DAAs: Exemplary Safety Profile Confirmed Across Broad Population

BOSTON, MA—Direct-acting antiviral (DAA) therapy “has an exemplarysafety profile across a broad population of patients treated in usual clinicalpractice,” reported study authors at The Liver Meeting® 2016.

They also found that “fewer than 2%of patients discontinued therapy due to adverse events.”

These results confirm the “outstandingsafety profile” observed in Phase 3 trials as well as provide details aboutadditional safety warnings brought to light by post-marketing surveillance,which has restricted the use of DAAs in patients with decompensated cirrhosis.

To evaluate detailed safety dataacross a broad spectrum of “real world” patients treated with DAAs, Michael W.Fried, MD, professor of medicine and director, University of North Carolina LiverCenter, Chapel Hill, NC, and coauthors examined data from the HCV-TARGETInternational Consortium, an investigator-initiated study of patients treated accordingto regional standards of care at 44 academic and 17 community medical centersin North America and 4 sites in Europe.

“Detailed information on demographics,clinical course, and adverse events was abstracted from medical records into acentralized data core and systematically monitored for accuracy,” Dr. Friednoted. Patients who initiated treatment with all-oral DAA regimens betweenJanuary 2014 and September 2016 were included in the safety analysis; excludedwere those missing bilirubin values or end-treatment dates.

A hepatologist assigned patientswith a clinically significant treatment emergent change in bilirubin (ΔTBIL ≥3mg/dL,selected to account for ribavirin effect) to one of three categories: acutemorbidity, benign drug-associated hyperbilirubinemia, or drug-associated liverevent. History of decompensation and treatment-emergent decompensating eventswere also noted.

A total of 4829 patients were included in the analysis. The treatment regimens included sofosbuvir (SOF) + ribavirin(RBV), SOF + simeprevir (SMV) ± RBV, ledipasvir/sofosbuvir (LDV/SOF) ± RBV, paritaprevir/ritonavir/ombitasvir with dasabuvir PrOD) ± RBV, and SOF + daclatasvir (DCV) ± RBV.

Of the patients, 4695 (97.2%)completed therapy, with 4612 (97.8%) having ΔTBIL <3mg/dL. Among the 67patients (1.4%) who discontinued treatment, 51 (1.1%) had ΔTBIL <3mg/dL.Reasons for discontinuation included lack of efficacy in 14 (0.3%) and “other”reasons in 38 (0.8%); 13 (0.3%) had died and in 2 patients, treatment wasongoing.

Results showed that “hyperbilirubinemia may be associated with acute comorbid medical conditions, benign DAA ± RBVeffects, or treatment emergent-drug associated liver events,” Dr. Fried reported.

The latter events were associatedboth with features of cirrhosis and use of RBV-containing regimens.

“Within this category differentiating progressive liver disease from potential drug-induced liver injury remains challenging,” he added.

The study also found that among patientswith a history of prior hepatic decompensation, RBV use is associated withtreatment-emergent hepatic decompensation.

Evaluation of drug-induced serious hepatotoxicity (eDISH) profiles “must be evaluated in the context of a patient’sunderlying liver disease,” the authors concluded.

They are performing further sensitivityanalyses “to evaluate impact on identifying cases of special concern.”

The study was funded in part by AbbVie, Bristol-MyersSquibb, Genentech, Gilead, GlaxoSmithKline, Janssen, Kadmon, Merck, and Vertex.