Impacto del riesgo de múltiples interacciones farmacológicas en el perfil de eventos adversos de pacientes con hepatitis C tratados con antivirales de acción directa pangenotípicos en España

Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. Original Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain Juan Turnes1, Antonio García-Herola2, Ramón Morillo-Verdugo3, Marinela Méndez4, Cándido Hernández5, Antoni Sicras-Mainar6 1Gastroenterology and Hepatology Department. CHU. Pontevedra. Spain. 2Digestive Medicine Department. Hospital Marina Baixa de Villajoyosa (Alicante). Spain. 3Hospital Pharmacy. Hospital de Valme. AGS Sur de Sevilla. Spain. 4Medical Affairs. Gilead Sciences S.L. Madrid. Spain. 5Global Medical Affairs. Gilead Sciences Europe Ltd. U.K. 6Health Economics and Outcomes Research. Atrys Health. Barcelona. Spain. ABSTRACT Objectives: Direct-acting antivirals (DAAs) share pharmacokinetic pathways with many comedications commonly administered to patients living with chronic hepatitis C virus (HCV) infection (PLWHCV). International guidelines recommend a thorough drug-drug interaction (DDI) risk assessment prior to starting DAA therapy and before starting comedications. This study aims to evaluate the impact of potential multiple DDIs in the real-life adverse event (AE) profile of PLWHCV treated with DAAs. Material and method: This is a retrospective, observational study using electronic medical records. Patients included were PLWHCV and were treated with either the protease inhibitor (PI) free DAA sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/ pibrentasvir (GLE/PIB) between 2017 and 2020. Potential (single and multiple) DDIs were identified using the Liverpool HEP Interaction Checker. AEs potentially associated to DDIs were identified during DAA treatment period. Results: 1620 patients with DAA prescriptions (SOF/VEL or GLE/PIB) were included. Of these, 123 were predicted to have multiple DDIs (multi-DDI). About 10% (123/1256) of the patients receiving ≥2 comedications were at risk of multi-DDI with DAA. Most comedication-associated AEs were recorded in this multi-DDI population (88.9%, 16/18), meaning that 13% (16/123) of the multi-DDI population suffered AEs. According to DAA regimen, more comedication-associated AEs were reported in GLE/PIB-treated as compared with SOF/VEL-treated patients (18.3% [13/71] vs 5.8% [3/52] p<0.05). These AEs were mainly reported by primary care physicians (62.5%). Discussion: PLWHCV predicted to have multiple DDIs are at high risk of AEs. Moreover, fewer comedication-associated AEs were identified with the PI-free DAA SOF/VEL as compared with GLE/PIB. Key words: adverse events; clinical pharmacology; drug combinations; hepatology; polypharmacy; virology. Text received: 11/07/2024 Text accepted: 16/10/2024 Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 98 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. INTRODUCTION Chronic hepatitis C virus (HCV) infection is a major public health issue which affects an estimated 58 million people globally1. The development of pangenotypic direct-acting antiviral agents (DAAs) has brought about a major advance in HCV treatment, with sustained virological response rates ≥ 95%2. As well as being highly effective, these agents are well tolerated, with few restrictions on their use. This favourable efficacy and safety profile is reflected in simplified treatment regimens recommended by the European Association for the Study of the Liver (EASL) to facilitate rapid treatment algorithms. However, the number of patients with comorbidities and associated polypharmacy has increased3,4. In patients with polypharmacy there is an increased risk of potential drug-drug interactions (DDIs), and an association between adverse drug reactions, which represent a public health issue, and DDIs have been recently reported5. Therefore, it is essential to consider patient comorbidities, comedication and polypharmacy of PLWHCV for potential DDIs when choosing a DAA6. Antiviral treatments for HCV comprise three families of DAAs, each acting in different phases of the HCV life cycle7. DAAs can act as substrate, inhibitor and/or inducer of drug transporters and metabolising CYP enzymes, meaning that they can lead to DDIs with the concomitant medications administered to the patient7-9. DAAs share pharmacokinetic pathways with comedications commonly administered to PLWHCV8–10, such as cardiovascular drugs, particularly statins and anti-hypertensives, neuropsychiatric drugs and proton pump inhibitors (PPIs). These drugs have a high potential for DDIs that either result in an increased exposure of the patient to comedication or DAA, with potential consequent drug toxicity, or a decrease in concentration of either DAA or comedication, and therefore reduced efficacy8,9. Moreover, polymedication increases the chance of multiple DDIs11. DDIs can be avoided by careful patient management. Awareness of DDIs can help avert potential drug toxicities and is essential to ensure optimal treatment outcomes10. Thanks to progress in HCV antiviral therapy, modern DAAs carry a significantly lower risk of DDIs than first-generation DAAs such as boceprevir and telaprevir12. Despite this, the prevalence of DDIs remains stable, affecting around 40% of PLWHCV, and attributable to polypharmacy (likely in an aging HCV patient population), or multiple comorbidities associated with HCV infection12,13. Current DDI evaluation with the Hep Interaction Checker developed by the University of Liverpool14 is based on a theoretical analysis of pharmacokinetic pathways shared by DAAs and comedications. However, there is a lack of clinical practice data on the impact of multiple DDIs in hepatitis treatment, including effectiveness and reported adverse events (AEs). Several previous studies have evaluated DDIs by studying pairwise interactions in HCV patients receiving DAAs and another medication3,15–20. However, this does not reflect the polypharmaceutical reality of many PLWHCV. Although a recent Italian study has characterized the polymedication regimens in PLWHCV treated with DAAs11, the association between comedicationassociated AEs and the multi-DDI profile of PLWHCV remains unknown. The aim of the present study was to evaluate for the first time the impact of potential multiple DDIs in the real-life adverse event profile of PLWHCV treated with the two currently widely used antiviral regimens in clinical practice in Spain: sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB). Demographic characteristics, comorbidities, and the real-life safety profile of patients with potential multi-DDIs treated with SOF/VEL or GLE/PIB were analysed. MATERIALS AND METHODS This observational, retrospective study was carried out on a total of 1.81 million patients, and was conducted using electronic medical records (EMR) data from primary care and hospitals in Spain integrated in the BIG-PAC® database18 and supplementary databases of public health services from seven autonomous communities in Spain. Briefly, the BIG-PAC® database contains demographic and clinical data, including comorbidities/comedication, and healthcare resources and costs from EMR of patients. Records are anonymised prior to their inclusion in the database. Patient’s data were analysed one month before treatment initiation, during DAA treatment (8 or 12 weeks) and in the 6-month post-treatment follow-up period. Patient demographics, comorbidities/comedications were identified at the index date (Figure 1) using the BIG-PAC® database. Patient comorbidities were recorded according to the International Classification of Diseases (9th edition) Clinical Modification (ICD- 09-CM) and were characterised based on the Charlson Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 99 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. Note: * Inclusion criteria: (i) active patients defined as ≥2 Electronic Medical Records (EMR) in the database at least 12 months before the index date, (ii) patients with regular monitoring (≥1 EMR during the DAA treatment period), and (iii) patients in the prescription program (≥1 prescription during the 6-month post-treatment follow-up period). Patients who transferred to other centres, were displaced, were out of the area or permanently institutionalized were excluded. DAA refer to SOF/VEL and GLE/PIB. AE, adverse events; DAA, directacting antivirals; DDI, drug-drug interactions; GLE/PIB, glecaprevir/pibrentasvir; SOF/VEL, sofosbuvir/velpatasvir. Figure 1. Study summaries. Study diagram. Observational retrospective study. 01/01/2017 31/12/2019 Treatment period included Individual patient* Follow-up during 8 or 12 weeks (DAA treatment) Baseline period (1 month before DAA treatment initiation) Post follow-up period (6 months after treatment) Analysis of AE potentially associated with DDIs DAA treatment restart Index date: date of treatment (DAA) initiation Analisys of: - Demographic characteristics - Comorbidities - Concomitant medications - Potential DDIs comorbidity index21. Patient comedication data were retrieved from prescription records (according to medical practice) and categorised under the Anatomical Classification (ATC) System22. Confidentiality of the EMR (anonymous and dissociated) was respected in accordance with the European General Data Protection Regulation (2016/679) and Organic Law (3/2018) on Data Protection and Guarantee of Digital Rights. This study was approved by the Clinical Research Ethics Committee of the Unió Catalana Balears de Hospitals de Barcelona, Spain (reference:15/49) and was carried out in compliance with the Helsinki Declaration of 1964, and its amendments. Patient consent was not obtained, as Spanish legislation excludes existing data aggregated for analysis. Patients included in the study were ≥18 years old and initiated DAA treatment with SOF/VEL or GLE/PIB (index date was the date of initiation) between 2017-2020. Patients were required to meet the following criteria: (i) active patients defined as ≥2 EMR in the database at least 12 months before the index date, (ii) patients with regular monitoring (≥1 EMR during the DAA treatment period), and (iii) patients in the prescription programme (≥1prescription during the 6-month post-treatment follow-up period). Patients who transferred to other centres, were displaced, out of the area or permanently institutionalised were excluded. There were no missing values in any patients; absence of treatment/ studied characteristic was assumed as the patient not having that treatment/characteristic. DDI analysis Potential DDIs between comedication taken by patients and either SOF/VEL or GLE/PIB treatment were identified at the index date using the University of Liverpool’s HEP Drug Interaction Checker (accessed November 2020)14. The University of Liverpool’s HEP Drug Interaction Checker is a free resource from the University of Liverpool used to check drug-drug interactions; its use to assess DDI interactions prior to starting new DAA therapy is recommended by the European Association for the Study of the Liver (EASL)6, the American Association Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 100 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. for the Study of Liver Diseases and the Infectious Disease Society of America (AASLD-IDSA)23,24 and the National Prisons Hepatitis Network (NPHN)25. Identified DDIs were recorded with the drug therapeutic group, the pharmacokinetic effect and the strength of the interaction as assigned in the Hep Drug Interaction Checker. Interactions were categorised as: • contraindications (drugs that should not be coadministered). Figure 2. Study summaries. Study diagram and patient populations stratified by comedication use and risk of DDIs. Overall population n=1620 All patients, independently of DDIs with: SOF/VEL (n=730) o GLE/PIB (n=890) DDI population n=444 (27.4%)* Patients prescribed a comedication with a potential DDI with either: SOF/VEL, n=231 (31.6%)* or GLE/PIB, n=213 (23.9%)* Multi-DDI population n=123 (9.8%)† Patients prescribed ≥2 comedications with ≥2 DDIs with either: SOF/VEL, n=52 (8.5%)† or GLE/PIB, n=71 (11.1%)† Patients prescribed with ≥2 comedications n=1256 (77.5%) with either: SOF/VEL, n=615 (84.2%)* or GLE/PIB, n=641 (72.0%)* SOF/VEL 1 comedication with DDI with SOF/VEL ≥2 comedications with DDI with SOF/VEL GLE/PIB 1 comedication with DDI with GLE/PIB ≥2 comedications with DDI with GLE/PIB Comedication Note: White dots represent SOF/VEL patients, and black dots, GLE/PIB patients. Grey dots symbolize the patients with potential DDI. One grey dot represents single potential DDI, two grey dots refer to multi-DDIs population; *Percentage relative to overall population; †Percentage relative to ≥2 comedication population. DDI, drug–drug interaction; GLE/PIB, glecaprevir/pibrentasvir; SOF/VEL, sofosbuvir/velpatasvir. Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 101 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. • potential or clinically significant interaction (requires additional monitoring, alteration of drug dosage or timing of administration). • weak interaction (additional action is unlikely). • no interaction expected. The effects of the DDI were categorised as: • an increase in plasma concentration of comedication. • an increase in plasma concentration of DAAs. • a decrease in plasma concentration of DAAs. Multiple DDI patients were those receiving ≥2comedications with potential DDIs with the DAA. AEs potentially connected to DDIs identified by the ICD-9-CM codes E930–E949 (identifies drugs, medicinal and biological substances causing adverse effects in therapeutic use) and 990-995 (identifies other unspecified effects of external causes) during the DAA treatment period were recorded together with the drug classification associated with these AEs. We also analysed the actions taken by physicians during the DAA treatment regarding comedication with potential multi-DDIs associated with AEs, the reporting medical specialty. Any modifications to treatment regimens, including discontinuation, dose decrease or change of comedications during DAA treatment, were recorded. Any requirement for a new DAA treatment within 6 months of the end of SOF/VEL or GLE/PIB treatment was considered as an indirect indicator of lack of effectiveness of the DAA regimen. Statistical analysis Data collected from the BIG-PAC® database were validated by Structured Query Language (SQL) commands and reviewed using an exploratory analysis to ensure quality and consistency18. A descriptive univariate statistical analysis was performed, and absolute and relative frequencies were calculated for qualitative data. Quantitative data were expressed using means, standard deviations (SD), medians and interquartile ranges (IQR). Bi-variant statistical analyses were carried out using the analysis of variance (ANOVA) and Chi-squared tests for independent groups. The duration of the DAA treatment was estimated in SOF/VEL and GLE/PIB treated patients. The statistical software IBM/SPSS was used for analyses. Values of p<0.05 were considered statistically significant. Patient and Public Involvement It was not appropriate or possible to involve patients or the public in the design, conduct, reporting or dissemination plans of our research. RESULTS Identification of the overall population and comedications prescribed A total of 1620 patients who met the selection criteria were included in the study (overall population), 730 patients were treated with SOF/ VEL and 890 patients with GLE/PIB (Figure 2). The demographic characteristics of the overall population are summarized in Table 1. Each of the 1620 patients were prescribed ≥1 comedication(s). In fact, 77.5% (1256/1620) were prescribed ≥2 comedications, 84.2% (615/730) with SOF/VEL treatment and 72.0% (641/890) with GLE/ PIB treatment (Figure 2). A higher mean number of comedications/ patient were prescribed in the SOF/ VEL treatment group compared with the GLE/PIB treatment group (3.8 vs 2.3, p<0.001) (Table 1). The most frequent comedication classes were related to the central nervous system (CNS, 35.8%), the alimentary tract and metabolism (24.1%), and the cardiovascular system (14.2%) (Table 1). Identification of patients with potential DDIs and multi-DDIs The Hep Drug Interaction Checker identified the comedications with potential DDIs with DAA regimens14. A total of 444 out of the 1620 patients (27.4%) were prescribed ≥1 comedication with a potential DDI with their DAA treatment, 231 in the group of patients treated with SOF/VEL and 213 in the GLE/PIB treatment group. These patients comprised the DDI population (Figure 2). Of the 1256 overall population patients prescribed ≥2 comedications, 123 patients were predicted to have multiple DDIs, defining the multi-DDI population (patients with ≥2 comedications with ≥2 DDIs with DAAs). Therefore, about 10% (123/1256) of the overall population prescribed ≥2 comedications with ≥2 DDIs are at risk of multi-DDI. The percentage of patients at risk of multi-DDI referring to the overall population was 7.6% (123/1620). Of 123 patients with multi-DDIs, 52 were in the SOF/VEL- treatment group and 71 in the GLE/PIB-treatment one (Figure2). Adverse events in the overall population In the overall population, 18 AEs associated with comedications were identified, each in a different patient, (14 vs 4 [p<0.05]) with GLE/PIB and SOF/ VEL, respectively) (Table 1; Figure 3A). All AEs reported were associated with the most prescribed Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 102 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. Table 1. Demographic and clinical characteristics, comedication and DDI profile, most common comedications, AEs by DAA, and actions taken during DAA treatment in the overall population. Overall population SOF/VEL (n = 730; 45.1%) GLE/PIB (n = 890; 54.9%) Total (N = 1,620; 100%) P value Demographic characteristics Median age, years (IQR) 55 (49-61) 53 (46-59) 54 (48-60) Male, n (%) 451 (61.8) 532 (59.8) 983 (60.7) 0.411 Clinical characteristics Comorbidities associated with CHC Arterial hypertension, n (%) 168 (23.0) 181 (20.3) 349 (21.5) 0.192 Diabetes, n (%) 102 (14.0) 100 (11.2) 202 (12.5) 0.097 Heart failure, n (%) 23 (3.2) 19 (2.1) 42 (2.6) 0.089 Renal insufficiency, n (%) 31 (4.2) 28 (3.1) 59 (3.6) 0.239 HIV, n (%) 33 (4.5) 28 (3.1) 61 (3.8) 0.148 General comorbidity Charlson index, mean (SD) 1.1 (1.7) 0.7 (1.3) 0.9 (1.5) <0.001 0, n (%) 347 (47.5) 528 (59.3) 875 (54.0) 1, n (%) 214 (29.3) 227 (25.5) 441 (27.2) 2, n (%) 75 (10.3) 62 (7.0) 441 (8.5) ≥3, n (%) 94 (12.9) 73 (8.2) 167 (10.3) <0.001 Disease severity Hepatic cirrhosis, n (%) 57 (7.8) 41 (4.6) 98 (6.0) 0.007 FIB-4 score, n (%) F0–F1, <1.45 points 299 (41.0) 425 (47.8) 724 (44.7) F2, 1.45–3.25 points 155 (21.2) 216 (24.3) 371 (22.9) F3–F4, >3.25 points 276 (37.8) 249 (28.0) 525 (32.4) <0.001 Other features Mean time since diagnosis, years (SD) 3.8 (4.1) 3.7 (3.9) 3.7 (4) 0.474 Mean BMI, kg/m2 (SD) 28.3 (4.1) 28 (3.8) 28.1 (4) 0.105 Comedication and DDI profile Total prescribed comedications, n 2,790 2,031 4,821 Prescribed comedications per patient (mean, SD) 3.8 (1.1) 2.3 (1.0) 3.0 (1.1) <0.001 Medicines administered with potential DDI, n (%)* 293 (10.5) 326 (16.1) 619 (12.8) Concomitant medications Number of active ingredients prescribed (n, %) 2,790 (57.9) 2,031(42.1) 4,821 (100) Active ingredients prescribed / patient (mean, SD) 3.8 (1.1) 2.3 (1.0) 3.0 (1.1) <0.001 ATC Therapeutic group (n, %) † A Digestive system and metabolism‡ 680 (24.4) 480 (23.6) 1.160 (24.1) B Blood and hematopoietic organs 110 (3.9) 72 (3.5) 181 (3.8) C Cardiovascular system‡ 408 (14.6) 277 (13.6) 685 (14.2) D Dermatological drugs 78 (2.8) 59 (2.9) 136 (2.8) G Genitourinary system 42 (1.5) 40 (2.0) 82 (1.7) H Systemic hormonal preparations 34 (1.2) 40 (2.0) 74 (1.5) J Anti-infectives for systemic use 48 (1.7) 23 (1.1) 71 (1.5) L Antineoplastics and immunomodulators 13 (0.5) 14 (0.7) 27 (0.6) M Musculoskeletal system 136 (4.9) 149 (7.4) 285 (5.9) N Nervous system‡ 1,032 (37.0) 692 (34.1) 1,724 (35.8) P Antiparasitic products 4 (0.1) 10 (0.5) 14 (0.3) R Respiratory system 163 (5.8) 132 (6.5) 295 (6.1) S Sense organs 44 (1.6) 37 (1.8) 81 (1.7) V Various 1 (0.0) 7 (0.3) 8 (0.2) <0.001 (continued) Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 103 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. Table 1. Demographic and clinical characteristics, comedication and DDI profile, most common comedications, AEs by DAA, and actions taken during DAA treatment in the overall population (continuation). Overall population SOF/VEL (n = 730; 45.1%) GLE/PIB (n = 890; 54.9%) Total (N = 1,620; 100%) P value Note. *Percentage relative to total prescribed comedications; †percentage relative to the total of active ingredients prescribed; ‡these therapeutic groups were the most prescribed; §n indicates the number of patients with AEs, N, the number of patients receiving the specific comedication (with DDI with any of the DAA regimens) /comedication class linked to AEs, the percentage is relative to patients treated with the comedication/comedication class with AEs; ||Percentage relative to the overall population; ¶AEs associated with comedications were reported by primary care physicians (61.1% [10/18]); **AEs associated with these comedications were reported by gastroenterologists (38.9% [7/18]). AE, adverse event; BMI, body mass index; CHC, chronic hepatitis C; DAA, direct-acting antiviral; DDI, drug–drug interaction; FIB-4, Fibrosis-4 Index for liver fibrosis; GLE/PIB, glecaprevir/pibrentasvir; HIV, human immunodeficiency virus; IQR, interquartile range; multi- DDI, multi drug-drug interaction; SD, standard deviation; SOF/VEL, sofosbuvir/velpatasvir. AEs by DAA treatment group and most common comedication Comedication group with AE Nervous system, n 0 4 Antipsychotics, n (%; n/N)§ 0 (0; 0/90) 2 (12.5; 2/16) (extrapyramidal, sedation) Fentanyl, n (%; n/N)§ 0 (0; 0/9) 1 (33.3; 1/3) (digestive) Oxcarbazepine, n (%; n/N)§ 0 (0; 0/4) 1 (33.3; 1/3) (digestive) Cardiovascular, n 4 9 Lipid-lowering drugs, n (%; n/N)§ 2 (5.0; 2/40) (myalgia/myopathy) 6 (17.1; 6/35) [myalgia/myopathy] <0.001 Enalapril, n (%; n/N)§ 1 (1.9; 1/52) (respiratory) 2 (6.1; 2/33) (respiratory) <0.05 Carvedilol, n (%; n/N)§ 1 (16.6; 1/6) (bradycardia) 1 (12.5; 1/8) (bradycardia) Alimentary, n 0 1 Omeprazole, n (%; n/N)§ 0 (0; 0/119) 1 (1.1; 1/95) (digestive) Total, n (%; n/total)|| 4 (0.5; 4/730) 14 (1.6; 14/890) Actions taken during DAA treatment for comedications with AE-associated comedications with potential DDIs AE 4 14 Clinical actions to manage DDI (number of patients, AE-associated comedication) Clinical monitoring 1, Simvastatin¶ 1, atorvastatin¶ Monitoring ECG (Electrocardiogram) 0 1, carvedilol¶ Discontinuation (DAA) 1, Carvedilol¶** 3, quetiapine**, atorvastatin (2)** Discontinuation (co-medication) 1, Atorvastatin¶ 2, oxcarbazepine¶, simvastatin** Dose Reduction 1, Enalapril¶ 5, pravastatin¶, paliperidone**, enalapril (2)¶, simvastatin¶ Switch 0 2, fentanyl**, omeprazole¶ Total 4 14 Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 104 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. comedication therapeutic groups, cardiovascular, CNS and alimentary comedications. For cardiovascular system comedications, most AE were associated with lipid-lowering drugs, with a greater number associated with atorvastatin or simvastatin (contraindicated for GLE/PIB) in the GLE/PIB group as compared to SOF/VEL treated patients (17.1% [6/35] vs 5% [2/40], respectively, p<0.001) (Table 1). No AEs were reported for CNS comedications in SOF/VEL-treated patients and no action from the physician was required. However, AEs were reported within the GLE/PIB-treated group involving antipsychotics, fentanyl, and oxcarbazepine (Table 1). Out of the two reported AEs associated with antipsychotics: one was related to paliperidone (sedation), requiring a dose reduction of the comedication and another with quetiapine (extrapyramidal syndrome), resulting in DAA discontinuation (Table 1). Adverse events associated with multiple potential DDIs Analysis of patients with recorded AEs showed that 88.9% (16/18) had a multi-DDI profile, therefore, 13.0% of the patients in the multi-DDI population (16/123) had AEs. Around three times more AEs were reported in GLE/PIB-treated patients as compared to SOF/VEL-treated patients (18.3% [13/71]) vs 5.8% [3/52] p<0.05) (Table 2; Figure 3B). Most multi- DDI patients with reported AEs (94% [15/16]) were prescribed ≥1 comedication with a potential DDI predicted to increase comedication exposure. Moreover, two thirds of the multi-DDI patients who reported AEs (62.5% [10/16]) were prescribed ≥2 comedications, all with a potential DDI predicted to increase comedication (Table 2). These AEs were mainly reported by primary care physicians (62.5%) and to a lesser extent by specialists that prescribed the DAA (37.5%) (Table 3). Resource utilization and medical actions taken for AE management in the multi-DDI population All AE required medical actions or resource utilizations. The most frequent actions were discontinuation (of comedication or DAA) and dose reduction of comedication, and these were more frequent in the GLE/PIB-treated group, as this group presented almost three times more AE than the SOF/VEL-treated group. Three DAA discontinuations were reported in GLE/PIB-treated patients, two associated with atorvastatin, and one with quetiapine; one was reported in the SOF/VEL treated group associated with carvedilol. Regarding dose reductions, all were reported in the GLE/PIB- treated group associated with paliperidone, enalapril and simvastatin (Table 3). Demographic characteristics and comorbidities in the multi-DDI population DDA treatment groups (SOF/VEL vs GLE/ PIB) in the multi-DDI population were compared by analysing the following: demographic variables, general comorbidity (estimated by the Charlson index), and hepatic fibrosis prediction according to the FIB-4 (Fibrosis-4 Index for liver fibrosis) score. In the multi-DDI population, 52 patients (median age, 59years; 57.7% male) were treated with SOF/VEL, and 71 patients (median age, 61 years; 53.5% male) were treated with GLE/PIB. Comorbidities were balanced between both treatment groups (Table3). DAA effectiveness and DDIs in the overall population and multi-DDI population DAA treatment effectiveness was assessed indirectly by recording new DAA regimens started within the 6 months following the end of the SOF/ VEL or GLE/PIB treatment (these was designated as a treatment restart). In total, 17 DAA restarts were recorded in 1% (17/1620) of the overall population; 1% (7/730) of the SOF/VEL-treated patients and 1% (10/890) of the GLE/PIB-treated patients (Table 4). Of the SOF/VEL-treated patients with DAA restarts, 5/7 patients had a risk of ≥1 DDI linked to decreased exposure to DAA. 10/10 of the GLE/PIB- treated patients with recorded DAA restarts had at least one potential DDI linked to decreased plasma concentration to DAA (Table 4). Regarding multi-DDI population, 9.8% (12/123) did not achieve effectiveness and had to restart with a new DAA within 6 months after completing DAA treatment: 9.9% (7/71) for GLE/PIB-treated and 9.6% (5/52) of SOF/VEL-treated patients. Of these, 91.7% (11/12) were multi-DDI patients with at least one predicted DDI decreasing DAA concentration (Table 4). DISCUSSION The development of effective, well-tolerated pangenotypic DAAs has allowed a wide population of PLWHCV to be considered for treatment. As the population eligible for therapy broadens, there is an increasing need to understand the potential Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 105 Juan Turnes, Antonio García-Herola, Ramón Morillo-Verdugo, Marinela Méndez, Cándido Hernández, Antoni Sicras-Mainar. Impact of potential multiple drug-drug interactions on the adverse event profile of patients with hepatitis C treated with pangenotypic direct-acting antivirals in Spain. Table 2. Reported AEs associated with comedications in SOV/VEL and GLE/PIB treated patients with a multi-DDI profile. DAA* Comedication group associated with AE† AE and comedication associated‡ % AE by therapeutic group (n/N)§ Comedications by potential DDI outcome|| Nº of patients with AEs¶ ↑ Comedication ↓ DAA ↑ DAA SOF/ VEL (n = 52) Cardiovascular (n = 24) Myalgia/myopathy (atorvastatin) 12.5% (3/24) Atorvastatin Carvedilol** Omeprazole 1 Myalgia/myopathy (simvastatin) Simvastatin Silodosin Omeprazole 1 Bradycardia (carvedilol) Carvedilol** Metamizole Omeprazole 1 GLE/ PIB (n = 71) Cardiovascular (n = 43) Myalgia/myopathy (atorvastatin) 18.6% (8/43) Atorvastatin Quetiapine Omeprazole 1 Myalgia/myopathy (simvastatin) Simvastatin Rabeprazole Candesartan 1 Myalgia/myopathy (atorvastatin) Atorvastatin Enalapril Dulaglutide Omeprazole 1 Myalgia/myopathy (atorvastatin) Atorvastatin Carvedilol** Repaglinide Tacrolimus Ranitidine 1 Myalgia/myopathy (simvastatin) Simvastatin Fentanyl Quetiapine Tacrolimus Metamizole Omeprazole 1 Bradycardia (carvedilol) Carvedilol** Amiodarone Liraglutide 1 Respiratory (enalapril) Atorvastatin Enalapril Metamizole Omeprazole 1 Respiratory (enalapril) Enalapril Metamizole 1 Nervous system (n = 29) Digestive (oxcarbazepine) 13.8% (4/29) Oxcarbazepine Omeprazole 1 Extrapyramidal (quetiapine) Carvedilol** Quetiapine 1 Sedation (paliperidone) Paliperidone Pantoprazole 1 Digestive (fentanyl) Fentanyl Bilastine Tacrolimus Omeprazole Sevelamer 1 Alimentary (n = 58) Digestive (omeprazole) 1.7% (1/58) Olmesartan Metamizole Omeprazole 1 Strength of interaction Contraindicated Significant Weak Total 16 Note. *Patients with multi-DDI profile treated with each DAA regimen (SOF/VEL or GLE/PIB). †Patients treated with comedications associated with an AE and stratified by comedication group (cardiovascular, nervous system or alimentary). The total number of patients within each therapeutic comedication group is higher than the total number of multi-DDI patients as patients are prescribed comedications from different therapeutic groups. ‡Comedication associated with an AE type; §Percentage of AEs by therapeutic group resulting from the ratio between n (the number of patients with AEs according to therapeutic classification), and N (the number of multi-DDI patients prescribed at least one comedication with a potential DDI with DAA and associated with AEs according to comedication therapeutic classification). ||Comedications associated with an AE in patients at risk of multiple DDIs are coloured according to strength of DDI. The potential outcome is defined as an increase in comedication (↑ comedication, associated with a possible impact on safety), a decrease in DAA (↓ DAA, possible impact on efficacy), and/or increase in DAA (↑ DAA, associated with a possible impact on safety); ¶Number of multi-DDI patients with AEs associated with comedication according to comedication therapeutic classification (cardiovascular, nervous system or alimentary); **Carvedilol is also predicted to increase DAA exposure. No AEs were reported in SOF/VEL-treated patients with potential multiple DDIs within the nervous system (0/24) or alimentary tract and metabolism (0/49) therapeutic classifications. AE, adverse event; DAA, direct-acting antiviral; DDI, drug–drug interaction; GLE/PIB, glecaprevir/pibrentasvir; SOF/VEL, sofosbuvir/ velpatasvir. Rev Esp Sanid Penit. 2024;26(3):98-112 10.18176/resp.00095 106