Combination DAA Therapy to Treat Established Recurrent Hepatitis C
The poor safety and efficacy of IFN-containing regimens in patients with end-stage liver disease and in LT recipients have hastened the development of IFN-free strategies for the prevention and treatment of recurrent HCV infection.
The HIV treatment paradigm suggests that combining DAAs, which target different steps of viral replication, should provide additive and possibly synergistic antiviral potency, prevent the emergence of DAA resistance and consequently remove the need for IFN. The first IFN-free DAA combinations against HCV consisted of a PI and a non-NUC-NS5B inhibitor—both DAA classes with low barriers to resistance. Unfortunately, rapid emergence of dual resistance resulted in high rates of virological breakthrough and relapse, especially in patients infected with HCV subtype 1a and prior null responders to IFN-based therapy.
Fortunately, the addition of a third DAA, an NS5A inhibitor, to a PI and non-NUC NS5B inhibitor (ABT-267/ABT-333-r/ABT-450; daclatasvir/asunaprevir/BMS-791325) prevents the emergence of resistance and improves efficacy to over 90% across all HCV GT-1 patient populations, including those infected with subtype 1a and prior null responders. These triple DAA regimens are now in Phase III registration studies for treatment of patients with chronic HCV infection GT-1. However, before they can be used to treat transplant recipients with recurrent HCV infection, extensive drug–drug interaction studies with the calcineurin inhibitors are required because both the PIs and the non-NUC NS5B inhibitors are substrates and inhibitors of CYP-3A4 and Pg-p metabolic pathways.
In contrast to the other DAA classes, the nucleotide polymerase inhibitors (NUCs) appear ideally suited for use following LT. Because these agents do not undergo hepatic metabolism, NUCs do not require dose adjustment in patients with allograft dysfunction and do not interact with calcineurin inhibitors. NUCs are chain terminators of HCV RNA synthesis. The target is the highly conserved catalytic site of the RNA-dependent RNA polymerase, thereby conferring pan-genotypic antiviral potency and a very high barrier to resistance. The uridine-based NUC sofosbuvir (SOF) was recently approved by the US Food and Drug Administration for the treatment of chronic HCV infection GT-1/2/3/5. In Phase III studies in non-LT patients, 24 weeks of SOF plus RBV achieved SVR in 97% patients infected with HCV GT-2 and 85% infected with GT-3. This same regimen achieves SVR12 in 55–84% patients with HCV GT-1 infection. No specific toxicities have been observed in more than 3000 patients treated to date.
The addition of an NS5A inhibitor (either daclatasvir or ledipasvir) to SOF increased the SVR rate to 100% across different patient populations including cirrhotic and prior nonresponders to both PEG-IFN/RBV and triple therapy with telaprevir or boceprevir.
The efficacy and safety of IFN-free SOF-based regimens in LT recipients with recurrent HCV were confirmed in the published case report of successful rescue of an LT recipient with cholestatic HCV following 24 weeks treatment with SOF plus daclatasvir—an NS5A inhibitor. At the time of treatment initiation, this patient had advanced allograft failure (jaundice, encephalopathy and refractory ascites with Model for End-Stage Liver Disease score of 24). Rapid viral suppression was accompanied by resolution of ascites and recovery of liver synthetic function, and at the time of writing, the patient remains well with normal allograft function and undetectable HCV RNA, more than 2 years posttreatment. Following this remarkable rescue of what had previously been a universally fatal condition, Gilead Sciences instituted a compassionate access program of SOF/RBV for LT recipients with allograft failure from severe recurrent hepatitis C. In the first 44 patients (almost half with fibrosing cholestatic hepatitis C), on-treatment viral suppression was achieved in 78% and SVR in 69%. Virological response was associated with resolution of clinical signs of decompensation. Eight patients died during this study from complications of liver failure, reflecting the severity of liver disease at study entry.
In the first open-label Phase II study, 40 LT recipients with compensated recurrent hepatitis C (all HCV genotypes) were treated with SOF/RBV for 24 weeks. All patients achieved RVR (undetectable HCV RNA at 4 weeks) and 77% achieved posttreatment SVR4.
It is expected that the addition of a second DAA will improve efficacy and shorten the duration of therapy to 12 weeks. Therefore, in the larger follow-on study, 300 patients with both compensated and decompensated recurrent hepatitis C will be randomized to either 12 or 24 weeks of the fixed dose combination of SOF plus the NS5A inhibitor ledipasvir plus RBV. This study is actively recruiting and primary efficacy results are expected in late 2014.
In another open-label Phase II study, 30 LT recipients with compensated recurrent hepatitis C (HCV GT-1 only) are being treated with the AbbVie triple DAA regimen combined with RBV for 24 weeks. Careful adjustment of the calcineurin inhibitor dose will be required because of the inhibition of CYP-3A4 by the ritonavir-boosted PI ABT-450. This study is fully recruited and primary efficacy results are expected in mid-2014.
In the latest open-label Phase II study, 40 patients with compensated recurrent hepatitis C (HCV subtype 1b only) will receive daclatasvir (NS5A inhibitor), combined with simeprevir (PI recently approved by the US Food and Drug Administration in combination with PEG-IFN/RBV) and RBV for 24 weeks. This study has not yet commenced recruitment and primary efficacy results are expected in mid-2015.