The Successful Use of Telaprevir to Treat Hepatitis C Recurrence After Liver Transplantation in an HIV Co-Infected Patient

Abstract

The protease inhibitors, telaprevir (TVR) and boceprevir, have revolutionized the treatment of chronic hepatitis C virus (HCV) genotype 1 infection (1). Both medications are substrates and inhibitors of the cytochrome P450 3A (CYP3A) which are important for the metabolism of many commonly used medications including those used to treat human immunodeficiency virus (HIV) infection and immunosuppressive agents (2). Therefore, these protease inhibitors are not currently approved by the Food and Drug Administration for use in orthotopic liver transplantation (OLT) recipients or HIV co-infected patients because of concerns about serious drug interactions. Limited data are available on using TVR-based triple therapy to treat HCV recurrence after OLT (3) and in HIV co-infected patients (4). Since the introduction of highly active antiretroviral therapy (HAART), chronic HCV infection has become a major cause of morbidity and mortality in the HIV-infected population, and OLT has been performed in selected HIV-HCV co-infected patients (5, 6). HCV recurrence after OLT in co-infected patients is a major issue with significant effect on transplant outcomes (7, 8). This provides rationale for treating HCV recurrence with the highly effective protease inhibitors despite concerns about interactions with both immunosuppressive and HIV medications. Here we report our experience in treating recurrent HCV after OLT in a patient with HIV co-infection with TVR-based triple therapy. A 62-year-old white man with a history of HIV infection, chronic HCV genotype 1b infection complicated by the development of cirrhosis, and hepatocellular carcinoma underwent OLT in August 2011. He developed recurrent hepatitis C with a grade 2/4 inflammation, and stage 2/4 fibrosis disease was found on his liver biopsy approximately 9 months after transplantation. HAART regimen included emtricitabine-tenofovir 200 to 300 mg daily, etravirine 200 mg twice daily, and darunavir-ritonavir 600 to 100 mg twice daily owing to failure of several previous regimens and development of significant HIV resistance. His CD4 count was 461 cells/μL and he was negative for HIV-1 RNA by polymerase chain reaction. His immunosuppression regimen consisted of tacrolimus 0.5 mg every 15 days (because he was on HIV protease inhibitors) and mycophenolate mofetil 500 mg twice daily. His transaminases were in the 150 to 300 U/L range. His baseline HCV RNA was at 4,920,000 IU/mL, and his interleukin 28B genotype was CT. Before starting TVR-based triple therapy, we stopped his darunavir-ritonavir and started raltegravir 400 mg twice daily to avoid having the patient on both HCV and HIV protease inhibitors. His tacrolimus level was increased to 0.5 mg twice daily during the transitioning period. On day 1 of TVR-based therapy, the patient was started on TVR 750 mg thrice daily, ribavirin 400 mg twice daily, and pegylated interferon α2a 180 μg weekly. In addition, he took 0.5 mg of tacrolimus, and the tacrolimus level was checked at 12 and 24 hours and every other day thereafter for 2 weeks to assess tacrolimus pharmacokinetics. No additional tacrolimus was given until the level was around 4 to 6 ng/mL. The mean area under the concentration time curve (AUC) for tacrolimus while on TVR was 348 ng·hr/mL compared to an expected AUC of 67 ng·hr/mL without TVR. The highest tacrolimus level that we encountered was 10 ng/mL (at 12-hr level after the initial dose). His maintenance dose of tacrolimus while on TVR was 0.5 mg every 5 days. His HCV RNA was detectable but not quantifiable (<43 IU/mL) at week 4 of HCV therapy and became undetectable at week 8. Laboratory tests while on HCV therapy are shown in Table 1. He completed the 12-week course of telaprevir, continued on ribavirin/pegylated interferon α2a, and switched back to his original HAART regimen. Different time points and changes to his HIV/immunosuppressive regimens are demonstrated in Figure 1. He completed a total of 48 weeks of HCV therapy and his HCV RNA was negative 12 weeks after the end of treatment, indicating that he achieved a sustained virologic response.TABLE 1: Laboratory tests and virological responsesFIGURE 1: Different treatment time points and changes to tacrolimus dose.This case demonstrates that telaprevir-based triple therapy can be used to treat HCV recurrence in HIV co-infected patients as long as they are followed up closely at centers experienced in transplanting HIV patients. Frequent adjustments to tacrolimus dosage were necessary, but this did not cause any harmful effects to the liver graft or renal function. Future studies are needed to assess the possibility of using telaprevir in combination with HIV protease inhibitors and calcineurin inhibitors in patients with OLT. Naim Alkhouri, MD 1 Gurshawn Singh, MD1 William D. Carey, MD1 John J. Fung, MD, PhD2 Nizar N. Zein, MD1 Bijan Eghtesad, MD2 Alan Taege, MD3 1Department of Gastroenterology and Hepatology, Digestive Disease Institute Cleveland Clinic Foundation Cleveland, OH 2 Department of Hepatopancreatobiliary and Transplant Surgery, Digestive Disease Institute, Cleveland Clinic Foundation Cleveland, OH 3 Department of Infectious Diseases Cleveland Clinic Foundation Cleveland, OH