icon-folder.gif   Conference Reports for NATAP  
  20th International Workshop
on Clinical Pharmacology of HIV
Hepatitis & Other Antiviral Drugs
May 14-16, 2019. Noordwijk, the Netherlands
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Ledipasvir Exposure Linked to SVR, But Overall Response Rate High
  International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
People with decompensated cirrhosis and HCV genotype 1 who fell into the lowest ledipasvir exposure quartile had lower sustained virologic response (SVR) rates with ledipasvir/sofosbuvir than people with higher ledipasvir levels [1]. But overall response to this anti-HCV combination was high in this real-world UK-Ireland study, above 90% even in people with Child-Turcotte-Pugh (CTP) class B cirrhosis.
Once-daily ledipasvir/sofosbuvir yields high SVR rates in people with HCV infection [2], even in those with decompensated cirrhosis. But UK researchers who conducted the new cohort study [1] noted that SVR rates with ledipasvir/sofosbuvir are marginally lower in patients with decompensated cirrhosis than in those with compensated cirrhosis liver disease. They planned this analysis to chart the relationship between ledipasvir exposure and SVR in people with genotype 1 HCV and advanced and decompensated liver disease.
The study involved 314 HCV-positive people with decompensated cirrhosis, 199 of them (63%) with HCV genotype 1 infection. Researchers used the total 314-person group for a pharmacokinetic analysis and the 199 people with genotype 1 for a pharmacodynamic analysis. Everyone received ledipasvir/sofosbuvir plus ribavirin for 12 weeks and gave steady-state samples 3 to 4 random times during treatment. The investigators used linear mixed-effects modeling to develop a pharmacokinetic model for ledipasvir. They calculated individual estimates for ledipasvir clearance (CL) and area under the concentration-time curve (AUC) and assessed the relationship of those values to SVR.
Age averaged 55 +/- 8 years in the whole study group and weight 82 +/- 16.6 kg. Two thirds of entire cohort (67.2%) had CTP class B cirrhosis when they started ledipasvir/sofosbuvir, 7% had CPT class C cirrhosis, and 46.8% were taking low-dose proton pump inhibitors (PPIs) when treatment began. Among the 199 people with HCV genotype 1, 67.3% had CPT class B cirrhosis, 6% had CPT class C, and 43.7% used PPIs at baseline.
A one-compartment model best described ledipasvir pharmacokinetics with population CL estimated at 13.9 L/h and 48% interindividual variability. Relative bioavailability of ledipasvir was 34% lower in people taking a PPI at baseline.
Among people with genotype 1 infection, overall SVR stood at 93.5%. Average ledipasvir AUC lay significantly higher in genotype 1 patients who attained SVR (P < 0.01). Among participants in the upper quartile of ledipasvir AUC (above 8.2 mg*h/L), 100% achieved SVR, a response rate significantly greater than the 88% among people in the lowest ledipasvir AUC quartile (below 5.1 mg*h/L).
Although SVR proved lower in people in the lowest ledipasvir exposure quartile, the researchers stressed that the overall response rate in people with HCV genotype 1 and advanced liver disease was high--above 90% in those with CTP class B cirrhosis.
1. Elsherif O, Pertinez H, Irving W, et al. Ledipasvir PK-PD (pharmacokinetics-pharmacodynamics): relationship between drug exposure and sustained virologic response rates in a cohort of patients with decompensated cirrhosis and HCV genotype 1 infection. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 19.
2. Jensen CM, Holle LM. Ledipasvir-sofosbuvir: a once-daily oral treatment option for chronic hepatitis C virus genotype 1 infection. Pharmacotherapy. 2016;36:562-574. doi 10.1002/phar.1748.