Data from the present analysis confirm the high effectiveness of elbasvir/grazoprevir in patients with HCV genotype 1b infection in a large nationwide VA population with considerable comorbidities, including cirrhosis, diabetes, and hypertension. Large proportions of patients in this analysis also had a history of drug or alcohol use or were taking concomitant proton pump inhibitor therapy (28.3%), which has been associated with reduced efficacy in patients receiving sofosbuvir-based regimens . Within this highly heterogeneous population, SVR was achieved by 97.5% of all participants, by 97.6% of those receiving elbasvir/grazoprevir for 12 weeks, and by 97.7% of treatment-naive participants with an APRI score < 0.7 receiving elbasvir/grazoprevir for 8 weeks. An 8-week regimen of elbasvir/grazoprevir is not approved for patients with HCV infection in the United States, although the regimen is approved in some European countries. Data regarding the rationale for selecting an 8-week regimen were not collected in this study. We are also unable to determine if an 8-week regimen was intended for participants in this study or if a longer 12-week treatment duration was intended but stopped early.
Data from the present analysis are consistent with those reported previously by Kramer and colleagues . This study included 2436 patients from the VA, of whom 1428 had HCV genotype 1b infection. SVR within this genotype 1b population was 96.6% (1379/1428) compared with 97.5% (3288/3371) in the present analysis. Further analysis of the genotype 1b population was not performed by Kramer and colleagues, so the influence of factors such as prior treatment history, fibrosis level, CKD, and drug or alcohol use on SVR rates in patients with HCV genotype 1b infection receiving elbasvir/grazoprevir was not established. In the present analysis, SVR rates in patients with cirrhosis were not dissimilar to the overall study population (96.6% vs. 97.5%, respectively); however, the regression analysis showed a negative association between the presence of cirrhosis and SVR. In contrast, the study by Kramer and colleagues (including patients with HCV GT1, GT2, GT3, and GT4 infection) reported similar rates of SVR in patients with and without cirrhosis. This mirrors the findings from phase 2/3 clinical trials where cirrhosis was also found to have no impact on treatment outcome [9, 15].
The present study therefore represents an important addition to the previous study, with the increased sample size permitting a detailed analysis of elbasvir/grazoprevir effectiveness in discrete patient sub-groups with HCV genotype 1b infection. The findings of the present analysis indicate that, following treatment with elbasvir/grazoprevir for 12 weeks, SVR rates are high in patients from the VA with significant comorbid conditions. These data suggest that across a wide spectrum of patients with HCV GT1b infection, a single regimen of elbasvir/grazoprevir offers a highly effective, convenient, once-daily treatment option.
The efficacy and safety of elbasvir/grazoprevir for 12 weeks in participants with HCV genotype 1b infection has been established in several phase 3 clinical trials conducted in a broad cross-section of participants with HCV genotype 1b infection. The results from these studies were summarized in an integrated analysis that included 1070 participants with HCV genotype 1b infection who received elbasvir/grazoprevir for 12 weeks . Compared with the VA healthcare population described in the present analysis, the population described in the integrated analysis was predominantly white (47% vs. 30%) and included more females (50% vs. 3%). In the current VA population, the proportion of patients who were black was 61% versus 9% in the integrated analysis population. SVR was achieved by 97.2% (1040/1070) of participants included in the integrated analysis, and, of those who failed to achieve SVR, 15 had non-virologic failure and 15 experienced relapse. In the supportive per-protocol analysis (which excluded non-virologic failures), SVR was achieved by 98.6% (1040/1055) of participants, with a virologic failure rate of 1.4%. SVR rates remained high across all sub-groups of patients examined in the integrated analysis, including an SVR12 rate of 94.7% (215/227) in patients with NS5A resistance-associated substitutions at baseline , reinforcing the US treatment recommendation that testing for NS5A resistance-associated substitutions prior to therapy is not required for patients with HCV genotype 1b infection receiving elbasvir/grazoprevir for 12 weeks .
The results from the present analysis are consistent with previous reports regarding the effectiveness of elbasvir/grazoprevir in real-world, HCV-infected populations from inside and outside the United States. Toyoda et al.  and Ogawa et al.  reported SVR rates of 97.4% (371/381) and 97.5% (275/282) in Japanese patients with primarily HCV genotype 1b infection who were prescribed elbasvir/grazoprevir for 12 weeks. In both studies, most patients were treatment-naive, and approximately one-third of patients were aged ≥ 75 years and one-third had CKD stage 3–5. SVR rates were generally unaffected by baseline characteristics, including presence of cirrhosis or history of hepatocellular carcinoma; however, the presence of NS5A resistance-associated substitutions, particularly in individuals who had previously received all-oral direct-acting antiviral therapy, was associated with virologic failure [18, 19]. Similar results have also been reported in a Spanish cohort of patients with HCV genotype 1 infection, 73% of whom had genotype 1b infection . In this analysis, of the 625 patients with data available at 12 weeks post-treatment, 570 (91.2%) achieved SVR12. In the modified intention-to-treat analysis, which excluded 37 patients lost to follow-up, SVR12 was 96.9% (570/588). Among the patients with HCV genotype 1b infection, SVR12 rates remained ≥ 96%, regardless of treatment history or presence of cirrhosis at baseline . Data from the TRIO network in the United States further supports the high effectiveness of elbasvir/grazoprevir in patients with HCV genotype 1 infection in a real-world setting . SVR12 rates in the per-protocol population were 98.5% (396/402) for patients with HCV genotype 1 infection and 99.1% (113/114) in the sub-group with CKD stage 4/5.
Our study has several strengths. First, we used data from the nationwide VA database, which is the largest integrated healthcare data source for patients with HCV infection, including those who are racially and clinically diverse. Second, missing data are relatively low because the VA healthcare system has an established electronic medical record system as well as a robust pharmacy benefits management system including prescription data across all VA facilities. Our data also indicate comparable rates of SVR compared with other HCV treatment regimens in real-world populations. SVR was achieved by 91.3% of treatment-naive veterans with HCV genotype 1 infection receiving sofosbuvir/ledipasvir and by 95.3% of treatment-naive patients with HCV genotype 1 infection from a TRIO network study [22, 23]. In a German real-world study, an SVR rate of 96.7% was attained within a treatment-naive, non-cirrhotic population with primarily HCV genotypes 1 or 3 infection receiving glecaprevir/pibrentasvir for 8 weeks . The SVR rate of 97.5% attained within the present study therefore indicates that elbasvir/grazoprevir for 12 weeks is an effective treatment option for this population of patients with genotype 1b infection, offering rates of SVR that are at least broadly comparable to those seen with other second-generation DAA treatment regimens.
Our study also has certain limitations. The VA population may not be generalizable to the entire US population owing to the potential for differing demographic risk factors. Some misclassification of diagnoses and comorbidities identified through ICD-9/10 codes might have also been present. Sample sizes were small for some subgroups (e.g., those receiving elbasvir/grazoprevir with ribavirin for 16 weeks). This study also used a per-protocol population that excluded patients with less than 11 weeks’ treatment duration. These data therefore do not take into account patients who discontinue treatment early, and the reported response rates cannot be generalized to patients with shorter treatment durations. Although 8- and 12-week elbasvir/grazoprevir regimens were examined in treatment-naive and -experienced patients with HCV genotype 1b infection, the rationale for different treatment durations could not be ascertained (and, as noted earlier, the 8-week regimen is not an approved regimen for use in the United States). Additionally, some laboratory data, including NS5A resistance-associated substitutions and other factors possibly related to virologic failure, were not available. Adverse events, adherence data, and data from any treatment received outside the VA were also not available in this study.