Effect of Hepatitis C Treatment with Ombitasvir/Paritaprevir/R + Dasabuvir on Renal, Cardiovascular and Metabolic Extrahepatic Manifestations: A Post-Hoc Analysis of Phase 3 Clinical Trials

Abstract

Introduction: We analyzed phase 3 trial data of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) ± ribavirin (RBV) in genotype 1 chronic hepatitis C patients to investigate the impact of 3D ± RBV on renal, cardiovascular and metabolic extrahepatic manifestations (EHMs), including persistency 52 weeks post treatment and differential impact by EHM disease severity.

Methods: Estimated glomerular filtration rate (eGFR), fasting triglyceride and fasting glucose values from clinical trials were used to assess renal, cardiovascular and metabolic EHMs, respectively. Two placebo-controlled trials were used to study the effect of treatment, while the pooled sample of treated patients was used to study the persistency and differential effect of treatment by baseline EHM disease severity, as defined by baseline values of respective EHM biomarkers. Changes in EHM outcomes from baseline were assessed with mixed models adjusting for patient baseline demographic and clinical characteristics.

Results: Treatment with 3D ± RBV resulted in statistically significant declines from baseline of triglycerides and glucose and no statistical change in eGFR. By 52 weeks post treatment patients with elevated triglycerides (-35.3 mg/dl), pre-diabetes (-4.4 mg/dl), diabetes (-34.2 mg/dl) and CKD stage 3 (+1.6 ml/min/1.73 m²) at baseline experienced a statistically significant improvement in their respective EHM values. Patients with CKD stages 2, 4 and 5 experienced no statistically significant change in eGFR from baseline.

Conclusion: Treatment with 3D ± RBV resulted in improvement or no worsening of cardiovascular, metabolic and renal EHM markers, especially in patients with severe EHMs at baseline, which persisted until 52 weeks post treatment.

Funding: Abbvie Inc.

Keywords: Dasabuvir; Extrahepatic manifestations; Glucose; Hepatitis c; Ombitasvir; Paritaprevir; Placebo; Ritonavir; Triglycerides; eGFR.

Fig. 1

a Predicted change in triglycerides from baseline: comparison of HCV-treated and placebo arms. Study conducted on treatment and placebo arms of SP1 [i.e., patients from placebo controlled phase 3a trials (SAPPHIRE I and II)]. All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed value of triglycerides at each time point on whether patients were in HCV-treated or placebo group and adjusted for baseline triglyceride level, fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. TGL triglycerides, BL baseline, W week. b Predicted triglyceride change from baseline until post-treatment week 52 among treated patients by baseline triglyceride levels. Fasting baseline TGLs greater than or equal to 150 mg/dl were defined as elevated TGLs. Study conducted on SP3. SP3 comprises of all the HCV-treated population from long-term phase 3b trials (TOPAZ I and II). All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed longitudinal triglyceride value on baseline triglyceride level categories and adjusted for fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. TGL triglycerides, BL baseline, W week, PTW post-treatment week

Fig. 2

a Predicted change in glucose from baseline: comparison of HCV-treated and placebo arms. Study conducted on treatment and placebo arms of SP1 [i.e., patients from placebo controlled phase 3a trials (SAPPHIRE I and II)]. All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed value of glucose at each time point on whether patients were in the HCV-treated or placebo group and adjusted for baseline glucose level, fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. BL baseline, W week. b Predicted glucose change from baseline until post-treatment week 52 among treated patients by baseline glucose levels. Patients with fasting baseline glucose value between 100 and 126 mg/dl were defined as pre-diabetic and glucose higher than 126 mg/dl were defined as diabetic. Study conducted on SP3. SP3 comprises all of the HCV-treated population from long-term phase 3b trials (TOPAZ I and II). All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed longitudinal glucose value on baseline glucose level categories and adjusted for fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. BL baseline, W week, PTW post-treatment week

Fig. 3

a Predicted change in eGFR from baseline: comparison of HCV-treated and placebo arms. Study conducted on treatment and placebo arms of SP1 [i.e., patients from placebo controlled phase 3a trials (SAPPHIRE I and II)]. All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed values of eGFR at each time point on whether patients were in the HCV-treated or placebo group and adjusted for baseline eGFR level, fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. eGFR estimated glomerular filtration rate, BL baseline, W week. b Predicted eGFR change from baseline until post-treatment week 52 among treated patients by baseline eGFR levels. Chronic kidney disease stages were defined based on guidelines as stage 1 (signs of kidney damage but normal or elevated (eGFR ≥90), stage 2 (eGFR 60–89), stage 3 (eGFR 30–59), stage 4 (eGFR 15–29) and stage 5 (eGFR <15 or dialysis dependent). Study conducted on SP2. SP2 comprises all of the HCV-treated population from long-term phase 3b trials (TOPAZ I and II). All patients in trials were GT1 patients. The graphs depict predicted change from baseline at individual time points based on longitudinal mixed model regression. The model regressed longitudinal eGFR value on baseline eGFR level categories and adjusted for fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. eGFR estimated glomerular filtration rate, BL baseline, W week, PTW post-treatment week. c Predicted eGFR change from baseline until post-treatment week 12 among treated patients with CKD stage 4 or 5 at baseline. Chronic kidney disease stages were defined based on guidelines as stage 1 [signs of kidney damage but normal or elevated (eGFR ≥90)], stage 2 (eGFR 60–89), stage 3 (eGFR 30–59), stage 4 (eGFR 15–29) or stage 5 (eGFR <15 or dialysis dependent). Study conducted on SP3. SP3 comprises all of the HCV-treated population from renal-specific phase 3b trials. All patients in trials were GT1 patients. The graphs depict predicted changes from baseline at individual time points based on longitudinal mixed model regression. The model regressed longitudinal eGFR value on baseline eGFR level categories and adjusted for fibrosis stages, genotype, age, BMI, presence of diabetes, treatment history, viral load and study enrollment. Error bars represent standard errors. eGFR estimated glomerular filtration rate, BL baseline, W week, PTW post-treatment week