Neil Osterweil

November 17, 2016

BOSTON — An investigational combination of direct-acting antiviral agents is associated with high sustained viral response rates in patients with renal impairment who are infected with chronic hepatitis C virus genotypes 1 to 6, new research shows.

The combination, from AbbVie, is a once-daily regimen of glecaprevir, a pangenotypic NS3/4A protease inhibitor, and pibrentasvir, a pangenotypic inhibitor of the NS5A replication complex.

"If you look at the AASLD guidance document, the only place in the whole document where pegylated interferon and ribavirin are still listed is for genotypes 2 and 3 patients with advanced kidney disease or dialysis," said study investigator Eric Lawitz, MD, vice-president of scientific and research development at the Texas Liver Institute in San Antonio.

"It's actually the one area where we have a huge unmet medical need," he told Medscape Medical News.

Results from the EXPEDITION-4 trial (NCT02651194) showed that the ribavirin-free regimen led to a sustained viral response at 12 weeks in patients with severe renal impairment or end-stage renal disease on hemodialysis, reported fellow study investigator Edward Gane, MD, from the University of Auckland in New Zealand.

In clinical studies, the combination has shown minimal metabolism and primary biliary excretion, with less than 1% renal excretion, which allow it to be delivered without dose adjustments to patients with chronic kidney disease, Dr Gane told the audience during a late-breaking abstracts session here at The Liver Meeting 2016.

The combination appears to be a good therapeutic option for patients with hepatitis C, especially those with the treatment-refractory genotype 1a or those with other genotypes who have moderate to severe impairment, marked by glomerular filtration rates (GFR) below 30 mL/min per 1.73 m², said Dr Lawitz.

EXPEDITION-4 involved 104 patients 18 years and older with hepatitis C genotypes 1 to 6 and stage 4 or 5 chronic kidney disease, determined on the basis of eGFR. The patients could be with or without compensated cirrhosis, and could have received previous treatment with pegylated interferon with or without ribavirin, or with sofosbuvir (Solvadi, Gilead Sciences) plus ribavirin with or without pegylated interferon.

Once a day for 12 weeks, patients took three pills that each contained glecaprevir 100 mg and pibrentasvir 40 mg, for a daily total of glecaprevir 300 mg and pibrentasvir 120 mg.

In the intention-to-treat efficacy analysis, 102 of the 104 patients achieved a sustained viral response at 12 weeks. There were no virologic breakthroughs or relapses during the 24-week follow-up. One of the patients who did not achieve viral response discontinued treatment after 3 weeks because of diarrhea related to gastrointestinal bleeding; the other died with an undetectable viral load from an intracerebral hemorrhage related to uncontrolled hypertension 2 weeks after the completion of therapy.

Twenty-five patients (24%) experienced serious adverse events, but none were deemed by treating physicians to be related to the study drug.

In addition to the patient who discontinued therapy because of diarrhea, three patients discontinued therapy after 8 weeks: one because of pruritus, one because of pulmonary edema and hypertensive cardiomyopathy with congestive heart failure, and one because of a hypertensive crisis. All three of these patients achieved a sustained viral response at 12 weeks and were included in the intention-to-treat analysis.

Adverse events included pruritus in 20% of patients, fatigue in 14%, and nausea in 12%.

Five patients experienced hemoglobin abnormalities of grade 3 or higher, and one patient experienced total bilirubin levels three to 10 times the upper limit of normal. There were no cases of elevated liver enzymes (aspartate transaminase or alanine transaminase).

"A Home Run"

"The efficacy of these combinations is just amazing, with 98% SVR in difficult-to-treat patients," said Ronald Sokol, MD, professor of pediatrics and head of the gastroenterology, hepatology, and nutrition section at the University of Colorado in Aurora, who was not involved in the study.

For patients with hepatitis C infections and renal impairment, the combination looks like "a home run," he told Medscape Medical News.

The study was supported by AbbVie. Dr Gane and Dr Lawitz report financial relationships with AbbVie and multiple other companies. Dr Sokol reports financial relationships several companies, but not AbbVie.

The Liver Meeting 2016: American Association for the Study of Liver Diseases (AASLD): Abstract LB-11. Presented November 15, 2016.

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