Glecaprevir/pibrentasvir effective for people with hepatitis C and severe kidney disease

A two-drug pangenotypic regimen combining AbbVie's glecaprevir and pibrentasvir demonstrated a high sustained response rate for people with chronic hepatitis C who have 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 people.

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 of 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 in drug levels in people with kidney disease.

Other studies presented at The Liver Meeting showed that glecaprevir/pibrentasvir cured 99% of people with hepatitis C with multiple genotypes and most people with hard-to-treat genotype 3.

EXPEDITION-4 enrolled 104 people with hepatitis C 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 one in five had compensated liver cirrhosis. People with decompensated cirrhosis were excluded, as were those with HIV/HCV co-infection.

All participants received glecaprevir/pibrentasvir (300/120mg) 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).

The overall SVR12 rate was 98% in an intention-to-treat analysis, or 100% in a modified analysis of people who completed treatment. One individual discontinued therapy early and one was lost to follow-up, but there were no viral breakthroughs or relapses.

Treatment was generally safe and well tolerated. About a quarter of individuals experienced serious adverse events, but none of these were considered study drug-related. There were four treatment discontinuations and one 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 haemodialysis."

European Association for the Study of the Liver (EASL) hepatitis C treatment guidelines list AbbVie's older paritaprevir/ritonavir/ombitasvir plus dasabuvir or '3D' regimen (Viekirax + Exviera) and Merck's grazoprevir/elbasvir (Zepatier) taken for 12 weeks as recommended options for people with severe kidney disease who have HCV genotype 1. The '2D' regimen without dasabuvir (Viekirax alone) or grazoprevir/elbasvir are recommended for those with genotype 4.

The RUBY-I study, also presented at The Liver Meeting, showed that the 3D regimen taken for 12 weeks cured 100% of people with genotype 1b with severe kidney impairment or end-stage renal disease. 3D plus ribavirin for 12 weeks cured 96% of people without cirrhosis and a 24-week course cured 89% of people with cirrhosis with harder-to-treat genotype 1a.

Similarly, in the RUBY-II study, the 3D regimen for 12 weeks demonstrated a 100% SVR12 rate for people with severe kidney disease with genotype 1a. In addition, the 2D regimen cured four out of five people with genotype 4; the individual who did not achieve SVR underwent kidney transplantation and stopped treatment at week 2.

Grazoprevir/elbasvir was found to be highly effective for people with advanced kidney disease in the C-SURFER study.

Regimens containing sofosbuvir (Sovaldi, Harvoni or 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 EASL guidelines suggest cautious use of sofosbuvir/velpatasvir (Epclusa) or sofosbuvir plus daclatasvir (Daklinza) with careful monitoring for people with advanced kidney disease with HCV genotype 2 or 3 who urgently need treatment, while current AASLD guidelines offer only pegylated interferon/ribavirin for people with genotypes 2, 3, 5 or 6.

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