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Schmit D, Milewicz U, Boerneke MA, Burley S, Walsworth K, Um J, Hecht D, Hermann T, Bergdahl BM. Syntheses and Binding Testing of N1-Alkylamino-Substituted 2-Aminobenzimidazole Analogues Targeting the Hepatitis C Virus Internal Ribosome Entry Site. Aust J Chem 2020. [DOI: 10.1071/ch19526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
A series of 2-aminobenzimidazole analogues have been synthesised and tested for binding to a previously established RNA target for viral translation inhibitors in the internal ribosome entry site (IRES) of the hepatitis C virus (HCV). Synthesis of new inhibitor compounds followed a highly convergent strategy which allowed for incorporation of diverse tertiary amino substituents in high overall yields (eight-steps, 4–22%). Structure–activity relationship (SAR) studies focussed on the tertiary amine substituent involved in hydrogen bonding with the RNA backbone at the inhibitor binding site. The SAR study was further correlated with in silico docking experiments. Analogous compounds showed promising activities (half maximal effective concentration, EC50: 21–89µM). Structures of the synthesised analogues and a correlation to their mode of binding, provided the opportunity to explore parameters required for selective targeting of the HCV IRES at the subdomain IIa which acts as an RNA conformational switch in HCV translation.
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Kuwashiro T, Iwane S, Jinghe X, Matsuhashi S, Eguchi Y, Anzai K, Fujimoto K, Mizuta T, Sakamoto N, Ikeda M, Kato N, Ozaki I. Regulation of interferon signaling and HCV‑RNA replication by extracellular matrix. Int J Mol Med 2018; 42:957-965. [PMID: 29786754 PMCID: PMC6034922 DOI: 10.3892/ijmm.2018.3693] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/09/2018] [Indexed: 01/08/2023] Open
Abstract
Although interferon (IFN)‑based treatment of patients with chronic hepatitis C virus (HCV) infection is widely applied, treatment resistance is often observed in patients with advanced liver fibrosis. Given that the molecular mechanisms of IFN resistance in liver fibrosis remain elusive, the present study investigated the effects of extracellular matrix (ECM) on IFN signaling in hepatic cells. The native HuH‑7 human hepatoma cell line and HuH‑7 cells were stably transfected with full‑length HCV‑RNA fused with Renilla luciferase (OR6 cells) were cultured on ECM‑coated dishes or non‑coated plastic dishes (NDs), and treated with human IFN‑α. In Huh‑7 cells cultured on coated dishes, the IFN‑stimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFN‑stimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFN‑α treatment, the amount of HCV‑RNA and viral protein produced by OR6 cells cultured on coated dishes was higher than that produced by cells cultured on NDs. When cells were treated with β1‑integrin‑blocking antibody to disrupt the cell‑matrix interaction, the ISRE luciferase activity was restored, and the protein expression of ISG was increased, while that of HCV proteins was suppressed. Treatment of cells with integrin‑linked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that β1‑integrin‑mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through β1‑integrin‑mediated signaling involving ILK and FAK.
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Affiliation(s)
- Takuya Kuwashiro
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Shinji Iwane
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Xia Jinghe
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Sachiko Matsuhashi
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Yuichiro Eguchi
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Keizo Anzai
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Kazuma Fujimoto
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Toshihiko Mizuta
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan
| | - Masanori Ikeda
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan
| | - Nobuyuki Kato
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan
| | - Iwata Ozaki
- Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study. Int J Infect Dis 2016; 53:46-51. [PMID: 27815225 DOI: 10.1016/j.ijid.2016.10.028] [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] [Received: 07/13/2016] [Revised: 10/13/2016] [Accepted: 10/25/2016] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.
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Velosa J. Why is viral eradication so important in patients with HCV-related cirrhosis? Antivir Ther 2016; 22:1-12. [PMID: 27553973 DOI: 10.3851/imp3077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2016] [Indexed: 02/07/2023]
Abstract
Approximately one-third of patients infected with chronic HCV have cirrhosis, and this is likely to increase in the near future. The risk of complications, mainly the development of hepatocellular carcinoma, depends on the presence of cirrhosis, and a significant increase in the incidence of cirrhosis-related events, including mortality, is likely in the following years. All-oral therapy with direct-acting antivirals (DAAs) offers a safe and short treatment, with cure rates over 90% in compensated cirrhosis. Cirrhotic patients should be given high priority for treatment because viral clearance has a significant impact on the natural history of HCV infection, halting the progression of the disease and inducing the regression of fibrosis, as well as reducing the need for liver transplantation and improving survival. The benefit of DAAs is great in patients with decompensated cirrhosis, up until recently a population for whom no alternative therapy was available. The efficacy of all-oral therapy has been reported to improve liver function in about 50% of Child-Pugh class C patients. The regression of cirrhosis observed in more than half of patients achieving viral eradication on prior interferon-based regimens still has to be demonstrated in patients treated with DAAs, although there is reason to believe that this will happen. Advanced cirrhosis will eventually become the last boundary of antiviral therapy that will soon be conquered with new drugs currently pending approval.
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Affiliation(s)
- José Velosa
- Hospital de Santa Maria - Gastroenterology and Hepatology, Lisbon, Portugal
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Cleo Study Group, Ascione A, Adinolfi LE, Amoroso P, Andriulli A, Armignacco O, Ascione T, Babudieri S, Barbarini G, Brogna M, Cesario F, Citro V, Claar E, Cozzolongo R, D'Adamo G, D'Amico E, Dattolo P, De Luca M, De Maria V, De Siena M, De Vita G, Di Giacomo A, De Marco R, De Stefano G, De Stefano G, Di Salvo S, Di Sarno R, Farella N, Felicioni L, Fimiani B, Fontanella L, Foti G, Furlan C, Giancotti F, Giolitto G, Gravina T, Guerrera B, Gulminetti R, Iacobellis A, Imparato M, Iodice A, Iovinella V, Izzi A, Liberti A, Leo P, Lettieri G, Luppino I, Marrone A, Mazzoni E, Messina V, Monarca R, Narciso V, Nosotti L, Pellicelli AM, Perrella A, Piai G, Picardi A, Pierri P, Pietromatera G, Resta F, Rinaldi L, Romano M, Rossini A, Russello M, Russo G, Sacco R, Sangiovanni V, Schiano A, Sciambra A, Scifo G, Simeone F, Sullo A, Tarquini P, Tundo P, Vallone A. Boceprevir or telaprevir in hepatitis C virus chronic infection: The Italian real life experience. World J Hepatol 2016; 8:949-956. [PMID: 27574549 PMCID: PMC4976214 DOI: 10.4254/wjh.v8.i22.949] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 06/23/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings. METHODS This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL). RESULTS All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.
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Affiliation(s)
- Cleo Study Group
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Ascione
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Luigi Elio Adinolfi
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Pietro Amoroso
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Angelo Andriulli
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Orlando Armignacco
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Tiziana Ascione
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Sergio Babudieri
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giorgio Barbarini
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Michele Brogna
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Francesco Cesario
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo Citro
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Ernesto Claar
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Raffaele Cozzolongo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giuseppe D'Adamo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Emilio D'Amico
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Pellegrino Dattolo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Massimo De Luca
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo De Maria
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Massimo De Siena
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giuseppe De Vita
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Di Giacomo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Rosanna De Marco
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giorgio De Stefano
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giulio De Stefano
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Sebastiano Di Salvo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Raffaele Di Sarno
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Nunzia Farella
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Laura Felicioni
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Basilio Fimiani
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Luca Fontanella
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giuseppe Foti
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Caterina Furlan
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Francesca Giancotti
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Giancarlo Giolitto
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Tiziana Gravina
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Barbara Guerrera
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Roberto Gulminetti
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Angelo Iacobellis
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Michele Imparato
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Angelo Iodice
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo Iovinella
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Izzi
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Alfonso Liberti
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Pietro Leo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Gennaro Lettieri
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Ileana Luppino
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Aldo Marrone
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Ettore Mazzoni
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo Messina
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Roberto Monarca
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo Narciso
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Lorenzo Nosotti
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Adriano Maria Pellicelli
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Alessandro Perrella
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Guido Piai
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Picardi
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Paola Pierri
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Grazia Pietromatera
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Francesco Resta
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Luca Rinaldi
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Mario Romano
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Angelo Rossini
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Maurizio Russello
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Grazia Russo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Rodolfo Sacco
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Vincenzo Sangiovanni
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Schiano
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Antonio Sciambra
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Gaetano Scifo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Filomena Simeone
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Annarita Sullo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Pierluigi Tarquini
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Paolo Tundo
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
| | - Alfredo Vallone
- Luigi Elio Adinolfi, Barbara Guerrera, Internal Medicine Unit, Second University of Naples, 80125 Marcianise, Italy
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Gane EJ, Rouzier R, Hassanein T, Stedman CA, Mazur W, Kupcova V, Le Pogam S, Eng S, Voulgari A, Morcos PN, Brennan BJ, Scalori A, Thommes J. Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis. Hepatol Int 2016; 10:478-87. [PMID: 26886127 DOI: 10.1007/s12072-015-9699-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 12/16/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis. METHODS An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24). RESULTS In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred. CONCLUSIONS Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.
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Affiliation(s)
- Edward J Gane
- Auckland Clinical Studies, Grafton, New Zealand. .,Auckland City Hospital, Auckland, 1442, New Zealand.
| | - Régine Rouzier
- Centre Cap, Centre Médical Odysséum, Montpellier, France
| | | | - Catherine A Stedman
- Christchurch Clinical Studies and University of Otago, Christchurch, New Zealand
| | - Wlodzimierz Mazur
- Department of Infectious Diseases, Medical University of Silesia, Katowice, Poland
| | - Viera Kupcova
- Medical Faculty of Comenius University, Dérer's Hospital, Bratislava, Slovakia
| | | | - Simon Eng
- Genentech, South San Francisco, CA, USA
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9
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Crespo J, Berenguer M, Pérez F, Fernández I, González O, Bárcena R, Buti M, López J, Calleja JL. [Lead-in period and week 8 as predictive tools for response to boceprevir therapy: a retrospective study of Spanish real clinical practice]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:517-24. [PMID: 25976446 DOI: 10.1016/j.gastrohep.2015.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 03/31/2015] [Accepted: 04/01/2015] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Most discontinuations due to lack of virological response occur during the first few weeks of hepatitis C virus (HCV) triple therapy. Improved knowledge of baseline factors and their correlation with boceprevir decision points may predict treatment success. METHODS An observational, retrospective study was conducted to describe the lead-in period as a clinical decision tool in HCV genotype 1 patients treated with boceprevir. Data were collected from the medical records of 186 consecutive patients distributed across 20 Spanish general hospitals. RESULTS This study included 171 patients. A total of 80% had fibrosis F3/F4, 74% were previously treated, and 26% were treatment-naïve. After the lead-in period, 54.5% of the patients had a reduction of ≥1 log10; this reduction occurred in 52.5% of those with advanced fibrosis. Boceprevir therapy was started in 94% of the patients. Discontinuations at week 4 were limited to null responders with cirrhosis. The baseline factors associated with virological response at week 4 were IL28B, previous response, and fibrosis score. At week 8, HCV-RNA was undetectable in 48.8% of the patients. The correlation between responses at weeks 8 and 12 was 88%. CONCLUSION In the Spanish clinical setting, lead-in was mainly used as a clinical decision point for non-responders with cirrhosis. The good correlation between stopping rules at weeks 8 and 12 could be used to anticipate discontinuation, thus saving adverse events and costs.
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Affiliation(s)
- Javier Crespo
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Marqués de Valdecilla, Santander, España.
| | - Marina Berenguer
- Departamento de Gastroenterología, Hospital Universitario La Fe, Valencia, España
| | - Francisco Pérez
- Departamento de Aparato Digestivo, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, España
| | - Inmaculada Fernández
- Departamento de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Olga González
- Departamento de Aparato Digestivo, Hospital Arnau de Vilanova, Lérida
| | - Rafael Bárcena
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - María Buti
- Departamento de Medicina Interna, Hospital Universitario Vall d'Hebrón, Barcelona, España
| | - Jesús López
- Medical Affairs Department, MSD, Madrid, España
| | - José Luis Calleja
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, España
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10
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Coppola N, Pisaturo M, Zampino R, Macera M, Sagnelli C, Sagnelli E. Hepatitis C virus markers in infection by hepatitis C virus: In the era of directly acting antivirals. World J Gastroenterol 2015; 21:10749-10759. [PMID: 26478667 PMCID: PMC4600577 DOI: 10.3748/wjg.v21.i38.10749] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/04/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
About 130-170 million people are infected with the hepatitis C virus (HCV) worldwide and more than 350000 people die each year of HCV-related liver diseases. The combination of pegylated interferon (Peg-IFN) and ribavirin (RBV) was recommended as the treatment of choice for chronic hepatitis C for nearly a decade. In 2011 the directly acting antivirals (DAA) HCV NS3/4A protease inhibitors, telaprevir and boceprevir, were approved to treat HCV-genotype-1 infection, each in triple combination with Peg-IFN and RBV. These treatments allowed higher rates of SVR than the double Peg-IFN + RBV, but the low tolerability and high pill burden of these triple regimes were responsible for reduced adherence and early treatment discontinuation. The second and third wave DAAs introduced in 2013-2014 enhanced the efficacy and tolerability of anti-HCV treatment. Consequently, the traditional indicators for disease management and predictors of treatment response should be revised in light of these new therapeutic options. This review article will focus on the use of the markers of HCV infection and replication, of laboratory and instrumental data to define the stage of the disease and of predictors, if any, of response to therapy in the DAA era. The article is addressed particularly to physicians who have patients with hepatitis C in care in their everyday clinical practice.
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11
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Boccaccio V, Russo ML, Carbone M, Bruno S. Treatment discontinuation with peg-interferon: what to consider. Expert Rev Clin Pharmacol 2015; 8:761-8. [PMID: 26437265 DOI: 10.1586/17512433.2015.1090872] [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: 11/08/2022]
Abstract
Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for years, the standard of care to achieve this goal. Several baseline and on-treatment predictors of response, associated with a lower chance to achieve sustained virological response after interferon-based treatment, were developed. In the past few years, the advent of direct acting antivirals has dramatically modified the landscape of antiviral therapy, leading to an evolution from interferon-based to interferon-free therapies. This review will focus on the usefulness of futility stopping rules that allow the discontinuation of therapy in patients with a reduced chance to obtain sustained virological response if treated with interferon-containing regimens.
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Affiliation(s)
- Vincenzo Boccaccio
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Maria Luisa Russo
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Marco Carbone
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Savino Bruno
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy.,b 2 Department of Internal Medicine, Humanitas University Medicine , Rozzano, Italy
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12
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Lepida A, Colombo M, Fernandez I, Abdurakhmanov D, Abrao Ferreira P, Strasser SI, Urbanek P, Mangia A, Calleja JL, Iraqi W, DeMasi R, Lonjon-Domanec I, Moreno C, Wedemeyer H. Final Results of the Telaprevir Access Program: FibroScan Values Predict Safety and Efficacy in Hepatitis C Patients with Advanced Fibrosis or Cirrhosis. PLoS One 2015; 10:e0138503. [PMID: 26398503 PMCID: PMC4580464 DOI: 10.1371/journal.pone.0138503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 08/29/2015] [Indexed: 12/12/2022] Open
Abstract
Background Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002. Methods 1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4. Results Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intention-to-treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events. Conclusions FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments. Trial Registration ClinicalTrials.gov NCT01508286
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Affiliation(s)
- Antonia Lepida
- Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Massimo Colombo
- Department of Medicine, Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita’ degli Studi di Milano, Milan, Italy
| | - Inmaculada Fernandez
- Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain
| | - Djamal Abdurakhmanov
- I.M. Sechenov First Moscow State Medical University, E.M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russia
| | - Paulo Abrao Ferreira
- Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil
| | - Simone I. Strasser
- AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred hospital and University of Sydney, Sydney, Australia
| | - Petr Urbanek
- Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic
| | - Alessandra Mangia
- Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - José L. Calleja
- Gastroenterology, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, CIBERehd, Madrid, Spain
| | | | - Ralph DeMasi
- Janssen Research and development, Titusville, New Jersey, United States of America
| | | | - Christophe Moreno
- Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
- * E-mail:
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Giménez-Manzorro Á, García-González X, Rodríguez-González CG, Ochoa-Palominos A, Sanjurjo-Sáez M, Clemente-Ricote G. [Cost-effectiveness and safety of telaprevir and boceprevir for chronic hepatitis C in real-world clinical practice]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:575-82. [PMID: 26321320 DOI: 10.1016/j.gastrohep.2015.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 05/19/2015] [Accepted: 07/13/2015] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Triple therapy with telaprevir or boceprevir has proven to be effective in the treatment of chronic hepatitis C with response rates of up to 88%. However, the treatment may be associated with important adverse effects and a high economic impact. OBJECTIVE To assess the cost-effectiveness and safety of triple therapy with telaprevir or boceprevir for the treatment of chronic hepatitis C. METHODS Retrospective observational study. We included all patients who had started treatment with protease inhibitors before July 31(st), 2013. We evaluated sustained virological response, the cost per patient achieving sustained virological response, and the cost of the supportive treatment for adverse events associated with triple therapy. RESULTS Fifty-nine patients were included; 35 had been treated with telaprevir (59.3%) and 24 with boceprevir (40.7%). Sustained virological response was achieved by 38 (64.4%) patients: 24 (68.6%) patients in the telaprevir treatment arm and 14 (58.3%) patients in the boceprevir treatment arm. The cost per patient with sustained virological response was 43,555 € (95% CI 35,389-51,722 €). There were no statistically significant differences between the overall costs of therapy with telaprevir, 43,494 € (95% CI 34,795 €-55,092 €) versus boceprevir, 42,005 € (95% CI 32,122-64,243€). The mean cost of supportive care per patient was 1,500 €, while the maximum cost was 11,374 €. Due to adverse events, 8 (13.6%) patients required hospital admission, 22 (37.3%) patients attended the accident and emergency department, and 26 (44.1%) patients needed additional medical consultations. CONCLUSIONS The treatment of triple therapy with telaprevir or boceprevir resulted in high cost per patient with sustained virological response. Due to adverse events, a high number of patients required supportive care, whose costs should be added to those of triple therapy.
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Affiliation(s)
| | | | | | | | - María Sanjurjo-Sáez
- Servicio de Farmacia, Hospital General Universitario Gregorio Marañón, Madrid, España
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Salmerón J, Vinaixa C, Berenguer R, Pascasio JM, Sánchez Ruano JJ, Serra M&A, Gila A, Diago M, Romero-Gómez M, Navarro JM, Testillano M, Fernández C, Espinosa D, Carmona I, Pons JA, Jorquera F, Rodriguez FJ, Pérez R, Montero JL, Granados R, Fernández M, Martín AB, Muñoz de Rueda P, Quiles R. Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis. World J Gastroenterol 2015; 21:9163-9174. [PMID: 26290644 PMCID: PMC4533049 DOI: 10.3748/wjg.v21.i30.9163] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 04/29/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.
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Al Marzooqi SH, Feld JJ. Sorting out cirrhosis: mechanisms of non-response to hepatitis C therapy. Liver Int 2015; 35:1923-33. [PMID: 25939775 DOI: 10.1111/liv.12861] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 04/26/2015] [Indexed: 12/14/2022]
Abstract
Although cirrhosis has long been recognized as an important negative predictor of treatment response for hepatitis C virus (HCV) therapy, the mechanisms underlying this association remain relatively poorly understood. Treatment has progressed rapidly with the introduction of highly effective all-oral therapies, with promising outcomes even in patients with advanced cirrhosis. However, even with the new therapies, it is clear that patients with cirrhosis require special attention. Efficacy continues to be somewhat reduced compared to non-cirrhotic patients and safety is an important concern. In this review, we explore the reasons for treatment non-response in patients with cirrhosis. We focus on how cirrhosis impacts on four important areas including drug delivery, drug uptake and metabolism, immune responses and drug toxicity with examples from the clinical and basic literature. Fortunately, as treatment continues to progress, many of the challenges of treating patients with cirrhosis will become less and less problematic.
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Affiliation(s)
- Saeed H Al Marzooqi
- Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada
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Bruno S, Bollani S, Zignego AL, Pascasio JM, Magni C, Ciancio A, Caremani M, Mangia A, Marenco S, Piovesan S, Chemello L, Babudieri S, Moretti A, Gea F, Colletta C, Perez-Alvarez R, Forns X, Larrubia JR, Arenas J, Crespo J, Calvaruso V, Ceccherini Silberstein F, Maisonneuve P, Craxì A, Calleja JL. Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program. J Viral Hepat 2015; 22:469-480. [PMID: 25311757 DOI: 10.1111/jvh.12342] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 09/03/2014] [Indexed: 12/11/2022]
Abstract
In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/μL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.
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Affiliation(s)
- S Bruno
- AO Fatebenefratelli e Oftalmico, Milano, Italy
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Romero-Gómez M, Turnes J, Ampuero J, Oyagüez I, Cuenca B, Gonzalez-Garcia J, Muñoz-Molina B, Aguilar R, Leal S, Planas R, Garcia-Samaniego J, Diago M, Crespo J, Calleja JL, Casado MA, Sola R. Prediction of week 4 virological response in hepatitis C for making decision on triple therapy: the Optim study. PLoS One 2015; 10:e0122613. [PMID: 25826755 PMCID: PMC4426774 DOI: 10.1371/journal.pone.0122613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 02/23/2015] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Virological response to peginterferon + ribavirin (P+R) at week 4 can predict sustained virological response (SVR). While patients with rapid virological response (RVR) do not require triple therapy, patients with a decline <1 log10 IU/ml HCVRNA (D1L) should have treatment discontinued due to low SVR rate. AIM To develop a tool to predict first 4 weeks' viral response in patients with hepatitis C genotype 1&4 treated with P+R. METHODS In this prospective and multicenter study, HCV mono-infected (n=538) and HCV/HIV co-infected (n=186) patients were included. To develop and validate a prognostic tool to detect RVR and D1L, we segregated the patients as an estimation cohort (to construct the model) and a validation cohort (to validate the model). RESULTS D1L was reached in 509 (80.2%) and RVR in 148 (22.5%) patients. Multivariate analyses demonstrated that HIV co-infection, Forns' index, LVL, IL28B-CC and Genotype-1 were independently related to RVR as well as D1L. Diagnostic accuracy (AUROC) for D1L was: 0.81 (95%CI: 0.76 ̶ 0.86) in the estimation cohort and 0.71 (95%CI: 0.62 ̶ 0.79) in the validation cohort; RVR prediction: AUROC 0.83 (95%CI: 0.78 ̶ 0.88) in the estimation cohort and 0.82 (95%CI: 0.76 ̶ 0.88) in the validation cohort. Cost-analysis of standard 48-week treatment indicated a saving of 30.3% if the prognostic tool is implemented. CONCLUSIONS The combination of genetic (IL28B polymorphism) and viral genotype together with viral load, HIV co-infection and fibrosis stage defined a tool able to predict RVR and D1L at week 4. Using this tool would be a cost-saving strategy compared to universal triple therapy for hepatitis C.
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Affiliation(s)
- Manuel Romero-Gómez
- UCM Digestive Diseases & ciberehd, Valme University Hospital,
Sevilla, Spain
- * E-mail:
| | - Juan Turnes
- Complejo Hospitalario de Pontevedra, Pontevedra, Spain
| | - Javier Ampuero
- UCM Digestive Diseases & ciberehd, Valme University Hospital,
Sevilla, Spain
| | - Itziar Oyagüez
- Pharmacoeconomics & Outcomes Research Iberia, Madrid,
Spain
| | | | | | | | | | | | - Ramon Planas
- Hospital Germans Trias i Pujol & ciberehd, Badalona, Barcelona,
Spain
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Stasi C, Piluso A, Arena U, Salomoni E, Montalto P, Monti M, Boldrini B, Corti G, Marra F, Laffi G, Milani S, Zignego AL. Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study. World J Gastroenterol 2015; 21:3013-3019. [PMID: 25780300 PMCID: PMC4356922 DOI: 10.3748/wjg.v21.i10.3013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 10/14/2014] [Accepted: 12/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. METHODS LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. RESULTS LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. CONCLUSION Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.
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Saab S, Manne V, Bau S, Reynolds JA, Allen R, Goldstein L, Durazo F, El-Kabany M, Han S, Busuttil RW. Boceprevir in liver transplant recipients. Liver Int 2015; 35:192-7. [PMID: 24673728 DOI: 10.1111/liv.12548] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/18/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease in liver transplant recipients. METHODS We retrospectively evaluated the safety and efficacy in liver transplant recipients treated for recurrent hepatitis C genotype 1 with the combination of peginterferon, ribavirin and boceprevir. RESULTS Twenty liver transplant recipients were treated for recurrent hepatitis C. Baseline alanine aminotransferase, total bilirubin and HCV RNA values (± SD) were 67.5 (±50.9) mg/dl, 1.78 (±1.99) U/L, and 16 955 510 (±21 620 675) IU/ml. Anaemia was a common adverse event requiring epoetin in 16 of 20 recipients and ribavirin dose reductions in 17 of 20 recipients. One-third of recipients required a blood transfusion. Filgrastim was used in 11 of 20 patients (55%) and eltrombopag in two of 20 recipients (10%) over the course of treatment. Serum creatinine level increased significantly from a baseline value of 1.33 mg/dl to 1.59 mg/dl at week 20 of boceprevir (P < 0.005). The overall sustained viral response (SVR) was 50%. Of the 14 patients who had a viral load less than 1000 IU/ml at week 4 of boceprevir, the SVR was 71%. The SVR was 83% of the 11 patients who had undetectable viral levels at week 4 of boceprevir. CONCLUSIONS Antiviral therapy utilizing boceprevir in liver transplant recipients requires close monitoring. Anaemia and neutropenia were common requiring growth factors in most recipients. On-treatment viral responses appear promising but long-term data are needed.
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Affiliation(s)
- Sammy Saab
- Departments of Medicine, The University of California, Los Angeles, CA, USA; Departments of Surgery, The University of California, Los Angeles, CA, USA
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Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis. Antimicrob Agents Chemother 2014; 59:1282-91. [PMID: 25512403 DOI: 10.1128/aac.04383-14] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.).
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Atsukawa M, Tsubota A, Shimada N, Kondo C, Itokawa N, Nakagawa A, Hashimoto S, Fukuda T, Matsushita Y, Narahara Y, Iwakiri K, Nakatsuka K, Kawamoto C, Sakamoto C. Serum 25-hydroxyvitamin D3 levels affect treatment outcome in pegylated interferon/ribavirin combination therapy for compensated cirrhotic patients with hepatitis C virus genotype 1b and high viral load. Hepatol Res 2014; 44:1277-85. [PMID: 24417888 DOI: 10.1111/hepr.12298] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 12/11/2013] [Accepted: 01/07/2014] [Indexed: 02/08/2023]
Abstract
AIM Much is unknown about the effect of 25-hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus-related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25-hydroxyvitamin D3 , that contribute to a sustained virological response (SVR) in patients with cirrhosis. METHODS We analyzed whether 25-hydroxyvitamin D3 contributes to the response to PEG IFN/RBV therapy among 134 cirrhotic patients. RESULTS SVR was achieved in 43 patients. The median 25-hydroxyvitamin D3 level was 20 ng/mL. Univariate analysis showed that the following factors contributed to SVR: low-density lipoprotein cholesterol, albumin, 25-hydroxyvitamin D3 , core a.a.70 (a.a.70) substitutions, the number of mutations at the interferon sensitivity-determining region and IL28B genotype. Multivariate analysis identified IL28B genotype and 25-hydroxyvitamin D3 as independent factors contributing to SVR. Subsequently, SVR rate was examined by using 25-hydroxyvitamin D3 and other important factors. The SVR rate was 51.8% in patients with core a.a.70 wild and ≥15 ng/mL of 25-hydroxyvitamin D3 , whereas the SVR rate was 7.1% in patients with core a.a.70 wild and <15 ng/mL of 25-hydroxyvitamin D3 . The SVR rate was 56.9% in patients with IL28B major genotype and ≥15 ng/mL of 25-hydroxyvitamin D3 . Surprisingly, the SVR rate was 0% in patients with IL28B minor genotype and <15 ng/mL of 25-hydroxyvitamin D3 . CONCLUSION IL28B genotype and 25-hydroxyvitamin D3 were identified as independent factors contributing to SVR. Stratified analyses according to core a.a.70 substitution and IL28B genotype suggested that 25-hydroxyvitamin D3 influences the outcome of PEG IFN/RBV therapy for cirrhosis.
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Affiliation(s)
- Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
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Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Okada H, Takabatake R, Tokumaru A, Sakai Y, Yamashita T, Lemon SM, Murakami S, Kaneko S. Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway. Hepatology 2014; 60:1519-30. [PMID: 24962339 DOI: 10.1002/hep.27277] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 06/20/2014] [Indexed: 12/14/2022]
Abstract
UNLABELLED Malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH-C) impairs interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of profibrotic signaling on IFN signaling is not known. Here, the effect of transforming growth factor (TGF)-β signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh-7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c-Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received pegylated-IFN and ribavirin combination therapy. TGF-β signaling was significantly up-regulated in the advanced fibrosis stage of CH-C. A significant positive correlation was observed between the expression of TGF-β2 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH-C patients. In Huh-7.5 cells, TGF-β1 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c-Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF-β1 also inhibited mTORC1 and IFN signaling. Interestingly, c-Jun and TGF-β signaling was up-regulated in treatment-resistant IL28B minor genotype patients (TG/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF-β receptor inhibitor canceled these effects and showed an additive effect on the anti-HCV activity of direct-acting antiviral drugs (DAAs). CONCLUSION Blocking TGF-β signaling could potentiate the antiviral efficacy of IFN- and/ or DAA-based treatment regimens and would be useful for the treatment of difficult-to-cure CH-C patients.
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Affiliation(s)
- Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
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Velosa J, Serejo F, Ramalho F, Marinho R, Rodrigues B, Baldaia C, Raimundo M, Ferreira P. A practical guide for antiviral therapy of chronic Hepatitis C. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2014. [DOI: 10.1016/j.jpge.2014.09.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Bonnet D, Guivarch M, Bérard E, Combis JM, Remy AJ, Glibert A, Payen JL, Metivier S, Barange K, Desmorat H, Palacin A, Nicot F, Abravanel F, Alric L. Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients. World J Hepatol 2014; 6:660-669. [PMID: 25276282 PMCID: PMC4179145 DOI: 10.4254/wjh.v6.i9.660] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 04/25/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null-responders or relapsers with severe liver fibrosis.
METHODS: One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon (peg-INF) α2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.
RESULTS: The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3 (2.3, 12.4), P≤ 0.001].
CONCLUSION: More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness.
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Chen YC, Bernaards C, Kulkarni R, Moreira S, Zhu Y, Chan A, Badman E, Ackrill A, Thommes J, Smith PF. Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies. Br J Clin Pharmacol 2014; 78:533-42. [PMID: 24602156 PMCID: PMC4243904 DOI: 10.1111/bcp.12369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/21/2014] [Indexed: 01/22/2023] Open
Abstract
AIMS The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C). METHODS We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin. RESULTS Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1). CONCLUSIONS Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.
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Affiliation(s)
| | | | | | | | | | - Anna Chan
- Hoffmann-La Roche Inc.Nutley, NJ, USA
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Pol S, Corouge M. Treatment of hepatitis C: perspectives. Med Mal Infect 2014; 44:449-54. [PMID: 25174659 DOI: 10.1016/j.medmal.2014.07.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 07/15/2014] [Accepted: 07/22/2014] [Indexed: 12/20/2022]
Abstract
The treatment of hepatitis C virus (HCV) infection has significantly improved in the last 2 decades. The association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR) for nearly 15 years i.e. a viral cure of the infection for 45% of genotype 1-, 65% of genotype 4-, 70% of genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleotide and non-nucleotide inhibitors, NS5A viral replication complex). The combination of first-generation protease inhibitors with PR demonstrated a high antiviral effectiveness (75% of SVR but restricted to genotypes 1) with substantial adverse effects for the first-generation protease inhibitors, which obtained market approval in 2011 (telaprevir and boceprevir), recommendations for use in HCV monoinfected patients in 2012, and in HCV/HIV coinfected in 2013. Then, the combination of second-generation protease inhibitors with PR increased SVR rates from 75 to 90%, while reducing treatment duration, adverse effects, and the number of pills. The next step will be using an interferon and ribavirin-free combination of DAAs; it should become the standard of care in 2015. These excellent results in "easy-to-treat" patients and in small populations in the first studies were confirmed in phase III studies and in "difficult-to-treat" patients (treatment-- especially protease inhibitors--previously treated patients, cirrhotic patients, liver and renal transplant patients, HIV coinfected patients, and multi-drug treated patients, at increased risk of drug interaction). The high antiviral potency of these new combinations has changed the definition of "difficult-to-treat patients". These unique achievements in drug history make any previous publication on hepatitis C treatment obsolete.
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Affiliation(s)
- S Pol
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM U-1016, Institut Cochin, Paris, France.
| | - M Corouge
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM U-1016, Institut Cochin, Paris, France
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27
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Abstract
The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.
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Affiliation(s)
- Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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De Luca A, Bianco C, Rossetti B. Treatment of HCV infection with the novel NS3/4A protease inhibitors. Curr Opin Pharmacol 2014; 18:9-17. [PMID: 25117198 DOI: 10.1016/j.coph.2014.07.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/22/2014] [Accepted: 07/23/2014] [Indexed: 12/27/2022]
Abstract
HCV NS3/4A serine protease inhibitors are the first class of direct acting antivirals (DAA) introduced in clinical practice. The first generation agents, selective against HCV genotype 1, are used in association with pegylated interferons and ribavirin allowing increased cure rates at the price of increased toxicity, significant drug interactions and high risk of selecting mutants conferring cross-resistance to the entire class. A large number of second-wave HCV protease inhibitors are currently in clinical development. Advancements include higher potency, activity against a wider number of genotypes, improved tolerability, easier dosing schedules, although their genetic barrier to resistance remains low, especially for subtype 1a, except for the most recent grazoprevir and ACH-2684. The most relevant progress regards the combination with other classes of DAA allowing construction of interferon-free regimens of short duration, good tolerability with exceptionally high cure rates.
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Affiliation(s)
- Andrea De Luca
- UOC Malattie Infettive Universitarie, Dipartimento di Medicina e Specialistica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Istituto di Clinica delle Malattie Infettive, Università Cattolica del S Cuore, Roma, Italy.
| | - Claudia Bianco
- UOC Malattie Infettive Universitarie, Dipartimento di Medicina e Specialistica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Barbara Rossetti
- UOC Malattie Infettive Universitarie, Dipartimento di Medicina e Specialistica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
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Cheng R, Tu T, Shackel N, McCaughan GW. Advances in and the future of treatments for hepatitis C. Expert Rev Gastroenterol Hepatol 2014; 8:633-47. [PMID: 24846594 DOI: 10.1586/17474124.2014.909725] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Enormous progress has been made in the understanding of the hepatitis C virus and the development of novel therapeutic agents since the identification of the virus 25 years ago. From initial interferon monotherapy providing only 6% viral clearance rate in the 1980s, pharmacotherapeutics has now entered an exciting new era with direct-acting antiviral agents demonstrating viral clearance rates of more than 70%. We are now at the beginning of an era where combinations of direct-acting antiviral agents may pave the way for interferon-free regimens, even improving the viral clearance rate to near 100%.
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Affiliation(s)
- Robert Cheng
- Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia
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Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials. J Hepatol 2014; 61:200-9. [PMID: 24747798 DOI: 10.1016/j.jhep.2014.03.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 03/12/2014] [Accepted: 03/19/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. METHODS Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. RESULTS Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. CONCLUSIONS BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.
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Hézode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, De Ledinghen V, Poynard T, Samuel D, Bourliere M, Alric L, Raabe JJ, Zarski JP, Marcellin P, Riachi G, Bernard PH, Loustaud-Ratti V, Chazouilleres O, Abergel A, Guyader D, Metivier S, Tran A, Di Martino V, Causse X, Dao T, Lucidarme D, Portal I, Cacoub P, Gournay J, Grando-Lemaire V, Hillon P, Attali P, Fontanges T, Rosa I, Petrov-Sanchez V, Barthe Y, Pawlotsky JM, Pol S, Carrat F, Bronowicki JP. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 2014; 147:132-142.e4. [PMID: 24704719 DOI: 10.1053/j.gastro.2014.03.051] [Citation(s) in RCA: 201] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/20/2014] [Accepted: 03/31/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
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Affiliation(s)
- Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Helene Fontaine
- Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, INSERM U1016, Paris, France
| | - Celine Dorival
- INSERM UMR-S 1136, Université Pierre et Marie Curie Paris 6, Paris, France
| | - Fabien Zoulim
- Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France
| | - Dominique Larrey
- Liver Unit-IRB-INSERM1040, Hôpital Saint Eloi, Montpellier, France
| | - Valerie Canva
- Department of Hepatology and Gastroenterology, Centre Hospitalier Régional et Universitaire Claude Huriez, Lille, France
| | - Victor De Ledinghen
- Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, Pessac, INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Thierry Poynard
- Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpétrière, AP-HP, Université Pierre et Marie Curie Paris 6, INSERM UMR-S938, Paris, France
| | - Didier Samuel
- Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, UMR-S785, Université Paris-Sud, INSERM U785, Villejuif, France
| | - Marc Bourliere
- Department of Hepatology and Gastroenterology, Hôpital Saint Joseph, Marseille, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, UMR-152, Toulouse III University, Toulouse, France
| | - Jean-Jacques Raabe
- Department of Hepatology and Gastroenterology, Centre Hospitalier Régional, Metz, France
| | - Jean-Pierre Zarski
- Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U823, Grenoble, France
| | - Patrick Marcellin
- Department of Hepatology, Hôpital Beaujon, AP-HP, Université Paris-Diderot, INSERM CRB3, Clichy, France
| | - Ghassan Riachi
- Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France
| | - Pierre-Henri Bernard
- Service d'Hépatologie et Gastroentérologie, Hôpital Saint-André, Bordeaux, INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Veronique Loustaud-Ratti
- Department of Hepatology and Gastroenterology, CHU Dupuytren, Université de Limoges, UMR INSERM U1092, Limoges, France
| | | | - Armand Abergel
- Department of Hepatology and Gastroenterology, CHU Estaing, Université d'Auvergne, UMR 6284, Clermont-Ferrand, France
| | - Dominique Guyader
- Service des Maladies du Foie, CHU Rennes, Université de Rennes 1, INSERM U991, Rennes, France
| | - Sophie Metivier
- Department of Hepatology and Gastroenterology, CHU Purpan, Toulouse, France
| | - Albert Tran
- Digestive Center, Centre Hospitalier Universitaire de Nice, INSERM U1065-8, Nice, France
| | - Vincent Di Martino
- Service d'Hépatologie, CHU Jean Minjoz, Université de Franche Comté, Besançon, France
| | - Xavier Causse
- Department of Hepatology and Gastroenterology and Digestive Oncology, CHR La Source, Orléans, France
| | - Thong Dao
- Department of Hepatology and Gastroenterology, CHU, INSERM U1075, Caen, France
| | - Damien Lucidarme
- Department of Hepatology and Gastroenterology, Groupe Hospitalier de l'Institut Catholique Lillois, Faculté Libre de Médecine, Lille, France
| | - Isabelle Portal
- Department of Hepatology and Gastroenterology, Hôpital de la Conception, Marseille, France
| | - Patrice Cacoub
- Department of Internal Medicine, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie Paris 6, INSERM, UMR-S959, CNRS, UMR 7211, Paris, France
| | - Jerome Gournay
- Department of Hepatology and Gastroenterology, Hôpital Hôtel-Dieu, Nantes, France
| | - Veronique Grando-Lemaire
- Department of Hepatology and Gastroenterology, Hôpital Jean Verdier, AP-HP, Université Paris 13, Bondy, France
| | - Patrick Hillon
- Department of Hepatology and Gastroenterology, CHU de Dijon, Université de Bourgogne, Dijon, France
| | - Pierre Attali
- Department of Hepatology and Gastroenterology, Hôpital de Bicêtre, AP-HP, Le Kremlin-Bicêtre, France
| | - Thierry Fontanges
- Department of Hepatology and Gastroenterology, Hôpital P Oudot, Bourgoin-Jallieu, France
| | - Isabelle Rosa
- Department of Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Créteil, France
| | - Ventzislava Petrov-Sanchez
- Unit for Basic and Clinical Research on Viral Hepatitis, French National Agency for Research on AIDS and Viral Hepatitis, Paris, France
| | - Yoann Barthe
- INSERM UMR-S 1136, Université Pierre et Marie Curie Paris 6, Paris, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Stanislas Pol
- Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, INSERM U1016, Paris, France
| | - Fabrice Carrat
- INSERM UMR-S 1136, Université Pierre et Marie Curie Paris 6, Paris, France; Department of Public Health, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, INSERM U954, Vandoeuvre-les-Nancy, France.
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KASL clinical practice guidelines: management of hepatitis C. Clin Mol Hepatol 2014; 20:89-136. [PMID: 25032178 PMCID: PMC4099340 DOI: 10.3350/cmh.2014.20.2.89] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 05/20/2014] [Indexed: 12/16/2022] Open
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Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Lawitz E, Zhou A, Bourque M, Bhanja S, Strizki J, Barnard RJO, Hwang PMT, DiNubile MJ, Mobashery N. Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of SVR in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis. Clin Gastroenterol Hepatol 2014; 12:1029-37.e5. [PMID: 24120953 DOI: 10.1016/j.cgh.2013.09.067] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 09/20/2013] [Accepted: 09/21/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. METHODS Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. RESULTS In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. CONCLUSIONS In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.
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Affiliation(s)
| | | | - Edward J Gane
- Auckland Clinical Studies, Ltd, Auckland, New Zealand
| | - Lawrence Serfaty
- Service d'Hépatologie, Université Pierre et Marie Curie, Paris, France
| | - Eric Lawitz
- Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas
| | - Amy Zhou
- Merck Sharp and Dohme, Whitehouse Station, New Jersey
| | | | | | - Julie Strizki
- Merck Sharp and Dohme, Whitehouse Station, New Jersey
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Coppola N, Pisaturo M, Sagnelli C, Sagnelli E, Angelillo IF. Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors. PLoS One 2014; 9:e94542. [PMID: 24728219 PMCID: PMC3984165 DOI: 10.1371/journal.pone.0094542] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 03/18/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND & AIM To compare the efficacy of pegylated-interferon (Peg-IFN) α-2a or α-2b and ribavirin given as dual therapy versus triple therapy (Peg-IFN and ribavirin plus boceprevir or telaprevir) in patients with HCV-1 chronic hepatitis naïve for anti-HCV therapy or relapsers to dual therapy in relation to the presence of constitutional, clinical and virological predictors of treatment response. METHODS Included in the meta-analysis were studies meeting these criteria: original data from randomized trials on the efficacy of dual versus triple therapy in therapy-naïve patients or relapsers; at least one primary outcome clearly defined: sustained virological response in patients with or without rapid virological response (RVR), with genotype 1a or 1b, low or high HCV load, IL28-B CC or non-CC genotype, mild or severe fibrosis; odds ratio estimates of relative risk (RR) and 95% confidence intervals; English language; and published up to the end of June 2013. RESULTS Seven original studies met the inclusion criteria, allowing a meta-analysis on 3,652 patients. Triple therapy was more effective than dual, regardless of IL-28B genotype, HCV sub-genotype, liver fibrosis, and baseline HCV load. In 1,045 patients who achieved RVR, SVR was more frequently achieved with dual therapy (RR = 1.11; p = 0.002) than triple. The same results were achieved when only the therapy-naïve patients were considered. CONCLUSIONS Triple therapy provides a significantly higher SVR rate than dual therapy, but dual therapy obtains a significantly higher SVR rate in patients with RVR. The data stress the clinical importance of a 4-week lead-in phase in direct-acting antiviral-based treatment.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Italo F. Angelillo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
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Kanwal F, White DL, Tavakoli-Tabasi S, Jiao L, Lin D, Ramsey DJ, Spiegelman A, Kuzniarek J, El-Serag HB. Many patients with interleukin 28B genotypes associated with response to therapy are ineligible for treatment because of comorbidities. Clin Gastroenterol Hepatol 2014; 12:327-333.e1. [PMID: 23978349 PMCID: PMC3971998 DOI: 10.1016/j.cgh.2013.08.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 06/27/2013] [Accepted: 08/19/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Interleukin (IL)-28B (interferon-λ 3) genotype is the strongest predictor of response of patients with hepatitis C virus (HCV) infection to antiviral therapy. However, patients with HCV infection often have physical or mental comorbidities that contraindicate or complicate treatment, regardless of their genotype. The potential role of IL28B genotype within the context of patients' clinical and social environment is therefore unclear. METHODS We characterized the IL28B genotype (for rs12980275 and rs8099917) in 308 patients (mean age, 56 y; 25% African American; 38% with advanced-stage fibrosis) with genotype 1 HCV infection seen at the Michael E. DeBakey Veterans Administration Medical Center in Houston, Texas, from May 1, 2009, through April 1, 2012. We evaluated their eligibility for antiviral treatment based on clinical and social factors such as physical or mental health comorbidity, ongoing alcohol or drug use, and noncompliance with treatment evaluation. RESULTS Of the 308 subjects, 40% were homozygous for rs12980275 (associated with response to therapy), 46% were heterozygous, and 15% were homozygous for alleles associated with reduced response to therapy. Overall, 36% of patients were considered to be ineligible for treatment; of these, 40% had the rs12980275 genotype. More than half of the patients with rs12980275 who were ineligible for treatment were excluded because of mental health comorbidities; one-third of these patients had advanced fibrosis. The reason(s) for treatment exclusion resolved in only 8% of patients during a mean 1.5 years of follow-up evaluation. CONCLUSIONS In a well-characterized cohort of patients with HCV, a large proportion (40%) with IL28B polymorphisms associated with response to therapy is ineligible for treatment because of contraindications. One potential role of IL28B genotype analysis could be to identify patients who, although not currently eligible for antiviral treatment, could become so by modifying fixable exclusions to treatment.
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Affiliation(s)
- Fasiha Kanwal
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
| | - Donna L White
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Shahriar Tavakoli-Tabasi
- Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Li Jiao
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Derek Lin
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - David J Ramsey
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Section of Health Services Research, Baylor College of Medicine, Houston, Texas
| | | | - Jill Kuzniarek
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Section of Health Services Research, Baylor College of Medicine, Houston, Texas
| | - Hashem B El-Serag
- Clinical Epidemiology and Outcomes Program, Houston VA Health Services Research and Development Center of Excellence, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Abstract
In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon-based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all-causes of mortality in all categories of patients with HCV-related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg-interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules. Recently, improvement in the knowledge of the HCV life-cycle, has resulted in the rapid development of many direct-acting antivirals (DAAs). Two first generation DAAs, boceprevir (BOC) and telaprevir (TVR), have been approved, and more than 40 new small molecules are still in development. However, only a few individuals with compensated cirrhosis were included in the phase III studies assessing the safety and efficacy of BOC or TVR in naïve and chronic hepatitis C genotype 1 patients in whom treatment had failed, and patients with either decompensation or end-stage liver disease were excluded. Therefore, the information available in these patients, which have shown significantly lower SVR compared with patients with mild to moderate fibrosis, are not fully reliable. In addition, in real practice, some studies that have not yet been fully published have shown that triple therapy with these two molecules was associated with low SVR and high serious adverse events (SAEs).
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Affiliation(s)
- Vincenzo Boccaccio
- Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy
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Coco B, Caraceni P, Aghemo A, Bitetto D, Bruno R, Ciancio A, Marzioni M, Petta S, Rendina M, Valenti L. Triple therapy with first-generation protease inhibitors for patients with genotype 1 chronic hepatitis C: recommendations of the Italian association for the study of the liver (AISF). Dig Liver Dis 2014; 46:18-24. [PMID: 24119482 DOI: 10.1016/j.dld.2013.08.243] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 08/03/2013] [Accepted: 08/27/2013] [Indexed: 12/11/2022]
Abstract
The first-generation Protease Inhibitors Boceprevir and Telaprevir administered in triple therapy regimens with Peg-interferon alpha and Ribavirin have been proven effective in increasing the rate of Sustained Virological Response in both naive and treatment-experienced patients with chronic genotype-1 hepatitis C. However, at the individual level, the therapeutic advantage of triple therapy is highly variable and results from the combination of multiple factors related to the characteristics of patient, viral status and liver disease. The recommendations presented are promoted by the Italian Association for the Study of the Liver, with the aim to help the physician in the decision-making process as well as to manage patients during treatment with triple therapy.
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Affiliation(s)
| | | | | | - Alessio Aghemo
- AISF Consulting Committee on the New Antiviral Hepatitis C Drugs
| | - Davide Bitetto
- AISF Consulting Committee on the New Antiviral Hepatitis C Drugs
| | - Raffaele Bruno
- AISF Consulting Committee on the New Antiviral Hepatitis C Drugs
| | | | | | - Salvatore Petta
- AISF Consulting Committee on the New Antiviral Hepatitis C Drugs
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Stasi C, Rosselli M, Zignego AL, Laffi G, Milani S. Serotonin and its implication in the side-effects of interferon-based treatment of patients with chronic viral hepatitis: Pharmacological interventions. Hepatol Res 2014; 44:9-16. [PMID: 23607322 DOI: 10.1111/hepr.12116] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 03/11/2013] [Accepted: 03/18/2013] [Indexed: 12/13/2022]
Abstract
Depression is a frequent side-effect of interferon-based treatment of patients with chronic viral hepatitis, that may lead to reduction or discontinuation of treatment. Clinical trials data showed the importance of therapy of psychiatric disorders for a successful antiviral treatment. Emerging evidence suggests that interferon may cause depression affecting serotonin synthesis via increased activity of indoleamine 2,3-dioxygenase. Serotonin reuptake inhibitors significantly improve mood disorders, but the use of these drugs requires caution because some studies reported the emergence of mania in patients treated for depression during antiviral therapy. Therefore, this review will examine and discuss the putative role of serotonin and its metabolism in the development of depression during antiviral therapy, focusing on pharmacological interventions to reduce side-effects.
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Affiliation(s)
- Cristina Stasi
- Department of Internal Medicine, University of Florence, Florence, Italy
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Vinaixa C, Aguilera V, Berenguer M. Avances en el tratamiento de la hepatitis C. Med Clin (Barc) 2013; 141:447-52. [DOI: 10.1016/j.medcli.2013.01.041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 01/30/2013] [Accepted: 01/31/2013] [Indexed: 12/15/2022]
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Shankar H, Bichoupan K, Dieterich DT. The pharmacokinetic evaluation of boceprevir for treatment of hepatitis C virus. Expert Opin Drug Metab Toxicol 2013; 9:1647-57. [PMID: 24079600 DOI: 10.1517/17425255.2013.840290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Boceprevir is an NS3/NS4A serine protease inhibitor that was approved for use in Hepatitis C virus (HCV) genotype 1 patients by the US Food and Drug Administration (FDA) in May 2011. The approval of this protease inhibitor marked a major paradigm shift in the treatment of HCV, as it was one of the first of many new small molecules specifically designed and approved for HCV. AREAS COVERED In this article, the authors summarize boceprevir's pharmacokinetic and pharmacodynamic properties. In addition, they review Phase II and III trials of boceprevir as well as its clinical efficacy, dosing and safety. EXPERT OPINION Boceprevir is a potent protease inhibitor for the treatment of genotype 1 HCV. It has a well-tolerated side-effect profile and increases the likelihood of SVR in naïve and previously treated patients. The impending release of newer more efficacious direct-acting antivirals may limit the use of boceprevir for patients infected with HCV.
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Affiliation(s)
- Hari Shankar
- Icahn School of Medicine at Mount Sinai, Department of Liver Disease , 1468 Madison Ave, Annenberg Building, Room 21-42, New York, NY10029 , USA +1 212 831 8116 ;
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Abstract
Advanced liver fibrosis is a recognized barrier to both access and response to triple therapy with protease inhibitors Boceprevir and Telaprevir, and is associated with an increased risk of severe treatment-related adverse events. While not properly addressed by registration trials enrolling highly selected populations, this nuance of protease inhibitors triple therapy for hepatitis C virus genotype 1 was highlighted by the observational study CUPIC conducted in France. The study enrolled a large number of patients, beyond the safety criteria of registration trials, thereby ending in worrisome safety profiles of protease inhibitors regimens in patients with severe liver impairment who in the past had safely, but unsuccessfully, been exposed to dual therapy with interferon and ribavirin. Indeed, protease inhibitors therapy led to alarming rates of infection and clinical decompensation, particularly in patients with reduced hepatic reserve as predicted by the low platelets and albumin levels. Ultimately antiviral therapy resulted in a death rate of up to 2% and a treatment discontinuation rate of 26%, not to mention the increased need of bone marrow stimulating factors and blood transfusions. The 16-week interim report of the HEP3002 trial expanded the access program to Telaprevir, enrolling patients with advanced fibrosis who fulfilled the safety criteria of registration trials only, and offered an unbiased evaluation of Telaprevir tolerability and safety in this most in-need population, since the rates of treatment discontinuation due to adverse events were up to 14%.
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Conteduca V, Sansonno D, Russi S, Pavone F, Dammacco F. Therapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents. J Infect 2013; 68:1-20. [PMID: 24012819 DOI: 10.1016/j.jinf.2013.08.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 08/07/2013] [Accepted: 08/22/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Chronic hepatitis C virus (HCV) infection represents a leading worldwide medical and social problem. The expanding knowledge of HCV lifecycle has led to the development of novel antiviral agents that: a) specifically target a viral function (direct-acting antivirals), or b) specifically inhibit viral replication. The present review describes the novel anti-HCV drugs that have been better studied at the time of this writing and the current two types of treatment, namely interferon-based and interferon-free regimens. In addition, predictive factors, virological responses, side-effects, and resistance mechanisms of the novel agents are summarized. CONCLUSIONS The introduction of novel antiviral agents is remarkably changing the therapeutic combinations aimed at improving virological responses both for easy-to-cure and difficult-to-treat patients. Since additional, effective drugs are under advanced development, it seems reasonable to expect that further therapeutic and prognostic improvements will be achieved in the near future.
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Affiliation(s)
- Vincenza Conteduca
- Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
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Hézode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, de Ledinghen V, Poynard T, Samuel D, Bourlière M, Zarski JP, Raabe JJ, Alric L, Marcellin P, Riachi G, Bernard PH, Loustaud-Ratti V, Métivier S, Tran A, Serfaty L, Abergel A, Causse X, Di Martino V, Guyader D, Lucidarme D, Grando-Lemaire V, Hillon P, Feray C, Dao T, Cacoub P, Rosa I, Attali P, Petrov-Sanchez V, Barthe Y, Pawlotsky JM, Pol S, Carrat F, Bronowicki JP. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59:434-441. [PMID: 23669289 DOI: 10.1016/j.jhep.2013.04.035] [Citation(s) in RCA: 370] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Revised: 04/05/2013] [Accepted: 04/25/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.
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Affiliation(s)
- Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
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Bruno S, Mangia A. Usefulness of Lead-In phase in determining risk/benefit of telaprevir treatment in patients with HCV cirrhosis. J Hepatol 2013; 58:1259. [PMID: 23376359 DOI: 10.1016/j.jhep.2013.01.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 01/11/2013] [Indexed: 12/04/2022]
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Tillmann HL. Hepatitis C infection and presence of advanced fibrosis: wait or treat? Why wait? There is no time to lose, is there? J Hepatol 2013; 58:412-4. [PMID: 23247067 DOI: 10.1016/j.jhep.2012.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 12/04/2012] [Indexed: 12/04/2022]
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