Program Newsletter
www.HepCChallenge.org
May 2009
In The News 1- 8
Clinical Trials, Cohort Studies, Pilot Studies 8-15
Basic and Applied Science, Pre-Clinical Studies 15-17
HIV/HCV Coinfection
17-19
Epidemiology, Diagnostics & Miscellaneous Works 19-22
In The News
New
Weapon Fights Hepatitis C
Experimental drug clears hurdle on its
way to joining standard drug combinations
http://www.sciencenews.org/view/generic/id/43337/title/New_weapon_fights_hepatitis_C
“Ten years ago, John McHutchison never
used the word “cure” when discussing hepatitis C with his patients. But the
results seen from drugs cleared for use since then — and particularly a new
drug now in the final stages of testing — are changing that, says the
gastroenterologist from Duke University in Durham, N.C. “As far as these
patients are concerned, they’re pretty much cured,” McHutchison says. “We don’t
need to see them anymore.”
The new drug, called telaprevir, works
with a standard hepatitis C drug combination to clear the virus from patients’
blood substantially better than the standard treatment alone, according to a
study coauthored by McHutchison and another study, both in the April 30 New
England Journal of Medicine. The new findings, in people getting their
first course of drugs for the disease caused by the virus, also indicate that
typically lengthy hepatitis C treatment could be halved with telaprevir’s
addition.” [truncated]
Debiopharm
Starts Phase IIb Study After Record Time Patient Randomisation
“Debiopharm Group a global
biopharmaceutical development specialist that focuses on serious medical
conditions, particularly in the field of oncology, announced that on April 7,
2009 the last patient was randomised to take part in a phase IIb clinical study
with Debio 025, a selective cyclophilin (Cyp) inhibitor with a potent
anti-hepatitis C (HCV) effect. In a record time of three months, a total of 290
patients were randomised in seven countries, including Poland, Germany,
Belgium, France, Spain, Italy and Romania. This double-blind,
placebo-controlled, parallel-group study will investigate the efficacy and
safety of three different treatment regimens combining Debio 025 with Peg
interferon alpha 2a (peg-IFN-alpha-2a) and ribavirin in treatment naive chronic
HCV genotype 1 patients.
"We are proud to have randomised
our patients in such a short period, this demonstrates the investigator's
confidence in our product," said Rolland-Yves Mauvernay, President and
Founder of Debiopharm Group. "The efficiency of the recruitment is very
motivating for us in our development of Debio 025, as we are eager to provide
HCV patients with a more effective treatment."” [truncated]
First Evidence For DNA-based
Vaccination Against Chronic Hepatitis C
http://www.sciencedaily.com/releases/2009/04/090423082642.htm
“ The first-proof-of-concept for a
DNA-based therapeutic vaccination against chronic hepatitis C was announced
April 23 at EASL 2009, the Annual Meeting of the European Association for the
Study of the Liver in Copenhagen, Denmark. In the first clinical trial of a
therapeutic vaccination using naked DNA delivered by in vivo electroporation
(EP), antiviral effects were shown in patients with hepatitis C (HCV).
Researchers hope that this will encourage further clinical development. The
data also provide further evidence for the antiviral role of the HCV-specific T
cell response.
It is estimated that some 3% of the
world's population is infected with HCV. In industrialised countries, hepatitis
C accounts for 70% of chronic hepatitis cases. One of the main concerns is that
HCV infection remains asymptomatic until advanced stages of the disease.
Clearance of HCV infection correlates
with activation of the host T cell response. Therefore, in this study,
researchers developed a T cell vaccine based on a codon-optimised HCV
non-structural (NS) 3/4A DNA-gene expressed under the control of the
cytomegalovirus immediate-early promoter (ChronVac-C®) delivered by in vivo
electroporation (EP). A first phase I/IIa clinical trial in HCV infected
patients is currently ongoing.” [truncated]
UPDATE 2-Schering hepatitis C Drug
Shines, but Anemia Seen
http://news.alibaba.com/article/detail/chemical/100090468-1-update-2-schering-hepatitis-c-drug.html
“A Schering-Plough Corp drug knocked
the hepatitis C virus down to undetectable levels in three-fourths of patients
in a mid-stage study, twice the effectiveness seen with standard treatments,
researchers said on Thursday. But half the patients taking the boceprevir
experimental medicine developed anemia -- a potential commercial disadvantage
to a similar pill called telaprevir that Vertex Pharmaceutical Inc is
developing.
Both drugs work through a new
mechanism -- by blocking a protein called protease that the virus needs to
replicate -- and are considered potential big-selling products. As many as 4
million Americans are believed to be infected with the virus, the leading
reason for liver transplants.
Results of the Phase II boceprevir
trial, involving 595 patients who were infected with the virus but had not
previously been treated, were presented in Copenhagen at the annual meeting of
the European Association for the Study of the Liver. Patients had genotype 1,
the most common form of the virus.” [truncated]
Scynexis
Sees Positive Results in Trial of Hepatitis C Drug
http://www.techjournalsouth.com/news/article.html?item_id=7331
“Scynexis Inc. says it saw positive
results in its Phase 1b clinical trial of its lead oral antiviral drug in
patients with hepatitis C infections. The drug, SCY-635, represents a new
pharmacological class of inhibitors of hepatitis C virus (HCV) replication.
In this 15-day study, SCY-635 was well-tolerated with no serious adverse
events, no discontinuations and no dose-limiting toxicities. At the highest
dose tested in the study (900 milligrams/day) SCY-635 exhibited clinically
relevant antiviral activity. “In this
single-agent study SCY-635 demonstrated highly potent antiviral activity that
was sustained throughout treatment with the nadir occurring on the last day of
the study, suggesting that with a longer treatment period we may see even
greater reductions in viral load,” said Dr. Sam Hopkins, SCYNEXIS’ Chief
Scientific Officer. The drug may eventually be used in combination with other
treatments for even greater effect, the company says.”
Amarillo Biosciences Supplies Oral
Interferon for Taiwanese Hepatitis C Study
http://startups.ulitzer.com/node/934619
Hepatitis at A.C. hospital probed
Fifteen dialysis patients at the
facility have contracted hepatitis C since 2005.
http://www.philly.com/inquirer/local/20090425_Hepatitis_at_A_C__hospital_probed.html
“New Jersey health officials are
trying to unravel how 15 dialysis patients at an Atlantic City hospital have
contracted hepatitis C, a serious liver disease, since 2005. Hospital
administrators at AtlantiCare Regional Medical Center City Campus contacted the
state this month after discovering five new hepatitis C cases during federally
required annual hepatitis C testing of all dialysis patients.
The testing, in late March and early
April, showed the five patients had become positive for the disease since
starting dialysis treatment at the hospital. It is unclear if the cases are
linked to the hospital, state Health Department officials said yesterday. All
new patients are tested for hepatitis C, according to a hospital policy.
Mohammed Mourad, who heads the hospital's division of nephrology, said it was
unknown when or how those patients contracted the disease.
After seeing the test results, the
hospital contacted the state, which asked the hospital to review four years of
patient records. Those records showed that 10 others had also been found to
have hepatitis C. The hospital said yesterday that those 15 testing positive
since 2005 had come from a total group of 245 patients. All 15 cases now been
officially reported to the state, as required by law.” [truncated]
HIV No Barrier to Liver Transplant
http://www.medpagetoday.com/Gastroenterology/LiverTransplantation/13895
“People with HIV do just as well as
others after a liver transplant -- as long s they don't have hepatitis C as
well, researchers said in Copenhagen. In one of the few studies with data on
long-term outcomes, those with HIV had one- and five-year survival rates of
86.5% and 74% respectively, according to John O'Grady, M.D., of Kings College
Hospital in London.
By comparison, HIV-negative liver
transplant patients in the prospective UK Transplant Database had rates of
87.1% and 78%, which were not significantly different, Dr. O'Grady reported at
the annual meeting of the European Association for the Study of the Liver.
"In terms of HIV, the clinical guidance is that theses patients do very
well, (and) they should be considered for transplant in the normal way," he
said. "They don't present any particular different clinical problem than
the general liver transplant population." On the other hand, he said,
patients with both HIV and hepatitis C are a significantly greater challenge.”
[truncated]
Anadys Hepatitis C Drug Shows Potent
Effect in Small Study
“San Diego-based Anadys
Pharmaceuticals generated a ton of buzz almost four months ago when it offered
an early peek at data suggesting its hepatitis C drug might be working, and now
a presentation of the full data appears to reinforce the first impression. Anadys’
lead drug candidate, ANA598, was able to wipe out more than 99 percent of the
hepatitis C virus at all three doses tested in a trial of 35 patients,
according to data presented today at the European Association for the Study of
the Liver meeting in Copenhagen, Denmark. No patients had any serious side
effects, and none showed signs of developing resistance to the drug or having
their virus bounce back while taking the pill twice-daily over three days.
“The potent antiviral activity
demonstrated at all three doses in this study is very encouraging for the
prospects of ANA598 when used in combination with other HCV agents,” said
Anadys CEO Steve Worland, in a statement. Hepatitis C is an infection of the liver
caused by virus.” [truncated]
More than 12,000 Patients are Being
Offered HIV and Hepatitis C Tests After a Healthcare Worker was Found to Have Both
Diseases. (England)
“All patients treated
by the worker, who had not been named, are to be contacted by NHS Lewisham and
offered the blood tests. The healthcare trust said that it understood how
concerned patients would be but emphasised that there was a small chance that
they would have contracted either disease.
Patients at the centre of the scare
include an 11-year-old boy whose father has talked of their family's anxiety. The
man, from Downham, south-east London, said that he had received a letter from
on Tuesday alerting him that his son was at risk and should have a blood test. He
said: "I was shocked to receive a letter like this and my first thought
was how something like this could be allowed to happen. "He is due to
start secondary school in September and we don't want anything to upset him so
we've had to lie to him about why he needs a blood test. "Even though we
know the chances of him having anything are slim, we are very worried."” [truncated]
Zymo Drug Kills Hep C Virus
http://www.seattlepi.com/xconomy/405494_xconomy21660.html
“ZymoGenetics a Seattle biotech
company, and partner Bristol-Myers Squibb said today that a drug they are
co-developing for hepatitis C was able to kill the virus with minimal side
effects in a small four-week study. The trial looked at pegylated interferon
lambda on its own, or in combination with a standard ribavirin treatment. The
full data was presented at the European Association for the Study of the Liver
meeting in Copenhagen, Denmark.” [truncated]
Metabolic Syndrome Hikes Mortality in
Hepatitis C
http://www.medpagetoday.com/Gastroenterology/Hepatitis/13878
“Patients with hepatitis C infection
appear more likely to die from the condition if they also suffer from one or
more components of metabolic syndrome, a researcher said. Excess body weight
and hypertension both significantly heightened the risk of liver-related
mortality in hepatitis C patients, according to data from the third National
Health and Nutrition Examination Survey (NHANES) series, reported Zobair
Younossi, M.D., of Inova Health System in Falls Church, Va.
Those two factors as well as the third component of metabolic syndrome -- type
2 diabetes -- also made death from all causes more likely during the study
period, said Dr. Younossi.” [truncated]
UPDATE 1-Roche Has Promising Results From
Hep C Trial
http://www.reuters.com/article/rbssPharmaceuticals%20-%20Diversified/idUSLR7218020090427
Hepatitis C combination study shows
"significant" potency
“ Roche Holding AG has announced
promising results from a study of a combination therapy for patients
chronically infected with hepatitis C. Roche announced the results along with
InterMune) and Pharmasset which they presented on Saturday at the annual
meeting of the European Association for the Study of the Liver in Copenhagen. They
said the study, which combined two oral direct-acting antivirals, R7227 and
R7128, showed no serious adverse effects during 14 days of dosing and showed
"significant" potency in reducing the viral load of hepatitis C
patients.
Roche is developing R7227, a protease
inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with
Pharmasset.” [truncated]
Avila Therapeutics May Have Found
“Achilles’ Heel” of Hepatitis C Virus
“Avila Therapeutics emerged from
stealth mode in December and told Xconomy about its secret sauce to
systematically create permanent, covalent bonds with protein disease targets.
Now the Waltham, MA-based biotech (pronounced AH-vill-uh) reports that its
experimental drug for hepatitis C virus may be able to wipe out multiple
variations and mutated forms of the virus.
The firm’s drug, dubbed AVL-181, is a
small molecule protease inhibitor intended to silence a key protein for the
survival and replication of the virus. The drug targets a region of the protein
that the company believes is common among many known forms of the virus, even
those that are resistant to standard treatments, meaning that the firm may have
found an “Achilles’ heel” of the protein, says Nagesh Mahanthappa, vice
president of business development and operations at the biotech. Over the
weekend, the company presented results of a study, in which infected mice were
treated with the drug, at the European Association for the Study of the Liver
meeting in Copenhagen, Denmark.
“When we look across all known
published genetic sequences of the hepatitis C protease, from a variety of
mutants, we find that the particular site where we get bond formation with our
drug is constant,” Mahanthappa says. “It remains possible that that site is
somehow critical for the protease’s normal function, or the general fitness of
the virus.”” [truncated]
70 Percent of Hepatitis C Cases
Curable With Early Treatment
“Up to 70 percent of hepatitis C cases
are curable if early treatment is sought, according to a new international
study. The study by National Centre for HIV Epidemiology and Clinical Research
(NCHECR) also found that a standard combination drug treatment was as effective
as a stronger regimen of therapy associated with serious side-effects.
Advocacy group Hepatitis Australia
estimates that more than 300,000 people in the country alone are infected with
chronic hepatitis C, yet fewer than two percent receive treatment. Most common
routes of infection include contact with infected needles and sexual
transmission. The findings were part of a trial involving 702 patients from
Australia, and 194 from New Zealand, Canada, Thailand, Argentina and Mexico.
All had hepatitis C genotype 1 - the most difficult to treat. Study co-author
Greg Dore, professor at NCHECR, said early treatment was vital to prevent the
onset of serious liver conditions. Hepatitis C is the principal reason for
liver transplants in Australia, said an NCHECR release.” [truncated]
Human Genome Sciences Releases Final
Test Results for Hepatitis C Drug
http://www.bizjournals.com/washington/stories/2009/04/27/daily11.html
“Human Genome Sciences Inc. released
final results from the last stage of clinical trials of its hepatitis C drug,
Albuferon, in a formal presentation at a scientific conference in Copenhagen.
While they didn’t differ from past
announcements of study results of the Albuferon trials, which finished one set
of phase III trials in December and a second set in March, Human Genome
Sciences officials said these latest presentations gave them a chance to look
more broadly at the results. “It talks about the results across the program,”
said Jerry Parrott, spokesman for Human Genome Sciences. “You’re looking at the
phase III results in an overall sense.”
Human Genome Sciences and Swiss giant
Novartis AG are developing Albuferon together, and they plan to request federal
authorization this fall to start selling the drug as early as next year.” [truncated]
Ironwood
Hosts Hepatitis C Conference
http://www.blythecanews.com/main.asp?SectionID=1&subsectionID=1&articleID=11246
“BLYTHE - In conjunction with the
University of California at San Francisco, Ironwood State Prison welcomed
Joanne Imperial, MD, Director, Hepatitis C Program at UCSF, Patricia Nachin,
Registered Nurse, Hepatitis Specialty Nurse and Tonia Woodson, Clinical
Services Filed Manager on March 18. The purpose of the visit was to give
continuing education and consultations regarding Hepatitis C, a disease that
harms the liver and is more prevalent in the prison system than in the general
population. The audience was made up of the staff from ISP and other California
state prisons, which included doctors, nurses, educators, custody, and
administrators. Dr. Imperial is the Director of the Hepatitis C Program at
UCSF, and is responsible for guidelines throughout the entire state, especially
in regard to the prison population.
Hepatitis C is a chronic disease that
could eventually lead to cirrhosis, liver cancer, and possibly death. Dr.
Imperial is also available to ISP and other prisons, via Telemedicine and
Warm-Line Consultations. Telemedicine involves an interactive, real-time
consultation whereby the doctor and patient are televised to teach other.” [truncated]
Hospital
Heads Axed After Hep C Infections
http://www.chinadaily.com.cn/china/2009-04/01/content_7637551.htm
“Twenty patients were infected with
Hepatitis C during hemodialysis treatment at two hospitals in Shanxi province,
the Ministry of Health said on Monday. The infected patients are among 47
people who received hemodialysis at the Taiyuan Public Transportation Company's
hospital and the Shanxi Coalmine Central Hospital, between December and
January. The heads of the two hospitals were held under investigation and those
directly responsible for the incident were removed from their posts, Xinhua
News Agency quoted the ministry's circular as saying.” [truncated]
STDs
Increase in Amsterdam Alarms Health Workers
http://www.radionetherlands.nl/news/zijlijn/6243468/VD-increase-in-Amsterdam-alarms-health-workers
“Figures released by Amsterdam's
health service show the number of local people who became infected with
sexually transmitted diseases in 2008 was dramatically up on the year before. Infections,
including HIV, chlamydia, syphilis, and Hepatitis C are all on the increase.
Health workers are alarmed by the steady and steep rise, fearing they may soon
face a peak in infections comparable to that of the mid-1980s.
There were 178 new diagnoses of HIV in
the capital in 2008, the largest number of new cases ever and nearly half of all
the new infections registered nationwide. This is partially explained by the
fact that more people than ever before are being tested for the HIV virus,
which can cause AIDS. The rise in cases of syphilis and Hepatitis C was most
marked in homosexual men, while the number of chlamydia infections in people
under 20 showed an explosive increase. Hepatitis C is being seen increasingly
often in gay men who are HIV positive and only about 60 percent of such cases
respond to treatment. Left untreated, Hepatitis C can lead to major problems
such as liver cancer.” [truncated]
Doctor's
License Suspension Sought After Infections
http://www.app.com/article/20090403/NEWS02/904030327/1070/NEWS02
“TOMS RIVER — Patients can have their
blood tested with their health care provider or at one of Community Medical
Center's outpatient laboratories, for which an appointment is not required.
Patients are asked to bring a copy of the health department's letter, an
insurance card and identification. For more information about locations or
hepatitis B, call the Ocean County Health Department at (732) 341-9700, ext.
7502. The state is seeking to temporarily suspend the license of a Toms River
doctor who is being investigated by health officials after five patients were
infected with hepatitis B. Dr. Parvez Dara, who has offices in Toms River and
the Whiting section of Manchester, has been ordered to appear today before the
state Board of Medical Examiners in Newark.” [truncated]
VA
Continues Notification Process for Veterans Affected by Reprocessing Issues
“The Department of Veterans Affairs
(VA) has announced 3,174 Veterans have already been notified of the results of
testing they underwent recently; that testing was conducted because of
improperly reprocessed endoscopy equipment that may have been used in their
care. These Veterans, in the Tennessee, Georgia and South Florida areas were
among 10,555 Veterans sent letters offering free testing.
VA patients, who believe that they may
have been exposed to cross contamination, were patients that received
endoscopic procedures at the VA's Murfreesboro, Tenn., facility from April 2003
to December 2008 and the VA's Augusta, Ga., hospital from January 2008 to
November 2008 and the VA's Miami hospital from May 2004 to March 2009.”
[truncated]
Components of Metabolic Syndrome
Increased Mortality in Hepatitis C Patients
http://www.endocrinetoday.com/view.aspx?rid=39264
“Higher overall and liver-related
mortality were associated with type 2 diabetes, obesity and hypertension in
patients with hepatitis C when compared with those without. “This is the
largest population-based study to provide the strongest evidence confirming an
association between components of metabolic syndrome, especially type 2
diabetes and obesity, with adverse mortality outcomes” for patients with
hepatitis C, Zobair Younossi, MD, MPH,
of the Center for Liver Diseases at Inova Fairfax Hospital in Falls Church,
Va., said in a press release.
The data were presented yesterday at
the Annual Meeting of the European Association for the Study of the Liver in
Copenhagen, Denmark.
Researchers examined data from the
Third National Health and Nutrition Examination Survey and Linked Mortality
Files to determine the effect of components of metabolic syndrome on the
mortality of people with hepatitis C. Study participants included 264 patients
with hepatitis C and 13,004 people without.” [truncated]
Schering-Plough
Highlights Hepatitis C Clinical Data Presentations at the European Association
for the Study of the Liver (EASL) Annual Meeting
Final results from three large
PEGINTRON(TM) clinical studies address key questions in the treatment of
hepatitis C
“Schering-Plough Corporation today
reported that final results of three large PEGINTRON(TM) (peginterferon
alfa-2b) clinical studies address longstanding questions in the hepatitis C
research community and provide important insights. The results of the studies,
involving a total of more than 2,700 patients, were presented at the 44th
European Association for the Study of the Liver (EASL) 2009 Annual Meeting.
"Physicians are constantly
looking for ways to improve hepatitis C treatment outcomes by increasing
response rates or reducing side effects and making treatment more tolerable for
their patients," said Robert J. Spiegel, M.D., chief medical officer and
senior vice president, Schering-Plough Research Institute. "We undertook
these large PEGINTRON studies to help investigators address these important
clinical issues. Conducting these studies demonstrates Schering-Plough's
longstanding commitment to investigating potential new treatment strategies for
patients with hepatitis C."
Combination therapy with peginterferon
and ribavirin is a recognized standard of care worldwide for treating chronic
hepatitis C virus (HCV) infection. Patients with HCV genotype 1, the most
common and hardest to treat form of hepatitis C, are typically treated for 48
weeks, while patients with HCV genotypes 2 or 3 are treated for 24 weeks. The
aim of the three PEGINTRON studies was to evaluate investigational regimens in
these patient populations compared to current standard practice.” [truncated]
Clinical
Trials, Cohort Studies, Pilot Studies
HALT-C in the final analysis: A
molehill out of a mountain. Almasio PL. J Hepatol. 2009 Mar 20. [Epub ahead of
print]
BACKGROUND: In patients
with chronic hepatitis C who do not have a response to antiviral treatment, the
disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and
death. Whether long-term antiviral therapy can prevent progressive liver
disease in such patients remains uncertain. METHODS: We conducted a
randomized, controlled trial of peginterferon alfa-2a at a dosage of 90mug per
week for 3.5 years, as compared with no treatment, in 1050 patients with
chronic hepatitis C and advanced fibrosis who had not had a response to
previous therapy with peginterferon and ribavirin. The patients, who were
stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and
428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy
at 1.5 and 3.5 years after randomization. The primary end point was progression
of liver disease, as indicated by death, hepatocellular carcinoma, hepatic
decompensation, or, for those with bridging fibrosis at baseline, an increase
in the Ishak fibrosis score of 2 or more points. RESULTS: We randomly
assigned the patients to receive peginterferon (517 patients) or no therapy
(533 patients) for 3.5 years. The level of serum aminotransferases, the level
of serum hepatitis C virus RNA, and histologic necroinflammatory scores all
decreased significantly (P<0.001) with treatment, but there was no
significant difference between the groups in the rate of any primary outcome
(34.1% in the treatment group and 33.8% in the control group; hazard ratio,
1.01; 95% confidence interval, 0.81-1.27; P=0.90). The percentage of patients
with at least one serious adverse event was 38.6% in the treatment group and
31.8% in the control group (P=0.07). CONCLUSIONS: Long-term therapy with
peginterferon did not reduce the rate of disease progression in patients with
chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had
not had a response to initial treatment with peginterferon and ribavirin.
High sustained virological response
rate to combination therapy in genotype 1 patients with histologically mild
hepatitis C. Gheorghe L, Iacob
S, Grigorescu M, et al. J Gastrointestin Liver Dis. 2009 Mar;18(1):51-56.
BACKGROUND: Patients
with mild hepatitis C have a significant risk of disease progression at medium-
and long-term follow-up and should be considered for antiviral therapy. AIM: To
evaluate the rate of sustained viral response (SVR) and predictive factors of
SVR in HCV genotype 1 patients with mild hepatitis C (fibrosis stage F0/F1)
treated with combination antiviral therapy. METHODS: 260 naïve patients
were followed-up during 72 weeks in three referral hepatology centers between
2004 and 2006. Univariate and multivariate logistic regression analysis was
conducted. RESULTS: Early virological response was 88.1% and SVR was
74.2%. In the univariate analysis, SVR was associated with young age (p=0.001),
very low (≤400,000 IU/mL) baseline viremia (p=0.03) and high
aminotransferase levels (p=0.04) and was not associated with gender, body mass
index, inflammatory activity, steatosis, ribavirin and peginterferon dose
changes, premature cessation of therapy. Multivariate analysis identified the
following independent predictors of SVR: age <50 years (p=0.0009), viral
load ≤400,000 IU/mL (p=0.03) and aminotransferase level >2 times
normal value (p=0.02). CONCLUSIONS: Genotype 1 HCV patients with mild
hepatitis have a high rate of SVR, similar to genotype non-1. Young age, very
low viremia and significant hepatocytolisis are independent predictors of SVR
in patients with mild hepatitis.
HCV genotype 1 is almost exclusively
present in Romanian patients with chronic hepatitis C. Grigorescu
M. J Gastrointestin Liver Dis. 2009 Mar;18(1):45-50.
AIM: To investigate the HCV
genotype distribution in Romania in the first national study, to establish the
correlations with epidemiological, biochemical, virological and histological
features and to compare our results with those from neighboring countries. PATIENTS
AND METHODS: Two distinct groups of patients and two methods were used: 153
patients in the frame of ACHIEVE study with genotyping and subtypes
determination (Versant HCV genotype 2.0 assay) and 461 patients in the frame of
an Epidemiological National Multicenter Study having only genotype
determination with a commercial kit (Roche Molecular System). Epidemiological,
biochemical, virological and histological features were investigated only in
the ENMS group. RESULTS: Genotype 1b was found in 93.46% (ACHIEVE study)
and genotype 1 (without subtype identification) in 99.13% of patients (ENMS
study). Percutaneous routes of transmission were found in 85.9% of cases. The
prevalence of HCV infection increased with age. A high viral load (≥
600,000 IU/ml) was found in 67.9% of patients, especially those older than 40
years. Significant fibrosis ≥ F2 was present in patients older than 40
years (70.9%). There were no correlations between HCV-RNA levels and histological
features or between ALT levels and METAVIR activity or fibrosis scores. A
similar homogeneity of HCV genotype distribution has been reported for Moldavia
(96%) and Hungary (94.5%). CONCLUSIONS: Type 1 HCV genotype was found
almost exclusively in Romanian patients with chronic hepatitis C by two
different methods of investigation. The pattern showed by this distribution in
Romania and some neighboring countries suggests an epidemic profile of HCV
infection.
High sustained virological response
rate to combination therapy in genotype 1 patients with histologically mild
hepatitis C. Gheorghe L, Iacob S, Grigorescu M, Sporea I, et al. J
Gastrointestin Liver Dis. 2009 Mar;18(1):51-56.
BACKGROUND: Patients
with mild hepatitis C have a significant risk of disease progression at medium-
and long-term follow-up and should be considered for antiviral therapy. AIM: To
evaluate the rate of sustained viral response (SVR) and predictive factors of
SVR in HCV genotype 1 patients with mild hepatitis C (fibrosis stage F0/F1)
treated with combination antiviral therapy. METHODS: 260 naïve patients
were followed-up during 72 weeks in three referral hepatology centers between
2004 and 2006. Univariate and multivariate logistic regression analysis was
conducted. RESULTS: Early virological response was 88.1% and SVR was
74.2%. In the univariate analysis, SVR was associated with young age (p=0.001),
very low (≤400,000 IU/mL) baseline viremia (p=0.03) and high
aminotransferase levels (p=0.04) and was not associated with gender, body mass
index, inflammatory activity, steatosis, ribavirin and peginterferon dose
changes, premature cessation of therapy. Multivariate analysis identified the
following independent predictors of SVR: age <50 years (p=0.0009), viral
load ≤400,000 IU/mL (p=0.03) and aminotransferase level >2 times
normal value (p=0.02). CONCLUSIONS: Genotype 1 HCV patients with mild
hepatitis have a high rate of SVR, similar to genotype non-1. Young age, very
low viremia and significant hepatocytolisis are independent predictors of SVR
in patients with mild hepatitis.
Re-treatment of patients with chronic
hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Jensen DM,
Marcellin P, Freilich B, et al. Ann Intern Med. 2009 Apr 21;150(8):528-40.
BACKGROUND: Many
patients with chronic hepatitis C have not responded to therapy with pegylated
interferon plus ribavirin. OBJECTIVE: To evaluate use of
peginterferon-alpha2a plus ribavirin to re-treat nonresponders to
peginterferon-alpha2b plus ribavirin. DESIGN: Randomized, parallel-group
trial conducted between September 2003 and February 2007. Patients and
researchers were not blinded to intervention assignment. Random assignment was
centralized, computer-generated, and stratified by geographic region, hepatitis
C virus (HCV) genotype, and histologic diagnosis. SETTING: 106
international centers. PATIENTS: 950 nonresponders to 12 or more weeks
of therapy with peginterferon-alpha2b plus ribavirin. INTERVENTION: Peginterferon-alpha2a,
360 microg/wk, for 12 weeks, then 180 microg/wk to complete 72 weeks (group A)
or 48 weeks (group B), or peginterferon-alpha2a, 180 microg/wk for 72 weeks
(group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200
mg/d. MEASUREMENTS: Sustained virologic response (SVR), defined as
undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment.
RESULTS: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156),
and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for
group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P =
0.006). Extended treatment duration increased SVR rates (16% for 72 weeks
[groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to
3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at
week 12 was achieved in 21% of patients in groups A and B and 13% of those in
groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719
patients) among those with and without complete viral suppression at week 12,
respectively. LIMITATION: Nonresponders to peginterferon-alpha2a plus
ribavirin were not evaluated. CONCLUSION: Re-treating nonresponders to
therapy with peginterferon-alpha2b plus ribavirin for 72 weeks significantly
increases SVR rates compared with re-treating them for 48 weeks. The overall
SVR rate was low, but patients who are most likely to respond to re-treatment
can be identified at week 12.
Mutations in the hepatitis C virus
core gene are associated with advanced liver disease and hepatocellular carcinoma.
Fishman SL, Factor SH, Balestrieri C, et al. Clin Cancer Res. 2009 Apr
21. [Epub ahead of print]
PURPOSE: Hepatitis C
virus (HCV) infection can promote the development of hepatocellular carcinoma
(HCC). Published data implicate the HCV core gene in oncogenesis. We tested the
hypothesis that core gene sequences from HCC patients differ from those of
patients without cirrhosis/HCC. EXPERIMENTAL DESIGN: Full-length HCV
sequences from HCC patients and controls were obtained from the investigators
and GenBank and compared with each other. A logistic regression model was
developed to predict the HCC risk of individual point mutations and other
sequence features. Mutations in partial sequences (bases 36-288) from HCC
patients and controls were also analyzed. The first base of the AUG start codon
was designated position 1. RESULTS: A logistic regression model
developed through analysis of full-length core gene sequences identified seven
polymorphisms significantly associated with increased HCC risk (36G/C, 209A,
271U/C, 309A/C, 435A/C, 481A, and 546A/C) and an interaction term (for
209A-271U/C) that had an odds ratio <1.0. Three of these polymorphisms could
be analyzed in the partial sequences. Two of them, 36G/C and 209A, were again
associated with increased HCC risk, but 271U/C was not. The odds ratio of
209A-271U/C was not significant. CONCLUSIONS: HCV core genes from
patients with and without HCC differ at several positions. Of interest, 209A
has been associated with IFN resistance and HCC in previous studies. Our
findings suggest that HCV core gene sequence data might provide useful
information about HCC risk. Prospective investigation is needed to establish
the temporal relationship between appearance of the viral mutations and
development of HCC.
An open pilot study exploring the
efficacy of fluvastatin, pegylated interferon and ribavirin in patients with
hepatitis C virus genotype 1b in high viral loads. Sezaki H,
Suzuki F, Akuta N, et al. Intervirology. 2009 Apr 17;52(1):43-48. [Epub ahead
of print]
Objective: Response to
pegylated (PEG) interferon (IFN) and ribavirin is achieved only in 40-50% of
patients infected with hepatitis C virus (HCV) of genotype 1 in high viral
loads, which needs to be improved. Methods:
In an open-label pilot study, fluvastatin (HMG-CoA reductase inhibitor), 20 mg
daily, was given along with PEG-IFN/ribavirin to 21 patients with chronic
hepatitis C. They were followed for HCV RNA in serum. Results: During treatment for 48
weeks, HCV RNA was lost from serum in 93% of the patients. In the 15 patients
who received 48-week therapy, a sustained virological response (SVR) with loss
of HCV RNA 24 weeks after completion was achieved in 10 (67%), including 7 of
the 9 (78%) male and 3 of the 6 (50%) female patients. In the remaining 6
patients who received 72-week therapy, SVR was gained in 4 (67%), including 1
of the 2 male and 3 of the 4 female patients aged 56, 58 and 62 years,
respectively. Conclusion:
Fluvastatin could be used safely to increase the response to PEG-IFN and
ribavirin, especially in aged women who respond poorly to combined
PEG-IFN/ribavirin.
Systemic autoimmune diseases in
patients with hepatitis C virus infection: Characterization of 1020 Cases (The
HISPAMEC Registry). Ramos-Casals M, Muñoz S, Medina F, et al. J
Rheumatol. 2009 Apr 15. [Epub ahead of print]
OBJECTIVE: To describe
the clinical and immunologic characteristics of a large series of patients with
systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus
(HCV) infection. METHODS: The HISPAMEC Registry is a multicenter
international study group dedicated to collecting data on patients diagnosed
with SAD with serological evidence of chronic HCV infection. The information
sources are cases reported by physicians of the HISPAMEC Study Group and
periodic surveillance of reported cases by a Medline search updated up to
December 31, 2007. RESULTS: One thousand twenty HCV patients with SAD
were included in the registry. Patients were reported from Southern Europe
(60%), North America (15%), Asia (14%), Northern Europe (9%), South America
(1%), and Australia (1%). Countries reporting the most cases were Spain (236
cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95
cases). The most frequently reported SAD were Sjögren's syndrome (SS; 483
cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus
(SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome
(59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases).
Twenty patients had 2 or more SAD. Epidemiological data were available in 677
cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male,
with a mean age of 49.5 +/- 1.0 years at SAD diagnosis and 50.5 +/- 1.1 years
at diagnosis of HCV infection. The main immunologic features were antinuclear
antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%,
hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential
aspect between primary and HCV-related SAD was the predominance of
cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over
specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic
citrullinated peptide) in patients with HCV. CONCLUSION: In the selected
cohort, the SAD most commonly reported in association with chronic HCV
infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of
SAD-HCV cases were reported from the Mediterranean area. In these patients,
ANA, RF and cryoglobulins are the predominant immunological features.
[Hepatic steatosis in chronic
hepatitis C: study of risk factors and relationship with the fibrosis stage.] [Article in
Spanish] Antón MD, Roselló E, Gómez F, Paredes JM, López A, Moreno-Osset E. Med
Clin (Barc). 2009 Apr 13. [Epub ahead of print]
BACKGROUND AND OBJECTIVE: Liver
steatosis (LS) is a frequent histological finding in chronic hepatitis C virus
(HCV) infection with prognostic implications. The aim of the present
prospective study was to analyse the risk factors of steatosis and its
relationship with the fibrosis stage in patients with chronic HCV infection. MATERIAL
AND METHOD: Eighty four consecutive HCV RNA positive patients, not treated
previously, in whom a liver biopsy was performed, were enrolled. In each
patient demographic, clinical, laboratory, viral, and histological variables
were obtained at the time of biopsy. Bivariate and multivariate analysis,
calculating the odds ratio (OR) and the 95% confidence interval (95%CI), were
performed. RESULTS: LS was present in 69% of patients. Risk factors of
steatosis were an increase of the body mass index (OR: 1.17; 95%CI: 1.01-1.35)
and chronic alcohol consumption (OR: 3.58; 95%CI: 1.1-11.6) whereas those of
fibrosis were chronic alcohol consumption (OR: 3.58; 95%CI: 1.1-11.6) and
increase of the liver inflammatory activity (OR: 1.31; 95%CI: 1.13-1.53). LS
was associated with genotype 3 virus infection, which was present in all
patients with this infection who had severe steatosis in a significantly
greater proportion than in patients with non-genotype 3 virus infection (41.7%
vs 2.8%; P<.001). LS was more frequent in patients with advanced fibrosis
stages than in patients with non-advanced fibrosis (78,9% vs 60,9%; P=.074). CONCLUSIONS:
LS is a frequent finding in HCV chronic infection related to both host and
viral factors. LS could be a worsening factor of hepatic injury.
Predicting mortality risk in patients
with compensated HCV-induced cirrhosis: A long-term prospective study. Bruno S,
Zuin M, Crosignani A, et al. [ ]50: Am J Gastroenterol. 2009 Apr 7. [Epub ahead
of print]
OBJECTIVES: The
identification of prognostic factors associated with mortality is crucial in
any clinical setting. METHODS:
We enrolled in a prospective study 352 patients with compensated hepatitis C
virus (HCV)-induced cirrhosis, consecutively observed between 1989 and 1992. At
entry, patients underwent upper endoscopy to detect esophageal varices, and were
then surveilled by serial clinical and ultrasonographic examination. The model
for end-stage liver disease (MELD) score was calculated with information
collected at enrollment. Baseline predictors and intercurrent events associated
with mortality were assessed using the Cox regression model. RESULTS: During a median follow-up
of 14.4 years, 194 subjects received a single course of interferon monotherapy,
131 patients developed decompensation (ascites, bleeding, hepatic
encephalopathy), 109 patients had hepatocellular carcinoma (HCC), 9 had liver
transplant, and 158 died. Esophageal varices were associated with development
of decompensation (hazard ratio (HR), 2.09; 95% confidence interval (CI),
1.33-3.30) and liver-related death (HR, 2.27; 95% CI, 1.41-3.66). A MELD score
of 10 predicted overall mortality (HR, 2.15; 95% CI, 1.50-3.09). Overall
survival of patients with MELD </=10 was 80% at 10 years. HCC occurrence
increased the risk of decompensation fivefold (HR, 5.52; 95% CI, 3.77-8.09).
Hepatic and overall mortality hazard ratios were 8.62 (95% CI, 5.57-13.3) and
3.80 (95% CI, 2.67-5.42), respectively, for patients who developed HCC, and
16.9 (95% CI, 9.97-28.6) and 7.08 (95% CI, 4.88-10.2) for those who experienced
decompensation. CONCLUSIONS:
In patients with compensated HCV-induced cirrhosis, the presence of esophageal
varices at baseline predicted decompensation and mortality. The development of
HCC during follow-up strongly hastens the occurrence of decompensation, which
is the main determinant of death. Patients with a MELD score </=10 at study
entry had a prolonged life expectancy.
Prevalence and treatment of
hyperlipidemia in patients with chronic hepatitis C infection.
Murthy GD,
Vu K, Venugopal S. Eur J Gastroenterol Hepatol. 2009 Apr 24. [Epub ahead of
print]
BACKGROUND: Patients
with chronic hepatitis C (HCV) infection can also have hyperlipidemia. Glucose
intolerance has been associated with HCV infection and treating hyperlipidemia
in this and other high-risk groups is warranted. We hypothesized that
hyperlipidemia is common in patients with hepatitis C and that it is
under-treated for fear of worsening liver function. DESIGN: From the Stratton Veterans Affairs Medical Center
computerized database, we collected information on patients with HCV infection
enrolled in hepatology clinic. We collected information on age, sex, duration
of HCV infection, concomitant diagnoses, medications they were on, laboratory
values including hepatic function, glucose, and lipid levels. We collected
information on the lipid levels and various cardiovascular risk factors. METHODS:
This is a retrospective study involving record review. We analyzed the data
collected from the records for prevalence of high cholesterol (as defined by
the National Cholesterol Education Program) and for prevalence of various
cardiovascular risk factors. We analyzed prevalence of treatment of
hyperlipidemia in various risk groups. In the patients who were treated for
hyperlipidemia, we collected information on any worsening hepatic function that
led to treatment discontinuation. RESULTS: Six hundred and twenty-eight
(70.5%) out of 891 patients with hepatitis C had hyperlipidemia. Of the 628
patients who had hyperlipidemia, 81 (12.7%) had positive antibody and RNA not
tested; 162 (25.4%) had positive antibody but negative RNA testing; and 385
(61.3%) had positive testing for viral RNA. Two hundred and eighty-four (45.2%)
of 628 patients with hyperlipidemia were eligible for treatment to lower it. Of
146 patients with hyperlipidemia and diabetes mellitus or arterial disease who
were qualified for treatment (LDL >99), 95 (65.1%) were treated with
lipid-lowering medication. Of 148 patients with hyperlipidemia and without
diabetes or arterial disease who were qualified for treatment, 64 (43.3%) were
treated with lipid-lowering medication. CONCLUSION: A high prevalence of
hyperlipidemia in patients infected with HCV is observed. Prevalence is highest
among those who are positive for viral RNA. About half the patients with
hyperlipidemia were eligible for treatment with drugs to lower it. Treatment of
hyperlipidemia with medication though surprisingly common could improve.
Hepatitis C virus-infected patients
are 'spared' from the metabolic syndrome but not from insulin resistance. A
comparative study of nonalcoholic fatty liver disease and hepatitis C
virus-related steatosis. Lonardo A, Ballestri S, Adinolfi LE, et al. [ ]14:
Can J Gastroenterol. 2009 Apr;23(4):273-8.
BACKGROUND:
Nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C feature
steatosis and insulin resistance (IR), conditions associated with the metabolic
syndrome (MS). OBJECTIVES: To assess the prevalence of MS and
determinants of IR in patients with NAFLD and chronic hepatitis C. METHODS:
Ninety-three consecutive patients with NAFLD, 97 with chronic hepatitis C virus
(HCV) genotypes 1 and 2, and 182 'healthy' controls without steatosis were
enrolled in the present study. The prevalence of MS was assessed by modified
Adult Treatment Panel III criteria and IR by the homeostasis model assessment
of insulin resistance (HOMA-IR). IR was defined as the 75th percentile of the
HOMA-IR of control subjects. RESULTS: While the prevalence of IR was
similar in NAFLD and HCV-infected subjects (70.0% and 78.7%, respectively), the
prevalence of MS was significantly higher in NAFLD patients than in HCV-infected
patients (27.9% versus 4.1%) and in controls (5.6%). With multivariate
analysis, IR was predicted by body mass index (OR 1.263; 95% CI 1.078 to 1.480)
and triglyceridemia (OR 1.011; 95% CI 1.002 to 1.020) in NAFLD and by sex (OR
for female sex 0.297; 95% CI 0.094 to 0.940) and fibrosis stage (OR 2.751; 95%
CI 1.417 to 5.340) in chronic hepatitis C. CONCLUSIONS: IR is
independently associated with body mass index and triglyceridemia in NAFLD, sex
and fibrosis in chronic HCV infection, and has a higher prevalence in NAFLD and
chronic hepatitis C than in controls. However, the frequency of MS in
HCVinfected patients, similar to that of controls, is significantly lower than
that seen in NAFLD patients. The current diagnostic criteria of MS are more likely
to 'capture' patients with NAFLD than with chronic hepatitis C, although both
groups are insulin resistant.
Basic
and Applied Science, Pre-Clinical Studies
Clinical
features and effect of antiviral therapy on anti-liver/kindey microsomal
antibody type 1 positive chronic hepatitis C.
Ferri S,
Muratori L, Quarneti C, et al. J Hepatol. 2009 Mar 26. [Epub ahead of print]
BACKGROUND/AIMS: Anti-liver/kidney microsomal antibody
type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is
also detected in a small proportion of patients with hepatitis C. This study
aimed to evaluate clinical features and effect of antiviral therapy in patients
with hepatitis C who are anti-LKM1 positive. METHODS: Sixty consecutive anti-LKM1 positive and 120 age and
sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at
diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72
anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by
indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes
and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. RESULTS: At diagnosis anti-LKM1
positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes
(p 0.022 and 0.046, respectively). Viral genotypes distribution and response to
therapy were identical. Hepatitic flares during antiviral treatment only
occurred in a minority of patients in concomitance with anti-LKM1 positivity. CONCLUSIONS: Immune system activation
is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly
representing the expression of autoimmune mechanisms of liver damage. Antiviral
treatment is as beneficial in these patients as in anti-LKM1 negative patients,
and the rare necroinflammatory flares are effectively controlled by
corticosteroids, allowing subsequent resumption of antiviral therapy.
Roles
for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in
hepatitis C virus replication. Berger
KL, Cooper JD, Heaton NS, et al. Proc Natl Acad Sci U S A. 2009 Apr 17. [Epub
ahead of print]
Hepatitis C virus (HCV) reorganizes
cellular membranes to establish sites of replication. The required host
pathways and the mechanism of cellular membrane reorganization are poorly
characterized. Therefore, we interrogated a customized small interfering RNA
(siRNA) library that targets 140 host membrane-trafficking genes to identify
genes required for both HCV subgenomic replication and infectious virus
production. We identified 7 host cofactors of viral replication, including
Cdc42 and Rock2 (actin polymerization), EEA1 and Rab5A (early endosomes),
Rab7L1, and PI3-kinase C2gamma and PI4-kinase IIIalpha (phospholipid
metabolism). Studies of drug inhibitors indicate actin polymerization and
phospholipid kinase activity are required for HCV replication. We found
extensive co-localization of the HCV replicase markers NS5A and double-stranded
RNA with Rab5A and partial co-localization with Rab7L1. PI4K-IIIalpha
co-localized with NS5A and double-stranded RNA in addition to being present in
detergent-resistant membranes containing NS5A. In a comparison of type II and
type III PI4-kinases, PI4Ks were not required for HCV entry, and only
PI4K-IIIalpha was required for HCV replication. Although PI4K-IIIalpha siRNAs
decreased HCV replication and virus production by almost 100%, they had no
effect on initial HCV RNA translation, suggesting that PI4K-IIIalpha functions
at a posttranslational stage. Electron microscopy identified the presence of
membranous webs, which are thought to be the site of HCV replication, in
HCV-infected cells. Pretreatment with PI4K-IIIalpha siRNAs greatly reduced the
accumulation of these membranous web structures in HCV-infected cells. We
propose that PI4K-IIIalpha plays an essential role in membrane alterations
leading to the formation of HCV replication complexes.
Angiotensin
1-7, an alternative metabolite of the renin-angiotensin system, is upregulated
in human liver disease and has antifibrotic activity in the bile duct ligated
rat. Lubel JS, Herath
CB, Tchongue J, et al. Clin Sci (Lond). 2009 Apr 16. [Epub ahead of print]
Angiotensin 1-7 (Ang-(1-7)) a peptide
product of the recently described angiotensin converting enzyme (ACE)
homologue, ACE2, opposes the harmful actions of angiotensin II (Ang II) in
cardiovascular tissues, but its role in liver disease is unknown. Our objective
was to assess plasma levels of Ang-(1-7) in human liver disease and determine
its effects in experimental liver fibrosis. Angiotensin peptide levels were
measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects
of Ang-(1-7) on experimental fibrosis were determined using the rat bile duct
ligation (BDL) model. Liver histology, hydroxyproline quantification and
expression of fibrosis related genes were assessed. Expression or
renin-angiotensin system components and the effects of Ang-(1-7) were examined
in rat hepatic cells (HSC). In human cirrhotics both plasma Ang-(1-7) and Ang
II concentrations were markedly elevated (P<0.001). Non-cirrhotic hepatitis
C patients had elevated Ang-(1-7) levels compared with controls (P<0.05),
but Ang II concentrations were not increased. In BDL rats, Ang-(1-7) improved
fibrosis stage, collagen picrosirius red staining, and reduced hydroxyproline
content together with reduced gene expression of collagen 1A1, alpha-SMA, VEGF,
CTGF, ACE and mas (the Ang-(1-7) receptor). Cultured HSC expressed AT1 and mas
receptors, and when treated with Ang-(1-7) or the mas receptor agonist AVE 0991
produced less alpha-SMA and hydroxyproline, an effect reversed by the mas
receptor antagonist, A779. Ang-(1-7) is upregulated in human liver disease and
has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas
axis represents a potential target for antifibrotic therapy in humans.
Hepatitis
C virus and disrupted interferon signaling promote lymphoproliferation via type
II CD95 and interleukins. Machida
K, Tsukiyama-Kohara K, Sekiguch S, et al. [ ]44: Gastroenterology. 2009 Apr 8.
[Epub ahead of print] Related
Articles, LinkOut
Background & Aims: The molecular mechanisms of
lymphoproliferation associated with the disruption of interferon (IFN)
signaling and chronic hepatitis C virus (HCV) infection are poorly understood.
Lymphomas are an extrahepatic manifestations of HCV infection; we sought to
clarify the molecular mechanisms of these processes. Methods: We
established interferon regulatory factor-1null ( irf-1 -/-) mice with inducible
and persistent expression of HCV structural proteins ( irf-1 / CN2 mice). All
the mice ( n =900) were observed for at least 600 days after Cre/loxP
switching. Histologic analyses, as well as analyses of lymphoproliferation,
sensitivity to Fas-induced apoptosis, colony formation, and cytokine production
were performed. Proteins associated with these processes were also assessed. Results:
Irf-1 / CN2 mice had extremely high incidences of lymphomas and
lymphoproliferative disorders and displayed increased mortality. Disruption of
irf-1 reduced the sensitivity to Fas-induced apoptosis and decreased the levels
of caspases -3/7 and -9 mRNA species and enzymatic activities. Furthermore, the
irf-1 / CN2 mice showed decreased activation of caspases -3/7 and -9 and
increased levels of IL-2, IL-10, and Bcl-2, as well as increased Bcl-2
expression, which promoted oncogenic transformation of lymphocytes. IL-2 and
IL-10 were induced by the HCV core protein in splenocytes. Conclusions:
Disruption of IFN signaling resulted in lymphoma development, indicating that
differential signaling occurs in lymphocytes compared with liver. This mouse
model, in which HCV expression and disruption of IFN signaling synergize to
promote lymphoproliferation, will be an important tool for the development of
therapeutic agents that target the lymphoproliferative pathway.
HIV/HCV
Coinfection
Hepatitis B and C virus coinfection: A
novel model system reveals the absence of direct viral interference. Bellecave P,
Gouttenoire J, Gajer M, et al. Hepatology. 2009 Mar 16. [Epub ahead of print]
Coinfection
with hepatitis B virus (HBV) and hepatitis C virus (HCV) has been associated
with severe liver disease and frequent progression to cirrhosis and
hepatocellular carcinoma. Clinical evidence suggests reciprocal replicative
suppression of the two viruses, or viral interference. However, interactions
between HBV and HCV have been difficult to study due to the lack of appropriate
model systems. We have established a novel model system to investigate interactions
between HBV and HCV. Stable Huh-7 cell lines inducibly replicating HBV were
transfected with selectable HCV replicons or infected with cell culture-derived
HCV. In this system, both viruses were found to replicate in the same cell
without overt interference. Specific inhibition of one virus did not affect the
replication and gene expression of the other. Furthermore, cells harboring
replicating HBV could be infected with cell culture-derived HCV, arguing
against superinfection exclusion. Finally, cells harboring replicating HBV
supported efficient production of infectious HCV. Conclusion: HBV and HCV can
replicate in the same cell without evidence for direct interference in vitro.
Therefore, the viral interference observed in coinfected patients is probably
due to indirect mechanisms mediated by innate and/or adaptive host immune
responses. These findings provide new insights into the pathogenesis of HBV-HCV
coinfection and may contribute to its clinical management in the future.
Hepatitis C virus coinfection does not
influence the CD4 cell recovery in HIV-1-infected patients with maximum
virologic suppression. Peters L, Mocroft A, Soriano V, Rockstroh JK, Losso
M, Valerio L, Aldins P, Reiss P, Ledergerber B, Lundgren JD; EuroSIDA Study
Group. J Acquir Immune Defic Syndr. 2009 Apr 15;50(5):457-63.
BACKGROUND: Conflicting
data exist whether hepatitis C virus (HCV) affects the CD4 cell recovery in
patients with HIV starting antiretroviral treatment. OBJECTIVE: To
investigate the influence of HCV coinfection on the CD4 recovery in patients
with maximum virologic suppression within the EuroSIDA cohort. METHODS:
Patients tested for anti-HCV antibodies and with at least 2 consecutive HIV viral
loads (VLs) <50 copies per milliliter after starting combination
antiretroviral therapy were eligible for inclusion. For each pair of VL <50
copies per milliliter, the annual change in CD4 count was calculated and
compared between (1) HCV-seronegative vs. HCV-seropositive patients, (2) HCV
genotypes 1-4 in HCV-RNA+ patients, and (3) viremic vs. aviremic (HCV-RNA <
615 IU/mL) in HCV-seropositive patients. Results were adjusted for known
confounders. RESULTS: Four thousand two hundred eight patients were included,
representing 39,474 pairs of HIV VL measurements with VL <50 copies per
milliliter and 12,492 person-years of follow-up. The unadjusted annual change
in CD4 count for HCV-seropositive and HCV-seronegative patients was 35.5 cells
per milliliter (95% confidence interval 27.2 to 43.9) and 38.3 cells per
milliliter (95%confidence interval 34.8 to 41.9), respectively. After
adjustment, there was no difference in CD4 change when comparing, according to
HCV serostatus (P = 0.17), between genotypes (P = 0.23) or when comparing HCV
viremic vs. aviremic patients (P = 0.57). Adjusting additionally for HCV
treatment and HCV-RNA VL did not change the findings. CONCLUSIONS: HCV
serostatus did not influence the CD4 recovery in patients with HIV with maximum
virologic suppression after starting combination antiretroviral therapy.
Furthermore, no difference in CD4 gain was found when comparing distinct HCV
genotypes in HCV-RNA+ patients or when comparing HCV viremic vs. aviremic
HCV-seropositive patients.
Pegylated interferon {alpha}2a plus
ribavirin versus pegylated interferon {alpha}2b plus ribavirin for the
treatment of chronic hepatitis C in HIV-infected patients. Berenguer J,
González-García J, López-Aldeguer J, et al. Antimicrob Chemother. 2009 Apr 10.
[Epub ahead of print]
Objectives: The two currently available types of pegylated
interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic
properties. It is unclear how these differences affect response to therapy. We
compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b,
both with ribavirin, against chronic hepatitis C virus (HCV) infection in
HIV-infected patients. Methods:
From the GESIDA HIV/HCV cohort, we analysed patients treated with
peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint
was a sustained virological response (SVR). Results: Both groups were well matched in baseline
characteristics except for a higher frequency of injection drug users in the
peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P =
0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the
peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P =
0.04). End-of-treatment response was significantly lower among patients treated
with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence
interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences
were found in SVR between patients treated with peg-IFN-alpha2b and those
treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P =
0.655). Therapy was interrupted due to adverse events in 33 (14%) patients
treated with peg-IFN-alpha2b and 47 (15%) patients treated with
peg-IFN-alpha2a. Conclusions:
No differences in effectiveness and safety were found between peg-IFN-alpha2b
and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected
patients.
Hepatitis C seropositivity and kidney
function decline among women with HIV: Data from the Women's Interagency HIV
Study. Tsui J, Vittinghoff E, Anastos K, Augenbraun M, et al. [ ]42: Am J Kidney
Dis. 2009 Apr 24. [Epub ahead of print]
BACKGROUND: How
coinfection with hepatitis C virus (HCV) impacts on the trajectory of kidney
function in human immunodeficiency virus (HIV)-infected patients is unclear.
This study examined the effect of HCV infection on kidney function over time in
women infected with HIV. STUDY DESIGN: Retrospective observational cohort. SETTING
& PARTICIPANTS: Study sample included participants from the Women's
Interagency HIV Study who were HIV infected and had undergone HCV antibody
testing and serum creatinine measurement at baseline. PREDICTOR: HCV
seropositivity. OUTCOMES & MEASUREMENT: Estimated glomerular
filtration rate (eGFR) calculated from semi-annual serum creatinine
measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD)
Study equation. Linear mixed models were used to evaluate the independent
effect of HCV seropositivity on eGFR over time, adjusting for demographic
factors, comorbid conditions, illicit drug use, measures of HIV disease status,
use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73
m(2)). RESULTS: Of 2,684 HIV-infected women, 952 (35%) were found to be
HCV seropositive. In 180 women with chronic kidney disease (CKD) at baseline (eGFR
< 60 mL/min/1.73 m(2)), HCV seropositivity was independently associated with
a fully adjusted net decrease in eGFR of approximately 5% per year (95%
confidence interval, 3.2 to 7.2) relative to women who were seronegative. In
contrast, HCV infection was not independently associated with a decrease in
eGFR in women without low eGFR at baseline (P < 0.001 for interaction). LIMITATIONS:
The MDRD Study equation has not been validated as a measure of GFR in persons
with HIV or HCV infection. Proteinuria was not included in the study analysis.
Because the study is observational, effects of residual confounding cannot be
excluded. CONCLUSIONS: In HIV-infected women with CKD, coinfection with
HCV is associated with a modest, but statistically significant, decrease in
eGFR over time. More careful monitoring of kidney function may be warranted for
HIV-infected patients with CKD who are also coinfected with HCV.
Epidemiology,
Diagnostics, and Miscellaneous Works
Perceived
knowledge of blood-borne pathogens and avoidance of contact with infected
patients. Kagan I,
Ovadia KL, Kaneti T. J Nurs Scholarsh. 2009 Mar;41(1):13-9.
PURPOSE:
To examine the
relationship between nurses' knowledge of blood-borne pathogens (BBPs), their
professional behavior regarding handwashing, compliance with standard
precautions (SPs), and avoidance of therapeutic contact with BBP-infected
patients. DESIGN: This
cross-sectional design study took place in a regional medical center in Central
Israel during 2003. METHODS: Of the
180 participants, 159 (88.3%) were women with an average educational level of
16.40 years (SD=2.66). The mean age of the sample was 39.41 (SD=10.1). Data
were collected using a structured questionnaire including sociodemographic
information, level of knowledge concerning three BBPs (human immunodeficiency
virus [HIV], hepatitis B virus [HBV], and hepatitis C virus [HCV]), level of
compliance with SPs, understanding of SP principles, and avoidance of
therapeutic contact with BBP-infected patients. FINDINGS: Levels of HIV-related knowledge were significantly higher
than were those of HBV- and HCV-related knowledge. Only 96 participants (54.5%)
stated that all patients should be treated as BBP-carriers. The understanding
of the basic principle of SPs did not influence the relationship between
perceived knowledge and self-reported compliance with SPs; 77.3% of the sample
reported that they avoid therapeutic contact with BBP-infected patients. The
level of perceived knowledge did not contribute to the nurses' avoidance of
care of BBP carriers. CONCLUSIONS:
Perceived knowledge of BBPs has a weak effect on compliance with SPs and
willingness to care for BBP-infected patients. RECOMMENDATIONS: Nurses must identify their preconceptions when
caring for BBP-carriers. Further research on this issue is needed to attempt to
understand the forces acting on our nursing staff, in order to ensure
appropriate care of BBP-infected patients. CLINICAL
RELEVANCE: Our study indicated some reluctance among nurses to care for
patients with blood-borne pathogens. This appears to be the result of value
systems and not a lack of knowledge, indicating a need to integrate a
psychoeducational approach to education of nurses.
Treatment
of chronic hepatitis C in Asia: when East meets West. Yu ML, Chuang WL. J Gastroenterol
Hepatol. 2009 Mar;24(3):336-45.
The issue of best treatment for
chronic hepatitis C virus (HCV) infection is in constant flux, not only in
Western countries but also in Asia. Currently, pegylated-interferon plus
ribavirin is the standard of care. Studies from Asia provide evidence to support
the same broad treatment strategies for Asian patients as recommended in
Western countries. Nevertheless, there is increasing evidence that Asians have
a higher likelihood of achieving a sustained virological response (SVR) than
their Caucasians counterparts when treated with the corresponding regimen. With
the recommended 'standard dose and duration treatment regimens', SVR is
achieved in Asia for around 70% of HCV genotype 1 (HCV-1) infected cases,
approximately 90% of HCV-2/3, approximately 65% of HCV-4, and approximately 80%
of HCV-6 patients. Difference of body weight in race might contribute the
superior response in Asian patients. HCV genotype distribution in Asia also
differs from North-America/Europe. HCV-6 and its variants, previously mistyped
as HCV-1, needs accurate genotyping. Increasing data support the proposal that
HCV genotype, baseline viral load and on-treatment virological response provide
information for decision-making so that treatment can be individualized. Beyond
the older recommendations, an abbreviated 24-week regimen could be suggested
for HCV-1/4 patients with baseline viral loads < 400 000 IU/mL and a rapid
virological response (RVR, HCV RNA undetectable at week 4), and an abbreviated
12-16 weeks of pegylated-interferon with weight-based doses of ribavirin could
be suggested for HCV-2/3 patients with a RVR. Such tailored treatment regimens
can reduce the costs of treatment and incidence of adverse events without
compromising efficacy. Hepatitis C virus (HCV) infection is one of the most
important causes of cirrhosis worldwide, and particularly in some countries of
Asia (notably Japan) where it is now more prevalent than chronic hepatitis B
virus infection. Hepatitis C virus infection can also lead to hepatocellular
carcinoma (HCC). It is estimated that there are more than 170 million people
chronically infected with HCV, and 3 to 4 million persons are newly infected
each year. The risk for developing cirrhosis 20 years after initial HCV
infection among those chronically infected varies between studies, but is
estimated at around 10%-15% for men and 1-5% for women. Once cirrhosis is
established, the rate of developing HCC is at 1%-4% per year. Approximately 280
000 deaths per year are related to HCV infection. Hepatitis C virus-related
end-stage liver disease and HCC have become the leading cause for liver
transplantation worldwide. In the Asia-Pacific area, the estimated prevalence
of antibodies to HCV (anti-HCV) range from 0.3% in New Zealand to 5.6% in
Thailand. In Japan, Middle East, Vietnam and Taiwan, several HCV hyper-endemic
areas have been reported with an anti-HCV prevalence rate of 12% to as high as
58%. In addition to the well-known endemic status of HBV infection in most
countries of the Asia-Pacific region, HCV infection presents another critical
scenario of public health issue in this region, as outlined in Guidelines by
the Asia-Pacific Association for Study of the Liver (APASL). Given the lack of
an effective vaccine, optimal treatment of chronic HCV infection is now
perceived as a 'must' in terms of public health strategies, as well as of the
clinical setting for individual patients.
The
impact of needle and syringe programs on HIV and HCV transmissions in injecting
drug users in Australia: A model-based analysis. Kwon JA, Iversen J, Maher L, Law MG,
Wilson DP. J Acquir Immune Defic Syndr. 2009 Apr 21. [Epub ahead of print]
OBJECTIVES: We aim to estimate how changes in
sterile syringe distribution through needle-syringe programs (NSPs) may affect
HIV and hepatitis C virus (HCV) incidence among injecting drug users (IDUs) in
Australia. METHODS: We develop a
novel mathematical model of HIV and HCV transmission among IDUs who share
syringes. It is calibrated using biological and Australian epidemiological and
behavioral data. Assuming NSP syringe distribution affects the number of times
each syringe is used before disposal, we use the model to estimate the
relationship between incidence and syringe distribution. RESULTS: HIV is effectively controlled through NSP distribution of
sterile syringes {with the effective reproduction ratio below 1 [0.66 median,
interquartile range (0.63-0.70)] under current syringe distribution}. In
contrast, HCV incidence is expected to remain high and its control is not
feasible in the foreseeable future. The proportion of injections that are
shared and the number of times each syringe is used before disposal are the
driving factors of HCV incidence. The frequency in which each syringe is used
can potentially be influenced by changes in syringe distribution. We estimate
that if syringe distribution or coverage doubled, then annual incidence is
likely to reduce by 50%. However, if it was decreased to one third of the current
level, then approximately 3 times the incidence could be expected. CONCLUSIONS: This research highlights
the large benefits of NSPs, puts forward a quantitative relationship between
incidence and syringe distribution, and indicates that increased coverage could
result in significant reductions in viral transmissions among IDUs.
Evaluation
of a patient referral contact tracing programme for hepatitis B and C virus
infection in drug injectors. Brewer
DD, Hagan H. Euro Surveill. 2009 Apr 9;14(14):5-9.
Effective contact tracing for
hepatitis B virus (HBV) and hepatitis C virus (HCV) infection could enhance
disease control, especially in populations with low HBV vaccination rates and
high prevalence of untreated HCV infection. We evaluated a low-cost approach to
HBV/HCV contact tracing in injection drug users (IDUs). Index cases (n=26) were
IDUs who seroconverted to HBV and/or HCV during a prospective cohort study in
Seattle. Interviewers elicited index cases' recent injection partners and
administered recall cues and other techniques to boost recall. Index cases
received vouchers for free hepatitis testing, which they were to give to
locatable partners. Persons redeeming vouchers also received small monetary
incentives. Most (26/40) seroconverters participated in the paid contact
interviews. Index cases reported many partners (mean=17), and in the aggregate,
index cases indicated they could refer more than one third of their elicited
partners for testing. Overall, only 17 persons were ultimately referred and
just eight of these were confirmed as partners sought for referral. The
supplementary elicitation techniques, and especially the recall cues, increased
reporting of injection partners substantially. The injection network
constructed from reported partnerships was mostly connected and cyclic.
Successful contact tracing in IDUs likely requires active involvement by public
health staff to locate and notify exposed injection partners.
Psychopathological
changes and quality of life in hepatitis C virus-infected, opioid-dependent
patients during maintenance therapy. Schäfer
A, Wittchen HU, Backmund M, et al. Addiction. 2009 Apr;104(4):630-40.
AIMS: To examine among maintenance patients
(methadone or buprenorphine) with and without hepatitis C virus (HCV) infection
(i) the frequency of psychopathological symptoms at baseline and 1-year
follow-up; (ii) the association between antiviral interferon (IFN) treatment
and psychopathological symptoms; and (iii) to explore whether IFN therapy has
an effect on 1-year outcome of maintenance treatment. DESIGN: Naturalistic
prospective longitudinal cohort design. SETTING:
A total of 223 substitution centres in Germany. PARTICIPANTS: A nationally representative sample of 2414
maintenance patients, namely 800 without and 1614 with HCV infection, of whom
122 received IFN therapy. MEASURES: HCV infection (HCV+/HCV-), IFN (IFN+/IFN-)
treatment status and clinical measures. Diagnostic status and severity (rated
by clinician), psychopathology (BSI--Brief Symptom Inventory) and quality of
life (EQ-5D--EuroQol Group questionnaire). FINDINGS:
HCV+ patients revealed indications for a moderately increased psychopathological
burden and poorer quality of life at baseline and follow-up compared to HCV-
patients. HCV+ patients showed a marked deterioration over time only in the BSI
subscale somatization (P = 0.002), and the frequency of sleep disorders almost
doubled over time (12.8% at baseline; 24.1% at follow-up; P < 0.01). IFN
treatment, received by 10% of HCV+ patients, did not impair efficacy or
tolerability of maintenance therapy and was associated overall with neither
increased psychopathological burden nor reduced quality of life. CONCLUSIONS: Findings suggest no
increased risk among HCV+ patients on maintenance therapy for depressive or
other psychopathological syndromes. In our patient sample, IFN treatment was
not associated with increased psychopathological burden, reduced quality of
life or poorer tolerability and efficacy of maintenance treatment.