Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Transplant Congress 2009

Boston, Massachusetts / May 30-June 3, 2009

As delegates heard here at the ATC, patients with hepatitis C (HCV) who require antiviral therapy (AVT) for recurrent disease following liver transplantation are more likely to achieve a sustained virological response (SVR) to treatment if they are on a cyclosporine (CsA)-based immunosuppressive regimen. Outcomes are also markedly improved if patients respond even temporarily to AVT than if they do not respond at all, according to a Toronto-based retrospective analysis.

As related by Dr. Leslie Lilly, Medical Director, GI Transplantation, UHN-Toronto General Hospital, Ontario, approximately 40% of patients involved in the University Health Network’s liver transplantation program are HCV patients - similar to liver transplant recipients around the world. Although there have been “tremendous advances” in the treatment of HCV in the non-transplantation population, “efforts to translate this success into the transplantation population have met with limited success,” he confirmed.

In a retrospective review of all HCV patients who received a liver transplant since the program was initiated in the 1990s, Toronto investigators identified 450 HCV patients, 172 of whom received treatment for recurrent disease. Patients received ribavirin plus pegylated interferon (86%) or interferon (14%) along with erythropoietin or granulocyte colony-stimulating factor support for management of cytopenias. “Patients were fairly evenly distributed between those who were on a CsA-based immunosuppressive regimen and those on a tacrolimus-based regimen,” as Dr. Lilly observed, “and by the time patients received treatment for recurrent disease, everyone had been switched to the microemulsion formulation.”

At a median post-treatment follow-up of 68 months, 50% of patients receiving AVT for a median of 48 weeks achieved a SVR, 13% relapsed and 37% did not respond to treatment. There was no difference in either the gender of those who responded or in body mass index. Younger donor age favourably influenced response to AVT as did a lower level of pre-treatment necroinflammatory activity in the liver. The influence that genotype had on treatment response was much more substantial: 76% of patients infected with genotype 2 and 3 virus achieved a SVR compared with 40% of those infected with genotype 1 and 4.

More than half of patients (56%) receiving a CsA-based regimen achieved a SVR compared with 44% of those on the other CNI-based regimen (P=0.05). Relapse rates were lower at 6% for those on a CsA-based regimen compared with 19% for those on the tacrolimus-based regimen (P=0.01). There was no difference in the proportion of non-responders based on background immunosuppression. Response to AVT also significantly affected long-term survival: 96% of patients who achieved a SVR—even if they relapsed—were alive at five years compared with 69% of non-responders (P<0.001).

As Dr. Lilly noted during the congress, there have been reports that CsA itself has some antiviral activity and in both laboratory studies and in some patient studies, it has been shown to suppress HCV. “Most studies show that both CsA and tacrolimus are essentially equivalent in terms of patient and graft survival so they are equally good at preventing rejection,” he remarked. “But because of the data we’ve shown here, we now routinely put all of our HCV patients on CsA because it seems to make an important difference in terms of how they respond to AVT.”

DIALIVER Study

The development of diabetes mellitus in any patient population including the transplantation population is associated with a heightened cardiovascular risk. Studies indicate that between 10% and 20% of liver transplant recipients develop new-onset diabetes after surgery within the first year of transplantation (NODAT) and that diabetes, in turn, is associated with reduced patient and graft survival and increased morbidity.

It is well documented that the incidence of NODAT is increased in the presence of the CNIs but they do not impart equal risk, according to Dr. Maria Rendina, Policlinico University Hospital, Bari, Italy. The DIALIVER study was designed to assess whether diabetes control improved when liver transplant recipients with tacrolimus-induced NODAT were switched to CsA. The primary objective of the DIALIVER study was to assess the safety and efficacy of converting patients to CsA microemulsion for improved diabetes control. Secondly, changes in fasting blood glucose before and after conversion, as well as changes in pre- and post-prandial blood glucose levels, were also assessed.

The mean age of the cohort was 46, the median time since transplantation was 50 months and the median time between transplantation and diabetes onset was 35 months.

Forty-six patients were initially converted from tacrolimus to CsA at a dose of 3 to 5 mg/kg during phase I of the study and were treated for two months. During phase II, 45 patients received a mean dose of CsA 2.1 mg/kg/day for an additional four months and 44 patients completed both phases of the study. During phase II, the dose of CsA was adjusted so as to achieve C2 blood levels of 605 ng/mL. Six patients were also receiving steroids, 12 of them were receiving an antimetabolite and 12 were HCV liver transplant recipients.

As reported by Dr. Rendina, 24% of patients were able to discontinue insulin following conversion to CsA during the first two-month phase of the study and this proportion increased to 46.7% with an additional four-month treatment. The mean number of units of insulin required by patients following conversion to CsA dropped by 9 units per day per patient by the end of phase I and by 14.6 units per day per patient by the end of phase II.

“There was also a significant reduction in fasting blood glucose levels from baseline (156.5 mg/dL) to the end of phase I (149 mg/dL) and this reduction became significant at the end of phase II (138.9 mg/dL; P<0.05),” Dr. Rendina observed. Investigators similarly observed a significant reduction in both pre- and post-prandial blood glucose levels (P<0.05) with the exception of pre- and post-prandial lunchtime values which did not achieve significance.

There was no difference in response to CsA conversion among HCV patients, as Dr. Rendina noted. Indeed, as she suggested, this particular conversion strategy could prove particularly beneficial in HCV-positive patients as the use of CsA in the setting of HCV might be expected to attenuate the risk of patients developing either the metabolic syndrome or diabetes.

As Dr. Lilly reported, a CsA-based regimen was significantly associated with a better response to AVT than a tacrolimus-based regimen and Dr. Rendina concurred that response to AVT might well be improved in HCV patients receiving a CsA-based regimen.

Only two patients in the DIALIVER study discontinued treatment due to adverse events, one for reversible bone marrow failure and the other due to acute renal insufficiency. Four other patients experienced serious adverse events but these were not related to the study drug, as Dr. Rendina noted. During the six-month study, there was only one episode of biopsy-proven acute rejection.

Dr. Rendina concluded that the conversion to CsA in liver transplant recipients with tacrolimus-induced NODAT allowed discontinuation of insulin in approximately 50% of patients at six months and improved both fasting blood glucose and pre-and post-prandial, breakfast and dinner blood glucose levels.