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Okubo T, Atsukawa M, Tsubota A, Toyoda H, Shimada N, Abe H, Kato K, Hayama K, Arai T, Nakagawa-Iwashita A, Itokawa N, Kondo C, Kawamoto C, Iio E, Tanaka Y, Kumada T, Iwakiri K. Efficacy and safety of ledipasvir/sofosbuvir for genotype 1b chronic hepatitis C patients with moderate renal impairment. Hepatol Int 2018; 12:133-142. [PMID: 29600429 DOI: 10.1007/s12072-018-9859-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/15/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIM To evaluate the efficacy and safety of ledipasvir and sofosbuvir therapy for genotype 1b in chronic hepatitis C patients with chronic kidney disease (CKD) stage 3. METHODS In a multicenter collaborative retrospective study, 706 patients who have received ledipasvir which is NS5A inhibitor, and sofosbuvir 400 mg which is NS5B nucleoside polymerase inhibitor daily for 12 weeks between September 2015 and January 2017 were subjected to this analysis. Virologic response and adverse events in patients with CKD stage 3 were compared with those in patients with CKD stages 1 and 2. RESULTS The rates of sustained virologic response (SVR) were 97.0% in patients with CKD stage 1, 97.1% in patients with CKD stage 2, and 94.7% in patients with CKD stage 3, respectively. There were no significant differences in the SVR rates between CKD stages 1 and 2, and CKD stage 1 and stage 3. The incidence of adverse events over than grade 2 was 0% in patients with CKD stage 1, 0.5% in patients with CKD stage 2, and 3.0% in patients with CKD stage 3, respectively. For treatment and follow-up period, eGFR levels in the patients with CKD stage 3 were not worsened compared to those at baseline. CONCLUSION This study suggested that the virologic response of ledipasvir and sofosbuvir in patients with CKD stage 3 was not inferior to those with CKD stages 1 and 2. In addition, administration of ledipasvir and sofosbuvir did not affect eGFR levels in the patients with CKD stage 3.
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Affiliation(s)
- Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, 3-19-18 Nishishinbashi, Minato-ku, Tokyo, 105-8471, Japan
| | - Hidenori Toyoda
- Division of Gastroenterology, Department of Internal Medicine, Ogaki Municipal Hospital, 4-86 Minaminokawachou, 503-0864, Ogaki, Gifu, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Otakanomori Hospital, 113 Toyoshiki, Kashiwa, Chiba, 277-0863, Japan
| | - Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba, 270-0034, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba, 270-0034, Japan
| | - Korenobu Hayama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Taeang Arai
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Ai Nakagawa-Iwashita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Chiaki Kawamoto
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Etsuko Iio
- Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 487-0001, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 487-0001, Japan
| | - Takashi Kumada
- Division of Gastroenterology, Department of Internal Medicine, Ogaki Municipal Hospital, 4-86 Minaminokawachou, 503-0864, Ogaki, Gifu, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
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Suda G, Ogawa K, Kimura M, Nakai M, Sho T, Morikawa K, Sakamoto N. Novel Treatment of Hepatitis C Virus Infection for Patients with Renal Impairment. J Clin Transl Hepatol 2016; 4:320-327. [PMID: 28097101 PMCID: PMC5225152 DOI: 10.14218/jcth.2016.00032] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/21/2016] [Accepted: 12/07/2016] [Indexed: 12/11/2022] Open
Abstract
Prevalence of hepatitis C virus (HCV) infection is high in patients with end-stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti-HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
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Carrier P, Essig M, Debette-Gratien M, Sautereau D, Rousseau A, Marquet P, Jacques J, Loustaud-Ratti V. Anti-hepatitis C virus drugs and kidney. World J Hepatol 2016; 8:1343-1353. [PMID: 27917261 PMCID: PMC5114471 DOI: 10.4254/wjh.v8.i32.1343] [Citation(s) in RCA: 14] [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: 03/26/2016] [Revised: 07/08/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) mainly targets the liver but can also induce extrahepatic manifestations. The kidney may be impacted via an immune mediated mechanism or a cytopathic effect. HCV patients are clearly at a greater risk of chronic kidney disease (CKD) than uninfected patients are, and the presence of CKD increases mortality. Interferon-based therapies and ribavirin are difficult to manage and are poorly effective in end-stage renal disease and hemodialysis. These patients should be given priority treatment with new direct anti-viral agents (DAAs) while avoiding peginterferon and ribavirin. The first results were convincing. To aid in the correct use of these drugs in patients with renal insufficiency, their pharmacokinetic properties and potential renal toxicity must be known. The renal toxicity of these new drugs was not a safety signal in clinical trials, and the drugs are generally efficient in these frail populations. These drugs are usually well tolerated, but recent cohort studies have demonstrated that these new regimens may be associated with renal side effects, especially when using sofosbuvir combinations. HCV, renal diseases and comorbidities are intimately linked. The close monitoring of renal function is required, particularly for at-risk patients (transplanted, HIV-coinfected, CKD, hypertensive or diabetic patients). New DAA regimens, which will soon be approved, will probably change the landscape.
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Ozeki I, Nakajima T, Yamaguchi M, Kimura M, Arakawa T, Kuwata Y, Ohmura T, Sato T, Hige S, Karino Y, Toyota J. Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy. Hepatol Res 2016; 46:1162-1167. [PMID: 26857426 DOI: 10.1111/hepr.12667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 01/09/2016] [Accepted: 02/01/2016] [Indexed: 12/13/2022]
Abstract
Patients 1 and 2 were treatment-naive women who had genotype 1b chronic hepatitis C. Both had IL-28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance-associated variants (RAV) in non-structural (NS)3 and NS5A regions confirmed wild-type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post-treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug-resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct-acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.
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Affiliation(s)
- Itaru Ozeki
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan.
| | - Tomoaki Nakajima
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Masakatsu Yamaguchi
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Mutsuumi Kimura
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Tomohiro Arakawa
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yasuaki Kuwata
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Takumi Ohmura
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Takahiro Sato
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Shuhei Hige
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Joji Toyota
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
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Determinant Factors of the Direct Medical Costs Associated with Genotype 1 Hepatitis C Infection in Treatment-Experienced Patients. Drugs R D 2016; 15:335-49. [PMID: 26416653 PMCID: PMC4662942 DOI: 10.1007/s40268-015-0109-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective Limited evidence is available on predictors of medical resource utilization (MRU) and related direct costs, especially in treatment-experienced patients infected with genotype 1 hepatitis C virus (HCV). This study aimed at investigating patient and treatment characteristics that predict MRU and related non-drug costs in treatment-experienced patients with chronic hepatitis C (CHC) treated with simeprevir (SMV) or telapravir (TVR) in combination with pegylated interferon and ribavirin (PegIFN/R). Patients and Methods A total of 709 patients who completed the 72-week ATTAIN trial were included in the study. Cost data were analysed from the UK NHS perspective. Descriptive statistics and regression analyses were used to determine patterns and predictors of total MRU-related costs associated with SMV/PegIFN/R and TVR/PegIFN/R. Results Independent predictors for total MRU-related costs were age, region and the following interaction terms: (1) gender × F3–F4 METAVIR score × baseline viral load (BLVL), (2) body mass index (BMI) × F3–F4 METAVIR score × prior response to PegIFN/R and (3) gender × achievement of SVR at 12 weeks (SVR12) × BLVL. A F3–F4 METAVIR score was a stronger predictor of total MRU-related costs than SVR12. Predictors of adverse events included older age, female gender, low BMI, TVR/PegIFN/R and SVR12. Wilcoxon rank sum test revealed comparable total MRU-related costs between SMV/PegIFN/R and TVR/PegIFN/R. Conclusion To the best of our knowledge, this study is the first to describe the relationship between commonly admitted predictors of MRU-related costs and their joint effect on total MRU-related costs in treatment-experienced patients with CHC. The identified predictors of MRU-related costs suggest that significant treatment costs can be avoided by starting treatment early before the disease progresses. Furthermore, adverse events seem to be the most important factor to take into consideration for the choice of treatment, especially when therapeutic options are associated with similar levels of medical resource utilization and associated costs. Electronic supplementary material The online version of this article (doi:10.1007/s40268-015-0109-5) contains supplementary material, which is available to authorized users.
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Estimated glomerular filtration rate but not solute carrier polymorphisms influences anemia in HIV-hepatitis C virus coinfected patients treated with boceprevir or telaprevir-based therapy. AIDS 2016; 30:2085-90. [PMID: 27149089 DOI: 10.1097/qad.0000000000001143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Ribavirin (RBV) induced anemia may be influenced by host genetic factors affecting RBV transport solute carrier (SLC) or metabolism inosine triphosphatase (ITPA), as already reported. We investigated the influence of single nucleotide polymorphisms (SNPs) on SLC genes on anemia, RBV trough concentration (Ctrough) and response in HIV-hepatitis C virus coinfected patients receiving triple therapy with boceprevir or telaprevir. METHODS Patients from the ANRS HC26/HC27 studies were genotyped for SLC28A3 SNPs (rs10868138 and rs56350726) and SL29A1 SNPs (rs760370). Hemoglobin (Hb) decline was collected at baseline day 0 (D0), week 4 (W4) and week 8 (W8), and RBV Ctrough was measured at W4 and W8 by HPLC. A multivariate analysis including SLC SNPs, estimated glomerular filtration rate (eGFR), ITPA deficiency and RBV Ctrough was performed to determine predictive factors of anemia and response. RESULTS SLC genotyping was performed in 130 patients. Neither SLC28A3 nor SLC29A1 SNPs were associated with Hb decline both at W4 and W8. No association was found between SLC polymorphisms and RBV Ctrough. Independent predictive factors of Hb decline at W4 were D0 Hb, ITPA deficiency and W4 RBV Ctrough in the multivariate analysis (P < 0.05). Only D0 Hb, W4 RBV Ctrough and eGFRD0-W8 were predictive of anemia at W8 (P < 0.05). Response was not influenced by SLC SNPs. CONCLUSION eGFR, but not SLC polymorphisms, influences anemia in HIV-hepatitis C virus coinfected patients receiving boceprevir-based or telaprevir-based therapy. RBV is still a cornerstone of hepatitis C treatment, thus renal function and RBV Ctrough should be monitored in patients receiving RBV regimen combined with first-generation direct-acting antiviral agent.
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D'Avolio A, Cusato J, De Nicolò A, Allegra S, Di Perri G. Pharmacogenetics of ribavirin-induced anemia in HCV patients. Pharmacogenomics 2016; 17:925-41. [PMID: 27248282 DOI: 10.2217/pgs.16.22] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Dual therapy (pegylated interferon plus ribavirin) was considered the standard of care for hepatitis C virus (HCV) treatment until 2011, when the first-wave direct-acting antivirals were added to this regimen for HCV genotype-1 patients to increase the sustained virological response rate. The second-wave direct-acting antivirals entered the clinical use also in some ribavirin (RBV)- and/or interferon-free combinations. Nevertheless, since some of the new therapeutic regimens also include RBV and its use results still associated with hemolytic anemia, this requires countermeasures to be prevented. These include the identification of several host predictive factors involved in RBV absorption, distribution, metabolism, elimination and many others that might influence this toxic effect. For this reason, we provided an overview of the potential role of pharmacogenomics in predisposing RBV-treated HCV patients to anemia.
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Affiliation(s)
- Antonio D'Avolio
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Jessica Cusato
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Amedeo De Nicolò
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Sarah Allegra
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
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Saxena V, Koraishy FM, Sise ME, Lim JK, Schmidt M, Chung RT, Liapakis A, Nelson DR, Fried MW, Terrault NA. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int 2016; 36:807-816. [PMID: 26923436 PMCID: PMC6453817 DOI: 10.1111/liv.13102] [Citation(s) in RCA: 235] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Accepted: 02/23/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Renal clearance is the major elimination pathway for sofosbuvir (SOF). We assessed the safety and efficacy of SOF-containing regimens in patients with varying baseline estimated glomerular filtration rate (eGFR). METHODS HCV-TARGET database is a multicentre, longitudinal 'real-world' treatment cohort. RESULTS A total of 1789 patients [genotypes 1 (72%), 2 (17%) 3 (9%), 4-6 (2%)] had baseline eGFR determination: 73 with eGFR≤45 (18 with eGFR≤30, 5 on dialysis) were compared to 1716 with eGFR>45 ml/min/1.73 m(2) . Patients with baseline eGFR≤45 vs. >45 differed in being female (55% vs. 36%), age ≥65 years (24% vs. 16%), Black race (22% vs. 12%), having cirrhosis with decompensation (73% vs. 24%) and being post-transplant (49% vs. 10%), all P < 0.05. All patients with eGFR≤45 were treated with SOF 400 mg/day (including those on haemodialysis) and had median starting ribavirin (RBV) dose of 800 mg (IQR: 400-1200). Sustained virologic response (SVR) frequencies were similar across eGFR groups, ranging from 82-83%. Patients with eGFR ≤45 more frequently experienced anaemia, worsening renal function and serious AEs (all P < 0.05), and these associations persisted when limiting analysis to RBV-free regimens. Patients with baseline eGFR≤30 and eGFR 31-45 had similar frequencies of efficacy and safety outcomes. CONCLUSIONS Sustained viral clearance was achieved in 83% of patients with renal impairment (eGFR ≤45 ml/min/1.73 m(2) ) treated with SOF-containing regimens. However, these patients had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV. Patient with renal impairment require close monitoring and should be treated by providers extensively experienced with SOF-containing regimens.
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Affiliation(s)
- Varun Saxena
- University of California San Francisco, San Francisco, CA, USA
| | | | | | - Joseph K Lim
- Yale University School of Medicine, New Haven, CT, USA
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Ichida A, Motohashi H, Kitano A, Takayama A, Inui KI, Yano Y. Telaprevir-Induced Renal Adverse Events in Japanese Patients Reported in the PMDA Adverse Drug Reactions Reporting Database. Ther Innov Regul Sci 2016; 50:355-360. [PMID: 30227075 DOI: 10.1177/2168479015618694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Telaprevir is a protease inhibitor currently used in the treatment of chronic hepatitis C virus (HCV) infection. One of its adverse effects is renal impairment. The Pharmaceutical and Medical Device Agency (PMDA) in Japan reported on telaprevir-related renal dysfunction in 2012. In this study, renal adverse events of telaprevir were investigated using the Japanese Adverse Drug Event Report database. Patient profiles with adverse events might provide useful information for HCV therapy. METHODS We screened the case reports in Japanese Adverse Drug Event Report database (JADER) of the PMDA. The profiles of patients with renal adverse events were analyzed. RESULTS The present results showed that reports of renal adverse events were most common in male patients between 60 and 69 years of age. Significant factors that affect the clinical outcomes of renal adverse events were not detected. However, it was suggested that anorexia is associated with renal adverse events. CONCLUSIONS The number of reports of renal adverse events were highest in male patients 60 to 69 years of age treated with telaprevir. In addition, our findings suggested that anorexia is correlated with renal adverse events after telaprevir treatment. Further investigation is required to clarify the mechanism of renal impairments during triple therapy. Such knowledge might improve the safety of telaprevir therapy.
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Affiliation(s)
- Ayami Ichida
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hideyuki Motohashi
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Asuka Kitano
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Akira Takayama
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Ken-Ichi Inui
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Yoshitaka Yano
- 1 Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan
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Kohjima M, Kurokawa M, Enjoji M, Yoshimoto T, Nakamura T, Ohashi T, Fukuizumi K, Harada N, Murata Y, Matsunaga K, Kato M, Kotoh K, Nakamuta M. Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C. Exp Ther Med 2016; 11:1781-1787. [PMID: 27168803 DOI: 10.3892/etm.2016.3133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 11/05/2015] [Indexed: 12/23/2022] Open
Abstract
Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Miho Kurokawa
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Munechika Enjoji
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Tsuyoshi Yoshimoto
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tsukasa Nakamura
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tomoko Ohashi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Kunitaka Fukuizumi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Naohiko Harada
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Yusuke Murata
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuhisa Matsunaga
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
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Ogawa E, Furusyo N, Dohmen K, Kajiwara E, Kawano A, Nomura H, Takahashi K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure. J Viral Hepat 2015; 22:992-1001. [PMID: 26075320 DOI: 10.1111/jvh.12427] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 04/24/2015] [Indexed: 02/07/2023]
Abstract
Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.
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Affiliation(s)
- E Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - N Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - K Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - E Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - A Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - H Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - K Takahashi
- Department of Medicine, Hamanomachi Hospital, Fukuoka, Japan
| | - T Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - K Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - M Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - T Koyanagi
- Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan
| | - K Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - S Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - J Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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12
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Kozielewicz D, Dybowska D, Karwowska K, Wietlicka-Piszcz M. Renal impairment in patients with chronic hepatitis C treated with first generation protease inhibitors. Expert Opin Drug Saf 2015; 14:1815-25. [PMID: 26513231 DOI: 10.1517/14740338.2015.1102882] [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: 12/22/2022]
Abstract
BACKGROUND The incidence, course and risk factors associated with renal impairment (RI) in patients treated with triple therapy (TT) with pegylated interferon, ribavirin and telaprevir/boceprevir (PR/TVR/BOC) vs. dual therapy (DT) with PR were analyzed in this study. The association between RI and the decline of hemoglobin (Hb) was also examined. METHODS Retrospective analysis included 110 patients with genotype 1b chronic HCV infection, aged 18 - 80 years, who underwent TT (48TVR/14BOC) or DT (48 patients). The estimated glomerular filtration rate (eGFR), serum creatinine concentration (SCr) and Hb were measured at baseline, at weeks 4, 12, 24, 48 of treatment, and post-treatment week 24. RESULTS RI occurred in 9/62 (14.5%) patients who underwent TT, eight of whom were treated with TVR, one with BOC, and none treated with DT. The risk factors associated with RI were the following: TT (p = 0.0078), usage of nephrotoxic drugs (p = 0.0288), and older age (p < 0.0001). RI was reversible. A drop of Hb was associated with RI, older age and TT. CONCLUSIONS RI is not a rare but a reversible complication of TT. It is necessary to monitor SCr and eGFR, especially in patients with a potential risk factor of RI occurrence. The Hb drop is more severe in patients with RI than in those without it.
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Affiliation(s)
- Dorota Kozielewicz
- a Department of Infectious Diseases and Hepatology, Faculty of Medicine , Nicolaus Copernicus University in Toruń , Bydgoszcz , Poland
| | - Dorota Dybowska
- a Department of Infectious Diseases and Hepatology, Faculty of Medicine , Nicolaus Copernicus University in Toruń , Bydgoszcz , Poland
| | - Kornelia Karwowska
- a Department of Infectious Diseases and Hepatology, Faculty of Medicine , Nicolaus Copernicus University in Toruń , Bydgoszcz , Poland
| | - Magdalena Wietlicka-Piszcz
- b Department of Theoretical Foundations of Biomedical Sciences and Medical Computer Science , Faculty of Pharmacy, Nicolaus Copernicus University in Toruń , Bydgoszcz , Poland
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de Kanter CT, Buti M, DeMasi R, Ouwerkerk-Mahadevan S, Dofferhoff AS, Witek J, Drenth JP, Zeuzem S, Burger DM. Ribavirin concentration determines treatment success of first-generation DAA-based chronic HCV therapy. Antivir Ther 2015; 21:153-9. [PMID: 26378941 DOI: 10.3851/imp2994] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies. METHODS Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response. RESULTS Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2-3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2-3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia. CONCLUSIONS We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.
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Affiliation(s)
- Clara Tmm de Kanter
- Department of Pharmacy, Radboud university medical center, Nijmegen, the Netherlands.
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14
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De Nicolò A, Abdi AM, Boglione L, Baiett L, Allegra S, Di Perri G, D'Avolio A. UPLC-MS/MS method with automated on-line SPE for the isomer-specific quantification of the first-generation anti-HCV protease inhibitors in peripheral blood mononuclear cells. J Pharm Biomed Anal 2015; 115:443-9. [PMID: 26291788 DOI: 10.1016/j.jpba.2015.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 07/31/2015] [Accepted: 08/03/2015] [Indexed: 01/01/2023]
Abstract
HCV infection affects over 170 million people worldwide. The current standard for treatment of genotype 1 infection is the association of the first generation protease inhibitors boceprevir or telaprevir to ribavirin and peginterferon α. Although the response rate has been improved with these new drugs, some pharmacokinetic/pharmacodinamic issues emerged in the past years. To date, some analytical methods are available for the quantification of these drugs in plasma; however, the real active concentrations of the two drugs are those in hepatocytes. Being the withdrawal of hepatocytes too invasive, in this work we aimed to develop and validate a chromatographic method coupled with tandem mass spectrometry capable of quantifying boceprevir and telaprevir isomers in peripheral blood mononuclear cells, used as an "in-vivo" cellular model of compartmentalization. The method used an on-line solid phase extraction protocol based on the new OSM(®) platform and was fully validated following FDA guidelines. This method showed mean intra- and inter-day inaccuracy and imprecision both lower than 15%, high and stable recovery and contained matrix effect, with a run time of 6min, comprehensive of SPE extraction. The method was then applied on 35 real samples from patients treated with boceprevir or telaprevir, with good analytical performances, thus assessing its eligibility for a possible future routine use. Peculiar pharmacokinetic data have been observed, suggesting the usefulness of investigating intracellular pharmacokinetics of these drugs. Further studies will be required to test the correlation of intracellular concentrations with effectiveness and toxicity of triple therapy.
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Affiliation(s)
- Amedeo De Nicolò
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
| | - Adnan Mohamed Abdi
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Lucio Boglione
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Lorena Baiett
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Sarah Allegra
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
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15
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Vespasiani-Gentilucci U, Galati G, Gallo P, De Vincentis A, Riva E, Picardi A. Hepatitis C treatment in the elderly: New possibilities and controversies towards interferon-free regimens. World J Gastroenterol 2015; 21:7412-7426. [PMID: 26139987 PMCID: PMC4481436 DOI: 10.3748/wjg.v21.i24.7412] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 04/10/2015] [Accepted: 05/20/2015] [Indexed: 02/06/2023] Open
Abstract
Due to the progressive aging of the hepatitis C virus (HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extra-hepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the well-known contraindications and side effects of interferon (IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn't mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the "old" IFN-based regimens and with the newer drugs. We will conclude that the availability of IFN-free regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.
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Rivero-Juarez A, Camacho A, Rivero A. Pharmacokinetic and pharmacodynamic evaluation of telaprevir for the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2015; 11:1157-65. [PMID: 26004270 DOI: 10.1517/17425255.2015.1049532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Telaprevir is one of the first direct-acting antiviral drugs approved for the treatment of the hepatitis C virus (HCV) genotype 1. Following its approval in 2011, new data regarding the pharmacokinetics and pharmacodynamics were reported, leading to important clinical applications. AREAS COVERED This article reviews the pharmacokinetic and pharmacodynamic properties of telaprevir for the treatment of the HCV. The areas covered include data regarding the drug's absorption, distribution, metabolism and excretion, in addition to the antiviral activity strategy such as the clinical dose selection and treatment duration. EXPERT OPINION Telaprevir presents several pharmacological properties that could limit its administration such a high-fat, high-calorie meal; the need to be administrated with pegylated IFN plus ribavirin; and the drug-drug interaction profile. As a consequence and considering the new therapeutic arsenal against the HCV, the use of telaprevir as part of HCV therapy will be limited.
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Affiliation(s)
- Antonio Rivero-Juarez
- Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Avda, Menendez Pidal s/n. 14004, Córdoba , Spain +34 9 5701 2421 ; +34 9 5701 1885 ;
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17
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Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients. AIDS 2015; 29:977-9. [PMID: 25784438 DOI: 10.1097/qad.0000000000000643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m) relative to baseline [93.6 (73.0-109.0)] was seen at weeks 4 [86.5 (34.0-112.0), P = 0.014], 8 [90.0 (49.0-111.0), P = 0.026] and 12 [89.5 (54.0-113.0), P = 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity.
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18
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Sise ME, Backman ES, Wenger JB, Wood BR, Sax PE, Chung RT, Thadhani R, Kim AY. Short and long-term effects of telaprevir on kidney function in patients with hepatitis C virus infection: a retrospective cohort study. PLoS One 2015; 10:e0124139. [PMID: 25923243 PMCID: PMC4414554 DOI: 10.1371/journal.pone.0124139] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 03/12/2015] [Indexed: 12/25/2022] Open
Abstract
Background Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment. Methods Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir. Results Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m2 compared to the group with baseline eGFR ≥ 90 mL/min/1.73m2 (12 vs. 18 mL/min/1.73m2, P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m2 decrease in estimated glomerular filtration rate at twelve months in an adjusted model. Conclusions Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m2 as previously reported.
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Affiliation(s)
- Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
- * E-mail:
| | - Elke S. Backman
- Department of Pharmacy, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
| | - Julia B. Wenger
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
| | - Brian R. Wood
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States of America
| | - Paul E. Sax
- Division of Infectious Diseases, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, United States of America
| | - Raymond T. Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
| | - Ravi Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
| | - Arthur Y. Kim
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, United States of America
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Andreocchi L, Toma V, Canonica-Lepori A, Magenta L, Györik S, Pellegrini L, Bernasconi E. Telaprevir-induced renal impairment: three clinical cases and a review of the literature. Infect Dis (Lond) 2015; 47:662-7. [PMID: 25901730 DOI: 10.3109/23744235.2015.1033004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Telaprevir (TPV) is one of the NS3/4A serine protease inhibitors on the market for the treatment of chronic hepatitis C genotype 1 in combination with peginterferon alpha and ribavirin. Well-documented potential adverse reactions of TPV are hematological, skin, and gastro-intestinal disorders. Until now, there were no conclusive data from clinical trials about renal adverse reactions of TPV. We report here three cases of renal impairment that occurred after a few days of TPV treatment and resolved in about 2 weeks after stopping the drug. Two of the patients were hospitalized because of this serious adverse drug reaction. Therefore, renal impairment seems to be a new adverse drug reaction of TPV and clinicians should be aware of this potentially serious complication of chronic hepatitis C therapy.
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Affiliation(s)
- Laura Andreocchi
- From the 1 Pharmacovigilance Center, Regional Hospital , Lugano , Switzerland
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20
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Telaprevir and ribavirin interaction: higher ribavirin levels are not only due to renal dysfunction during triple therapy. Antimicrob Agents Chemother 2015; 59:3257-62. [PMID: 25801562 DOI: 10.1128/aac.04795-14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 03/15/2015] [Indexed: 01/19/2023] Open
Abstract
A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin Cmin) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin Cmin for triple therapy (4.08 μg/ml; range, 2.14 to 5.56 μg/ml) was higher than that observed after telaprevir withdrawal (1.96 μg/ml; range, 0.41 to 3.45 μg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 μg/ml; range, 0.41 to 5.56 μg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r(2) = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC0-12) (r(2) = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. NCT01818856.).
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Reduced-dose telaprevir-based triple antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Transplantation 2015; 98:994-9. [PMID: 25099704 DOI: 10.1097/tp.0000000000000166] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION The feasibility of telaprevir-based triple therapy for recurrent hepatitis C after liver transplantation (LT) has not been evaluated in Asian patients. METHODS Eleven Japanese patients received reduced-dose telaprevir (1500 mg) and adjusted-dose cyclosporine after LT. Six patients were nonresponders and three were transient responders to dual therapy. RESULTS Rapid viral response, early viral response, end of treatment response, and sustained viral response were achieved in 27.3%, 90.9%, 90.9%, and 81.8% of patients, respectively. One patient had viral breakthrough at week 8 with a T54A mutation in NS3. Deep sequence analysis showed that the T54A mutation reverted to wild-type after stopping telaprevir administration. Seven patients developed severe anemia, and six received blood transfusions (4-20 U). Their hemoglobin and estimated glomerular filtration rate remained significantly lower than pretreatment values at 36 weeks after treatment. Four patients developed plasma cell hepatitis after completing telaprevir treatment, and it was treated by increasing the immunosuppressants. Although the cyclosporine level/dose ratio was 2.7 times higher at week 4 than before treatment, it was 0.7 times lower at week 36. CONCLUSIONS Reduced-dosed telaprevir-based triple antiviral therapy achieved a high viral clearance rate in Japanese patients after LT. Major adverse events included severe anemia, renal dysfunction, and plasma cell hepatitis.
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Bodeau S, Nguyen-Khac E, Solas C, Bennis Y, Capron D, Duverlie G, Brochot E. Patients treated with first-generation HCV protease inhibitors exhibit high ribavirin concentrations. J Clin Pharmacol 2015; 55:517-24. [PMID: 25535910 DOI: 10.1002/jcph.454] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/19/2014] [Indexed: 01/16/2023]
Abstract
Anemia is a well-known RBV-related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460 ng/mL vs. 1843 ng/mL; P < .0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (P = .002). The proportion of patients with a >20 mL/min/1.73 m(2) decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (P = .025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG-IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia.
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Affiliation(s)
- Sandra Bodeau
- Department of Pharmacology, Amiens University Medical Center, Amiens, France
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Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2015; 59:2179-88. [PMID: 25645847 DOI: 10.1128/aac.04618-14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro, but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.).
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Akamatsu S, Hayes CN, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Chayama K. Ribavirin dose reduction during telaprevir/ribavirin/peg-interferon therapy overcomes the effect of the ITPA gene polymorphism. J Viral Hepat 2015; 22:166-74. [PMID: 24930407 DOI: 10.1111/jvh.12275] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 05/14/2014] [Indexed: 01/16/2023]
Abstract
Treatment success of chronic hepatitis C virus genotype 1 infection has improved with the advent of telaprevir plus peg-interferon/ribavirin triple combination therapy. However, the effect of inosine triphosphatase (ITPA) polymorphism on dose reduction during triple therapy, especially during the postmarketing phase, has not been sufficiently evaluated. We analysed 273 patients with genotype 1 infection who were treated with triple therapy and assessed the effect of the ITPA polymorphism on dose reduction. ITPA and IFNL4 SNP genotypes were determined by the Invader assay. A stepwise multivariate regression analysis was performed to identify factors associated with outcome of the therapy. The overall sustained viral response (SVR) rate 12 weeks after the end of therapy was 80.2% (219/273). Decline of haemoglobin was significantly faster, and ribavirin was more extensively reduced in patients with ITPA SNP rs1127354 genotype CC than CA/AA. Extensive reduction of ribavirin resulted in mild reduction of telaprevir and peg-interferon, but no significant increase in viral breakthrough. Although the amount of telaprevir given was slightly higher in CA/AA patients, the total dose of peg-interferon and the SVR rate did not differ between the two groups. Multivariate analysis showed that IFNL4 but not ITPA SNP genotype, platelet count and peg-interferon adherence were significantly associated with outcome of therapy. Postmarketing-phase triple therapy resulted in a high SVR rate in spite of extensive ribavirin dose reduction in a diverse patient population, indicating the importance of treatment continuation and appropriate management of adverse events.
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Affiliation(s)
- S Akamatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
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25
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Cotte L, Barrail-Tran A, Vincent C, Valantin MA, Fournier I, Lacombe K, Chevaliez S, Aboulker JP, Taburet AM, Molina JM. Telaprevir enhances ribavirin-induced anaemia through renal function impairment. Antivir Ther 2015; 20:479-86. [PMID: 25560644 DOI: 10.3851/imp2929] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Alterations in renal function have been described with telaprevir (TVR). We examined the relationship between ribavirin (RBV) trough concentration (C), estimated glomerular filtration rate (eGFR) and severe anaemia, before and after TVR introduction in HIV-HCV-coinfected patients included in ANRS HC26 TelapreVIH study. METHODS 69 HIV-HCV genotype-1 coinfected patients received 4 weeks of pegylated interferon (PEG-IFN)-α2a/RBV, followed by 12 weeks of TVR/PEG-IFN/RBV, then 32 to 56 weeks of PEG-IFN/RBV. RBV C was determined at week (W)4, W8 and W20/24. eGFR was estimated by the Modification of the Diet in Renal Disease (MDRD) equation. Severe anaemia was defined as haemoglobin <70 g/l, RBV dose reduction, prescription of erythropoietin or blood transfusion. RESULTS 67 patients were analysed. eGFR remained normal between baseline (97.9 ml/min) and W4 (103.4 ml/min), declined to 86.3 ml/min at W8 (P<0.0001), stabilized until W16 and increased back to baseline level at W20 (98.4 ml/min). RBV C increased from 1.88 mg/l at W4 to 2.88 mg/l at W8 (P<0.0001), then decreased to 2.73 mg/l at week 20/24 (P=0.015). An inverse correlation was observed between W8 eGFR and W8 RBV C (r2=0.429; P=0.0005). RBV C≥3 mg/l was observed in 12% of patients at W4, 45% at W8 (P<0.0001) and 38% at W20/24 (P=0.0005). Severe anaemia was observed in 23.9% of patients at W4 and 45.3% at W8. RBV C≥3 mg/l at W8 (OR 7.7 [95% CI 2.2, 27.4]) and baseline haemoglobin <150 g/l (OR 6.4 [1.7, 23.8]) were independently associated with W8 severe anaemia. CONCLUSIONS Association of TVR to PEG-IFN/RBV was associated with a decrease in eGFR and increase in RBV C, leading to severe anaemia in 45% of patients.
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Affiliation(s)
- Laurent Cotte
- Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.
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Adjusting the starting dose of telaprevir according to renal function decreases adverse effects and affects the sustained virological response rate. Eur J Gastroenterol Hepatol 2015; 27:55-64. [PMID: 25370853 DOI: 10.1097/meg.0000000000000208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Telaprevir (TVR) plays a major role in renal damage and anemia associated with TVR/pegylated interferon/ribavirin therapy for chronic hepatitis C. Adjusting the TVR starting dose may reduce these adverse effects. We aimed to determine whether adjusting the starting dose according to renal function reduces TVR-associated renal damage and anemia and affects the sustained virological response (SVR). PATIENTS AND METHODS Our study included 112 patients infected with hepatitis C genotype 1 treated with pegylated interferon/ribavirin/TVR triple therapy. The TVR starting dose adjusted according to renal function was calculated as TVR/unadjusted estimated glomerular filtration rate (eGFR) ratio=TVR/(eGFR×body surface area/1.73). RESULTS A TVR/unadjusted eGFR ratio of 32 or greater was a predictor of renal impairment and anemia in multivariate analysis (odds ratio 12.09, P<0.001, and OR 4.14, P<0.001, respectively). Patients with a TVR/unadjusted eGFR ratio of 32 or greater developed significant renal impairment and anemia (P<0.001 and P=0.002, respectively). SVR was significantly reduced in patients with a TVR/unadjusted eGFR ratio less than 23 versus 23 or greater (66.7 and 87.2%, respectively, P=0.045). SVR tended to increase stepwise [<23.0 (66.7%), ≥23 to <32 (84.8%), and ≥32 (89.6%), respectively]. The TVR/unadjusted eGFR ratio was correlated significantly with the serum TVR concentration (r=0.541, P<0.001). CONCLUSION Adjusting the TVR starting dose according to the TVR/unadjusted eGFR ratio decreased adverse effects and affected the SVR rate. The TVR starting dose should be adjusted by a TVR/unadjusted eGFR ratio of 23 or greater to less than 32 to safely achieve SVR.
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Loustaud-Ratti V, Rousseau A, Carrier P, Vong C, Chambaraud T, Jacques J, Debette-Gratien M, Sautereau D, Essig M. eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance? Liver Int 2015; 35:71-8. [PMID: 25039814 DOI: 10.1111/liv.12631] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Renal toxicity of first generation protease inhibitors (PIs) was not a safety signal in phase III clinical trials, but was recently reported in recent studies. It appeared important to determine the clinical significance of these findings. METHODS We retrospectively analysed 101 HCV patients receiving triple therapy with telaprevir (n = 36) or boceprevir (n = 26) or double therapy (n = 39) with peginterferon and ribavirin and having a close monitoring of eGFR (MDRD formula) during and after treatment. EGFR decline over time was assessed by a linear mixed-effects model (LMEM) with search for possible explanatory covariates. RESULTS Patients treated with telaprevir presented a significant decrease of eGFR with the same kinetics: initial decrease at W (week) 4, nadir at W8 (mean decrease 17.0 ± 18.9 ml/min/1.73 m(2)) and return to baseline at W16. The W8 eGFR was correlated with the D0 eGFR (R(2) = 0.49). The LMEM showed that interindividual variability in the slope of eGFR vs time between D0 and W8 was non-significant and eGFR nadir could be predicted from eGFR obtained at D0. In multivariate analysis, eGFR intercept (i.e. baseline value) was associated with older age and male sex. CONCLUSION The eGFR significantly varied in telaprevir group only. Our model showed that eGFR nadir mainly depended on initial eGFR. As telaprevir has been shown to inhibit mostly the drug transporter OCT2 which interacts with creatinine transport, the early decrease of eGFR observed could be a benign phenomenon. However, as unpredictable true renal toxicity may occur during therapy, we recommend a thorough follow-up of eGFR.
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Affiliation(s)
- Véronique Loustaud-Ratti
- Service d'Hépato-gastroentérologie, CHU de Limoges, 2 avenue Martin-Luther-King, 87042, Limoges, France; Inserm UMR 1092, Faculté de médecine de Limoges, Université de Limoges, Limoges, France
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Menna P, Gallo P, Vespasiani Gentilucci U, Salvatorelli E, Galati G, Minotti G, Picardi A. Telaprevir raises the plasma/whole blood ribavirin ratio: trying to come full circle on a dangerous relationship. J Viral Hepat 2014; 21:e136-e137. [PMID: 24935352 DOI: 10.1111/jvh.12264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- P Menna
- Clinical Pharmacology, Center for Integrated Research, Rome, Italy
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Prediction of Sustained Virological Response to Telaprevir-Based Triple Therapy Using Viral Response within 2 Weeks. HEPATITIS RESEARCH AND TREATMENT 2014; 2014:748935. [PMID: 25328696 PMCID: PMC4195394 DOI: 10.1155/2014/748935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 09/21/2014] [Accepted: 09/22/2014] [Indexed: 01/04/2023]
Abstract
The aim of the present study was to predict sustained virological response (SVR) to telaprevir with pegylated interferon (PEG-IFN) and ribavirin using viral response within 2 weeks after therapy initiation. Thirty-six patients with genotype 1 hepatitis C virus (HCV) and high viral load were treated by telaprevir-based triple therapy. SVR was achieved in 72% (26/36) of patients. Significant differences between the SVR group and non-SVR group were noted regarding response to prior PEG-IFN plus ribavirin, interleukin (IL)28B polymorphism, amino acid substitution at core 70, cirrhosis, hyaluronic acid level, and HCV-RNA reduction within 2 weeks. Setting 4.56 logIU/mL as the cut-off value for HCV-RNA reduction at 2 weeks, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 77%, 86%, 95%, 50%, and 79%, respectively, and for neither the IL28B minor allele nor core 70 mutant were 80%, 71%, 91%, 50%, and 78%, respectively. In conclusion, evaluation of viral reduction at 2 weeks or the combination of IL28B polymorphism and amino acid substitution at core 70 are useful for predicting SVR to telaprevir with PEG-IFN and ribavirin therapy.
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De Nicolò A, Boglione L, Ciancio A, Cusato J, Strona S, Cardellino CS, Abdi AM, Cariti G, Troshina G, Caviglia GP, Smedile A, Rizzetto M, Di Perri G, D'Avolio A. Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner. Antiviral Res 2014; 109:7-14. [PMID: 24956496 DOI: 10.1016/j.antiviral.2014.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 06/09/2014] [Accepted: 06/12/2014] [Indexed: 01/25/2023]
Abstract
The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.
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Affiliation(s)
- Amedeo De Nicolò
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
| | - Lucio Boglione
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Alessia Ciancio
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Jessica Cusato
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Silvia Strona
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Chiara Simona Cardellino
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Adnan Mohamed Abdi
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giulia Troshina
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Gian Paolo Caviglia
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Antonina Smedile
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Mario Rizzetto
- Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
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Renal dysfunction associated with telaprevir-containing triple therapy for chronic hepatitis C: is early prediction possible? Eur J Gastroenterol Hepatol 2014; 26:996-1002. [PMID: 25072384 DOI: 10.1097/meg.0000000000000081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Renal dysfunction has recently been described as a potential complication of tritherapy with telaprevir (TVR) in patients with chronic hepatitis C. This study aimed to identify predictive factors for and consequences of TVR-associated renal dysfunction. PATIENTS AND METHODS A retrospective-prospective study was carried out in 96 patients with chronic hepatitis C, genotype 1, treated with TVR-based tritherapy in 2012-2013, in whom regular serum creatinine measurements were performed during the first 12 weeks of treatment. The patients received standard doses of peginterferon, ribavirin and TVR (2250 mg/day). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. RESULTS eGFR decreased significantly from baseline at weeks 4, 8 and 12, the mean maximum decrease being 22.0±23.6 ml/min, with a significant correlation between baseline and minimum eGFR (r=0.58, P<10), stronger between week 2 and minimum eGFR in the subgroup of 62 patients in whom creatinine measurement was performed at week 2. Thirteen patients had an eGFR below 60 ml/min during treatment. Age and baseline eGFR were independent predictors of eGFR below 60 ml/min in the entire population, and only week 2 eGFR when available. The decrease in haemoglobin was significantly correlated with the decrease in eGFR. Age, baseline haemoglobin and the maximum variation in eGFR were independent predictors for minimum haemoglobin. The patients with decreased eGFR had more severe anaemia, and received more blood transfusions and erythropoietin. Renal dysfunction regressed in all patients after stopping TVR. CONCLUSION The reversible decrease in eGFR in patients receiving TVR-containing tritherapy can be predicted early, possibly allowing measures aimed at preventing anaemia.
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Pariente A, Rémy AJ, Lesgourgues B, Hagège H. Risk factors for severe anaemia during telaprevir-based triple therapy: is acquired renal dysfunction the missing link? Liver Int 2014; 34:e163-4. [PMID: 24571470 DOI: 10.1111/liv.12510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Virlogeux V, Pradat P, Bailly F, Funingana G, Gonçalves F, Maynard M, Hartig-Lavie K, Amiri M, Zoulim F. Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end-stage liver disease score. J Viral Hepat 2014; 21:e98-e107. [PMID: 24612466 DOI: 10.1111/jvh.12237] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 12/17/2013] [Indexed: 12/13/2022]
Abstract
Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.
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Affiliation(s)
- V Virlogeux
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France; Lyon University, Lyon, France; Inserm U1052, Lyon, France; ENS, Lyon, France
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Nakamuta M, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J. Influence of low-density lipoprotein cholesterol on virological response to telaprevir-based triple therapy for chronic HCV genotype 1b infection. Antiviral Res 2014; 104:102-9. [PMID: 24462955 DOI: 10.1016/j.antiviral.2014.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/06/2014] [Accepted: 01/12/2014] [Indexed: 12/12/2022]
Abstract
Elevated serum low-density lipoprotein cholesterol (LDL-C) level has been associated with sustained virological response (SVR) by chronic hepatitis C patients treated with pegylated-interferon (PEG-IFN) α and ribavirin (RBV). The aim of this study was to investigate the relation between the baseline LDL-C level and the treatment outcome from telaprevir (TVR)-based triple therapy. This prospective, multicenter study consisted of 241 treatment-experienced patients infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The SVR rate was 81.3% (196 of 241) by intention-to-treat analysis. Higher LDL-C level was strongly associated with SVR (P=1.3×10⁻⁸). The area under the receiver operating characteristic curve for predicting SVR was 0.78 and the cutoff value for the LDL-C level at baseline was 95 mg/dL. In multivariable logistic regression analysis of predictors of SVR, LDL-C ≥95 mg/dL (odds ratio [OR] 3.60, P=0.0238), α-fetoprotein ≤5.0 ng/mL (OR 5.06, P=0.0060), prior relapse to PEG-IFNα and RBV (OR 5.71, P=0.0008), and rapid virological response (HCV RNA undetectable at week 4) (OR 5.52, P=0.0010) were extracted as independent predictors of SVR. For prior partial and null responders, the SVR rates of the groups with LDL-C ≥95 mg/dL were significantly higher than those of the <95 mg/dL groups with IL28B TG/GG and pretreatment platelet count <150×10⁹/L (both P<0.05). The baseline LDL-C level exerted a potent influence on the SVR of treatment-experienced patients treated with TVR-based triple therapy, especially for prior partial and null responders to PEG-IFNα and RBV.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | | | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Yuichi Tanabe
- Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
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Agnesod D, De Nicolò A, Simiele M, Mohamed Abdi A, Boglione L, Di Perri G, D'Avolio A. Development and validation of a useful UPLC-MS/MS method for quantification of total and phosphorylated-ribavirin in peripheral blood mononuclear cells of HCV+ patients. J Pharm Biomed Anal 2013; 90:119-26. [PMID: 24366212 DOI: 10.1016/j.jpba.2013.11.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Revised: 11/21/2013] [Accepted: 11/22/2013] [Indexed: 12/29/2022]
Abstract
The current standard-of-care therapy in HCV consists in ribavirin (RBV) plus pegylated-interferon-α 2a or 2b and, for HCV-1 infected patients, also directly acting antivirals (DAAs). Despite the increase in the number of patients who reach sustained virological response (SVR) for HCV-1, a great inter-individual variability in the response to therapy remains. Whether new drugs are available in combination with RBV and Peg-IFN for HCV-1, the treatment of the other viral genotypes remains the same: this issue highlights the lasting importance of RBV and Peg-IFN in anti-HCV treatment. Moreover, a strong limiting factor to the usefulness of anti-HCV treatment remains the occurrence of adverse events, first of all hemolytic anemia, which have increased with the addition of DAAs, but is mainly an RBV-dependent effect. For these reasons, the monitoring of RBV exposure in the various compartments should be important. Since the routinely determination of RBV in the target cells as the hepatocytes is impracticable for of its invasiveness, the quantification in easier to obtain cells could be a good choice. In this work, we developed and validated an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay method to quantify RBV concentrations in peripheral blood mononucleated cells (PBMCs). QCs were prepared with RBV and RBV-monophosphate (RMP). Each sample was divided into two aliquots, which undergone the same extraction procedure: one was treated with acid phosphatase to convert RBV phosphorylated metabolites into free RBV, the other one was not-treated. The extracts were analyzed with reverse-phase column with UPLC-MS/MS. Calibration curves fitted a least squares model (weighed 1/X) for ribavirin levels in a range from 0.1 ng to 200 ng (mean r(2)=0.9993). Accuracy, intra-day and inter-day precision of the methods were in accordance with FDA guidelines. Moreover, phosphorylated QCs were used to assess the correct determination of total RBV concentration. We tested this method by monitoring RBV concentrations in PBMCs from 20 HCV+ patients, receiving alpha interferon-plus RBV combination therapy. This method showed to be reliable, precise, accurate and suitable for evaluation of intracellular RBV concentrations.
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Affiliation(s)
- Danilo Agnesod
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Amedeo De Nicolò
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Marco Simiele
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Adnan Mohamed Abdi
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Lucio Boglione
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Laboratory of Clinical Pharmacology and Pharmacogenetic; Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
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