Hepatitis C Caring Ambassadors Program Newsletter
In The News.................................................................................................. 1
Clinical Trials, Cohort Studies, Pilot Studies................................... 8
Basic and Applied Science, Pre-Clinical Studies................................ 15
HIV/HCV Coinfection................................................................................ 19
Complementary & Alternative Therapies............................................21
Miscellaneous Works............................................................................... 22
SALEM -- Gov. Ted Kulongoski vetoed a bill Tuesday that would stop the state from limiting the types of drugs used to treat hepatitis C patients enrolled in the Oregon Health Plan. In a letter to House Speaker Karen Minnis, R-Wood Village, the governor said House Bill 2480 would inhibit the state's ability to effectively manage the Oregon Health Plan fee-for-service drug benefit. The letter also said the Department of Human Services already provides effective treatments for people on the plan who have hepatitis C that are consistent with national treatment guidelines. The bill passed both the House and Senate with bipartisan support.
Advocates, including grass-roots organizations like Hepatitis C Caring Ambassadors of Oregon City and pharmaceutical companies, argued that patients should have access to all available hepatitis C drugs because it is a difficult disease to treat. Opponents of HB2840 said pharmaceutical companies have a financial interest in overturning restrictions on drugs available through the Oregon Health Plan. The 2001 Legislature created a law that included a list of lower cost drugs doctors must prescribe to Oregon Health Plan patients. The requirement did not apply to prescription drugs used to treat mental illness, HIV, AIDS and cancer. HB2480 would have put hepatitis C drugs in a similar category. One year of drug therapy for a person diagnosed with hepatitis C can cost about $36,000.
OREGON CITY, Ore.--(BUSINESS WIRE)--July 20, 2005--The Hepatitis C Caring Ambassadors Program (HCCAP) announced that they had received notification on July 19th from the office of Oregon Governor Ted Kulongoski that he had vetoed hepatitis C legislation overwhelmingly passed by both the Oregon House and Senate. The legislation, HB 2480, would have prevented the Oregon Department of Human Services from restricting the drugs available to patients with hepatitis C covered by the Oregon Health Plan's fee-for service program. The bill was introduced in February 2005 at the request of the Hepatitis C Caring Ambassadors Program, a national nonprofit hepatitis C education and advocacy organization based in Oregon City, Oregon. Existing statutory limitations are already in place to prevent the Oregon Department of Human Services from restricting patient access to potentially life-saving drugs used to treat other life-threatening diseases including cancer, HIV/AIDS, and mental illnesses. Governor Kulongoski's veto of HB 2480 is particularly remarkable given the overwhelming support for the bill in the Oregon legislature. HB 2480 was approved with 41 ayes to 15 nays in the House, and 27 ayes to 1 nay in the Senate, demonstrating the strong bipartisan support for the bill. Governor Kulongoski reportedly began talk of vetoing HB 2480 in early February 2005, long before the bill reached the floor of the House or the Senate.
Hepatitis C is the most common chronic, blood-borne viral infection in the United States. Hepatitis C is the leading cause of chronic liver disease in the U.S., which now ranks among the top ten killers of adults over the age of 25 years. An estimated 3.9 to 4.5 million Americans have been infected with the hepatitis C virus including at least 64,000 Oregonians. The current methamphetamine crisis is likely to fuel an expanding hepatitis C epidemic in Oregon, a startling backdrop to Governor Kulongoski's veto of HB 2480.
Hepatitis C Caring Ambassadors Program Manager Lorren Sandt stated, "We are deeply distressed by Governor Kulongoski's use of his executive power to exercise his minority opposition to HB 2480. Like cancer and HIV/AIDS, chronic hepatitis C is a life-threatening illness. Medical treatment decisions to optimize care for illnesses that threaten both individual lives and the overall health and safety of the public should be made on a case-by-case basis by treating physicians, not a political bureaucracy. The Governor's veto of HB 2480 has dealt a blow to all Oregonians, not just those currently infected with hepatitis C. All people with hepatitis C should have access to the drugs that are most likely to be effective, regardless of the source of payment. But with the Governor's veto of HB 2480, hepatitis C patients receiving care under the Oregon Health Plan's fee-for-service program are now in a position to have to take whatever drugs the state deems they can have access to."
The Hepatitis C Caring Ambassadors Program will continue efforts to inform state and national policy-makers about the urgent personal and public health threats posed by the hepatitis C epidemic. Hepatitis C Caring Ambassadors Program Medical Director, Dr. Tina M. St. John, stated, "While we must respectfully agree to disagree with Governor Kulongoski on his veto of HB 2480, we will continue to work with the governor, the state legislature, and the Oregon Department of Human Service to ensure optimized care for all Oregonians with chronic hepatitis C, and to fully implement effective hepatitis C control and prevention."
Schering-Plough Corporation today reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has issued a positive opinion recommending approval of revised dosing instructions which allow a shorter, 24-week course of weight-based PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800 - 1,200 mg) daily combination therapy among a subgroup of patients with hepatitis C virus (HCV) genotype 1 infection and low viral load (< 600,000 IU/ml). A shorter 24-week course of therapy can be considered for these patients who have achieved rapid virologic response, defined as undetectable virus (HCV-RNA negative) at week 4 of treatment that is maintained through week 24. A 92 percent sustained virologic response was achieved with 24 weeks of treatment among the 41 percent of patients who met the criteria for early response.
PEGINTRON and REBETOL combination therapy was previously approved in the EU for a 48-week course of therapy for all patients with genotype 1 who exhibit virological response at week 12. Approval of this shorter PEGINTRON and REBETOL combination treatment regimen cuts by half the duration of therapy for a subset of hepatitis C patients with genotype 1 and low viral load. This is the only treatment regimen approved in the European Union (EU) for a 24-week course of therapy in certain genotype 1 patients.
The CHMP recommendation serves as the basis for a European Commission approval of this labeling change. A Commission Decision will result in Marketing Authorization with unified labeling that will be valid in the current EU 25 member states as well as in Iceland and Norway.
"The important results of this clinical study with PEGINTRON and REBETOL reflect the ongoing efforts of Schering-Plough to define optimal dose and treatment schedules for specific HCV patient groups," said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute.
Small RNA molecules targeted against the hepatitis B virus
Researchers have found a way of delivering small RNA molecules targeted against the hepatitis B virus at doses that are low enough to allow this new therapeutic approach to be used in people. In the August issue of Nature Biotechnology, David Morrissey and his colleagues incorporate so-called small interfering RNAs (siRNAs) into lipid (fat-like) particles that protect them against digestive enzymes in the blood, thereby increasing their stability when injected into mice and reducing the dose needed for therapeutic effect. These enzymes normally degrade RNA molecules in cells or the circulation.
A new treatment for Hepatitis C which includes a longer-acting form of interferon has been found to cure more patients and cause less side effects, in a study conducted in 81 medical centers.The experimental treatment includes a once-a-week shot of Pegasys, a long-acting form of interferon known as pegylated interferon, along with daily antiviral pills called ribavirin. The standard treatment for Hepatitis C has been three shots of shorter-acting interferon per week along with the ribavirin pills.
In the recently completed study, one group was given the new Pagasys treatment, one group the standard treatment, and a third group was given Pagasys only, without the ribavirin pills. The treatment lasted for 48 weeks. Six months after the treatment stopped, 56 patients saw all traces of the virus eliminated with the new program, compared to 44 percent with the standard treatment. Additionally, Twenty-nine percent of those in a third group who received Pegasys shots alone were cured.
"This is one of the first times where we have more than half the people we treat have a good response," said lead researcher Dr. Michael W. Fried, director of liver disease treatment at University of North Carolina-Chapel Hill. The study of 1,121 patients worldwide, was published in the September 26, 2002 edition of the New England Journal of Medicine. Fried said after 12 weeks of treatment, doctors can tell which patients Pegasys probably will cure. The others can stop the lengthy treatment, and avoid the serious side effects.
Mass Spectrometry for Genotyping Hepatitis C Virus: A Promising New Approach
Hepatits C virus (HCV) infection is a growing health problem worldwide, with more than 170 million individuals currently infected (1). Because no vaccine is currently available, the mainstay of control is treatment of infected individuals. Although the first attempts at treatment with interferon-α produced sustained responses in only ~25% of patients, more recent combination treatment regimens consisting of pegylated interferon-α plus ribavirin have led to sustained response rates approaching 60% (2, 3). In spite of intense study, the specific HCV gene(s) controlling the response to combination therapy have not been identified. Instead, the best predictor is the HCV genotype of the strain present in the patient (4). HCV is an extremely diverse virus, with 6 major genotypes and more than 60 subtypes identified (5, 6). Genotype 1 is the most common genotype in the United States and Europe, and genotypes 2 and 3 are also common in these areas. Frequently, the virus within a given infected individual diverges during the course of chronic infection into multiple viral lineages with related sequences (known as quasispecies). Less frequently, an individual may become infected with a mixture of 2 or more genotypes. In spite of the wide sequence variation present in HCV, multiple studies have clearly shown a lower response rate to combination therapy with pegylated interferon-α plus ribavirin for patients who are infected with genotype 1 compared with the other genotypes (7). Thus, 2 therapeutic schemes are used: a 48- week course of therapy for patients infected with genotype-1 HCV and a 24-week course for those infected with other genotypes of the virus (8). The dramatically different response rates place a premium on the accurate assignment of the HCV genotype(s) causing a given patient's infection.
A variety of methods are available to genotype HCV-positive samples. The current gold standard method is direct sequencing of the nonstructural 5, envelope 1, or core (NS5, E1, or C) region. In contrast to these 3 regions, which contain multiple genotype- specific base pair changes over several hundred base pairs of sequence, the 5' untranslated region (5'UTR) has conserved domains and has fewer genotype-specific base pair changes (9). In spite of the lower variability in this region, at present the most commonly used methods in clinical laboratories are based on analysis of the 5'UTR by use of hybridization approaches (such as the line probe assay or melting analysis), direct sequencing of the 5'UTR, or restriction fragment length polymorphism (RFLP) analysis. The 5'UTR- based line probe assay and RFLP methods have been shown to have fair to very good agreement with sequencing of the 5'UTR, ranging from ~84% to 99% for genotype and from 68% to 86% for subtype (10). However, even direct sequencing of the 5'UTR is less informative than sequencing of the NS5, E1, or C region, especially at the subtype level (11), because of the limited variability of the 5'UTR. Nevertheless, the presence of conserved domains within the 5'UTR makes PCR amplification of this region more robust than amplification of the NS5, E1, or C region; thus, the 5'UTR-based methods are more sensitive and are favored by most clinical laboratories.
In this issue, Kim et al. (12) report a promising new approach to determining HCV genotype, which they term restriction fragment mass polymorphism (RFMP) analysis. The technique is based on PCR amplification of the 5'UTR of HCV, using primers that introduce recognition sites for type US restriction enzymes. Type US restriction enzymes have the important characteristic of cleaving DNA strands at points outside their recognition site. Cleavage of the HCV PCR product by such enzymes yields multiple oligonucleotide fragments of defined length representing hypervariable regions of HCV. Kim et al. then use an elegant matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS) approach to identify these hypervariable regions, allowing assignment of HCV genotype.
InterMune and Array expand Hep C collaboration
Intermune and Array BioPharma have agreed to extend and expand their current Hepatitis C (HCV) drug discovery collaboration. The main area of focus, protease inhibitors, represents a promising class of drugs for HCV because of its involvement in viral replication and suppressive effects on host response to viral invasion. According to the Centres for Disease Control an estimated 3.9 million Americans have been infected with HCV, of whom 2.7 million are chronically infected, and the prevalence of chronic HCV is increasing. Currently available therapies are insufficient, creating a need for the development of novel therapeutic approaches.
The program, which began in 2002, has produced novel small molecule inhibitors of the Hepatitis C Virus (HCV) NS3/4 protease. In addition to extending the current agreement, the program has been expanded to allow Array and InterMune to enhance their discovery efforts. Array will continue to conduct process research and cGMP scale-up of drug candidates to support clinical development. "We have expanded the collaboration to accelerate the development of this important class of novel HCV inhibitors," said Dan Welch, chief executive officer and President of InterMune. "In addition to our protease inhibitor program, we are advancing our late stage HCV pipeline in PEG-nonresponders and growing our marketed brand, Infergen (interferon alfacon-1) for the retreatment of chronic HCV," he added.
Additional terms of the agreement will see InterMune fund drug discovery, preclinical and process development at Array. InterMune maintains responsibility for clinical development and commercialisation of the resulting products. Array will be entitled to receive milestone payments based on the selection and progress of clinical drug candidates, as well as royalties on net sales of products derived from the collaboration. Other terms were not disclosed.
The current standard of care for chronic HCV is a combination of an interferon-alpha product and ribavirin. Sales of HCV drugs are expected to grow due to improved market penetration through increased awareness and improved diagnosis rates and therapies.
Hepatitis C Breakthrough May Save Lives
New York, July 18, 2005 - Scientists have for the first time produced an infectious form of the hepatitis C virus in the laboratory that is expected to lead to more effective treatments that could save millions of lives. Hepatitis C, which like HIV is spread by blood and body fluids, can lead to chronic liver disease, cancer and death. But it can take many years to develop, and 80 per cent of infected people show no symptoms. An estimated 170 million people around the world are affected by the disease.
Professor Charles Rice, from Rockefeller University in New York, who led the new research published today in the journal Science, said: "The inability to reproduce aspects of the hepatitis C virus life cycle in cell culture has slowed research progress on this important human pathogen." Like all viruses, hepatitis C (HCV) cannot replicate by itself. Instead it takes over the machinery of a host cell to make copies of itself. But much about the life cycle of HCV remains poorly understood because scientists have been unable to reproduce an infectious form of the virus they can observe in cell cultures. The virus enters liver cells before unloading genetic material and proteins.
HCV carries its genetic information in Ribonucleic acid (RNA) and not Deoxyribonucleic acid (DNA). This information is separated from the protein, copied, and joined with new protein components before being released to infect other cells. The scientists named their infectious cell culture virus HCVcc.
Already, it is yielding new knowledge about the hepatitis C virus. In separate experiments, the researchers used HCVcc to confirm that a molecule that sits on the surface of human cells plays a crucial role in allowing the virus in.
Hepititis C Decision
20 July 2005 11:30 - Hepatitis C sufferers are furious that the introduction of a Government-backed action plan to help victims of the disease and prevent more infections has been halted. Norwich Primary Care Trust has revealed it does not plan to implement the Hepatitis C Action Plan for England in the city because it does not have the cash.
The move has left city sufferers such as Anne Walker and Michael
Colyer extremely concerned about the pending explosion in Hepatitis C and angry
their efforts to roll out the plan have been wasted. The action plan would have
involved more publicity about the risks and symptoms of the disease, more
screening and easier access to treatment.
But Alastair Roy, chief executive of Norwich Primary Care Trust, wrote in a letter to Norwich South MP Charles Clark in June: "I am sorry to say that I am still unable to give you a firm commitment to the action plan at this time. If the situation changes in the near future I will contact you again."
Mr Colyer, of Colman Road, who spearheaded the campaign to get the
Department of Health-backed campaign rolled out, said: "I am appalled by
this. We had created a second draft of the action plan and now it's
The 54-year-old haemophiliac was infected with Hepatitis C after receiving contaminated blood products through the NHS in the 1960s or 1970s. He organised a meeting in November with Norwich Primary Care Trust, the other primary care trusts in Norfolk and organisations to get the project off the ground. He said: "The action plan would have meant we would have been able to kick start the process of gathering data on people in Norfolk which no-one has done yet." He said it would also have led to more screenings of possible carriers of the disease. He said he was amazed the virus was 16 years old and still nothing was done when it was suspected there were 5,000 people in Norwich with the illness.
"The message is not getting through. Ninety per cent of those infected have used drugs in the past such as cocaine or drugs injected through needles." He said others at risk were nurses and healthcare workers who had needle stick injuries and people with tattoos, pierced ears and those like him who had had blood transfusions prior to 1991. "This is a time bomb already going off because of the lack of action. The implications are awful because of the effect it is going to have on the lives of people who fall ill and it's going to be an enormous drain on the NHS. The Government can either pay out now to prevent it or they can pay for treatment."
Co founder of the Norwich C Hepatitis Group, Ms Walker, 50, said: "I can't believe after all the efforts the professionals have put into it that it's not being put into action. It seems as though the liver is always put at the bottom of the list. I can't understand it because in 10 years' time there is going to be a huge demand for livers when people realise they have got Hepatitis C. We are so sick of nothing happening." Ms Walker was infected with Hepatitis C in 1974 when she had a routine NHS blood transfusion.
Alastair Roy, chief executive of Norwich Primary Care Trust, said: "We recognise this as an important element in disease prevention along with a range of other initiatives. "This financial year we are concentrating on avoiding hospital acquired infections and full implementation of the Norfolk wide Hepatitis C policy will be considered with other initiatives for the next financial year."
Authors Lloyd Wright & Melody Beattie Kick-Off Hepatitis C Awareness Campaign http://www.prweb.com/releases/2005/7/prweb267001.htm
Author Lloyd Wright continues Hepatitis C Awareness Campaign with WA radio appearance. Wright (Triumph Over Hepatitis C) to be featured Wednesday, August 3rd on the KKNW radio show (1150 AM) "Creating Your Day with Cameron & Lucia" at 9 am in Seattle, WA (also live and archived on the Internet*).
Malibu, CA (PRWEB) July 30, 2005 -- Author Lloyd Wright continues Hepatitis C Awareness Campaign with WA radio appearance. Wright (Triumph Over Hepatitis C) to be featured Wednesday, August 3rd on the KKNW radio show (1150 AM) "Creating Your Day with Cameron & Lucia" at 9 am in Seattle, WA (also live and archived on the Internet*).
"Hepatitis C Awareness has a long way to go," says author Lloyd Wright, who likens the situation to the early days of AIDS. And he knows how bad it is out there. Practically every day, he speaks with the people who have Hep C who call his hotline. One common theme of these conversations is the discrimination faced by "Heppers". Take Katie, a caller who was fired from her job as a bartender for a catering company after her Hepatitis C status became known. Ironically Katie had mentioned it to a fellow worker with AIDS as a way to show her support for him. When Wright spoke to her employer, the man said it was the perception of the people who hire his catering firm that got Katie fired, not his own beliefs. The man said he just wanted to stay in business.
"There is much education that needs to take place in regards to Hepatitis C, both about how it is spread** and about options for patients," observes best-selling author Melody Beattie, who discovered her Hep C positive status two years ago after a routine medical exam. To make the spotlight shine brighter on the many facets of Hepatitis C, Lloyd Wright, a best-selling author himself, decided it was important to bring celebrities like mega-author Melody Beattie on board. "The reason I asked Melody to come forward to talk about having Hep C is that people listen to celebrities," says Wright. "Celebrities got involved in the AIDS issue, and look at how open the discussion about it has become. Hepatitis C should be the same way."
Wright and Beattie agree that their campaign needs to both educate the general public AND reach out specifically to those who have Hep C. "People with a Hepatitis C diagnosis need to understand that they didn't just receive a death sentence," notes Beattie. "They have options, even though the person who gave them their diagnosis may not be aware of those options." At present, most Hep C patients are steered toward Interferon treatment.
A search for alternatives to the standard medical protocol is what initially brought Beattie into Wright's world. His book, Triumph Over Hepatitis C, which has sold over 200,000 copies, outlines the alternative medicine solution he developed. Over the years, it has been used successfully by patients around the world. Wright himself had Hep C, contracted from a blood transfusion after a building site accident.
Lloyd Wright's hotline [877-676-1615 and website [www.hepatitiscfree.com remain active. Over the years, he has talked to thousands of patients. However since the disease affects 15 to 25 million people in the U.S. alone, he knows there are many others he has yet to reach.
One angle of the Hep C story that Wright would like to get out to more people is what Heppers should avoid in order to get better or stay well. This includes actions that are likely to raise their viral load (a measure of the quantity of Hep C virus in a patient's blood). "Many prescription drugs can raise the viral load, including antibiotics and antidepressants. Another drug that does is Viagra, but I don't know of anyone else who is talking about that."
you get Hep C, it is possible to make choices and take action so that you
eventually die from something else, rather than from the Hepatitis," says
Beattie. "People need to be empowered to make the choices that are right
for them, and they can't do that unless they are aware of all of their options.
Information truly is power."
Kidman’s Film Under Fire for Hepatitis C Joke
Officials at the American Liver Foundation are fuming with a joke in NICOLE KIDMAN's new movie BEWITCHED, which pokes fun at those suffering with Hepatitis C.In the film, a woman spurns MICHAEL CAINE's character by telling him she has the blood disease.
But the ALF's president FREDERICK THOMPSON isn't laughing: "This remarkably tasteless comment plays into the stigma that many people with hepatitis C have to cope with every single day. "I can't imagine anyone in Hollywood making a joke about HIV infection, for instance."
TORONTO, July 27 - Transition Therapeutics Inc. ("Transition") (TSX: TTH), announced today that patient enrolment has commenced for a Phase I/II clinical trial of its Interferon Enhancing Therapy, HCV-I.E.T. in hepatitis C patients. The goal of this trial is to evaluate the efficacy of HCV-I.E.T. in the 45% of hepatitis C patients that do not respond to standard interferon and ribavirin combination therapy and have no treatment options available.
"Transition's interferon enhancer EMZ702, a non-toxic agent that has strong anti-viral synergy with interferon, is an ideal candidate for combination with current standard hepatitis C treatments. Positive clinical data in this patient population would have a large impact in the management of the disease and can potentially offer an expedited route to product approval," said Dr. Tony Cruz, Chairman and CEO of Transition. In the phase I/II clinical trial, twenty-eight hepatitis C patients who have not responded to pegylated interferon and ribavirin, will receive twice-weekly treatments of EMZ702 administered along with standard pegylated interferon and ribavirin. The primary efficacy endpoint will be the reduction of HCV RNA viral load, a clinical endpoint indicative of positive response to therapy. The principal investigator for the trial is Dr. Morris Sherman, a leading clinician in hepatitis C research at the University of Toronto.
HCV-I.E.T. combines Transition's interferon enhancer, EMZ702, with the current standard of care for hepatitis C, a combination therapy of pegylated interferon alpha and ribavirin. EMZ702 has an excellent safety profile and the combination of EMZ702 with interferon and ribavirin in surrogate models for hepatitis C has demonstrated a two to three fold increase in anti-viral potency compared to interferon and ribavirin alone. The strong anti-viral response observed in surrogate models has enabled the rapid advancement of HCV-I.E.T. into clinical development with hepatitis C patients.
Interferon Enhancing Therapy is a key development initiative for Transition and has resulted in the discovery and development of two drug products: MS-I.E.T. for multiple sclerosis ("MS"), which is currently in phase II studies in MS patients, and HCV-I.E.T. for hepatitis C, which is currently in phase I/II studies with hepatitis C patients. Transition's interferon enhancers have demonstrated more potent anti-viral and anti-proliferative effects than interferon alone and may also have application in various forms of cancer and in hepatitis B. Worldwide sales of interferon products are estimated to be in excess of US$ 5 billion annually.
IAS: Hepatitis C treatment should last for 48 weeks in HIV co-infected patients, study shows
HIV-positive patients co-infected with the hepatitis C virus (HCV) should be treated with anti-HCV therapy for 48, and not 28 weeks, according to the results of an Italian randomised controlled trial presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro on July 25th.
Treatment of HCV in co-infected patients with a combination of peginterferon alfa and ribavirin is known to be effective in clearing HCV infection in most patients. However, some uncertainty surrounds the optimal duration of therapy. For patients with the varieties of HCV called genotypes 2 or 3, a course of anti-HCV therapy of 48 weeks is recommended. However, some experts have called this into question by advocating the use of HCV drugs for only 24 weeks, as is recommended for HIV-negative patients. In contrast, others have found that this shorter treatment results in an elevated risk of relapse after HCV therapy is stopped.
examine the effect of treatment duration in HIV co-infected patients,
researchers from Italy recruited 128 patients with CD4 cell counts above 200
cells/mm3 and HIV viral loads below 10,000 copies/ml, or who had
been on highly active antiretroviral therapy for at least six months. All of
the patients had HCV infection confirmed by a blood test and a liver biopsy at
least three years prior to the start of the study. Although it was restricted
to those with genotypes 2 or 3, Massimo Puoti, presenting, claimed that almost
all of the patients had genotype 3, as genotype 2 is very rare among HIV
co-infected patients in Italy.
For the first 24 weeks, all of the patients received a combination of 180 µg peginterferon alfa 2a (Pegasys) once a week and ribavirin at a dose of 800 to 1200mg once a day, depending on body weight. At the end of this period, 74 of the 82 patients who had not dropped out of the study had become HCV-negative. These patients were then randomised either to receive a further 24 weeks of anti-HCV therapy or to remain off treatment. Twenty-four weeks later, 15 (40%) of the 38 patients who stopped treatment after 28 weeks had relapsed, following detection of HCV in their blood. In contrast, only two (10%) of the 20 patients who were still HCV-negative after completing 48 weeks of treatment had relapsed after 24 weeks. This was significantly lower than in the patients who were treated for 28 weeks (p = 0.02).
Using a multivariate analysis, the investigators calculated that the patients treated for 48 weeks were 5.46 times more likely to achieve a ‘sustained virological response’ (SVR), defined as persistent HCV negativity 24 weeks after the end of treatment. Other factors that were significantly associated with SVR were and having a higher number of platelets in the blood (OR = 1.01; p = 0.019) and being HCV-negative after four weeks of treatment (odds ratio [OR] = 5.57; p < 0.001). However, the researchers found that a successful response at four weeks in an individual patient did not mean that a shorter duration of treatment would necessarily be possible.
Puoti acknowledged that his study included a high number of patients who
discontinued therapy early. These drop-outs were mostly due to side-effects and
intolerance of HCV therapy, with more than half of these patients relapsing to
being HCV-positive after leaving the study. However, he said that the incidence
of side-effects was lower after the first 28 weeks of HCV treatment. “These
results suggest that the optimal duration of treatment in HIV-positive
[patients] with HCV genotypes 2 or 3 is at least of 48 weeks,” he concluded.
[Zanini B et al. The optimal duration of treatment for HIV-infected patients with chronic hepatitis C (CHC) and genotype 2 or 3 is 48 weeks: results of a randomised controlled trial. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract MoPpLB0103, 2005.]
GlobeImmune Initiates Phase 1b Study of GI-5005 for
Chronic Hepatitis C Infection
DENVER, July 26 /PRNewswire/ -- GlobeImmune, Inc., a biopharmaceutical company that discovers, develops and manufactures immunotherapeutic products known as Tarmogens(TM) to treat cancer and infectious disease, today announced that it has initiated a Phase 1b study of GI-5005, a Tarmogen for the treatment of chronic hepatitis C infection (HCV). This study is being conducted under an Investigational New Drug application (IND) that was filed with the U.S. Food and Drug Administration in March 2005.
The Phase 1b study is a double-blind, placebo controlled, dose-escalation, multi-center trial evaluating the safety, immunogenicity, and efficacy of GI- 5005, a Tarmogen expressing a NS3-Core fusion protein. NS3 and Core are HCV protein antigens that are expressed in infected cells and are essential for virus replication. GI-5005 has demonstrated robust activity in preclinical models of HCV. Because Tarmogens elicit a balanced immune response that is similar to the response occurring in the minority of individuals who successfully clear primary hepatitis C infection, the Company believes that the GI-5005 Tarmogen may represent a successful approach to treating this difficult disease.
"Hepatitis C is an area of major unmet medical need," said Timothy C. Rodell, M.D., CEO of GlobeImmune. "We are hopeful that GI-5005 will ultimately be able to treat the significant proportion of patients for whom there is currently no effective therapy. This is a significant event for GlobeImmune, as this milestone represents the second Tarmogen product to enter human clinical trials in 18 months and the first clinical trial of a Tarmogen for the treatment of an infectious disease."
Chronic hepatitis C infection, a viral liver disease, is a global health epidemic. Currently, there are approximately 170 million people worldwide who are infected with the hepatitis C virus. Of these, 4-5 million live in the United States with an additional 5 million living in Western Europe. Approximately 20-30% of all hepatitis C patients will face life threatening complications as a result of their disease. Hepatitis C accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepatocellular carcinoma (liver cancer) and 30% of liver transplants in the United States.
The incidence of new symptomatic infections with hepatitis C has been estimated to be 13 cases/100,000 persons annually. For every one person that is infected with the AIDS virus, there are more than four infected with hepatitis C. The Centers for Disease Control Prevention (CDC) estimate that there are up to 230,000 new hepatitis C infections in the United States every year. Currently, 8,000 to 10,000 deaths each year are attributed to the disease.
in the interferon-gamma gene at position +874 in patients with chronic
hepatitis C treated with high-dose interferon-alpha and ribavirin. Dai CY, et al. Antiviral Res. 2005 Jul 25;
To investigate the influence of the T-to-A polymorphic sequence at position +874 in the interferon (IFN)-gamma gene (+874 IFN-gamma) on the response to combination therapy with high-dose interferon and ribavirin, the single nucleotide polymorphisms were determined by using a polymerase chain reaction sequence-specific primers approach in 150 histologically proved chronic hepatitis C (CHC) patients. The distribution of genotypes for +874 IFN-gamma were T/T: 6 (4.0%), T/A: 31 (20.7%) and A/A: 113 (75.3%) and 24.7% (37/150) of patients were inherited T allele. After undergoing combination therapy with high-dose IFN-alpha and ribavirin, 70.7% (106/150) of patients achieved sustained viral response (SVR). Based on multivariate regression analyses, the independent factors predicting HCV SVR after combination therapy were HCV genotype non-1b (P<0.001) and low pretreatment HCV RNA levels (P=0.041) (odds ratios/95% C.I.: 10.150/4.023-25.609 and 0.581/0.345-0.979, respectively). No association between genotypes, A or T alleles of +874 IFN-gamma and response to combination therapy with high-dose IFN-alpha and ribavirin. In conclusion, we found that with high SVR rates after combination therapy with high-dose IFN-alpha and ribavirin, HCV genotypes and pretreatment serum HCV RNA levels, but not inheritance of the IFN-gamma polymorphism at the position +847, were predictors for SVR.
C Virus-specific reactivity of CD4+-lymphocytes in children born from
HCV-infected women. Della Bella S, et al. J Hepatol. 2005 Jul 12
BACKGROUND/AIMS: T-lymphocyte reactivity against viral antigens may represent the only immunological marker of host contact with a virus. Aim of the present study was to investigate whether vertical exposure to hepatitis C virus (HCV) could activate HCV-specific T-cell responses that may represent a biomarker of previous contact with the virus, and possibly contribute to the low rate of vertical HCV transmission. METHODS: We studied 28 children born from chronically HCV-infected mothers. HCV-specific activation and proliferation of CD4+-lymphocytes and cytokine production were evaluated in cultures of peripheral blood mononuclear cells (PBMCs) stimulated in vitro with HCV-peptides. RESULTS: HCV-specific CD4+-cell reactivity was observed in 20 out of the 28 children (71%). The proliferation of HCV-specific CD4+-cells was more frequent and vigorous in children than in their mothers. In children, but not in the mothers, activation of CD4+-cells upon stimulation with HCV-peptides was directly correlated with proliferation. Early upon stimulation with HCV-peptides, lymphocytes from children produced lower levels of IL-10 than lymphocytes from the mothers. CONCLUSIONS: Vertical exposure to HCV induces the development of viral-specific CD4+-cell-mediated immune responses, possibly endowed with protective function against infection, which may contribute to the low rate of vertical HCV transmission.
thrombocytopenic purpura in patients with hepatitis C virus infection. Nakajima H, et al.
Hepatogastroenterology. 2005 Jul-Aug;52(64):1197-200.
BACKGROUND/AIMS: Immune thrombocytopenic purpura could occur as an extrahepatic manifestation of hepatitis C virus infection. The aim of this study was to clinically analyze hepatitis C virus-positive cases with immune thrombocytopenic purpura and to examine the relationship between hepatitis C virus and immune thrombocytopenic purpura. METHODOLOGY: Eight hepatitis C virus-positive patients with immune thrombocytopenic purpura were compared with 67 cases with chronic hepatitis C without immune thrombocytopenic purpura. We examined various clinical and hematological parameters including platelet and platelet-associated immunoglobulin G. RESULTS: Two men and 6 women with hepatitis C virus infection (age 58.0 +/- 11.8) were diagnosed with immune thrombocytopenic purpura. Platelet counts (x10(4)/mm3) were significantly lower in these 8 patients (2.9 +/- 2.1) than in chronic hepatitis C patients without immune thrombocytopenic purpura (16.7 +/- 0.3) (P<0.001). Hepatitis C virus infection predated immune thrombocytopenic purpura in 6 patients and none of the patients with immune thrombocytopenic purpura was infected with hepatitis C virus after the diagnosis. Three of the 6 patients with chronic hepatitis C, which predated immune thrombocytopenic purpura, were treated with interferon and 2 developed immune thrombocytopenic purpura after the treatment. None of them eradicated hepatitis C virus by interferon. CONCLUSIONS: The fact that hepatitis C virus infection predated immune thrombocytopenic purpura in 6 of 8 patients suggests that hepatitis C virus could potentially induce immune thrombocytopenic purpura and interferon itself might induce immune thrombocytopenic purpura.
of interferon, ribavirin and ursodeoxycholic acid in patients with hepatitis C
Ljubuncic P, et al. Hepatogastroenterology. 2005 Jul-Aug;52(64):1191-6.
BACKGROUND/AIMS: Combination therapy of interferon-alpha (IFNalpha) and the oral nucleoside analog, ribavirin is the standard treatment for individuals suffering from hepatitis C virus (HCV) infection. Several studies have shown combination therapy of IFN and antioxidants is therapeutically beneficial in these patients. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid possessing antioxidant properties. This study evaluated the clinical outcome and extent of oxidative stress in a group of non-responding and disease-relapsed HCV patients treated with IFNalpha, ribavirin and UDCA (triple therapy) for 6 months. METHODOLOGY: Twenty patients with chronic HCV disease were treated with triple therapy for six months. During this period, they were monitored for the presence of HCV RNA, standard serum parameters of liver function and the plasma levels of lipid peroxides (LP) and glutathione (GSH) as indices of oxidative stress. The patients were reassessed six months after completion of treatment. RESULTS: During the 6-month treatment period, the health status of the patients improved reflected by falls in the serum activities of alanine and aspartate aminotransferases and gamma-glutamyl transpeptidase and an initial lowering of viral (HCV RNA) load. Six months after cessation of treatment, the patients showed biochemical and virological evidence of disease relapse. The elevated plasma LP levels normalized during the treatment period and remained within normal levels 6 months after completion of treatment. Plasma GSH levels fluctuated within the normal range over the 12-month observation period. CONCLUSIONS: Treatment of individuals with chronic HCV hepatitis with triple therapy comprising IFNalpha, ribavirin and UDCA improves the health status, as well as lowering the extent of oxidative stress in these individuals. This treatment regimen also resulted in a sustained lowering of plasma lipid peroxide levels in the face of laboratory evidence of disease relapse. This preliminary study is unable to provide an apt explanation for the persistence of normal plasma LP levels in the face of evidence of disease relapse 6 months after completion of treatment. However, we believe these preliminary findings are sufficiently intriguing to warrant further study. Such investigations should include more patients with assessment of the extent of hepatic fibrosis during and after completion of treatment to determine whether this treatment can modify the natural progress of the disease.
protein expression in chronic hepatitis C; effect of interferon alpha 2b
therapy. Panasiuk A, Prokopowicz D, Dzieciol J. Hepatogastroenterology. 2005
Genep53 plays an important role in apoptosis or regeneration of damaged tissues. HCV activates gene p53 directly and/or indirectly. In chronic hepatitis, hepatocyte regeneration is regulated by gene p53 and growth factors. The aim of the study was the evaluation of protein p53 expression on hepatocytes in chronic hepatitis C regarding inflammatory activity and fibrosis as well as the influence of interferon alpha 2b (IFNalpha2b) on gene p53 activity. METHODOLOGY: In 24 patients with chronic hepatitis C treated with IFNalpha2b (18MU sc/week/48 weeks), in whom liver biopsies were performed before and after IFNalpha2b treatment. The immunohistochemical method determined protein p53 in formalin-fixed, paraffin-embedded liver tissue sections. The percentage of p53-positive hepatocytes and intensity of protein p53 accumulation were evaluated under a light microscope. RESULTS: IFN treatment caused the increase in the percentage of p53-positive hepatocytes and the intensity of protein p53 accumulation. The highest level of protein p53 expression was observed in IFNalpha2b-treated tissues with the decrease in inflammatory activity and fibrosis. HCV infection elimination did not affect protein p53 expression. We observed the decrease in p53-positive hepatocytes in tissues without improvement of morphological regeneration during IFNalpha2b therapy. CONCLUSIONS: The increase in protein p53 expression can be considered a prognostic marker of the positive effect of IFNalpha2b treatment and HCV elimination. It may result from the effect of the increase in regeneration or apoptosis of HCV infected hepatocytes.
of interferon on incidence of hepatocellular carcinoma in patients with chronic
Soga K, Shibasaki K, Aoyagi Y. Hepatogastroenterology. 2005 Jul-Aug;52(64):1154-8
BACKGROUND/AIMS: The aim of this study was to evaluate whether IFN prevents the development of HCC in patients with chronic hepatitis C. METHODOLOGY: 103 patients with chronic hepatitis C received IFN and 30 control patients were enrolled in this study. RESULTS: In 33 patients (32.0%) who received IFN, alanine aminotransferase (ALT) decreased to normal range and HCV RNA became negative (complete response: CR). In 7 patients (6.7%), ALT decreased to less than 50 IU/L or stayed within the normal range, but HCV RNA remained positive (biochemical response: BR). In 63 patients (61.1%) and 30 control patients, ALT did not change and HCV RNA remained positive (no response: NR). HCC developed in 5 (4.9%) of the 103 patients who received IFN and 7 (23.3%) of the control patients (p<0.01). In 5 patients who developed HCC, the response to IFN was NR and no HCC developed in patients with CR or BR. In addition, 5-year cumulative rate of development of HCC in 63 IFN NR patients and in control was 7.9% and 23.3% (p<0.05). CONCLUSIONS: IFN decreased the development of HCC in not only patients with CR or BR but also patients with NR.
combination of genetic polymorphisms increases the risk of progressive disease
in chronic hepatitis C. Richardson MM, et al. J Med Genet. 2005
BACKGROUND: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression. METHODS: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis. RESULTS: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of > or =3, > or =4, or > or =5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort. CONCLUSIONS: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management.
of interferon-alpha/beta receptor protein in liver of patients with hepatitis C
virus-related chronic liver disease. Meng XW, et al. World J Gastroenterol. 2005
AIM: To study the expression of interferon-alpha/beta (IFN-alpha/beta) receptor protein in liver of patients with hepatitis C virus (HCV)-related chronic liver disease and its clinical significance. METHODS: A total of 181 patients with HCV-related chronic liver disease included 56 with HCV-related liver cirrhosis (LC) and 125 with chronic hepatitis C (CHC). CHC patients were treated with five megaunits of interferon-alpha 1b six times weekly for the first 2 weeks and then every other day for 22 wk. The patients were divided into interferon (IFN) treatment-responsive and non-responsive groups, but 36 patients lost follow-up shortly after receiving the treatment. The expression of IFN-alpha/beta receptor (IFN-alpha/betaR) protein in liver of all patients was determined with immunofluorescence. RESULTS: In liver of patients with HCV-related chronic liver disease, the expression of IFN-alpha/betaR protein in liver cell membrane was stronger than that in cytoplasm and more obvious in the surroundings of portal vein than in the surroundings of central vein. Moreover, it was poorly distributed in hepatic lobules. The weak positive, positive and strong positive expression of IFN-alpha/betaR were 40% (50/125), 28% (35/125), 32% (40/125), respectively in CHC group, and 91.1% (51/56), 5.35% (3/56), and 3.56% (2/56), respectively in LC group. The positive and strong positive rates were higher in CHC group than in LC group (P<0.01). In IFN treatment responsive group, 27.8% (10/36) showed weak positive expression; 72.2% (26/36) showed positive or strong positive expression. In the non-responsive group, 71.7% (38/53) showed weak positive expression; 28.3% (15/53) showed positive or strong positive expression. The expression of IFN-alpha/betaR protein in liver was more obvious in IFN treatment responsive group than in non-responsive group. CONCLUSION: Expression of IFN-alpha/betaR protein in liver of patients with HCV-related chronic liver disease is likely involved in the response to IFN treatment.
history of major complications in hepatitis C virus-related cirrhosis evaluated
by per-rectal portal scintigraphy. Kawamura E, et al. World J Gastroenterol. 2005
AIM: To examine the correlation between the porto-systemic hypertension evaluated by portal shunt index (PSI) and life-threatening complications, including hepatocellular carcinoma (HCC), liver failure (Child-Pugh stage progression), and esophagogastric varices. METHODS: Two hundred and twelve consecutive subjects with HCV-related cirrhosis (LC-C) underwent per-rectal portal scintigraphy. They were allocated into three groups according to their PSI: group I, PSI<=10%; group II, 10%<PSI<30%; and group III, 30%<=PSI. Of these, selected 122 Child-Pugh stage A (Child A) subjects were included in analysis (a mean follow-up period of 5.9+/-5.4 years, range 6 mo-21 years). RESULTS: No significant correlation between PSI and cumulative probability of HCC incidence was observed. Cumulative probability of Child A to B progression was tended to be higher in group III than in group I, and significantly higher in group III than in group II (62% vs 34%, 62% vs 37%; P = 0.060, <0.01; respectively). Cumulative probability of varices tended to be higher in group III than in group I (31% vs 12%, P = 0.090). On multivariate analyses, significant correlation between PSI and Child A to B progression was observed, and no significant correlation between PSI and HCC incidence or varices progression was observed. CONCLUSION: Patients with LC-C of Child A will progress to Child B rapidly after their PSI reaches 30% or higher. PSI can be used to predict occult progressive porto-systemic shunting and liver failure non-invasively. It indicates that PSI may play an important role in follow-up of the porto-systemic hypertension gradient for outpatients with LC unlike hepatic venous catheterization.
and efficacy of peginterferon plus ribavirin in patients with chronic hepatitis
C and bridging fibrosis or cirrhosis. Marrache F, et al. J Viral Hepat. 2005
The combination of pegylated interferon and ribavirin is the most effective therapy in patients with chronic hepatitis C. We evaluated this combination in unselected patients with bridging fibrosis or cirrhosis. Eighty patients were treated with peginterferon alpha-2b plus ribavirin. Hepatitis C virus serum RNA was monitored. Tolerance and safety were evaluated by the rate of treatment's discontinuation for any reason, and occurrence of serious clinical adverse events, respectively. Sustained virologic response (SVR) rate was 36.3% overall, and was observed in every group of patients except those who had previously failed to respond to the combination of interferon and ribavirin. No serious clinical adverse event occurred. Treatment was withdrawn in 18.7% of patients. Variables associated with discontinuation of treatment were low prothrombin index [OR: 1.16 (1.05;1.27)] and low body mass index [OR: 1.47 (1.12;1.92)]. Initial blood count abnormalities were not associated with cessation of treatment. Furthermore, early virologic response at week 8 and week 12 of treatment had similar predictive value for SVR. Combination therapy with peginterferon plus ribavirin seems effective in this group of patients, except in those who had previously failed to respond to the combination of interferon and ribavirin. This therapy is safe with appropriate monitoring, but tolerance seems worse in patients with the most advanced liver disease.
of nitric oxide (NO) in interferon-alpha therapy for hepatitis C. Hokari A, et al. J Infect. 2005
BACKGROUND AND AIM: The role of nitric oxide in infectious disease is gaining increased attention because antiviral effects of nitric oxide. In addition, there is evidence that nitric oxide synthase-2 expression was noted in chronic hepatitis C found within mononuclear cells. METHODS: We studied serum levels of nitrite and nitrate before and during interferon alpha therapy in 66 patients with chronic hepatitis C. RESULTS: There was no significant difference of their levels between the healthy control subjects and the patients before the treatment with interferon (55.9+/-21.8 microM vs. 60.9+/-30.0 microM). Their levels were determined at 2 weeks after the initiation of treatment with interferon and compared with those before the treatment in the patients with chronic hepatitis C. In the total patients treated, there was no significant difference between their levels before and at 2 weeks after the treatment (60.9+/-30.0 microM vs. 65.5+/-30.0 microM, P=0.14). However, when the levels were compared between sustained responders, in whom hepatitis C virus was eradicated, and non-responders, in whom the virus was not eradicated, the former had significantly higher levels of nitrite and nitrate than the latter at 2 weeks after the initiation of treatment (83.7+/-40.9 microM vs. 57.6+/-19.5 microM, P<0.01). The multivariate logistic regression analysis showed that the rise of nitrite and nitrate was an independent predictive factor for efficacy of interferon treatment. CONCLUSIONS: Nitric oxide may be an important factor for antiviral therapy by interferon treatment for chronic hepatitis C, which suggests an additional therapeutic pathway for further study.
function changes during interferon and ribavirin treatment in patients with
chronic hepatitis C. Huang FC, Shih MH, Tseng SH, Lin SC, Chang TT. Cornea. 2005 Jul;24(5):561-6.
PURPOSE: To evaluate symptoms and changes in tear function and the ocular surface with interferon and ribavirin therapy for chronic hepatitis C. METHODS: Nineteen patients with chronic hepatitis C undergoing a course of interferon alfa-2b/ribavirin therapy and 19 age- and sex-matched controls participated in this prospective study. Patients were evaluated for dry eye subjectively (15-symptom assessment questionnaire) and objectively, including ophthalmologic examination, Schirmer test, tear clearance rate (TCR), tear function index (TFI), and nucleus/cytoplasm (N/C) ratio of conjunctival epithelial cell by impression cytology. All tests were performed before antiviral therapy (baseline); at 1, 3, and 6 months after initiation of therapy; and at 3 and 6 months after completing the 6-month course of treatment. All the tear functional tests and impression cytology results in controls were compared with pretreatment baseline of study group, using the Student t test. A paired t test was used to compare mean patient follow-up values with mean patient baseline values. RESULTS: Patients' mean score on the dry eye symptom assessment questionnaire was significantly (P < 0.05) higher than baseline after 1 and 3 months of therapy, peaked after 6 months of therapy, remained significantly elevated at 3 months after completion of therapy, but had decreased to almost baseline by 6 months after cessation of therapy. Compared with baseline, mean Schirmer test values showed a significant change only at 1 month after the start of treatment. In contrast, mean TCR, mean TFI, and mean N/C ratio were significantly different from baseline at every examination, including 6 months after discontinuation of therapy. After 6 months of therapy, 4 patients (21%) had advanced squamous metaplasia (stage 3 or 4), but 2 patients still had mild squamous metaplasia (stage 2) even 6 months after the completion of therapy. CONCLUSIONS: Impairment of tear dynamics and squamous metaplastic changes in the ocular surface occurred in patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin. Symptoms of dry eye were mild and reversible; however, abnormalities in tear dynamics and the ocular surface persisted even 6 months after discontinuation of treatment.
relationship between hepatitis C virus core and the development of type 2
diabetes mellitus in a hepatitis C virus hyperendemic area: a pilot study. Kawaguchi T, et al. Int J Mol Med. 2005 Jul;16
Hepatitis C virus (HCV) infection may contribute to the development of type 2 diabetes mellitus. However, this association at the population level remains unclear. The aim of this pilot study is to examine the relationship between HCV infection and the development of type 2 diabetes mellitus in an HCV hyperendemic area where we conducted health screenings in 1995. After 7 years of follow-up, we evaluated the relative risk of the development of type 2 diabetes mellitus in anti-HCV-inhabitants. Among 71 subjects free of diabetes mellitus in 1995, 7 developed type 2 diabetes mellitus during the 7-year follow-up evaluation. Overall, anti-HCV-positive subjects were nearly 3-fold as likely as anti-HCV-negative subjects to develop diabetes mellitus, but this difference was not statistically significant (p=0.08). After stratification of the anti-HCV-positive group according to serum HCV core titer, a significant increase in the incidence of diabetes was seen in subjects with high titer of HCV core compared to anti-HCV-negative subjects (p=0.02; relative hazard, 5.60; 95% confidence interval, 1.41 to 37.42). In conclusion, HCV infection potentially has a significant role in the development of type 2 diabetes mellitus at the population level. Further large-scale studies are needed to confirm these preliminary findings.
of treatment outcome in chronic hepatitis C patients based on early viral
dynamics during high-dose induction interferon and ribavirin therapy. Kim TH, et al. Intervirology. 2005 Jul-Aug; 48(4):230-8.
OBJECTIVE: In chronic hepatitis C, early viral load decline after interferon administration is dose dependent and reflects the intrinsic viral susceptibility to the antiviral action of interferon. We examined whether the augmented suppression of susceptible viral loads by high-dose induction interferon could possibly discriminate responsive patients from non-responsive patients at an early stage of treatment. METHODS: Fifty-nine chronic hepatitis C patients were randomly allocated to receive one of two treatment regimens; 3 MU interferon three times weekly plus ribavirin 1,000 mg/day for 24 weeks in the CR group (n = 30), and the same regimen as in the CR group except 10 MU interferon daily for the first week in the HR group (n = 29). Changes in viral loads during the first week of treatment were analyzed in terms of sustained virological response (SVR). RESULTS: The positive predictive values of undetectable (<100 IU/ml) or low serum HCV RNA (<2,000 IU/ml) after 1 week of treatment for SVR were 100% in both treatment groups, whereas the negative predictive values of the low viral titer were 91% in the HR group and 70% in the CR group. CONCLUSION: One-week virological response to high-dose induction interferon/ribavirin combination therapy is more predictive of SVR than conventional combination therapy in chronic hepatitis C. Copyright (c) 2005 S. Karger AG, Basel.
study of interferon gamma for chronic hepatitis C. Soza A, et al. J Hepatol. 2005 Jul; 43(1):67-71.
Epub 2005 Apr 26.
BACKGROUND/AIMS: Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C. METHODS: Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400 microg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels. RESULTS: Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (-41% from baseline) and hematocrit (-5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered. CONCLUSIONS: Although relatively well tolerated, interferon gamma in doses of 100-400 microg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies.
Prediction of treatment outcome in chronic hepatitis C patients based on early viral dynamics during high-dose induction interferon and ribavirin therapy. Kim TH, et. al. Intervirology. 2005 Jul-Aug; 48(4):230-8.
OBJECTIVE: In chronic hepatitis C, early viral load decline after interferon administration is dose dependent and reflects the intrinsic viral susceptibility to the antiviral action of interferon. We examined whether the augmented suppression of susceptible viral loads by high-dose induction interferon could possibly discriminate responsive patients from non-responsive patients at an early stage of treatment. METHODS: Fifty-nine chronic hepatitis C patients were randomly allocated to receive one of two treatment regimens; 3 MU interferon three times weekly plus ribavirin 1,000 mg/day for 24 weeks in the CR group (n = 30), and the same regimen as in the CR group except 10 MU interferon daily for the first week in the HR group (n = 29). Changes in viral loads during the first week of treatment were analyzed in terms of sustained virological response (SVR). RESULTS: The positive predictive values of undetectable (<100 IU/ml) or low serum HCV RNA (<2,000 IU/ml) after 1 week of treatment for SVR were 100% in both treatment groups, whereas the negative predictive values of the low viral titer were 91% in the HR group and 70% in the CR group. CONCLUSION: One-week virological response to high-dose induction interferon/ribavirin combination therapy is more predictive of SVR than conventional combination therapy in chronic hepatitis C.
Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus. Halfon P, et al. Comp Hepatol. 2005 Jul 11;4(1):6 [Epub ahead of print]
BACKGROUND: In patients with chronic hepatitis C virus, liver biopsy is the gold standard for assessing liver disease stage; nevertheless, it is prone to complications, some of them serious. Non-invasive methods have been proposed as surrogate markers for liver fibrosis. It was shown that serum hyaluronic acid (HA) level increases with the development for liver fibrosis. The aim of this study was to evaluate the diagnostic value of HA as well as to determine the HA level cut-off for predicting the presence or absence of fibrosis, severe fibrosis, and cirrhosis. RESULTS: 405 patients with chronic hepatitis C were prospectively included with biomarker measurement and liver biopsy done the same day: 151 in the training set (only biopsy lengths of 25 mm or more) and 254 in the validation set. For the discrimination of significant fibrosis, severe fibrosis, and cirrhosis in the training set, the areas under curve (AUCs) were 0.75+/-0.03, 0.82+/-0.02, and 0.89+/-0.03, respectively. Absence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 16, 25, and 50 ug/l, respectively (with negative predictive values of 82%, 89%, and 100%, in the same order). Presence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 121, 160, and 237 ug/l, respectively (with positive predictive values of 94%, 100%, and 57%, in the same order). CONCLUSION: In the validation set, HA was accurate in predicting significant fibrosis, severe fibrosis, and cirrhosis with AUCs of 0.73, 0.77, and 0.97, respectively. Moreover, accurate HA level cut-offs were defined for predicting significant fibrosis, severe fibrosis, and cirrhosis. Thus, the study supports that HA level may be clinically useful as a non-invasive marker for liver fibrosis and/or cirrhosis.
cannabis smoking as a risk factor for progression of fibrosis in chronic
Hezode C, et al. Hepatology. 2005 Jul;42(1):63-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15892090&query_hl=2
Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): daily cannabis use (OR = 3.4 [1.5-7.4]), Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]), age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]), genotype 3 (OR = 3.4 [1.5-7.7]), excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0 [1.0-4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5-7.5]). Finally, severe fibrosis (> or =F3) was also predicted by daily cannabis use (OR = 2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use.
Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Watashi K, et al.
Mol Cell. 2005
Viruses depend on host-derived factors for their efficient genome replication. Here, we demonstrate that a cellular peptidyl-prolyl cis-trans isomerase (PPIase), cyclophilin B (CyPB), is critical for the efficient replication of the hepatitis C virus (HCV) genome. CyPB interacted with the HCV RNA polymerase NS5B to directly stimulate its RNA binding activity. Both the RNA interference (RNAi)-mediated reduction of endogenous CyPB expression and the induced loss of NS5B binding to CyPB decreased the levels of HCV replication. Thus, CyPB functions as a stimulatory regulator of NS5B in HCV replication machinery. This regulation mechanism for viral replication identifies CyPB as a target for antiviral therapeutic strategies.
Helper T cell cytokine response to ribavirin priming before combined treatment with interferon alpha and ribavirin for patients with chronic hepatitis C. Furusyo N, et al. Antiviral Res. 2005 Jul;67(1):46-54.
The viral genotype and serum viral level influence the response to interferon (IFN) treatment in patients with chronic hepatitis C virus (HCV) viremia. The aim of this study was to investigate a possible relationship between early virological response and helper T (Th) cell cytokine expansion by 4 weeks of ribavirin (RIB) alone followed by IFN and RIB combined in patients with genotype 1b and a high HCV RNA level, patients reported not to respond well to IFN treatment. Eighty-one patients with genotype 1b and a high HCV RNA level, over 100 international unit per milliliter (KIU/mL) (by Amplicor HCV Monitor), were assigned to two groups: Group A (N = 40) with a 4-week RIB administration followed by a 24-week combination treatment, and Group B (N = 41) with a 24-week combination treatment only. Blood was obtained from each patient on the following schedule: at Baseline (4 weeks before day 0), on day 0 (initiation day of the RIB and IFN combination treatment), weeks 4 (4 weeks after the start of the combination treatment), and at the end of the combination treatment. Flow cytometry was used to investigate sequential changes of IFN-gamma producing (Th1) and interleukin-4 producing (Th2) cells from whole blood samples after stimulation with PMA and ionomycin. Serum HCV RNA clearances were 32.5% at week 4, 43.2% at week 8, 85.7% at the end of the combination treatment, and 22.9% within the 24-week follow-up in Group A; and 17.1%, 27.0%, 66.7% and 19.4% in Group B, respectively. The mean Th1/Th2 ratio significantly increased from 15.9 at baseline to 17.6 at day 0 with a decrease of Th2 cells, and then significantly decreased from 17.6 at day 0 to 15.5 at week 4 in Group A, while there was no significant change in Group B between baseline and day 0. In Group A, 13 patients with HCV RNA clearance within 4 weeks had a significantly increased Th1/Th2 ratio, from 14.0 at baseline to 22.1 at day 0, and then a significantly decreased ratio, from 22.1 at day 0 to 15.0 at week 4, while the others had no significant change in the ratio. RIB administration preceding combined treatment of RIB with IFN was more effective in Th2 cell expansion than the usual combined treatment of IFN with RIB and led to a relatively early virological clearance in chronic hepatitis C patients with genotype 1b and a high HCV RNA level.
C Virus Core Protein and Hepatitis Activity Are Associated through
Transactivation of Interleukin-8. Hoshida Y, et al. J Infect Dis. 2005 Jul
15;192(2):266-75. Epub 2005 Jun 13.
BACKGROUND: We evaluated the association between variations in hepatitis C virus (HCV) core protein and hepatitis severity in patients with chronic HCV infection who achieved remission without viral eradication and had a biochemical response to interferon (IFN) therapy, to evaluate the effect of HCV core sequence in the absence of the influence of host factors. METHODS: Using serum from 10 patients with a biochemical response and 10 patients with no response, we measured serum levels of interleukin (IL)-1 beta , IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN- gamma , and tumor necrosis factor- alpha before and after IFN therapy. Expression vectors with the core region were transfected into Huh7 cells, and cytokine induction was evaluated by reporter assay. RESULTS: In biochemical responders, only IL-8 levels decreased after IFN therapy (P=.04). Changes in the C-terminal hydrophobic region were observed more frequently in biochemical responders. Activation of the IL-8 promoter by HCV core protein was significantly decreased in biochemical responders after IFN therapy (P=.04). When 69 C-terminal amino acids from before IFN therapy were replaced with those from after IFN therapy in 3 biochemical responders, their ability to transactivate IL-8 decreased. CONCLUSIONS: Differences in amino acids in the HCV core protein correlates with hepatitis activity through the modulation of IL-8 induction in HCV-infected patients.
of hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase activity by
the NS3 protease domain and by HCV RNA-dependent RNA polymerase. Zhang C et al. J Virol. 2005 Jul; 79(14):8687-97
Hepatitis C virus (HCV) nonstructural protein 3 (NS3) possesses multiple enzyme activities. The N-terminal one-third of NS3 primarily functions as a serine protease, while the remaining two-thirds of NS3 serve as a helicase and nucleoside triphosphatase. Whether the multiple enzyme activities of NS3 are functionally interdependent and/or modulated by other viral NS proteins remains unclear. We performed biochemical studies to examine the functional interdependence of the NS3 protease and helicase domains and the modulation of NS3 helicase by NS5B, an RNA-dependent RNA polymerase (RdRp). We found that the NS3 protease domain of the full-length NS3 (NS3FL) enhances the NS3 helicase activity. Additionally, HCV RdRp stimulates the NS3FL helicase activity by more than sevenfold. However, the helicase activity of the NS3 helicase domain was unaffected by HCV RdRp. Glutathione S-transferase pull-down as well as fluorescence anisotropy results revealed that the NS3 protease domain is required for specific NS3 and NS5B interaction. These findings suggest that HCV RdRp regulates the functions of NS3 during HCV replication. In contrast, NS3FL does not increase NS5B RdRp activity in vitro, which is contrary to a previously published report that the HCV NS3 enhances NS5B RdRp activity.
of interleukin-10 receptor-a novel approach to stimulate T-helper cell type 1
responses to hepatitis C virus. Rigopoulou EI, Abbott WG, Haigh P, Naoumov NV. Clin Immunol. 2005 Jul 7
Chronic hepatitis C virus (HCV) infection is associated with weak CD4+ T-helper type 1 reactivity and enhanced interleukin-10 production to HCV antigens. Here we demonstrate in vitro that monoclonal antibody-induced blockade of IL-10 receptor (IL-10R) generates a favorable balance of CD4+ T-cell responses to HCV. The addition of anti-IL-10R to mononuclear cells leads to a dose-dependent increase of T-cell proliferative response to HCV core, non-structural proteins 3 and 4. In competition experiments, anti-IL-10R reversed the inhibitory effect of IL-10 on HCV-specific T-cell proliferation. Furthermore, the blockade of IL-10R altered the balance towards type 1 antiviral T-cell reactivity with an increased frequency of HCV-specific IFN-gamma producing T-cells and IFN-gamma secretion. The impact of IL-10R blockade on T-cell reactivity to HCV demonstrates the major role of IL-10 in suppressing antiviral T-cell responses. Blocking IL-10 activity may be a useful immunotherapy approach to enhance the efficacy of antiviral treatment in chronic hepatitis C.
C virus-replicating hepatocytes induce fibrogenic activation of hepatic
stellate cells. Schulze-Krebs A, et al. Gastroenterology. 2005
BACKGROUND & AIMS: The mechanism by which hepatitis C virus induces liver fibrosis remains largely obscure. To characterize the profibrogenic potential of hepatitis C virus, we used the hepatitis C virus replicon cell line Huh-7 5-15, which stably expresses the nonstructural hepatitis C virus genes NS3 through NS5B, and hepatic stellate cells as fibrogenic effector cells. METHODS: Rat and human hepatic stellate cells were incubated with conditioned media from replicon cells, and expression of fibrosis-related genes was quantified by using real-time polymerase chain reaction, protein, and functional assays. Transforming growth factor beta1 activity was determined by bioassay. RESULTS: Hepatitis C virus replicon cells release factors that differentially modulate hepatic stellate cell expression of key genes involved in liver fibrosis in a clearly profibrogenic way, up-regulating procollagen alpha1(I) and procollagen alpha1(III) and down-regulating fibrolytic matrix metalloproteinases. Transforming growth factor beta1 expression and bioactivity were increased severalfold in hepatitis C virus-replicating vs mock-transfected hepatoma cells. However, transforming growth factor beta1 activity was responsible for only 50% of the profibrogenic activity. CONCLUSIONS: Hepatitis C virus nonstructural genes induce an increased expression of transforming growth factor beta1 and other profibrogenic factors in infected hepatocytes. The direct induction of profibrogenic mediators by hepatitis C virus in infected hepatocytes explains the frequent observation of progressive liver fibrosis despite a low level of inflammation and suggests novel targets for antifibrotic therapies in chronic hepatitis C.
C825T polymorphism and response to interferon-alfa/ribavirin treatment in
patients with hepatitis C virus genotype 1 (HCV-1) infection. Sarrazin C, et al. J Hepatol. 2005 Jul
BACKGROUND/AIMS: The outcome of infection with the hepatitis C virus (HCV) has been shown to be influenced by genetic host factors. The G protein beta3 subunit (GNB3) C825T polymorphism has been shown to determine immune cell functions in vitro. We investigated the association of GNB3 genotypes with treatment response in HCV-infected patients. METHODS: We genotyped 1781 HCV-free blood donors and 232 HCV-infected patients treated with interferon-alfa/ribavirin. Sustained virologic response (SVR) was defined by undetectable HCV RNA 24 weeks after discontinuation of therapy. Non-response (NR) was defined by positive HCV RNA at the end of at least 24 weeks of treatment. GNB3 genotypes were determined by DNA restriction enzyme analyses. RESULTS: Genotype distribution was not significantly different in healthy controls and HCV-infected patients. Only in HCV genotype 1-infected patients a significant correlation between GNB3 CC genotype and NR could be observed (6 TT, 42 TC, 54 CC) versus SVR (11 TT, 25 TC, 19 CC) patients (P=0.004). In a logistic regression analysis including biochemical and virologic characteristics, only GNB3 CC genotype was significantly associated with NR (OR 4.9; 95% CI=1.4-16.5; P=0.011). CONCLUSIONS: The GNB3 825 CC genotype is associated with NR in HCV-1-infected patients.
of 8-nitroguanine in the liver of patients with chronic hepatitis C. Horiike S, et al. J Hepatol. 2005 Jul 12
BACKGROUND/AIMS: Nucleic acid damage by reactive nitrogen and oxygen species may contribute to inflammation-related carcinogenesis. To investigate the extent of nucleic acid damage in hepatitis C virus infection and its change after interferon treatment, we measured 8-nitroguanine and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the liver of patients with chronic hepatitis C (CHC) before and after interferon therapy. METHODS: Hepatic accumulation of 8-nitroguanine and 8-OHdG was immunohistochemically evaluated in 20 CHC patients and 7 control patients with non-alcoholic fatty liver. RESULTS: Immunoreactivities of 8-nitroguanine and 8-OHdG were strongly detected in the liver from patients with CHC, but not in control livers. 8-Nitroguanine accumulation was found not only in infiltrating inflammatory cells, but also hepatocytes particularly in the periportal area. The accumulation of 8-nitroguanine and 8-OHdG increased with inflammatory grade (8-nitroguanine; P=0.0019, 8-OHdG; P=0.0009). In the sustained virological responder group after interferon therapy, 8-nitroguanine and 8-OHdG accumulation were markedly decreased in the liver (8-nitroguanine; P=0.018, 8-OHdG; P=0.018). CONCLUSIONS: In this study, we demonstrated for the first time that 8-nitroguanine accumulated in the liver of patients with CHC. 8-Nitroguanine is a useful biomarker to evaluate the severity of HCV-induced chronic inflammation in relation to hepatocellular carcinoma.
production of five hepatitis C virus-derived antigens in three Saccharomyces
cerevisiae host strains. Parolin C, et al. J Biotechnol. 2005
In this study, the production of recombinant Hepatitis C virus (HCV) derived proteins from transformed Saccharomyces cerevisiae yeast cells is reported. Three different yeast strains (GRF18U, BY4743-4A and CENPK 113-5D) have been transformed for the intracellular expression of five antigens of different dimensions (from 32.8 to 85.2kDa), all derived from the non-structural (NS) region of different HCV viruses' genotypes and posed under the control of a glycolytic promoter. The putative trans-membrane domains contained in four antigens seem responsible of their accumulation as protein aggregates. Good productions of the smaller and of the bigger antigens (50 and 30mgl(-1), respectively) have been observed in simple flask batch cultures. Productions are strongly dependent from the genetic background of the yeast host and from the cellular localization of the antigen, while they appear independent from the growth rate of the transformed hosts. For every recombinant antigen tested, the highest production levels were achieved with the CENPK 113-5D-host strain, while the GRF18U strain shows symptoms of a heavily stressed phenotype.
interacts with filovirus glycoproteins and the spike protein of SARS
coronavirus. Gramberg T, et al. Virology. 2005 Jul 25
Cellular attachment factors like the C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) can augment viral infection and might promote viral dissemination in and between hosts. The lectin LSECtin is encoded in the same chromosomal locus as DC-SIGN/R and is coexpressed with DC-SIGNR on sinusoidal endothelial cells in liver and lymphnodes. Here, we show that LSECtin enhances infection driven by filovirus glycoproteins (GP) and the S protein of SARS coronavirus, but does not interact with human immunodeficiency virus type-1 and hepatitis C virus envelope proteins. Ligand binding to LSECtin was inhibited by EGTA but not by mannan, suggesting that LSECtin unlike DC-SIGN/R does not recognize high-mannose glycans on viral GPs. Finally, we demonstrate that LSECtin is N-linked glycosylated and that glycosylation is required for cell surface expression. In summary, we identified LSECtin as an attachment factor that in conjunction with DC-SIGNR might concentrate viral pathogens in liver and lymph nodes.
Interferon-alpha/beta upregulate IL-15 expression in vitro and in vivo: analysis in human hepatocellular carcinoma cell lines and in chronic hepatitis C patients during interferon-alpha/beta treatment. Yamaji K, et al. Cancer Immunol Immunother. 2005 Jul 22;1-10
Type I interferon (IFN) possesses antiviral and antitumor activities and also having an immune regulatory effect, activating cellular immune response and upregulating several cytokines. Recent study has shown that type I IFN upregurates the dendritic cell production of IL-15 capable of activating natural killer cells and CD8(+) memory T lymphocytes. However, it is still unknown if type I IFN induces IL-15 production in non-immune cells and if type I IFN affects IL-15 production in vivo. The present study investigated the effect of type I IFNs on IL-15 expression in hepatocellular carcinoma (HCC) cell lines in vitro and in patients with chronic hepatitis C in vivo. When three HCC cell lines, Huh7, HepG2, and JHH4 were cultured in vitro, IFN upregulation of IL-15 expression was observed at both the mRNA and protein levels. In experiments using Huh7 cells, upregulation of IL-15 expression occurred within 24 h of the start of IFN stimulation, and both IFN-alpha and -beta dose-dependently increased IL-15 production in the range from 100 U/ml to 10,000 U/ml of concentration. IFN-beta showed stronger activity in IL-15 production induction in vitro than IFN-alpha. For in vivo examination, sera were obtained from 21 chronic hepatitis C patients treated with IFN and 29 healthy individuals, and the serum IL-15 level was quantified by ELISA. The serum IL-15 level of chronic hepatitis C patients before IFN treatment was similar to that of the healthy controls and significantly increased only during the IFN administration period. These results confirm that IFN-alpha/beta induce IL-15 production and also suggest that IL-15 may be associated with type I IFN-induced immune response.
Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells. Machida K, et al J Virol. 2005 Jul; 79(13):8079-89.
Hepatitis C virus (HCV) is one of the leading causes of chronic liver diseases and B-lymphocyte proliferative disorders, including mixed cryoglobulinemia and B-cell lymphoma. It has been suggested that HCV infects human cells through the interaction of its envelope glycoprotein E2 with a tetraspanin molecule CD81, the putative viral receptor. Here, we show that the engagement of B cells by purified E2 induced double-strand DNA breaks specifically in the variable region of immunoglobulin (V(H)) gene locus, leading to hypermutation in the V(H) genes of B cells. Other gene loci were not affected. Preincubation with the anti-CD81 monoclonal antibody blocked this effect. E2-CD81 interaction on B cells triggered the enhanced expression of activation-induced cytidine deaminase (AID) and also stimulated the production of tumor necrosis factor alpha. Knockdown of AID by the specific small interfering RNA blocked the E2-induced double-strand DNA breaks and hypermutation of the V(H) gene. These findings suggest that HCV infection, through E2-CD81 interaction, may modulate host's innate or adaptive immune response by activation of AID and hypermutation of immunoglobulin gene in B cells, leading to HCV-associated B-cell lymphoproliferative diseases.
a transgenic mice model harboring structural genes of hepatitis C virus. Ren JY, Zhonghua Gan Zang Bing Za Zhi. 2005
OBJECTIVES: To establish an animal model of HCV transgenic mice to elucidate the pathogenesis of hepatitis C virus infection and function of the viral structural proteins. METHODS: Structural gene of HCV were amplified and recombined into eukaryotic expression vectors, pcDNA4HisMax and pMT/BiP/V5-His A, after their expressive activity was confirmed to detect the structural protein in the transfected COS7 and S2 cells by Western blot. The fertilized expression element, which contained CMV or pMT promoter, structural gene of HCV and polyadenylation signal sequence, was microinjected into 1736 C57BL/6 mouse fertilized ova. The ova were then replanted into the oviducts of 69 pseudopregnant recipient mice. RESULTS: Twenty-five recipient mice were impregnanted and later produced 105 newborns; 49 of them died from unknown causes and 57 survived. After the specific HCV structural genes were identified by PCR and Southern blot hybridization, 26 founders were obtained; among them 10 were stable expression mice and 16 were the inducible ones. The rate of founders developed from implanted embryos was only 1.50%. Through hybridization with normal mice, 58 hybrid mice have been obtained at present. CONCLUSION: Two kinds of different transgenic mice of HCV were developed; one is of stable expression, and the other is inducible. This transgenic mice model may create an opportunity for studying the function of the structural gene of HCV and elucidate its pathogenicity.
domain of hepatitis C virus core protein is essential for secretion. Choi SH, et al. World J Gastroenterol. 2005
Jul 7; 11(25):3887-92.
AIM: We have previously demonstrated that hepatitis C virus (HCV) core protein is efficiently released into the culture medium in insect cells. The objective of this study is to characterize the HCV core secretion in insect cells. METHODS: We constructed recombinant baculoviruses expressing various-length of mutant core proteins, expressed these proteins in insect cells, and examined core protein secretion in insect cells. RESULTS: Only wild type core was efficiently released into the culture medium, although the protein expression level of wild type core was lower than those of other mutant core proteins. We found that the shorter form of the core construct expressed the higher level of protein. However, if more than 18 amino acids of the core were truncated at the C-terminus, core proteins were no longer secreted into the culture medium. Membrane flotation data show that the secreted core proteins are associated with the cellular membrane protein, indicating that HCV core is secreted as a membrane complex. CONCLUSION: The C-terminal 18 amino acids of HCV core were crucial for core secretion into the culture media. Since HCV replication occurs on lipid raft membrane structure, these results suggest that HCV may utilize a unique core release mechanism to escape immune surveillance, thereby potentially representing the feature of HCV morphogenesis.
analysis of CD8 T-cell responses to HIV and hepatitis C virus in a cohort of
co-infected haemophiliacs. Harcourt GC, et al. AIDS. 2005 Jul
OBJECTIVE: To investigate CD8 T-cell responses to HIV and hepatitis C virus (HCV) over time in a group of co-infected children with haemophilia to assess the influence of the virus infections on each other and on clinical outcome. DESIGN: The HIV and HCV CD8 T-cell response of HLA-A2 co-infected individuals in the cohort were analysed at two time points, looking at the frequency and phenotype of HIV-specific T cells and assessing overall responses to the two viruses. METHODS: Peripheral blood mononuclear cells (PBMC) from 72 HLA-A2 co-infected individuals were analysed using an HIV HLA-A2 tetramer and by IFN-gamma ELISpot using a panel of HIV and HCV antigens. PBMC from a group of 26 HLA-A2 HIV mono-infected adults were also analysed as a comparison. RESULTS:: We identified two distinct patterns of response: some patients had a limited response to either virus whilst others made responses to a range of HIV epitopes. HCV responses were detected only in those who made multiple responses to HIV epitopes (P<0.0001). HCV infection had an influence on the phenotype of HIV-specific CD8 T cells, with a reduction in relative perforin and CD57 expression. Lack of functional or tetramer-positive HIV-specific T cells was associated with a decline in absolute CD4 T-cell counts between the time points (up to 7 years; P = 0.005). CONCLUSION: HCV infection has an impact on the phenotype of HIV-specific CD8 T cells. In this well-defined cohort, failure to maintain effective CD8 T-cell responses against HIV may contribute to disease progression.
enzymes elevation after HAART in HIV-HCV co-infection. Servin-Abad L, et al. J Viral Hepat. 2005
Hepatitis C virus (HCV) co-infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well-understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations. Between January 1996 and March 2002, 85 HIV-HCV co-infected patients began HAART and continued follow up for at least 1 year. The incidence of severe toxicity [grades 3 + 4 LEE: >5 and >10 times the upper limit of normal (ULN) of ALT or AST] was calculated at 4% per person-years. There were no clinical manifestations of liver toxicity, and patients continued their treatment with a trend towards a decrease of their enzymes. No statistical differences in opportunistic infections or mortality were evident. The variables associated with severe hepatotoxicity were a higher baseline AST, higher international normalized ratio (INR) and lower albumin. A baseline AST < 2.1 ULN had a negative predictive value of 92% of leading to severe hepatotoxicity. In HIV-HCV co-infected patients therefore, the group at a higher risk of developing higher transaminase elevations is the one with a higher baseline AST, higher INR and lower albumin.
of IL-2 on hepatitis C virus RNA levels in patients co-infected with human
immunodeficiency virus receiving HAART. Tedaldi EM, et al. J Viral Hepat. 2005
The effect of interleukin-2 (IL-2) on the plasma levels of hepatitis C RNA (HCV-RNA) has varied in published reports. We measured the impact of IL-2 on plasma HCV RNA levels in 54 human immunodeficiency virus (HIV)/HCV coinfected patients enrolled in a randomized trial of 512 participants designed to compare the virologic and immunologic effects of cycled IL-2 plus antiretroviral therapy (ART) vs ART alone in the treatment of HIV in patients with CD4 cell counts > or =300 cells/mm(3). The mean decreases in average HCV RNA levels (copies/mL, log (10)) were 0.28 log in the IL-2 group (n = 26) and 0.04 log in the ART alone group (n = 28) at 12 months (P = 0.18). The changes in HCV RNA level were not associated with baseline or nadir CD4 cell counts, baseline aspartate aminotransferanse, CD4 cell response to IL-2, or changes in plasma HIV RNA values. Compared with those participants who only had HIV, the HIV/HCV co-infected patients did not have a significantly different CD4 cell response to IL-2 therapy. Intermittent IL-2 therapy does not produce a significant sustained decrease in plasma HCV RNA levels among patients co-infected with HIV/HCV who are on highly active ART.
of Hepatitis C Virus (HCV) in Serum and Peripheral-Blood Mononuclear Cells from
HCV-Monoinfected and HIV/HCV-Coinfected Persons. Blackard JT, et al. J Infect Dis. 2005 Jul
15;192(2):258-65. Epub 2005 Jun 7.
It has been speculated that hepatitis C virus (HCV) replicates in peripheral-blood mononuclear cells (PBMCs), which, therefore, may be a site for interaction with human immunodeficiency virus (HIV). We used strand-specific real-time polymerase chain reaction to detect HCV RNA in 28 HCV-monoinfected and 20 HIV/HCV-coinfected women. At the first visit, positive-strand HCV RNA was detected in serum samples from 89% of the women, whereas positive-strand HCV RNA was detected in PBMC samples from 32% and 55% of the HCV-monoinfected and HIV/HCV-coinfected women, respectively. After initiation of antiretroviral therapy, the HIV/HCV-coinfected women were significantly more likely to have detectable positive- and negative-strand HCV RNA in the PBMC compartment than were the HCV-monoinfected women. HIV and HCV RNA levels were not correlated. Serum HCV RNA levels were correlated over time; HCV RNA levels in the serum and PBMC compartments were not. These data suggest differential regulation of HCV RNA in the serum and PBMC compartments and may partially explain the limited HCV antiviral response rates observed in coinfected persons.
Prediction of hepatic fibrosis in HIV/HCV co-infected patients using serum fibrosis markers: the SHASTA index. Kelleher TB, et al. J Hepatol. 2005 Jul;43(1):78-84. Epub 2005 Apr 25.
BACKGROUND/AIMS: To examine if serum fibrosis biomarkers could accurately identify the stage of liver disease amongst hepatitis C (HCV) and HIV co-infected patients. METHODS: One hundred and thirty seven HIV/HCV co-infected persons were randomly selected from the Johns Hopkins HIV Clinic cohort. Ninety five had complete testing for fibrosis markers in sera collected at the time of liver biopsy. Biopsies were scored according to Ishak modified histological activity index (F0 no fibrosis to F6 cirrhosis). Fibrosis was evaluated against alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST to platelet ratio (APRI), albumin, total bilirubin, hyaluronic acid (HA) and YKL-40. RESULTS: Sixty nine (73%) had no or minimal portal fibrosis (F0-2) and were compared with remaining subjects (F3-6). Fibrosis scores > or =F3 were found 27 times more often in persons with HA levels >86 ng/ml and 5.5 times more often in persons with HA levels 41-86 ng/ml. Less substantial associations were detected with levels of albumin <3.5 g/dl (OR 4.85) and AST >60 iu (OR 5.91). All 35 subjects who had favorable results of HA, albumin, and AST had minimal fibrosis (F0-2). CONCLUSIONS: Amongst HIV/HCV co-infected patients, serum testing for HA, albumin, and AST (SHASTA Index) was able to accurately stage mild and advanced fibrosis.
copper and zinc concentrations in patients with chronic hepatitis C. Cesur S, et al. J Infect. 2005 Jul;
The aim of this study was to measure the alterations in serum trace elements, including zinc and copper in patients with chronic hepatitis C and to compare them with the results of healthy individuals. Seventeen patients with chronic hepatitis C and 17 healthy individuals were included in this study. Serum zinc and cooper concentrations were measured by using atomic absorption spectrophotometer of patients with chronic hepatitis C and the results were statistically compared with those of healthy individuals. Serum zinc concentrations were 105.6+/-22.8 microg/dl in patients with chronic hepatitis C and 94.41+/-19 microg/dl in healthy controls, respectively. Serum copper concentrations were 103.17+/-20.8 microg/dl in patients with chronic hepatitis C and 90.8+/-14.3 microg/dl in healthy subjects, respectively. Serum zinc and copper concentrations were not found statistically different in patients with chronic hepatitis C compared with those of healthy individuals (p>0.05). In conclusion, serum trace element concentrations did not show statistical alterations in patients with chronic hepatitis C compared to healthy subjects.
medicine Ninjinyoeito ameliorates ribavirin-induced anemia in chronic hepatitis
C: A randomized controlled trial. Motoo Y, et al.World J Gastroenterol.2005 Jul
[Japan] AIM: Ribavirin (RBV) shows a strong antiviral effect on hepatitis C virus when used in combination with interferon. However, RBV-induced anemia is a major problem in this therapy. It would be of great clinical importance to ameliorate the anemia without reducing the RBV dose. We report here that, Ninjinyoeito (NYT), a herbal medicine can reduce the RBV-induced anemia. METHODS: Twenty-three patients with chronic hepatitis C were treated with interferon alpha 2b plus RBV with (NYT group) or without (control group) NYT by a randomized selection. Eighteen patients completed the treatment schedule, and hemato-biochemical and virological effects were evaluated. RESULTS: There was no significant difference in biochemical and virological responses between the two groups. However, anemia was significantly reduced in the NYT group compared with the control group. The maximal decrease of Hb in the NYT group (2.59+/-1.10 g/dL) was significantly (P = 0.026) smaller than that in the control group (3.71+/-0.97 g/dL). There was no significant difference in serum glutathione peroxidase activity, serum RBV concentration, and Th1/Th2 balance between the two groups. There was no specific adverse effect in NYT administration. CONCLUSION: These results suggest that NYT could be used as a supportive remedy to reduce the RBV-induced anemia in the treatment of chronic hepatitis C.
The effect of zinc supplementation on the treatment of chronic hepatitis C patients with interferon and ribavirin. Ko WS, et. al. Clin Biochem. 2005 Jul;38(7):614-20.
[Taiwan] OBJECTIVES: To evaluate the effects of zinc supplementation on serum zinc and copper levels, and the severity of adverse reactions and virologic responses in chronic hepatitis C patients undergoing interferon (IFN)/ribavirin therapy. DESIGN AND METHODS: Forty subjects were randomly assigned to receive IFN-alpha-2a/ribavirin with or without zinc gluconate for 24 weeks, then a period of 6 months for follow-up. Twenty healthy controls were also enrolled in the study. Blood samples were collected at different time points during therapy and at 6 months after the completion of therapy and were analyzed for zinc and copper levels. The adverse reactions and the virologic responses were also examined accordingly. RESULTS: Serum zinc levels were significantly lower in chronic hepatitis C patients than in healthy controls and further depressed by IFN/ribavirin treatment. However, serum zinc levels in patients were remediable by zinc supplements. No apparent difference was seen in virologic responses between subjects with or without zinc supplements, but certain adverse side effects associated with the zinc therapy were significantly decreased. CONCLUSIONS: Zinc supplementation may be a complementary therapy in chronic hepatitis C patients to increase the tolerance to IFN-alpha-2a and ribavirin.
Hepascore: An Accurate Validated Predictor of Liver Fibrosis in Chronic Hepatitis C Infection. Adams LA, et al. Clin Chem. 2005 Jul 28; [Epub ahead of print]
BACKGROUND: Staging hepatic fibrosis by liver biopsy guides prognosis and treatment of hepatitis C, but is invasive and expensive. We sought to create an algorithm of serum markers that accurately and reliably predict liver fibrosis stage among hepatitis C patients. METHODS: Ten biochemical markers were measured at time of liver biopsy in 117 untreated hepatitis C patients (training set). Multivariate logistic regression and ROC curve analyses were used to create a predictive model for significant fibrosis (METAVIR F2, F3, and F4), advanced fibrosis (F3 and F4) and cirrhosis (F4). The model was validated in 104 patients from other institutions. RESULTS: A model (Hepascore) of bilirubin, gamma-glutamyltransferase, hyaluronic acid, alpha2-macroglobulin, age, and sex produced areas under the ROC curves (AUCs) of 0.85, 0.96, and 0.94 for significant fibrosis, advanced fibrosis, and cirrhosis, respectively. In the training set, a score >/=0.5 (range, 0.0-1.0) provided a specificity and sensitivity of 92% and 67% for significant fibrosis, a score <0.5 was 81% specific and 95% sensitive for advanced fibrosis, and a score <0.84 was 84% specific and 71% sensitive for cirrhosis. Among the validation set, the AUC for significant fibrosis, advanced fibrosis, and cirrhosis were 0.82, 0.90, and 0.89, respectively. A score >/=0.5 provided a specificity and sensitivity of 89% and 63% for significant fibrosis, whereas scores <0.5 had 74% specificity and 88% sensitivity for advanced fibrosis. CONCLUSIONS: A model of 4 serum markers plus age and sex provides clinically useful information regarding different fibrosis stages among hepatitis C patients.
of hepatitis C virus by saliva? Ferreiro MC, Dios PD, Scully C. Oral Dis. 2005 Jul;11(4):230-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15984954&query_hl=14
Saliva can contain a range of infectious agents and, despite several antimicrobial mechanisms, transmission of these can occur. Hepatitis C virus (HCV) is of increasing importance, and HCV is transmitted by unknown routes as well as by the percutaneous route and sexual contact. Contact with blood or other body fluids may be responsible, as may be receipt of unscreened blood or blood product transfusions. HCV-RNA can be detected by the polymerase chain reaction which also shows that HCV may be present in the saliva of HCV-infected patients. This might provide an argument for the possible transmission of HCV via contaminated saliva. Epidemiological studies however, suggest that the infective capacity of HCV viral particles in saliva is low, but it has not been possible to determine their infective potential. Moreover, HCV-specific receptors have not been defined on oral epithelial cells, nor has the role of host defence mechanisms been determined. New experimental animal models and the recently described infectious HCV pseudoparticles, capable of simulating HCV replication in vitro, could be useful in establishing any role of saliva in the transmission of HCV infection.
hepatitis, STD, and HIV services into a drug rehabilitation program. Gunn RA, et al. Am J Prev Med. 2005
BACKGROUND: Considering the difficulties in providing screening and vaccination services for inmates in short-stay incarceration facilities, an evaluation was conducted of the integration of prevention services in an alternative sentencing drug rehabilitation program (alternative to incarceration) in San Diego CA. METHODS: During the period April 1999 to December 2002, clients were asked to complete a brief risk-assessment questionnaire, and were offered hepatitis B virus (HBV) vaccination, HBV and hepatitis C virus (HCV) serologic testing, STD screening, and HIV counseling and testing. RESULTS: Of the estimated 1125 rehabilitation program enrollees, 930 (83%) participated in the integration program services. Most clients were male (64%), were aged >30 years (64%), and few (7%) reported previous HBV vaccination. Of the 854 clients eligible for hepatitis B vaccination, 98% received the first dose, 69% the second dose, and 42% completed the series. Eleven percent of clients had prior HBV infection, and 14.7% had HCV infection, with positivity rates being highest among those with a history of injection drug use-HBV, 19%, and HCV, 36%. HIV infection was rare (prevalence, 0.3%), and STDs were uncommon (chlamydia prevalence, 2%, and gonorrhea prevalence, 0.6%). Total annual cost of integration services (excluding HIV testing) was dollar 31,994 equating to dollar 122 per client served. CONCLUSIONS: Alternative sentencing drug rehabilitation programs provide a venue to efficiently deliver integrated hepatitis and other prevention services. Considering the vast number of high-risk persons in drug rehabilitation, probation, parole, and inmate release programs, an opportunity exists to greatly expand hepatitis services.
transmission of hepatitis C in Egypt. Mohamed MK, et al. Hepatology. 2005 Jul 19;
[Epub ahead of print]
The incidence of hepatitis C (HCV) infection and associated risk factors were prospectively assessed in a cohort of 6,734 Egyptians from 2 rural villages who were negative for antibodies to HCV (anti-HCV). Initial and follow-up sera were tested for anti-HCV by enzyme immunoassay (EIA), and possible incident cases were confirmed by using the microparticle enzyme immunoassay (MEIA) and tested for HCV RNA. All follow-up serum samples converting from negative to positive without detectable HCV-RNA were further tested by recombinant immunoblot assay. Over an average of 1.6 years, asymptomatic anti-HCV seroconversion occurred in 33 people (3.1/1,000 person-years [PY]), including 28 (6.8/1,000 PY) in the Nile Delta village (AES), where prevalence was 24% and 5 (0.8/1,000 PY) in the Upper Egypt village (baseline prevalence of 9%). The strongest predictor of incident HCV was having an anti-HCV-positive family member. Among those that did, incidence was 5.8/1,000 PY, compared (P < .001) with 1.0/1,000 PY; 27 of 33 incident cases had an anti-HCV-positive family member. Parenteral exposures increased the risk of HCV but were not statistically significant; 67% of seroconverters were younger than 20 years of age, and the highest incidence rate (14.1/1,000 PY) was in children younger than 10 who were living in AES households with an anti-HCV-positive parent. In conclusion, young children would especially benefit from measures reducing exposures or preventing infection with HCV.
Does prevalence of transfusion-transmissible viral infection reflect corresponding incidence in United States blood donors? Wang B, et al. Transfusion. 2005 Jul;45(7):1089-96.
BACKGROUND: Calculation of viral residual risk is dependent on estimating incidence, which is not easily obtainable by most blood centers. Prevalence, however, is readily available. Understanding whether prevalence reflects corresponding incidence may help blood centers monitor disease risks. STUDY DESIGN AND METHODS: With data on 12 million allogeneic donations, prevalence and incidence of transfusion-transmitted viral infections (TTVIs) were calculated. Relationships between prevalence (in total, first-time, and repeat donations) and incidence were analyzed for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) relative to temporal and donor demographic stratifications, respectively. RESULTS: Overall prevalence of HIV, HBV, and HCV did not consistently reflect corresponding incidence. The relationship between prevalence and incidence varied with time and donors' age and was virus-specific. CONCLUSION: Incidence of TTVIs cannot be easily predicted from overall prevalence. Accurate assessment of TTVI risk necessitates knowledge about donation histories and person-years at risk. Establishing comprehensive frameworks for monitoring blood donations and infectious disease markers remains a key to monitoring blood safety.
Knowledge of hepatitis among active drug injectors at a syringe exchange program. Carey J, et al. J Subst Abuse Treat. 2005 Jul;29(1):47-53
Injecting drug users (IDUs) are at high risk for contracting and spreading viral hepatitis through nonsterile injection practices, unprotected sexual contact, and unsanitary living conditions. We sought to characterize hepatitis knowledge, prior testing, and vaccination history among IDUs at a New York City syringe exchange program (SEP). IDU subjects generally had a poor understanding of viral hepatitis transmission and prevention. We also found low vaccination rates: only 8% reported receiving hepatitis A vaccine and 11%, hepatitis B vaccine. Educating IDUs about risky behaviors and medical preventive interventions, such as vaccines for hepatitis A and B and treatment for hepatitis C, may help prevent disease and reduce transmission. Stronger linkages between health-care centers and SEPs, drug treatment programs, and other service delivery centers where IDUs are encountered may promote hepatitis education and vaccination.
assessment of hepatitis C virus infection among health-care workers of the
National Cancer Institute of Naples, Southern Italy. Montella M, et al. Eur J Public Health. 2005
Jul 21; [Epub ahead of print]
[Italy] BACKGROUND: As many people with chronic hepatitis C virus (HCV) infection are asymptomatic, HCV infection could spread easily among the health-care workers of the National Cancer Institute of Naples (especially before the identification of HCV and in the absence of good, effective preventative measures, e.g. sterile syringe use, gloves, protective glasses). METHODS: In order to determine whether there is a transmission risk for HCV infection from patient to health-care worker, we carried out a cross-sectional study of a cohort of National Cancer Institute health-care workers in Naples, Southern Italy. RESULTS: The chi(2)-test was not significant; we did not find any significant risk for HCV in the 'other untrained staff' group [odds ratio (OR) 2.2; 95% confidence interval (CI) 0.4-10.9] or in the health-care workers group (OR 1.6; 95% CI 0.4-7.0). In the health-care worker subgroups, doctors were the reference category because of the low prevalence of HCV in this subgroup (3.3%). A non-significant association was found in the professional nurses group (OR 2.7; 95% CI 0.8-8.8), as well as in the categories of technicians and biologists. CONCLUSIONS: No excessive risk was found among the health-care workers as a whole or among the different categories of personnel, confirming that health-care employees have benefited sufficiently from preventative measures.