1 INTRODUCTION

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.

2 METHODS

3 RESULTS

4 DISCUSSION

Data reported here confirm that G/P treatment has a good safety profile in patients with CC, including those with platelet count <100 × 10⁹/L. G/P was well tolerated in patients with platelet count <100 × 10⁹/L, with few patients experiencing AEs leading to treatment discontinuation and serious AEs related to the study drug (1.1% and 0.5% in the clinical trial cohort and 3.6% and 0 in the PMOS cohort, respectively). G/P was also well tolerated in patients with a Child-Pugh score of 5 and 6, with few patients experiencing AEs leading to treatment discontinuation (0.1% and 1.3% in the clinical trial cohort and 1.6% and 0% in the PMOS cohort, respectively) and serious AEs related to the study drug (0.1% and 0 in the clinical trial cohort and 0 in the PMOS cohort). Overall, the AE rates, including AEs leading to discontinuation and serious AEs related to the study drug in patients with platelet count <100 × 10⁹/L, were comparable to those seen in patients with platelet count ≥100 × 10⁹/L, as well as between the Child-Pugh score 5 and 6 subgroups, in both the clinical trial and PMOS cohorts.

Overall AE rates (and rates of AEs considered possibly related to DAA therapy) were higher in the clinical trial cohort versus the PMOS cohort. This is an expected finding, as safety is often underreported in observational studies compared with clinical trials, for which it is mandatory. As such, caution should be exercised when comparing safety outcomes reported in clinical trial and real-world data sets. Results are consistent with previously reported real-world G/P data, which showed low rates of severe AEs and AEs of special interest.^{36, 37}

In both cohorts, normalization of laboratory parameters was observed across the subgroups. Platelet normalization was rare; however, as low platelet count is a consequence of portal hypertension, platelet count rarely normalizes, even in patients who undergo a liver transplant as the spleen remains large. AST and ALT elevation was transient, often below Grade 3, returned to normal after treatment completion, and was not associated with other findings that would suggest liver decompensation. Therefore, this can reassure non-liver specialists that in most cases AST and ALT elevations are limited and do not suggest liver decompensation.^{38, 39} The analysis of safety data from subgroups defined by individual noninvasive measures (such as baseline platelet count and Child-Pugh score) affords comparison of the utility/interchangeability of individual measures for identifying patients at low risk for liver-related outcomes. The overlap and similar safety profile observed in the patient subgroups of platelet count < or ≥ 100 × 10⁹/L and Child-Pugh score of 5 or 6, demonstrates the similar safety of patients with CC, regardless of markers of portal hypertension or synthetic dysfunction, compared with those without markers.

While this analysis has strengths, including sample size and use of both clinical trial and PMOS populations, some limitations should be acknowledged. Firstly, there was a lack of available laboratory data and MELD score values for the PMOS cohort compared with the clinical trial cohort due to differences in real-world clinical monitoring practices compared with controlled clinical trials. Another limitation is that the small number of liver-related AEs and AEs that led to treatment discontinuation means it is not possible to use these data to identify risk factors for the occurrence of liver-related events. In addition, subgroups contained some overlap, as they were not mutually exclusive, and the number of patients with Child-Pugh score of 6 was relatively small. Lastly, because the population was exclusively those with compensated cirrhosis, the proportion of patients with recent illicit drug use was low, though should be anticipated because active drug users are generally younger and without long-term HCV infection that would facilitate liver disease progression to cirrhosis.

The results presented here are supported by other studies that concluded that G/P is well tolerated in patients with advanced renal disease, HIV and solid organ transplants.^{40, 41} In summary, the findings of the present post hoc analysis confirm the known safety profile in CC patients with more advanced liver disease, treated with G/P according to the label. Therefore, these data provide reassurance that when prescribed per label in patients with CC, even in those with platelet count <100 × 10⁹/L, G/P can be safely used with appropriate long-term follow-up to monitor for development of HCC.^{14, 42} It is because of this long-term monitoring that patients demonstrating clinical signs of advanced liver disease may preferentially benefit from HCV care by experienced centers. However, simplified treatment algorithms may be particularly useful in countries, such as the United States and France, which allow HCV treatment in the community setting.^42-44 In addition, expanding the pool of patients eligible for shorter duration G/P therapy to include those with CC has the potential to support the global goal of HCV elimination.^{41, 45}

AUTHOR CONTRIBUTIONS

All authors had access to relevant data and participated in the writing, review and approval of the manuscript. JJF, XF, DED, MB, FT, MB, JM, ZZ, AE and IMJ contributed to study concept and design. All authors contributed to acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. JF is acting as the guarantor of this manuscript and all authors approved this final version.

FUNDING INFORMATION

AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the manuscript. Medical writing support was provided by Annie Massa, MBiolSci, and Tom Owen, PhD, of Fishawack Communications, Ltd; and funded by AbbVie. Glecaprevir was identified by AbbVie and Enanta.

CONFLICT OF INTEREST

Jordan J Feld: Research support/consultant: AbbVie, Arbutus, Enanta, Gilead, Janssen, Merck, and Roche. Xavier Forns: Advisor for AbbVie and Gilead Douglas E Dylla, Mark Bondin, Fernando Tatsch, Margaret Burroughs, John Marcinak, Zhenzhen Zhang, Amanda Emmett: Employees of AbbVie and may hold stock/share options. Hiromitsu Kumada: Honoraria: MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Eisai Co., Ltd., AbbVie GK., Gilead Sciences Inc. Victor de Ledinghen: AbbVie, Echosens, Gilead, Hologic, Intercept Pharma, MSD, MYR-Pharma, Siemens, Tillotts. Lai Wei: Consulting for Gilead Sciences, Johnson & Johnson, Pfizer, and Roche; and research grants to the institution from AbbVie and Gilead Sciences. Robert S Brown Jr: Research support from AbbVie, Gilead, Merck, Intercept, and Bristol-Myers Squibb, and has acted as an advisor for AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Merck, Shionogi, and Dova. Robert Flisiak: Advisor for AbbVie, Gilead, and Merck. Pietro Lampertico: Speaker bureau and/or advisory board: AbbVie, Alnylam, Arrowhead, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Gilead Sciences, GSK, Janssen, MSD, MYR Pharmaceuticals, Roche, and Spring Bank. Dominique Thabut: Consultant for AbbVie, Alfasigma, Gilead, Gore, Medday, MSD. Ira M Jacobson: Grant/research support: Assembly Biosciences, Bristol-Myers Squibb, Eli Lilly, Gilead, Genfit, Enanta, and Janssen; consultant/advisor: AbbVie, Arrowhead, Atea, Assembly Biosciences, Bristol-Myers Squibb, Intercept, Janssen, Gilead, GSK, Merck, Novo Nordisk, Poptest, Redhill, and Siemens.

ETHICAL APPROVAL

For all included studies, written informed consent was obtained from each patient, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the appropriate institutional review committee.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

Permission was obtained to reproduce material where appropriate.