Extended Triple Therapy After Liver Transplant Improves Hepatitis C Virologic Response, But at a Cost of Toxicity

Triple therapy consisting of a protease inhibitor combined with pegylated interferon alfa and ribavirin (PR) may increase sustained viral response (SVR12), but it may be more difficult to tolerate than PR therapy alone.

In liver transplant (LT) recipients, hepatitis C virus (HCV) may recur, which is associated with increased patient mortality and morbidity, including graft failure. Triple therapy consisting of a protease inhibitor combined with pegylated interferon alfa and ribavirin (PR) may increase sustained viral response (SVR12), but it may be more difficult to tolerate than PR therapy alone.

During a poster session at the annual meeting of the American Association for the Study of Liver Disease (AASLD), held November 1-5, 2013 in Washington, DC, R. Todd Stravitz, MD, a professor of internal medicine and gastroenterology at Virginia Commonwealth University, presented clinical data evaluating the safety and efficacy of triple therapy for HCV recurrence after LT.

Stravitz and co-investigators, who are members of the Consortium to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C), examined data on 125 LT recipients drawn from 6 US transplant centers. Patient characteristics included a mean age of 58 years old; 75% male and 25% female; and 48% with advanced fibrosis. Additionally, 47% of the study group had previously been treated after LT for HCV recurrence, while 48% had been null responders. Immunosuppressant use across the group was described as 59% cyclosporine, 29% tacrolimus, and 13% unidentified other immunosuppressant. Seventy-nine percent of patients also received mycophenolate.

While examining efficacy, the investigators limited their analysis to patients who received a PR lead-in of less than 90 days and completed at least 56 weeks of triple therapy, as well as the ensuing follow-up. In contrast, all patients contributed to the study’s safety data.

Of the 90 patients who were eligible for the efficacy analysis, 59 (66%) had end-of-treatment response (EOTR), while 53 (59%) achieved SVR12. Extended rapid virologic response (eRVR) was seen in 56 patients (64%); of that group, EOTR was seen in 91% and SVR12 in 86%. By comparison, only 22% of patients without eRVR achieved EOTR, and 16% SVR12 (P <0.001).

Among patients with a triple therapy duration of only 36 weeks or less, eRVR continued to be important, as SVR12 was seen in 5 out of 10 patients with eRVR, and 1 out of 21 without. Similarly, when triple therapy lasted longer than 36 weeks, 43 out of 46 patients with eRVR achieved SVR12, as compared to 4 out of 11 without eRVR.

Triple therapy had to be interrupted in 7% of patients and discontinued in 20% due to adverse events. However, rejection was relatively infrequent, as it occurred in just 3% of patients, and no graft losses were reported due to rejection.

Creatinine rose in patients on triple therapy, with maximum serum creatinine increasing by a median 0.4 mg/dl. Erythropoietin use was reported in 84% of patients, and just over half (56%) required blood transfusion (median 4 units) during the first 16 weeks of treatment. Pegylated interferon alfa dosing was reduced in 38% of patients and ribavirin was decreased in 86%. Overall, 9 patients (7%) died, and 8 of those deaths occurred from liver-related complications.

While discussing the poster’s findings, Stravitz noted that “for post-transplant patients, the cure for triple therapy is about twice as good as we see in standard PR therapy, but it comes at quite a cost of toxicity.” Adding a protease inhibitor to traditional PR therapy doubles SVR12 rates in this population, but with notable increase in renal dysfunction and anemia when compared to non-LT patients, Stravitz said.

The data supported a longer duration of triple therapy, since SVR12 improves markedly with extended treatment, especially in patients who are not achieving eRVR.