|
1
|
Lin JJ, Loucks CM, Trueman JN, Drögemöller BI, Wright GEB, Yoshida EM, Ford JA, Lee SS, Kim RB, Al-Judaibi B, Schwarz UI, Ramji A, Tam E, Ross CJ, Carleton BC. Novel variant in glycophorin c gene protects against ribavirin-induced anemia during chronic hepatitis C treatment. Biomed Pharmacother 2021; 143:112195. [PMID: 34562771 DOI: 10.1016/j.biopha.2021.112195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/08/2021] [Accepted: 09/11/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia. METHODS We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants. RESULTS We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04-0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P = 0.0437). CONCLUSIONS GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.
Collapse
Affiliation(s)
- Jennifer J Lin
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, Vancouver, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Catrina M Loucks
- BC Children's Hospital Research Institute, Vancouver, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Jessica N Trueman
- BC Children's Hospital Research Institute, Vancouver, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Britt I Drögemöller
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Galen E B Wright
- Department of Pharmacy and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, Canada
| | - Jo-Ann Ford
- Division of Gastroenterology, University of British Columbia, Vancouver, Canada
| | - Samuel S Lee
- Liver Unit, University of Calgary Cumming School of Medicine, Calgary, Canada
| | - Richard B Kim
- Division of Clinical Pharmacology, Department of Medicine, Western University, London, Canada
| | - Bandar Al-Judaibi
- Division of Transplantation, University of Rochester, Rochester, United States; Department of Liver Transplantation and Hepatobiliary Surgery, King Faisal Special Hospital and Research Center, Saudi Arabia
| | - Ute I Schwarz
- Division of Clinical Pharmacology, Department of Medicine, Western University, London, Canada
| | - Alnoor Ramji
- Division of Gastroenterology, University of British Columbia, Vancouver, Canada; Pacific Gastroenterology Associates, Vancouver, Canada
| | | | - Colin J Ross
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, Vancouver, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
| | - Bruce C Carleton
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, Vancouver, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada; Pharmaceutical Outcomes Program, British Columbia Children's Hospital, Vancouver, Canada.
| |
Collapse
|
|
2
|
Feld JJ, Bernstein DE, Younes Z, Vlierberghe HV, Larsen L, Tatsch F, Ferenci P. Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. Liver Int 2018; 38:1571-1575. [PMID: 29377566 PMCID: PMC6175401 DOI: 10.1111/liv.13708] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 01/18/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. METHODS We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. RESULTS Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). CONCLUSIONS Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia.
Collapse
Affiliation(s)
- Jordan J. Feld
- Toronto Centre for Liver DiseaseToronto General HospitalTorontoONCanada
| | | | | | | | | | | | | |
Collapse
|
|
3
|
Foster GR, Coppola C, Derbala M, Ferenci P, Orlandini A, Reddy KR, Tallarico L, Shiffman ML, Ahlers S, Bakalos G, Hassanein T. Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort. PLoS One 2016; 11:e0151703. [PMID: 27018988 PMCID: PMC4809570 DOI: 10.1371/journal.pone.0151703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 03/02/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.
Collapse
Affiliation(s)
- Graham R. Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, United Kingdom
| | - Carmine Coppola
- Unità Operativa Epatologia ed Ecografia Interventistica Ospedale Gragnano, Naples, Italy
| | | | | | - Alessandra Orlandini
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - K. Rajender Reddy
- University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | | | - Mitchell L. Shiffman
- Liver Institute of Virginia, Bon Secours Health System, Newport News/Richmond, Virginia, United States of America
| | | | | | - Tarek Hassanein
- University of California San Diego, San Diego, California, United States of America
| | | |
Collapse
|
|
4
|
Veillon P, Fouchard-Hubert I, Larrey D, Dao MT, D'alteroche L, Boyer-Darrigand N, Picard N, Le Guillou-Guillemette H, Saulnier P, Ducancelle A, Loustaud-Ratti V, Lunel-Fabiani F. Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C? J Interferon Cytokine Res 2016; 36:204-14. [PMID: 26700738 DOI: 10.1089/jir.2015.0131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon α-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.
Collapse
Affiliation(s)
- Pascal Veillon
- 1 Department of Virology, University Hospital of Angers , Angers, France
- 2 HIFIH Research Unit, Faculty of Medicine, UPRES 3859, SFR 4208, University of Angers , Angers, France
| | - Isabelle Fouchard-Hubert
- 2 HIFIH Research Unit, Faculty of Medicine, UPRES 3859, SFR 4208, University of Angers , Angers, France
- 3 Department of Hepatology and Gastroenterology, University Hospital of Angers , Angers, France
| | - Dominique Larrey
- 4 Department of Hepatology and Transplantation, University Hospital of Montpellier , Montpellier, France
| | - Manh Thông Dao
- 5 Gastroenterology and Nutrition, University Hospital of Caen , Caen, France
| | - Louis D'alteroche
- 6 Department of Hepatology and Gastroenterology, University Hospital of Tours , Chambray-les-Tours, France
| | - Nathalie Boyer-Darrigand
- 7 Department of Hepatology, Physiopathology and Treatment of Viral Hepatitis, Hospital of Beaujon , Clichy, France
| | - Nicolas Picard
- 8 INSERM UMR-850, Department of Pharmacology, Toxicology and Pharmacovigilance, University Hospital of Limoges , Limoges, France
| | - Hélène Le Guillou-Guillemette
- 1 Department of Virology, University Hospital of Angers , Angers, France
- 2 HIFIH Research Unit, Faculty of Medicine, UPRES 3859, SFR 4208, University of Angers , Angers, France
| | - Patrick Saulnier
- 9 Micro and Nanomedecines biomimetics, INSERM UMRS 1066, University of Angers , Angers, France
| | - Alexandra Ducancelle
- 1 Department of Virology, University Hospital of Angers , Angers, France
- 2 HIFIH Research Unit, Faculty of Medicine, UPRES 3859, SFR 4208, University of Angers , Angers, France
| | - Véronique Loustaud-Ratti
- 10 Department of Hepatology and Gastroenterology, University Hospital of Limoges , INSERM UMR 1092, Limoges, France
| | - Françoise Lunel-Fabiani
- 1 Department of Virology, University Hospital of Angers , Angers, France
- 2 HIFIH Research Unit, Faculty of Medicine, UPRES 3859, SFR 4208, University of Angers , Angers, France
| |
Collapse
|
|
5
|
Wu LS, Jimmerson LC, MacBrayne CE, Kiser JJ, D'Argenio DZ. Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus. CPT Pharmacometrics Syst Pharmacol 2016; 5:65-73. [PMID: 26933517 PMCID: PMC4761234 DOI: 10.1002/psp4.12058] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 12/30/2015] [Indexed: 12/17/2022] Open
Abstract
Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure-anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and interleukin 28B (IL28B) genetics were found to be significant covariates. Clinical trial simulations predicted that anemia is least severe in IL28B non-CC (rs12979860, CT or TT), ITPA variant subjects, followed by IL28B non-CC, ITPA wild-type, IL28B CC, ITPA variant, and IL28B CC, ITPA wild-type subjects (most severe). Reducing the ribavirin dose from 1,200/1,000 mg to 800/600 mg could reduce the proportions of grade 2 anemia by about half. The resulting model framework will aid the development of dosing strategies that minimize the incidence of anemia in treatment regimens that include ribavirin.
Collapse
Affiliation(s)
- LS Wu
- University of Southern California, Biomedical EngineeringLos AngelesCaliforniaUSA
| | - LC Jimmerson
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - CE MacBrayne
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - JJ Kiser
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - DZ D'Argenio
- University of Southern California, Biomedical EngineeringLos AngelesCaliforniaUSA
| |
Collapse
|
|
6
|
Hwang JJ, Lo CC, Lin CH, Cheng HS, Hung IW, Tsai WJ, Hung CH. Association between IPTA gene polymorphisms and hematological abnormalities in hepatitis C virus-infected patients receiving combination therapy. Gut Liver 2015; 9:214-23. [PMID: 25287171 PMCID: PMC4351029 DOI: 10.5009/gnl14095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background/Aims Hematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon α and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combination treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the association between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy. Methods In this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy. Results The ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86×10−6) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055). Conclusions The ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy.
Collapse
Affiliation(s)
- Jow Jyh Hwang
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital and Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
| | - Ching Chu Lo
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Chien Hung Lin
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Hsu Sheng Cheng
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - I Wen Hung
- Outpatient Nursing Section, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Wan Ju Tsai
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
| | - Chien Hui Hung
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
| |
Collapse
|
|
7
|
Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
Collapse
|
|
8
|
Liu CH, Liu CJ, Huang CF, Lin JW, Dai CY, Liang CC, Huang JF, Hung PH, Tsai HB, Tsai MK, Lee CY, Chen SI, Yang SS, Su TH, Yang HC, Chen PJ, Chen DS, Chuang WL, Yu ML, Kao JH. Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial. Gut 2015; 64:303-311. [PMID: 24747867 DOI: 10.1136/gutjnl-2014-307080] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Data comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited. DESIGN In this randomised trial, 172 patients received 24 weeks of peginterferon alfa-2a 135 μg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 μg/week (n=86). The efficacy and safety endpoints were sustained virological response (SVR) rate and adverse event (AE)-related withdrawal rate. RESULTS Compared with monotherapy, combination therapy had a greater SVR rate (74% vs 44%, relative risk (RR): 1.68 [95% CI 1.29 to 2.20]; p<0.001). The beneficial effect of combination therapy was more pronounced in patients with baseline viral load ≥800,000 IU/mL than those with baseline viral load <800,000 IU/mL (RR: 3.08 [95% CI 1.80 to 5.29] vs. RR: 1.11 [95% CI 0.83 to 1.45]; interaction p=0.001). Patients receiving combination therapy were more likely to have a haemoglobin level of <8.5 g/dL (70% vs. 8%, risk difference (RD): 62% [95% CI 50% to 73%]; p<0.001) and required a higher dosage [mean: 13,417 vs. 6667 IU/week, p=0.027] of epoetin β to manage anaemia than those receiving monotherapy. The AE-related withdrawal rates were 6% and 3% in combination therapy and monotherapy groups, respectively (RD: 2% [95% CI -4% to 9%]). CONCLUSIONS In treatment-naive haemodialysis patients with HCV-2 infection, combination therapy with peginterferon plus low-dose ribavirin achieved a greater SVR rate than peginterferon monotherapy. Most haemodialysis patients can tolerate combination therapy. TRIAL REGISTRATION NUMBER ClinicalTrial.gov number, NCT00491244.
Collapse
Affiliation(s)
- Chen-Hua Liu
- 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
| | - Chun-Jen Liu
- 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
| | - Chung-Feng Huang
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Jou-Wei Lin
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Chao Liang
- Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Peir-Haur Hung
- Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi, Taiwan
| | - Hung-Bin Tsai
- Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Chia-Yi, Taiwan
| | - Meng-Kun Tsai
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-I Chen
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Sheng-Shun Yang
- Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tung-Hung Su
- 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
| | - Hung-Chih Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Department of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- 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
| | - Ding-Shinn Chen
- 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 Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 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
| |
Collapse
|
|
9
|
Opravil M, Rodriguez-Torres M, Rockstroh J, Snoeck E, Chung RT, Tietz A, Torriani FJ. The Dose-Response Relationship of Peginterferon Alfa-2a and Ribavirin in the Treatment of Patients Coinfected with HIV-HCV. HIV CLINICAL TRIALS 2015. [DOI: 10.1310/hct1301-33] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
10
|
Dienstag JL, Delemos AS. Viral Hepatitis. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1439-1468.e7. [DOI: 10.1016/b978-1-4557-4801-3.00119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
11
|
Muir AJ, Arora S, Everson G, Flisiak R, George J, Ghalib R, Gordon SC, Gray T, Greenbloom S, Hassanein T, Hillson J, Horga MA, Jacobson IM, Jeffers L, Kowdley KV, Lawitz E, Lueth S, Rodriguez-Torres M, Rustgi V, Shemanski L, Shiffman ML, Srinivasan S, Vargas HE, Vierling JM, Xu D, Lopez-Talavera JC, Zeuzem S. A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. J Hepatol 2014; 61:1238-46. [PMID: 25064437 DOI: 10.1016/j.jhep.2014.07.022] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 07/03/2014] [Accepted: 07/15/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
Collapse
Affiliation(s)
- Andrew J Muir
- Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | | | | | | | - Jacob George
- Westmead Hospital, Westmead Millennium Institute and University of Sydney, Westmead, NSW, Australia
| | - Reem Ghalib
- Texas Clinical Research Institute, Arlington, TX, USA
| | | | - Todd Gray
- ZymoGenetics, Bristol-Myers Squibb, Seattle, WA, USA
| | | | | | - Jan Hillson
- ZymoGenetics, Bristol-Myers Squibb, Seattle, WA, USA
| | | | | | | | | | - Eric Lawitz
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
| | - Stefan Lueth
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | | | | | | | - John M Vierling
- Advanced Liver Therapies at St. Luke's Episcopal Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Dong Xu
- Research and Development, Bristol-Myers Squibb, Wallingford, CT, USA
| | | | - Stefan Zeuzem
- Department of Medicine, JW Goethe University Hospital, Frankfurt, Germany
| | | |
Collapse
|
|
12
|
Rosina F, Tosti ME, Borghesio E, Masocco M, Mele A, Coppola C, Milella M, Borgia G, Andreone P, Koch M, Zignego AL, Romano M, Carrara M, Almasio PL, Azzola E, Nardone G, Benedetti A, Carosi G, Mazzotta F, Sagnelli E, Rizzetto M. Pegylated interferon α plus ribavirin for the treatment of chronic hepatitis C: a multicentre independent study supported by the Italian Drug Agency. Dig Liver Dis 2014; 46:826-832. [PMID: 24986781 DOI: 10.1016/j.dld.2014.05.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 05/12/2014] [Accepted: 05/18/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in "real world" chronic hepatitis C patients in Italy. METHODS Independent observational multicentre study including consecutive patients receiving Peg-interferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. RESULTS 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase. Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%). During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and γ-glutamil-transpeptidase >2 times the normal limit were associated with poorer response. CONCLUSIONS The response to Peg-interferon/ribavirin therapy in "real world" clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-to-treat than among difficult-to-treat hepatitis C virus genotypes.
Collapse
Affiliation(s)
- Floriano Rosina
- Gastroenterology & Hepatology Unit, Gradenigo Hospital, Torino, Italy.
| | - Maria Elena Tosti
- National Centre for Epidemiology, Surveillance and Health Promotion, Italian National Institute of Health (ISS), Rome, Italy
| | | | - Maria Masocco
- National Centre for Epidemiology, Surveillance and Health Promotion, Italian National Institute of Health (ISS), Rome, Italy
| | - Alfonso Mele
- National Centre for Epidemiology, Surveillance and Health Promotion, Italian National Institute of Health (ISS), Rome, Italy
| | - Carmine Coppola
- Hepatology & Interventional Ultrasound Unit, Gragnano Hospital, Gragnano (NA), Italy
| | - Michele Milella
- Institute of Infectious Diseases, Bari University, Bari, Italy
| | - Guglielmo Borgia
- Infectious and Parasitic Diseases Unit, Federico II University, Napoli, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Bologna University, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Maurizio Koch
- Gastroenterology & Hepatology Unit, San Filippo Neri Hospital, Rome, Italy
| | - Anna Linda Zignego
- Department of Experimental and Clinical Medicine, Florence University, Florence, Italy
| | - Mario Romano
- Internal Medicine I & Hepatology Unit, S. Pertini Hospital, Rome, Italy
| | - Maurizio Carrara
- Hepatology Unit - Gastroenterology Unit, Orlandi Hospital, Bussolengo (VR), Italy
| | - Piero Luigi Almasio
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., Palermo University, Palermo, Italy
| | - Emilio Azzola
- Gastroenterology & Digestive Endoscopy Unit, Santa Corona Hospital, Pietra Ligure (SV), Italy
| | - Gerardo Nardone
- Department of Clinical Medicine & Surgery, Gastroenterology Unit, Federico II University, Napoli, Italy
| | - Antonio Benedetti
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy
| | - Giampiero Carosi
- Institute of Infectious and Tropical Diseases, Brescia University, Brescia, Italy
| | | | - Evangelista Sagnelli
- Infectious and Tropical Diseases Unit, S. Anna and S. Sebastiano Hospital, Naples Second University, Caserta, Italy
| | - Mario Rizzetto
- Gastroenterology & Hepatology Unit, Torino University, Torino, Italy
| |
Collapse
|
|
13
|
Quiles-Pérez R, Pavón-Castillero EJ, Muñoz-de-Rueda P, Carmona I, Salmerón J. Valor de la genética en la era de la terapia triple frente al virus de la hepatitis C. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:427-37. [PMID: 24948442 DOI: 10.1016/j.gastrohep.2014.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 04/09/2014] [Accepted: 04/15/2014] [Indexed: 12/19/2022]
|
|
14
|
Salmon-Ceron D, Arvieux C, Bourlière M, Cacoub P, Halfon P, Lacombe K, Pageaux GP, Pialoux G, Piroth L, Poizot-Martin I, Rosenthal E, Pol S. Use of first-generation HCV protease inhibitors in patients coinfected by HIV and HCV genotype 1. Liver Int 2014; 34:869-89. [PMID: 24138548 DOI: 10.1111/liv.12363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 10/13/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND In HCV genotype 1-infected patients with HIV co-infection, tritherapy [HCV protease inhibitors (PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern. METHODS Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver (AFEF) on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV monoinfection was examined to determine whether it could be used in the context of HIV/HCV coinfection. RESULTS These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts.
Collapse
Affiliation(s)
- Dominique Salmon-Ceron
- Paris Descartes University, Paris, France; APHP, Department of Internal Medicine, Infectious Diseases Unit, Cochin Hospital, Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Dixit VK, Ghosh JK, Lamtha SC, Kaushik P, Goyal SK, Behera MK, Singh N, Jain AK. Clinical Profile and Response to Treatment with Pegylated Interferon α 2b and Ribavirin in Chronic Hepatitis C-A Reappraisal from a Tertiary Care Center in Northern India. J Clin Exp Hepatol 2014; 4:101-5. [PMID: 25755547 PMCID: PMC4116705 DOI: 10.1016/j.jceh.2014.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 05/22/2014] [Indexed: 12/12/2022] Open
Abstract
AIM To assess the clinical profile of 80 chronic hepatitis C patients in a tertiary health care center in Northern India and also to study the efficacy and tolerability of pegylated interferon (Peg-IFN) α 2b and ribavirin therapy in a cohort of chronic hepatitis C patients. METHODS Thirty subjects with chronic hepatitis C (CH-C) with genotypes 2 and 3 received Peg-IFN α 2b 1.5 μg/kg subcutaneously weekly plus daily ribavirin 800 mg for 24 weeks .Subjects with genotype 1 infection received therapy for 48 weeks with ribavirin 1000 mg/day and Peg-IFN α 2b dose remained the same. The primary end point was the sustained viral response (SVR). Drug dosage was modified or temporarily discontinued if anemia or bone marrow suppression developed. RESULTS The clinical profile of chronic hepatitis C infected patients showed decompensated cirrhosis in the more elderly patients. Genotype 3 was the commonest genotype and was seen in 21 (70%) patients. The mean baseline HCV RNA was high. SVR was achieved less commonly with genotype 1 than with genotype 2/3. Patients who became negative for HCV RNA at 4-weeks (rapid virological response or RVR) and 12 weeks (early virological response or EVR) of treatment showed significantly higher sustained virological response (SVR) rates. Similarly, patients who showed normalization of ALT level at 4-weeks and 12-weeks of treatment showed significant high rate of SVR. Overall treatment was well tolerated. CONCLUSION In our region, CHC subjects have high viral load and genotype 3 being the most common. Treatment with Peg-IFN α 2b and ribavirin is effective and well tolerated. Genotype 1 was more resistant to the treatment. Patients who achieved RVR and EVR are more likely to achieve SVR. Although the numbers of patients in this study was small, considering the paucity of data of treatment from India, the data is relevant.
Collapse
Affiliation(s)
- Vinod K. Dixit
- Address for correspondence: Vinod K. Dixit, Professor, Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India. Tel.: +91 9415202449 (mobile).
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
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.
Collapse
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 ;
| |
Collapse
|
|
17
|
Walzer N, Flamm SL. Pegylated IFN-α and ribavirin: emerging data in the treatment of special populations. Expert Rev Clin Pharmacol 2014; 2:67-76. [PMID: 24422772 DOI: 10.1586/17512433.2.1.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and is currently the leading indication for liver transplantation in the USA. Pegylated IFN-α (PEG-IFN-α) and ribavirin comprise the standard of care for the treatment of chronic HCV. The expansion of antiviral therapy to include special populations that were not well represented or excluded from registration trials has occurred in recent years. Data have emerged that demonstrate that these groups have variable responses to therapy and, in some cases, different side-effect profiles. The etiologies for the varied response rates remain under investigation. This review will address the clinical efficacy and safety profiles of PEG-IFN-α and ribavirin in populations of patients coinfected with HIV, obese patients, liver transplant recipients, children and African-Americans.
Collapse
Affiliation(s)
- Natasha Walzer
- Northwestern Feinberg School of Medicine, 675 N St Clair Galter 15-250, Chicago, IL 60611, USA
| | | |
Collapse
|
|
18
|
Fernández-Rodríguez CM, Morillas RM, Masnou H, Navarro JM, Bárcena R, González JM, Martín-Martín L, Poyato A, Miquel-Planas M, Jorquera F, Casanovas T, Salmerón J, Calleja JL, Solà R, Alonso S, Planas R, Romero-Gomez M. Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:1-8. [PMID: 24360571 DOI: 10.1016/j.gastrohep.2013.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/01/2013] [Accepted: 10/08/2013] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). OBJECTIVES To assess the impact of high doses of RBV on SVR in patients with G3 and HVL. METHODS Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13). RESULTS RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. CONCLUSIONS G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609).
Collapse
Affiliation(s)
| | - Rosa María Morillas
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Helena Masnou
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - José María Navarro
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Rafael Bárcena
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - José Manuel González
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Leticia Martín-Martín
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Antonio Poyato
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Mireia Miquel-Planas
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Francisco Jorquera
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Teresa Casanovas
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Javier Salmerón
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - José Luis Calleja
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Ricard Solà
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Sonia Alonso
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Ramón Planas
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| | - Manuel Romero-Gomez
- Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain
| |
Collapse
|
|
19
|
Omer MO, AlMalki WH, Shahid I, Khuram S, Altaf I, Imran S. Comparative study to evaluate the anti-viral efficacy of Glycyrrhiza glabra extract and ribavirin against the Newcastle disease virus. Pharmacognosy Res 2014; 6:6-11. [PMID: 24497736 PMCID: PMC3897011 DOI: 10.4103/0974-8490.122911] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 08/26/2013] [Accepted: 12/12/2013] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The Newcastle disease represents as one of the most infectious viral disease, which afflicts almost every species of the birds. The causative agent of the disease is a single-stranded RNA virus with rapid replication capability. OBJECTIVE This study was performed to evaluate the comparative anti-viral efficacy and toxicity of Glycyrrhiza glabra aqueous extract and ribavirin against the Newcastle disease virus. MATERIALS AND METHODS The embryonated eggs were divided into six groups (A, B, C, D, E and F). Groups A, B, C, and D were further subdivided into three subgroups. The virus was identified by hemagglutination inhibition test. Spot hemagglutination test and viability of embryos were also evaluated. Three different concentrations i-e., 30 mg/100 ml, 60 mg/100 ml, and 120 mg/100 ml of the Glycyrrhiza aqueous extract and 10 μg/ml, 20 μg/ml, and 40 μg/ml ribavirin in deionized water were evaluated for their toxicity and anti-viral activity in the embryonated eggs. RESULTS 60 mg/100 ml concentration of Glycyrrhiza extract did not produce any toxicity in the embryonated eggs and showed anti-viral activity against the virus. Similarly, 20 μg/ml ribavirin was non-toxic in the embryonated eggs and contained anti-viral activity. CONCLUSION It may conclude from the presented study that 60 mg/100 ml Glycyrrhiza extract inhibits replication of Newcastle disease virus and is non-toxic in the embryonated eggs. So, Glycyrrhiza glabra extract may be further evaluated in future to determine the potentially active compounds for their anti-viral activity against Newcastle disease virus. Furthermore, the mechanism of action of these active phytochemicals as an antiviral agent would be helpful to elucidate the pathogenesis of the disease.
Collapse
Affiliation(s)
- Muhammad Ovais Omer
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Waleed Hassan AlMalki
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, P. O. Box 13174, Makkah, The Kingdom of Saudi Arabia
| | - Imran Shahid
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, P. O. Box 13174, Makkah, The Kingdom of Saudi Arabia
| | - Shahzada Khuram
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Imran Altaf
- WTO Quality Control Lab, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Saeed Imran
- WTO Quality Control Lab, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| |
Collapse
|
|
20
|
Aljumah AA, Murad MH. Pegylated versus standard interferon plus ribavirin in chronic hepatitis C genotype 4: A systematic review and meta-analysis. Hepatol Res 2013; 43:1255-63. [PMID: 23458104 DOI: 10.1111/hepr.12084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 01/23/2013] [Accepted: 01/29/2013] [Indexed: 02/08/2023]
Abstract
AIM Treatment of hepatitis C genotype 4 (HCV-G4) with pegylated interferon (PEG IFN) has not been adequately studied and is considered to be challenging. The aim of this meta-analysis is to systematically review and evaluate the effectiveness of 48 weeks of combined PEG IFN plus ribavirin (RBV) compared to standard interferon (IFN) plus RBV. The outcome of interest is sustained virological response (SVR). METHODS We searched for eligible randomized controlled trials (RCT) through May 2012. Random effects meta-analysis was used to pool the risk ratio (RR) of achieving SVR across trials. RESULTS Five RCT enrolling 386 patients were included. The PEG IFN/RBV group had increased likelihood of achieving SVR (RR = 1.51, 95% confidence interval [CI] = 1.08-2.10). SVR was significantly higher in PEG IFN-α-2a compared to the -α-2b group (P = 0.02). There was no statistically significant effect of ribavirin dosage on SVR (P = 0.55). The quality of evidence was moderate overall and limited by heterogeneity. CONCLUSION In treatment-naive patients with HCV-G4, treatment with PEG IFN plus RBV achieves higher SVR rate than treatment with IFN plus RBV.
Collapse
Affiliation(s)
- Abdulrahman A Aljumah
- Hepatology Division, Department of Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City and King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
| | | |
Collapse
|
|
21
|
Romero-Gómez M, Berenguer M, Molina E, Calleja JL. Management of anemia induced by triple therapy in patients with chronic hepatitis C: challenges, opportunities and recommendations. J Hepatol 2013; 59:1323-30. [PMID: 23867320 DOI: 10.1016/j.jhep.2013.07.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 06/20/2013] [Accepted: 07/08/2013] [Indexed: 12/13/2022]
Abstract
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.
Collapse
Affiliation(s)
- Manuel Romero-Gómez
- UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain
| | | | | | | |
Collapse
|
|
22
|
Clark PJ, Aghemo A, Degasperi E, Galmozzi E, Urban TJ, Vock DM, Patel K, Thompson AJ, Rumi MG, D'Ambrosio R, Muir AJ, Colombo M. Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy. J Viral Hepat 2013; 20:858-66. [PMID: 24304455 DOI: 10.1111/jvh.12113] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 03/07/2013] [Indexed: 12/13/2022]
Abstract
Anaemia frequently complicates peginterferon/ribavirin therapy for chronic hepatitis C infection. Better prediction of anaemia, ribavirin dose reduction or erythropoietin (EPO) need, may enhance patient management. Inosine triphosphatase (ITPA) genetic variants are associated with ribavirin-induced anaemia and dose reduction; however, their impact in real-life clinic patient cohorts remains to be defined. We studied 193 clinic patients with chronic hepatitis C infection of mixed viral genotype (genotype 1/4 n = 123, genotype 2/3, n = 70) treated with peginterferon/ribavirin. Patients were genotyped for ITPA polymorphisms rs1127354 and rs7270101 using Taqman primers. Hardy-Weinberg equilibrium was present. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe, n = 126/40/24/3, respectively). Multivariable models tested the association with anaemia at 4 weeks of treatment [including decline in haemoglobin (g/dL); haemoglobin <10 g/dL and haemoglobin decline >3 g/dL]; ribavirin dose reduction and EPO use and explored sustained viral response (SVR) to peginterferon/ribavirin. More severe ITPA deficiency was associated with less reduction in haemoglobin level (P <0.001; R(2) = 0.34), less ribavirin dose reduction (OR 0.42; (95% CI = 0.23-0.77); P = 0.005) and less EPO use [OR 0.53; (0.30-0.94); P = 0.029]. ITPA deficiency was associated with SVR [OR: 1.70; (1.02-2.83); P = 0.041] independently of clinical covariates (adjusted R(2) = 0.31). In this clinical cohort, ITPA deficiency helped predict the risk of on-treatment anaemia, ribavirin dose reduction, need for EPO support and was associated with SVR. For patients on HCV regimens including peginterferon/ribavirin, testing for ITPA deficiency may have clinical utility.
Collapse
Affiliation(s)
- P J Clark
- GI/Hepatology, Duke Clinical Research Institute, Durham, NC, USA; Princess Alexandra Hospital, Brisbane, Qld, Australia; Queensland Institute of Medical Research, Brisbane, Qld, Australia
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Zhou H, Luo H, Xiao S, Wang H, Gong G. Predictors for dose reduction of antiviral therapy in older patients infected with hepatitis C virus: a meta-regression analysis. Eur J Clin Microbiol Infect Dis 2013; 33:491-8. [PMID: 24193376 DOI: 10.1007/s10096-013-1992-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 09/30/2013] [Indexed: 01/19/2023]
Abstract
Treatment-related adverse events (AE) were more frequent in older patients treated by pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC), and most of them required dose reduction. A meta-regression analysis was conducted to explore the possible reasons for this occurrence. We searched MEDLINE, EMBASE, and Web of Science through May 2013, for clinical trials examining the safety of PEG-IFN plus RBV in elderly patients with CHC. Data were extracted for host, viral, and outcome information. Single-arm meta-analysis was performed to evaluate AE. Meta-regression analysis was conducted to explore predictors for dose reduction secondary to AE. Eighteen observational studies met the inclusion criteria. The overall incidences of AE were 61.3%. Dose reductions due to AE were 54.2%. In patients with genotype 1, the rate of sustained virological response (SVR) was 36.9%. In patients with genotypes 2 or 3, the rate of SVR was 72.8%. Patients with more dose reduction due to AE have a tendency toward a lower likelihood of obtaining SVR (coefficient:-0.529), especially for genotype 1 patients. Host factors (male gender, coefficient 4.403; higher body weight, coefficient 0.140; and advanced fibrosis stage, coefficient 1.582) and viral factors (HCV genotype 1, coefficient 2.279) have a significant impact on dose reduction due to AE. Some host and viral factors affected dose reduction due to AE. Increasing rates of fibrosis with age may play a role as a mechanism affecting dose reduction secondary to AE and SVR in different age groups.
Collapse
Affiliation(s)
- H Zhou
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, 139 Renming Middle Road, Changsha, Hunan Province, 410011, China
| | | | | | | | | |
Collapse
|
|
24
|
Amjad M, Moudgal V, Faisal M. Laboratory Methods for Diagnosis and Management of Hepatitis C Virus Infection. Lab Med 2013. [DOI: 10.1309/lmasroyd8brs0gc9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
|
|
25
|
Tamai H, Mori Y, Shingaki N, Kawashima A, Tsukuda H, Higashi K, Moribata K, Kawaguchi M, Ueda K, Deguchi H, Inoue I, Maekita T, Iguchi M, Kato J, Ichinose M. Low-dose pegylated interferon-α2a plus ribavirin therapy for elderly and/or cirrhotic patients with HCV genotype-1b and high viral load. Antivir Ther 2013; 19:107-15. [PMID: 24162072 DOI: 10.3851/imp2696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Pegylated interferon (PEG-IFN) plus ribavirin therapy is still recommended for elderly and/or cirrhotic patients. This study examined whether sustained virological response (SVR) to low-dose PEG-IFN-α2a plus ribavirin therapy for elderly and/or cirrhotic patients could be predicted based on viral reduction within 2 weeks after therapy initiation or interleukin IL-(28B) polymorphism and viral mutations. METHODS Participants comprised 115 elderly (≥65 years) and/or cirrhotic patients with genotype-1b and high viral load. Reduced doses of PEG-IFN-α2a (90 μg/kg/week) and ribavirin (400-800 mg/day) were administered for 48-72 weeks based on virological response of each patient. RESULTS SVR was achieved in 34% (39/115), and treatment was discontinued in 15% (17/115). Univariate analysis identified age, α-fetoprotein, fibrosis marker, interferon sensitivity-determining region (ISDR), IL-28B polymorphism and level of viral reduction within 2 weeks as factors contributing significantly to SVR. However, no significant differences were noted in core amino acid substitutions. Multivariate analysis identified age, hyaluronic acid, ISDR and viral reduction as factors independently associated with SVR. Positive predictive value (PPV) and negative predictive value (NPV) of SVR based on the level of viral reduction at 2 weeks (cutoff level, 1.7 log IU/ml) were 83% and 84%, respectively. The PPV of SVR based on IL-28B major and ISDR mutant was 70%, and the NPV of SVR based on IL-28B minor and wild-type ISDR was 89%. CONCLUSIONS Evaluations of viral reduction at 2 weeks or both IL-28B and ISDR are useful to predict SVR to low-dose PEG-IFN-α2a plus ribavirin therapy for elderly and/or cirrhotic patients.
Collapse
Affiliation(s)
- Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama City, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Lin KH, Yu HC, Hsu PI, Tsai WL, Chen WC, Lin CK, Chan HH, Tsay FW, Lai KH. Baseline high viral load and unfavorable patterns of alanine aminotransferase change predict virological relapse in patients with chronic hepatitis C genotype 1 or 2 obtaining rapid virological response during antiviral therapy. HEPATITIS MONTHLY 2013; 13:e11892. [PMID: 24348635 PMCID: PMC3842527 DOI: 10.5812/hepatmon.11892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 08/27/2013] [Accepted: 09/28/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Rapid virological response (RVR) strongly predicts sustained virological response (SVR) in patients with chronic hepatitis C (CHC), and abbreviates antiviral therapy in some patients. OBJECTIVES To identify factors predicting virological relapse (VR) in CHC patients who attained RVR. PATIENTS AND METHODS Medical records of 133 CHC patients with an RVR after completing 24 weeks of antiviral therapy (a combination of pegylated interferon-α and ribavirin) were analyzed. Baseline characteristics and on-treatment responses were compared between the patients with an SVR and those with VR. Patients with normal alanine aminotransferase (ALT) levels at weeks 4 and 12 and at the end-of-treatment (EoT) and patients with elevated, but constantly decreasing, ALT levels were classified as having favorable patterns of ALT change. A trend of increasing ALT levels either between weeks 4 and 12 or between weeks 12 and EoT was classified as unfavorable. A high viral load (HVL) was defined as a baseline HCV RNA ≥ 600000 IU/mL. RESULTS In total, 116 (87.2%) patients had a SVR and 14 (10.5%) had VR. The VR rates were comparable between patients with genotype-1 (13.1%) and genotype-2 infection (8.7%) (P = 0.572). Multivariate analysis revealed that HVL (P = 0.015; odds ratio [OR] = 14.754; 95% confidence interval (CI) = 1.671-130.240), and unfavorable ALT patterns (P = 0.039; OR = 4.397; 95% CI = 1.078-17.930) independently predicted VR. In subgroup analysis, low viral load (LVL) patients had a minimal VR rate (1.8%). Among the HVL patients, the VR rate of those using peg-IFN-α-2a was relatively low (9.1%). Patients using peg-IFN-α-2b had a slightly higher VR rate (23.8%; P = 0.128), and patients with favorable patterns of ALT changes had a lower VR rate (10.3%) compared to the 53.8% in patients with unfavorable ALT patterns (P = 0.005). CONCLUSIONS In southern Taiwan, 24 weeks of antiviral therapy achieved a high SVR rate in patients with CHC attaining RVR, except in the subgroup of patients treated with peg-IFN-α-2b with HVL and on-treatment unfavorable ALT patterns.
Collapse
Affiliation(s)
- Kung-Hung Lin
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Physical Examination Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Hsien-Chung Yu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Corresponding author: Hsien-Chung Yu, Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Tel: +886-73422121, Fax: +886-73468237, E-mail:
| | - Ping-I Hsu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wei-Lun Tsai
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wen-Chi Chen
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chun-Ku Lin
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Fong-Wei Tsay
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Kwok-Hung Lai
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
27
|
Abstract
Despite the incontestable benefits of telaprevir and boceprevir-based triple therapy in patients infected with genotype 1, the practitioner faces a number of new challenges. In daily clinical practice, a checklist approach may facilitate the management of triple therapy. Before initiation, several specific issues should be reviewed with the patient in order to optimize adherence and treatment outcome: potential drug to drug interaction, treatment duration and stopping rules, possible treatment outcomes, side effects, dose and administration with food advice, management of side effects. Because treatment failure is associated with the emergence of resistance-associated variants with reduced sensitivity to protease inhibitors, adherence is of major importance. In this setting, the role of educational nurse should be emphasized for the management of triple therapy in daily clinical practice.
Collapse
Affiliation(s)
- Lawrence Serfaty
- Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Service d'Hépatologie, INSERM UMR_938, Hôpital Saint-Antoine, Paris, France.
| |
Collapse
|
|
28
|
Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother 2013; 57:6097-105. [PMID: 24080649 DOI: 10.1128/aac.00608-13] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.
Collapse
|
|
29
|
Kim JS, Ahn SM, Jung YK, Kwon OS, Kim YS, Choi DJ, Kim JH. The impact of inosine triphosphatase variants on hemoglobin level and sustained virologic response of chronic hepatitis C in Korean. J Korean Med Sci 2013; 28:1213-9. [PMID: 23960450 PMCID: PMC3744711 DOI: 10.3346/jkms.2013.28.8.1213] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Accepted: 05/22/2013] [Indexed: 01/30/2023] Open
Abstract
TWO VARIANTS OF THE INOSINE TRIPHOSPHATASE (ITPA rs1127354, rs7270101) gene cause ITPA deficiency and protect against the hemolytic toxicity of ribavirin. We investigated the clinical significance of ITPA variants in Korean patients treated with pegylated interferon (PEG-IFN) plus ribavirin. Of the 133 patients, 108 were CC and 25 were non-CC at rs1127354 (groups A and B, respectively). On the other hand, at rs7270101 all 133 were AA. The mean values of Hemoglobin (Hgb) after 4, 8, and 12 weeks of treatment in groups A and B were 12.2 and 14.0, 11.8 and 13.2, and 11.5 and 12.9, respectively (P=0.001, 0.036, 0.036). Sustained virologic response (SVR) was achieved in 67.8% (40/59) of genotype 1 patients and in 75% (27/36) of non-genotype 1 patients. Regarding ITPA variants, SVR was achieved by 66% and 80% of genotype 1 (P=0.282), and by 78% and 71% (P=0.726) of non-genotype 1. SVR was not significantly different in groups A and B. In conclusion, non-CC at rs1127354 without involvement of rs7270101 is strongly associated with protection from ribavirin-induced anemia, however, ITPA genotype is not associated with SVR.
Collapse
Affiliation(s)
- Ju Seung Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| | - Sung-Min Ahn
- Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Young Kul Jung
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| | - Oh Sang Kwon
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| | - Yun Soo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| | - Duck Joo Choi
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| | - Ju Hyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, Korea
| |
Collapse
|
|
30
|
Slim J, Mildvan D, Han J, Korner E. The association of cytopenias and weight loss with hepatitis C virus virologic response in HIV/HCV-coinfected patients treated with PEG-IFN and RBV. J Int Assoc Provid AIDS Care 2013; 12:354-62. [PMID: 23873217 DOI: 10.1177/2325957413494828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Pegylated interferon (PEG-IFN)/ribavirin (RBV)-related cytopenias have been associated with improved virological outcomes among hepatitis C virus (HCV)-monoinfected patients. This analysis evaluated PEG-IFN/RBV-related cytopenias with virological responses among HIV/HCV-coinfected patients. METHODS Pooled data from PARADIGM and AIDS Pegasys Ribavirin International CO-infection Trial (APRICOT) trials of HIV/HCV-infected patients treated with PEG-IFN/RBV. Virologic response was categorized as HCV RNA detectable (end of treatment nonresponders [ET-NR]) or nondetectable (end of treatment responders [ETR]). Declines in hemoglobin (Hgb), platelets, neutrophils, lymphocytes, and weight between the groups were compared via analysis of covariance and Cochran-Mantel-Haenszel test. RESULTS A total of 474 patients, 291 ET-NR and 183 ETR (67 relapsers, 116 with sustained virologic response), 81% male, 52% Caucasian, 88% noncirrhotic, and 67% nondetectable HIV. The ETR experienced greater Hgb declines (≥3.0 g/dL) from baseline (73.8% versus 55.0%; P < .0001), neutrophils ≤1 and ≤ 0.5 × 10(9)/L (66.1% versus 56.4%; P = .0334 and 42.6% versus 33.3%; P = .0312, respectively), and lymphocytes ≤1.5 and ≤0.5 × 10(9)/L (99.5% versus 87.6%; P < .0001 and 24.6% versus 14.9%; P =.0079, respectively). CONCLUSIONS The HIV/HCV-coinfected patients with ETR experienced greater declines in Hgb, neutrophils, and lymphocytes than the ET-NR patients.
Collapse
Affiliation(s)
- Jihad Slim
- St Michael's Medical Center, Newark, NJ, USA
| | | | | | | |
Collapse
|
|
31
|
Ravi S, Nasiri Toosi M, Karimzadeh I, Ahadi-Barzoki M, Khalili H. Adherence to chronic hepatitis C treatment regimen: first report from a referral center in iran. HEPATITIS MONTHLY 2013; 13:e11038. [PMID: 24032043 PMCID: PMC3759779 DOI: 10.5812/hepatmon.11038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Revised: 04/08/2013] [Accepted: 05/25/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Various aspects of adherence to HCV treatment such as frequency, risk factors as well as causes of non-adherence, and its real role in clinical and virological outcome of the infected patients have remained largely unknown. OBJECTIVES The current study aimed to evaluate patients' adherence to anti-HCV medications in Iran. MATERIALS AND METHODS From October 2010 to March 2011, socio-demographic characteristics, features of HCV infection, clinical properties, and habitual history of 190 patients were collected. Adherence of each patient to anti-HCV medications was determined at months 1, 3, and 6 of treatment by self-reporting and pill or empty ampoule counting. Adherence to anti-HCV treatment regimen was determined based on the 80/80/80 rule. RESULTS Adherence rate to interferon, ribavirin, or a combination of them over the first 6 months of therapy in Iranian HCV patients measured by both methods of self-reporting and pill counting were 35.4-65.8%, 46.3-56.8%, and 28.4-51.1%, respectively. Delay in receiving new prescription, financial issues, and adverse drug reactions were the most common causes of non-adherence in the patients. Adherence to ribavirin was identified as an independent predictor of achieving the end of treatment response, or sustained virological response. CONCLUSIONS The rate of adherence to interferon and ribavirin varied significantly according to the method of calculation. Over the treatment course, adherence to interferon alpha and ribavirin, each or their combination, diminished significantly.
Collapse
Affiliation(s)
- Saeedeh Ravi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
- Department of Clinical Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, IR Iran
| | - Mohsen Nasiri Toosi
- Department of Gastroenterology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Iman Karimzadeh
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehdi Ahadi-Barzoki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Zanjan University of Medical Sciences, Zanjan, IR Iran
| | - Hossein Khalili
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Hossein Khalili, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box: 14155/6451, Tehran, IR Iran. Tel: +98-9122979329, Fax: +98-2166461178, E-mail:
| |
Collapse
|
|
32
|
Slim J, Afridi MS. Managing adverse effects of interferon-alfa and ribavirin in combination therapy for HCV. Infect Dis Clin North Am 2013; 26:917-29. [PMID: 23083824 DOI: 10.1016/j.idc.2012.08.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
This article focuses on the adverse effects of hepatitis C therapy, which includes pegylated interferon alfa-2a or -2b with ribavirin. The hepatitis C virus provider should remain cognizant of the various organ systems that can be affected, which adverse effects should be addressed with the help of an expert, and the presentation of symptoms as they occur throughout the course of therapy. A systems-based approach should help to characterize the nature of the adverse effects that patients experience, and also to determine when patients should be further investigated by a consultant.
Collapse
Affiliation(s)
- Jihad Slim
- St. Michaels Medical Center, 111 Central Avenue, Newark, NJ 07102, USA.
| | | |
Collapse
|
|
33
|
AlMalki WH. HCV infection: an enigma, recent advances and new paradigms for its treatment. Future Virol 2013. [DOI: 10.2217/fvl.13.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
HCV infection is a serious human liver health problem and has infected 200 million people worldwide. Persistent HCV infection can lead to chronic hepatitis C, which is a significant risk of serious hepatic diseases such as hepatic steatosis, hepatic fibrosis and hepatocellular carcinoma. The current standard-of-care options to treat HCV infection are limited, expensive and produce side effects in infected patients that often cause termination of the therapy. Recently, the approval of direct-acting antivirals represents a major breakthrough for the improvement of treatment strategies against chronic HCV infection. Similarly, the development of more effective, safe and well-tolerated interferon therapy is opening a new era in HCV therapeutics. Moreover, a new vaccine technology has been tested in mice for its therapeutic efficacy against the most conserved regions of the HCV genome. This review article will focus on the recent advances in HCV therapeutics and discuss new paradigms to develop the most convenient drugs and treatment strategies.
Collapse
Affiliation(s)
- Waleed Hassan AlMalki
- Department of Pharmacology & Toxicology, College of Pharmacy, Umm Al-Qura University, PO Box 13578, Makkah, Saudi Arabia
| |
Collapse
|
|
34
|
Heo NY, Lim YS, Lee HC, Lee YS, Kim KM, Byun KS, Han KH, Lee KS, Paik SW, Yoon SK, Suh DJ. High effectiveness of peginterferon alfa-2a plus ribavirin therapy in Korean patients with chronic hepatitis C in clinical practice. Clin Mol Hepatol 2013; 19:60-9. [PMID: 23593611 PMCID: PMC3622857 DOI: 10.3350/cmh.2013.19.1.60] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 12/27/2012] [Accepted: 01/10/2013] [Indexed: 02/07/2023] Open
Abstract
Background/Aims Identifying the impact of a patient's ethnicity on treatment responses in clinical practice may assist in providing individualized treatment regimens for chronic hepatitis C (CHC). The effectiveness of standard peginterferon plus ribavirin therapy and the need for triple combination therapy with protease inhibitors in Koreans remain matters of debate. These issues were investigated in the present study. Methods The clinical data of 272 treatment-naïve Korean CHC patients who were treated in a community-based clinical trial (Clinical Trial group; n=51) and in clinical practice (Cohort group; n=221), were analyzed and compared. All were treated with standard protocols of peginterferon alfa-2a plus ribavirin therapy. Results For patients with hepatitis C virus (HCV) genotype 1, the sustained virological response (SVR) rates in the Clinical Trial and Cohort groups were 81% (21/26) and 55% (58/106), respectively, by intention-to-treat (ITT) analysis (P=0.02), and 100% (13/13) and 80% (32/40), respectively, in treatment-adherent patients (P=0.18). For patients with HCV genotype 2, the SVR rates in these two groups were 96% (24/25) and 88% (101/115), respectively, by ITT analysis (P=0.31). Adherence and treatment duration were independent predictors of SVR for genotypes 1 and 2, respectively (P<0.01 for each). Korean patients with CHC achieved high SVR rates with peginterferon alfa-2a plus ribavirin in both the clinical trial and clinical practice settings. Conclusions Measures to raise adherence to standard therapy in clinical practice may improve the SVR rates in these patients as effectively as adding protease inhibitors, thus obviating the need for the latter.
Collapse
Affiliation(s)
- Nae-Yun Heo
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Chávez-Tapia NC, Ridruejo E, Alves de Mattos A, Bessone F, Daruich J, Sánchez-Ávila JF, Cheinquer H, Zapata R, Uribe M, Bosques-Padilla F, Gadano A, Sosa A, Dávalos-Moscol M, Marroni C, Muñoz-Espinoza L, Castro-Narro G, Paraná R, Méndez-Sánchez N. An update on the management of hepatitis C: guidelines for protease inhibitor-based triple therapy from the Latin American Association for the Study of the Liver. Ann Hepatol 2013; 12 Suppl 2:s3-s35. [PMID: 23559487 DOI: 10.1016/s1665-2681(19)31404-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Hepatitis C is a common cause of end-stage liver disease, and the main indication for liver transplantation in Latin America. Treatment of hepatitis C infected patients improves important long-term outcomes as mortality. Sustained viral response is reached in near 50% of patients with the previous management based in pegylated interferon and ribavirin. Recently new drugs were available increasing sustained viral response significantly, changing the standard of care to triple therapy. This guidelines provides a framework for practitioner in Latin America, to the management of patients with hepatitis C chronic infection.
Collapse
|
|
36
|
Lo Re V, Teal V, Localio AR, Amorosa VK, Kaplan DE, Gross R. Adherence to hepatitis C virus therapy in HIV/hepatitis C-coinfected patients. AIDS Behav 2013; 17:94-103. [PMID: 22907288 DOI: 10.1007/s10461-012-0288-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Adherence to hepatitis C virus (HCV) therapy has been incompletely examined among HIV-infected patients. We assessed changes in interferon and ribavirin adherence and evaluated the relationship between adherence and early (EVR) and sustained virologic response (SVR). We performed a cohort study among 333 HIV/HCV-coinfected patients who received pegylated interferon and ribavirin between 2001 and 2006 and had HCV RNA before and after treatment. Adherence was calculated over 12-week intervals using pharmacy refills. Mean interferon and ribavirin adherence declined 2.5 and 4.1 percentage points per 12-week interval, respectively. Among genotype 1/4 patients, EVR increased with higher ribavirin adherence, but this association was less strong for interferon. SVR among these patients was higher with increasing interferon and ribavirin adherence over the first, second, and third, but not fourth, 12-week intervals. Among HIV/HCV patients, EVR and SVR increased with higher interferon and ribavirin adherence. Adherence to both antivirals declined over time, but more so for ribavirin.
Collapse
Affiliation(s)
- Vincent Lo Re
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | | | | | | | | | | |
Collapse
|
|
37
|
Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res 2013; 43:1-34. [PMID: 23332085 DOI: 10.1111/hepr.12020] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
-
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Tokyo Medical and Dental University
| |
Collapse
|
|
38
|
Leroy V, Serfaty L, Bourlière M, Bronowicki JP, Delasalle P, Pariente A, Pol S, Zoulim F, Pageaux GP. Protease inhibitor-based triple therapy in chronic hepatitis C: guidelines by the French Association for the Study of the Liver. Liver Int 2012; 32:1477-92. [PMID: 22891751 DOI: 10.1111/j.1478-3231.2012.02856.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 07/02/2012] [Indexed: 12/13/2022]
Abstract
The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed.
Collapse
Affiliation(s)
- Vincent Leroy
- Centre de Recherche INSERM-UJF U823, Institut Albert Bonniot et Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, CHU, Grenoble, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Kobayashi T, Hige S, Terashita K, Nakai M, Horimoto H, Sho T, Nakanishi M, Ogawa K, Chuma M, Sakamoto N, Asaka M. Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C. J Gastroenterol 2012; 47:1228-37. [PMID: 22460221 DOI: 10.1007/s00535-012-0579-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 02/28/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND An inosine triphosphatase (ITPA) single-nucleotide polymorphism (SNP) is associated with anemia induced by pegylated interferon and ribavirin (RBV) combination therapy in patients with chronic hepatitis C (CHC). However, there are very few reports on the hematological effects of RBV monotherapy. Here, hematological changes were monitored in patients with CHC who received RBV monotherapy, and the mechanism of these changes was investigated. METHODS Patients with CHC (n = 30) received RBV monotherapy for 4 weeks. The RBV dose was determined on the basis of body weight. Complete blood count, and serum erythropoietin (EPO) and thrombopoietin (TPO) levels were assessed. The associations between these parameters and the ITPA SNP (rs1127354) were analyzed. RESULTS Over the 4 weeks, the median hemoglobin level of all patients decreased significantly, from 13.6 (10.5-16.6) to 11.7 (9.4-14.9) g/dl (P < 0.001), and the platelet counts increased, from 14.0 × 10(4) (8.9-37.4 × 10(4)) to 15.8 × 10(4) (10.2-40.6 × 10(4)) /mm(3) (P = 0.003). At week 4, hemoglobin levels differed between patients with the ITPA CC genotype and those with the AA or AC genotypes [11.1 (9.4-13.5) vs. 12.9 (12.5-14.9) g/dl, P = 0.001]. The platelet change ratio (i.e., platelet count at week 4/platelet count at baseline) in the patients with developing anemia was correlated with the increase in the serum EPO level over 4 weeks (r = 0.88, P = 0.002), but not with the increase in the serum TPO level over 4 weeks. CONCLUSIONS RBV monotherapy induced anemia and affected thrombocytosis in patients with CHC. Elevated endogenous EPO may stimulate platelet production.
Collapse
Affiliation(s)
- Tomoe Kobayashi
- Department of Gastroenterology, Hokkaido University Hospital, North 17 Jo, West 5 Cho-me, Kita-ku, Sapporo 060-8638, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
You BC, Kim YS, Kim HI, Kim SH, Park SS, Seo YR, Kim SG, Lee SW, Kim HS, Jeong SW, Jang JY, Kim BS. A reduced dose of ribavirin does not influence the virologic response during pegylated interferon alpha-2b and ribavirin combination therapy in patients with genotype 1 chronic hepatitis C. Clin Mol Hepatol 2012; 18:272-8. [PMID: 23091807 PMCID: PMC3467430 DOI: 10.3350/cmh.2012.18.3.272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 11/25/2011] [Accepted: 12/01/2011] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS When combined with pegylated interferon alpha-2b (Peg-IFN α-2b) for the treatment of genotype 1 chronic hepatitis C (CHC) in Korea, the current guideline for the initial ribavirin (RBV) dose is based on body weight. However, since the mean body weight is lower for Korean patients than for patients in Western countries, current guidelines might result in Korean patients being overdosed with RBV. METHODS We retrospectively reviewed the medical records of patients with genotype 1 CHC who were treated with Peg-IFN α-2b and RBV combination therapy. We divided the patients into groups A (≥15 mg/kg/day, n=23) and B (<15 mg/kg/day, n=26), given that the standard dose is 15 mg/kg/day. The clinical course in terms of the virologic response, adverse events, and dose modification rate was compared between the two groups after therapy completion. RESULTS The early response rates (92.0% vs. 83.3%, P=0.634) and sustained virologic response rates (82.6% vs. 73.1%, P=0.506) did not differ significantly between the two groups. During the treatment period, the RBV dose reduction rate was significantly higher in group A than in group B (60.9% vs. 23.1%, P=0.01). CONCLUSIONS RBV dose reduction is performed frequently when patients are treated according to the current Korean guidelines. Given that lowering the RBV dose did not appear to decrease the virologic response during therapy, reducing RBV doses below the current Korean guideline may be effective for treatment, especially in low-weight patients.
Collapse
Affiliation(s)
- Byung Chul You
- Department of Internal Medicine, Soon Chun Hyang University Bucheon Hospital, Soon Chun Hyang University College of Medicine, Bucheon, Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Is early virological response as predictive of the hepatitis C treatment response in dialysis patients as in non-uremic patients? Int J Infect Dis 2012; 17:e50-3. [PMID: 23041364 DOI: 10.1016/j.ijid.2012.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 08/23/2012] [Accepted: 09/03/2012] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE The aim of the present study was to determine whether hepatitis C virus (HCV) RNA present at week 12 is a good predictor of the response to interferon (IFN) monotherapy in hemodialysis patients with hepatitis C. METHODS Hemodialysis patients with hepatitis C who were treated between 1997 and 2008 with IFN monotherapy for 48 weeks without dose reduction were included. The predictive value of HCV RNA at week 12 for achieving a sustained virological response (SVR) was determined. RESULTS Forty patients (mean age 47±9 years; 75% males and 80% with genotype 1) were included. Septal fibrosis or cirrhosis was observed in 38% of these patients. Twelve (30%) of the 40 patients achieved SVR. HCV RNA was undetectable at week 12 in 68%. The positive predictive value of HCV RNA at week 12 was 45% and the negative predictive value was 100%. CONCLUSIONS The presence of HCV RNA at week 12 had a high negative predictive value for SVR in hemodialysis patients with chronic hepatitis C treated with IFN for 48 weeks. Therefore, if HCV RNA is detected at week 12, treatment should be discontinued due to the low probability of a sustained response.
Collapse
|
|
42
|
Chung WJ. Impact of ribavirin dose reduction during treatment in chronic hepatitis C genotype 1 patients. Clin Mol Hepatol 2012; 18:268-71. [PMID: 23091806 PMCID: PMC3467429 DOI: 10.3350/cmh.2012.18.3.268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 08/20/2012] [Indexed: 11/05/2022] Open
|
|
43
|
Palmer M, Rubin R, Rustgi V. Randomised clinical trial: pre-dosing with taribavirin before starting pegylated interferon vs. standard combination regimen in treatment-naïve patients with chronic hepatitis C genotype 1. Aliment Pharmacol Ther 2012; 36:370-8. [PMID: 22708649 PMCID: PMC3492905 DOI: 10.1111/j.1365-2036.2012.05188.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/05/2012] [Accepted: 05/30/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND Combination therapy with the ribavirin (RBV) prodrug taribavirin (TBV) and pegylated interferon (PIFN) has produced lower rates of anaemia than with RBV and PIFN. Studies have demonstrated that the sharpest decline in viral load during TBV therapy occurs at Weeks 4 through 6, when TBV reaches steady-state blood levels. AIM The current proof-of-concept study was conducted to examine whether first-order viral kinetics could be influenced by pre-dosing TBV to steady state before introducing PIFN. METHODS Therapy-naïve patients with chronic hepatitis C virus (HCV) genotype 1 (G1) were randomised to receive (i) TBV 600 mg BID monotherapy for 4 weeks followed by combination therapy with PIFN [pre-dosing arm (n = 23)] or (ii) TBV administered concurrently with PIFN [standard dosing arm (n = 19)]. RESULTS More patients achieved undetectable virus or a ≥2-log(10) reduction of HCV RNA at Week 4 in the pre-dosing vs. the standard dosing arm [33% vs. 22% (P = 0.497)]. There was also a trend towards greater reduction in mean log(10) change in HCV RNA in the pre-dosing vs. the standard dosing arm, which was statistically significant at Day 1 [-0.34 ± 0.46 vs. 0.09 ± 0.32 (P < 0.003)] but not at other time points up to Week 24. No significant difference was observed in the rates of anaemia (haemoglobin <10 g/dL) between study arms (4.5% vs. 5.3%). CONCLUSIONS Pre-dosing TBV prior to starting PIFN produces a trend towards improved efficacy although statistical significance was not reached in this small patient population. These results warrant larger clinical trials of TBV pre-dosing.
Collapse
Affiliation(s)
- M Palmer
- Liver Center of Long IslandPlainview, NY, USA
| | - R Rubin
- Liver Center of Long IslandPlainview, NY, USA
| | - V Rustgi
- Liver Center of Long IslandPlainview, NY, USA
| | | |
Collapse
|
|
44
|
Krishnan SM, Dixit NM. A formula to estimate the optimal dosage of ribavirin for the treatment of chronic hepatitis C: influence of ITPA polymorphisms. Antivir Ther 2012; 17:1581-92. [PMID: 22809728 DOI: 10.3851/imp2251] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Greater cumulative exposure to ribavirin increases response to interferon-ribavirin combination therapy for hepatitis C but also induces more severe anaemia. Polymorphisms in the ITPA gene protect against ribavirin-induced anaemia. The maximum dosage of ribavirin that can be tolerated by patients with different ITPA polymorphisms remains unknown. METHODS We developed a mathematical model of haemoglobin (Hb) decline in patients undergoing combination therapy. Using it to analyse published patient data, we estimated the average erythrocyte lifespan in patients with different ITPA polymorphisms. Coupled with a previous population pharmacokinetic study, we derived a formula for predicting the optimal ribavirin dosage, D(opt), above which anaemia becomes intolerable (Hb<10 g/dl). RESULTS Our model provided good fits to patient data of ribavirin accumulation in erythrocytes and the ensuing Hb decline during therapy. With the current treatment protocol, the average erythrocyte lifespan was approximately 36 days in patients with wild-type ITPA activity, and approximately 43 days and 55 days, respectively, in patients with mild and moderate ITPA deficiency. Our model yielded a facile formula for estimating D(opt) given a patient's weight, creatinine clearance, pretreatment Hb and ITPA polymorphism. Patients with moderate ITPA deficiency are predicted to tolerate twice the ribavirin dosage as patients with wild-type ITPA. CONCLUSIONS Our formula for D(opt) presents an avenue for personalizing ribavirin dosage. By keeping anaemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates. Response rates may be increased further by the higher dosages recommended for patients with ITPA deficiency.
Collapse
Affiliation(s)
- Sheeja M Krishnan
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | | |
Collapse
|
|
45
|
Muller K, Rodgers A, Wundke R, Waddell V, Altus R, Gordon DL, Wigg A. Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward. Intern Med J 2012; 42:765-72. [DOI: 10.1111/j.1445-5994.2012.02798.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
|
|
46
|
Birerdinc A, Estep M, Afendy A, Stepanova M, Younossi I, Baranova A, Younossi ZM. Gene expression profiles associated with anaemia and ITPA genotypes in patients with chronic hepatitis C (CH-C). J Viral Hepat 2012; 19:414-22. [PMID: 22571903 DOI: 10.1111/j.1365-2893.2011.01564.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Anaemia is a common side effect of ribavirin (RBV) which is used for the treatment of hepatitis C. Inosine triphosphatase gene polymorphism (C to A) protects against RBV-induced anaemia. The aim of our study was to genotype patients for inosine triphosphatase gene polymorphism rs1127354 SNP (CC or CA) and associate treatment-induced anaemia with gene expression profile and genotypes. We used 67 hepatitis C patients with available gene expression, clinical, laboratory data and whole-blood samples. Whole blood was used to determine inosine triphosphatase gene polymorphism rs1127354 genotypes (CC or CA). The cohort with inosine triphosphatase gene polymorphism CA genotype revealed a distinct pattern of protection against anaemia and a lower drop in haemoglobin. A variation in the propensity of CC carriers to develop anaemia prompted us to look for additional predictors of anaemia during pegylated interferon (PEG-IFN) and RBV. Pretreatment blood samples of patients receiving a full course of PEG-IFN and RBV were used to assess expression of 153 genes previously implicated in host response to viral infections. The gene expression data were analysed according to presence of anaemia and inosine triphosphatase gene polymorphism genotypes. Thirty-six genes were associated with treatment-related anaemia, six of which are involved in the response to hypoxia pathway (HIF1A, AIF1, RHOC, PTEN, LCK and PDGFB). There was a substantial overlap between sustained virological response (SVR)-predicting and anaemia-related genes; however, of the nine JAK-STAT pathway-related genes associated with SVR, none were implicated in anaemia. These observations exclude the direct involvement of antiviral response in the development of anaemia associated with PEG-IFN and RBV treatment, whereas another, distinct component within the SVR-associated gene expression response may predict anaemia. We have identified baseline gene expression signatures associated with RBV-induced anaemia and identified its functional pathways. In particular, we identified the hypoxia response pathway and the apoptosis/survival-related gene network, as differentially expressed in chronic hepatitis C patients with anaemia.
Collapse
Affiliation(s)
- A Birerdinc
- Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA 22042, USA
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Protease inhibitors for the treatment of chronic hepatitis C genotype-1 infection: the new standard of care. THE LANCET. INFECTIOUS DISEASES 2012; 12:717-28. [PMID: 22647717 DOI: 10.1016/s1473-3099(12)70060-9] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
For the past decade, the standard treatment for chronic hepatitis C infection has been pegylated-interferon plus ribavirin. With US Food and Drug Administration approval of boceprevir and telaprevir--two protease inhibitors--the standard-of-care treatment for genotype-1 infection, the main genotype worldwide, is now peginterferon plus ribavirin and a protease inhibitor. Rates of sustained virological response or cure with triple combination treatment have improved substantially, both in patients who have had previous treatment and in those who have not. Improvements have been most substantial in populations regarded as difficult to treat, such as individuals with cirrhosis. However, despite improved response rates, protease inhibitors have incremental toxic effects, high costs, increased pill burden, and many drug interactions. Moreover, because new antiviral drugs directly inhibit hepatitis C virus, viral resistance has become an important issue, essentially precluding use of protease inhibitor monotherapy, and potentially restricting future treatment options for patients who consequently do not achieve sustained virological response. Protease inhibitors are the first of many antiviral medications that will probably be combined in future interferon-free regimens.
Collapse
|
|
48
|
Tsubota A, Shimada N, Yoshizawa K, Furihata T, Agata R, Yumoto Y, Abe H, Ika M, Namiki Y, Chiba K, Fujise K, Tada N, Aizawa Y. Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients. Liver Int 2012; 32:826-836. [PMID: 22212648 DOI: 10.1111/j.1478-3231.2011.02727.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 11/20/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND Standard-dose ribavirin is crucial for the standard-of-care treatment of chronic hepatitis C virus (HCV) infection. Equilibrative nucleoside transporter 1 (ENT1), encoded by SLC29A1 gene, is the main transporter that imports ribavirin into human hepatocytes. AIMS To determine whether single nucleotide polymorphisms (SNPs) at the SLC29A1 gene could influence the probability of treatment response compared with other baseline and host genetic factors. METHODS A total of 526 East Asian patients monoinfected with HCV genotype 1b who had received pegylated interferon alpha plus ribavirin therapy were enrolled in this study. They were assigned randomly to the derivation and confirmatory groups. SNPs related to the IL28B, ITPA and SLC29A1 genes were genotyped using real-time detection polymerase chain reaction. Factors associated with sustained virological response (SVR) were analysed using multiple logistic regression analysis. RESULTS Multivariate analysis for the derivation group identified six baseline variables significantly and independently associated with SVR: age [P = 0.023, odds ratio (OR) = 0.97], gender (P = 0.0047, OR = 2.25), platelet count (P = 0.00017, OR = 1.11), viral load (P = 0.00026, OR = 0.54), IL28B SNP rs12979860 (P = 1.09 × 10(-7) , OR = 8.68) and SLC29A1 SNP rs6932345 (P = 0.030, OR = 1.85). Using the model constructed by these independent variables, positive and negative predictive values and predictive accuracy were 73.3, 70.1 and 71.9% respectively. For the confirmatory group, they were 71.4, 84.6 and 75.3% respectively. The SLC29A1 and IL28B SNPs were also significantly associated with rapid virological response. CONCLUSIONS The SNP at the major ribavirin transporter ENT1 gene SLC29A1 was one of significantly independent factors influencing treatment response, although the impact on the prediction was small.
Collapse
Affiliation(s)
- Akihito Tsubota
- Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Nguyen DL, Morgan TR. Management of Adverse Events During the Treatment of Chronic Hepatitis C Infection. Clin Liver Dis (Hoboken) 2012; 1:54-57. [PMID: 25688295 PMCID: PMC4327830 DOI: 10.1002/cld.33] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Douglas L. Nguyen
- From the Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA
| | | |
Collapse
|
|
50
|
Kagawa T, Kojima SI, Shiraishi K, Takashimizu S, Nagata N, Shiozawa H, Nishizaki Y, Ikeda A, Tei Y, Atsukawa K, Kamochi JI, Wasada M, Numata M, Arase Y, Hirose S, Yamada T, Hata Y, Watanabe N, Morizane T, Mine T. Weight-based high- and low-dose ribavirin in combination with peginterferon α-2b therapy for genotype 2 chronic hepatitis C: A randomized trial. Hepatol Res 2012; 42:351-358. [PMID: 22176474 DOI: 10.1111/j.1872-034x.2011.00944.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIM The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. METHODS We compared the efficacy and tolerability of the 24-week peginterferon α-2b (1.5 µg/kg/week) therapy in combination with a weight-based higher dose (600-1000 mg) and lower dose (400-800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. RESULTS A total of 120 patients were randomized to a higher-dose or a lower-dose group. Sustained virological response (SVR) by intention-to-treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6-89.5) patients in the higher-dose group and 41/60 (68.3%, 90% CI: 58.5-78.2) patients in the lower-dose group (difference, -12.7%; 90% CI, -25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher-dose and the lower-dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs <9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41-7.92; P = 0.006). Twenty-one (36.2%) in the higher-dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower-dose group (P < 0.01). Three of the higher-dose group and two of the lower-dose group required premature termination of therapy. CONCLUSIONS Weight-based lower-dose ribavirin regimen was not equivalent to the higher-dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low-dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight-based higher dose (600-1000 mg) remains the standard-of-care treatment for this genotype.
Collapse
Affiliation(s)
- Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara Division of Gastroenterology, Department of Internal Medicine, Tokai University Hachioji Hospital, Hachioji Ikegami General Hospital Division of Gastroenterology, Department of Internal Medicine, Tokai University Tokyo Hospital, Tokyo Division of Gastroenterology, Department of Internal Medicine, Tokai University Oiso Hospital, Nakagun Hadano Red Cross Hospital, Hadano Japan Medical Alliance Ebina General Hospital, Ebina Hiratsuka City Hospital, Hiratsuka Tomei-Atsugi Hospital, Atsugi Chigasaki Municipal Hospital, Chigasaki Kanagawa Dental College, Yokosuka, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|