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AASLD 2016: Glecaprevir/ Pibrentasvir Effective for Hepatitis C Patients with Severe Kidney Disease

A 2-drug pangenotypic regimen combining AbbVie's glecaprevir and pibrentasvir demonstrated a high sustained response rate for chronic hepatitis C patients with severe kidney impairment, according to results from the EXPEDITION-4 study presented at the 2016 AASLD Liver Meeting last month in Boston.

Direct-acting antivirals used in interferon-free regimens can now cure more than 90% of people with all hepatitis C virus (HCV) genotypes, but there is still room for better options for the most difficult-to-treat patients.

People with hepatitis C have an increased risk of chronic kidney disease, experience more rapid kidney disease progression, and are more likely to require dialysis. People with serious kidney impairment may be advised not to take certain medications and may be at greater risk for adverse events.

Edward Gane from Auckland City Hospital in New Zealand presented results from AbbVie's EXPEDITION-4 trial, which tested the investigational glecaprevir/pibrentasvir regimen in people with severe renal impairment.

Glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an NS5A inhibitor; both drugs are pangenotypic, or active against all HCV genotypes. Neither drug undergoes significant excretion by the kidneys, and early studies showed no clinically relevant increases drug levels in patients with kidney disease. Other studies presented at the Liver Meeting showed that glecaprevir/pibrentasvir cured 99% of hepatitis C patients with multiple genotypes and most people with hard-to-treat genotype 3.

EXPEDITION-4 enrolled 104 hepatitis C patients with stage 4 or 5 chronic kidney disease who had an estimated glomerular filtration rate or eGFR -- a method of estimating creatinine clearance -- below 30 mL/min/1.73m² (normal is over 90). Most (88%) had stage 5 kidney disease (eGFR 15-29 or dialysis) and 82% were on dialysis.

About 80% were men and 25% were black (a group at higher risk for kidney disease); the median age was 57 years (older age is also a risk factor). About half had HCV genotype 1 (22% with 1a and 28% with 1b), 16% had genotype 2, 11% had genotype 3, 19% had genotype 4, and 1% had genotypes 5 and 6.

Participants could either be previously untreated for hepatitis C (58%) or treatment-experienced using interferon- or sofosbuvir-based regimens (40%). About 1 in 5 had compensated liver cirrhosis. People with decompensated cirrhosis were excluded, as were those with HIV/HCV coinfection.

All participants received glecaprevir/pibrentasvir (300/120 mg) once-daily for 12 weeks. The primary study endpoint was sustained virological response, or undetectable HCV RNA at 12 weeks after the end of treatment (SVR12).

Results

• The overall SVR12 rate was 98% in an intention-to-treat analysis, or 100% in a modified analysis of patients who completed treatment.
• 1 patient discontinued treatment early and 1 was lost to follow-up; there were no relapses.
• Treatment was generally safe and well-tolerated.
• 24% of patients experienced serious adverse events, but none of these were considered study drug-related.
• There were 4 treatment discontinuations and 1 death due to serious adverse events, again not deemed study drug-related.
• The most common adverse events were pruritus (20%), fatigue (14%), and nausea (12%).
• Grade 3 or higher laboratory abnormalities were rare.

The researchers concluded that the results of EXPEDITION-4 "demonstrate that a ribavirin-free glecaprevir/pibrentasvir regimen achieves a high SVR12 rate in this population with severe renal impairment and end-stage renal disease on hemodialysis."

Treatment Options for Kidney Disease Patients

AASLD/IDSA hepatitis C treatment guidelines list Merck's grazoprevir/elbasvir (Zepatier) taken for 12 weeks as a recommended regimen for patients with HCV genotypes 1a, 1b, or 4 with creatinine clearance <30 mL/min who are being treated before kidney transplantation. This regimen was found to be highly effective in the C-SURFER study.

AbbVie's older paritaprevir/ritonavir/ombitasvir plus dasabuvir or "3D" regimen (Viekira Pak or Viekira XR) is also a recommended option for severe kidney disease patients with HCV genotype 1b.

The RUBY-I study, also presented at the Liver Meeting, showed that the 3D regimen taken for 12 weeks cured 100% of genotype 1b patients with severe kidney impairment or end-stage renal disease. 3D plus ribavirin for 12 weeks cured 96% of non-cirrhotic patients and a 24-week course cured 89% of cirrhotic patients with harder-to-treat genotype 1a.

Similarly, in the RUBY-II study, the 3D regimen for 12 weeks demonstrated a 100% SVR12 rate for severe kidney disease patients with genotype 1a. In addition, the "2D" regimen without dasabuvir (Technivie) cured 4 out of 5 genotype 4 patients; the individual who did not achieve SVR underwent kidney transplantation and stopped treatment at week 2.

Regimens containing sofosbuvir (Sovaldi, Harvoni, Epclusa) are generally not recommended for people with severe renal disease because it is excreted by the kidneys, and impaired kidney function can lead to elevated drug levels. However, people with mild to moderate renal impairment (creatinine clearance 30-80 mL/min) can safely use sofosbuvir without dose adjustments.

Current AASLD guidelines offer only pegylated interferon/ribavirin for advanced kidney disease patients with HCV genotypes 2, 3, 5, or 6, although the EASL European guidelines allow for cautious use of sofosbuvir/velpatasvir (Epclusa) or sofosbuvir plus daclatasvir (Daklinza) with careful monitoring for patients with genotype 2 or 3 who urgently need treatment.

Fortunately, the results from EXPEDITION-4 show that glecaprevir/pibrentasvir, when approved, could be a good pangenotypic option for this population.

12/15/16

Sources

D Pugatch, Y Lei, MP Kosloski, E Gane, et al. EXPEDITION-IV: Safety and Efficacy of GLE/PIB in Adults with Renal Impairment and Chronic Hepatitis C Virus Genotype 1-6 Infection. AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract LB-11.

JM Vierling, E Lawitz, KR Reddy, et al. RUBY-I: Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with or without Ribavirin in Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection with Severe Renal Impairment or End-Stage Renal Disease. AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 886.

EJ Gane, R Solà, Eric Cohen, et al. RUBY-II: Efficacy and Safety of a Ribavirin-free Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir Regimen in Patients with Severe Renal Impairment or End-Stage Renal Disease and HCV Genotypes 1a or 4 Infection. AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 935.