Recurrence of hepatitis C post orthotopic liver transplantation (OLT) is universal. Response rates to interferon and ribavirin are suboptimal, with appreciable side effects leading to discontinuation in 30%.

In this study, a standardized protocol of pegylated interferon α-2b (Peg-Intron) and ribavirin therapy was implemented in January 2001 to treat patients with histological recurrent hepatitis C virus post OLT.

Patients were commenced on pegylated interferon alfa 2b and ribavirin at doses of 1.5 million units/week and ribavirin 11mg/kg. Patients who did not respond or were unable to tolerate therapy were switched to an escalating regimen of pegylated interferon α-2a (Pegasys) commenced at 90mcg/week, titrating up to 180 mcg/week over 3 months and ribavirin at 7mg/kg up to 11mg/kg over 3 months.

Hematopoietic growth factors were used for Hb < 12.0g/dL and for total WBC

< 1.5 x 103 u/L. Response to therapy was assessed as on treatment virological response (OTR) and side effects were recorded in a retrospective chart review.

Results

Twenty-seven patients underwent treatment for recurrent HCV with the above protocol. The majority of patients (80%) were genotype 1.

Ten (37%) patients discontinued therapy early (< 6 months) due to side effects. Eight (30%) had significant weight loss (>5kg). Twenty-two (81%) developed anemia and 10 were treated with erythropoietin, 9 (33%) developed neutropenia and 8 were treated with G-CSF. Seven patients (26%) required antidepressant therapy. Eight (30%) achieved OTR following 1 year of therapy.

Ten (37%) patients were switched to an escalating pegylated interferon α-2a and ribavirin regimen due to lack of OTR in 2, constitutional side effects in 5, arthritis in 1 and symptomatic anemia and neutropenia unresponsive to growth factor support in 2.

These patients had been on therapy for a mean of 6.2 months (range 2 - 13) prior to switching and only 1 had achieved OTR.

After switching to pegylated interferon α-2a, 3 additional patients (33%) achieved OTR and no patients discontinued therapy after a mean of 5.5 months on therapy.

Conclusions

The authors conclude, “Our initial data suggest that an escalating peg-interferon α-2a combination regimen may be tolerated better than combination peg-interferon α-2b in some patients post OLT and thus allow better OTR.”

“Those problematic patients who do not tolerate combination therapy post OLT may tolerate therapy better using an escalating combination regimen with aggressive growth factor support.”

06/04/04

Reference
N Kontorinis and others. Switching from Peg-Interferon α-2b to an Escalating Peg-Interferon α-2a Regimen for Recurrent Hepatitis C Post Liver Transplantation May Improve Virological Response and Tolerability. Abstract 1177 (poster). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

In a Large US Cohort, Race Had No Effect on Survival Time of Liver Transplant Recipients

Previous analyses of data from the United Network for Organ Sharing (UNOS) showed that African American (AA) patients undergoing liver transplantation (OLT) had survival significantly inferior to recipients of other races (Lancet 2002). The reason for this disparity is unclear.

The objective of the current study was to compare survival of AA and non-AA OLT recipients and causes of death at high-volume OLT centers.

Two NIH-sponsored multi-center databases prospectively enrolled OLT recipients at 4 centers. Data including demographics, liver disease diagnosis and postOLT follow-up were extracted in 2851 adult patients undergoing primary OLT between 1985 and 2000.

Results

The racial distribution of the cohort included 135 AA (4.8%), 2448 Caucasian, and 240 other race. Similar to the UNOS data, AA recipients were younger than non-AAs (mean ages: 43.1 vs. 49.6, p<.01).

Fulminant hepatic failure was more common (14.8% vs. 4.2%) and alcoholic (7.4% vs. 12.8%) and cholestatic (15.6% vs. 23.6%) disease less common among AAs than non-AAs (p<0.01). The proportion of hepatitis C was similar (21.5% vs. 23.8%).

Subsequent to OLT, 765 recipients died including 35 AAs (4.6% of all deaths).

The authors conclude, survival was indistinguishable between AAs and non-AAs. Graft survival was also similar. In the table that describes causes of death in 716 patients with identifiable causes, there was no difference between AA and non-AA recipients.

Conclusions

In contrast to the nation-wide data from UNOS that showed significantly shorter survival for AA recipients, in this large cohort of carefully selected OLT recipients at high-volume centers, race had no effect on post-OLT survival.

The authors conclude, “These data suggest that patient selection or post-OLT care in these select centers can overcome any biologic differences (e.g., higher incidence of rejection) that may exist across racial categories.

05/24/04

Reference
W R Kim and others. Why Should African American Liver Transplant Recipients Have Poorer Survival Than Others? Abstract 223 (oral). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

www.hivandhepatitis.com

Keeping Transplanted Livers Healthy is a Challenge, Say Doctors
by John C. Martin	Article Date: 06-02-04

http://www.hepatitisneighborhood.com/content/in_the_news/archive_1856.aspx
 

Study May Improve Survival of Transplanted Livers

Embargoed until 12:01 a.m. EDT Monday, May 24, 2004 May 20, 2004
Study may improve survival of transplanted livers

By JULIA BRITTAIN
UNC School of Medicine

(Embargoed) CHAPEL HILL -- Newswise — New research at the University of North Carolina at Chapel Hill School of Medicine shows that treatment with nitric oxide after storage may dramatically improve the viability of transplanted livers.

About 5,000 liver transplants are performed annually in the United States, and a key factor ensuring success is maintaining a healthy donor organ that can function effectively in the recipient. However, transplanted livers typically incur substantial damage when blood flow is restored to the organ after the transplant.

This damage occurs when ischemic, or oxygen-deprived, tissue is re-introduced, or reperfused, to adequate blood flow.

The study, to be published in the June issue of the journal Hepatology, showed that use of nitric oxide during reperfusion protected cultured rat liver cells, or hepatocytes, from cell death typically occurring as a result of reperfusion stress.

"Reperfusion stress precipitates the death of the tissue, but our results suggest that the way we reperfuse the liver can reduce injury to it," said Dr. John Lemasters, professor of cell and developmental biology at UNC and senior investigator for the study.

Preventing such damage is relevant in liver transplants and essential to the success of organ transplantation in general, UNC researchers said.

This injury also is central to the nature and development of shock, stroke and heart attacks, Lemasters added.

Cell death due to reperfusion stress results from damage to the hepatocyte's mitochondria, the cellular site of generation for the primary energy molecule in a cell, called adenosine triphosphate (ATP). This damage, known as mitochondrial permeability transition (MPT), opens up the mitochondria to small molecules entering the organelle and interrupting generation of ATP. Then, cell death occurs.

Nitric oxide exerted its protective effects in the study's model by blocking the MPT-based injury to the hepatocyte, the study showed.

"Our cell culture model mimics severe ischemia, and nitric oxide was still effective in blocking cell death," said Dr. Jae-Sung Kim, the primary study author and assistant professor of cell and developmental biology.

Use of nitric oxide after cold storage of the donated organ may help maintain normal liver function after the transplant, the study indicated.

"Nitric oxide protects the liver during the reperfusion phase, after ischemia has occurred, and this means we can intervene in a meaningful way," said Lemasters. "We can treat after disease onset."

Because it reacts rapidly with oxygen, nitric oxide can cause damage to the transplanted liver at certain levels. Therefore, the appropriate concentration of nitric oxide is vital to guarantee its protective effects, the scientists said.

The researchers also discovered that nitric oxide exerts its protective effects by stimulating the liver cells to produce cell-signaling molecules - cGMP, which activates protein kinase G - required for other protective agents in the body to function.

"Our result suggests that cGMP analogues or other agents that elevate cGMP levels in liver cells may also induce this protective effect," said Lemasters.

One of these agents, atrial natriuretic factor, has been shown to protect against the reperfusion stress that occurs after a heart attack.

"Our next step is to test our hypothesis that atrial natriuretic factor will be protective against ischemia-reperfusion injury in the liver," said Kim.

The researchers also want to determine if nitric oxide can be protective in an animal liver transplant model.

Drs. Shigetoshi Ohshima and Peter Pediaditakis, postdoctoral researchers, also were authors on the study.

This research was supported by grants from the National Institutes of Health.
- 30 -

Digestive Disease Week (DDW 2004)
  May 15 - 20, 2004, New Orleans, Louisiana

Improved Efficacy and Tolerability in Treating Post-Transplant HCV Utilizing an Escalating Regimen of Pegylated Interferon Alfa-2a (Pegasys) and Ribavirin with Hematopoietic Growth Factors

Initial data suggests that therapy for recurrent hepatitis C virus (HCV) post orthotopic liver transplantation (OLT) with interferon and ribavirin is poorly tolerated with at least a 30% early discontinuation rate due to side effects.

In this study, HCV Patients (pts.) post OLT with documented histological recurrence were prospectively commenced on a standardized escalating protocol of pegylated interferon alfa-2a (Pegasys) and ribavirin at doses of 90 mcg/week and 7 mg/kg BID respectively for the first month, to a full dose (180 mcg/week and 14 mg/kg BID) by the third month.

Response to therapy was assessed as "on treatment" virological response (OTR) at 6 months.

Anemia was defined as hemoglobin (Hb) < 12g/dL, with neutropenia defined as a total white cell count (WCC) of < 1.5 x 103 u/L. Below this threshold hematopoietic growth factors (EPO and G-CSF) were used to maintain hematological parameters.

Results

Twenty five pts. were treated for recurrent HCV post OLT. There were no early discontinuations of therapy. Two pts. who had recurrent decompensated cirrhosis underwent a trial of antiviral therapy but subsequently died.

The mean stage of fibrosis prior to therapy was 1.64 +/- 1.29. The majority of pts. were genotype 1.

Thirteen (52%) demonstrated OTR at 6 months after a mean duration of 2.57 months of therapy; 12/19 (63%) with stage 0-2 fibrosis and only 1/6 (17%) with stage 3-4 fibrosis had OTR (p = 0.22).

Twenty one (84%) received EPO for symptomatic anemia and 11 (44%) were treated with G-CSF for neutropenia. The mean WCC at the start of therapy was 5.02 x103 u/L (range 2.4-9.5), the nadir on therapy was 2.09 x 103 u/L (range 1.0-5.4), with a mean drop in WCC of 2.94. This occurred at a mean of 3.96 months into therapy.

The mean platelet count at the start of therapy was 134 (range 87-253), the nadir on therapy was 79 (range 26-187), with a mean drop in platelet count of 55. Four patients (15%) developed significant depression requiring antidepressants. No patients developed infection or bleeding with 1 documented episode of histological rejection.

Conclusions

The authors conclude, “Pegylated interferon alfa-2a and ribavirin are effective and well tolerated for post transplant HCV using an escalating dose regimen. Our data demonstrates that aggressive use of hematopoietic growth factors is essential to prevent early discontinuation, achieve adequate dosing and improve response rates of therapy.”

06/07/04

Reference
N Kontorinis and others. Improved Efficacy and Tolerability in Treating Post-Transplant HCV Utilizing an Escalating Regimen of Pegylated Interferon alfa-2a and Ribavirin with Hematopoietic Growth Factors: A Prospective Study. Abstract 45 (oral). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

http://www.hivandhepatitis.com/2004icr/ddw2004/docs/0607/060704_c.html

Preliminary Results Presented at American Transplant Congress on Largest Ever Hepatitis C Trial Conducted in Liver Transplant Recipients

 Early Data Shows Steroid-Free Protocol May Be Safe with Low Rejection Rates

    CINCINNATI, June 15 /PRNewswire/ -- CTI Clinical Trial and Consulting
Services announced that Goran Klintmalm, M.D., Ph.D., chief of Baylor Regional
Transplant Institute and principle investigator of a study comparing 3
immunosuppressant treatment regimens in liver transplant recipients with
hepatitis C, presented preliminary data from the trial at the American
Transplant Congress meeting last month in Boston and the International Liver
Transplantation Society meeting last week in Kyoto, Japan.  A total of 312
patients enrolled in this prospective, multicenter, randomized study at 18
leading U.S. transplant programs.  Enrollment began in August 2002 and
concluded in March 2004.  All patients will be followed for 2 years. Hepatitis
C is present in approximately 4 million Americans, and affects 50% of all
patients receiving liver transplants.  Hepatitis C frequently recurs following
liver transplantation, leading to death or retransplantation.
    Corticosteroids have been the cornerstone of immunosuppression in
transplantation since the 1960s, however there is much controversy that
corticosteroids may in fact increase recurrence of hepatitis C.  In addition,
the role and effect of mycophenolate mofetil, an immunosuppressant
(non-steroid), in hepatitis C liver transplant patients is unclear.
    "The purpose of this study is to determine the effect that the withdrawal
of steroids, as an immunosuppressant, has on the recurrence of hepatitis C, as
well as whether mycophenolate mofetil can reduce and slow down the development
of hepatitis C as it recurs in the transplanted liver," said Dr. Klintmalm.
"While definitive analysis and conclusions will have to await completion of
the trial in approximately 2 years, the early results are very encouraging."
Patients were randomized to one of the three treatment regimens at the time of
transplantation and will be maintained on this regimen for two years.
Treatment regimen 1 includes conventional therapy (tacrolimus) and
corticosteroids, but no mycophenolate mofetil; treatment regimen 2 includes
tacrolimus, corticosteroids and mycophenolate mofetil; and treatment regimen 3
includes tacrolimus, mycophenolate mofetil and daclizumab (an antibody given
to prevent early acute rejection), but no steroids.  Liver biopsies will be
performed at various times throughout the study to assess treatment failure.
Data presented by Dr. Klintmalm on 261 patients enrolled through Dec. 31,
2003, focused on day 90 post transplant data.
    The early data from this trial showed that the steroid-free protocol may
be safe with low rejection rates.  This preliminary analysis demonstrated that
all three regimens had similar excellent early patient survival rates ranging
between 95-100%, and graft survival rates ranging between 95-97%.  In
addition, protocol-defined acute rejection rates and hepatitis C recurrence
rates were low in all three regimens.  The complete avoidance of
corticosteroids in regimen 3 had no negative impact on acute rejection
incidence or recurrent hepatitis C.  However, there appeared to be a decrease
in diabetes and hypertension in this group of patients. Further, the use of
mycophenolate mofetil in regimens 2 and 3 did not increase hepatitis C
recurrence or severity at 90 days post transplant. Finally, in regimen 3,
daclizumab appeared to be safe and did not increase early hepatitis C
recurrence or severity.
    "The data obtained from this study will provide important information to
improve the management of hepatitis C patients after liver transplantation,"
Dr. Klintmalm said. Baylor University Medical Center at Dallas initiated this
trial and recruited the other 17 participating study sites.  CTI, Clinical
Trial and Consulting Services, is managing the trial on behalf of Baylor.
Other participating members of the study include Emory University School of
Medicine, Lahey Clinic, Mayo Clinic in Rochester, Mayo Clinic in Scottsdale,
Medical University of South Carolina, New York Presbyterian Hospital, New York
University School of Medicine, Northwestern University Feinberg School of
Medicine, Oregon Health and Science University, University of Alabama at
Birmingham School of Medicine, University of California - San Francisco
Medical Center, University of Chicago Medical Center, University of Cincinnati
Medical Center, University of Medicine and Dentistry in New Jersey, University
of Southern California Keck School of Medicine, University of Texas Health
Science Center at San Antonio, and University of Virginia Medical Center.
    "It was particularly gratifying to work with this group of committed liver
transplant programs on this study.  Enrollment was completed early and
participating investigators have been diligent about obtaining all protocol
specified procedures," stated Lynn Fallon, senior vice president, CTI. For
more information about this research, visit http://www.baylorhealth.com .

    About CTI Clinical Trial and Consulting Services
    CTI Clinical Trial and Consulting Services provides innovative clinical
trial services and consulting solutions for the pharmaceutical industry in the
specific areas of transplantation, infectious disease and end stage organ
disease, including dialysis and liver function.
    CTI's experience encompasses over 20 years of designing and implementing
drug development programs.  CTI's involvement spans the entire lifecycle of
the product from drug development pathway design, clinical trial design,
strategic marketing plan development, product management and sales.   CTI is
capable of managing all phases of the clinical trial process from pre-study
planning and concept development to the preparation of the final trial
manuscript.  Combining market and industry expertise gives CTI the ability to
evaluate information and drug compounds from every possible perspective,
incorporating both clinical and market driven endpoints and interpretations.