Safety and Tolerability of Elbasvir/Grazoprevir in Chronic Hepatitis C Virus Therapy

Integrated Analysis From Clinical Trials

Gayatri Nangia; John M. Vierling; Paul Kwo; Deborah D. Brown; Stephanie O. Klopfer; Michael N. Robertson; Barbara A. Haber; K. Rajender Reddy

Disclosures

J Viral Hepat. 2020;27(11):1222-1233. 

In This Article

Results

Safety and Tolerability in Participants Receiving EBR/GZR for 12 Weeks

A total of 1743 clinical trial participants from eight controlled trials received EBR/GZR for 12 weeks (Table 1).[5–12] This population comprised similar proportions of white and Asian participants (44.5% and 46.2%, respectively), with fewer African American participants (8.0%). Most had HCV GT1b (63.5%) or GT1a (27.6%) infection, and 17.6% had liver cirrhosis.

A total of 1068 participants (61.3%) reported at least one AE, of whom 491 (28.2%) had AEs that were related to study medication (Table 2). Serious AEs were reported by 37 participants (2.1%), and 12 participants (0.7%) discontinued treatment due to an AE. The most frequently reported AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.7%), nausea (5.1%) and diarrhoea (5.0%) (Figure 1A). Alanine aminotransferase elevations 1.25–2.5× ULN, 2.6–5.0× ULN, 5.1–10.0× ULN and >10× ULN were reported by 2.6%, 1.4%, 0.7% and 0.7% of participants, respectively. Bilirubin levels ≥2.6× ULN occurred in 0.3% of participants; creatinine elevations ≥1.1× ULN occurred in 1.5% of participants; and Hgb levels <9.0 g/dL occurred in 0.4% of participants (Table 2).

Figure 1.

Adverse events in (A) in all participants receiving EBR/GZR for 12 wk (N = 1743) and (B) according to the presence or absence of cirrhosis in participants receiving EBR/GZR for 12 wk (adverse events occurring in >5% of participants in either treatment group). Abbreviations: EBR/GZR, elbasvir/grazoprevir; URTI, upper respiratory tract infection

The incidence of safety events was similar in those with and those without cirrhosis. Adverse events (64.1% vs 60.7%), drug-related AEs (28.4% vs 28.2%) and serious AEs (2.6% vs 2.0%) occurred at similar frequencies in participants with and those without cirrhosis, respectively (Table 2). Adverse events occurring in ≥5% of participants in either group (cirrhosis versus no cirrhosis) were headache (9.8% vs 10.7%), fatigue (7.5% vs 9.0%), nasopharyngitis (2.6% vs 6.4%), nausea (3.3% vs 5.4%), diarrhoea (4.2% vs 5.2%), upper respiratory tract infections (5.2% vs 4.1%) and dizziness (5.2% vs 2.7%) (Figure 1B). Laboratory values were also largely similar in participants with and those without cirrhosis receiving EBR/GZR for 12 weeks. (Table 2) Alanine aminotransferase elevations >5× ULN occurred in 2.6% of cirrhotic participants and 1.2% of noncirrhotic participants, and bilirubin elevations ≥2.6× ULN occurred in 1.3% of those with cirrhosis and in 0.1% of those without cirrhosis. There were no Hy's Law events. Creatinine elevations and declining Hgb levels were generally rare (Table 2).

There were no episodes of hepatic decompensation among participants enrolled in the clinical trials included in this analysis. One treatment-experienced participant with cirrhosis was hospitalized after approximately 2 weeks of treatment with EBR/GZR with new-onset, rapidly progressing ascites. The participant developed renal failure, sepsis and peritonitis that led to death. The autopsy revealed lymphoma with studding of the liver, abdominal cavity and pericardium. From the time of randomization to death, there was no evidence of hepatic decompensation, and the AEs and death were considered unrelated to study medication.

Participants With Stage 4/5 Chronic Kidney Disease Receiving EBR/GZR for 12 Weeks

A total of 235 participants with stage 4/5 CKD received EBR/GZR for 12 weeks in the C-SURFER study, with 122 participants initially randomized to EBR/GZR for 12 weeks and 113 randomized to placebo for 12 weeks followed by deferred EBR/GZR therapy.[16] Participants in this study were primarily white (n = 109, 46.4%) or African American (n = 108, 46.0%) with HCV GT1a (n = 122, 51.9%) or GT1b (n = 112, 47.7%) infection (Table S3). Overall, 81.3% of participants had stage 5 CKD, 76.2% were receiving dialysis, and 19.1% had previous renal transplant. Common aetiologies for renal disease in this population were diabetes and hypertension.

During the initial treatment phase, AEs were reported in 93 (76.2%) participants receiving EBR/GZR and 96 (85.0%) receiving placebo (Table 3). Drug-related AEs (34.4% vs 34.5%) and serious AEs (13.1% vs 17.7%) also occurred at similar frequencies in the EBR/GZR and placebo populations, and discontinuations due to an AE occurred in five participants receiving placebo and none receiving EBR/GZR (4.4% vs 0%). The most common AEs in participants with stage 4/5 CKD receiving EBR/GZR (versus placebo) were headache (18.9% vs 16.8%), nausea (14.8% vs 15.9%), fatigue (10.7% vs 15.0%), abdominal pain (8.2% vs 2.7%) and insomnia (8.2% vs 10.6%) (Figure 2A). Elevations in ALT and bilirubin were generally rare and occurred at similar frequencies in EBR/GZR and placebo recipients (Table 3). Creatinine elevations 1.9–3.4× ULN (14.8% vs 16.8%) and ≥3.5× ULN (63.9% vs 67.3%) occurred at similar frequencies in EBR/GZR and placebo recipients. Haemoglobin levels ≤8.9 g/dL were reported in 13 participants (10.6%) receiving EBR/GZR and nine participants (8.0%) receiving placebo.

Figure 2.

Adverse events in participants receiving EBR/GZR or placebo for 12 wk (A) with chronic kidney disease stage 4/5, (B) with inherited blood disorders, or (C) on opioid agonist therapy (adverse events occurring in >5% of participants in either treatment group). Abbreviations: EBR/GZR, elbasvir/grazoprevir

Participants With Inherited Blood Disorders Receiving EBR/GZR for 12 Weeks

A total of 159 participants were randomized to receive EBR/GZR (n = 107) or placebo (n = 52) for 12 weeks in the C-EDGE Inherited Blood Disorders Study (Table S4).[17] Participants were enrolled based on the presence of sickle cell anaemia (18.2%), beta-thalassaemia (38.4%), or haemophilia A/B or von Willebrand Disease (43.4%). Overall, 36.5% had F3-F4 liver fibrosis, including 23.9% of participants with cirrhosis.

Adverse events were reported in 78 (72.9%) participants receiving EBR/GZR and 34 (65.4%) receiving placebo (Table 3). The most frequently reported AEs were headache (21.5% vs 11.5%), fatigue (16.8% vs 7.7%), nausea (8.4% vs 15.4%) and asthenia (7.5% vs 3.8%), occurring at similar frequencies in the EBR/GZR and placebo treatment groups, respectively (Figure 2B). Drug-related AEs (33.6% vs 30.8%) and serious AEs (2.8% vs 11.5%) also occurred at similar frequencies in participants receiving EBR/GZR or placebo (Table 3). One participant in this study, who was receiving placebo, discontinued treatment due to an AE. Creatinine elevations were rare in both treatment groups, and ALT elevations were more common among participants receiving placebo (only one participant receiving EBR/GZR had an ALT elevation >2.6× ULN). Bilirubin elevations >2.6× ULN were reported by 20 participants (18.7%) receiving EBR/GZR and 12 (23.1%) of those receiving placebo. Haemoglobin levels ≤8.9 g/dL occurred in 22 participants (20.6%) receiving EBR/GZR and 10 (19.3%) participants receiving placebo.

Participants on Opioid Agonist Therapy Receiving EBR/GZR for 12 Weeks

A total of 301 participants receiving opioid agonist therapy were randomized to receive EBR/GZR (n = 201) or placebo (n = 100) (Table S5).[18] All were receiving either methadone or buprenorphine with or without naloxone opioid agonist therapy, and 59.2% of participants had a positive urine drug screen (UDS) test at the beginning of treatment. The most common positive UDS results were for cannabinoids (28.9%), benzodiazepines (24.8%) and opioids (21.1%). A total of 21 participants in this study had HCV/HIV coinfection.

Adverse events were reported in 83.3% of participants receiving EBR/GZR and 83.0% of those receiving placebo (Table 3). Drug-related AEs (40.8% vs 34.0%), serious AEs (3.5% vs 4.0%) and discontinuations due to an AE (0.5% vs 1.0%) were also comparable between EBR/GZR and placebo treatment arms. The most frequently reported AEs in the EBR/GZR and placebo treatment arms, respectively, were fatigue (15.9% vs 20.0%), headache (12.4% vs 13.0%), nausea (10.9% vs 9.0%), diarrhoea (9.5% vs 9.0%) and constipation (8.5% vs 4.0%) (Figure 2C). There were also no notable differences in laboratory values between EBR/GZR and placebo treatment arms (Table 3).

EBR/GZR + RBV for 16–18 Weeks

A total of 171 participants received EBR/GZR plus RBV for 16–18 weeks (Table 1), most of whom were white (n = 135, 78.9%) and recruited at study centres in the United States (n = 65, 38.0%) or Europe (n = 51, 29.8%).[11,14,15] In this population, 81 participants (47.4%) had cirrhosis and 139 (81.3%) had previously failed interferon-based anti-HCV treatment.

Adverse events were reported in 155 (90.6%) of participants with fatigue (32.7%), headache (21.6%), nausea (15.8%), anaemia (15.2%), pruritus (15.2%), asthenia (12.3%) dyspnoea (12.3%), cough (11.7%), insomnia (11.7%), accidental overdose (11.1%) and rash (10.5%) (Figure 3A). AEs were also reported at generally similar frequencies in cirrhotic and noncirrhotic participants (87.7% vs 93.3%). The most commonly reported AEs in participants receiving EBR/GZR + RBV for 16–18 weeks without cirrhosis and with cirrhosis, respectively, were fatigue (32.2% vs 33.3%), headache (18.9% vs 24.7%), nausea (17.8% vs 13.6%), anaemia (17.8% vs 12.3%), asthenia (14.4% vs 9.9%) and pruritus (14.4% vs 16.0%) (Figure 3B). Drug-related AEs (77.8% vs 76.7%), serious AEs (3.7% vs 2.2%) and discontinuations due to an AE (4.9% vs 2.2%) were each reported at generally similar frequencies in cirrhotic and noncirrhotic participants (Table 2). Changes in ALT and creatinine levels were uncommon, but bilirubin elevations and declining Hgb levels were common in participants receiving RBV. Bilirubin levels ≥2.6× ULN were reported in 11 participants (6.4%), and Hgb levels ≤8.9 g/dL were reported by 6 participants (3.5%) (Table 2).

Figure 3.

Adverse events (A) in all participants receiving EBR/GZR plus ribavirin for 16–18 wk (adverse events occurring in >10% of all participants) and (B) according to the presence or absence of cirrhosis in participants receiving EBR/GZR plus ribavirin for 16–18 wk (AEs occurring in >5% of participants in either treatment group). Abbreviations: EBR/GZR, elbasvir/grazoprevir

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