Direct Acting Antiviral Therapy After Liver Transplantation

Paul Y. Kwo


Curr Opin Gastroenterol. 2016;32(3):152-158. 

In This Article

Abstract and Introduction


Purpose of review Historically, postliver transplant patients with chronic hepatitis C have had worse outcomes than nonhepatitis C-related causes because of accelerated fibrosis posttransplantation and the lack of effective well tolerated therapies for hepatitis C, and posttransplant hepatitis C patients have been considered a special population. Since 2013, we have entered the era of all oral direct acting antiviral agents for hepatitis C with sustained response rates that are consistently above 90% in nontransplant patients.

Recent findings The introduction of direct acting antiviral agents to posttransplant patients has demonstrated that sustained virologic response rates that are comparable with nontransplant patients can be achieved with excellent tolerability. The combinations of sofosbuvir/ribavirin, ledipasvir/sofosbuvir/ribavirin, daclatasvir/sofosbuvir/ribavirin, sofosbuvir/simeprevir ± ribavirin, and paritaprevir/ombitasvir/dasabuvir/ribavirin have all achieved high sustained response rates posttransplants. The previously dreaded complication of fibrosing cholestatic hepatitis C can now be effectively treated.

Summary In the era of all oral therapies, no patient who undergoes transplant for hepatitis C-related cirrhosis should have their graft fail because of recurrent hepatitis C. It is expected that long-term survival of those who undergo orthotopic liver transplant for HCV-related cirrhosis will be comparable to those without hepatitis C.


Hepatitis C remains the most common indication for orthotopic liver transplant (OLT) worldwide.[1] In the US hepatitis C-related cirrhosis is the leading cause of hepatocellular cancer in the setting of cirrhosis.[2] Similar data have been reported by Europe, where viral hepatitis is the leading indication for OLT with hepatitis C accounting for approximately two-thirds of these transplants.[3] Prior to the era of direct acting antiviral (DAA) agents recurrence of hepatitis C was universal and a seminal study demonstrated that HCV recurrence post-OLT led to reduced survival in HCV-infected individuals post-OLT compared to other causes.[4] This historically poor survival has been related to the inability to effectively eradicate hepatitis C prior to transplant in those with decompensated cirrhosis where significant complications were reported in those receiving interferon-based therapies.[5] Moreover, posttransplantation therapy with peginterferon and ribavirin is less well tolerated in the setting because of cytopenias, immunosuppression, a reduction in GFR and anemia. In 2011, the addition of the first generation protease inhibitors telaprevir and boceprevir improved sustained response rates in nontransplant patients with genotype 1 hepatitis C. However, posttransplant therapy with peginterferon, ribavirin, and first-generation protease inhibitors were poorly tolerated with problematic cytopenias and anemia though sustained virologic response (SVR) rates did improve in many difficult to treat populations.[6,7] Moreover, the introduction of first generation protease inhibitors raised for the first time a series of drug–drug interactions that must be accounted for when administering DAA agents in the setting of posttransplant immunosuppression.[8] We have now entered the era of all oral DAA therapy for hepatitis and posttransplant patients can now achieve SVR rates not different from those who are not liver transplant recipients.

The backbone immunosuppressive agents that have been used post-OLT include tacrolimus, cyclosporine, everolimus and sirolimus, azathioprine, mycophenolate mofetil, and myfortic mycophenolic acid. Some classes of DAA agents are potentially capable of altering both the Cmax and AUC of these agents that serve as antirejection medicines (Table 1).[9] However, of the currently approved DAA agents, the majority are typically not associated with significant interactions other than the ritonavir boosted protease paritaprevir, which is given with ombitasvir, and dasabuvir. This ritonavir boosted regimen increases cyclosporine AUC levels and tacrolimus AUC levels substantially and requires a dose reduction of cyclosporine to one-fifth of the daily dose when given together and if tacrolimus is the backbone, a reduction of tacrolimus dosing to 0.5 mg every 1–2 weeks when given with this regimen. Interactions are also expected with sirolimus and everolimus based on the mechanisms of action.[9] DAA agents can also be victims of drug interactions as both cyclosporine and tacrolimus affect DAAs metabolism (Table 2). To date, one important reported interaction with cyclosporine and simeprevir has been reported, where the use of cyclosporine in those taking simeprevir has been reported to increase simeprevir, Cmax, and AUC levels substantially, raising the risk of drug-induced liver injury. For this reason, simeprevir should not be given to those who are taking cyclosporine-based antirejection regimens.

To date, there are no meaningful interactions with the current generation of DAA agents and azathioprine. Though not yet studied, the combination of paritaprevir, ombitasvir, and dasabuvir may raise mycophenolate mofetil levels and if used, a dose reduction should be considered.