Transplant Articles 2003

Treatment of Recurrent HCV after Liver Transplantation

That Produces a Strong, Long-lasting CD4+ T Cell Response Is Predictive of HCV Eradication and a Sustained Response

Patients with recurrent hepatitis C virus (HCV)-infection after liver transplantation (OLTx) may develop an early, multi-specific, preferentially intrahepatic CD4+ T cell response.

Researchers at multiple German medical centers conducted a study to determine whether there is a correlation between the HCV-specific CD4+ T cell response and treatment outcome in patients who receive interferon (IFN)-alfa /ribavirin.

Liver- and blood-derived T cell lines of 20 patients were studied in parallel before, under, at the end and after antiviral treatment. Virus-specific IFN-alfa production at a single cell level to HCV-proteins (core, non-structural protein (NS)3/4, NS5) was determined by enzyme-linked immunospot assay.

Study Results

In 6/7 non-responders a weak HCV-specific CD4+ T cell response was detectable. All six sustained responders developed a strong, at NS3/4 and NS5 directed and long-lasting CD4+ T cell response, which was mainly detected in peripheral blood mononuclear cells.

This reaction was significantly stronger: (1) in the responders than in the non-responders; and (2) within the responders at the end of treatment than before (P<0.03). Seven transient-responders showed a weak and/or transient HCV-specific CD4+ T cell response.

The authors conclude, “In patients with recurrent HCV-infection after OLTx, who receive antiviral treatment, a strong, at NS3/4 and NS5 directed and long-lasting CD4+ T cell response is associated with HCV-elimination whereas no or a weak/transient response is associated with treatment failure.” 08/20/03

Reference: CA Schirren and others. Antiviral treatment of recurrent hepatitis C virus (HCV) Infection after liver transplantation: association of a strong, multispecific, and long-lasting CD4+ T cell response with HCV-elimination. Journal of Hepatology 39(3): 397-404. September 2003.

http://www.hivandhepatitis.com/hep_c/news/082003b.html

Preventive Treatment for HCV Recurrence in Patients with Decompensated Post-hepatitis C Cirrhosis Before Liver Transplantation: An Editorial

There is no consensus or compelling evidence for a single, standard approach to treatment for the prevention of HCV recurrence following liver transplantation, which unfortunately occurs almost universally.

In the following editorial, published in the Journal of Hepatology (September 2003), researchers in the Gastroenterology Department at the Michallon Hospital in Grenoble, France review the most recent therapeutic approaches to this serious post transplantation complication:

“After liver transplantation (LT), hepatitis C virus (HCV) recurrence is almost universal, particularly if HCV RNA is detectable at the time of transplant and can lead in a great number of patients to recurrent cirrhosis and graft failure.

This recurrence is often rapid (1). Several studies have shown that combination therapy using interferon alfa and ribavirin is possible after liver transplantation but the virological response rate is low and the treatment is usually associated with major side effects, requiring dose reduction or stopping treatment.

Another strategy is the eradication of HCV RNA before LT in order to prevent HCV recurrence after LT and reduction in the level of HCV RNA to reduce the severity of post-transplantation liver disease.

Forns et al evaluated the efficacy and safety of antiviral therapy in 30 patients with post-hepatitis C cirrhosis awaiting liver transplantation. Only patients having an expected time on the waiting list shorter than four months were included. Patients with hepatic encephalopathy, renal failure or co-infection by hepatitis B virus or human immunodeficiency virus were excluded. Patients were treated with interferon alfa-2b (Intron A) 3MUI/day and ribavirin 800 mg/day. Dose reductions were utilized according to the laboratory recommendations.

Fifty patients were screened during a 15-month period, but 19 (38%) were excluded due to contra-indication or refusal. The median duration of treatment was 12 weeks (2-33). Virological response was observed in nine patients (30%). Variables associated with a good response to treatment were age, ALT level, genotype non 1 and low viral load. A decrease of viral load > or = 2 log had a positive predictive value of 100% at week 4.

After liver transplantation, among the nine patients with virological response, HCV infection recurred in only three patients at week 2, 4, 5, respectively after liver transplantation. All these patients were infected with genotype 1b.

Six patients became HCV RNA negative after a mean follow-up of 46 weeks (24-80). Indeed, 4/5 patients also tested in the liver were HCV RNA negative. Side effects were frequent. Two patients developed sepsis; in both cases, neutrophil counts were above 1.2×109/l at the time of hospital admission.

Interferon dose reduction was necessary in 60% of cases and ribavirin dose reduction in 24% of cases. Eleven patients required filgrastim due to neutropenia and eight erythropoïetin due to anemia. No patients died during therapy.

Assessment of interferon in patients with decompensated chronic hepatitis C was until now based on limited small case series. A gradually increasing dose regimen of combination therapy with interferon and ribavirin has been used in patients with both compensated and decompensated cirrhosis due to hepatitis C by Everson et al. (5).

Patients were started on low dose of interferon (1.5 MUI, tiw) and ribavirin (600 mg/day) with slowly increasing dose of both drugs every 2 weeks as tolerated. Preliminary results of treating 91 patients, the majority infected with genotype 1, were recently reported.

On-treatment virological responses occurred in 38% and a sustained virological response in 22% of patients. Sustained responses were more common in patients treated for more than 6 months. Eight patients who were treated and were HCV RNA negative at the time of transplantation remained virus free post-transplantation.

On the other hand, recurrent and persistent HCV infection of the allograft was observed in all patients with detectable HCV RNA at the time of transplantation. No significant change was observed regarding the hepatic synthetic function and/or Child Pugh score. Indeed, 27 of non-responders were reported to develop adverse events.

Less favorable outcome has been reported by Crippin et al. (6) in a collaborative study of five US liver transplant centers. Patients were treated with a common protocol using low dose of interferon with or without low dose of ribavirin. Only half the patients screened for the study were enrolled, many being excluded because of severe cytopenias. All patients had advanced liver disease with a mean Child-Pugh score of 12, as well as elevated serum bilirubin, prolonged prothrombin time and moderated impaired renal function.

On treatment, 33% of patients became HCV RNA negative. Two patients underwent liver transplantation and both developed recurrent infection. Adverse events were common and sometimes severe, including profound thrombocytopenia, marked neutropenia, new-onset hepatic encephalopathy and life-threatening infections that ultimately led to the early termination of the study.

Of course, because both studies did not include an untreated control group for comparison, it is unclear whether interferon and ribavirin combination therapy per se precipitated these life-threatening infections or whether they merely represented complications of end stage liver disease.

All together these three studies suggest that antiviral therapy with post-hepatitis C cirrhosis awaiting liver transplantation is possible and can prevent HCV disease recurrence in several patients, especially in patients with favorable predictive factors of response.

However, recurrence of HCV infection after LT is possible even if HCV RNA is negative in the serum or the liver at the time of transplantation. Two explanations can be proposed to explain this discrepancy: first the method of detection of HCV RNA was not sensitive enough; in this case it would be interesting to compare this result with a more sensitive method of detection such as real-time PCR.

The second explanation could be the persistence of the virus in a second compartment such as peripheral blood mononuclear cells; to confirm this hypothesis, it is necessary to study quasispecies distribution in each compartment.

The best results observed by Everson et al. (5) and Forns et al. (4) suggest that the treatment is better tolerated in patients with Child A and B than in patients with Child C and leads to less severe complications such as neutropenia and thrombocytopenia.

All these studies clearly show also that it is necessary in some cases to use growth factors including GM-CSF and erythropoïetin to boost peripheral blood cell counts in patients with severe neutropenia and erythropenia to prevent profound cytopenias and infections.

From these studies, it seems very difficult to define the best regimen. In Forns et al. study (4), authors used daily dose of recombinant interferon. By contrast, Everson et al. (5) as well as Crippin et al. (6) used low doses of interferon three times a week.

There are no data on the safety and/or efficacy of peginterferon with or without ribavirin in patients with decompensated post hepatitis C cirrhosis. Indeed, the combination of peginterferon plus ribavirin was only tested in patients with severe fibrosis (F3 and F4) and was well tolerated. (7)

However, because peginterferon regimens are associated with higher rate of neutropenia and thrombocytopenia, treatment is likely to be associated with even greater infection complications than regimens using standard infection interferon and slower recovery from these complications when the interferon is stopped [emphasis added—Ed.]

It will be very interesting in the future to compare these different regimens. Indeed, the best duration of treatment remains to be defined.

The rationale for Forns et al. (4) to treat for a short time was that most virological responders had a viral load decrease of > or = 2 log 10 at week 4 and were HCV RNA negative by week 12. However these results are very surprising, especially in patients with genotype 1b and were not found by others, and we do not know which treatment schedule is more convenient.

In conclusion, in patients with decompensated HCV cirrhosis, antiviral therapy as suggested by Wright et al. (8) in the last American consensus conference should be considered experimental and not be administered outside of prospective trials.

If the results of these prospective trials are confirmed, this strategy could be then used in patients with post-hepatitis C cirrhosis without severe hepatocellular insufficiency awaiting LT.” 08/20/03

Source: J-P Zarski and M-N Hilleret. Treatment of patients with decompensated post-hepatitis C cirrhosis before liver transplantation: strategy to prevent hepatitis C virus (HCV) recurrence? Editorial. Journal of Hepatology 39 (3): 435-436. September 2003.

References
1. M. Berenguer, L. Ferrell, J. Watson, M. Prieto, M. Kim, M. Raon et al., HCV-related fibrosis progression following liver transplantation: increase in recent years, J Hepatol 32 (2000) 673-684.
2. L.M. Forman, J.D. Lewis, J.A. Berlin, H.I. Feldman, M.R. Lucey, The association between hepatitis C infection and survival after orthotopic liver transplantation, Gastroenterology 122 (2002) 889-896.
3. D. Samuel, T. Bizollon, C. Feray, B. Roche, S.N. Ahmed, C. Lemonnier et al., Interferon alfa-2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study, Gastroenterology 124 (2003) 642-650.
4. X. Forns, M. García-Retortillo, T. Serrano, A. Feliu, F. Suarez, M. de la Mata, J.C. García-Valdecasas et al., Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation, J Hepatol 39 (2003) 389-396.
5. G. Everson, J. Trotter, M. Kugelmas, Long-term outcome of patients with chronic hepatitis C and decompensated liver disease treated with the LADR protocol (low accelerating-dose regimen), Hepatology 36 (2002) 297A.
6. J.S. Crippin, T. McCashland, N.A. Terrault, P. Sheiner, M.R. Charlton, A pilot study of the tolerability and efficacy of antiviral therapy in HCV-infected patients awaiting liver transplantation, Liver Transpl 8 (2002) 350-355.
7. E.J. Heathcote, M.L. Shiffman, G.E. Cooksly, G.M. Dusheiko, S.S. Lee, L. Ballart et al., Peg interferon alfa 2a in patients with chronic hepatitis C and cirrhosis, N Engl J Med 343 (2000) 1673-1680.
8. T. Wright, Treatment of patients with hepatitis C and cirrhosis, Hepatology 36 (2002) S185-S194.

http://www.hivandhepatitis.com/hep_c/news/082003c.html

Kidney Failure a Major Problem in Transplants

A study finds the lifesaving drugs that fight rejection may play a role.

By Ed Edelson
HealthDay Reporter

WEDNESDAY, Sept. 3 (HealthDayNews) -- Kidney failure is a disturbingly high risk for all transplant patients, says the largest survey ever done.

Ironically, the major cause of those kidney failures is an unavoidable side effect of the rejection-suppressing drugs that made transplantation possible, experts say.

"The five-year risk of chronic renal [kidney] failure after transplantation of a non-renal organ ranges from 7 to 21 percent, depending on the type of organ transplanted," says a report in the Sept. 4 issue of the New England Journal of Medicine by transplant specialists at the University of Michigan.

Kidney failure in those patients more than quadruples the risk of death, the researchers say.

"The magnitude of the problem is much higher than what one would expect based on what we see day-to-day in the clinic," says study leader Dr. Akinlolu O. Ojo, an associate professor of medicine at Michigan. "A number of 20 percent is higher than one would come up with if one had to make a guess."

The numbers come from a study of nearly 70,000 persons who received other-than-kidney transplants (liver, heart, lung, heart-lung or intestine) in the United States in the 1990s. Overall, 11,426 of those patients suffered kidney failure in the first three years after surgery, an incidence of 16.5 percent.

"While this report does not specifically say so, previous work would suggest that the main cause of kidney disease that arises after transplantation are these drugs," says Dr. Colin C. Magee, a staff physician in the renal division of Brigham and Women's Hospital, the teaching hospital of Harvard Medical School.

Two drugs are the mainstays of efforts to prevent the immune attack that kills transplanted tissues -- cyclosporine, whose appearance in the early 1980s revolutionized transplantation, and tacrolimus, which was introduced later.

"It is important to remember that these are drugs are lifesaving drugs," Magee says. "Without these drugs, transplantation would not be possible."

But the high incidence of kidney failure after transplantation not only worsens the quality of life but also can translate into a requirement for artificial kidney treatment or kidney transplants for many thousands of patients, which can strain medical resources, Magee says. While fewer than 1 percent of Medicare patients have kidney failure, they account for almost 6 percent of the Medicare budget, the editorial says.

There are ways to lessen the problem, Ojo and Magee say. It might be possible to use lower doses of cyclosporine and tacrolimus in selected patients, and to use newer rejection-preventing drugs in those patients, Magee says. But doctors will be cautious about changing the existing regimens, because any new dosage schedules might not be as effective, he says.

Ojo proposes a strategy based on other findings of the survey -- that a number of factors other than drug therapy contribute to the risk of kidney failure. Those factors include older age, being a woman, having hepatitis C infection, high blood pressure and diabetes, the survey shows. Those factors can be combined in a formula to determine a patient's overall risk, he says.

"We need a way to stratify people before they get transplants so that we could reduce the amount of drugs we use or use the newer drugs in these patients to avoid toxicity," Ojo says. But he advises caution in use of the newer drugs, because they may not be as effective in preventing rejection as the two older medications.

Transplant centers, including the one at Michigan, are not now using the risk-stratifying strategy because the risk factors have not been laid out clearly, Ojo says. The surgery results may help promote the strategy, he says.

More information

Read more about organ transplantation at the United Network for Organ Sharing", and you can learn about kidney disease from the National Institute of Diabetes and Digestive and Kidney Diseases.

Last Updated: September 03, 2003

Subject: INFO:

Factors influencing the outcome of liver retransplantation

SourceURL:http://www.gastrohep.com/news/news.asp?id=2244 Factors influencing the outcome of liver retransplantation Liver retransplantation is associated with a greater rate of complications, and lower patient and graft survival, find physicians in the September issue of Liver Transplantation. Whether the outcome of liver retransplantation is dependent on the indication for retransplantation or the cause of liver disease is unknown. In this study, physicians from Baltimore, Maryland, compared the outcome of retransplantation in adults with that of primary liver transplantation (PLT). They assessed whether the outcome of retransplantation was dependent on its indication. The research team used data from the United Network for Organ Sharing from 1988 to 2001. Hepatitis C virus infection is an independent predictor of mortality after liver retransplantation. Liver Transplantation Overall, the team identified 34,267 patients who met their inclusion criteria. Of these, 761 patients underwent liver retransplantation for primary graft nonfunction (PGNF) (group 1), 3428 patients underwent retransplantation for other reasons (group 2), and 30,078 patients underwent PLT (group 3). The researchers identified a greater incidence of PGNF and regrafting in the retransplant groups when compared with the PLT group. In addition, analysis showed significantly lower short- and long-term patient and graft survival in the retransplant groups compared with the PLT group. Furthermore, the team found that patients in group 1 had lower patient and graft survival compared with group 2. However, when data was analyzed using Cox regression they found that graft survival not patient survival was lower in group 1. The team also found that patients with hepatitis C virus (HCV) infection who underwent retransplantation had lower patient and graft survival compared with those without HCV infection. HCV was identified as an independent predictor of mortality after liver retransplantation. Dr Hwan Yoo's team concluded, "Retransplantation was associated with a greater rate of complications and lower patient and graft survival compared with PLT". "Retransplantation for PGNF and HCV infection was associated with lower patient and graft survival compared with retransplantation for other causes". Liver Transpl 2003; 9: 897-904 29 August 2003

Doctors Urge Pre-Transplant Liver Screenings to Avoid Complications Later
Author: John C. Martin Author Date: 8/18/2003

For more than two decades, "James", a California minister, was faced with a debilitating autoimmune disease that was slowly destroying his liver. Just five years ago, James hit rock bottom; his health had deteriorated to the point that he was forced to place his name on the liver transplant waiting list.

While his wife volunteered to donate a section of her liver, she later learned it was not the right size. Miraculously, a local acquaintance, "Charles" (not his real name) learned of the minister's plight, and stepped forward, offering part of his liver instead.

Before the surgery, doctors explained to Charles that he would be required to undergo a liver biopsy to ensure that his organ was completely healthy, thus maximizing the chances of a successful transplant.

The operation took place in February 2003 at Cedars-Sinai Medical Center in Los Angeles, and it wound up successfully.

"Today, I feel better than I have for the past 15 years," said James. "I see [Charles] often, and constantly wonder how can I ever fully repay a kindness like the one he gave me."

The Effectiveness of Preoperative Biopsy
Doctors at the Los Angeles hospital credit the success of the liver transplant procedure to the preoperative biopsy that was performed. Normally performed to evaluate liver function in those with symptoms of disease, in this case, the biopsy was conducted to pre-empt any potential complications during transplant surgery. The biopsy offers a glimpse of abnormalities in potential donors that might go unnoticed through the usual laboratory and imaging tests.

In fact, doctors at Cedars-Sinai are so convinced that preoperative biopsy is so effective, they began a study to assess it more thoroughly, and unveiled the findings at a medical conference this past spring.(1)

"We wanted to really look to see if there were any ways that we could improve upon the safety for both the donor and the recipient," explained Tram Tran, M.D., Cedars-Sinai Medical Center's assistant director of hepatology, who took part in the study.

'A Learning Curve'
Biopsies are not included in the standard battery of tests given before liver transplantation at all hospitals in the U.S. In fact, an unrelated study earlier this year found that of the 122 living donor liver transplant programs in this country, a mere 14 percent require liver biopsies of their donors.(2)

"Adult-to-adult living donor [transplantation] has really only been done since 1998," Tran said, in a telephone interview. "So, I think every program is still on somewhat of a learning curve."

She said there is a wide variability in the types of preoperative tests that are performed. Some centers require biopsies of all patients; some biopsy only a certain number of patients; and other programs do not require preoperative biopsies at all. "Given what we found, we think that it is useful to do biopsies on all candidates," Tran explained.

When a biopsy is performed, the physician marks the outline of your liver, and injects a local anesthetic to numb the area. A small incision is then made on your right side near your rib cage, and a biopsy needle is inserted to retrieve a sample of liver tissue.

The tissue is then examined for signs of damage or disease. Looking at the liver tissue itself is the best way to determine the liver's health.(3)

Liver Biopsies Provide Better Detection
In the research done at Cedars-Sinai, doctors examined 56 donors who had donated a lobe of their liver between May 2001 and October 2002. All of them were screened for hepatitis and other potential health problems that would have prevented them from undergoing the procedure through a series of physical exams, extensive blood testing, imaging and further clinical evaluations.

The investigators found that all donors had no obvious abnormalities. But when biopsies were subsequently conducted, the physicians found that cases of chronic hepatitis, a fatty condition of the liver called steatosis, and other liver-related complications had gone undetected. In fact, they found that less than a third of these donors had livers that were as healthy as the previous screenings had indicated.

In steatosis, for example, the risk of bleeding during surgery is higher than that of non-steatotic livers, Tran explained.

Two years ago, doctors at Cedars-Sinai began routinely including liver biopsy as an evaluative tool used to screen liver donors. "Based on the results of our analysis, we're now recommending that all centers offering living donor liver transplants consider adding a pre-transplant donor biopsy to their screening process," said James Vierling, M.D., medical director of the Multi-Organ Transplant Program at Cedars-Sinai, in a statement.

Vierling points out that while the need for transplant livers far outnumbers the available organs each year, more and more living donors are coming forward to donate parts of their liver. Because of that, he says it's essential to develop better ways to conduct pre-screening and evaluation processes for these patients.

Added Tran: "Any abnormality that we deem as infectious or at risk to either the donor or the recipient is going to eliminate them from being able to donate."

1. Digestive Disease Week 2003. 2003 May 17-22. Orlando, FL.
2. Brown, Jr., RS et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med 2003 Feb 27;348:818-25.
3. National Digestive Diseases Information Clearinghouse. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Liver Biopsy.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.