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Altintas Z, Altintas E. The Impact of Organic Anion-Transporting Polypeptide (OATP) Variants on the Side Effects of Direct-Acting Antivirals in Hepatitis C Patients. Cureus 2025; 17:e82213. [PMID: 40370892 PMCID: PMC12075992 DOI: 10.7759/cureus.82213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Background Organic anion-transporting polypeptides (OATPs) are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. The aim of our study was to determine whether variations in OATP1B1 and OATP1B3 affect the side effects experienced by hepatitis C patients treated with direct-acting antivirals (DAAs). Methods This study included 199 hepatitis C patients treated with DAAs. Ledipasvir/sofosbuvir or ombitasvir/paritaprevir/ritonavir ± dasabuvir and 162 control individuals without hepatitis C. Treatment-related side effects were recorded. The OATP1B1 gene variations c.388A>G and c.521T>C and the OATP1B3 gene variations c.334T>G and c.699G>A were analyzed via the polymerase chain reaction-restriction fragment length polymorphism method. Allele/genotype combinations of OATP1B1 and OATP1B3 haplotypes were evaluated. Results Side effects were observed in 53 (26.6%) of 199 hepatitis C patients. There were skin mucosal lesions in 19 patients (36%), fatigue in 18 patients (34%), pruritus in 11 patients (20.5%), and other in five patients (9.5%). There was a significant relationship between the c.334T>G variant and side effects (p = 0.030). The frequency distribution of the c.334T>G variant was in Hardy-Weinberg equilibrium. The frequencies of the patient group and the control group were 65.3% and 63%, respectively. We found a significant difference between the patient and control groups in terms of the haplotype ratios of c.388A>G and c.521T>C (p = 0.036). Conclusions We found a significant relationship between the c.334T>G variant in OATP1B3 and DAA-related side effects in hepatitis C patients.
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Affiliation(s)
- Zuhal Altintas
- Medical Genetics, Faculty of Medicine, Mersin University, Mersin, TUR
| | - Engin Altintas
- Gastroenterology and Hepatology, Faculty of Medicine, Mersin University, Mersin, TUR
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Fagiuoli S, Toniutto P, Coppola N, Ancona DD, Andretta M, Bartolini F, Ferrante F, Lupi A, Palcic S, Rizzi FV, Re D, Alvarez Nieto G, Hernandez C, Frigerio F, Perrone V, Degli Esposti L, Mangia A. Italian Real-World Analysis of the Impact of Polypharmacy and Aging on the Risk of Multiple Drug-Drug Interactions (DDIs) in HCV Patients Treated with Pangenotypic Direct-Acting Antivirals (pDAA). Ther Clin Risk Manag 2023; 19:57-65. [PMID: 36699017 PMCID: PMC9868280 DOI: 10.2147/tcrm.s394467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/29/2022] [Indexed: 01/19/2023] Open
Abstract
Purpose The study aims at investigating the impact of polymedication and aging in the prevalence of multiple drug-drug interactions (DDIs) on HCV patients treated with sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). Patients and Methods This is a retrospective analysis based on administrative data covering around 6.9 million individuals. Patients treated with SOF/VEL or GLE/PIB over November 2017-March 2020 were included. Index date corresponded to SOF/VEL or GLE/PIB first prescription during such period; patients were followed up for treatment duration. Analyses were then focused on patients with ≥2 comedications at risk of multiple DDIs. The severity and the effect of multiple DDI were identified using the Liverpool University tool. Results A total of 2057 patients with SOF/VEL and 2128 with GLE/PIB were selected. Mean age of SOF/VEL patients was 58.5 years, higher than GLE/PIB ones (52.5 years) (p < 0.001), and patients >50 years were more present in SOF/VEL vs GLE/PIB cohorts: 72% vs 58%, (p < 0.001). Most prescribed co-medications were cardiovascular, alimentary and nervous system drugs. Proportion of patients with ≥2 comedications was higher in SOF/VEL compared to GLE/PIB cohort (56.5% vs 32.3%, p < 0.001). Those at high-risk of multiple DDIs accounted for 11.6% (N = 135) of SOF/VEL and 19.6% (N = 135) of GLE/PIB (p < 0.001) patients with ≥2 comedications. Among them, the potential effect of DDI was a decrease of DAA serum levels (11% of SOF/VEL and GLE/PIB patients) and an increased concentration of comedication serum levels (14% of SOF/VEL and 42% of GLE/PIB patients). Conclusion This real-world analysis provided a thorough characterization on the burden of polymedication regimens in HCV patients treated with SOF/VEL or GLE/PIB that expose such patients to an increased risk of DDIs. In our sample population, SOF/VEL regimen was more frequently detected on elderly patients and on those with ≥2 comedications at risk of multi-DDI, ie, among patients characterized by higher rates of comorbidities and polypharmacy.
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Affiliation(s)
- Stefano Fagiuoli
- Department of Medicine and Surgery, University of Milan Bicocca & Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Ospedaliero Universitaria, Udine, Italy
| | - Nicola Coppola
- Infectious Diseases Unit, University of Campania L. Vanvitelli, Naples, Italy
| | | | - Margherita Andretta
- UOC Assistenza Farmaceutica Territoriale, Azienda Ulss 8 Berica, Vicenza, Italy
| | | | - Fulvio Ferrante
- Dipartimento Diagnostica Ed Assistenza Farmaceutica – ASL Frosinone, Frosinone, Italy
| | | | - Stefano Palcic
- Farmaceutica Territoriale- Azienda Sanitaria Universitaria Integrata Giuliano-Isontina (ASUGI), Trieste, Italy
| | | | - Davide Re
- Servizio Farmaceutico Territoriale ASL Teramo, Teramo, Italy
| | | | | | | | - Valentina Perrone
- Clicon S.r.l., Health Economics and Outcomes Research, Bologna, Italy
| | - Luca Degli Esposti
- Clicon S.r.l., Health Economics and Outcomes Research, Bologna, Italy,Correspondence: Luca Degli Esposti, CliCon S.r.l. Società Benefit, Health, Economics & Outcomes Research, Via Murri, 9, Bologna, 40137, Italy, Tel +390544 38393, Email
| | - Alessandra Mangia
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, 24127, Italy
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Hui VWK, Au CL, Lam ASM, Yip TCF, Tse YK, Lai JCT, Chan HLY, Wong VWS, Wong GLH. Drug-drug interactions between direct-acting antivirals and co-medications: a territory-wide cohort study. Hepatol Int 2022; 16:1318-1329. [PMID: 36074319 DOI: 10.1007/s12072-022-10402-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 07/09/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND The increasing number of direct-acting antiviral (DAA) regimens along with limited number of subjects and co-medications involved in clinical trials results in drug-drug interactions (DDIs) with DAAs is to be determined. We aimed to examine the prevalence and degree of DDIs between DAAs and other co-medications in a territory-wide cohort of chronic hepatitis C virus (HCV) patients. METHODS DDIs were assigned to three risk categories: Category 1-no clinically significant DDI; category 2-potential clinically significant interaction (monitoring and caution required); category 3-contraindicated (should not be co-administered). RESULTS Of 2981 patients (mean age 59.3 ± 12.3 years; male 60.6%), 810 (48.8%) had genotype 1 and 552 (33.2%) genotype 6 HCV among the 1661 patients with HCV genotype tested; 769 (25.8%) received sofosbuvir/velpatasvir, 510 (17.1%) sofosbuvir/ledipasvir, and 865 (29.0%) glecaprevir/pibrentasvir. More than one-fourth (26.3%) of the patients have polypharmacy (≥ 3 co-medications) in all patients, 27.0% in patients received sofosbuvir/velpatasvir, 25.1% in elbasvir/grazoprevir, and 21.2% in glecaprevir/pibrentasvir. 2037 (68.3%) patient experienced DDI (Category 2: 53.1%; Category 3: 15.2%). The commonest drugs leading to DDIs were calcium channel blockers (31.5%) and proton pump inhibitors (23.0%) in category 2; statins (10.2%), antiplatelet/anticoagulants (3.0%) and antipsychotics (2.9%) in category 3. Changing medication was the most common response from physicians in both category 2 and 3 DDIs. CONCLUSION The commonest co-medications leading to contraindication during DAA treatment were statins and antipsychotics. Category 2 and 3 DDIs are often managed by appropriate dose adjustments or temporary discontinuation of relevant co-medications. Careful assessment for potential DDI before DAA use is mandatory to avoid potential harmful effects.
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Affiliation(s)
- Vicki Wing-Ki Hui
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Christopher Langjun Au
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Amy Shuk Man Lam
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jimmy Che-To Lai
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- Union Hospital, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Abstract
The development of direct-acting antivirals (DAA) has revolutionized the treatment of chronic hepatitis C, enabling cure of hepatitis C virus (HCV) infection in more than 95% of cases. There are essentially no contraindications, so almost any patient can now be successfully treated. The result is the prevention or amelioration of cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Consequently, the 2020 Nobel Prize in Medicine and Physiology was awarded for the discovery of HCV. Due to the high efficacy of therapy, even global HCV elimination is conceivable even without a vaccine. Here, we would like to venture a SWOT analysis of current HCV therapies aimed at HCV elimination.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology, and Endocrinology, 9177Hannover Medical School Hannover, Hannover, Germany.,Centre for Individualised Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Mangia A, Scaglione F, Toniutto P, Pirisi M, Coppola N, Di Perri G, Alvarez Nieto G, Calabrese S, Hernandez C, Perrone V, Degli Esposti L, Fagiuoli S. Drug-Drug Interactions in Italian Patients with Chronic Hepatitis C Treated with Pangenotypic Direct Acting Agents: Insights from a Real-World Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:7144. [PMID: 34281080 PMCID: PMC8296917 DOI: 10.3390/ijerph18137144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 12/22/2022]
Abstract
This Italian observational real-world study aims to assess in chronic hepatitis C virus (HCV) patients treated with pangenotypic direct acting agents (pDAAs) glecaprevir/pibrentasvir (GLE/PIB) or sofosbuvir/velpatasvir (SOF/VEL) the potential drug-drug interactions (DDIs) with concomitant medications prescribed, with a focus on cardiovascular and system nervous (CNS) co-medications. Data were collected from administrative databases covering 6.9 million health-assisted individuals. All patients prescribed SOF/VEL or GLE/PIB between 11/2017 and 12/2018 were included. Patients were analyzed while on DAA. DDIs were identified according to the Liverpool University tool. Overall, 3181 HCV patients were included: 1619 in the GLE/PIB cohort and 1562 in the SOF/VEL cohort. SOF/VEL patients were generally older than GLE/PIB ones (mean age 58.4 vs. 53.1, p < 0.001) and had more cardiovascular and CNS comorbidities (58% vs. 42%, p < 0.001 and 33% vs. 28%, p = 0.002, respectively). Contraindications due to DDIs in the GLE/PIB cohort affected 9.3% and 3.2% of patients before and on DAA, respectively, while the percentages in the SOF/VEL cohort were 3.2% before and 0.4% after pDAAs initiation. Among GLE/PIB patients, 2.7% had cardiovascular drugs (all statins) contraindicated while on DAA. The potential DDIs between cardiovascular drugs and SOF/VEL were mainly with statins (5%). SOF/VEL was prescribed in patients with older age and with more cardiovascular and CNS comorbidities. Despite this, a proportion of contraindicated drugs lower than that of GLE/PIB was registered.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, Fondazione “Casa Sollievo Della Sofferenza” IRCCS, 71013 San Giovanni Rotondo, Italy;
| | - Francesco Scaglione
- Department of Oncology and Onco-Hematology, University of Milan, 20122 Milan, Italy;
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Ospedaliero Universitaria, 33100 Udine, Italy;
| | - Mario Pirisi
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Nicola Coppola
- Department of Mental Health and Public Medicine–Infectious Diseases Unit, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy;
| | - Giovanni Di Perri
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy;
| | - Gema Alvarez Nieto
- Gilead Sciences, Medical Affairs Italy, 202124 Milan, Italy; (G.A.N.); (S.C.)
| | - Stefano Calabrese
- Gilead Sciences, Medical Affairs Italy, 202124 Milan, Italy; (G.A.N.); (S.C.)
| | - Candido Hernandez
- Gilead Sciences, Global Medical Affairs, Stockley Park, London UB11 1BD, UK;
| | - Valentina Perrone
- CliCon S.r.l. Health, Economics & Outcomes Research, 40137 Bologna, Italy;
| | - Luca Degli Esposti
- CliCon S.r.l. Health, Economics & Outcomes Research, 40137 Bologna, Italy;
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy;
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Identification and management of contraindicated drug–drug interactions through pharmaceutical care programs: Experience in direct-acting antivirals therapy. J Formos Med Assoc 2021; 121:58-65. [DOI: 10.1016/j.jfma.2021.01.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 12/07/2020] [Accepted: 01/12/2021] [Indexed: 12/21/2022] Open
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Schulte B, Wübbolding M, Marra F, Port K, Manns MP, Back D, Cornberg M, Stichtenoth DO, Höner Zu Siederdissen C, Maasoumy B. Frequency of Potential Drug-Drug Interactions in the Changing Field of HCV Therapy. Open Forum Infect Dis 2020; 7:ofaa040. [PMID: 32104719 PMCID: PMC7033915 DOI: 10.1093/ofid/ofaa040] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/31/2020] [Indexed: 12/12/2022] Open
Abstract
Background With the introduction of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, drug-drug interactions (DDIs) emerged as significant challenge. Since then, HCV therapy and the infected population have rapidly changed. So far, very limited data are available regarding the clinical relevance of DDIs when using most modern DAA regimens. We aimed to assess how the importance of DDIs has evolved over time. Methods From January 2014 to July 2018, 668 consecutive HCV patients were evaluated for their outpatient medication and assessed for DDIs with DAAs. Different time periods were defined based on market approval of key DAAs: A (01/2014-11/2014), B (11/2014-08/2016), and C (08/2016-07/2018). Results The frequency of patients with real-world DDIs was highest in period B (A: 37.1%, B: 49.6%, C: 38.8%). The recently approved DAAs (period C) theoretically showed a lower DDI risk profile. However, real-world DDIs were still comparable to period A, as HCV patients' characteristics changed (eg, age ≥75 years: A: 3.1%, B: 9.8%, C: 5.6%; polypharmacy/patients with ≥8 drugs: A: 11.1%, B: 15.2%, C: 17.2%). Furthermore, although DDIs via CYP 3A4 became less important for some modern regimens, other mechanisms like an altered pH value in the stomach, causing reduced bioavailability, evolved. Relevant DDIs most frequently occurred with proton pump inhibitors, metamizole, statins, and carvedilol. Conclusions DDIs during antiviral treatment still affect about 40% of HCV patients. The lower DDI potential of modern DAA regimens is partly counteracted by changing patient characteristics. Therefore, DDIs should not be underestimated.
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Affiliation(s)
- Benjamin Schulte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - Maximilian Wübbolding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fiona Marra
- University of Liverpool, Clinical Pharmacology, Liverpool, United Kingdom
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - David Back
- University of Liverpool, Clinical Pharmacology, Liverpool, United Kingdom
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - Dirk O Stichtenoth
- Department of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
| | | | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), partner site Hannover-Braunschweig, Hannover, Germany
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9
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Sicras Mainar A, Navarro Artieda R, Hernández I, Morillo R. Prevalence of the potential drug-drug interactions between pangenotypic direct-acting antivirals and the concomitant medications associated with patients with chronic hepatitis C virus infection in Spain. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:465-475. [PMID: 31451229 DOI: 10.1016/j.gastrohep.2019.03.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 03/11/2019] [Accepted: 03/29/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To determine the comorbidity and potential for drug-drug interactions (DDIs) among pangenotypic direct-acting-antivirals (pDAAs) and the concomitant medications associated with chronic hepatitis C (CHC) patients in routine clinical practice in Spain. METHODS Retrospective observational study. Included patients were ≥18 years, diagnosed with CHC, on antiviral treatment and required medical attention during 2017. Two groups were differentiated according to age ranges (<50 and ≥50 years). The variables collected were: age, gender, general/specific comorbidity, concomitant medication and potential DDIs (www.hep-druginteractions.org). The pDAAs analysed were: a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Bivariate statistical analysis, P<.05. RESULTS 3,430 patients with a mean age of 56.9 years and 60.3% males were enrolled. The average Charlson index was 0.8. Age range distribution: 18-49 years (28.9%) and ≥50 years (71.1%). The average number of medications per patient/year was 3.1 (SD 2.6). The total percentage of potential DDIs was: 8.6% minor DDIs, 40.5% clinically significant DDIs and 10.0% contraindicated medication. These DDIs were greater in patients ≥50 years (8.6%, 43.8% and 12.4%, respectively, P<.001). For all ages, SOF/VEL showed a lower percentage of: minor interactions (1.3% vs. 6.6% and 5.9%, P<.001); clinically significant interactions (53.4%, vs. 77.4% and 66.3%, P<.001) and contraindicated medication (1.7% vs. 8.3% and 10.7%, P<.001) compared to GLE/PIB and SOF/VEL/VOX, respectively. CONCLUSIONS Patients with CHC present high comorbidity and concomitant medication use, particularly elderly patients, thus implying a greater exposure to potential DDIs. Although the DDI rate was considerable with the three combinations analysed, SOF/VEL showed a lower number of clinically significant interactions.
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Affiliation(s)
| | - Ruth Navarro Artieda
- Documentación Médica. Hospital Germans Trias i Pujol, Badalona, Barcelona, España
| | - Ignacio Hernández
- Health Economics & Outcomes Research, Real Life Data, Madrid, España
| | - Ramón Morillo
- Farmacia Hospitalaria, Hospital de Valme, AGS Sur de Sevilla, España
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10
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Liu CH, Kao JH. Letter: contraindicated drug-drug interactions before and after initiation of direct-acting anti-viral agents in chronic hepatitis C patients in Taiwan. Authors' reply. Aliment Pharmacol Ther 2019; 50:115-116. [PMID: 31184389 DOI: 10.1111/apt.15329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Linked ContentThis article is linked to Liu et al and Shao papers. To view these articles, visit https://doi.org/10.1111/apt.15011 and https://doi.org/10.1111/apt.15303.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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11
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Shao SC, Lai ECC, Chang KC, Chan YY, Chen HY, Chien RN. Letter: contraindicated drug-drug interactions before and after initiation of direct-acting anti-viral agents in chronic hepatitis C patients in Taiwan. Aliment Pharmacol Ther 2019; 50:113-115. [PMID: 31184385 DOI: 10.1111/apt.15303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Shih-Chieh Shao
- Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Kai-Cheng Chang
- Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yuk-Ying Chan
- Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Pharmaceutical Materials Management, Chang Gung Medical Foundation, Taoyuan, Taiwan
| | - Hui-Yu Chen
- Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Sandmann L, Schulte B, Manns MP, Maasoumy B. Treatment of Chronic Hepatitis C: Efficacy, Side Effects and Complications. Visc Med 2019; 35:161-170. [PMID: 31367613 DOI: 10.1159/000500963] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis and its complications. Viral eradication is essential to prevent disease progression and reduces liver-related mortality and morbidity. Since the availability of direct-acting antivirals (DAA), HCV treatment has changed significantly. Current treatment strategies for different groups of patients as well as potential risks and caveats will be discussed in this review. Summary Interferon-free (IFN-free) treatment not only shortens treatment duration, but also achieves high rates of viral clearance and is overall well tolerated. Genotype-restricted but also pangenotypic combinations are available. Usually two DAA of different drug classes are combined. For the majority of the patients, treatment duration ranges from 8 to 12 weeks. Liver and kidney function as well as prior treatment experience and potential drug-drug interactions influence substance choices and treatment duration. However, modern IFN-free treatment is not only safer, but also overall far more simplified and effective. Global HCV eradication might be an ambitious but not completely unrealistic goal to pursue. Key Messages IFN-free antiviral treatment is safe and well tolerated. Patients can be treated almost independently of liver function or concomitant disease. Viral eradication is associated with reduced morbidity and mortality and better quality of life.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Schulte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Ruzicka DJ, Tetsuka J, Fujimoto G, Kanto T. Comorbidities and co-medications in populations with and without chronic hepatitis C virus infection in Japan between 2015 and 2016. BMC Infect Dis 2018; 18:237. [PMID: 29793436 PMCID: PMC5968711 DOI: 10.1186/s12879-018-3148-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 05/15/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Direct-acting anti-viral agents have improved the treatment of chronic hepatitis C virus (HCV) infection, but this treatment is challenging for patients using co-medications because of potential drug-drug interactions. This study aimed to examine the comorbidities and co-medications of Japanese chronic HCV patients by age group, compared with a non-HCV patient population. METHODS This was a retrospective observational study using a hospital-based medical claims database. We extracted data of patients with chronic HCV aged ≥18 years, and age-, sex-, and hospital-matched patients without HCV, for the period from January 2015 to November 2016, and then examined chronic comorbidities, long-term co-medications, and medications prescribed at least once during the study period. RESULTS We analysed data from 128,967 chronic HCV patients and 515,868 non-HCV patients. The median age was 70 years, and 51.0% of patients were male. More chronic HCV patients than non-HCV patients (70.5% vs. 47.1%) had at least one comorbidity, and older patients had more comorbidities than younger patients. The most common comorbidities in chronic HCV patients were diseases of oesophagus, stomach and duodenum (41.7%), followed by hypertensive diseases (31.4%). Chronic HCV patients used co-medications more commonly than non-HCV patients, and older patients used more co-medications. The most common long-term co-medications in chronic HCV patients were proton pump inhibitors (14.0%), which were prescribed to 31.9% of chronic HCV patients at least once during the study period. CONCLUSIONS Patients with chronic HCV in Japan had more comorbidities than patients without chronic HCV regardless of age. Particularly older patients, who constitute the majority of the HCV patient population in Japan, commonly had multiple comorbidities and used co-medications. To optimise HCV treatment, physicians need to know the exact medication profiles of patients and take appropriate action to manage drug-drug interactions.
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Affiliation(s)
- Daniel J. Ruzicka
- Medical Affairs, MSD K.K, Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667 Japan
| | - Jumpei Tetsuka
- Medical Affairs, MSD K.K, Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667 Japan
| | - Go Fujimoto
- Biostatistics and Research Decision Sciences, MSD K.K, Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667 Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology Department of Liver Disease, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516 Japan
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Shebley M, Liu J, Kavetskaia O, Sydor J, de Morais SM, Fischer V, Nijsen MJMA, Bow DAJ. Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus Three Direct-Acting Antiviral Regimen: Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir. Drug Metab Dispos 2017; 45:755-764. [PMID: 28483778 DOI: 10.1124/dmd.116.074518] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 05/02/2017] [Indexed: 12/31/2022] Open
Abstract
To assess drug-drug interaction (DDI) potential for the three direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir, and paritaprevir, in vitro studies profiled drug-metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, organic anion-transporting polypeptide (OATP) 1B1/1B3, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations, but additional physiologically based pharmacokinetic modeling was necessary to achieve the same for drug transporters. When perpetrator interactions were assessed, ritonavir was responsible for the strong increase in exposure of sensitive CYP3A substrates, whereas paritaprevir (an OATP1B1/1B3 inhibitor) greatly increased the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to moderately increase plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir, and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates) but were not affected by strong CYP3A4 inhibitors, since ritonavir (a CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increased plasma exposure of dasabuvir (a major CYP2C8 substrate), OATP1B1/1B3 inhibitors increased plasma exposure of paritaprevir (an OATP1B1/1B3 substrate), and P-gp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increased plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability may enable better clinical management of nonstudied drug combinations with the 3D regimen.
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Affiliation(s)
- Mohamad Shebley
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Jinrong Liu
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Olga Kavetskaia
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Jens Sydor
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Sonia M de Morais
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Volker Fischer
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Marjoleen J M A Nijsen
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
| | - Daniel A J Bow
- Drug Metabolism, Pharmacokinetics, and Bioanalysis (M.S., J.L., O.K., J.S., S.M.d.M., V.F., M.J.M.A.N., D.A.J.B.) and Clinical Pharmacology and Pharmacometrics (M.S.), AbbVie Inc., North Chicago, Illinois
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Changes in renal function indices in cirrhotic chronic hepatitis C patients treated with sofosbuvir-containing regimens. Oncotarget 2017; 8:90916-90924. [PMID: 29207613 PMCID: PMC5710894 DOI: 10.18632/oncotarget.18701] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 06/04/2017] [Indexed: 12/15/2022] Open
Abstract
This study aimed to explore changes in hepatic and renal function indices in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAAs). Forty-three CHC patients treated with sofosbuvir (SOF)-containing regimens were enrolled. At the end of treatment, the estimated glomerular filtration rate (eGFR) level was significantly decreased and the serum creatinine (Scr) and uric acid (UA) levels were significantly increased compared with baseline levels (eGFR: 86.7 ± 20.4 vs 80.5 ± 21.3, P01 = 0.005; Scr: 83.9 ± 19.1 vs 89.6 ± 21.1, P01 < 0.001; UA: 323.7± 86.2 vs 358.5 ± 93.2, P01 < 0.001); no significant improvements were observed at 24 w post-treatment (eGFR: 86.7 ± 20.4 vs 81.4 ± 18.6, P02 = 0.013; Scr: 83.6 ± 17.9 vs 87.9 ± 18.3, P02 = 0.014; UA: 320.8 ± 76.3 vs 349.3 ± 91.0, P02 = 0.004). When the patients were grouped by liver conditions, non-cirrhotic patients and cirrhotic patients had decreased eGFR levels and increased Scr levels at the end of treatment; at 24 w post-treatment, the eGFR and Scr levels were significantly improved in non-cirrhotic patients (88.4 ± 21.7 vs 83.8 ± 18.5, P02 = 0.142; 84.4 ± 20.4 vs 87.0 ± 16.9, P02 = 0.088), while no obvious improvements were observed in cirrhotic patients (84.3 ± 18.7 vs 78.1 ± 18.6, P02 = 0.002; 83.2 ± 17.7 vs 89.2 ± 20.6, P02 = 0.006). Clinical physicians should closely monitor renal function in patients treated with SOF-containing regimens, especially in cirrhotic patients.
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Papatheodoridi Μ, Dalekos GN, Goulis J, Manolakopoulos S, Triantos C, Zachou K, Koukoufiki A, Κourikou Α, Ζisimopoulos Κ, Τsoulas C, Papatheodoridis GV. Prioritization for interferon-free regimens and potential drug interactions of current direct-acting anti-hepatitis C agents in routine clinical practice. Ann Gastroenterol 2017; 30:542-549. [PMID: 28845110 PMCID: PMC5566775 DOI: 10.20524/aog.2017.0170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/12/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND We determined the proportions of patients with chronic hepatitis C (CHC) in association with possible prioritized indications for interferon-free regimens and the use of co-medications with potential drug-drug interactions (DDIs). METHODS Five hundred consecutive mono-infected CHC patients seen in 2015 at 5 Greek centers were included. Priorities for interferon-free regimens were based on liver disease severity, contraindication(s) for interferon and prior interferon-treatment failure. All co-medications were classified into those with no DDIs/no clear data for DDIs, potential DDIs, and contraindication due to DDI for each agent, according to the HEP Drug Interaction Checker. RESULTS Of the 500 patients, 1% had undergone liver transplantation, whereas 6.6% had decompensated cirrhosis, 21.8% F4, 17.1% F3, 10.4% F2, and 34.8% F0-1 fibrosis. Contraindications for interferon were present in 38.5% of non-transplant patients with compensated liver disease. The probability of contraindications/potential DDIs was greater for boceprevir/telaprevir and ombitasvir/paritaprevir/ritonavir±dasabuvir, compared to all other agents (P<0.001), and least for sofosbuvir (P<0.05). Contraindications/potential DDIs were more frequently present in patients ≥50 than <50 years old (P≤0.034), and more common in F3-4 than F0-2, and F4 than F0-3 fibrosis (P≤0.019) for all direct-acting antivirals (DAAs). CONCLUSIONS The expansion of the criteria for prioritization of interferon-free regimens from cirrhosis to F3 and perhaps F2 fibrosis will increase the proportion of patients with DAA access by only 10-15% and 10%, respectively. A potential for DDIs is frequently present with protease inhibitors, but also exists with other DAAs. The probability of DDIs is higher in patients with priority for DAAs, including those who have advanced liver disease and are usually of older age.
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Affiliation(s)
- Μargarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens (Margarita Papatheodoridi, George V. Papatheodoridis), Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece (George N. Dalekos, Kalliopi Zachou), Greece
| | - John Goulis
- 4 of Internal Medicine, Medical School of Αristotle University of Thessaloniki (John Goulis, Argyro Koukoufiki), Greece
| | - Spilios Manolakopoulos
- 2 of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens (Spilios Manolakopoulos, Anastasia Kourikou), Greece
| | - Christos Triantos
- Department of Gastroenterology, University Hospital of Patras (Konstantinos Zisimopoulos), Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece (George N. Dalekos, Kalliopi Zachou), Greece
| | - Argyro Koukoufiki
- 4 of Internal Medicine, Medical School of Αristotle University of Thessaloniki (John Goulis, Argyro Koukoufiki), Greece
| | - Αnastasia Κourikou
- 2 of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens (Spilios Manolakopoulos, Anastasia Kourikou), Greece
| | | | - Christos Τsoulas
- Medical Department, Gilead Sciences Hellas (Christos Tsoulas), Greece
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens (Margarita Papatheodoridi, George V. Papatheodoridis), Greece
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Langness JA, Nguyen M, Wieland A, Everson GT, Kiser JJ. Optimizing hepatitis C virus treatment through pharmacist interventions: Identification and management of drug-drug interactions. World J Gastroenterol 2017; 23:1618-1626. [PMID: 28321163 PMCID: PMC5340814 DOI: 10.3748/wjg.v23.i9.1618] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/12/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process.
METHODS As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics.
RESULTS Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex patients.
CONCLUSION DDIs are common with HCV medications and management can require medication adjustments and increased monitoring. An interdisciplinary team including a clinical pharmacist can optimize patient care.
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Talavera Pons S, Boyer A, Lamblin G, Chennell P, Châtenet F, Nicolas C, Sautou V, Abergel A. Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C. Br J Clin Pharmacol 2017; 83:269-293. [PMID: 27530469 PMCID: PMC5237698 DOI: 10.1111/bcp.13095] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 07/21/2016] [Accepted: 07/26/2016] [Indexed: 12/16/2022] Open
Abstract
Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.
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Affiliation(s)
| | - Anne Boyer
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
| | - Geraldine Lamblin
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
| | - Philip Chennell
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
- EA 4676 C‐BiosenssUniversité d'AuvergneClermont‐FerrandCedexFrance
| | | | - Carine Nicolas
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
| | - Valérie Sautou
- Service de Pharmacie Centre Hospitalier UniversitaireClermont‐FerrandFrance
- EA 4676 C‐BiosenssUniversité d'AuvergneClermont‐FerrandCedexFrance
| | - Armand Abergel
- Service de Médecine Digestive et Hépato‐biliaire Centre Hospitalier Universitaire EstaingClermont‐FerrandFrance
- Unité Mixte de Recherche Université d'Auvergne, CNRS 6284University of Clermont‐FerrandFrance
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Smolders EJ, Berden FA, de Kanter CT, Kievit W, Drenth JP, Burger DM. The majority of hepatitis C patients treated with direct acting antivirals are at risk for relevant drug-drug interactions. United European Gastroenterol J 2016; 5:648-657. [PMID: 28815028 DOI: 10.1177/2050640616678151] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/06/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Direct-acting antivirals have improved treatment of chronic hepatitis C virus infection significantly. Direct-acting antivirals inhibit/induce and can also be substrates of drug-metabolising enzymes and transporters. This increases the risk for drug-drug interactions. OBJECTIVE The purpose of this study was to predict drug-drug interactions with co-medication used by hepatitis C virus-infected patients. METHODS We assembled a nationwide cohort of hepatitis C patients and collected cross-sectional data on co-medication use. We compiled a list of currently available direct-acting antiviral regimens and cross-checked for potential drug-drug interactions with used co-medication. RESULTS The cohort included 461 patients of which 77% used co-medication. We identified 260 drugs used as co-medication. Antidepressants (7.4%), proton pump inhibitors (7.1%) and benzodiazepines (7.1%) were most frequently used. Of the patients, 60% were at risk for a clinically relevant drug-drug interaction with at least one of the direct-acting antiviral regimens. Interactions were most common with paritaprevir/ritonavir/ombitasvir/dasabuvir and least interactions were predicted with grazoprevir/elbasvir. CONCLUSION Co-medication use is rich in frequency and diversity in chronic hepatitis C patients. The majority of patients are at risk for drug-drug interactions which may affect efficacy or toxicity of direct-acting antivirals or co-medication. The most recently introduced direct-acting antivirals are associated with a lower risk of drug-drug interactions.
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Affiliation(s)
- Elise J Smolders
- Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands
| | - Floor Ac Berden
- Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, The Netherlands
| | - Clara Tmm de Kanter
- Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wietske Kievit
- Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands
| | - Joost Ph Drenth
- Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, The Netherlands
| | - David M Burger
- Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands
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20
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Vermehren J, Peiffer KH, Welsch C, Grammatikos G, Welker MW, Weiler N, Zeuzem S, Welzel TM, Sarrazin C. The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther 2016; 44:856-65. [PMID: 27549000 DOI: 10.1111/apt.13769] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/26/2016] [Accepted: 07/27/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Direct antiviral therapies for chronic hepatitis C virus (HCV) infection have expanded treatment options for neglected patient populations, including elderly patients who are ineligible/intolerant to receive interferon (IFN)-based therapy. AIM To investigate the efficacy, tolerability and potential for drug-drug interactions (DDIs) of IFN-free treatment in patients aged ≥65 years in a large real-world cohort. METHODS A total of 541 patients were treated with different combinations of direct antiviral agents (DAAs: ledipasvir/sofosbuvir ±ribavirin; daclatasvir/sofosbuvir ±ribavirin; paritaprevir/ombitasvir ±dasabuvir ±ribavirin or simeprevir/sofosbuvir ±ribavirin in genotype 1/4, and daclatasvir/sofosbuvir ±ribavirin or sofosbuvir/ribavirin in genotype 2/3). Efficacy, safety and potential DDIs were analysed and compared between patients aged <65 years (n = 404) and patients aged ≥65 years (n = 137) of whom 41 patients were ≥75 years. RESULTS Sustained virological response rates were 98% and 91% in patients aged ≥65 years and <65 years, respectively. Elderly patients took significantly more concomitant medications (79% vs. 51%; P < 0.0001). The number of concomitant drugs per patient was highest in patients ≥65 years with cirrhosis (median, three per patient; range, 0-10). Based on the hep-druginteractions database, the proportion of predicted clinically significant DDIs was significantly higher in elderly patients (54% vs. 28%; P < 0.0001). The number of patients who experienced treatment-associated adverse events was similar between the two age groups (63% vs. 65%; P = n.s.). CONCLUSIONS Elderly patients are at increased risk for significant DDIs when treated with DAAs for chronic HCV infection. However, with careful pre-treatment assessment of concomitant medications, on-treatment monitoring or dose-modifications, significant DDIs and associated adverse events can be avoided.
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Affiliation(s)
- J Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
| | - K-H Peiffer
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - C Welsch
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - G Grammatikos
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - M-W Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - N Weiler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - S Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - T M Welzel
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - C Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
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21
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Polepally AR, Badri PS, Parikh A, Rodrigues L, Da Silva-Tillmann BA, Mensing S, Podsadecki TJ, Awni WM, Dutta S, Menon RM. Effect of co-medications on paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials. Antivir Ther 2016; 21:707-714. [PMID: 27584548 DOI: 10.3851/imp3079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined. METHODS Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ss value were examined as covariates for an effect on apparent clearance (CL/F). RESULTS More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ss ratio ≤0.5 or ≥2.0) on paritaprevir exposures. However, when these classes were included in the paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%). CONCLUSIONS No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.
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Affiliation(s)
| | - Prajakta S Badri
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | - Apurvasena Parikh
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | - Lino Rodrigues
- Infectious Disease Development, AbbVie Inc., North Chicago, IL, USA
| | | | - Sven Mensing
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | | | - Walid M Awni
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
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22
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Herzer K, Papadopoulos-Köhn A, Walker A, Achterfeld A, Paul A, Canbay A, Timm J, Gerken G. Daclatasvir, Simeprevir and Ribavirin as a Promising Interferon-Free Triple Regimen for HCV Recurrence after Liver Transplant. Digestion 2016; 91:326-33. [PMID: 25999053 DOI: 10.1159/000382075] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 03/31/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recurrent hepatitis C infection after liver transplantation (LT) is associated with lower rates of graft and patient survival. METHODS Here we describe the first use of daclatasvir, simeprevir, and ribavirin (RBV) as an all-oral triple regimen administered to 6 liver transplant recipients with recurrent hepatitis C, one with GT 1a and 5 with GT 1b. All patients were treated for 24 weeks. Trough levels of immunosuppression, laboratory measures, and potential adverse effects were closely monitored. RESULTS For all patients, viral load became undetectable between treatment weeks 4 and 12. One patient experienced a viral breakthrough at the 10th week of treatment; this was associated with the selection of resistance-associated variants (D168Y in NS3 and ΔP32 in NS5A). For the other 5 patients, end-of-treatment response and for 4 patients SVR24 was achieved. Viremia recurred in one patient 4 weeks after the end of treatment, which was again associated with the selection of resistance-associated variants (D168V in NS3 and ΔP32 in NS5A). Clinical measures of liver function improved substantially for all patients. Adverse events were few and limited to moderate anemia caused by RBV. Importantly, adjustments to the immunosuppressant dosage were not required. CONCLUSIONS The described regimen appears to be safe and effective for liver transplant patients and will be a promising treatment regimen for post-LT patients.
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Affiliation(s)
- Kerstin Herzer
- Departments of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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23
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Badri PS, King JR, Polepally AR, McGovern BH, Dutta S, Menon RM. Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy. Clin Pharmacokinet 2016; 55:275-95. [PMID: 26330025 PMCID: PMC4761011 DOI: 10.1007/s40262-015-0317-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.
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Affiliation(s)
- Prajakta S Badri
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA.
| | - Jennifer R King
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Akshanth R Polepally
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Barbara H McGovern
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
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24
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Höner Zu Siederdissen C, Maasoumy B, Marra F, Deterding K, Port K, Manns MP, Cornberg M, Back D, Wedemeyer H. Drug-Drug Interactions With Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort. Clin Infect Dis 2015; 62:561-7. [PMID: 26611779 DOI: 10.1093/cid/civ973] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. METHODS Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-druginteractions.org and the relevant prescribing information. RESULTS The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir ± dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. CONCLUSIONS A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Fiona Marra
- Department of Molecular and Clinical Pharmacology, University of Liverpool Pharmacy Department, Gartnavel General Hospital, Glasgow, Scotland, United Kingdom
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - David Back
- Department of Molecular and Clinical Pharmacology, University of Liverpool
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
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25
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
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26
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González-Colominas E, Broquetas T, Retamero A, García-Retortillo M, Cañete N, Coll S, Pellicer R, Giménez MD, Cabrero B, Bory F, Knobel H, Salas E, Solà R, Carrión JA. Drug-drug interactions of telaprevir and boceprevir in HCV-monoinfected and HIV/HCV-coinfected patients can modify the adherence. Liver Int 2015; 35:1557-65. [PMID: 25385188 DOI: 10.1111/liv.12729] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 10/28/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The first generation protease inhibitors, boceprevir (BOC) and telaprevir (TVR), are both CYP3A4 inhibitors, which predispose drug-drug interactions (DDIs). The aim of this study was to evaluate the prevalence of potential DDIs, the management of outpatient medication and its impact on adherence and efficacy to antiviral treatment in hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients receiving BOC and TVR. METHODS The usual medication starting with BOC or TVR was screened by the pharmacist of the multidisciplinary support programme (MSP) for potential DDIs. Recommendations were made to avoid significant DDIs, and changes in the baseline medication were recorded. Adherence to antiviral treatment was considered as 80/80/95% of total doses. Sustained virological response was assessed at week 12 (SVR12). RESULTS At least one potential DDI was found in 70 (64.8%) patients, 45 (54.2%) being HCV-monoinfected and 25 (100%) HIV/HCV-coinfected (P < 0.01). Baseline treatment modifications were required in 38 (35.2%) patients. Adherence and SVR12 were higher in patients without DDIs (86.8%) and (67.6%) compared to those with DDIs (62.8%) (P = 0.021) and (47.2%) (P = 0.097) respectively. CONCLUSIONS More than half of the patients were at risk of presenting DDIs, leading to changes in the baseline medication in one-third of the patients. Drug interactions are frequent in patients with lower adherence.
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Affiliation(s)
- Elena González-Colominas
- Pharmacy Department, Hospital del Mar. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
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Martinez JP, Sasse F, Brönstrup M, Diez J, Meyerhans A. Antiviral drug discovery: broad-spectrum drugs from nature. Nat Prod Rep 2015; 32:29-48. [PMID: 25315648 DOI: 10.1039/c4np00085d] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Covering: up to April 2014. The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with scepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has re-bloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, with particular focus on natural products as promising starting points for antiviral lead development.
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Affiliation(s)
- J P Martinez
- Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
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28
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Viral hepatitis C therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 2014; 53:409-27. [PMID: 24723109 DOI: 10.1007/s40262-014-0142-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.
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29
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[New direct-acting antiviral agents for the treatment of chronic hepatitis C in 2014]. Internist (Berl) 2014; 55:390-400. [PMID: 24652513 DOI: 10.1007/s00108-013-3416-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The development of direct-acting antiviral agents (DAA) against the hepatitis C virus (HCV) has seen enormous progress in recent years. In 2011, the first protease inhibitors boceprevir (BOC) and telaprevir (TLV) were approved, which still need to be combined with pegylated interferon α (PEG-IFN α) and ribavirin (RBV) and are used only in patients with genotype 1. With sofosbuvir (SOF) and simeprevir (SMV), two new DAA are available. More DAA are in clinical development. OBJECTIVES Which changes in the treatment of chronic hepatitis C infection can be expected with the approval of the new DAA in 2014? Relevant phase IIb and phase III studies for the approval in 2014 were considered for drugs approved by the FDA or EMA at the editorial deadline. CURRENT DATA For patients with genotype 1, the combination of SOF, SMV or faldaprevir with PEG-IFN α and RBV was successfully evaluated in phase III studies. In contrast to previous treatment with PEG-IFN α, RBV and telaprevir (TLV) or boceprevir (BOC), therapy can be shortened in most cases with a significantly improved side-effect profile. Cure rates above 80 % are possible. Data are also available for an interferon-free therapy with either SOF and RBV or SOF and SMV in GT-1 patients. SVR rates exceeding 60 % and up to 90 % are possible. However, treatment experience with these combinations is low and an unrestricted interferon-free therapy for genotype 1 should not be expected before 2015. For patients with genotypes 2 and 3, valid data for interferon-free therapies are available. The combination of SOF and RBV for 12 weeks in genotype 2 and 24 weeks for genotype 3 is effective and shows equal or superior cure rates with fewer side effects than the PEG-IFN α/RBV therapy. CONCLUSION For patients with genotype 1, the duration of therapy can be further reduced with better side effect profile. In certain situations, therapy without PEG-IFN α is possible and should be considered. For patients with genotypes 2 and 3, an interferon-free therapy will be standard of care in 2014.
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Lauffenburger JC, Mayer CL, Hawke RL, Brouwer KLR, Fried MW, Farley JF. Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential. Eur J Gastroenterol Hepatol 2014; 26:1073-82. [PMID: 25014625 PMCID: PMC4156548 DOI: 10.1097/meg.0000000000000152] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND With the advent of the direct-acting antiviral agents, significant drug-drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential. METHODS Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010. Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available. RESULTS Patient comorbidity burden was high and increased over the study period. Medication use was investigated in 53 461 patients with chronic HCV. Twenty-one (53%) of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure. Of these, 59 and 41% were listed in a common DDI resource but not in medication-prescribing information, 77 and 77% had not been investigated in DDI studies, 41 and 36% did not have clear recommendations for DDI management, and only 14 and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively. CONCLUSION Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential. However, DDI potential may not be reflected in prescribing information.
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Affiliation(s)
- Julie C. Lauffenburger
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Christina L. Mayer
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roy L. Hawke
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kim L. R. Brouwer
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Michael W. Fried
- UNC Liver Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Joel F. Farley
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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31
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Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential. Eur J Gastroenterol Hepatol 2014. [PMID: 25014625 DOI: 10.1097/med.00000000000152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND With the advent of the direct-acting antiviral agents, significant drug-drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential. METHODS Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010. Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available. RESULTS Patient comorbidity burden was high and increased over the study period. Medication use was investigated in 53 461 patients with chronic HCV. Twenty-one (53%) of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure. Of these, 59 and 41% were listed in a common DDI resource but not in medication-prescribing information, 77 and 77% had not been investigated in DDI studies, 41 and 36% did not have clear recommendations for DDI management, and only 14 and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively. CONCLUSION Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential. However, DDI potential may not be reflected in prescribing information.
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Rosso C, Abate ML, Ciancio A, Strona S, Caviglia GP, Olivero A, Touscoz GA, Rizzetto M, Pellicano R, Smedile A. IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients. World J Gastroenterol 2014; 20:13146-13152. [PMID: 25278709 PMCID: PMC4177494 DOI: 10.3748/wjg.v20.i36.13146] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 02/18/2014] [Accepted: 05/12/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G)/rs1297860 in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.
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Rose L, Bias TE, Mathias CB, Trooskin SB, Fong JJ. Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection. Ann Pharmacother 2014; 48:1019-1029. [PMID: 24811396 DOI: 10.1177/1060028014534194] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct-acting antiviral (DAA), and others. STUDY SELECTION AND DATA EXTRACTION Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. DATA SYNTHESIS Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. CONCLUSION In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naïve and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs..
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Affiliation(s)
- Lucia Rose
- Western New England University, Springfield, MA, USA
| | | | | | | | - Jeffrey J Fong
- MCPHS University-Worcester/Manchester, Worcester, MA, USA
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Koff RS. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther 2014; 39:478-87. [PMID: 24387618 DOI: 10.1111/apt.12601] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 12/07/2013] [Accepted: 12/10/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND The treatment of chronic hepatitis C is changing rapidly. AIM To review clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C. METHODS Using PubMed and search terms 'sofosbuvir,' 'emerging HCV treatment,' and 'HCV polymerase inhibitor,' literature on the clinical development of sofosbuvir, as well as abstracts presented at the November 2013 annual meeting of the American Association for the Study of Liver Diseases (AASLD), was reviewed. The last search was undertaken on 15 November 2013 [corrected]. RESULTS In a dose of 400 mg once daily, the drug has been safe and generally well tolerated with most adverse reactions attributable to the concurrent use of ribavirin or peginterferon plus ribavirin. A high barrier to resistance has been demonstrated. In genotype 1 (G1) patients, the addition of sofosbuvir to peginterferon plus ribavirin yielded sustained virological response rates at week 12 after discontinuation of treatment (SVR12) of about 90% with slightly lower levels in G1b and in patients with cirrhosis, but with no major impact of IL28B genotype, high viral load, body mass index (BMI), alanine aminotransferase (ALT) or race/ethnicity. In genotype 2 (G2), sofosbuvir and ribavirin for 12 weeks also resulted in SVR12 of 90% or better with little effect from cirrhosis. In contrast, genotype 3 (G3) was less responsive to 12 weeks of sofosbuvir plus ribavirin, especially in the presence of cirrhosis. CONCLUSION The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signal a new era in treatment.
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Affiliation(s)
- R S Koff
- Department of Gastroenterology and Hepatology, Department of Medicine, University of Connecticut Health Science Center, Farmington, CT, USA
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Abstract
INTRODUCTION Combination therapy with pegylated interferon, ribavirin and the two first-generation NS3/4A protease inhibitors (PIs), telaprevir (TVR) and boceprevir (BOC), is the new standard-of-care therapy for patients who are chronically infected with genotype 1 hepatitis C virus. These combinations significantly increase sustained virological response (SVR) rates, but they also increase the rates of adverse events (AEs). Appearance of significant AEs may necessitate dose reduction or discontinuation of treatment, and may impact on virological response. AREAS COVERED In registration trials, IFN-related AEs were a dominant feature in both types of therapy. Some events were more frequent with PI-containing regimens, like anemia and dysgeusia with BOC and anemia, pruritus, rash and anorectal symptoms with TVR. This review addresses the early identification and management of AEs to improve tolerance, and to avoid reduction in SVR rates. EXPERT OPINION Every patient will experience adverse effects to differing degrees; a systematic approach to their management can be very helpful. Early recognition and intervention can help clinicians ensure that patients are able to complete therapy where possible and achieve the goal of viral eradication. Treatment with the next generation of antivirals will improve safety and efficacy.
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Affiliation(s)
- Ezequiel Ridruejo
- Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC", Department of Medicine, Hepatology Section , Avda. Las Heras 2939, (C1425ASG) Ciudad Autónoma de Buenos Aires , Argentina +54 11 5299 1221 ; +54 11 5299 0600 ext 5900 ;
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