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2005 Research

Care of the Cirrhotic Patient 6/7/05
	Article Date: 06-07-05

Combination Therapy of Low Dose Ribavirin and Pegylated Interferon for Patients with HCV and End-Stage Renal Disease on Dialysis

Hepatitis C virus (HCV) is associated with an increased prevalence of renal (kidney) disease.  Standard treatment for HCV is pegylated interferon (Peg-IFN) and ribavirin (RBV). However, there is no recommendation regarding anti-HCV treatment in patients (pts) with end-stage renal disease (ESRD).

In pts with ESRD on dialysis, combination Peg-IFN and RBV therapy is contraindicated because of concern about its accumulation and side effects in addition to anemia. Effectiveness and safety of low dose RBV and Peg-IFN combined with erythropoietin is still unknown.

The objective of the current study was to determine the efficacy and safety profile of a modified combination of Peg-IFN and RBV in pts with HCV and ESRD on dialysis.

This is an open label, prospective cohort study involving eight pts with HCV and ESRD with dialysis three times a week. All pts were started on combination of Peg-IFN alpha 2a (Pegasys) 135mcg-weekly and ribavirin 200-mg daily.

The pts remained on erythropoietin 10,000 units three times a week and low dose iron supplements. These pts were followed biweekly to monitor tolerability and treatment response.

The mean age of cohort was 50.7 years (+10.9 SD), mean weight was 73.6 kg (+14.3 SD). There were 7 males (87.5%), 7 African Americans (87.5%), and 1 Hispanic (12.5%).

100% of cohort was genotype (GT) 1 with median HCV RNA 318,500 IU/ml (IQR 190,000-809,000), median ALT 30.5 U/L (IQR 18-76), median albumin 3.85 (IQR 3.8-4.1), median hemoglobin 12.25 g/dL (IQR 10-13.4), and median platelet 196.5 (164-240).

Liver biopsy scores were mean grade of 1 and fibrosis stage of 1. All pts have reached week 12 of the study.

Results

·         Median hemoglobin decrease was 0.5 g/dL at week 12.

·         4 out of 8 patients (50%) achieved an early virological response (EVR), 3 had undetectable HCV RNA PCR (<100 cps/ml) and one pt had a 3 log drop in HCV RNA by week 12.

·         3 pts had < 2 but >1 log drop in HCV RNA by week 12.

·         One pt had no change in HCV RNA and therapy was discontinued.

·         There were no statistically significant changes in laboratory values including ALT, albumin, and platelets.

·         The treatment was uniformly well tolerated.

·         The most common reported side effect was malaise.

Conclusions

Based on these results, the authors conclude, “Our data demonstrate that a combination therapy of Peg-IFN alpha 2a and low dose RBV daily can be well tolerated and effective in pts with HCV and ESRD.”

06/01/05

Reference
J Park and others. Safety and Tolerability of Combination Therapy of Low Dose Ribavirin and Pegylated Interferon for Patients with Hepatitis C Virus and End-Stage Renal Disease on Dialysis. Abstract S1562. DDW 2005. May 14-18, 2005. Chicago, IL.

http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_060105_g.html

Prior studies have shown neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis.

Ten validated neuropsychological tests were administered to 201 CHC patients. Standard scores for individual tests were calculated using normative population data that controlled for age, gender, and/or education. Lifetime psychiatric history, alcohol consumption, and mood status were also determined.

Results

·         33% of patients met criteria for cognitive impairment (i.e. standard score <40 on at least 4 tests).

·         Mild impairment in verbal recall and working memory were noted with other domains remaining intact.

·         Liver disease severity and lifetime psychiatric abuse or substance abuse history did not correlate with group mean cognitive test results or the presence of cognitive impairment.

·         In contrast, IQ and depression scores were significant and independent predictors of cognitive impairment (ROC=0.84).

In conclusion, the authors write, “33% of patients entering the HALT-C trial have evidence of a mild, non-focal subcortical processing deficit which was highly correlated with IQ, education, and occupation. Future studies of cognitive function in CHC patients should control for general cognitive ability.”

06/06/05

Reference
R J Fontana and others. Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial. Journal of Hepatology. Published online May 31, 2005.

http://www.hivandhepatitis.com/hep_c/news/2005/ad/060605_a.htm

Starting treatment earlier and staying on treatment longer may increase
          treatment response rates for certain hepatitis C patients

    CHICAGO, May 16 /PRNewswire/ -- Starting hepatitis C treatment before
liver disease progresses and identifying the correlation between early
response and sustained virological response, are two potential approaches that
may optimize treatment outcomes in certain patients according to data from two
Pegasys(R) (peginterferon alfa-2a) studies presented today at the Digestive
Disease Week (DDW) Meeting, May 14-19, in Chicago, Illinois.
    These findings were from pooled analyses of data from Pegasys pivotal
trials in patients with genotype 1 hepatitis C, the most prevalent and
difficult to treat strain of the virus in the United States.  Pegasys is the
most prescribed hepatitis C treatment in the United States and is approved for
use alone and in combination with Copegus(R) (ribavirin, USP).
    "Studies have shown that approximately 50 percent of genotype 1 hepatitis
C patients respond to 48 weeks of treatment with Pegasys combination therapy,"
said Mitchell Shiffman, MD, Chief of Hepatology, VCU Medical College of
Virginia.  "This research suggests that we may be able to improve those odds
by treating hepatitis C earlier in the course of the disease, and extending
treatment for patients who have a delayed response to therapy."

    Treatment Efficacy Linked to Liver Damage
    An analysis of data from 328 patients treated for 48 weeks with Pegasys
and Copegus showed that patients with the genotype 1 hepatitis C, who had no
or little liver damage (no fibrosis or portal fibrosis) had higher sustained
virological response rates compared to patients with more advanced liver
disease (incomplete septa or cirrhosis).  Response rates were 56 percent vs.
42 percent.  The authors concluded that therapy should not be delayed for
patients until liver damage progresses because it reduces the patients' chance
of responding to treatment.

    Longer Therapy for Late Responders
    Results from an analysis in 569 treatment-naive patients infected with
hepatitis C genotype 1 and treated for 48 weeks with Pegasys and ribavirin
showed that sustained virologic response rates were highest among patients who
had undetectable HCV RNA levels at weeks 4 or 12.  However patients classified
as late responders with a delayed viral clearance had the lowest sustained
virological response rate, indicative of a high relapse rate according to the
study authors. The authors suggested that additional prolonged therapy may
benefit these patients, but that a prospective trial would be needed to
confirm this.
    Pegasys and Copegus(R) (ribavirin, USP) are approved by the U.S. Food and
Drug Administration for the treatment of chronic hepatitis C and are the only
combination regimen FDA-approved for the treatment of chronic hepatitis C in
patients coinfected with hepatitis C and HIV whose HIV is clinically stable.
    Hepatitis C is a blood-borne virus that chronically infects an estimated
2.7 million Americans.  The virus is a leading cause of cirrhosis and liver
cancer and is the number-one reason for liver transplants in the U.S.

    About Pegasys for Hepatitis C
    Pegasys, a pegylated alpha interferon, and Copegus are indicated for use
in combination for the treatment of adults with chronic hepatitis C who have
compensated liver disease and have not previously been treated with interferon
alpha.  Patients in whom efficacy was demonstrated include patients with
compensated liver disease and histological evidence of cirrhosis.
    Pegasys is the first and only pegylated interferon approved by the U.S.
Food and Drug Administration for the treatment of hepatitis C in patients
infected with HIV, and for the treatment of chronic hepatitis B.
    Pegasys is dosed at 180mcg as a subcutaneous injection taken once a week.
Copegus is dosed at 1000 to 1200 mg daily and is administered orally.
    Roche has backed Pegasys with the most extensive clinical research program
ever undertaken in hepatitis C, with major studies initiated to advance
treatment for hepatitis C patients with unmet needs, including patients
co-infected with HIV and HCV, African Americans, patients with cirrhosis, and
patients who have failed to respond to previous therapy.
    Please see attached additional information about Pegasys indication and
safety.

    About Roche - More Than a Century in the U.S. and the World
    Founded in 1896 and headquartered in Basel, Switzerland, Roche is one of
the world's leading innovation-driven healthcare groups. Its core businesses
are pharmaceuticals and diagnostics. Roche is one of the world's leaders in
diagnostics, the leading supplier of pharmaceuticals for cancer, as well as a
leader in virology and transplantation. As a supplier of products and services
for the prevention, diagnosis and treatment of disease, the Group contributes
on many fronts to improve people's health and quality of life. Roche employs
roughly 65,000 people in 150 countries, including approximately 15,000 in the
United States.
    Roche's U.S. operations celebrate their American Centennial in 2005. In
another milestone this year, Roche was named in January to Fortune magazine's
list of Best Companies to Work for in America. One of an increasingly rare
breed of major healthcare companies that still bear their original name, Roche
today has more than a dozen U.S. sites located in California, Colorado,
Indiana, New Jersey and South Carolina, as well as in Puerto Rico. Roche has
alliances and research and development agreements with numerous partners,
including majority ownership interests in Genentech and Chugai. Roche's
Pharmaceuticals Division offers a portfolio of leading medicines in
therapeutic areas including cancer, HIV/AIDS, hepatitis C, transplantation,
dermatology and influenza. Roche's Diagnostics Division supplies a wide array
of innovative testing products and services to researchers, physicians,
patients, hospitals and laboratories world-wide. For further information,
please visit our worldwide and U.S. websites (Global: http://www.roche.com and
U.S.: http://www.roche.us).

    Facts About Pegasys (Peginterferon alfa-2a) in Combination with Copegus
    PEGASYS, alone or in combination with COPEGUS, is indicated for the
treatment of adults with chronic hepatitis C virus infection who have
compensated liver disease and have not been previously treated with interferon
alpha. Patients in whom efficacy was demonstrated included patients with
compensated liver disease and histological evidence of cirrhosis (Child-Pugh
class A) and patients with HIV disease that is clinically stable (eg,
antiretroviral therapy not required or receiving stable antiretroviral
therapy).
    Pegasys is indicated for the treatment of adult patients with HBeAg
positive and HBeAg negative chronic hepatitis B who have compensated liver
disease and evidence of viral replication and liver inflammation.
    Alpha interferons, including PEGASYS(R) (Peginterferon alfa-2a), may cause
or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic,
and infectious disorders. Patients should be monitored closely with periodic
clinical and laboratory evaluations. Therapy should be withdrawn in patients
with persistently severe or worsening signs or symptoms of these conditions.
In many, but not all cases, these disorders resolve after stopping PEGASYS

therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in
complete product information).
    Use with Ribavirin. Ribavirin, including COPEGUS(R), may cause birth
defects and/or death of the fetus. Extreme care must be taken to avoid
pregnancy in female patients and in female partners of male patients.
Ribavirin causes hemolytic anemia. The anemia associated with ribavirin
therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic
and mutagenic and should be considered a potential carcinogen (see
CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete
product information).
    PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or
any of its components, autoimmune hepatitis, and hepatic decompensation
(Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected
patients before or during treatment.  Pegasys is also contraindicated in
hepatic decompensation with Child-Pugh score greater than or equal to 6 in
cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS
is also contraindicated in neonates and infants because it contains benzyl
alcohol. Benzyl alcohol is associated with an increased incidence of
neurological and other complications in neonates and infants, which are
sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated
in patients with a hypersensitivity to COPEGUS or any of its components, in
women who are pregnant, men whose female partners are pregnant, and patients
with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
    COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE
PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY.
Women of childbearing potential and men must use two forms of effective
contraception during treatment and during the 6 months after treatment has
concluded. Routine monthly pregnancy tests must be performed during this time.
If pregnancy should occur during treatment or during 6 months post-therapy,
the patient must be advised of the significant teratogenic risk of COPEGUS
therapy to the fetus. Healthcare providers and patients are strongly
encouraged to immediately report any pregnancy in a patient or partner of a
patient during treatment or during 6 months after treatment cessation to the
Ribavirin Pregnancy Registry at 1-800-593-2214.
    Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of
hepatic decompensation and death when treated with alpha interferons,
including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly
active antiretroviral therapy (HAART) and interferon alfa-2a with or without
ribavirin appear to be at increased risk for the development of hepatic
decompensation compared to patients not receiving HAART. During treatment,
patients' clinical status and hepatic function should be closely monitored,
and PEGASYS treatment should be immediately discontinued if decompensation
(Child-Pugh score greater than or equal to 6) is observed.
    Exacerbations of hepatitis during hepatitis B therapy are not uncommon and
are characterized by transient and potentially significant increases in serum
ALT.  Patients experiencing ALT flares should receive more frequent monitoring
of liver function.  Pegasys dose reduction should be considered in patients
experiencing transaminase flares.  If ALT increases are progressive despite
reduction of Pegasys dose or are accompanied by increased bilirubin or
evidence of hepatitic decompensation, Pegasys should be immediately
discontinued.
    The most common adverse events reported for PEGASYS and COPEGUS
combination therapy observed in clinical trials (N=451) were fatigue/asthenia
(65%), headache (43%), pyrexia (41%), myalgia (40%),
irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%),
neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%),
injection site reaction (23%), arthralgia (22%), depression (20%), pruritus
(19%) and dermatitis (16%).  The adverse event profile of coinfected patients
treated with PEGASYS and COPEGUS was generally similar to that shown for
monoinfected patients.  Events occurring more frequently in coinfected
patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%) weight
decrease (16%) and mood alteration (9%).  The adverse event profile of
hepatitis B patients treated with Pegasys was generally similar to that shown
for hepatitis C patients treated with Pegasys monotherapy except for
exacerbations of hepatitis.
    Serious adverse events included neuropsychiatric disorders (suicidal
ideation and suicide attempt), serious and severe bacterial infections
(sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia),
cardiovascular disorders (hypertension, arrhythmias and myocardial
infarction), hypersensitivity (including anaphylaxis), endocrine disorders
(including thyroid disorders and diabetes mellitus), autoimmune disorders
(including thrombotic thrombocytopenia purpura, psoriasis and lupus),
pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans,
interstitial pneumonitis and sarcoidosis), colitis (ulcerative and
hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders
(decrease or loss of vision, retinopathy including macular edema and retinal
thrombosis/hemorrhages, optic neuritis and papilledema).