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

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.