Safety Analysis of Glecaprevir/Pibrentasvir in Patients With Markers of Advanced Liver Disease in Clinical and Real-world Cohorts

Jordan J. Feld; Xavier Forns; Douglas E. Dylla; Hiromitsu Kumada; Victor de Ledinghen; Lai Wei; Robert S. Brown Jr; Robert Flisiak; Pietro Lampertico; Dominique Thabut; Mark Bondin; Fernando Tatsch; Margaret Burroughs; John Marcinak; Zhenzhen Zhang; Amanda Emmett; Ira M. Jacobson


J Viral Hepat. 2022;29(12):1050-1061. 

In This Article

Abstract and Introduction


Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor–containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 109/L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 109/L (n = 800), platelet count <100 × 109/L (n = 215), a Child-Pugh score of 5 (n = 915) and a Child-Pugh score of 6 (n = 95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets.


An estimated 57 million people were estimated to be infected with hepatitis C virus (HCV) globally in 2020.[1] If left untreated, HCV leads to cirrhosis in 5%–25% of patients within 10–20 years of infection, with approximately 20% of liver cancer cases and deaths estimated to result from HCV infection globally.[2–4] Patients with cirrhosis can experience impaired liver function, portal hypertension, and the development of hepatocellular carcinoma (HCC).[5] Successful HCV treatment is associated with an approximately 70% reduced risk of HCC (adjusted hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.43–0.59 among patients with cirrhosis, and 0.32, 95% CI 0.28–0.37 among patients without cirrhosis)[6,7] and a 61% reduced risk of liver-related mortality,[8] compared with no HCV treatment.

The availability of highly effective and well-tolerated pangenotypic direct-acting antivirals (DAAs) means that sustained virologic response (SVR) can be achieved in the vast majority of patients infected with HCV, including those with more advanced liver disease.[9,10] The DAA regimen of glecaprevir/pibrentasvir (G/P) is approved in Europe and the United States for 8 weeks of therapy in all treatment-naive patients infected with HCV genotype (GT) 1, 2, 3, 4, 5 or 6, without cirrhosis or with compensated cirrhosis (CC).[11,12] Clinical trials have shown G/P to be well tolerated and highly effective with an overall sustained virologic response at post-treatment Week 12 (SVR12) rate of 98%.[13]

Historically, advanced fibrosis and cirrhosis were associated with negative treatment outcomes in patients treated with interferon (IFN)-based regimens.[14] The availability of IFN-free pangenotypic DAA regimens has changed the treatment paradigm, particularly in patients with advanced liver disease, with similar SVR rates seen in patients with CC and patients without cirrhosis.[14] Indeed, similar SVR rates are now reported in patients with and without cirrhosis, with 1 real-world meta-analysis of IFN-free DAA regimens reporting SVR12 rates of 97.8% in patients with cirrhosis and 97.0% in patients without cirrhosis,[15] and another real-world study reporting SVR12/24 rates of 97.9% in patients with cirrhosis and 99.2% in patients without cirrhosis.[16] Treatment of HCV in patients with advanced liver disease is important, as demonstrated by reduced all-cause mortality and HCC incidence in patients who achieve SVR versus those who do not.[17]

While there are clear benefits in treating HCV patients with advanced liver disease, there have been concerns surrounding the safety of DAA treatment, namely regimens containing an HCV NS3/4A protease-inhibitor (PI). In August 2019, the US Food and Drug Administration issued a Drug Safety Communication warning about the rare occurrence of liver failure in patients treated with PI-containing regimens, including G/P, elbasvir/grazoprevir and sofosbuvir (SOF)/velpatasvir/voxilaprevir.[18] The agency identified 63 cases of hepatic decompensation, some leading to liver failure.[18] However, most of these cases occurred in patients with moderate to severe liver impairment (Child-Pugh score ≥7), in whom PI-containing regimens are not indicated for treatment of HCV infection. It remains unclear if this was due to lack of awareness of the interdiction on treatment of decompensated cirrhotic patients with PIs, underestimation of the degree of liver disease by the treating provider, a conscious decision based on other comorbidities, lack of other therapeutic options (e.g. re-treatment), or drug–drug interactions. In cases presenting in patients with CC or without cirrhosis, the FDA also stated there was evidence of portal hypertension or other significant pre-existing risk factors that may have contributed to clinical worsening of liver disease. Indeed, one active-comparator cohort study found that portal hypertension was significantly associated with an increased risk of decompensation (HR, 2.75; 95% CI, 1.92–3.94) regardless of whether the DAA regimen contained a PI.[19] Studies have also demonstrated that decompensation events are not isolated only to patients treated with PI-containing regimens.[20] A retrospective analysis of propensity-score-matched cohorts treated with PI-based or non-PI-based DAAs found no increased risk of severe hepatic dysfunction (HR 1.23; 95% CI, 0.64–2.38) or hepatic decompensation (HR 1.01; 95% CI, 0.41–1.87) comparing these groups.[21] To further evaluate the safety profile of G/P in HCV-infected patients, we herein review data from pooled clinical trials and real-world studies comparing patients with compensated cirrhosis (F4 at baseline) and with and without laboratory signs of more advanced liver disease.