Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin: Twelve-Week Post-treatment Follow-up

We previously reported a decreased warfarin dose-response in patients receiving direct-acting antiviral agents for hepatitis C virus (HCV); specifically, a 12-week treatment of sofosbuvir-containing regimens or the fixed regimen of ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBVPTV/r-DSV), both with and without ribavirin (RBV). We presumed the mechanism to be a drug-drug interaction (DDI) between the ritonavir component of OBV-PTV/rDSV with warfarin as well as between RBV and warfarin. In the absence of either agent, sofosbuvir/ledipasvir also led to a significantly decreased warfarin dose-response despite lack of evidence suggesting any meaningful interaction with warfarin. It has been speculated that HCV eradication could improve liver function, leading to a decreased warfarin dose-response. If true, such a mechanism would result in persistent reduction of warfarin doseresponse beyond antiviral treatment completion. If DDI is the only cause, the warfarin dose-response would eventually return to baseline after HCV treatment completion. To evaluate this, we followed our original cohort to assess warfarin dose-response 12 weeks after HCV treatment completion. Of 271 patients in the previous study, 31 were excluded as a result of loss to follow-up, warfarin interruption, or other interacting drugs introduced. We also excluded 21 receiving simeprevir or interferon to focus on current antiviral regimens. The final analysis included 219 patients, of whom 123 received ritonavir and/or RBV (sofosbuvir with RBV, sofosbuvir/ledipasvir with RBV, or OBV-PTV/rDSV with and without RBV) and 96 received sofosbuvir/ ledipasvir alone. As previously described, the warfarin sensitivity index (WSI) was calculated, representing the warfarin dose-response by dividing the steady-state international normalized ratio (INR) by average daily warfarin dose calculated from the previous 7 days of cumulative warfarin doses. Each WSI was calculated by using an average of the 2 closest INRwarfarin dose pairs at each time point. For patients with regimens containing ritonavir and/or RBV, the mean WSI decreased from the start to end of HCV treatment by 34% and rebounded back to 12% below baseline 12 weeks after treatment completion. For sofosbuvir/ ledipasvir alone, the mean WSI decreased by 15% during therapy and remained 10% below baseline 12 weeks after treatment Completion (Figure 1)The mean WSI 12 weeks after treatment completion remained significantly reduced in both groups when compared with the WSI at the start of treatment (both P < 0.001). There was no difference in mean WSI decrease 12 weeks after treatment completion between the 2 groups (12% vs 10%; P = 0.827). These findings reinforce the presumption of a significant DDI between ritonavir and RBV with warfarin because concurrent treatment resulted in a profound decrease in WSI with a return back toward baseline after treatment ended. A lesser but still significantly reduced WSI persisted 12 weeks after stopping either drug, an effect very similar to 12 weeks after treatment with sofosbuvir/ledipasvir alone. This finding lends credibility to an additional contributing mechanism of improved liver function leading to decreased warfarin dose-response. If this effect is attributable to HCV eradication, similar effects may occur with other newer antiviral regimens for treating HCV. Clinicians managing warfarin therapy should be aware of these issues to maintain effective warfarin anticoagulation during and after HCV treatment.