Efficacy of Elbasvir and Grazoprevir in Participants With Hepatitis C Virus Genotype 4 Infection

A Pooled Analysis

Tarik Asselah; Hendrik Reesink; Jan Gerstoft; Victor de Ledinghen; Paul J. Pockros; Michael Robertson; Peggy Hwang; Ernest Asante-Appiah; Janice Wahl; Bach-Yen Nguyen; Eliav Barr; Rohit Talwani; Lawrence Serfaty

Disclosures

Liver International. 2018;38(9):1583-1591. 

In This Article

Results

Overall, the GT4-infected participants had a median age of 47.9 years, a mean HCV RNA at baseline of 6.0 log10 IU/mL, and 68% were male, 85% White race, and 47% were infected with GT4a and 41% with GT4d (Table 1). Participants in this analysis were infected by 11 subtypes of GT4 (Table 1). The group of treatment-naïve participants had a lower percentage of cirrhotics than treatment-experienced participants (13.5% vs 40.9%), a higher percentage of IL28B CC genotype (24.3% vs 11.4%) and a higher percentage of HCV/HIV co-infection (26.1% vs 11.4%) (Table 1).

Efficacy rates with EBR/GZR were high in participants infected with GT4. Overall, the SVR12 rates were 96.4% (107/111) in treatment-naïve participants treated with 12 weeks of EBR/GZR ± RBV, 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of EBR/GZR without RBV, 88.6% (39/44) in treatment-experienced participants treated with 12 or 16 weeks of EBR/GZR ± RBV, and 87.5% (14/16) in treatment-experienced participants treated with 12 weeks of EBR/GZR without RBV (Figure 2). The regimens of EBR/GZR approved by the US Food and Drug Administration for GT4-infected individuals are 12 weeks of EBR/GZR for treatment-naïve individuals and 16 weeks of EBR/GZR plus RBV for peg-interferon/RBV treatment-experienced individuals.[32] The regimens of EBR/GZR approved by the European Medicines Agency (EMA) and the European Association for the Study of the Liver (EASL) Guidelines are 12 weeks of EBR/GZR without RBV for treatment-naïve and treatment-experienced GT4 individuals (with or without cirrhosis) with HCV RNA ≤800 000 IU/mL and 16 weeks of EBR/GZR for treatment-naïve and treatment-experienced GT4 individuals (with or without cirrhosis) with HCV RNA >800 000 IU/mL.[33,34] With these approved regimens for GT4-infected individuals, the SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of EBR/GZR and 100% (8/8) in treatment-experienced participants treated with 16 weeks of EBR/GZR plus RBV (Figure 2).

Figure 2.

Efficacy rates (SVR12) of elbasvir/grazoprevir with or without ribavirin in HCV GT4-infected participants (Full Analysis Set). Full analysis set included all participants who received at least 1 dose of study drug. Sustained virologic response rates at 12 wk after the end of treatment (SVR12) and 95% confidence intervals are shown for HCV treatment-naïve (TN) participants who received elbasvir/grazoprevir ± ribavirin for 12 wk and for HCV treatment-experienced (TE) participants who received elbasvir/grazoprevir ± ribavirin for 12 or 16 wk. The Clopper-Pearson exact method was used to determine two-sided 95% confidence intervals. The full analysis set included all participants who received at least 1 dose of the study drug. n = number of participants with indicated outcome

Subgroup analyses did not reveal any significant decreases in the SVR12 rates with 12 weeks of EBR/GZR in subgroups of sex, race, age, baseline HCV RNA levels, HIV/HCV co-infection, cirrhosis status or HCV GT4 subtype (Figure 3; Table S5). Specifically, the SVR12 rates were 91% (20/22) in participants with cirrhosis vs 96% (91/95) in those without cirrhosis, and 96% (51/53) in participants infected with GT4a vs 94% (46/49) in those infected with GT4d (Figure 3). In treatment-experienced participants treated with 12 weeks of EBR/GZR, the SVR12 rate was numerically lower (88% [14/16]) compared with treatment-naïve participants (96% [97/101]). In the small numbers of participants infected with GT4k, GT4p, GT4r, GT4v, GT4c, GT4f, GT4 g, GT4o and GT4 l, the SVR12 rate was 93% (14/15; the one virologic failure had GT4 g) with 12 weeks of EBR/GZR and 100% (4/4) with 12 weeks of EBR/GZR + RBV (Table 2). The characteristics (baseline HCV RNA, presence of cirrhosis, age, race, IL28B genotype, presence of HIV/HCV co-infection) of the 6 participants who failed virologically are shown in Table 2. Baseline NS5A resistance-associated substitutions (RASs) did not impact the SVR12 rate in GT4-infected participants treated with 12 weeks of EBR/GZR. The prevalence of NS5A RASs was 36.8% (42/114) in GT4-infected participants in this analysis (Figure 4). The in vitro activities of EBR and GZR against GT4 RASs are shown in Tables S3 and S4. Among GT4-infected participants treated with 12 weeks of EBR/GZR, the SVR12 rate in participants with NS5A RASs (97.2% [41/42; 95% CI = 87.4–99.9]) was not significantly different from the SVR12 in participants without NS5A RASs (97.6% [70/72; 95% CI = 90.3–99.7]) (Figure 4).

Figure 3.

Subgroup analysis. Sustained virologic response rates at 12 wk after the end of treatment (SVR12) and 95% confidence intervals are shown for various subgroups of HCV GT4-infected participants in this Forest plot. The Clopper-Pearson exact method was used to determine two-sided 95% confidence intervals. The full analysis set included all participants who received at least 1 dose of the study drug. Results not shown for Asian subgroup (SVR12 = 100% [2/2; 95% CI = 16, 100]) and the missing or other race subgroup (SVR12 = 100% [2/2; 95% CI = 16, 100])

Figure 4.

Effect of baseline resistance-associated substitutions on SVR12 after treatment with 12 wk of elbasvir/grazoprevir. Resistance analysis population includes available samples from participants with either SVR12 or viral failure. NS5A RASs = any change from reference at nine amino acid positions in NS5A: 24, 28, 30, 31, 32, 38, 58, 92 and 93 by population nucleotide sequencing (25% sensitivity threshold)

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