Milk Thistle Drug May Help Control HCV Replication after Liver Transplant

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Silibinin, a medication derived from the milk thistle plant, lowered hepatitis C virus (HCV) levels in patients awaiting liver transplantation in a pilot study, which may help reduce the risk of HCV recurrence in the new liver, Spanish researchers reported in the March 2013 Journal of Hepatology.

Over years or decades chronic hepatitis C can lead to advanced liver disease including cirrhosis or hepatocellular carcinoma, which may necessitate liver transplantation. Unfortunately HCV almost always reinfects the new liver, typically within months. Interferon, ribavirin, and recently approved direct-acting antivirals have side effects that people with severe liver damage may be unable to tolerate, and their success is limited in this population.

Intravenous silibinin is a 1:1 mixture of silibinin A and silibinin B, available as an antidote for amanita mushroom poisoning.

Peri-transplant

In the first study, Zoe Mariño and Xavier Forns from IDIBAPS in Barcelona and colleagues assessed the antiviral activity and safety of intravenous silibinin administered daily during the peri-transplant period.

This prospective single-center pilot study included 14 hepatitis C patients awaiting liver transplants. Within this group, 11 were randomly assigned to receive silibinin while 3 received placebo. Treatment was used for a maximum of 21 days prior to transplantation and 7 days after the procedure.

Results

"This proof-of-concept study in patients in the waiting list for liver transplantation indicates that daily intravenous silibinin has evident antiviral properties and is well tolerated in the peri-liver transplantation period," the study authors concluded. "A longer treatment regimen with silibinin (alone or in combination with other agents) should be assessed in clinical trials for the prevention of hepatitis C recurrence."

Post-transplant

In the second study, described in the same issue, Rafael Bárcena and colleagues with the Hospital Ramón y Cajal Liver Transplant Groupin Madrid looked at the safety and antiviral efficacy of prolonged intravenous silibinin started immediately before liver transplantation and continuing into the post-transplant period.

This prospective, single center study included 9 consecutive liver transplant patients with genotype 1 HCV who received 20 mg/kg/dayintravenous silibinin as monotherapy for at least 21 days, starting when the diseased liver was removed, along with an immunosuppressive regimen of basiliximab (Simulect), steroids, delayed tacrolimus (Prograf), and mycophenolate (Cellcept). A control group of 7 patients received only the immunosuppressive regimen.

Results

Silibinin partial responders had larger HCV RNA decreases than untreated patients in the control group, but smaller than those of complete responders. Again, silibinin was well tolerated with no clinical adverse effects, though it caused asymptomatic transient hyperbilirubinemia (elevated bilirubin).

"Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV RNA breakthrough during administration," the researchers concluded. "However, HCV RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft."

Editorial

In accompanying editorial, Peter Ferenci and Sandra Beinhardt from the Medical University of Vienna in Austriareviewed the available limitedoptions for preventing graft reinfection successfully treating reinfected patients or after transplantation.

Given the suboptimal results using standard interferon-based therapy, silibinin received orphan drug status from the European Medicines Agency after 2 case reports of successful HCV eradication after transplantation.

"Both studies [described in this issue] confirmed the robust antiviral efficacy and the safety of IV silibinin in this difficult-to-treat patients, with the apparent lack of interaction with immunosuppressants," they wrote, "but not surprisingly, both approaches failed to eradicate the virus in a single patient, although quite a few had undetectable HCV RNA at the end of IV silibinin administration."

"It is quite clear that giving an antiviral drug as monotherapy for just 21days is not able to eradicate HCV," they added, noting that so far 12 weeks is the shortest successful treatment of genotype 1 patients with the favorable IL28B CC gene pattern using pegylated interferon, ribavirin, and telaprevir (Incivek).

In summary, these studies showed that IV silibinin "is safe but by the currently used applications cannot prevent graft reinfection or eradicate HCV from the transplanted liver in most patients."

"At present there is no alternative of an interferon-free approach in the peri-transplant setting and silibinin may be the ideal drug until safe and effective HCV RNA polymerase inhibitors with a high genetic barrier become available," Ferenci and Beinhardt concluded. "Nevertheless, there is a need for improvements in treatment schedules before such a treatment can be recommended. Flushing the liver graft with a solution containing silibinin as it has been done to prevent oxidative damage to the liver should be tested in order to determine if it helps prevent recurrence."

Another recent study found that administering N-acetylcysteine to protect the donor liver prolonged post-transplant graft survival.

2/28/13

References

Z Mariño, G Crespo, M D'Amato, X Forns, et al. Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period. Journal of Hepatology 58(3):415-420. March 2013.

R Bárcena, A Moreno, MA Rodríguez-Gandía, S Del Campo, et al. Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. Journal of Hepatology 58(3):421-426. March 2013.

P Ferenci and S Beinhardt. Silibinin: An old drug in the high tech era of liver transplantation. Journal of Hepatology 58(3):409-411. March 2013.