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

Discussion

This comprehensive analysis includes data from all participants receiving EBR/GZR in a total of 12 clinical studies and thus provides a unique opportunity to evaluate the safety profile of this drug combination in a large and heterogeneous population. These safety and tolerability analyses included participants with clinically important comorbidities (ie CKD, opioid agonist therapy and inherited blood disorders), participants with and those without cirrhosis, treatment-naive and treatment-experienced participants, and those receiving different durations of therapy or combination therapy with RBV. The design of several of these studies allowed a placebo-controlled evaluation of safety events in populations with substantial comorbidities, thereby allowing drug-related toxicity to be distinguished from the underlying disease-related morbidities.

Data from the present analysis indicate that EBR/GZR was well-tolerated across a wide spectrum of participants with HCV infection. Because changes in Hgb and total bilirubin levels tended to be more common among participants with inherited blood disorders, occurring at similar rates in the placebo and EBR/GZR treatment groups, these events were more likely to be related to the underlying comorbidity than to the antiviral therapy. Similarly, abnormal sCr was reported more frequently among those with CKD and occurred at similar frequencies in both placebo and EBR/GZR treatment groups, indicating that these changes were attributable to underlying CKD. Rare ALT elevations were observed (1.4% [25/1743] of participants receiving EBR/GZR for 12 weeks had a grade 3 or grade 4 ALT elevation) but were not associated with a specific population or cirrhosis status. Importantly, there were no Hy's Law events.

A unique part of the clinical trial programme has been the study of the efficacy and safety of EBR/GZR in a large cohort of participants with CKD, a challenging population. The demonstrated safety and efficacy in this population has led investigators to confidently venture into the novel strategy of transplanting HCV-infected kidneys into uninfected renal transplant recipients and subsequently treating newly acquired HCV infection with EBR/GZR-based regimens.[20,21] The efficient treatment of such recipients has been demonstrated to provide long-term benefit and has shortened waiting time for renal transplant recipients.[20,22,23] To expand on this further, cardiac transplants have now been performed with HCV-infected organs transplanted into uninfected recipients followed by subsequent treatment for HCV infection.[24]

Data from this analysis also indicate that participants receiving RBV had a greater frequency of RBV-related AEs, such as fatigue (which occurred in nearly one-third of participants treated with RBV), anaemia and pruritus (both reported at a frequency of approximately 15% compared with <5% in those receiving EBR/GZR alone). Insomnia and dyspnoea also occurred in approximately 10% of participants receiving RBV. The most common AEs reported in participants receiving EBR/GZR occurred at higher frequencies in those receiving concomitant RBV compared with those receiving EBR/GZR alone (fatigue, 32.7% vs 8.7%; headache, 21.6% vs 10.6%; nausea, 15.8% vs 5.1%). The safety profile of EBR/GZR was generally similar across the three special populations—(1) individuals with CKD, (2) those on opioid substitution therapy and (3) those with inherited blood disorders. Overall, rates of treatment discontinuation due to safety events was low, even among participants on opioid agonist therapy, and the rates of AEs, serious AEs and discontinuations were generally similar in placebo and EBR/GZR treatment groups.

In conclusion, these data from a large and diverse population of clinical trial participants with HCV infection indicate that EBR/GZR is safe and represents a treatment option for individuals with HCV GT1 or GT4 infection without any unique follow-up requirements. No episodes of hepatic decompensation were recorded among clinical trial participants receiving EBR/GZR-based treatment regimens. These data provide safety information in large cohorts of unique populations of participants with CKD, those with inherited haematologic disorders or those receiving opioid substitution therapy, which instills confidence in healthcare providers who treat people with these conditions. The design of these studies, that is, using a placebo group that rolled over to receive EBR/GZR, provided a singular opportunity to assess AEs in placebo-treated participants as a control population, prior to receiving deferred active treatment. The results indicated that many AEs are more likely related to underlying comorbidities than to therapy with EBR/GZR.

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