1
|
Abaalkhail F, Al-hamoudi W, Altraif I, Mohamed H, Aleid H, Broering D, Alqahtani S. Treatment with Grazoprevir/Elbasvir in Post-kidney Transplant Patients with Hepatitis C Virus Genotype 4 Infection. HEPATITIS MONTHLY 2021; 21. [DOI: 10.5812/hepatmon.110260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Background: Kidney transplant (KT) recipients have a high rate of hepatitis C virus (HCV) infection, which can impact long-term graft and patient survival rates. Although direct-acting antivirals (DAAs) are effective for treating HCV, there is limited data on their use in post-KT patients with HCV genotype 4 infection. Objectives: To evaluate the effectiveness and occurrence of adverse events with grazoprevir/elbasvir combination treatment without ribavirin in post-KT patients with HCV genotype 4 infection. Methods: In this case series, nine therapy-naïve adult post-KT patients with HCV genotype 4 infection were recruited. They had stable graft function and received a fixed dose of grazoprevir/elbasvir (50 mg/100 mg) combination without ribavirin daily for 12 weeks. Patients co-infected with hepatitis B virus, HIV, or with evidence of decompensated liver disease were excluded from the study. Patients were monitored for viral load, laboratory values, and adverse events associated with drug treatment. The response was defined by the sustained virologic response at 12 weeks (SVR12) after the end of treatment. Results: All nine patients completed the treatment period and achieved SVR12 with no treatment failure or relapse. Of them, six patients had HCV genotype 4 infection alone, and three had HCV of mixed genotypes 1 and 4. Two (22%) patients showed a rapid HCV clearance at four weeks. No adverse events or serious adverse events were reported. The patients’ renal function was stable during and after the treatment with no deterioration of graft function, and no adjustments to the immunosuppressive therapy were required. Conclusions: Grazoprevir/elbasvir combination without ribavirin is an effective and safe treatment option for post-KT patients with genotype 4 HCV infection.
Collapse
|
2
|
El-Tahan RR, Ghoneim AM, Zaghloul H. 5' UTR and NS5B-based genotyping of hepatitis C virus in patients from Damietta governorate, Egypt. J Adv Res 2018; 10:39-47. [PMID: 30046475 PMCID: PMC6057237 DOI: 10.1016/j.jare.2018.01.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 01/04/2018] [Accepted: 01/07/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a main health problem in Egypt causing high rates of mortalities. Egypt has the highest HCV prevalence in the world, with specific HCV subtypes epidemic and circulating extensively in the country. Different antiviral therapy protocols have been implemented for treating Egyptian HCV patients. Due to the limited data about HCV in Egypt, this study aimed to genotype HCV strains circulating in the Nile Delta Damietta governorate and to investigate the variation in the nonstructural 5B (NS5B) region targeted by the newly approved antiviral drugs. Thirty HCV samples from treatment-naïve patients were genotyped by restriction fragment length polymorphism. Some samples were genotyped by direct sequencing of their 5' untranslated region (UTR) and NS5B regions. Phylogenetic analysis was also performed on the sequences of their NS5B regions. Fourteen new sequences have been deposited in the GenBank database. Results showed that subtype 4a was prevalent in addition to subtype 1g. None of the previously reported NS5B substitutions were detected in the sequenced isolates from treatment-naïve patients, which may be a good predictor for efficient treatment of HCV Egyptian patients with Sofosbuvir. Further studies on Sofosbuvir treated-HCV Egyptian patients are required to investigate whether any NS5B substitutions can confer resistance to treatment.
Collapse
Affiliation(s)
- Radwa R. El-Tahan
- Zoology Department, Faculty of Science, Damietta University, New Damietta, P.O. 34517, Damietta, Egypt
| | - Ahmed M. Ghoneim
- Zoology Department, Faculty of Science, Damietta University, New Damietta, P.O. 34517, Damietta, Egypt
| | - Hosam Zaghloul
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
3
|
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.
Collapse
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
| | | |
Collapse
|
4
|
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; 6:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [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) 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). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications. 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 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 sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 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 withdrawn or discontinued DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (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.Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on 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, then the meta-analysis result showed no evidence of a difference.DAAs on the market or under development seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I² = 77%, 6886 participants, 32 trials, very low-quality evidence) and 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).Withdrawn or discontinued DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I² = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I² = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.Most of all outcome results were short-term results; therefore, we could neither confirm nor reject any long-term effects of DAAs. 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 Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. 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 seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.
Collapse
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
| |
Collapse
|
5
|
Vidal LL, Soares MA, Santos AF. NS3 protease polymorphisms and genetic barrier to drug resistance of distinct hepatitis C virus genotypes from worldwide treatment-naïve subjects. J Viral Hepat 2016; 23:840-849. [PMID: 26775769 DOI: 10.1111/jvh.12503] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 12/02/2015] [Indexed: 12/26/2022]
Abstract
Hepatitis C virus (HCV) NS3 protease inhibitors have been primarily designed against genotype 1, the one with the lowest response to dual therapy. However, less evidence of their efficacy on non-1 genotypes is available, and any such information is mostly concentrated on genotypes 2-4. This study evaluated HCV protease resistance profiles in the major six HCV genotypes and identified genetic barrier (GB) profiles to each available protease inhibitor across HCV strains from different locations worldwide. We obtained 15 099 HCV sequences from treatment-naïve subjects retrieved at the Los Alamos HCV Sequence Database. The wild-type codons of different HCV genotypes were used to analyse the smallest number of nucleotide substitution steps required for changing that codon to the closest one associated with drug resistance. The 36L and 175L RAVs were found as genetic signatures of genotypes 2-5, while the 80K RAV was found in all genotype 5 sequences. Genotypes 4 and 6 showed a higher GB to RAV mutations conferring resistance to telaprevir, while genotypes 2-5 presented baseline resistance to that drug, carrying the 36L mutation. Genotype 4 had a higher GB to simeprevir resistance, requiring three substitutions to acquire the 155K mutation. Subtype 1b showed a higher GB than subtype 1a to resistance for most PIs, with RAVs at codons 36 and 155. Geographic disparities were also found in frequencies of certain RAVs in genotypes 2 and 3. Under a scenario of unprecedented evolution of anti-HCV direct-acting agents, the genetic composition of the circulating HCV sequences should be evaluated worldwide to choose the most appropriate/feasible therapeutic schemes with the highest genetic barriers to resistance.
Collapse
Affiliation(s)
- L L Vidal
- Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - M A Soares
- Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Programa de Genética, Instituto Nacional do Câncer, Rio de Janeiro, Brazil
| | - A F Santos
- Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| |
Collapse
|
6
|
Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 2016; 64:486-504. [PMID: 26409317 DOI: 10.1016/j.jhep.2015.09.011] [Citation(s) in RCA: 348] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 09/15/2015] [Accepted: 09/15/2015] [Indexed: 02/08/2023]
Abstract
Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents (DAA) is associated with high rates of sustained virologic response. Remaining factors associated with treatment failure include advanced stages of liver fibrosis, response to previous antiviral therapy and viral factors such as baseline viral load and suboptimal interaction of the DAA with the target based on viral variants. Heterogeneity within NS3, NS5A, and NS5B areas interacting with DAAs exist between HCV geno- and subtypes as well as HCV isolates of the same geno- and subtype and amino acid polymorphisms associated with suboptimal efficacy of DAAs are termed resistance-associated variants (RAVs). RAVs may be associated with virologic treatment failure. However, virologic treatment failure typically occurs only if other negative predictive host or viral factors are present at the same time, susceptibility to additional antiviral agents is reduced or duration of treatment is suboptimal. In this review geno- and phenotypic resistance testing as well as clinical data on the importance of RAVs for conventional triple therapies with sofosbuvir, simeprevir, and daclatasvir and available interferon-free DAA combinations are discussed.
Collapse
Affiliation(s)
- Christoph Sarrazin
- J. W. Goethe-University Hospital, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| |
Collapse
|
7
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| |
Collapse
|
8
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016; 22:1411-1420. [PMID: 26819510 PMCID: PMC4721976 DOI: 10.3748/wjg.v22.i4.1411] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/01/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
|
9
|
Abdel-Ghaffar TY, Sira MM, El Naghi S. Hepatitis C genotype 4: The past, present, and future. World J Hepatol 2015; 7:2792-2810. [PMID: 26668691 PMCID: PMC4670951 DOI: 10.4254/wjh.v7.i28.2792] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/02/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) genotype (GT) 4 represents 12%-15% (15-18 million) of total global HCV infection. It is prevalent in Northern and Equatorial Africa and the Middle East, and is also present in some countries in Europe. GT-4 (and subtype 4a in particular) dominates the HCV epidemic in Egypt. In underdeveloped countries, risk factors associated with HCV infection may be due to unsafe medical practices or other factors such as familial transmission, mother’s HCV status, or illiteracy. HCV prevention and control programs should include health education, increased community awareness towards the disease, controlling infection distribution in health-care centers, proper sterilization of medical and dental instruments, and ensuring safe supply of blood and blood-products. Response rates to a 48-wk combined pegylated-interferon (PEG-IFN) and ribavirin (RBV) treatment range from 40%-69%, and HCV-GT-4 has been considered better than GT-1 but worse than GT-2 and GT-3 in treatment with PEG-IFN/RBV. However, with the introduction of the HCV-GT-1 effective protease inhibitors boceprevir and telaprevir in 2011, HCV-GT-4 became the “most difficult (GT) to treat”. Recently, the direct-acting antivirals (DAAs) with pan- genotypic activities simeprevir, sofosbuvir, and daclatasvir have been recommended in triple regimens with PEG-IFN/RBV for the treatment of HCV-GT-4. An IFN-free regimen will be available for treatment of all genotypes of HCV in the near future. To date, several DAAs have been developed and are currently being evaluated in various combinations in clinical trials. As new regimens and new agents are being approved by the Food and Drug Administration, we can expect the guidelines for HCV treatment to be changed. The availability of shorter, simpler, and more tolerable treatment regimens can reduce the morbidity and mortality associated with HCV infection. With such a large number of therapeutic agents available, we can end up with a range of choices that we can select from to treat patients.
Collapse
|
10
|
Abstract
PURPOSE OF REVIEW The hepatitis C virus remains a global health issue, and the established standard of care has consisted of pegylated interferon alpha in conjunction with ribavirin. However, this regimen is associated with significant side-effects and poor sustained virological responses. The aim of this review is to assess the effects of the direct-acting antivirals upon hepatitis C genotypes 2-6 from publications from the past 18 months. RECENT FINDINGS The impact of direct-acting antivirals has already substantially improved treatments for genotypes 2-6, with the size of improvement much less marked for genotype 3. Although still responsive to these agents, genotype 3 has inherent resistance to treatments possibly owing to its effects on host metabolic pathways. These treatments have moved sustained virological responses to the threshold of 90%, with reduced side-effects and shortened courses of treatment and some options for interferon-free therapy. These newer medications are transforming clinical guidelines at a rapid rate, but this will have to be balanced with the impact it places on global health budgets. SUMMARY Although direct-acting antivirals are transforming the treatment of all hepatitis C genotypes, ongoing studies will optimize treatment duration and provide interferon-free alternatives.
Collapse
|
11
|
Aygen B, Yıldız O, Akhan S, Çelen MK, Ural O, Koruk ST, Köse Ş, Korkmaz F, Kuruüzüm Z, Tuna N, Taheri S, Sayan M, Demir NA, Sümer Ş, Altınok ES. Retreatment of Chronic Hepatitis C Infection with Telaprevir: Preliminary Results in Turkey. Balkan Med J 2015; 32:266-72. [PMID: 26185714 DOI: 10.5152/balkanmedj.2015.15366] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 01/11/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The use of pegylated interferon alpha and ribavirin (PegIFN/RBV) for the retreatment of chronic hepatitis C virus (HCV) infection without a sustained virological response (SVR) prior to PegIFN/RBV treatment has resulted in low success rates. AIMS To investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN/RBV in patients infected with HCV genotypes 1 and 4 who were previously treated with PegIFN/RBV and failed to achieve SVR. STUDY DESIGN Multi-center, retrospective, cross-sectional study. METHODS The study included 111 patients: 80 prior relapsers, 25 prior null responders, and six prior partial responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-week PegIFN/RBV treatment; virological response results were assessed at weeks 4, 12, and 24. Treatment was discontinued in patients with HCV RNA >1000 IU/mL at week 4 or with negative RNA results at week 4 but >1000 IU/mL at week 12. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), and virological response at 24th week of treatment were evaluated. The side effects of combination therapy and the rates of treatment discontinuation were investigated. RESULTS The mean age of the patients was 56.02±9.96 years and 45.9% were male. Ninety-one percent of the patients were infected with viral genotype 1, 69.6% with the interleukin (IL) 28B genotype CT and 20.2% were cirrhotic. The RVR rate was 86.3% in prior relapsers, 56% in prior null responders, and 50% in prior partial responders (p=0.002). EVR rates in those groups were 91.3%, 56%, and 83.3%, respectively (p<0.001). eRVR rates were 83.8% in prior relapsers, 48% in prior null responders, and 50% in prior partial responders (<0.001). The virological response at the 24th week of treatment was found to be the highest in prior relapsers (88.8%); it was 56% in prior null responders and 66.7% in prior partial responders (p<0.001). Common side effects were fatigue, headache, anorexia, malaise, anemia, pruritus, dry skin, rash, dyspepsia, nausea, pyrexia, stomachache, and anorectal discomfort. All treatments were discontinued due to side effects in 9.9% of patients. CONCLUSION High virological response rates were obtained with TVR/PegIFN/RBV treatment. Although side effects were frequently observed, the discontinuation rate of combination therapy was low.
Collapse
Affiliation(s)
- Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Orhan Yıldız
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Sıla Akhan
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Mustafa Kemal Çelen
- Department of Infectious Diseases and Clinical Microbiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey
| | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Süda Tekin Koruk
- Department of Infectious Diseases and Clinical Microbiology, Harran University Faculty of Medicine, Şanlıurfa, Turkey
| | - Şükran Köse
- Department of Infectious Diseases and Clinical Microbiology, Tepecik Training and Research Hospital, İzmir, Turkey
| | - Fatime Korkmaz
- Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey
| | - Ziya Kuruüzüm
- Department of Infectious Diseases and Clinical Microbiology, Dokuz Eylül University Faculty of Medicine, İzmir Turkey
| | - Nazan Tuna
- Department of Infectious Diseases and Clinical Microbiology, Sakarya University Faculty of Medicine, Sakarya, Turkey
| | - Serpil Taheri
- Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Murat Sayan
- Clinical Laboratory, PCR Unit, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Nazlım Aktuğ Demir
- Department of Infectious Diseases and Clinical Microbiology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Şua Sümer
- Department of Infectious Diseases and Clinical Microbiology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Elif Sargın Altınok
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| |
Collapse
|
12
|
Hézode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, Marcellin P, Hall C, Schnell G, Pilot-Matias T, Mobashery N, Redman R, Vilchez RA, Pol S. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; 385:2502-9. [PMID: 25837829 DOI: 10.1016/s0140-6736(15)60159-3] [Citation(s) in RCA: 206] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. METHODS In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. FINDINGS Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. INTERPRETATION An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. FUNDING AbbVie.
Collapse
Affiliation(s)
- Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm, Créteil, France.
| | - Tarik Asselah
- Centre de Recherche sur l'Inflammation (CRI), Inserm UMR, Université Paris Diderot, Service d'Hépatologie, AP-HP Hôpital Beaujon, Clichy, France
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Tarek Hassanein
- Southern California Liver Centers and Southern California Research Center, Coronado, CA, USA
| | - Marina Berenguer
- Hepatology Unit, Hospital Universitario La Fe, Universidad de Valencia and Ciberehd, Valencia, Spain
| | - Katarzyna Fleischer-Stepniewska
- Department of Infectious Disease, Liver Diseases and Acquired Immune Deficiencies, Wroclaw Medical University, Wroclaw, Poland
| | | | | | | | | | | | | | | | - Stanislas Pol
- Groupe Hospitalier Cochin-Saint Vincent De Paul, Université Paris Descartes, Inserm, Institut Pasteur, Paris, France
| |
Collapse
|
13
|
Rivero-Juarez A, Camacho A, Rivero A. Pharmacokinetic and pharmacodynamic evaluation of telaprevir for the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2015; 11:1157-65. [PMID: 26004270 DOI: 10.1517/17425255.2015.1049532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Telaprevir is one of the first direct-acting antiviral drugs approved for the treatment of the hepatitis C virus (HCV) genotype 1. Following its approval in 2011, new data regarding the pharmacokinetics and pharmacodynamics were reported, leading to important clinical applications. AREAS COVERED This article reviews the pharmacokinetic and pharmacodynamic properties of telaprevir for the treatment of the HCV. The areas covered include data regarding the drug's absorption, distribution, metabolism and excretion, in addition to the antiviral activity strategy such as the clinical dose selection and treatment duration. EXPERT OPINION Telaprevir presents several pharmacological properties that could limit its administration such a high-fat, high-calorie meal; the need to be administrated with pegylated IFN plus ribavirin; and the drug-drug interaction profile. As a consequence and considering the new therapeutic arsenal against the HCV, the use of telaprevir as part of HCV therapy will be limited.
Collapse
Affiliation(s)
- Antonio Rivero-Juarez
- Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Avda, Menendez Pidal s/n. 14004, Córdoba , Spain +34 9 5701 2421 ; +34 9 5701 1885 ;
| | | | | |
Collapse
|
14
|
Cunningham ME, Javaid A, Waters J, Davidson-Wright J, Wong JLC, Jones M, Foster GR. Development and validation of a "capture-fusion" model to study drug sensitivity of patient-derived hepatitis C. Hepatology 2015; 61:1192-204. [PMID: 25330450 DOI: 10.1002/hep.27570] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023]
Abstract
UNLABELLED Emerging therapies for chronic hepatitis C viral (HCV) infection involve inhibition of viral enzymes with drug combinations. Natural, or treatment-induced, enzyme polymorphisms reduce efficacy. We developed a phenotyping assay to aid drug selection based on viral transfer from monocytes to hepatocytes. We studied HCV in monocytes from infected patients and developed a model in which patient-derived HCV is "captured" by the cell line THP-1 and replication assessed after fusion to hepatoma cells. We found that monocytes from HCV-infected patients harbor virus that replicates when cells are fused to hepatocytes. THP-1 cells incubated with infected sera capture HCV, which replicates when fused to hepatocytes. Inhibitable replication of all HCV genotypes was achieved (42 of 52 isolates). We measured sensitivity of telaprevir (TVR) and alisporivir (AVR) in different genotypes, and showed differences in 50% inhibitory concentration (IC50 ) correlating with clinical response (TVR IC50 for genotype (G)1 was 0.042 ± 0.003 vs. 0.117 ± 0.015 μM for G3, whereas AVR IC50 for G1 was 0.139 ± 0.013 vs. 0.044 ± 0.007 μM for G3). We tested TVR-resistant viral isolates and identified changes in IC50 . One patient with a poor clinical response to TVR and wild-type viral sequence showed reduced TVR sensitivity in our assay. We studied samples from a 2-week TVR monotherapy study in which 5 of 8 patients with G3 HCV did not respond whereas 3 of 8 patients did. The "capture-fusion" assay correctly identified responders. CONCLUSION The capture-fusion model represents a promising new technique that may help identify appropriate treatment strategies for patients with chronic HCV infection.
Collapse
Affiliation(s)
- Morven E Cunningham
- The Liver Unit, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | | | | | | | | | | | | |
Collapse
|
15
|
Dynamics of HCV genotype 4 resistance-associated variants during virologic escape with pIFN/RBV+daclatasvir: a case study using ultra deep pyrosequencing. J Clin Virol 2015; 66:38-43. [PMID: 25866334 DOI: 10.1016/j.jcv.2015.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 01/23/2015] [Accepted: 02/03/2015] [Indexed: 01/12/2023]
Abstract
BACKGROUND Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. OBJECTIVES Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV+DCV, as assessed by ultra-deep sequencing. STUDY DESIGN Five treatment-naïve GT4 patients (GT4a [n = 1], GT4d [n = 3], GT4o [n = 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV±DCV. RESULTS Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and <0.6% at Wk4, 8 and 9). CONCLUSIONS This is the first report to describe DCV-resistance in patients infected with GT4d, supporting a possible role for a recently described RAV (L28S), and presenting the dynamics of HCV quasispecies during therapy failure, with indications of changes of diversity and association of mutations.
Collapse
|
16
|
Sefcik RK, Bichoupan K, Martel-Laferrière V, Odin JA, Liu LU, Perumalswami P, Bansal M, Dieterich DT, Ahmad J, Schiano TD, Branch AD. Telaprevir activity in treatment-naive patients infected with hepatitis C virus genotype 4. J Infect Dis 2014; 210:1855-6. [PMID: 24970848 DOI: 10.1093/infdis/jiu360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Roberta K Sefcik
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Kian Bichoupan
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | | | - Joseph A Odin
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Lawrence U Liu
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Ponni Perumalswami
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Meena Bansal
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Douglas T Dieterich
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Jawad Ahmad
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Thomas D Schiano
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| | - Andrea D Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York
| |
Collapse
|
17
|
Abdel-Razek W, Waked I. Optimal Management of HCV Genotype 4. CURRENT HEPATOLOGY REPORTS 2014; 13:286-294. [DOI: 10.1007/s11901-014-0243-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
18
|
Waked I, Doss W, El-Sayed MH, Estes C, Razavi H, Shiha G, Yosry A, Esmat G. The current and future disease burden of chronic hepatitis C virus infection in Egypt. Arab J Gastroenterol 2014; 15:45-52. [PMID: 25097045 DOI: 10.1016/j.ajg.2014.04.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 04/20/2014] [Indexed: 02/08/2023]
|
19
|
De Meyer S, Ghys A, Dierynck I, Beumont M, Luo D, Picchio G. Virologic characterization of genotype 4 hepatitis C virus variants in patients treated with telaprevir. Virol J 2014; 11:93. [PMID: 24886541 PMCID: PMC4030523 DOI: 10.1186/1743-422x-11-93] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 05/02/2014] [Indexed: 02/08/2023] Open
Abstract
Background Study C210 was a Phase IIa, exploratory trial to assess the activity of telaprevir on hepatitis C virus (HCV) early viral kinetics in treatment-naïve patients infected with genotype 4 (G4) HCV. Methods Patients were randomized to receive peginterferon and ribavirin alone, telaprevir monotherapy (T arm), or telaprevir in combination with peginterferon/ribavirin (TPR arm) for 15 days, followed by a 46- or 48-week standard treatment phase. The current analysis aimed to characterize the genotype and phenotype of HCV G4 variants emerging during telaprevir treatment. Results Five of the 8 (62.5%) patients in the telaprevir (T) arm had viral breakthrough (vBT) during the investigational treatment phase (between baseline and Day 15), compared to no patients in the TPR arm. HCV G4 viral variants with a T54A/T mutation were detected in two of these patients, as well as two other patients with detectable HCV RNA at the end of telaprevir treatment. Emergence of the T54A/T mutation was associated with a 2- to 4-fold decreased susceptibility to telaprevir. All patients with vBT during the investigational treatment phase or with a T54A/T mutation achieved undetectable HCV RNA 12 or 24 weeks after end of treatment with subsequent peginterferon/ribavirin treatment. Conclusions In this analysis in G4 HCV-infected patients, more patients in the telaprevir monotherapy arm experienced vBT with resistant variants compared to none with telaprevir combination therapy. The most commonly selected mutation T54A in telaprevir-treated G4 HCV patients was previously described in the context of G1 infection. Trial registration The trial was registered with ClinicalTrials.gov (NCT00580801).
Collapse
Affiliation(s)
- Sandra De Meyer
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, B2340 Antwerpen, Beerse, Belgium.
| | | | | | | | | | | |
Collapse
|
20
|
Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
21
|
Deneke M, Dranoff J, Duarte-Rojo A. Successful eradication of genotype 4 HCV with telaprevir-based triple antiviral therapy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2014. [DOI: 10.1016/j.rgmxen.2014.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
|
22
|
Deneke MG, Dranoff JA, Duarte-Rojo A. [Successful eradication of genotype 4 HCV with telaprevir-based triple antiviral therapy]. REVISTA DE GASTROENTEROLOGIA DE MEXICO 2014; 79:64-66. [PMID: 24679642 DOI: 10.1016/j.rgmx.2013.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Revised: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 06/03/2023]
Affiliation(s)
- M G Deneke
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU
| | - J A Dranoff
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU.; Servicio de Investigación, Servicio de Salud Veterans Affairs de Arkansas Central, Little Rock, AR, EE. UU
| | - A Duarte-Rojo
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU..
| |
Collapse
|