Combination Treatment with Ombitasvir, Paritaprevir/Ritonavir, Dasabuvir, and Sofosbuvir in Patients with Genotype 1 HCV Infection

“Optimal retreatment strategies for patients with chronic hepatitis C virus (HCV) infection who have failed treatment with direct-acting antiviral (DAA) regimens are not yet clearly defined,” said Fred Poordad, MD, PhD, of the Texas Liver Institute/University of Texas Health Science Center in San Antonio, at a presentation at Digestive Disease Week 2016, a joint meeting of the American Academy for the Study of Liver Diseases (AASLD), American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

Prior treatment with NS5A inhibitors, such as ledipasvir, ombitasvir, daclatasvir, and elbasvir, increases the risk for the emergence of resistance-associated variants (RAVs), which can persist up to 96 weeks after treatment. Consequently, patients who fail regimens with NS5A inhibitor are likely to require a multi-targeted approach to effective treat their infection.

High sustained virologic response rates have been achieved with the 3-DAA (3D) regimen of ombitasvir (OMV) co-formulated with paritaprevir (with the pharmaco-enhancer ritonavir [PTV/r]) and dasabuvir (DSV) with or without ribavirin (RBV) in adults with chronic HCV genotype 1 infection. Sofosbuvir (SOF) is a nucleoside NS5B polymerase inhibitor with potent pangenotypic activity and no cross-resistance with the components of the 3D regimen. There are no meaningful drug-drug interactions between 3D and sofosbuvir. The multi-targeted combination of 3D and sofosbuvir may offer a treatment option for patients who have previously failed DAA combination therapy.

The QUARTZ-I study was a phase 2, open-label, multicenter study designed to investigate the safety and efficacy of OBV/PTV/r plus DSV plus SOF in DAA-experienced patients with HCV genotype 1 infection. Patients with genotype 1a infection without cirrhosis received OBV/PTV/r (25/150/100 mg once daily) plus DSV (250 mg twice daily) plus SOF (400 mg once daily) with weight-based ribavirin for 12 weeks. Patients with genotype 1a infection with cirrhosis received the same regimen but for 24 weeks. Patients with genotype 1b infection with or without cirrhosis received the same regimen without ribavirin for 12 weeks. All patients had a history of DAA treatment failure either due to on-treatment breakthrough or relapse. The presence of RAVs was assessed by deep sequencing.

A total of 22 DAA-experienced patients with genotype 1 were enrolled, including 20 patients with genotype 1a infection and 6 patients with compensated cirrhosis. Of these, 14 patients had previously been treated with OBV/PTV/r plus DSV, 2 patients each had been treated with OBV/PTV/r or telaprevir plus PEG-interferon/RBV, and 1 patient each had been treated with SOF plus PEG-interferon, SOF plus RBV, simeprevir plus samatasvir, and simeprevir plus SOF.

At Baseline, 82% (18/22) of patients exhibited RAVs in at least one of the three DAA targets. Of these, 6 patients had RAVs in two targets, and four had RAVs in all three targets. All but 1 patient had HCV-RNA <15 IU/mL by treatment Week 4.

Overall, 95% of patients were HCV-RNA suppressed <25 IU/mL by treatment Week 4. One patient with genotype 1a without cirrhosis had treatment extended to 24 weeks in response to having an HCV-RNA >25 IU/mL at treatment Week 4. A total of 93% (14/15) of patients achieved SVR12 amount those receiving 12 weeks of treatment. One patient with genotype 1a and prior telaprevir plus PEG-interferon/ribavirin experience and no baseline RAVs relapsed at post-treatment Week 12. All patients with genotype 1a with cirrhosis (6/6) had achieved SVR.

Two patients experienced serious adverse events of pneumonia and cellulitis; however, neither were related to study drugs. The patient with pneumonia discontinued treatment at Week 10 but achieved SVR 12. Grade 3 laboratory abnormalities were rare.

“Overall, an SVR12 of 93% (14/15) was achieved for patients treated with the multi-targeted regimen of OBV/PTV/r plus DSV plus SOF with or without RBV in patients with DAA treatment experience, including those with RAVs at baseline. Treatment was well tolerated with no discontinuations due to treatment-related AEs and no reported treatment-related serious adverse events,” he explained.

“These findings suggest that a multi-targeted treatment regimen can achieve high response rates in prior DAA failures, including those patients who have previously failed 3D therapy, as well as those with persistent NS5A RAVs,” he concluded.