Telbivudine

Dec 1, 2006
Formulary

NOVARTIS

Synthetic thymidine nucleoside analogue approved for the treatment of
chronic HBV

Telbivudine was approved on October 25, 2006, for the treatment of chronic
hepatitis B virus (HBV) in adult patients with evidence of viral replication
and either evidence of persistent elevations in serum aminotransferases (ALT
or AST) or histologically active disease. This agent is phosphorylated by
cellular kinases to its active triphosphate form, which inhibits HBV DNA
polymerase, thus inhibiting HBV replication.

Efficacy. The efficacy of telbivudine was evaluated in the 007 GLOBE study,
which enrolled 1,367 nucleoside-naïve patients with chronic HBV, evidence of
HBV infection with viral replication (HBsAg-positive, HBeAg-positive or
HBeAg-negative, HBV DNA detectable by PCR assay), elevated ALT levels
≥1.3 times the upper limit of normal, and chronic inflammation on
liver biopsy compatible with chronic viral hepatitis. Patients were
randomized to receive either telbivudine 600 mg once daily or lamivudine 100
mg once daily for up to 104 weeks. The primary data analysis was performed
at Week 52. The primary outcome for evaluating therapeutic response was a
composite serologic end point requiring suppression of HBV DNA to <5 log10
copies/mL plus either loss of serum HBeAg or normalization of ALT. At Week
52, 75% of both HBeAg-positive and HBeAg-negative patients treated with
telbivudine had achieved a therapeutic response, whereas 67% of
HBeAg-positive and 77% of HBeAg-negative patients treated with lamivudine
had achieved a therapeutic response. HBeAg-positive and HBeAg-negative
patients who were treated with telbivudine achieved mean HBV DNA reduction
from baseline of –6.45 and –5.23 log10 copies/mL, respectively, compared
with –5.54 and –4.40 log10 copies/mL among lamivudine-treated HBeAg-positive
and HBeAg-negative patients, respectively.

Safety. Lactic acidosis and severe hepato-megaly with steatosis, including
fatal cases, have been reported in patients using nucleoside analogues alone
or in combination with antiretroviral drugs. Severe acute exacerbations of
HBV have been reported in patients who have discontinued anti-HBV therapy.
Hepatic function should therefore be monitored closely with clinical and
laboratory follow-up for at least several months in patients discontinuing
anti-HBV therapy. Uncomplicated myalgia has been reported in patients
treated with telbivudine. Cases of myopathy have been reported in
telbivudine-treated patients several weeks to months after therapy
initiation. If myopathy is suspected, telbivudine therapy should be
interrupted; if myopathy is diagnosed, telbivudine therapy should be
discontinued. The most common adverse events reported in association with
telbivudine treatment include fatigue and malaise, abdominal pain, headache,
cough, nausea and vomiting, influenza-like symptoms, and diarrhea. Increases
in creatine kinase levels also have been reported. Periodic monitoring of
hepatic function during treatment is recommended.

Dosing. The recommended dosage of telbivudine for the treatment of chronic
HBV in patients with creatinine clearance &#8805;50 mL/min is 600 mg once
daily. In patients with creatinine clearance 30 to 49 mL/min, telbivudine
600 mg should be administered once every 48 hours, and in patients with
creatinine clearance <30 mL/min, telbivudine 600 mg should be administered
once every 72 hours. In patients with end-stage renal disease, telbivudine
600 mg should be administered after hemodialysis once every 96 hours.

http://www.formularyjournal.com/formulary/article/articleDetail.jsp?id=393073

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Tillmann HL, , , , , .Antiviral therapy and resistance with hepatitis B
virus infection.
World J Gastroenterol 2007 January;13(1):125-140

Antiviral therapy and resistance with hepatitis B virus infection

Tillmann HL, , , , , .

University of Leipzig, Philipp-Rosenthal Street 27, Leipzig 04103, Germany.
hans.tillmann@...

Hepatitis B virus (HBV) infection is still the most common cause of
hepatocellular carcinoma and liver cirrhosis world wide. Recently, however,
there has been quite dramatic improvement in the understanding of HBV
associated liver disease and its treatment. It has become clear that high
viral replication is a major risk factor for the development of both
cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine
lowers the risk of HBV associated complications. There are currently three
nucleos(t)ides licensed, in addition to interferon, and there are more drugs
coming to the market soon. Interferon or its pegylated counterpart are still
the only options for treatment with defined end points, while nucleos(t)ides
therapy is used mostly for long term treatment. Combination therapies have
not been shown to be superior to monotherapy in naive patients, however, the
outcome depends on how the end point is defined. Interferon plus lamivudine
achieves a higher viral suppression than either treatment alone, even though
Hbe-seroconversion was not different after a one year treatment.
HBV-genotypes emerge as relevant factors, with genotypes "A" and "B"
responding relatively well to interferon, achieving up to 20% HBsAg
clearance in the case of genotype "A". In addition to having a defined
treatment duration, interferon has the advantage of lacking resistance
selection, which is a major drawback for lamivudine and the other
nucleos(t)ides. The emergence of resistance against adefovir and entecavir
is somewhat slower in naive compared to lamivudine resistant patients.
Adefovir has a low resistance profile with 3%, 9%, 18%, and 28% after 2, 3,
4, and 5 years, respectively, while entecavir has rarely produced resistance
in naive patients for up to 3 years.

http://www.wjgnet.com/1007-9327/abstract_en.asp?f=125&v=13

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Gastroenterology
Volume 131, Issue 6 , December 2006, Pages 1743-1751
Clinical–liver, pancreas, and biliary tract
Long-term Therapy With Adefovir Dipivoxil for HBeAg-Negative Chronic
Hepatitis B for up to 5 Years

Stephanos J. Hadziyannis, , , Nicolaos C. Tassopoulos‡, E. Jenny Heathcote§,
Ting–Tsung Chang, George Kitis¶, Mario Rizzetto#, Patrick Marcellin, Seng
Gee Lim‡‡, Zachary Goodman§§, Jia Ma, Carol L. Brosgart, Katyna
Borroto–Esoda, Sarah Arterburn, Steven L. Chuck and Adefovir Dipivoxil 438
Study Group

#Azienda Ospedaliera San Giovanni Battista, Turin, Italy
‡Metropolitan Hospital, Athens, Greece
‡‡Division of Gastroenterology, National University Hospital, Singapore
Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece
Service d’Hepatologie, INSERM Unité 481, Centre de Recherche Claude Bernard
sur les Hepatites Virales, Hôpital Beaujon, Clichy, France
Department of Internal Medicine, National Cheng Kung University Hospital,
Tainan, Taiwan
Gilead Sciences, Foster City, California
§Toronto Western Hospital, University of Toronto, Toronto, Canada
§§Armed Forces Institute of Pathology, Washington, DC
¶Georgios Papanikolaou Hospital, Thessaloniki, Greece

Received 15 June 2006;  accepted 7 September 2006.  Available online 20
September 2006.




Background & Aims: Treatment with adefovir dipivoxil for 48 weeks resulted
in clinical improvement in patients with hepatitis B e antigen
(HBeAg)-negative chronic hepatitis B that was lost when treatment was
discontinued. We investigated the efficacy, safety, and resistance profile
of adefovir dipivoxil treatment for up to 240 weeks. Methods: HBeAg-negative
patients were treated double blind with placebo or adefovir dipivoxil 10 mg
once daily for 48 weeks, followed by adefovir dipivoxil from week 49 to 96.
At week 97, 125 patients enrolled in a 144-week, open-label phase. Patients
received adefovir dipivoxil for up to 192 or 240 weeks. Results: Serum
hepatitis B virus (HBV) DNA levels were less than 1000 copies per milliliter
in 67% of patients, and alanine aminotransferase (ALT) levels normalized in
69% after 240 weeks. After 192 or 240 weeks of treatment, over 83% of
patients had improvement in necroinflammation, and over 73% had improvement
in fibrosis. Ishak fibrosis scores improved compared with baseline in 35%,
55%, and 71% of patients after 48, 192, and 240 weeks of adefovir dipivoxil,
respectively. After 240 weeks, the cumulative probability of HBV polymerase
mutations was 29%, but the cumulative probability of mutations with
virologic resistance was 20% and of mutations, virologic resistance, and ALT
elevations was 11%. Slight elevations in creatinine were confirmed in 4 (3%)
patients. Conclusions: Treatment with adefovir dipivoxil for up to 240 weeks
was well tolerated and produced significant, increasing improvement in
hepatic fibrosis, durable suppression of HBV replication, normalization of
liver enzymes, and delayed development of resistance.

Abbreviations: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface
antigen; HBV, hepatitis B virus; LLQ, lower limit of quantification.


Other members of the Adefovir Dipivoxil 438 Study Group are listed in the
Appendix.
Address requests for reprints to: Stephanos J. Hadziyannis, MD, Department
of Medicine, Henry Dunant Hospital, 107 Mesogion Ave, Athens 11526, Greece.
fax: (30) 2106 972 974.

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Incidence of Steatosis in Hepatitis Patients Traced to Race
SUNDAY, Jan. 7 (HealthDay News) -- White hepatitis C patients are more
likely to have a complication known as steatosis than black patients, says a
new study.

Hepatic steatosis, or fat in the liver, is a condition common among people
with the hepatitis C virus. It indicates more advanced disease.

In a study published in the January issue of Hepatology, researchers, led by
Hari Conjeevaram of the Division of Gastroenterology at the University of
Michigan at Ann Arbor, set out to investigate racial differences in
steatosis in people with the hepatitis C virus, genotype I.

The study included 194 black patients and 205 white patients with hepatitis
C. The participants were involved in a study of a treatment for hepatitis C.

Sixty-one percent of the black patients and 65 percent of the white patients
had hepatic steatosis.

After adjusting for other factors associated with steatosis, including body
mass index and insulin resistance, the researchers found that blacks were
approximately half as likely as whites to have hepatic steatosis.

Both insulin resistance and fibrosis were important in how responsive the
patients were to hepatitis C treatment, while obesity and steatosis were
less important, the researchers said.

The study authors concluded that "the importance of these findings is that
insulin resistance is a potentially modifiable factor, so that responses to
antiviral therapy in hepatitis C may be improved by modulation of insulin
signaling and improvements in insulin resistance and glucose control."

More information

The National Digestive Diseases Information Clearinghouse has more about
hepatitis C.

SOURCE: Hepatology, news release, Jan. 2, 2007
http://www.patientlinx.com/healthday/20070107/H600707.cfm

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Parents in Xinjiang drop discrimination suit
By Mure Dickie in Beijing

Published: November 17 2006 13:24 | Last updated: November 17 2006 13:24

An attempt to sue authorities in China's northwestern Xinjiang region over
discrimination against children infected with the Hepatitis B virus has
foundered after parents dropped the case under what activists say was heavy
pressure from local officials.

The failure of the lawsuit highlights the difficulties faced by Chinese who
seek to challenge local authorities in the courts, even in cases where
officials appear to be defying national policy.

Parents of seven Hepatitis B-infected children recently expelled by a top
school in Urumqi, the capital of Xinjiang, sued city education authorities
to compel them to allow the children to resume their studies.

The children were among a group of 19 expelled students despite a national
ban on discrimination against the estimated 120m Chinese who carry the
Hepatitis B virus, which is mainly transmitted at birth, through sexual
contact, or by use of contaminated needles.

China's health ministry says carriers can live, work and study normal, but
Urumqi officials have defended the expulsions as necessary to protect other
pupils and have banned the local student-led health education group that
first publicised the case.

"The families of the seven pupils involved in the lawsuit came under
pressure from local government departments to withdraw it," said Lu Jun, a
health activist and organiser of a popular website for Hepatitis B carriers.

Some parents had been taken to local police stations and told to put their
seal on pre-prepared forms applying for the lawsuit to be withdrawn, and
some who refused had been subjected to round-the-clock close surveillance,
Mr Lu said.

Another person familiar with the case also said harassment by local
authorities had forced the families to drop the suit.

Court officials and Xinjiang police declined to comment. The families of the
expelled pupils could not be reached yesterday.

Zhang Yuanxin, a lawyer representing the families, declined to comment on
the treatment of the plaintiffs.

However, he said he had been ordered not to make contact with his clients
and had only heard about the withdrawal of the lawsuit when informed by the
district court.

The expulsions were a disaster for pupils who had won coveted subsidised
boarding places at the Urumqi No. 15 Middle School but have since had to
return to home villages and towns with vastly inferior educational
facilities.

Mr Zhang said the lawsuit had offered the possibility of an independent
review of local authorities' judgement of the threat posed by Hepatitis B.
"Without a clear verdict, I think similar cases will continue to happen in
Xinjiang," he said.

Activists say prejudice against virus carriers has grown in recent years
amid confusion about how it is transmitted and widespread advertising of
Hepatitis B treatments which has stoked public fears about the disease.

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Risk Factors Identified for New-Onset Diabetes Mellitus After Liver
Transplantation

Laurie Barclay, MD

January 5, 2006 — The emergence of new-onset diabetes mellitus (NODM) after
liver transplant (LT) is related to risk factors that can be detected before
grafting, such as maximum lifetime body mass index (BMI), impaired fasting
glucose (IFG), and hepatitis C virus infection, according to the results of
an observational multicenter study reported in the January issue of Liver
Transplantation.

"[NODM] remains a common complication of [LT]," write Faouzi Saliba, from
the Hôpital Paul Brousse in Villejuif, France, and colleagues from the
Diapason Study Group. "We studied incidence and risk factors in 211 French
patients who had undergone a primary LT between 6 and 24 months previously."

In this cross-sectional and retrospective study, the investigators collected
data on consecutive patients at a single, routine post-LT consultation,
including demographics, immunosuppressive regimens, family and personal
histories, hepatitis status, and cardiovascular risk. These data were
compared between those who developed NODM (American Diabetes
Association/World Health Organization criteria) and those who did not
develop diabetes.

NODM developed in 22.7% of patients overall (24% in tacrolimus (Tac)-treated
patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n =
36; 17.1%). Of these cases, 81% were diagnosed within 3 months of LT. NODM
incidence was 41.7% among hepatitis C virus (HCV)–infected patients compared
with 18.9% among HCV-negative patients (P = .008).

In Tac-treated patients, the incidence of NODM in the HCV-positive patients
was higher than in the HCV-negative patients (46.7% vs 19.3%; P = .0014).
One (16.7%) of 6 HCV-positive patients treated with cyclosporine developed
NODM. Other factors that independently predicted risk for NODM included IFG
before transplantation and a maximum lifetime BMI greater than 25 kg/m2.

"Emergence of NODM after LT is related to risk factors that can be detected
prior to the graft, like maximum lifetime BMI, IFG, and HCV status," the
authors write. "Tac induced a significantly higher incidence of NODM in the
HCV[-positive] compared to the HCV[-negative] patients. The treatment should
therefore be tailored to the patient's risk especially in case of HCV
infection."

Study limitations include cross-sectional and retrospective design.

"Given the insidious onset of the condition and the potential for saving
lives through judicious management tailored to risk profile, it is important
to be vigilant in screening for the presence of NODM in recipients of liver
transplants," the authors conclude. "Our study suggests that it may
eventually be possible to derive a composite risk factor equation for the
development of NODM following liver transplantation with appropriate
weighting for each variable, perhaps similar to the risk assessment
instruments developed for the primary prevention of cardiovascular disease."

The authors report no relevant financial relationships.

In an accompanying editorial, Paul J. Thuluvath, from Johns Hopkins
University School of Medicine in Baltimore, Maryland, points out that this
study confirms the high incidence of NODM after liver transplantation,
although nearly all cases were in patients receiving steroids.

"It is probable that NODM will have an impact on long-term survival, and
therefore it is important to continue to study the impact of NODM and its
intervention on long-term graft and patient survival in patients with and
without HCV," Dr. Thuluvath writes. "As we develop newer immunosuppressive
drugs, we now have the ability to improve the diabetic control by tailoring
and manipulating the medications in liver transplant recipients."

Liver Transplantation. 2007;13:136-144.
Laurie Barclay, MD is a freelance reviewer and writer for Medscape.


Medscape Medical News 2007. © 2007 Medscape
http://www.medscape.com/viewarticle/550334?sssdmh=dm1.237890&src=nldne

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IAC Express
Immunization news from the Immunization Action Coalition

A web page version of this issue is available at
http://www.immunize.org/express/issue639.asp
===============================================================
Issue Number 639
January 8, 2007

CONTENTS OF THIS ISSUE

1. New: CDC, AAP, and AAFP release the 2007 Recommended
     Immunization Schedules for Persons Ages 0-18 Years
2. Reminder: Be sure to continue administering influenza vaccine
     during the early months of 2007
3. Don't miss it: January 10, kaisernetwork.org will present a
     live web cast about administering HPV vaccine
4. Registration begins January 10 for the satellite broadcast
     Epidemiology & Prevention of Vaccine-Preventable Diseases
5. IAC updates its hepatitis C screening questionnaire for adult
     patients
6. Time's running out: January 12 is the early-bird registration
     deadline for the 2007 National Immunization Conference
7. February 9 is the nomination deadline for the fourth annual
     "Natalie J. Smith, MD, Award"
8. Tenth Annual Conference on Vaccine Research scheduled for
     April 30-May 2 in Baltimore

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Response to Pegylated Interferon [alpha]-2b and Ribavirin in Children With
Chronic Hepatitis C.

Liver, Pancreas, and Biliary Tract

Journal of Clinical Gastroenterology. 41(1):111-114, January 2007.
Baker, Robert D. MD, PhD; Dee, Deborah RN, FNP; Baker, Susan S. MD, PhD
Abstract:
Goals: The purpose of this communication is to report our observations on
the treatment of a diverse group of adolescent patients who were chronically
infected with hepatitis C and received pegylated interferon and ribavirin.

Background: The currently accepted optimal therapy for adults with chronic
hepatitis C is weekly injections of pegylated interferon and twice daily
oral ribavirin. Information on interferon alone or in combination with
ribavirin for chronic hepatitis C in children is limited. There is no
published information on pegylated interferon and ribavirin in pediatric
patients who previously failed interferon therapy.

Report: Ten patients 11 to 18 years old received weekly pegylated interferon
and twice daily ribavirin for hepatitis C. Treatment continued for 48 weeks,
except for 1 patient with hepatitis C virus type 3a who was treated for 24
weeks and 1 patient who did not complete the course of treatment. The period
of observation continued from November 2002 to December 2004. Within this
group were 3 pediatric patients who had previously failed interferon therapy
for hepatitis C.

Results: All but 1 patient had a viral response (no detectable virus) at
some time during or after the treatment. Three patients achieved sustained
viral response (no detectable virus 6 mo after the therapy). One patient who
previously failed interferon therapy was among the sustained responders.

Conclusions: In response to treatment with pegylated interferon and
ribavirin, children and adolescents with chronic hepatitis C achieve results
similar to those seen in adults. Previous antiviral therapy does not
preclude positive response to pegylated interferon and ribavirin.

(C) 2007 Lippincott Williams & Wilkins, Inc.

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Active Immunization to Prevent De Novo Hepatitis B Virus Infection in
Pediatric Live Donor Liver Recipients

Authors: Lin, C.-C.1; Chen, C.-L.; Concejero, A.1; Wang, C.-C.1; Wang,
S.-H.1; Liu, Y.-W.1; Yang, C.-H.1; Yong, C.-C.1; Lin, T.-S.1; Jawan, B.2;
Cheng, Y.-F.3; Eng, H.-L.4

Source: American Journal of Transplantation, Volume 7, Number 1, January
2007, pp. 195-200(6)

Publisher: Blackwell Publishing
Abstract:

This study aims to evaluate the efficacy of HBV vaccination as an
alternative preventive measure against de novo HBV infection in pediatric
living donor liver transplantation (LDLT). Sixty recipients were enrolled in
this study. Thirty received grafts from anti-HBc(+) donors, and another 30
received grafts from anti-HBc(−) donors. HBV vaccine was given
pretransplant to every candidate. Posttransplant, lamivudine was routinely
given to recipients receiving anti-HBc(+) grafts for about 2 years.
Forty-seven (78%) recipients achieved high levels of anti-HBs titer (>1000
IU/L). Two (3.3%) recipients developed de novo HBV infection where one
received an anti-HBc(−) graft and another received an anti-HBc(+)
graft. Both recipients were in the lower anti-HBs titer group (<1000 IU/L).
The incidence of de novo HBV infection was significantly higher in the lower
titer group (15.4% vs. 0%, p = 0.04). The median follow-up period was 51
months in recipients with anti-HBc(&#8722;) grafts and 57 months in those
with anti-HBc(+) grafts. Active immunization is an effective method to
prevent de novo HBV infection. It can result in high levels of anti-HBs
titer (>1000 IU/L) which may prevent de novo HBV infection in pediatric
patients with efficient primary vaccination undergoing LDLT.

DOI: 10.1111/j.1600-6143.2006.01618.x

Affiliations: 1: Departments of Surgery and Liver Transplantation Program 2:
Anesthesiology and Liver Transplantation Program 3: Diagnostic Radiology and
Liver Transplantation Program 4: Pathology and Liver Transplantation
Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung,
Taiwan

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American Journal of Otolaryngology
Volume 28, Issue 1 , January 2007, Pages 28-30

Original contribution

Amoxicillin-clavulanic acid–induced hepatitis

Jason Cundiff MD, a,  and Stephanie Joe MDa,

aDepartment of Otalaryngology-Head and Neck Surgery, University of Illinois,
Chicago, IL, USA

Received 17 March 2006.  Available online 9 December 2006.




Abstract
Objectives
The aim of this study was to report a rare side effect of
amoxicillin-clavulanic acid resulting in drug-induced hepatitis in the
treatment of chronic rhinosinusitis.

Methods
This is a case report and literature review of amoxicillin-clavulanic
acid–induced hepatitis in the treatment of chronic rhinosinusitis. A MEDLINE
search of the published literature from 1966 to 2006 was performed using the
term “amoxicillin-clavulanic acid + hepatitis.”

Results
We report a case of a 53-year-old man who developed drug-induced hepatitis
after the use of amoxicillin-clavulanic acid for the treatment of chronic
rhinosinusitis. After a 4-week course of amoxicillin-clavulanic acid, the
patient developed pruritus and jaundice. Liver function tests revealed
elevated aminotransferase levels. Serologic examination result for hepatitis
A, B, and C was negative. The amoxicillin-clavulanic acid was discontinued
and the patient was treated conservatively. The pruritus and jaundice
gradually resolved and the patient had no long-term complications. The
literature review revealed this is the first reported case of
amoxicillin-clavulanic acid–induced hepatitis for the treatment of chronic
rhinosinusitis.

Conclusions
Drug-induced hepatitis is a rare side effect of amoxicillin-clavulanic acid.
Care must be taken in prescribing this drug to elderly patients and patients
with liver disease. In general, the hepatitis is mild to moderate, rarely
leads to liver failure, and can be managed conservatively.

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Hello: Just to let you know about some important updates at
www.hcvadvocate.org and www.hbvadvocate.org


Weekly News Review: Week Ending January 6th, 2007
http://www.hcvadvocate.org/news/newsRev/2007/NewsRev-186.html


January 2007 Newsletter
http://www.hcvadvocate.org/news/newsLetter/2007/advocate0107.html



HBV Journal Review, January 2007
http://www.hbvadvocate.org/news/NewsUpdates_pdf/News_Review_2007/HBJ-4.1.pdf


Study: Health Care Provider Communication
http://www.hcvadvocate.org/community/monmouth.htm


HIV/HCV Coinfection: Pegasys plus Copegus (Updated 2007)
http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Peg_coinfection_2007.pdf



HCV Drug Pipeline **Updated Dec 28th**
http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html



For the Team at HCSP

CD Mazoff, PhD
Managing Editor, Webmaster
HCV Advocate
www.hcvadvocate.org
HBV Advocate
www.hbvadvocate.org

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DIABETICS AT RISK OF HEPATITIS B DUE TO BAD MEDICAL PRACTICES
BY TRUDY SIMPSON

Diabetic residents in nursing and care homes may be at increased risk of
contracting hepatitis B because some staff continue to flout health care
rules by re-using single-use disposable lancing devices.

Despite no shortage of lancing devices, several health care workers are
still using the wrong devices against the advice of health experts, the
Medicines and Healthcare products Regulatory Agency (MHRA) and the Health
Protection Agency (HPA) said.

MHRA healthcare specialists told The Voice that they were still
investigating cases of hepatitis B, a potentially fatal liver damaging
infection, which have apparently spread from resident-to-resident because
staff had re-used disposable lancing devices.

Since 2004, health officials including the local NHS and the Commission for
Social Care Inspection (CSCI), which monitors social care homes, have
recorded 18 cases of inappropriate use in at least six nursing and care
homes, mostly in London.

“Healthcare and care workers taking blood samples from multiple patients
should check that the lancing device that they are using is intended for
multiple patient use,” the MHRA said.


WARNING
Four people have died where hepatitis B was seen as a contributing factor,
they said.

The last death was in June 2005, but health officials issued their third
warning in two years following a suspected case of infection in October
2006.

“The inappropriate use of certain lancing devices by healthcare workers to
take blood samples from diabetic residents in nursing homes and care homes
has been implicated in the transmission of hepatitis B between residents.
This has resulted in acute infections and deaths,” the MHRA said.

The MHRA and the HPA have renewed their calls for increased vigilance and
better management of how these lancing devices are used.

“It is crucial that healthcare workers and other staff within these nursing
and care homes are aware of the correct procedures to prevent infections
such as hepatitis B from being passed onto other patients,” said Dr Mary
Ramsay, who is co-ordinating the investigation for the Health Protection
Agency.

“Our local health protection units have advised staff of the necessary
infection control measures including giving vaccination to all residents and
staff who haven’t previously been vaccinated against, or built up any
immunity to hepatitis B and investigating possible causes of infection.

They also worked to ensure the patients, families and staff members were all
fully informed of the situation,” Ramsay said.

Published: 04 January 2007
Issue: 1250

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In Chronic HCV, African Americans Have Leaner Livers

   By Michael Smith, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of
Pennsylvania School of Medicine.
January 03, 2007

ANN ARBOR, Mich., Jan. 3 -- African Americans with chronic hepatitis C (HCV)
are significantly less likely than Caucasians to have a fatty liver,
according to researchers here. Action Points

Explain to interested patients that hepatic steatosis, or fatty liver, is
common in patients with chronic hepatitis C.


Note that this study found that African-Americans -- for any given level of
obesity and insulin resistance -- had about half the likelihood of steatosis
than did Caucasians.


Caution that in this study, steatosis did not seem to be associated with a
poorer response to therapy.
After controlling for risk factors such as obesity and insulin resistance,
African Americans with chronic HCV had a 46% lower occurrence of hepatic
steatosis than Caucasians, said Hari Conjeevaram, M.D., of the University of
Michigan.


The finding comes from an analysis of volunteers in the Virahep-C trial, a
multicenter study of combination peginterferon and ribavirin in the
treatment of genotype 1 of chronic HCV, Dr. Conjeevaram and colleagues
reported in the January issue of Hepatology.


Steatosis, which has been thought to be associated with a poor response to
therapy, is common in chronic HCV and in this study liver biopsy revealed
the condition in 63% of patients.


The researchers were able to analyze biopsies from 399 of the 401 patients
in the study and found that overall prevalence was similar among 194 African
Americans and 205 Caucasians, at 61% and 65% respectively.


Severity was generally mild, with only 6.5% of the patients having moderate
to severe fat, the researchers found.


The researchers compared the groups on anthropometric, clinical, and
biochemical factors, as well as insulin resistance estimated by the
homeostasis model assessment index, or HOMA-IR.


In a univariate analysis, Dr. Conjeevaram and colleagues reported, steatosis
was associated with insulin resistance, body mass index, waist
circumference, serum triglycerides, aminotransferase level, and histological
scores for inflammation and fibrosis.


But after adjusting for those factors -- which tended to be higher in
African Americans -- an analysis showed a lower risk of steatosis for
African-Americans, compared to Caucasians. The odds ratio was 0.54, with a
95% confidence interval from 0.32 to 0.91, which was significant at P=0.02.


"For a given degree of overweight and obesity or insulin resistance," the
researchers said, "African-Americans were approximately half as likely to
have hepatic steatosis as Caucasian-Americans."


Even mild steatosis was correlated with increased disease severity, as
measured by aminotransferase levels and histological scores for inflammation
and fibrosis, the researchers said.


For instance, the researchers said, bridging fibrosis or cirrhosis was twice
as prevalent in patients with steatosis as in those without - 45% versus
23%, which was statistically significant at P<0.0001.


Fat in the liver was also highly correlated with physical factors associated
with overweight and obesity, such as higher waist-to-hip ratio and body mass
index, they said.


However, the researchers found, in this study steatosis was not associated
with a significantly poorer response to therapy, although insulin resistance
and fibrosis were significant predictors.


One of the authors, Steven Zacks, M.D., of the University of North Carolina
at Chapel Hill, is on the speakers' bureau of Roche and has also received
grants from Salix Pharmaceuticals. The remaining authors reported no
potential conflicts.


http://www.medpagetoday.com/InfectiousDisease/Hepatitis/dh/4795

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Active Immunization to Prevent De Novo Hepatitis B Virus Infection in
Pediatric Live Donor Liver Recipients
Authors: Lin, C.-C.1; Chen, C.-L.; Concejero, A.1; Wang, C.-C.1; Wang,
S.-H.1; Liu, Y.-W.1; Yang, C.-H.1; Yong, C.-C.1; Lin, T.-S.1; Jawan, B.2;
Cheng, Y.-F.3; Eng, H.-L.4

Source: American Journal of Transplantation, Volume 7, Number 1, January
2007, pp. 195-200(6)

Publisher: Blackwell Publishing

Abstract:

This study aims to evaluate the efficacy of HBV vaccination as an
alternative preventive measure against de novo HBV infection in pediatric
living donor liver transplantation (LDLT). Sixty recipients were enrolled in
this study. Thirty received grafts from anti-HBc(+) donors, and another 30
received grafts from anti-HBc(−) donors. HBV vaccine was given
pretransplant to every candidate. Posttransplant, lamivudine was routinely
given to recipients receiving anti-HBc(+) grafts for about 2 years.
Forty-seven (78%) recipients achieved high levels of anti-HBs titer (>1000
IU/L). Two (3.3%) recipients developed de novo HBV infection where one
received an anti-HBc(−) graft and another received an anti-HBc(+)
graft. Both recipients were in the lower anti-HBs titer group (<1000 IU/L).
The incidence of de novo HBV infection was significantly higher in the lower
titer group (15.4% vs. 0%, p = 0.04). The median follow-up period was 51
months in recipients with anti-HBc(&#8722;) grafts and 57 months in those
with anti-HBc(+) grafts. Active immunization is an effective method to
prevent de novo HBV infection. It can result in high levels of anti-HBs
titer (>1000 IU/L) which may prevent de novo HBV infection in pediatric
patients with efficient primary vaccination undergoing LDLT.
Keywords: De novo hepatitis B virus infection; immunization; living donor
liver transplantation; pediatric

Document Type: Research article

DOI: 10.1111/j.1600-6143.2006.01618.x

Affiliations: 1: Departments of Surgery and Liver Transplantation Program 2:
Anesthesiology and Liver Transplantation Program 3: Diagnostic Radiology and
Liver Transplantation Program 4: Pathology and Liver Transplantation
Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung,
Taiwan

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CDC 01/02/07

MAINE:   "Hepatitis B, Influenza B on Maine Radar"
Bangor Daily News    (12.29.06):: Diana Bowley

Officials in Maine have alerted health care providers to watch for symptoms
of hepatitis B following an outbreak in the Bangor area since June and for
influenza B after the state's first case was recently confirmed.

Geoff Beckett, assistant state epidemiologist for the Maine Center for
Disease Control and Prevention, said the hepatitis B outbreak involves some
eight cases. "We have seen a fairly steady stream of hepatitis B cases in
northern, central, and eastern Maine over the past several months," he said.
While some of the cases are believed to have been transmitted sexually,
others were not, he added. Maine typically records an average of 12
hepatitis B cases per year.

Vaccination against hepatitis B has reduced US rates of the infection since
the 1970s and 1980s, said Beckett. Hepatitis B symptoms include jaundice,
abdominal discomfort and joint pain. Around 5-10 percent of people infected
with hepatitis B can develop chronic infection. "It's a significant health
program," he said.

On Dec. 21, Maine recorded its first case of influenza B, which affects the
respiratory system and can cause high fever, Beckett said. The strain is not
as dangerous as influenza A, which led to a pandemic in the early 20th
century.

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Journal of Hepatology
Volume 46, Issue 1 , January 2007, Pages 6-8

Editorial

Does treatment with interferon-based therapy improve the natural history of
chronic hepatitis B infection?

George K.K. Lau, a,

aDepartment of Medicine, Li Ka Shing Faculty of Medicine, The University of
Hong Kong, Rm 1838, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong
Kong SAR, China

Available online 7 November 2006.

Worldwide, approximately 400 million people are chronically infected with
hepatitis B virus (HBV). Most of them reside in the Asia-Pacific region,
such as Southern China and Taiwan, where chronic HBV infection is highly
prevalent (>10%). Among them, around 25–40% will eventually die of liver
disease (viz. cirrhosis with or without hepatocellular carcinoma), largely
due to protracted hepatic necroinflammation (chronic active hepatitis). In
greater China, it is estimated that more than half-a-million deaths were due
to HBV-related liver complications annually [1]. For those patients with
chronic active HBV infection, progression to cirrhosis occurs at an annual
rate of 2–6% in hepatitis B e antigen (HBeAg) positive and 8–10% for HBeAg
negative patients [2], [3] and [4]. Once cirrhosis is established, the
yearly incidence of hepatic decompensation is about 3% [5] and the annual
incidence of hepatocellular carcinoma will be markedly increased from close
to zero percent in inactive HBV carriers [6] to over 2%, with a cumulative
5-year incidence of 15–20% [2] and [7].

The diversity of clinical outcome of HBV infection in humans, either
resolution (immunity) or persistence of infection with protracted hepatic
necroinflammation (immunopathogenesis), is dependent on the host immune
response to the virus [8]. For those with an impaired host immune control to
the virus, there will be protracted hepatic necroinflammation. Therefore, it
is not surprising that among the various risk factors identified for the
progression to cirrhosis and hepatocellular carcinoma, a high level of HBV
replication DNA level (a reflection of impaired host immune control on the
virus) has been identified as the most important factor. The adjusted
relative risk of cirrhosis was 2.3 (95% CI, 1.6–3.5) and 9.3 (95% CI,
6.5–13.1) for baseline serum HBV DNA > 104 and 106, respectively [9], and
for hepatocellular carcinoma, the adjusted odds ratio for patients with the
highest quintile (5.91–10.81 log10 copies/mL) versus those with lowest
quantile (2.77–3.61 log10 copies/mL) of serum HBV DNA was 7.26 (95% CI =
3.54–14.89) [10]. Logically, most of the treatment guidelines emphasize the
necessity of reducing hepatitis B viral load levels in those patients with
active hepatic necroinflammation, as a measure of the effectiveness of
therapy with a long-term goal to reduce the development of liver cirrhosis
and hepatocellular carcinoma [8].

By the year 2006, there are seven agents registered for treatment of chronic
HBV infection. Two are immunomodulatory agents, namely conventional
interferon-á2b and pegylated interferon-á2a, which aim to restore host
immune control on HBV and thus lead to sustained off-treatment disease
remission. The other three agents are all nucleos(t)ide analogues
(lamivudine, adefovir, entecavir and telbuvidine) with direct anti-viral
activity. However, direct antiviral agents have little impact on host immune
response, as reflected by a low rate of HBeAg seroconversion and negligible
hepatitis B surface antigen (HBsAg) seroconversion, and thus most patients
treated with these agents need prolonged or even life-long therapy. The
major limitations of immunomodulatory therapy are: [1] lack of efficacy in
40–60% of patients treated and [2] side effect profile. This has limited its
usage, especially in those patients with decompensated liver cirrhosis,
immune incompetent, other immune-mediated diseases, marrow insufficiency and
psychiatric disorders. On the other hand, the risk of development of viral
resistance increases with prolonged therapy with pure anti-viral agents,
running a risk of worsening of liver function [8].

A million-dollar question is whether these agents really transform the
natural history of chronic HBV infection? Most importantly, does the use of
these agents reduce the risk of liver complications, such as liver cirrhosis
and hepatocellular carcinoma, and hence improve the survival of chronic HBV
patients? These questions could only be answered by well-conducted long-term
follow-up studies (Table 1) [11], [12], [13] and [14]. With the continued
use of lamivudine, disease progression has been shown to be significantly
reduced in chronic HBV patients with advanced fibrosis/cirrhosis. However,
this beneficial effect was markedly diminished with the development of
lamivudine resistance, which increased with prolonged therapy [14]. An
alternative to avoid the use of prolonged maintenance therapy in chronic HBV
patients with nucleos(t)ide analogues is to induce disease remission with
the use of interferon-based therapy at an earlier stage. In keeping with
this, sustained disease remission has been shown to be accelerated in
chronic HBV patients with active hepatitis, treated with conventional
interferon. In Caucasians, it has been demonstrated that treatment with a
finite course of conventional interferon not only will hasten disease
remission but those who have responded were shown to have a better long-term
prognosis with a significant reduction of liver-related mortality [11] and
[13]. In Asians, so far, the long-term follow-up data on the use of
interferon-based therapy on chronic HBV patients with active hepatitis are
limited [12].

Table 1.

Long-term follow-up on chronic HBV patients with active hepatitis or advance
fibrosis/cirrhosis treated with finite duration of conventional interferon
or continuous lamivudine

C, Caucasian; A, Asians; IFN, conventional interferon; LAM, lamivudine.
a Treatment arm was lamivudine instead of interferon.



In this important study by Lin et al., the long-term outcome of interferon-á
therapy in HBeAg positive patients was examined [15]. Altogether, 233
Chinese patients with active hepatitis (baseline serum ALT is 175 IU/l)
treated with a finite course of interferon-based therapy were followed up
for a median of 6.8 years (range 1.1–16.8 years). All treated and untreated
controls were followed up at intervals of at least 3–6 months. Compared to
untreated controls (n = 233) with persistent HBeAg positivity, HBeAg
seroconversion in untreated and interferon-treated patients had a
significantly lower incidence of liver cirrhosis and cancer. This supports
the use of HBeAg seroconversion as a measure of treatment efficacy for HBeAg
positive chronic active hepatitis. An added value of HBeAg seroconversion is
that it is a prerequisite for HBsAg seroconversion and it occurs in up to
one-tenth of those patients treated with interferon-based therapy and
experienced HBeAg seroconversion [16]. Serological clearance of HBsAg is of
paramount importance in the natural history of chronic hepatitis B as its
development will be close to a cure, provided the patient has not already
developed liver cirrhosis or hepatocellular carcinoma [8].

As pointed out by Lin et al., the result of this retrospective study is in
contrast with other reports which showed that interferon therapy has a
minimal effect on reducing the risk of cirrhosis, hepatocellular carcinoma
and liver-related mortality. Compared to the other studies, the present
study has the superiority of studying more patients with appropriate disease
characteristics (active hepatitis) and for a long-enough duration. This is
reflected in the expected outcome of the untreated control group, with an
incidence of liver-related mortality of 11% [15]. This supports the validity
of the design and the conduct of this long-term follow-up study. From the
scientific point of view, having a well-matched control group in a
retrospective study is still only second to ideal design with a long-term
prospective follow-up from the original randomised registration study.
However, with the availability of effective agents for controlling the viral
replication, it is perhaps difficult to keep patients untreated.
Nonetheless, in collaboration with the industrial partners, longer term
off-treatment follow-up study comparing patients treated with
interferon-based therapy to those new and recent more potent nucleos(t)ide
analogues will be awaited.


References <CUT>

Tel.: +852 28184300; fax: +852 28184030.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W7C-4M942B3-6&_user=1\
0&_handle=C-WA-A-BB-BB-MsSAYWA-UUW-U-U-BB-U-U-AAZYEWBECY-AAZZCUVDCY-ACYDYCUWW-BB\
-U&_fmt=full&_coverDate=01%2F31%2F2007&_rdoc=8&_orig=browse&_srch=%23toc%236623%\
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rsion=0&_userid=10&md5=0c1e7663972405ab489ecd83b93b2edd

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Diet Seen to Affect Hepatocellular Cancer Risk

By David Douglas

NEW YORK (Reuters Health) Jan 02 - Certain foods, among them milk and fruit,
appear to reduce the risk of hepatocellular carcinoma (HCC), according to
Italian researchers.

Their study, Dr. Renato Talamini told Reuters Health, "indicated that diet
has a relevant role in the risk of this cancer. As for other types of
cancer, particularly fruits and vegetables seem to confer a protective
effect."

As reported in the December 15th issue of the International Journal of
Cancer, Dr. Talamini of Istituto Nazionale Tumori, Aviano and colleagues
conducted a hospital-based study of 185 HCC patients and 412 controls
without neoplastic disease.

Responses to dietary questionnaires showed a significant inverse correlation
between intake of various foods and HCC risk. After adjustment, the odds
ratio with high intakes of milk and yoghurt was 0.28. For white meat, it was
0.44, for eggs, the corresponding value was 0.31 and for fruit, it was 0.48.
However, overall the apparently protective effects of vegetables did not
reach significance.

The researchers observe that the findings held good for patients with
hepatitis B and hepatitis C virus infection.

Summing up, Dr. Talamini added that from an HCC prevention point of view one
should "adopt a correct diet, rich in fruits and vegetables." Also
important, he added, "is limiting consumption of alcohol beverages and
avoiding HCV infection by practicing safe sex and eliminating needle
sharing."

Int J Cancer 2006;119:2916-2921.
http://www.medscape.com/viewarticle/550120?sssdmh=dm1.236689&src=nldne

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6,000 in Md. Suburbs Barred From Class
Students Lack Required Proof of Vaccinations Despite Big Push by Schools

By Susan Levine
Washington Post Staff Writer
Wednesday, January 3, 2007; Page B01

Despite a "Herculean effort" to get the word out, more than 6,000 students
in Washington's Maryland suburbs were excluded from class yesterday because
they failed to comply with a state vaccination requirement that took effect
with the new year.

Students in grades 6 through 9 who had not provided a record of chickenpox
and hepatitis B vaccinations -- or, in the case of chickenpox,
month-and-year documentation of when they had the disease -- were told they
could not return until they had the necessary paperwork in hand. The only
exceptions were to be those who arrived with proof that they have
appointments to get the shots by Jan. 22.

Some students were held for the day in special rooms or centers in their
schools. Others were sent home.

According to a preliminary count in Prince George's County, more than 4,000
students were without the vaccine records. Spokesman John White said
administrators were discouraged by the lack of response from so many parents
despite repeated outreach and opportunities for free immunizations.

"With there not being a monetary barrier, it's just frustrating," he said.

Statewide, students were given specific notes -- "letters of suspension" in
at least one county -- that administrators hope will get families' attention
in a way that months of announcements, calls, visits and admonitions from
principals have not.

"We've had quite a challenging day," said Helen Monk, the health specialist
in the Frederick County schools, where 327 children remained out of
compliance. Although that figure was down by more than half the total just
before the holiday break, she sounded incredulous that anyone still needed
vaccinations.

"It's been a Herculean effort," Monk said. "You wouldn't believe the time
and work that have gone into this."

The numbers, which local school and health staff members spent frenetic
hours amassing yesterday, ranged from the low hundreds in some counties to
nearly 1,000 or more in other jurisdictions. State officials were not
tallying either the overall public count or that of private and parochial
students.

In St. Mary's County, 381 students had not met the requirement; in Anne
Arundel County, 993.

"It's so crucial for these students to be in school," said Kathleen Lyon,
executive director of student services in St. Mary's. "They're ending the
first semester and preparing for exams."

Montgomery County cut its total by nearly 90 percent from mid-December, to
about 500 students, who took home another warning letter from principals
yesterday after they were barred from class.

"It is of utmost importance that we receive the required documentation as
soon as possible to ensure that your child's instructional program will not
be further interrupted," the letter concluded.

Hours later, schools spokesman Brian Edwards reiterated that message.
"Parents have got to get these situations resolved with their students and
get these students back in school," he said. "Every day missed is a problem
for them."

Some jurisdictions are taking a lenient approach, viewing the weeks until
Jan. 22 as a grace period that allows flexibility. More than 1,600 Howard
County students hadn't supplied verification as of mid-December, the last
count available, but as officials called homes again yesterday, no one was
kept from class.

"We're assisting them to make appointments," said Donna Heller, coordinator
for Howard's school health services. With the health department, the school
system has a free clinic scheduled tomorrow.

Chickenpox and hepatitis B were added to the state's vaccination schedule
for older students because of their potential risks and complications. The
District includes both for every grade. Virginia mandates hepatitis B
immunization for all students and chickenpox shots for those born after Jan.
1, 1997.

States usually set the start of school as the deadline for vaccinations, but
Maryland delayed its date from the fall because of concerns that so many
children would fall short of the expanded requirement. By September 2009,
all grades will need to be immunized against the two infectious diseases to
begin school.

http://www.washingtonpost.com/wp-dyn/content/article/2007/01/02/AR2007010201028.\
html?referrer=email

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SciClone and Sigma-Tau Complete Enrollment in Phase 3 Triple Therapy
Hepati..

Market Wire - 28-Dec-2006

This trial is being conducted by Sigma-Tau in Europe and has enrolled a
total of 553 patients. ZADAXIN is SciClone's brand of a pure synthetic
preparation of thymalfasin, a substance which circulates in the blood
naturally. Because stimulation of Th1 cells is associated with a vigorous
antiviral immune response, thymalfasin's effects on the immune system can
explain its effectiveness in treatment of viral infections in animal models
and previous clinical studies.


Summary
• and its European partner Sigma-Tau S.p.A. today announced that full
patient enrollment is complete for its phase 3 clinical trial evaluating the
use of ZADAXIN® (thymalfasin or thymosin alpha 1) in combination with
pegylated interferon alpha and ribavirin to treat patients infected with the
hepatitis C virus (HCV).
• This trial is being conducted by Sigma-Tau in Europe and has enrolled a
total of 553 patients.
• "We believe that ZADAXIN could increase the therapeutic efficacy of
standard HCV treatment without additional side effects, particularly for
non-responder HCV patients infected with a high viral load of the genotype 1
strain of the virus," said Friedhelm Blobel, Ph.D., President and Chief
Executive Officer of SciClone Pharmaceuticals, Inc.
• "Having met our 2006 milestones with interim survival data from the phase
2 ZADAXIN melanoma trial announced last week and a regulatory submission in
China for the DC Bead(TM) filing announced today, we believe that our
management team continues to execute on our primary strategic objectives of
building a leading pharmaceutical business in China and developing ZADAXIN
for the U.S. and European markets."
• "In the U.S. and Europe, there are more than seven million people
chronically infected with the hepatitis C virus, and current therapy is
insufficient for close to half of all patients," added Roberto Camerini,
M.D., Research and Development for Sigma-Tau S.p.A.
• "Patients need new therapeutic alternatives, whether novel agents or
additive compounds like ZADAXIN, which address the large and growing group
of patients who have failed to respond to the current standard of care."
• The phase 3, multi-center, double-blinded, randomized study enrolled 553
predominately genotype 1 HCV patients who have not responded to previous
treatment with pegylated interferon alpha and ribavirin.
• Patients have been randomized to receive either ZADAXIN or a placebo, and
all patients are receiving pegylated interferon alfa-2a and ribavirin.

http://www.therapeuticsdaily.com/news/summary.cfm?id=1187227&channelID=31

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http://www.medscape.com/viewarticle/546599

American College of Gastroenterology 2006 Annual Scientific Meeting and
Postgraduate Course

Hepatitis B -- What's New and What's on the Horizon?
Disclosures

Nancy S. Reau, MD

Las Vegas, Nevada; Tuesday, October 24, 2006 -- The diagnosis and treatment
of hepatitis B is rapidly evolving. Currently, there are 5 US Food and Drug
Administration-approved therapies available for hepatitis B, including
standard interferon alfa-2b, lamivudine, adefovir, peginterferon alfa-2a,
and entecavir, with several compounds in various stages of development. Over
the last decade there has been a shift in the treatment paradigm for chronic
hepatitis B infection from that of limited treatment to long-term viral
suppression. This change is a result of emerging data suggesting that viral
suppression decreases downstream risk of complications, including
hepatocellular carcinoma (HCC), coupled with the availability of
well-tolerated oral agents. As the benefits of effective treatment become
clear, a fundamental reappraisal of this disease is being performed. Several
of these issues were addressed during the annual scientific meeting of the
American College of Gastroenterology (ACG).

Natural History
Disease Prevalence
Although hepatitis B surface antigen (HBsAg) is a serologic hallmark of
hepatitis B infection, hepatitis B virus (HBV) may be present in the absence
of HBsAg. This concept of occult hepatitis B is gaining recognition and it
is most prevalent in certain high-risk groups, being previously described in
hemodialysis patients, injection-drug users, patients coinfected with HIV
and hepatitis C virus (HCV), and in those with cryptogenic cirrhosis.[1-3]
The clinical implications of this discovery are controversial. Kikuchi and
colleagues[4] found a high prevalence of occult HBV infection -- 16% -- in a
retrospective review of HCV-infected patients. This finding was associated
with a significant decrease in the effectiveness of interferon therapy.
Agarwal and colleagues[5] found a high prevalence of hepatitis B (1.07%
HBsAg-positive and 4.1% with occult HBV infection) among healthcare workers
in India. In this population, 15.06% were never vaccinated against HBV,
demonstrating the importance of vaccination compliance in this at-risk
patient group. Because occult HBV infection may have clinical
implications,[6,7] it is reasonable to assess for HBV DNA in patients at
high risk for the disease, such as hemodialysis patients, patients
coinfected with HCV or HIV, and injection-drug users -- especially those
from endemic areas. The importance of vaccination in groups at risk for
exposure cannot be overemphasized.

Practice Patterns
Several studies focused on practice patterns among physicians treating
patients with hepatitis B. An evaluation of 2 Minneapolis gastroenterology
practices found that between 1999 and 2003, only 25% of all patients with
chronic hepatitis B underwent treatment even though 50% had viremia
documented greater than 104 copies/mL.[8] This finding may be a reflection
of practice guidelines recommendations during that time, which emphasized
elevated alanine aminotransferase levels (ALT) levels, as well as of the
available antiviral agents. However, by 2001,[9] recommendations were
evolving to include broader subsets of patients. Another study presented
during this year's ACG meeting examined practice patterns through a survey
distributed to physicians attending hepatitis B educational programs.[10]
Most physicians surveyed had practice patterns that were quite independent
of current treatment guidelines. Over 25% offered testing for noninvasive
fibrosis markers and HBV genotyping, which are not recommended in current
guidelines. However, only 15% of physicians would discontinue therapy 6-12
months after hepatitis B e antigen (HBeAg) loss or seroconversion. Ten
percent of physicians chose to treat this population indefinitely,
independent of the presence of significant fibrosis; few monitored genotypic
resistance, and those that did chose to do so only after combined clinical
and viral breakthrough. These findings strongly suggest that even physicians
attending educational forums may not use our clinical tools optimally and
may not be following evidence-based endpoints.

The Management of Special Populations
Acute HBV Infection
Most acute hepatitis B is subclinical, and less than 1% of patients
experience acute liver failure.[11] In addition, less than 5% of infected
adults progress from acute to chronic disease.[12] However, occult HBV
infection (HBsAg-negative, but HBV-DNA PCR [polymerase chain
reaction]-positive) with histologic changes can be demonstrated years after
recovery.[13] The efficacy of antiviral therapy in the setting of acute
hepatitis B is largely unknown. Despite this, many patients with severe
acute hepatitis B are empirically placed on treatment in hopes of
ameliorating symptoms and decreasing the risk for a fulminant course.

Previous uncontrolled studies have suggested that treatment with lamivudine*
may improve the clinical course of patients with acute severe hepatitis
B.[14,15] In a study presented during this year's ACG meeting, Kumar and
colleagues[16] contradicted these findings. In their placebo-controlled
evaluation of 71 patients with severe acute hepatitis B, 31 received
lamivudine. Although antiviral therapy was associated with a greater fall in
HBV-DNA level, there was minimal clinical benefit and a trend towards a
lower chance for hepatitis B surface antibody seroconversion. These study
findings suggest that further evaluation is needed before nucleos(t)ide
antiviral therapy is considered standard of care for severe acute hepatitis
B.

Inactive Carrier
HBeAg-negative patients with normal serum ALT and low-level viremia are
often labeled "inactive carriers" and are thought to have a more favorable
prognosis. It is recognized that viral replication continues in this
population.[17] Kumar and colleagues[18] demonstrated that one third of
inactive carriers continued to have significant viremia (HBV DNA > 5 log
copies/mL), with inflammation or fibrosis on liver biopsy. This finding
nicely reminds us that this population continues to be at risk for
significant liver disease and should be monitored closely.

Vertical Transmission
The risk for maternal-fetal transmission of hepatitis B is as high as
90%.[19] Previous studies have suggested that HBeAg status and level of
viremia contribute to this risk.[20,21] This relationship was confirmed by
following HBsAg-positive women in a New Delhi antenatal clinic.[22] The
authors found a strong linear correlation between maternal HBV-DNA level and
transplacental HBV-DNA transmission, defined as cord blood positive for
HBsAg and HBV DNA. However, HBeAg negativity had little influence. These
study results emphasize the importance of standard hepatitis B
immunoglobulin administration regardless of HBeAg status and of vaccination
for infants born to HBsAg-positive mothers. They also suggest a role for
antiviral therapy in mothers with high levels of viremia.

The Role of Genotype
Unlike in HCV infection, where viral genotype has a well-established role in
treatment, the utility of HBV genotype is controversial. There is growing
evidence that genotype may influence treatment response and clinical course,
including the risk of developing HCC.[23] However, even with this knowledge,
genotype may not truly influence treatment decisions in hepatitis B, except
with respect to consideration of the use of interferon in the genotype A
population, which has increased seroconversion compared with other
genotypes.

Concluding Remarks
Our understanding of hepatitis B continues to evolve, resulting not only in
a shift in the treatment paradigm but also in our basic understanding of the
viral-host relationship. Today's sessions offered insight into the growing
clinical challenges surrounding this complicated disease. This serves as an
excellent preface to future research where these issues will certainly be
revisited.

*The US Food and Drug Administration has not approved this medication for
this use.
References<cut>

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http://www.medscape.com/viewarticle/548122

The Liver Meeting: 57th Annual Meeting of the American Association for the
Study of Liver Diseases  |  AASLD 2006: Viral Hepatitis
AASLD 2006 - Clinical Advances in Hepatitis B and Hepatitis C  CME
Disclosures

Tram T. Tran, MD

Hepatitis B
New therapies for the treatment of hepatitis B have emerged over the past
several years, demonstrating excellent therapeutic results in viral
suppression and leading to improvement in liver injury from chronic
hepatitis B infection. There are 6 therapies currently approved by the US
Food and Drug Administration (FDA) for the treatment of hepatitis B in
adults: interferon alfa-2b; lamivudine; adefovir dipivoxil; entecavir;
pegylated interferon alfa-2a; and the oral antiviral agent telbivudine,
which received approval just last month. Research presented at this year's
meeting of the American Association for the Study of Liver Diseases (AASLD)
focused on these therapeutic options as well as on new strategies in
applying these agents, including the utility of early viral suppression as a
determinant of response to therapy.

Lamivudine
Lamivudine is a potent nucleoside analog and was the first oral therapy
approved for the treatment of hepatitis B. Unfortunately, high rates of
viral resistance, manifesting as the YMDD mutation, emerged after even short
periods of lamivudine therapy (24% resistance at 1 year, increasing up to
70% by 4 years of therapy).[1] However, despite this high rate of viral
resistance, due to its relatively low cost and ready availability,
lamivudine remains widely used worldwide.

Yuen and colleagues[2] examined the long-term impact of rapid early viral
suppression at week 12 of lamivudine therapy on seroconversion rates, viral
resistance, and alanine aminotransferase (ALT) normalization in 74 patients
with chronic hepatitis B. As defined by the study, using hepatitis B virus
[HBV] DNA of 4 logs as a cut-off level for good response, if patients
achieved viral suppression to < 4 logs, they were able to attain higher
rates of seroconversion (90% vs 20%), ALT normalization (100% vs 51%), and
lower resistance (63% vs 0%) compared with patients with HBV DNA > 4 logs,
after 5 years of therapy. The sensitivity and specificity of using this
cut-off level for determination of good response was 50% and 100%,
respectively, in this small study.

Rapid and profound suppression of viral replication may be a good predictor
of long-term outcomes and resistance, but larger studies are needed to
determine true negative and positive predictive values and the most
clinically relevant time points.

Adefovir
Adefovir is a nucleotide analog with effective antiviral activity against
the lamivudine-resistant YMDD viral strain. Previously, once resistance had
developed to lamivudine, therapy was initiated with adefovir and lamivudine
was often discontinued after some period of overlap. However, recent data
have suggested that the addition of adefovir to lamivudine, instead of the
switch from lamivudine to adefovir monotherapy, may be more effective in
preventing the development of adefovir resistance.[3] Marzano and
colleagues[4] studied the impact of add-on vs switch therapy with adefovir
on HBV viral suppression in a group of 52 patients with clinical or
genotypic lamivudine resistance. Patients were randomly assigned to adefovir
alone or lamivudine plus adefovir (ie, adefovir combined with ongoing
lamivudine). The investigators reported that overall viral response to
adefovir monotherapy vs combined adefovir + lamivudine therapy was similar
in patients with lower viral levels, confirming previous findings.[5]
However, patients with high viral loads (HBV DNA > 5 log copies/mL) were
less likely to achieve viral suppression with a shift to adefovir
monotherapy, and were at higher risk for the development of adefovir
resistance. Thus, combination therapy, either as a rescue strategy after
development of resistance or as therapy in the naive patient, may be
beneficial for the prevention of resistance; additional, larger studies are
warranted.

The current treatment paradigm for patients with hepatitis B e antigen
(HBeAg)-negative chronic hepatitis B is continued, indefinite viral
suppression because of the high relapse rates once suppressive antiviral
therapy is discontinued. Hadziyannis and colleagues[6] assessed relapse in
HBeAg-negative patients who had been on long-term adefovir therapy. The
study involved patients on adefovir therapy for 4-5 years who had achieved
and maintained biochemical remission (ALT normalization), had viral
suppression (HBV DNA < 1000 copies/mL), and had no detectable adefovir
resistance mutations; antiviral therapy was discontinued and subjects were
monitored for relapse. Results showed that although all patients had some
evidence of viral rebound (¡Ü 50,000 copies/mL), 67% were able to maintain
normalized serum ALT. Patients with biochemical relapse were successfully
re-treated with resumption of therapy. Thus, on the basis of these study
findings, discontinuation of antiviral therapy in the difficult-to-manage
HBeAg-negative chronic hepatitis B patient population may be feasible,
although all patients experience virologic relapse and the possibility of
biochemical flare.

Entecavir
Entecavir was approved for the treatment of hepatitis B in 2005, and data
continue to be reported on the long-term outcomes of patients. The phase 3
randomized study comparing entecavir with lamivudine in the treatment of
nucleoside-naive HBeAg-positive patients was continued for a total of 96
weeks. Thereafter, patients who had achieved virologic suppression (HBV DNA
< 0.7 Meq/mL), but had not yet lost HBeAg or seroconverted, were allowed to
enter into the follow-up roll-over study for continued monitoring.[7] A
total of 122 patients were enrolled into this follow-up study, and endpoints
included HBeAg loss or seroconversion, normalization of serum ALT, and viral
suppression to HBV DNA < 300 copies/mL. Of note, these patients were given a
higher dose of entecavir than that used in the original study (1.0 mg
entecavir vs 0.5 mg) due to the roll-over study design. Results showed that
by week 144, 90% of patients who continued entecavir treatment achieved
complete viral suppression, 80% normalized ALT, and an additional 33% lost
HBeAg; 16% had seroconversion in the third year on therapy (cumulative
seroconversion rate was not reported). Safety profile was similar to that
reported in previous studies, with no major changes to the entecavir safety
profile. Thus, continued entecavir treatment to 3 years in the
nucleoside-naive HBeAg-positive patient appears to result in high rates of
viral suppression and normalization of serum ALT, along with improved
chances of HBeAg seroconversion.

Long-term treatment with any antiviral therapy leads to concerns regarding
the potential development of viral resistance mutations, the loss of
efficacy, and histologic and biochemical rebound. As mentioned previously,
lamivudine resistance, with the development of the YMDD mutation, has been
well established at high rates approaching 70% at 4 years[1]; adefovir
resistance is now reported at 29% with 5 years of therapy.[8] Colonno and
colleagues[9] reported the 3-year resistance data for patients treated with
entecavir during this year's AASLD meeting. All patients with detectable HBV
DNA (> 300 copies/mL) and any patient experiencing a viral rebound of > 1
log during entecavir therapy were analyzed for genotypic mutations
conferring entecavir resistance. The authors reported entecavir resistance
to be less than 1% in each of the 3 years on therapy for nucleoside-naive
patients receiving treatment. Cumulatively, genotypic mutations to entecavir
occurred in 6%, 14%, and 29% of patients with baseline lamivudine resistance
prior to entecavir therapy for years 1, 2, and 3 of entecavir treatment.
Thus, entecavir appears to have an excellent 3-year resistance profile in
nucleoside-naive patients, with resistance rates of < 1% per year on
therapy. Patients with previous lamivudine resistance are at higher risk of
developing entecavir resistance.

Telbivudine
Telbivudine is the most recent FDA-approved therapy for the treatment of
chronic HBV infection, and is a nucleoside analogue that inhibits the HBV
polymerase. The 2-year results from the phase 3 trial comparing telbivudine
with lamivudine in chronic hepatitis B (GLOBE) were presented by Lai and
colleagues[10] during AASLD 2006. Patients (n = 1367) were randomized to
telbivudine 600 mg orally once daily or lamivudine 100 mg once daily, with
the usual inclusion criteria (ALT > 1.3-10 X upper limit of normal; HBV DNA
  > 6 log10 copies/mL; compensated liver disease). Results showed superior
efficacy for telbivudine vs lamivudine by week 104 in HBeAg-negative chronic
hepatitis B patients with regard to HBV DNA suppression (HBV DNA
undetectable: 82% vs 57%). In the HBeAg-positive cohort, telbivudine was
also more effective than lamivudine with respect to HBV DNA suppression to
undetectable levels and normalization of serum ALT; seroconversion was
achieved in 30% of patients by week 104 in the telbivudine group (vs 25% in
the lamivudine group; NS). Resistance occurred in patients receiving both
therapies, with rates of 8.1% (HBeAg-negative) and 21% (HBeAg-positive)
observed in the telbivudine arms. It is interesting to note that analysis of
patients who achieved rapid viral suppression at week 24 was predictive of
lower resistance rates for telbivudine (2% for the HBeAg-negative cohort; 4%
for the HBeAg-positive cohort).

Bzowej and colleagues[11] presented findings from a study assessing the
efficacy of telbivudine vs adefovir in 135 patients with HBeAg-positive
chronic hepatitis B. Patients were randomized initially to treatment with
telbivudine or adefovir for 24 weeks, and then a secondary randomization at
24 weeks took place in those patients receiving adefovir, to either continue
adefovir therapy or switch to telbivudine. Telbivudine demonstrated
significantly greater efficacy in viral suppression in the first 24 weeks
compared with adefovir (38% vs 12% undetectable HBV DNA); this trend
continued into the 52-week data, with better virologic response rates seen
in those patients either on (or switched to) telbivudine compared with those
who remained on adefovir.

Thus, telbivudine demonstrates better efficacy than lamivudine for most
clinical endpoints of treatment. Virologic breakthrough due to resistance
was statistically lower in the telbivudine-treated patients than in those
treated with of lamivudine, and some prediction of resistance may be
possible on the basis of early viral response at week 24. In addition,
telbivudine appears to have better viral suppression than adefovir at 24 and
52 weeks, although rates of HBeAg seroconversion and ALT normalization were
not significantly different.

Pegylated Interferon
Pegylated interferon is indicated for the treatment of chronic hepatitis B,
but due to issues of cost and associated side effects, is not as widely used
as the oral antiviral therapies. However, a finite duration of treatment and
the lack of concern for viral resistance still make interferon-based therapy
a viable option for some patients.

Marcellin and colleagues[12] reported follow-up data from a large trial of
HBeAg-negative chronic hepatitis B patients previously treated with
pegylated interferon with or without lamivudine vs lamivudine alone for a
total of 48 weeks. Data from the initial 48 weeks of therapy have been
previously reported, and revealed that no additional benefit was associated
with combined pegylated interferon plus lamivudine compared with pegylated
interferon alone.[13] The current study[12] evaluated the durability of
response to pegylated interferon with or without lamivudine for up to 2
years post treatment. They found that in the pegylated interferon
monotherapy group, at 24 months post treatment, 28% of patients were able to
maintain HBV DNA levels < 10,000 copies/mL and 32% were able to maintain
normal ALT levels. Data also confirmed that the addition of lamivudine to
pegylated interferon did not provide any benefit with regard to virologic or
biochemical sustained response.

Patients with HBeAg-negative chronic hepatitis B represent a more
difficult-to-treat population due to the high relapse rates post therapy.
Immunomodulation with interferon for 1 year appears to have some positive
benefit in 28% of patients, even 24 months after therapy.

_________________________________________________________________
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http://www.medscape.com/viewarticle/548122

The Liver Meeting: 57th Annual Meeting of the American Association for the
Study of Liver Diseases  |  AASLD 2006: Viral Hepatitis
AASLD 2006 - Clinical Advances in Hepatitis B and Hepatitis C  CME
Disclosures

Tram T. Tran, MD

Hepatitis C
Pegylated Interferon
The mainstay of treatment for patients with hepatitis C has been combination
therapy with pegylated interferon and ribavirin, which overall yields
sustained response rates in approximately 50% of patients treated. Few
options are available for those patients who do not respond to therapy, are
unable to tolerate the side effects of the interferon or ribavirin, or who
relapse after discontinuation of the medications.

More information has been accumulated in the past several years on early
predictors of nonresponse to therapy, whereby the lack of at least a 2-log
drop in the baseline viral load at week 12 was able to identify those
patients who had little chance of responding to therapy (early viral
response [EVR] rule). Clinicians, using this EVR rule, were able to
discontinue therapy in patients earlier, sparing them significant side
effects and associated costs. More recently, a positive 4-week hepatitis C
virus (HCV) RNA level has been shown to be predictive of higher rates of
relapse post therapy, and the use of this so-called rapid viral response
(RVR) is now gaining clinical applicability.

Shiffman and colleagues[14] reported results from the ACCELERATE trial
involving 1463 patients infected with HCV genotype 2 or 3 who were treated
with pegylated interferon alfa-2a plus ribavirin for either 16* or 24 weeks.
Currently, the standard of care is treatment for 24 weeks for patients with
HCV genotype 2 or 3. Results showed that, overall, patients who received 24
weeks of therapy had a 90% sustained virologic response (SVR) rate compared
with 82% of patients treated for 16 weeks. RVR and EVR rule were both highly
predictive of achieving SVR. Thus, RVR (HCV RNA undetectable at week 4 by
polymerase chain reaction [PCR]) and EVR are both highly predictive of
response to therapy in patients infected with HCV genotypes 2/3. Decreasing
duration of therapy to 16 weeks may be reasonable in patients who achieve an
RVR and have significant difficulty or side effects with treatment.

Pearlman and colleagues[15] examined the effect of longer duration of
therapy using pegylated interferon alfa-2b plus weight-based ribavirin
dosing in patients infected with HCV genotype 1 who, despite meeting the
criteria for EVR (> 2-log drop in baseline HCV RNA by PCR), were still HCV
RNA PCR detectable until week 24 of therapy. This group of "slower viral
responders" was then treated for either the usual 48 weeks or was extended
to 72 weeks* of therapy. Results showed a 39% SVR in the 72-week arm
compared with 18% SVR in the 48-week arm; treatment extension did not seem
to result in an increase in dose reductions or discontinuations. Thus,
treatment of hepatitis C has now evolved to a more individualized regimen,
using weight-based dosing of ribavirin and an adjusted duration of therapy,
depending on how rapidly patients respond to therapy. Longer duration of
therapy may improve sustained response rates in patients with slower viral
suppression.

Agents on the Horizon
Although great advances have been made with interferon and ribavirin-based
therapy, the most exciting new development on the horizon for hepatitis C is
the use of therapies that specifically target steps in the cycle of
hepatitis C replication as opposed to general immunomodulators or
antivirals. VX-950* is an oral HCV protease inhibitor that has been shown to
dramatically reduce HCV viral loads to undetectable levels within 2-4 weeks
in phase 2 trials.[16] However, some viral variants emerged with this
therapy. During this year's AASLD meeting, Kieffer and colleagues[17]
reported a detailed analysis of these variants; data were presented on 16
patients treated with VX-950 750 mg 3 times daily (n = 8) vs VX-950 750 mg 3
times daily plus pegylated interferon (n = 8) for 14 days. HCV RNA was
isolated after the treatment period for variants in the NS3 protease domain.
Six of 8 patients treated with VX-950 monotherapy had detectable mutations
by the end of the 14 days, whereas 4 of 8 of patients receiving combination
pegylated interferon plus VX-950 also had detectable virus (resistant or
wild-type) at day 8. After the 14 days of therapy, 15 of 16 patients were
treated with the standard pegylated interferon plus ribavirin and all
responded with complete viral suppression by week 24. This suggests that
although there may be some viral resistance due to mutations with the use of
the protease inhibitor, viral suppression occurs successfully with the
addition of pegylated interferon and ribavirin.

In a late-breaking abstract presented by Roberts and colleagues,[18] another
target-specific HCV therapy, R1626*, a nucleoside analog oral polymerase
inhibitor, was administered in a phase 1b trial involving 47 treatment-naive
patients infected with HCV genotype 1. Patients were given R1626 at doses of
500, 1500, 3000, and 4500 mg twice daily vs placebo for 14 days. The authors
found that a dose-dependent viral suppression occurred, with 5 of 9 patients
in the 4500-mg treatment arm having undetectable HCV RNA at day 15. Anemia
occurred in some patients; headache and gastrointestinal side effects were
noted at the highest dose.

New therapies targeting specific sites in the HCV replication cycle, such as
these protease or polymerase inhibitors, show early promise, although viral
resistance and side effects need further study in larger, phase 2 trials.

Consensus Interferon
One of the most difficult clinical issues in liver transplantation is the
recurrence of hepatitis C after transplantation. Recurrence is nearly
universal, and studies have shown a more aggressive course of HCV
progression after transplant, with up to 20% of patients developing
cirrhosis by 5 years.[19] Treating the cirrhotic patient before liver
transplant may reduce the likelihood of recurrence; however, treatment is
limited by constitutional side effects, anemia, thrombocytopenia, and
neutropenia in this patient population.

Bacon and colleagues[20] presented their results from the DIRECT (Daily-dose
consensus Interferon and Ribavirin Efficacy of Combined Therapy) trial using
consensus interferon* plus ribavirin in patients who previously failed to
respond to pegylated interferon + ribavirin therapy. Of note, 29% of
patients in this study were cirrhotic by liver biopsy and more than 50% had
bridging fibrosis. Patients received consensus interferon at a dose of 9
micrograms (mcg)/day or 15 mcg/day in combination with ribavirin vs no
treatment. Preliminary analysis at the end of treatment revealed a 29%
end-of-treatment response in patients with greater than 80% compliance with
the 15-mcg/day consensus interferon + ribavirin regimen. The lower dose of
consensus interferon demonstrated lower response rates (15%), and patients
with cirrhosis had very low response rates (< 8%). The most common side
effects were neutropenia and fatigue, with an overall 10% to 17%
discontinuation rate.

Consensus interferon has demonstrated some moderate success in the very
difficult-to-treat group of patients who have nonresponse to combination
pegylated interferon plus ribavirin. Early treatment of HCV infection offers
more benefit, as the more advanced the histologic disease, the lower the
chance of success with any therapy thus far.

Conclusion
Exciting new advances were presented in viral hepatitis at this year's AASLD
meeting. Our therapeutic armamentarium for hepatitis B now includes several
oral antiviral therapies, as well as immunomodulatory agents. The major
issues of viral resistance and predictors of response and resistance are now
under active study.

Hepatitis C is entering a new era of drug development with specifically
targeted therapies, although these strategies remain very early in clinical
development. Again, issues of safety and viral resistance will come to the
forefront in this arena. Individualized therapy with the current standard of
care, pegylated interferon plus ribavirin, is key to optimizing patient
outcomes.

*The US Food and Drug Administration has not approved this medication for
this use.

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Liver Steatosis Highly Prevalent in Children With HCV

NEW YORK (Reuters Health) Dec 28 - As many as half of children with chronic
hepatitis C virus (HCV) infection are likely to develop liver steatosis,
according to a study conducted by Italian and Spanish researchers and
published in the current issue of the American Journal of Gastroenterology.

Principal investigator Dr. Maria Guido of the University of Padova, Italy,
and colleagues studied the prevalence and severity of liver steatosis in 21
Italian and 45 Spanish children with HCV.

They found that 18 of 66 children, or 27%, had liver steatosis. Ten of the
21 Italian children and 7 of the 45 Spanish children had the HCV-related
lesion. All but two of the 18 children with steatosis were infected with HCV
genotype 1.

Fibrosis was present in 60 of the 66 children with chronic HCV and liver
steatosis.

BMI was associated with both the presence and the severity of liver
steatosis. BMI and serum triglycerides were also higher in children with the
complication.

Mean BMI for age among children without steatosis was slightly above the
60th percentile, was at the 88th percentile for children with any degree of
steatosis, and was above the 97th percentile for the seven children with
severe steatosis.

Steatosis negatively affects antiviral response in adults, and Dr. Guido's
team concludes that "adjuvant treatments for steatosis should be considered
for children with HCV-related chronic hepatitis and high BMI."

Editorialists Drs. Nizar N. Zein of the Cleveland Clinic Foundation and John
H. Poterucha of the Mayo Clinic in Rochester, Minnesota, posit that
steatosis may be the missing link to metabolic abnormalities in HCV.

Strategies to minimize liver damage and treatment of hepatic inflammation
associated with HCV infection are already being employed, the editorialists
note. The study indicates that weight loss, insulin sensitization and tumor
necrosis factor-alpha neutralization may also correct HCV-related metabolic
abnormalities and affect liver disease progression.

Am J Gastroenterol 2006;101:2611-2615, 2616-2617.
http://www.medscape.com/viewarticle/550041

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Tenofovir Plus Emtricitabine Shows Efficacy in Resistant HBV Infection

NEW YORK (Reuters Health) Dec 29 - A switch from adefovir to tenofovir plus
emtricitabine may achieve undetectable viral levels in chronic hepatitis B
virus (HBV) infection when an adefovir-containing regimen fails,
investigators at Mount Sinai School of Medicine in New York report.

In a study published in the December issue of the European Journal of
Gastroenterology and Hepatology, Dr. Stephanie A. Santos and colleagues
describe seven patients with chronic HBV infection who failed to achieve
undetectable levels of HBV DNA on adefovir or an adefovir-containing
regimen.

Patients were all HIV- seronegative. They had been on adefovir for a mean of
ten months at enrollment and median HBV DNA was 430,000 copies/ml with a
median fall in HBV DNA of 2.0 log10copies/ml.

Dr. Santos' team changed treatment to tenofovir, 300 mg daily, and
emtricitabine, 200 mg daily.

After a median treatment duration of 23 months with tenofovir, the HBV DNA
fall was 3.0 log10copies/ml.

All seven patients achieved undetectable HBV DNA levels with tenofovir.
Anti-hepatitis B e seroconversion occurred in one patient.

There were no significant changes in serum creatinine levels and none of the
patients reported serious adverse effects.

"Given the possibility of significant morbidity and mortality with hepatitis
B, it is imperative that new treatment options be explored," the
investigators point out. "It has been shown that lower levels of HBV DNA
correlate with an improved histologic, biochemical and serologic response."

While adefovir is the treatment of choice for chronic HBV infection,
resistance develops in more than one-quarter of patients, the authors write.
The response in this series of patients to tenofovir after treatment failure
with adefovir indicates that it may be an effective option for patients with
resistant HBV infection.

Eur J Gastroenterol Hepatol 2006;18:1247-1253.

http://www.medscape.com/viewarticle/550081

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Ask the Experts about Liver Disease
From Medscape Gastroenterology

Approach to the Hepatitis B Patient With Lamivudine Resistance

Question
A patient with chronic hepatitis B has developed resistance to lamivudine.
Is it reasonable to continue lamivudine in combination with a second
antiviral medication for a short period of time before stopping the
lamivudine? What are alternative options for the management of antiviral
drug resistance emerging during treatment of chronic hepatitis B with
lamivudine?


Response from  Emmet B. Keeffe, MD, MACP
Professor of Medicine, Stanford University School of Medicine, Stanford,
California; Chief of Hepatology, Co-Director of Liver Transplant Program,
Stanford University Medical Center, Stanford, California

Management options for patients who develop hepatitis B virus (HBV)
antiviral drug resistance during treatment with lamivudine are summarized in
the Table , which was developed on the basis of the updated US treatment
algorithm.[1] The oral antiviral agents adefovir and entecavir are both
acceptable alternatives that are licensed by the US Food and Drug
Administration (FDA) for the treatment of patients with lamivudine
resistance. However, adefovir may be preferred over entecavir on the basis
of emerging data showing a cumulative 32% rate of entecavir resistance after
3 years of therapy in patients with preexisting lamivudine resistance.[1,2]
Whether adefovir is given as monotherapy or in combination with continued
lamivudine may depend on the status of the patient's liver disease. Data
from a recent study in compensated patients revealed mild increases in
alanine aminotransferase (ALT) levels in some patients when switching from
lamivudine to adefovir, but no patient experienced clinically significant
ALT elevations.[3] These observations suggest that switching patients from
lamivudine to adefovir, with or without an overlap period of combination
lamivudine and adefovir, may be a safe strategy in many patients.

However, because the consequences of returning wild-type HBV infection are
potentially more hazardous in patients with advanced liver disease and
switching to adefovir is associated with a 15% to 19% rate of adefovir
resistance after 2 years in lamivudine-resistant patients,[4,5] the addition
of adefovir to continued lamivudine therapy is preferred in patients with
cirrhosis. Pending the availability of future data from studies currently
under way, the addition of adefovir to lamivudine may be preferred to
switching to adefovir monotherapy in all patients with lamivudine
resistance, in order to avoid the increased rate of developing adefovir
genotypic resistance in lamivudine-resistant patients (15% to 19%) when
compared with naive patients treated with adefovir (0% at Year 1, 2% at Year
2, 11% at Year 3, 18% at Year 4, and 29% at Year 5).[6] Entecavir is
associated with a 5-log10 reduction in serum HBV DNA levels in
lamivudine-refractory patients, but this potency needs to be weighed against
the development of genotypic resistance and virologic breakthrough, which
occur in 6% and 1% of patients, respectively, at Year 1, and increase by
Year 3 to 32% and 25%, respectively.[2] Potential future therapy for
managing lamivudine resistance may involve adding tenofovir or switching to
the combination of emtricitabine and tenofovir, which preliminary data
suggest are effective regimens (not currently FDA approved), or switching to
the combination of telbivudine plus tenofovir, which theoretically should be
effective but has not been studied.[1]


Posted 12/12/2006


--------------------------------------------------------------------------------



Table. Potential Management Options for Patients With Hepatitis B Antiviral
Drug Resistance to Lamivudine*[1]


References
Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for the
management of chronic hepatitis B virus infection in the United States: an
update. Clin Gastroenterol Hepatol. 2006;4:936-962. Abstract
Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows
high barrier to resistance is maintained in entecavir-treated nucleoside
naïve patients while resistance emergence increases over time in lamivudine
refractory patients [abstract]. Hepatology. 2006;44(Suppl 1):229A-230A.
Peters M, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in
combination with lamivudine in patients with lamivudine resistance and
chronic hepatitis B. Gastroenterology. 2004;126:91-101. Abstract
Lee YS, Suh DJ, Lim YS, et al. Emergence of rtA181V/T and rtN236T mutations
after 48 weeks of adefovir dipivoxil therapy in patients with
lamivudine-resistant chronic hepatitis B [abstract]. Hepatology.
2005;42(Suppl 1):578A.
Lok AS, Fung SK, Han SH, et al. Virological response and resistance to
adefovir (ADV) therapy in liver transplant (OLT) patients [abstract].
Hepatology. 2005;42(Suppl 1):232A.
Hadziyannis S, Tassopoulos N, Chang TT, et al. Long-term adefovir dipivoxil
treatment induces regression of liver fibrosis in patients with
HBeAg-negative chronic hepatitis B: Results after 5 years of therapy
[abstract]. Hepatology. 2005;42(Suppl 1):754A.

Disclosure: Emmet B. Keeffe, MD, MACP, has disclosed that he has received
grants for clinical research from Roche, and has received grants for
educational activities from Bristol-Myers Squibb, Gilead, GlaxoSmithKline,
and Roche. Dr. Keeffe has also disclosed that he has served as an advisor or
consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche, and
Valeant.

http://www.medscape.com/viewarticle/548391

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Ask the Experts about Liver Disease
From Medscape Gastroenterology

Approach to the Patient With Hepatitis C and Hepatitis B Coinfection?

Question
What is the recommended approach to medical management in patients
coinfected with hepatitis C and hepatitis B? What is the goal of treatment
in this setting?


Response from  David Bernstein, MD
Chief, Digestive Disease Institute, North Shore University Hospital-Long
Island Jewish Medical Center, Manhasset, New York; Associate Professor of
Medicine, New York University School of Medicine, New York, NY




Hepatitis B and hepatitis C are common infections and therefore it is not
uncommon to see patients coinfected with both of these viruses. The
combination of both infections appears to lead to an increased risk for
liver damage as well as an increased risk for the development of
hepatocellular carcinoma. The treatment of hepatitis B and hepatitis C
coinfection is complicated by the lack of an approved recommended therapy
for this combination of infection. Usually, in the evaluation of these
patients, 1 of the 2 viruses will predominate; this can generally be
determined by the level of serum hepatitis B virus (HBV) DNA or serum
hepatitis C virus (HCV) RNA. Studies have shown that both viruses can
inhibit the replication of the other virus. Of note, in most cases, HCV
predominates over HBV.

The approach to therapy for patients coinfected with hepatitis B and
hepatitis C involves treating the predominant infection. If hepatitis C is
predominant, then treatment should be initiated with a combination of
pegylated interferon and ribavirin. Pegylated interferon may have a
suppressive effect on HBV, as pegylated interferon is approved for the
treatment of hepatitis B infection, although it has not been shown to date
to be effective in the treatment of HBV/HCV coinfection. The goal of therapy
in hepatitis C-predominant disease is to eradicate HCV and have a sustained
viral response.

If hepatitis B is the predominant virus, then treatment should be initiated
for HBV infection. Currently approved therapies for hepatitis B infection
include interferon, pegylated interferon, lamivudine, adefovir, entecavir,
and telbivudine. Care should be taken when initiating these regimens because
interferons should not be used in patients with hepatitis B-related
cirrhosis and lamivudine should not be used at all secondary to concerns
regarding the development of antiviral mutations. Once treatment is
initiated, the goal of therapy is similar to that for the monoinfected
hepatitis B patient: The goal of therapy in patients infected with wild-type
virus is e antigen seroconversion, whereas the goal of therapy in patients
infected with precore mutant strains is prolonged viral suppression.


Posted 01/02/2007

http://www.medscape.com/viewarticle/549739
--------------------------------------------------------------------------------

Suggested Readings
Crockett SD, Keefe EB. Natural history and treatment of hepatitis B virus
and hepatitis C virus coinfection. Ann Clin Microbiol Antimicrob. 2005;4:13.
Dai CY, Yu ML, Chuang WL, et al. Influence of hepatitis C virus on the
profiles of patients with chronic hepatitis B virus infection. J
Gastroenterol Hepatol. 2001;16:636-640.
Zarski JP, Bohn B, Bastie A, et al. Characteristics of patients with dual
infection by hepatitis B and C viruses. J Hepatol. 1998;28:27-33

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Peginterferon Alfa-2b May Be Effective When Standard HBV Therapy Fails

NEW YORK (Reuters Health) Dec 27 - Approximately one-third of patients with
HBeAg-positive chronic hepatitis B who failed previous treatment with
standard interferon (IFN) or lamivudine will respond to peginterferon
alfa-2b (Peg-IFN alfa2b), research suggests.

High serum alanine aminotransferase (ALT) levels at the start of Peg-IFN
alfa2b therapy is the best predictor of response in these patients, note
researchers in the November American Journal of Gastroenterology.

Dr. Hajo J. Flink from Erasmus Medical Center, Rotterdam, The Netherlands,
and an international team investigated the efficacy -- defined as loss of
HBeAg at the end of follow up -- of Peg-IFN alfa2b in 76 previous
non-responders to standard IFN or lamivudine. Thirty-seven had failed IFN,
17 had failed lamivudine, and 22 had failed both therapies.

All subjects received 52 weeks of Peg-IFN alfa2b (100 micrograms once
weekly) combined with either 100 milligrams lamivudine daily or placebo.
Subjects were followed for 26 weeks after the end of treatment.

Thirteen nonresponders to previous IFN (35%), 5 nonresponders to previous
lamivudine therapy (29%), and 4 nonresponders to both drugs (22%) responded
to treatment with Peg-IFN alfa2b, Dr. Flink and colleagues report.

The combination of Peg-IFN alfa2b and lamivudine did not lead to higher
response rates relative to Peg-IFN alfa2b alone for any of the previous
nonresponder groups, they note.

The best predictor of response to Peg-IFN alfa2b in previous nonresponders
was a baseline ALT of greater than 4 times the upper limit of normal.
Fifty-three percent of patients with this ALT level responded to Peg-IFN
alfa2b compared with 20% of those with lower ALT levels at the start of
treatment.

Am J Gastroenterol 2006;101:2523-2529.

http://www.medscape.com/viewarticle/549942?src=mp

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A Painkiller Reminder
FDA Label Proposal Reinforces Advice to Proceed With Caution on
Over-the-Counter Medicines

By January W. Payne
Washington Post Staff Writer
Tuesday, January 2, 2007; Page HE01

A recent Food and Drug Administration proposal to add stronger warning
labels to several popular types of over-the-counter painkillers, noting they
pose a risk of liver and stomach damage, shouldn't scare most consumers into
avoiding the products entirely, experts say. But the news should remind
patients to take the lowest dose needed for the shortest possible time and
to be aware of the ingredients contained in all of their medications,
particularly when taking more than one medicine.

Under the FDA's proposal, warnings would be added to the labels of all OTC
medicines containing acetaminophen and nonsteroidal anti-inflammatory drugs
(NSAIDs), including aspirin, naproxen and ibuprofen, which are used to treat
headaches, pain, fever, menstrual cramps and muscle aches. Affected products
include such popular brands as Tylenol, Aleve, Motrin and Advil. The
warnings would "include important safety information regarding the potential
for stomach bleeding and liver damage and when to consult a doctor," the FDA
reports in a written statement.



For most people, over-the-counter pain relievers taken occasionally in
recommended doses pose few risks. (By Pat Sullivan -- Associated Press)


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"In general, I think occasional use is safe," except in high-risk patients,
said Jack A. Di Palma, immediate past president of the American College of
Gastroenterology. High-risk patients include people older than 60, those
taking the medications for longer than directed, patients taking blood
thinners or more than one medication containing an NSAID and patients who
have experienced ulcers or stomach bleeding.

Gastroenterologists have been discouraging the use of NSAIDs for patients in
these groups for years, he said. When such patients disregard this advice,
Di Palma said, "we've suggested trying to do things to limit injury," such
as taking proton pump inhibitors (stomach-protecting medications) to protect
the gastrointestinal tract. For most other patients, he says, risks are
minimal.

Doctors have known for years that NSAIDs can cause kidney damage and
gastrointestinal bleeding in some patients, even when taken at recommended
dosages. They've also known acetaminophen can cause severe liver damage when
taken at higher than recommended doses or in combination with three or more
alcoholic drinks per day. The FDA has defended the pace of agency action,
citing regulatory procedures. But Public Citizen, a Washington-based
consumer advocacy group, said the FDA's proposal comes "decades late"; the
group wants the agency to require warnings in painkiller ads and make public
service announcements about the change.

The FDA also is considering whether to impose limits on the number of
acetaminophen tablets sold per bottle; such limits exist in Britain, where
acetaminophen overdose is a leading cause of suicide.

About 56,000 Americans visit emergency rooms each year because of
acetaminophen poisoning, according to the FDA; about 100 people die annually
because of unintentional overdoses. More than 200,000 Americans go to the
hospital each year because of NSAID reactions; an estimated 16,000 die.

It's expected to be a year before stronger labels appear on OTC medication
bottles. In the meantime, suggests Edward Langston, chair-elect of the board
of trustees for the American Medical Association, consumers should ask
themselves these questions before taking any OTC medications: "How much of
the OTC medicine can [I] take and for how long? And what can I take
together?"

For non-chronic conditions, it's almost always best to take medications for
as short a period as possible, and to avoid or limit taking medicines
together, he said.

If you're unsure of the answers, Langston said, "the most handy -- and
underutilized -- source of information is to talk to your pharmacist."
Alternately, call your doctor, he suggested.

It's also important to know which ingredients are contained in your
prescription medications: Some prescribed drugs, such as Ultracet,
Darvocet-N and ketoprofen (all used for pain relief), contain NSAIDs or
acetaminophen.

Many OTC cold and arthritis medicines, such as Advil Cold & Sinus, NyQuil
and Tylenol Arthritis Pain, also contain NSAIDs or acetaminophen, making it
risky for patients to combine them with nonprescription pills they may be
taking for a headache, fever or pain.

Under the proposed changes, all affected products would bear labels
containing beefed-up warnings about interactions with alcohol and
prominently displaying the product's main ingredient. Some drug
manufacturers have voluntarily added stronger safety warnings in the past
few years.

Among the FDA's proposed changes:


· NSAIDs would carry added warnings that they pose a risk for stomach
bleeding in people older than 60, in those taking the medications for longer
than directed, in patients taking blood thinners or more than one medication
containing an NSAID and in patients who've experienced ulcers or stomach
bleeding.


· NSAIDs and acetaminophen would bear warnings against taking them with even
moderate amounts of alcohol -- three or more drinks per day.


· Acetaminophen, best known under the brand name Tylenol, would get warnings
advising consumers of the possibility of liver toxicity -- especially when
taken in high doses or with other acetaminophen-containing products.

Wire services contributed to this report.
http://www.washingtonpost.com/wp-dyn/content/article/2006/12/29/AR2006122901731.\
html?referrer=email

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============================================================
Clinical Care Options for Hepatitis
------------------------------------------------------------

CME-Certified Expert Recap With Downloadable Slides

Clinical Updates in HBV Treatment

CCO Independent Conference Coverage of the 2006 American Association for the
Study of Liver Diseases Annual Meeting* October 27-31, 2006 | Boston,
Massachusetts

Robert G. Gish, MD, provides the audio commentary in this slide-based Expert
Recap that discusses key hepatitis B studies presented at the 2006 Boston
meeting, highlighting the implications for your clinical practice. Listen to
and view this interactive CME-certified activity at
http://lists.clinicaloptions.com/t/2951/54129/812/0/

Downloadable Slideset
Use the slideset as a self-study resource or for your own presentations and
educational discussions. To download, go to
http://lists.clinicaloptions.com/t/2951/54129/813/0/


This Expert Recap is located online at:
http://lists.clinicaloptions.com/t/2951/54129/452/0/


*CCO is an independent medical education company that provides
state-of-the-art medical information to healthcare professionals through
conference coverage and other educational programs.
------------------------------------------------------------

Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care
Options, LLC.

Release date: December 12, 2006
Expiration date: December 11, 2007

Supported by an unrestricted educational grant from Bristol-Myers Squibb
Company.

------------------------------------------------------------
Copyright 2006 Clinical Care Options, LLC. All rights reserved.
1894 Preston White Dr., Suite 110, Reston, VA 20191-5433

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J Infect Dis. 2007 Jan 15;195(2):230-5. Epub 2006 Dec 11.


Mortality in Siblings of Patients Coinfected with HIV and Hepatitis C Virus.

Hansen AB, Gerstoft J, Kronborg G, Pedersen C, Sorensen HT, Obel N.

Department of Infectious Diseases, Odense University Hospital, DK-5000
Odense C, Denmark. ann-brit.eg.hansen@....

Background. Coinfection with hepatitis C virus (HCV) is a poor prognostic
factor for human immunodeficiency virus (HIV)-infected patients. We examined
whether the increased mortality in these patients is partly explained by a
familial excess risk of death.Methods. Danish HIV-infected patients who had
had at least 1 HCV test were included (n=3531). In addition, 336,652
population control subjects matched for sex, age, and residency were
identified from the Danish Civil Registration System. For both HIV-infected
patients and population control subjects, we identified all siblings born
after 1951, with dates of death or emigration. Siblings of HIV-infected
patients were classified according to the patients' HCV serostatus. Survival
after age 20 years was compared among the groups of siblings.Results. We
identified 437 siblings of HIV/HCV-coinfected patients, 1856 siblings of
HIV-monoinfected patients, and 285,509 siblings of population control
subjects. Mortality was substantially higher in siblings of
HIV/HCV-coinfected patients than in either siblings of HIV-monoinfected
patients (mortality rate ratio [MRR], 2.97 [95% confidence interval {CI},
1.98-4.45]) or siblings of control subjects (MRR, 4.23 [95% CI, 3.09-5.79]).
Siblings of HIV-monoinfected patients had slightly higher mortality (MRR,
1.43 [95% CI, 1.10-1.85]) than siblings of control subjects.Conclusions. HCV
infection is a marker of familial factors that affect the survival of
HIV-infected patients independently of the pathogenicity of HCV.

PMID: 17191168 [PubMed - in process]

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