Editor: Paul Kwo, Stanford University, CA, USA
Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population.
The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan.
Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10).
HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.
HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with current DAAs. In this study, 169 patients seropositive for HCV RNA with a mean age of 65.6 years were enrolled. All patients received at least one comedication. The median number of comedications per person was 6. The most common comedication classes were ESRD-associated medications, cardiovascular drugs and antidiabetic drugs. ESRD-associated medications were excluded from DDI analysis. The potential DDIs between comedications and DAAs differed, with the most potential DDIs occurring with SOF/VEL/VOX and the fewest potential DDIs occurring with EBR/GZR. Among the pangenotypic regimens currently recommended for DAA-naive patients, SOF/VEL had the lowest rate of DDIs.
Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver cirrhosis, hepatocellular carcinoma (HCC) and liver-related death. The global prevalence of chronic HCV infections in 2015 was estimated to be 1.0%, corresponding to 71.1 million people [
Taiwan has the highest prevalence and annual incidence of end-stage renal disease (ESRD) worldwide [
Direct‐acting antivirals (DAAs) have become the first‐line treatment for HCV infection [
All procedures performed in studies involving human participants were in accordance with the ethical standards of Institutional Review Board of Kaohsiung Medical University Chung-Ho Memorial Hospital (IRB No.: KMUHIRB-E(I)-20180325) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
This observational study recruited chronic HCV-infected patients with ESRD on hemodialysis from 23 hemodialysis centers of the Formosan Coalition for the Study of Liver Disease in Chronic Kidney Disease (FORMOSA-LIKE group) in Taiwan between January 2019 and November 2019 [
All patients were interviewed, assessed for their anthropomorphic measurements, and had their medical records reviewed at enrollment to capture patient demographics, comorbidities and concurrent medications. HCV RNA and genotypes were measured using a real-time PCR assay (RealTime HCV; Abbott Molecular, Des Plaines, IL, USA) [
Patient demographics and clinical characteristics were summarized using the mean±standard deviation, median (interquartiles), and number (percentage) when appropriate. The comorbidity analysis results were described with numbers and percentages. Similarly, the DDI analysis results were summarized with numbers and percentages. All tests were two-sided. All analyses were performed with the SPSS version 19.0 statistical package (SPSS, Inc., Chicago, IL, USA).
Of 2,015 patients on hemodialysis, 169 patients with HCV viremia were enrolled in the study to analyze comedications and predict their DDIs with DAAs. The clinical characteristics of the patients are listed in
All patients received at least one comedication, with a median comedication number of 6 (IQR, 3–9) (
A total of 158 patients who received medications other than ESRD-associated medications were included in the DDI analysis.
Next, we analyzed the frequency of potential DDIs of each comedication, other than ESRD-associated medications, with each possible DAA regimen (
Then, we evaluated the number of comedications with red-category DDIs in each class (
To the best of our knowledge, this is the first real‐world study to investigate comedications and potential DDIs with DAAs in hepatitis C patients with ESRD on hemodialysis. In the current study, we demonstrated that 93.5% of hepatitis C patients on hemodialysis had at least one comedication other than ESRD-associated medications. The chance of having a contraindicated DDI was much higher, at 19–25.3%, if the patients were commencing SOF/VEL/VOX or GLE/PIB than if the patients were taking EBR/GZR, SOF/LDV, or SOF/VEL, at only 1.3–6.3%. Of the 755 comedications other than ESRD-associated medications in 158 patients, lipid-lowering agents (n=62) were the most common comedication class with contraindicated DDIs to all DAA regimens, and cardiovascular agents (n=210) were the most common comedication class with potential clinically significant DDIs to all DAA regimens.
The present study included an elderly population with a mean age of 65.6 years, which is similar to the general population of HCV patients in Taiwan and Japan [
In the current study, we assessed the potential DDIs of five widely used DAA regimens, including sofosbuvir-based regimens. Sofosbuvir-based regimens were not recommended for patients with an eGFR <30 mL/min or those on dialysis because of concerns of increased plasma concentrations of the primary sofosbuvir metabolite GS-331007 and unvalidated drug safety and efficacy. Recently, several studies have demonstrated the safety and efficacy of these drugs for this special population [
The proportion of patients with at least one potential red-category DDI was higher among those taking SOF/VEL/VOX (25.3%) or GLE/PIB (19.0%) but was much lower among those taking EBR/GZR (1.3%), SOF/LDV (6.3%) or SOF/VEL (5.7%). We also analyzed the prevalence of potential DDIs for each possible DAA regimen. SOF/VEL/VOX had the highest proportion of red-category DDIs and orange-category DDIs, followed by GLE/PIB, while EBR/GZR had the lowest proportion of red-category DDIs and orange-category DDIs among the five DAA regimens. The high prevalence of significant DDIs with SOF/VEL/VOX may be ascribed to the more components of the HCV nonstructural protein 3/4A (NS3/4A) inhibitor (voxilaprevir), NS5B inhibitor (sofosbuvir) and NS5A inhibitor (velpatasvir). However, SOF/VEL/VOX is mainly recommended for patients who fail prior DAA therapy [
The distribution of each drug class with potential contraindicated DDIs was also assessed. The potential red-category DDIs were mainly associated between cardiovascular drugs and SOF/LDV and SOF/VEL, lipid‐lowering agents and SOF/VEL/VOX and GLE/PIB, and CNS agents and EBR/GZR. Amiodarone was the only cardiovascular drug with contraindicated DDIs for sofosbuvir-based DAAs, given the risk of symptomatic bradycardia [
For certain comedications with red/orange-category DDIs, such as lipid-lowering agents, antihypertensive medications, anti-diabetic drugs, and acid-reducing agents (e.g., proton pump inhibitors [PPIs], H2 receptor antagonists, and antacids), it can be relatively straightforward to switch to appropriate alternative regimens or discontinue the treatment given the short duration of DAA therapies [
There are several limitations to our study. First, our study investigated potential DDIs between DAAs and comedications, rather than actual DDIs in clinical practice. This methodology may limit the analyses of the efficacy of DAA treatments in this special population. However, previous reports have demonstrated that DAAs are effective for HCV patients with ESRD [
In conclusion, hepatitis C patients with ESRD on hemodialysis had a high prevalence of comedication use. The potential DDIs between these comedications and DAA regimens differed, with the most potential DDIs occurring with SOF/VEL/VOX and the fewest potential DDIs occurring with EBR/GZR. A careful assessment of the patient’s concurrent medications and a comprehensive evaluation of their potential DDIs with each DAA regimen are essential to selecting the appropriate DAA regimen and optimizing safety and efficacy.
Conception and design: Yi-Wen Chiu, Ming-Lung Yu
Data collection: all authors
Data analysis and interpretation: Po-Yao Hsu, Yi-Wen Chiu, Ming-Lung Yu
Manuscript drafting or critical revising: all authors
All named authors have read and approved the final version of the manuscript
We thank the participation of the members of the Formosan Coalition for the study of Liver Disease in Chronic Kidney Disease (FORMOSA-LIKE group): Dr. Lii-Jia Yang, Kaohsiung Municipal Cijin Hospital; Dr. Ming-Hsing Sung, Hsing-Yi Clinic; Dr. Shih-Pi Lin, Lenity Clinic; Dr. Fei-Ching Li, Yu-Sheng Clinic; Dr. Jheng-Tai Shien, Chung-Ching Clinic; Dr. Chen-Hung Shih, Wu-Fu Clinic; Dr. June-Ming Yang, June-Ming Clinic; Dr. Cheng-Hsueh Lee, Ming-Gang Clinic; Dr. Yi-Cheng Chen, Shih-Chuan Clinic; Dr. Yen-chao Wang, Gang-Shan Clinic; Dr. Meng-Chang Yang, Park Medicines Clinic; Dr. June-Tse Yang, Yung Ho General Hospital; Dr. Pei-Ing Kong, Yong Ding Clinic; Dr. Hsuan-Sheng Chuang, Shun Tai Clinic; Dr. Chi-Chin Wu, Shinkao Hospital; Dr. Shih-Meng Yeh, You Zhen Clinic; Dr. Tung-Chang Chuang, People Clinic; Dr. Ying-Chih Lin, PingTung Hospital and Dr. Jer-Ming Chang, Wen-Hsiung Hospital. The authors thank secretary help from Taiwan Liver Research Foundation (TLRF).
Supplementary material is available at Clinical and Molecular Hepatology website (
Baseline patient laboratory characteristics
Frequency of comedication by classes
Red-category drug-drug interactions between HCV DAAs and comedications
Number of potential orange-category drug-drug interactions (DDIs) in each drug class for each possible direct-acting antiviral (DAA) regimen. SOF, sofosbuvir; LDV, ledipasvir; VEL, velpatasvir; VOX, voxilaprevir; EBR, elbasvir; GZR, grazoprevir; GLE, glecaprevir; PIB, pibrentasvir.
antibodies to hepatitis C virus
central nervous system
cytochrome P450
direct-acting antivirals
drug-drug interactions
elbasvir
estimated glomerular filtration rate
end-stage renal disease
Food and Drug Administration
fibrosis-4
Formosan Coalition for the Study of Liver Disease in Chronic Kidney Disease
glecaprevir
grazoprevir
hepatocellular carcinoma
hepatitis C virus
interquartile
ledipasvir
organic anion transporting polypeptide
pibrentasvir
proton pump inhibitors
sofosbuvir
velpatasvir
voxilaprevir
Proportion of patients with the most severe potential drug-drug interactions (DDIs) for each possible direct-acting antiviral (DAA) regimen (n=158). SOF, sofosbuvir; LDV, ledipasvir; VEL, velpatasvir; VOX, voxilaprevir; EBR, elbasvir; GZR, grazoprevir; GLE, glecaprevir; PIB, pibrentasvir.
Frequency of potential drug-drug interactions (DDIs) of each comedication, other than end-stage renal disease-associated medications, with each possible direct-acting antiviral (DAA) regimen (number of interactions, 755). SOF, sofosbuvir; LDV, ledipasvir; VEL, velpatasvir; VOX, voxilaprevir; EBR, elbasvir; GZR, grazoprevir; GLE, glecaprevir; PIB, pibrentasvir.
Number of potential red-category drug-drug interactions (DDIs) in each drug class for each possible direct-acting antiviral (DAA) regimen. SOF, sofosbuvir; LDV, ledipasvir; VEL, velpatasvir; VOX, voxilaprevir; EBR, elbasvir; GZR, grazoprevir; GLE, glecaprevir; PIB, pibrentasvir.
Therapeutic drug classes of comedication in HCV-viremic patients with ESRD under hemodialysis
End-stage renal disease-associated medications | |
Medications for hyperphosphatemia or secondary hyperparathyroidism (calcium carbamide/calcium carbonate, aluminum hydroxide/aluminum acetate, calcitriol/vitamin D) | |
Medications for anemia (erythropoiesis stimulating agents, iron supplements) | |
Potassium-lowering drug (calcium polystyrene sulfonate) | |
Micronutrient supplements (zinc gluconate/zinc oxide, vitamin supplements, folic acid) | |
Anti-diabetic drugs | |
Lipid‐lowering agents | |
Cardiovascular agents | |
Anti-platelet/anti-coagulant | |
Hypertension/heart failure agents | |
Anti-arrhythmics | |
Gastrointestinal agents | |
Proton pump inhibitors (PPIs) | |
H2 receptor antagonists (H2RAs) | |
Antacid | |
Laxatives | |
Gastroprokinetic agents | |
Diosmectite/dimethylpolysiloxane | |
Central nervous system agents | |
Anti-convulsants | |
Anti-depressants | |
Anti-psychotics/neuroleptics | |
Parkinsonism agents | |
Anti‐microbials | |
Anti-bacterials | |
Anti-virals | |
Anti-fungals | |
Anti-tuberculous drugs | |
Anti-protozoals | |
Hepatitis drugs | |
Immunosuppressants | |
Immunosuppressants | |
Steroids | |
Other agents | |
Anti-histamine | |
Medications for thyroid diseases | |
Medications for lung diseases | |
Medications for hyperplasia of prostate | |
Analgesics | |
Hormone therapy | |
Urate-lowering drugs | |
Liver protectants (silymarin, ursodeoxycholic acid) |
Baseline patient demographic characteristics and clinical features
Variable | Patients with HCV viremia (n=169) |
---|---|
Age (years) | 65.6±9.8 |
<50 | 8 (4.7) |
≥50 and <65 | 66 (39.1) |
≥65 | 95 (56.2) |
Male gender | 87 (51.5) |
Body height (cm) | 160.7±8.3 |
Duration of hemodialysis (years) | 5.8 (3.0, 12.6) |
Body weight after hemodialysis (kg) | 58.5±12.4 |
Major causes of end-stage renal disease | |
Diabetes | 92 (54.4) |
Hypertension | 12 (7.1) |
Focal segmental glomerulosclerosis | 4 (2.4) |
Polycystic kidney disease | 3 (1.8) |
Systemic lupus erythematosus | 2 (1.2) |
Hyperuricemia | 2 (1.2) |
Urinary tract stones | 1 (0.6) |
Renal tuberculosis | 1 (0.6) |
Other chronic glomerulonephritis | 44 (26.0) |
Other chronic interstitial nephritis | 5 (3.0) |
Unknown | 3 (1.8) |
HCV genotype | |
1a | 5 (3.0) |
1b | 71 (42.0) |
2 | 81 (47.9) |
6 | 9 (5.3) |
Mixed | 2 (1.2) |
Unclassified | 1 (0.6) |
Prior treatment experience with IFN-based therapies | 1 (0.6) |
Seropositive for HBsAg | 11 (6.5) |
Values are presented as mean±standard deviation, median (interquartiles), or number (%).
HCV, hepatitis C virus; IFN, interferon; HBsAg, hepatitis B surface antigen.