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PRIORITY PRESS - 18th Annual International Congress of the International Liver Transplantation Society

San Francisco, California / May 16-19, 2012

San Francisco - Long-term outcome of patients undergoing liver transplantation as a result of the complications of hepatitis C viral (HCV) infection is predicted to improve with studies demonstrating that immunosuppressive drugs can be used simultaneously with aggressive antiviral regimens. Cirrhosis and hepatocellular carcinoma generated by HCV represent the leading indications for liver transplantation in most registries. While graft survival in patients with an HCV complication still typically trails that of patients without HCV, aggressive antiviral treatments that eradicate or control HCV recurrence after transplantation are being shown to be feasible. The potential to improve outcomes is credited to advances in differentiating and managing the adverse events associated with immunosuppressive regimens. However, new studies also suggest that HCV therapies can be introduced with the intention to eradicate or control infection to improve graft survival.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Hepatitis C viral (HCV) infection causes cirrhosis and is associated with a high rate of hepatocellular carcinoma (HCC). Liver transplantation due to HCV complications has been challenging because most patients with detectable HCV before transplantation will develop recurrent infection afterwards. New data that better clarify the risk factors for early graft failure in HCV patients and expand data on the simultaneous use of antiviral and immunosuppressive therapies are promising important advances in outcome.

“In our experience over the last 10 years, the long-term survival of HCV patients has been mostly dependent on the management in the first post-transplant year,” reported Dr. Itxarone Bilbao, Hospital Vall d’Hebron, Barcelona, Spain. Noting that current organ allocation algorithms often limit control over donor characteristics, she indicated that the focus for improving outcome should be on titration of an immunosuppressive regimen with the least likelihood of contributing to complications inherent in a challenging patient population.

Risk Factors for Mortality

In a series from Dr. Bilbao’s institution, 272 liver transplantations in 223 HCV patients performed over a 14-year period were analyzed. Of these, 57% received tacrolimus and 43% received cyclosporine. Both were administered with steroids. Even though a higher proportion of the tacrolimus group were older than 65 years (P=0.08), received more organs from donors older than age 70 (P=0.001) and had HCC as an indication for transplant (P=0.05), the rate of acute rejection was significantly lower (P=0.03).

Dr. Bilbao reported, “At 1, 5 and 10 years, the tacrolimus group had a lower incidence of hypertension, hypercholesterolemia and renal insufficiency. Risk factors for mortality in the entire cohort included higher ischemic time (P=0.05), immunosuppression with cyclosporine requiring conversion during the first year (P=0.01), acute rejection in the first year (P=0.02), higher cytomegalovirus infection (P=0.013) and steroids beyond the first year (P=0.0001).”

Potential Strategy

In patients with early recurrence of HCV, the newer protease inhibitors (PIs) may offer a strategy for eliminating a risk factor for poor outcome. In a report characterized as the first multicentre experience of PIs for severe HCV recurrence after liver transplantation, a series of 7 patients, including one who was co-infected with HIV, were treated with boceprevir, interferon alpha 2b (IFNa-2b) and ribavirin along with either tacrolimus or cyclosporine as primary immunosuppressive agents. Although treatment was stopped prematurely in 3 patients because of severe anemia, 2 of the remaining 4 had undetectable HCV and 2 had a viral load <2 logs at 12 weeks.

Both the immunosuppressive regimens and the HCV therapies were modified to manage adverse events, but “interactions between immunosuppression and boceprevir were easily controlled,” according to Dr. Audrey Coilly, AP-HP Hôpital Paul Brousse, Villejuif, France. “We think that our results encourage wider indications for PIs after liver transplant as a potential means to improve graft and patient survival.”

Long-term survival in patients with HCV, including those co-infected with HIV, is routinely achieved even if rates are lower than in those without HCV. Not surprisingly, sustained viral response (SVR) is one of the predictors, according to Dr. Bruce Gelb, New York University, New York. In a series of 73 patients with HCV who survived for >10 years after transplant (40% of those who were transplanted with HCV), 44 had been treated with pegylated IFNa-2a plus ribavirin of which 26 (59%) achieved SVR. Rates would be expected to be higher with the new, more effective PIs.

Co-infection with HIV is widely considered a negative risk factor for graft survival in patients with HCV. This was not an independent predictor of graft failure in a recent comparison of 89 HIV/HCV co-infected individuals to 235 transplant recipients who had HCV alone, according to Dr. Peter G. Stock, University of California, San Francisco. In this analysis, independent risk factors included a simultaneous kidney and liver transplant, a body mass index of ≤21 kg/m² and receipt of an HCV-positive organ.

Simplifying Immunosuppression Regimens

Simplified immunosuppressive regimens after transplant are extremely appealing in HCV/HIV co-infected individuals because of the large pill burden demanded by the co-existing conditions. One recent step forward, according to data presented here at the 2012 ILTS, is a prolonged-release formulation of tacrolimus, one of the mainstays for preventing graft rejection. Among studies evaluating the prolonged-release formulation of tacrolimus, a meta-analysis demonstrated similar pharmacodynamics and comparable outcomes for the once-daily (q.d.) prolonged-release relative to the twice-daily (b.i.d.) formulation. In data presented by Dr. Anbin Hu, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China, there was no heterogeneity in a large array of comparisons in 891 patients participating in 8 studies.

“Trough levels at all measured time points were comparable. Although dosage adjustments were required with either drug, they were not more common on one than another. Most importantly, rejection rates were low and similar on the 2 formulations,” Dr. Hu reported.

A separate study was undertaken to assess whether the hemodynamic characteristics were similar in patients who were switched from a b.i.d. to a q.d. tacrolimus formulation. In this study of 104 patients, renal and splanchnic hemodynamic parameters were measured prior to the switch and then again at least 2 months after, according to Dr. Federico Orozco, Hospital Aleman, Buenos Aires, Argentina. The total dose on a milligram basis was the same before and after the switch.

“There were no significant differences in any of the hemodynamic measurements. Our results are consistent with a series of published studies demonstrating that the conversion to q.d. tacrolimus is safe and effective in stable patients after liver transplantation,” Dr. Orozco reported. He characterized the q.d. administration as a substantial advance, “because we have data to demonstrate that one way to improve compliance with immunosuppressive drugs is to use regimens that require less frequent dosing.”

From the clinical perspective, another study of the tacrolimus q.d. formulation demonstrated an improved quality of life (QOL) after conversion from the b.i.d. formulation. The study was conducted in 72 patients with a follow-up of ≥24 months. According to study lead author Dr. Luca Toti, University Tor Vergata, Rome, Italy, safety analyses were conducted along with a questionnaire administered to patients to determine QOL and compliance.

“All patients were satisfied and 89% of them declared an improvement in QOL after conversion,” Dr. Toti reported. While a more convenient dosing strategy is welcome, he also emphasized that there was no evidence of change in liver enzyme levels, creatinine or lipids, while glycemic levels actually improved significantly (P<0.05) after the conversion.

Developing simpler regimens is particularly relevant to improve transplant outcomes in the HCV-infected patient. Long-term graft survival in HCV patients relative to non-infected individuals has been climbing with progress in understanding and managing the characteristics that determine outcome. An effective strategy for controlling HCV in the context of preventing rejection is a critical goal in all patients whether or not they have HIV infection. A retrospective chart review reported by Dr. Lilian A. Curvelo, Hospital Israelita Albert Einstein, São Paulo, Brazil, reinforced the importance of post-transplant HCV control while preventing rejection.

For predictors of HCV recurrence in this series of 153 patients, “the present data show no correlation with the donor or recipient age, cold or warm ischemia time, MELD score, genotypes, rejection, use of corticosteroids, diabetes or kidney disease,” Dr. Curvelo reported. While this suggests that “other factors may be involved, such as genetic polymorphisms of the immune innate system,” it also suggests that there is an urgent need for progress in identifying better methods of HCV control that can be implemented with convenient, effective and well-tolerated immunosuppressive regimens.

Summary

HCV is the single most important etiologic factor in the pathophysiological events leading to liver transplant. While liver transplantation can extend the lives of such individuals, recurrence of HCV is an important risk factor for an adverse outcome. Aggressive antiviral regimens appear promising for controlling infection and appear to be feasible while continuing adequate immunosuppression. Effective immunosuppressive regimens and sustained tolerability with simpler dosing schemes are factors likely to move this approach forward.