DDAs for Chronic HCV Infection in Liver Transplant Patients
Abstract and Introduction
Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug–drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV.
Chronic hepatitis C virus (HCV) infection is a global epidemic affecting almost 180 million people, with an estimated 3–4 million new infections every year. Unfortunately, low treatment uptake combined with an aging HCV-infected cohort effect has resulted in increasing rates of complications. The proportion of the HCV-infected population with established cirrhosis is projected to double over the next decade and numbers with hepatocellular carcinoma (HCC) and liver failure will treble by 2030. HCV-related liver failure and HCC are already the leading indications for liver transplantation (LT).
In a patient with active HCV infection at the time of LT, infection of the allograft is universal at the time of reperfusion. The natural history of HCV is accelerated following LT with 20–40% progressing to cirrhosis within 5 years. As a result, graft and patient survival following transplantation for HCV cirrhosis is reduced compared with other elective indications.
The increasing demand for transplantation for HCV-related end-stage liver disease, combined with the negative impact of recurrent HCV on patient and graft survival, has made recurrent hepatitis C the biggest unmet medical need facing LT units.
The primary goal in the management of recurrent HCV is prevention of graft loss through delay or prevention of fibrosis progression. Although several baseline viral, donor and recipient factors are associated with more rapid progression of HCV recurrence, few can be prospectively altered (Table 1). The only intervention that has been demonstrated to improve graft and patient outcomes is successful eradication of HCV infection with antiviral therapy either before or after LT.
The effectiveness of antiviral therapy against chronic HCV mono-infection has improved dramatically over the past decade, with expected sustained virological response (SVR) rates of almost 75% in previously untreated patients, regardless of genotype. For patients infected with HCV genotype (GT)-2 or -3, the current standard of care is pegylated interferon plus ribavirin (PEG-IFN/RBV) for 24 weeks. For patients infected with HCV GT-1, the addition of one of the two recently approved first-generation protease inhibitors (PIs), telaprevir and boceprevir, to PEG-IFN/RBV for 48 weeks has increased the SVR rate from 45% to 75% and allowed shortened duration of therapy in most patients to 24–28 weeks.
However, these major advances in the treatment of HCV have not delivered a similar impact in the treatment of HCV recurrence. Post-LT patients represent a challenging population with multiple baseline negative predictors for viral response to IFN, including (i) host factors such as non-CC IL-28B genotype which is a negative predictor for response to retreatment with currently licensed; (ii) viral factors such as high prevalence of HCV GT-1 infection and high pretreatment viremia levels 1–2 logs higher than pretransplant, usually exceeding 10 units/mL; (iii) direct effects of immunosuppression on IFN efficacy through blunting of HCV-specific T cell immune responses. The most negative predictor for viral response is lack of tolerability from PEG-IFN/RBV—more than 80% of patients dose reduce and almost 30% cease therapy because of adverse effects. This reflects the co-morbidity spectrum associated with LT encompassing renal dysfunction, cytopenias and diabetes mellitus.
This review focuses on recent advances in antiviral therapy against HCV and their relevance to management of HCV infection before and after LT. We highlight the specific safety and tolerability issues associated with directly acting antiviral agents (DAAs) and summarize the efficacy of these DAA regimens in Phase II studies in these difficult-to-treat patient populations (Figure 1).
Specific targets of the direct acting antiviral agents.