Two DAA regimen in cirrhotic HCV GT1b patients
Posted on July 23, 2015
New Phase 2 clinical trial results indicate that an all-oral interferon- and ribavirin-free regimen of ombitasvir, paritaprevir, and ritonavir is generally well tolerated and associated with high rates of SVR12 in both cirrhotic and noncirrhotic patients with HCV genotype 1b infection who were treatment-naive or treatment experienced, including prior null responders, a population for whom antiviral treatment information has been lacking.
HCV genotype 1b is the most prevalent HCV subtype worldwide, particularly in parts of Europe and Asia, whereas genotype 1a is more prevalent in North America. The 3 DAA regimen of ombitasvir (an inhibitor of the HCV NS5A protein), paritaprevir (an NS3/4A protease inhibitor), and dasabuvir (a nonnucleoside NS5B polymerase inhibitor) has been approved in the United States and Europe for the treatment of patients with HCV genotype 1a and genotype 1b infections. This 3 DAA regimen also contains ritonavir, a pharmacokinetic enhancer that inhibits the metabolism of paritaprevir to enable once-daily dosing.
Eric Lawitz, MD, AGAF, CPI, and colleagues recently published encouraging phase 2 trial results regarding the efficacy and tolerability of the 2 DAA regimen of ombitasvir, paritaprevir, plus ritonavir (25 mg/150 mg/100 mg once daily) without ribavirin in patients (18 to 70 years of age) with chronic HCV genotype 1b infection (≥6 months) with and without compensated cirrhosis (Lawitz E, et al. Gastroenterology. 2015. Jul 10 [Epub ahead of print]).
- The patient populations addressed in this article are derived from the PEARL-I clinical trial (ClinicalTrials.gov identifier: NCT01685203). Pearl-I is an ongoing, randomized, open-label, phase 2b, combination treatment study evaluating the safety and efficacy of ombitasvir, paritaprevir, plus ritonavir (25 mg/150 mg/100 mg once daily) with or without ribavirin in treatment-naive and pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 1b or genotype 4 infection. This study is being conducted at 47 sites in France, Hungary, Italy, Poland, Puerto Rico, Romania, Spain, Turkey, and the United States. Screening for the trial began in August 2012, and the last patient completed treatment in March 2014.
The duration of treatment in genotype 1b HCV patients was 12 weeks in those without cirrhosis and 24 weeks in those with cirrhosis. Of 181 total patients who received ≥1 dose of study medication:
- 82 patients without cirrhosis included 42 treatment-naive and 40 prior null responder patients. A greater percentage of null responder versus treatment-naive patients were female, white, had a non-CC IL28B genotype, or had fibrosis stage F0–F1.
- 99 patients with cirrhosis included 47 treatment-naive and 52 pegylated interferon and ribavirin treatment-experienced patients. Nearly half of the treatment-experienced patients with cirrhosis were prior null responders (n=25 [48.1%]). Baseline characteristics in treatment-naive and treatment-experienced patients with cirrhosis were similar.
- The vast majority of patients had a non-CC IL28B genotype
The majority of all patients (96.1%) completed treatment, with only 7 patients discontinuing prematurely.
- All but 3 patients achieved rapid virologic response at week 4.
- SVR12 rates were similarly high in patients with and without cirrhosis
- Treatment-naïve patients without cirrhosis: 95.2% (n=40/42; 95% CI, 83.8%–99.4%)
- Prior null responder patients without cirrhosis: 90.0% (n=36/40; 95% CI, 76.3%–97.2%)
- Treatment-naïve patients with cirrhosis: 97.9% (n=46/47; 95% CI, 88.7%–99.9%)
- After the primary database lock, 1 treatment-naïve patient who was thought to be lost to follow-up returned for a visit and had undetectable HCV RNA levels, making the SVR12 rate following the database lock 100% (n=47/47)
- Treatment-experienced patients with cirrhosis: 96.2% (n=50/52; 95% CI, 86.8%–99.5%)
- No clinically meaningful differences in SVR12 rates were observed between any of these groups
- No patient experienced relapse after having achieved SVR12
- Virologic Failure
- Five patients (2%; 5/181) experienced virologic failure: 4 prior null responder patients without cirrhosis and 1 treatment-experienced (prior null responder) patient with cirrhosis; all patients had CT IL28B genotype
- All 5 patients had resistance-associated variants (RAVs) in both NS3 and NS5A at the time of failure, including 2 patients who had RAVs at baseline (both NS5A)
- Resistance-Associated Variants (RAVs)
- Overall, RAVs in NS3 and NS5A were detected in 1.1% and 17.6% of patients at baseline, respectively, although the study authors noted that many of the NS5A RAVs do not confer resistance to ombitasvir in vitro as single variants
- No association was observed between specific baseline NS3 and NS5A RAVs and SVR12
- SVR12 rates were similar between patients with and without virus harboring RAVs at baseline (92.9% vs 96.3%); these findings suggest a high resistance barrier for ombitasvir, paritaprevir, and ritonavir in the treatment of HCV genotype 1b infection
- Similar rates of treatment-emergent AEs were reported across patient groups, and most were mild in severity. The most commonly reported events were headache (17.3%–33.3%), asthenia (5.0%–21.3%), pruritus (0%–17.0%), and diarrhea (0%–14.9%).
- AEs resulted in 3 patients prematurely discontinuing treatment; all 3 patients were treatment-naive with cirrhosis
In this phase 2b, international, multicenter, clinical trial in 181 patients from North America and Europe with HCV genotype 1b infection, an interferon- and ribavirin-free regimen of ombitasvir, paritaprevir, and ritonavir resulted in high SVR12 rates of 90% to 98% in patients without cirrhosis or with compensated cirrhosis, including patients who were prior null responders. The study authors note that these results provide information that was previously lacking in prior null responder patients with genotype 1b infection. Rates of AEs in patients with cirrhosis were similar to those in patients without cirrhosis, and only 1 patient with cirrhosis discontinued treatment because of an AE related to the study drug. These results suggest that a 24-week course of therapy does not increase the risk of AEs compared with a shorter 12-week course. The study authors conclude the following: “an all-oral interferon- and ribavirin-free regimen of ombitasvir, paritaprevir, and ritonavir was generally well tolerated and achieved high rates of SVR12 in both cirrhotic and noncirrhotic patients with HCV genotype 1b infection who were treatment-naive or treatment experienced, including prior null responders.”