+) and CD8(+) T lymphocytes, and cells lacking IL-7Ralpha (CD127) demonstrate impaired IL-2 secretion and have a short life-span. Chronic HCV is characterized by T cells that are functionally impaired and exhibit an immature phenotype. To investigate the potential role of IL-7/IL-7Ralpha in the outcome of HCV infection, we used multiparameter flow cytometry to characterize patients with acute infection (n = 24), long-term chronic infection (12) and normal subjects (13). HCV infection per se resulted in downregulation of CD127 on total CD4(+) and CD8(+) T lymphocytes as compared to normal controls. Total expression was lowest in those patients who subsequently developed persistence and intermediate in those patients with acute-resolving infection. This reduction affected both naive and effector/memory T cells. CD127 correlated phenotypically with upregulation of chemokine receptors CCR7 and CXCR4, expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2), and enhanced IL-2 production. In six HLA A2-positive patients, we longitudinally tracked tetramer responses to HCV and CMV epitopes; at baseline, reflecting the expression of CD127 on whole T cell populations, viral-specific CTLs in patients who became chronic demonstrated lower CD127. In conclusion, CD127 is a useful marker of functional CD4(+) and CD8(+) T cells and its expression correlates with virologic outcome of acute HCV. These data provide a mechanistic basis for the observation that CTLs generated in early infection rapidly decline as chronicity is established; CD127 expression should be considered in the design of novel immunotherapeutic approaches.
We studied the effect of combination therapy consisting of IFN-beta and ribavirin on mouse hepatitis virus (MHV) infection in mice. It was found that the combination of IFN-alpha and ribavirin was more effective in increasing survival time than IFN-alpha treatment alone. It was also shown that the combination of ribavirin and IFN-beta was more effective than IFN-beta mono-treatment, and this treatment was as effective as the combination of ribavirin and IFN-alpha. Furthermore, IFN-beta treatment before treatment with ribavirin and IFN-alpha was more effective than treatment with IFN-alpha. These data indicate the possibility that pretreatment with IFN-beta once or twice a day before combination therapy with IFN-alpha and ribavirin enhances the clinical effects of combination therapy using IFN-alpha and ribavirin in chronic hepatitis C patients.
Hepatitis C virus (HCV) research and drug discovery has been facilitated by the introduction of cell lines with self-replicating, subgenomic HCV replicons. Early attempts to carry out robust, high throughput screens (HTS) using HCV replicons have met with limited success. Specifically, selectable replicons have required laborious RT-PCR quantitation and reporter replicons have generated low signal to noise ratios. In this study, we constructed a dicistronic single reporter (DSR)-selectable HCV replicon that contained a humanized Renilla luciferase (hRLuc) gene separated from the selectable marker, Neo(R) by a short peptide cleavage site. The mutations E1202G, T1280I and S2197P were introduced to enhance replicative capability. A dicistronic dual reporter HCV replicon cell line (DDR) was subsequently created by transfection of Huh-7 cells with the DSR replicon to monitor antiviral activity and by the introduction of the firefly luciferase (FLuc) reporter gene into the host cell genome to monitor cytotoxicity. The DDR cell line demonstrated low signal variability within the HTS format by a calculated Z' value of 0.8. A pilot HTS consisting of 20, 96-well plates with single concentrations (10 microM) of 1760 different compounds was executed. Hits were defined as compounds that reduced hRLuc and FLuc signals by >/=50 and </= 40%, respectively, relative to a compound-free control. Good reproducibility was demonstrated with a calculated confirmation rate of >75%. The development of a robust, high throughput HCV replicon assay where the effect of inhibitors can be monitored for antiviral activity and cytotoxicity should greatly facilitate HCV drug discovery.
N-linked oligosaccharides are known to be important in modulating immunogenicity of some viral proteins. However, the roles of N-glycans of hepatitis C virus (HCV) E2 envelope glycoprotein in specific cellular immune responses remain elusive. Previous studies showed that the epitopes aa481-500 and aa551-570 of E2 might be important for immunoreactivity and that the binding site of E2 for hCD81 is located at aa480-493 and aa544-551 within the E2 protein. Here, we made plasmids containing genes encoding either wild type or mutant E2 proteins in which N-glycosylation sites (N560NT and N576ST) close to these important regions were mutated separately or in combination. The immunogenicities of wild type E2 and three mutated E2 proteins were analyzed in BALB/c mice using DNA vaccination. The E2-M2 mutant (at N576ST) significantly enhanced (compared to control) E2-specific CTL activity (P<0.05), expression of IFN-gamma (P<0.05) and suppression of tumor growth (P<0.05). Also, high IgG2a/IgG1 ratios were elicited in a Th1-type response. These results indicate that engineering of the N-glycosylation site N576ST of HCV E2 protein enhances specific cellular immune responses, providing insights into the development of E2-based DNA vaccines with enhanced immunogenicity.
Hepatitis C virus (HCV) readily sets up persistence after acute infection. Cellular immune responses are thought to play a major role in control of the virus. Failure of CD4+ T-cell responses in acute disease is associated with viral persistence but the dynamics of this are poorly understood. We aimed to assess such responses using a novel set of Class II tetrameric complexes (tetramers) to study helper T-cells ex vivo in acute disease. We analysed the HCV-specific CD4+ T-cell response in a patient with acute hepatitis c infection. We were able to track the virus-specific CD4+ T-cells directly ex vivo with HLA DR4 tetramers. Proliferative responses were absent initially, recovered as viral load dropped and were lost again during relapse. Longitudinal tetramer analyses showed expanded populations of antiviral CD4+ T-cells throughout acute infection despite lack of proliferation. A pattern of transient CD4+ T-cell proliferative responses as HCV is partially controlled is observed. Failure to control virus is associated with emergence of 'dysfunctional' CD4+ T-cell populations. Failure to control HCV in acute disease may relate to the capacity to sustain efficient immune responses as virus attempts to 'bounce back' after partial control.
Anaemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy is common in human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients despite the use of lower doses of RBV than are recommended for HIV-seronegative persons. In addition, concurrent zidovudine (ZDV) may exacerbate the anaemia caused by PEG-IFN and RBV. We retrospectively analysed the incidence of anaemia, RBV dose reduction and epoetin-alpha (EPO) use among coinfected patients treated with PEG-IFN and weight-based RBV (800-1400 mg/day) who enrolled in two clinical trials and had haemoglobin (Hb) levels assessed at baseline and after 4 and/or 12 weeks of HCV treatment. Overall, 217 patients were included; pre-treatment Hb levels (mean 14.7 g/dL) were similar in all patients, including ZDV users (29% of patients). After 4 weeks of therapy, the mean Hb decline was greater among ZDV recipients (3.13 g/dL) compared with those on other anti-retroviral treatment (ART) (2.13 g/dL) or on no ART (1.47 g/dL) (P < 0.0001). RBV dose reduction and EPO use were more common in patients taking ZDV compared with those not taking ZDV (P < 0.0001). RBV dose was not associated with Hb reduction, RBV dose reduction or EPO use. Virologic response after 12 weeks of therapy and the treatment discontinuation rate did not differ by ZDV use. The use of ZDV but not weight-based RBV dosing was associated with an increased risk of anaemia, RBV dose reduction or EPO use in coinfected patients treated with PEG-IFN/RBV. However, ZDV use was not associated with higher rates of treatment discontinuation or lower early virologic response rates. HIV and hepatitis C care providers should be cognizant of these data.
Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life.
To analyse the barriers for anti-hepatitis C virus (anti-HCV) treatment in human immunodeficiency virus (HIV)-HCV coinfected patients, we surveyed 71 physicians specializing in infectious disease (39%), internal medicine (27%), HIV/AIDS information and care (17%), haematology (10%) and hepatology (6%). A standard data collection form was used to identify patients observed in 7 days in November 2004. Three hundred and eighty patients with the following characteristics were included: male gender 71%; mean age 41.5 years; HIV diagnosed 12 years ago; routes of transmission via injection drug use (78%); undetectable HIV viral load (235/373, 63%) or <10 000 copies/mL (86/373, 23%). HCV RNA was positive in 325 of 369 (88%) patients; HCV genotype was 1 or 4 in 65% and liver biopsy had been carried out in 56%. There were several explanations for the nontreatment of HCV in 205 of the 380 (54%) patients, with 2.4 reasons per patient: anti-HCV treatment was deemed questionable (n = 109) because of minor hepatic lesions, alcohol consumption, or active drug use; no liver biopsy had been performed (n = 68); treatment was contraindicated (n = 62), mainly for psychiatric reasons; there was physician conviction of poor patient compliance (n = 62) and patient refusal (n = 33). Patients having received anti-HCV treatment (n = 91) compared with those who had never received any (n = 205) were more commonly of European origin, had better control of their HIV infection, were followed by a hepatologist more often, had a liver biopsy more often and had more commonly a high HCV viral load (P < 0.001). In 'real life' in France in 2004, more than half of the HIV-HCV coinfected patients have never received anti-HCV treatment. The main reasons are a treatment that may be deemed questionable (minimal hepatic lesions, alcohol, active drug use), a lack of available liver biopsy, a psychiatric contraindication and physician conviction of poor patient compliance.
BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is unusual in the general population aged <60 years. Various reports indicate a much higher incidence of monoclonal gammopathy among human immunodeficiency virus (HIV)-infected patients and a significantly younger age at diagnosis. We sought to describe the laboratory findings and clinical course of MGUS, including association with plasma cell disorders, other malignancies, and infections, in 25 HIV-infected patients with a detectable serum monoclonal protein. METHODS: We reviewed the patients' demographic characteristics, stage of HIV infection, and clinical course. Laboratory studies included determination of CD4(+) T lymphocyte cell counts, HIV type 1 loads, and quantitative immunoglobulin levels; serum and urine protein immunoelectrophoresis; and determination of serum viscosity indices. Skeletal surveys and bone marrow biopsies were performed in selected cases. RESULTS: Twenty-four of 25 patients were male, and the median age of patients was 50 years (range, 21-69 years). The median CD4(+) T lymphocyte count was 350 cells/ microL (range, 40-1029 cells/ microL; mean, 355 cells/ microL), and the median HIV load was <75 copies/mL (range, <50 to 100,000 copies/mL; mean, 20,800 copies/mL). Thirteen of 25 patients had HIV viremia, despite receiving highly active antiretroviral therapy (HAART). After a mean follow-up duration of 21 months, 7 patients (28%) received a diagnosis of a malignancy (multiple myeloma, in 1 patient; non-Hodgkin lymphoma, in 1; Hodgkin lymphoma, in 1; Kaposi sarcoma, in 2; and plasmacytoma, in 2). Ten patients were coinfected with hepatitis B virus and/or hepatitis C virus; 6 were anemic. No patients developed renal failure or hypercalcemia. Nine (56%) of 19 evaluable patients had a decrease of serum monoclonal protein (mean, 0.5 g/dL) while receiving HAART. CONCLUSIONS: Patients in our study were characterized by the detection of a monoclonal protein at a younger age and the increased presence of other viral infections (infection with hepatitis B or C virus or Kaposi sarcoma herpesvirus) than is typically seen in an HIV-uninfected cohort. CD4(+) T lymphocyte counts were relatively robust. HAART appeared to have a favorable impact on the serum monoclonal protein level in 9 patients. Long-term follow-up is needed to better define the natural history of MGUS and the link to other possible contributing factors.
Although liver transplantation (LTx) in HIV-positive patients receiving highly active antiretroviral therapy (HAART) has been successful, some have reported poorer outcomes in patients coinfected with hepatitis C virus (HCV). Here we discuss the impact of recurrent HCV on 27 HIV-positive patients who underwent LTx. HIV infection was well controlled posttransplantation. Survival in HIV-positive/HCV-positive patients was shorter compared to a cohort of HIV-negative/HCV-positive patients matched in age, model for end-stage liver disease (MELD) score, and time of transplant, with cumulative 1-, 3- and 5-year patient survival of 66.7%, 55.6% and 33.3% versus 75.7%, 71.6% and 71.6%, respectively, although not significantly (p = 0.07), and there was a higher likelihood of developing cirrhosis or dying from an HCV-related complication in coinfected subjects (RR = 2.6, 95%CI, 1.06-6.35; p = 0.03). Risk factors for poor survival included African-American race (p = 0.02), MELD score >20 (p = 0.05), HAART intolerance postLTx (p = 0.01), and postLTx HCV RNA >30 000 000 IU/mL (p = 0.00). Recurrent HCV in 18 patients was associated with eight deaths, including three from fibrosing cholestatic hepatitis. Among surviving coinfected recipients, five are alive at least 3 years after LTx, and of 15 patients treated with interferon-alpha/ribavirin, six (40%) are HCV RNA negative, including four with sustained virological response. Hepatitis C is a major cause of graft loss and patient mortality in coinfected patients undergoing LTx.
Access to HCV (Hepatitis C virus) care for HIV/HCV-co-infected patients is an urgent public health concern. The objective of the present study was to describe the self-reported health status of HIV/HCV-co-infected and HCV-mono-infected injection drug users and to describe their access to HCV-related care. Beginning in May 1996, persons who had injected illicit drugs in the previous month were recruited into the Vancouver Injection Drug User Study (VIDUS). At baseline and then semi-annually, participants complete an interviewer-administered questionnaire. Blood is drawn at each semi-annual interview and tested for HIV and Hepatitis C infection. Data for this descriptive, cross-sectional study were drawn from the most recent of either the July 2003 or December 2003 nurse-administered questionnaire. Statistics used were the chi-square, Wilcoxon Rank Sum and Student's t-test. Logistic regression was used to examine factors independently associated with accessing HCV care. There were 707 individuals eligible for this analysis, including 240 HIV/HCV-co-infected and 467 HCV-mono-infected persons. Co-infected individuals were more likely to be female, younger, of Aboriginal ethnicity and less likely to use heroin daily. The HCV-mono-infected group tended to report higher rates of HCV-related symptoms, including fatigue, liver pain, nausea, night-sweats and stomach pain. However, it was the HIV/HCV-co-infected group who were more likely to report that they believed their hepatitis C was affecting them. The HIV/HCV-co-infected group were also more likely to report having received any hepatitis-related follow-up care, including blood work, liver biopsies and referrals to specialists. In logistic regression analysis, factors independently associated with ever receiving any hepatitis C related follow-up were HIV/HCV-co-infection (AOR 3.1; 95% CI: 2-4.7), being older (AOR 1.04; 95% CI: 1.02-1.06 per year older), using heroin daily (AOR 0.54; 95% CI: 0.36-0.82) and believing that hepatitis C was affecting one's health (AOR 1.4; 95% CI: 1.0-2.1). In conclusion, our data indicate more HCV healthcare utilization among those HIV/HCV-co-infected.
Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2alpha under oxidative stress. MacCallum PR, et al.
Chronic hepatitis C is often associated with oxidative stress. Hepatitis C virus (HCV) utilizes an internal ribosome entry site (IRES) element for translation, in contrast to cap-dependent translation of the majority of cellular proteins. To understand how virus translation is modulated under oxidative stress, HCV IRES-mediated translation was compared with cap-dependent translation using a bicistronic reporter construct and hydrogen peroxide (H(2)O(2)) as a stress inducer. In H(2)O(2)-sensitive HeLa cells, H(2)O(2) repressed translation in a time- and dose-dependent manner, concomitant with the kinetics of eIF2alpha phosphorylation. A phosphomimetic of eIF2alpha, which mimics the structure of the phosphorylated eIF2alpha, was sufficient to repress translation in the absence of H(2)O(2). In H(2)O(2)-resistant HepG2 cells, H(2)O(2) activated both HCV IRES-mediated and cap-dependent translation, associated with an increased level of phospho-eIF2alpha. It was postulated that H(2)O(2) might stimulate translation in HepG2 cells via an eIF2alpha-independent mechanism, whereas the simultaneous phosphorylation of eIF2alpha repressed part of the translational activities. Indeed, the translational repression was released in the presence of a non-phosphorylatable mutant, eIF2alpha-SA, resulting in further enhancement of both translational activities after exposure to H(2)O(2). In HuH7 cells, which exhibited an intermediate level of sensitivity towards H(2)O(2), both HCV IRES-mediated and cap-dependent translational activities were upregulated after treatment with various doses of H(2)O(2), but the highest level of induction was achieved with a low level of H(2)O(2), which may represent the physiological level of H(2)O(2). At this level, the HCV IRES-mediated translation was preferentially upregulated compared with cap-dependent translation.
CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. Uchiyama S, et al. J Biol Chem. 2006 Oct 20;281(42):31713-9. Epub 2006 Aug 20.
Elevated hepatic reactive oxygen species play an important role in pathogenesis of liver diseases, such as alcohol-induced liver injury, hepatitis C virus infection, and nonalcoholic steatohepatitis. In the present study, we investigated and compared the hepatic lipid metabolisms of liver-specific Sod2 (superoxide dismutase 2) knock-out (Sod2 KO), Sod1 knock-out (Sod1 KO), and Sod1/liver-specific Sod2 double knock-out mice (double KO). We observed significant increases in lipid peroxidation and triglyceride (TG) in the liver of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. We also found that high fat diet enhanced fatty changes of the liver in Sod1 KO and double KO mice but not in Sod2 KO mice. These data indicated that CuZn-SOD deficiency caused lipid accumulation in the liver. To investigate the molecular mechanism of hepatic lipid accumulation in CuZn-SOD-deficient mice, we measured TG secretion rate from liver using Triton WR1339. We found significant decrease of TG secretion in CuZn-SOD-deficient mice. Furthermore, we observed marked degradation of apolipoprotein B (apoB) in the liver and plasma of CuZn-SOD-deficient mice, indicating that degradation of apoB impairs secretion of lipoprotein from the liver. Our data suggest that oxidative stress enhances hepatic lipid accumulation by impaired lipoprotein secretion due to the degradation of apoB in liver.
Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission.
BACKGROUND: Observational studies have generally not provided evidence that delivery by caesarean section reduces perinatal hepatitis C virus (HCV) transmission. However, these studies have methodological weaknesses with potential for bias and their findings should be interpreted with caution. OBJECTIVES: To assess the evidence from randomised controlled trials that a policy of delivery by planned caesarean section versus vaginal delivery reduces mother to infant HCV transmission. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2006) and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: Controlled trials using random or quasi-random participant allocation that compared a policy of planned elective caesarean section versus vaginal birth for mothers with HCV infection. DATA COLLECTION AND ANALYSIS: We did not identify any randomised controlled trials. MAIN RESULTS: We did not identify any randomised controlled trials. AUTHORS' CONCLUSIONS: Currently, there is no evidence from randomised controlled trials upon which to base any practice recommendations regarding planned caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. In the absence of trial data, evidence to inform women and carers is only available from observational studies that are subject to biases. Systematic review of these studies is needed. There is a need to determine whether women and healthcare providers would support a large pragmatic randomised controlled trial to provide evidence regarding the benefits and harms of planned elective caesarean section versus planned vaginal birth for women with HCV infection.
Management and treatment of hepatitis C viral infection: recommendations from the department of veterans affairs hepatitis C resource center program and the national hepatitis C program office.
Chronic hepatitis C virus (HCV) infection affects approximately 1.3% of the general U.S. population and 5-10% of veterans who use Department of Veterans Affairs medical services. Chronic HCV is clearly linked to the development of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation. The consequences of HCV infection constitute a significant disease burden and demonstrate the need for effective medical care. Treatment of chronic HCV is aimed at slowing disease progression, preventing complications of cirrhosis, reducing the risk of HCC, and treating extrahepatic complications of the virus. As part of a comprehensive approach to HCV management, antiviral therapy with peginterferon alfa combined with ribavirin is the current standard of care. Antiviral therapy should be provided to those individuals who meet criteria for treatment and who are at greatest risk for progressive liver disease. Many of these patients may have comorbid medical and psychiatric conditions, which may worsen while on antiviral therapy. Current antiviral regimens are associated with significant adverse effects that can lead to noncompliance, dose reduction, and treatment discontinuation. To overcome these barriers and to address these issues, it has become crucial to facilitate a multidisciplinary team who can respond to and provide HCV-specific care and treatment. Screening for HCV, preventing transmission, delaying disease progression, ensuring appropriate antiviral therapy, and managing treatment-related adverse effects can improve patient quality of life, treatment adherence, and ultimately, improve patient outcomes.
BACKGROUND: Although the current standard of care for controlling anaemia and neutropenia during anti-viral therapy for hepatitis C is to use dose reduction of ribavirin and pegylated interferon, respectively, erythropoietin and granulocyte colony-stimulating factor are now being advocated as alternatives to dose reduction. AIM: To determine the cost-effectiveness of erythropoietin and granulocyte colony-stimulating factor as an alternative to anti-viral dose reduction during antihepatitis C therapy. METHODS: Decision analysis was used to assess cost-effectiveness by estimating the cost of using a growth factor per quality-adjusted life-year gained. RESULTS: Under baseline assumptions, the cost per quality-adjusted life-year of using growth factors ranged from 16,247 US dollars for genotype 1 with neutropenia to 145,468 US dollars for genotype 2/3 patients with anaemia. These findings are sensitive to the relationship between dose reduction and sustained virological response. CONCLUSIONS: Based upon our findings and the varying strength of the evidence for a relationship between dose reduction and sustained virological response: granulocyte colony-stimulating factor may be cost-effective for genotype 1 patients; erythropoietin is probably not cost-effective for genotype 2/3 patients; no conclusion can be reached regarding the cost-effectiveness of erythropoietin for genotype 1 patients or granulocyte colony-stimulating factor for genotype 2/3 patients. Randomized trials are needed to firmly establish the relationship between dose reduction and sustained virological response.