1. Both 8 and 12-week regimens of glecaprevir-pibrentasvir were highly efficacious in producing sustained virologic response in patients infected with hepatitis C virus (HCV) genotypes 1 and 3, and the 8-week treatment duration was noninferior to 12-week duration.
2. Similar low rates of serious adverse events or clinically significant laboratory abnormalities with seen with both the 8 and 12-week combination regimen.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Treatment options for patients with chronic HCV continue to evolve, and effective agents with shorter treatment duration are needed to decrease morbidity. The coformulation of the nonstructural (NS) 3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir was approved for the treatment of patients with HCV genotypes 1-6 without cirrhosis has demonstrated pangenotypic efficacy, a favorable safety profile, high barrier to resistance, and synergistic antiviral activity. Data also suggests suitable efficacy of the drug combination with both 8 and 12-week regimens. This reports the findings of two open-label, randomized trials (ENDURANCE 1 and 3) evaluating glecaprevir-pibrentasvir for patients with HCV genotype 1 or 3, and compare the efficacy of glecaprevir-pibrentasvir to sofosbuvir-daclatasvir for HCV genotype 3. The results demonstrated a high rate of sustained virologic response at 12 weeks (primary end point) in patients with HCV genotype 1 or 3 treated with glecaprevir-pibrentasvir. Noninferiority was shown in glecaprevir-pibrentasvir treatment for 8 versus 12 weeks in patients with either genotype, and between glecaprevir-pibrentasvir and sofobusvir-daclatasvir for patients with HCV genotype 3. Among secondary end points, there was no statistical difference in virologic relapse or failure after 8 weeks or 12 weeks of glecaprevir-pibrentasvir in patients with either genotype. The safety profile of glecaprevir-pibrentasvir was similar with 8 or 12-week treatment and associated with few serious adverse events or laboratory abnormalities.
Strengths of this study include validated clinical guidelines and historical clinical data to calculate noninferiority margins. However, the study was not powered to calculate superiority or compare across subgroups according to baseline characteristics. The noninferior efficacy of a shorter duration of treatment may improve medication adherence in patients infected with HCV genotypes 1 and 3.
In-Depth [randomized controlled trial]: This study reports two phase 3, open-label, randomized trials of patients with HCV genotype 1 (ENDURANCE 1) or genotype 3 (ENDURANCE 3). Those in ENDURANCE 1 were randomized in a 1:1 ratio to glecaprevir-pibrentasvir for either 8 (n = 351) or 12 (n = 352) weeks. Those in ENDURANCE 3 were randomized in a 2:1 ratio to either glecaprevir-pibrentasvir (n = 233) or sofosbuvir-daclatasvir (n = 115) for 12 weeks, or 8 weeks of glecaprevir-pibrentasvir (n = 157). Eligible patients had higher than 1000 IU per milliliter HCV RNA at screening. The primary end point in all groups was sustained virologic response at week 12 after treatment. Secondary end points included the percentage of patients with virologic failure and post-treatment relapse.
The rate of sustained virologic response at 12 weeks in HCV genotype 1 patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group, demonstrating noninferiority in the 8-week group (-0.6 percentage points; 95% CI, -2.3 to 0.9). The sustained virologic response in HCV genotype 3 patients treated with glecaprevir-pibrentasvir for 12-weeks was 95% (95% CI, 93 to 98) compared to 97% (95% CI, 93 to 99.9) in those treated with 12 weeks of sofosbuvir-daclatasvir, demonstrating noninferiorty of the glecaprevir-pibrentasvir group (-1.2 percentage points; 95% CI, -5.6 to 3.1). The group of HCV genotype 3 patients treated with 8-week glecaprevir-pibrentasvir had a sustained virologic response of 95% (95% CI, 91 to 98), which demonstrated noninferiority when compared to 12-week glecaprevir-pibrentasvir (difference -0.4 percentage points; 97.5% CI, -5.4 to 4.6). Similar safety profiles were seen in patients treated with glecaprevir-pibrentasvir for 8 or 12 weeks. Elevations in aminotransferase or bilirubin levels were rare (<1% of patients) and typically mild.
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