Glecaprevir-Pibrentasvir Effective in Patients With HCV, CKD

Pam Harrison

October 16, 2017

Glecaprevir-pibrentasvir produces a sustained virologic response in virtually all patients with both hepatitis C virus (HCV) infection and severe chronic kidney disease (CKD), the phase 3 EXPEDITION-4 trial indicates.

"Currently, ribavirin-free treatment options for patients with end-stage renal disease and concomitant HCV genotype 1 infection are limited, and no approved interferon-free and ribavirin-free treatment options are available for patients infected with HCV genotype 2, 3, 5, or 6," Edward Gane, MD, from Auckland City Hospital, New Zealand, and colleagues write. "As a result, large numbers of these patients remain untreated."

The study was published in the October 12 issue of the New England Journal of Medicine.

"In this trial involving patients who were infected with one of the six major HCV genotypes, had stage 4 or 5 chronic kidney disease, and could have been undergoing hemodialysis at baseline, the rate of sustained virologic response was 98% (102 of 104 patients) after 12 weeks of treatment with coformulated glecaprevir–pibrentasvir," the researchers explain. None of the patients in the study exhibited either virologic failure during treatment or virologic relapse after treatment had been completed, they add.

The open-label trial included 104 patients, 52% of whom had genotype 1 infection.

Patients received three coformulated tablets, each containing glecaprevir 100 mg and pibrentasvir 40 mg (total, 300 mg glecaprevir and 120 mg pibrentasvir), once daily for 12 weeks. A sustained virologic response, the primary efficacy end point of the study, was an HCV RNA level of less than 15 IU/mL 12 weeks after treatment had been completed.

Most patients had stage 5 CKD, and 82% of the group required hemodialysis at baseline. Among those not receiving dialysis at baseline, the mean estimated glomerular filtration rate was 20.6 mL/minute per 1.73 m2. Almost half the study group (42%) had received previous treatment for HCV infection, most with a combination of interferon and ribavirin. The adverse effect profile of interferon is well known in this patient population, and ribavirin is excreted in the urine, the authors observe. In patients with severe CKD, ribavirin also tends to accumulate where it causes pruritus, among other well-known adverse effects, "exacerbating adverse events in a population that is already at high risk for anemia and cardiovascular events," the researchers explain.

No patients experienced virologic failure, but two patients did not achieve a sustained virologic response at 12 weeks for reasons other than drug failure. At 24 weeks, the sustained virologic response was 96% (95% confidence interval, 95% - 100%), but this is because several patients were lost to follow-up between 12 and 24 weeks, and so could not be further assessed.

Importantly, patients achieved the same response to the glecaprevir-pibrentasvir coformulation regardless of the genotype being treated or the presence or absence of cirrhosis at baseline.

Adverse Events

Pruritus, fatigue, and nausea were all documented in at least 10% of the group overall. In contrast, the adverse event rate among patients who required hemodialysis at baseline and those who did not was similar in both groups. "Serious adverse events were reported in 24% of the patients," the investigators note, but none were felt by investigators to be caused by the study drug. "Clinically relevant laboratory abnormalities were rare," they add.

Investigators also point out that of those patients who did not require dialysis at baseline, there was no sign that the glecaprevir-pibrentasvir coformulation adversely affected kidney function. This is in contrast to the direct-acting antiviral agent sofosbuvir, the principal metabolite of which is excreted largely through the kidneys, producing exposure to drug levels that are up to 20 times higher than they should be, the researchers note.

Indeed, progressive deterioration of renal function has been reported in patients treated with a sofosbuvir-based regimen, they add. For this reason, regimens containing sofosbuvir are not recommended for patients with severe renal impairment, although they appear to be relatively safe and effective in patients with early-stage CKD, as reported by Medscape Medical News.

"In contrast, neither glecaprevir nor pibrentasvir is excreted through the kidney, and minimal change in drug exposure is observed in patients with advanced renal disease," study authors note.

"Huge Unmet Need"

There is a "huge unmet need" for better options for patients with advanced kidney disease as well as patients receiving dialysis who are infected with HCV, Meghan Sise, MD, assistant in medicine, Massachusetts General Hospital, Boston, emphasized to Medscape Medical News.

"The only currently approved regimens for patients with advanced kidney disease cover only genotypes 1 and 4, so there's been a big hole for genotypes 2, 3 5, and 6," Dr Sise explained.

Furthermore, the prevalence of HCV among patients receiving dialysis is somewhere between five and 10 times that of the general population, so a sizeable percentage of patients receiving dialysis have HCV.

Importantly as well, most treatment-naive patients receiving dialysis who do not have cirrhosis require only 8 weeks of treatment, which is easier for patients to take, Dr Sise noted.

Two months of treatment with the glecaprevir-pibrentasvir coformulation also "only" costs about $26,500 wholesale.

"At this price, [the glecaprevir-pibrentasvir coformulation] is actually much more affordable than other anti-HCV regimens," Dr Sise observed, with other anti-HCV treatment regimens costing between $50,000 and $80,000 for a 12- to 24-week treatment course.

The EXPEDITION-4 study is funded by AbbVie. The authors have disclosed a variety of financial relationships, including receipt of consulting fees, speaking fees, personal fees, research fees, and other support and serving on advisory boards, with numerous companies. Full disclosures can be found on the journal website. Dr Sise reports receiving research grants from Gilead, AbbVie, and Merck and has served on scientific advisory boards for AbbVie and Merck as well. She has also performed some independent consulting for AbbVie.

N Engl J Med. 2017;377:1448-1455. Abstract

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