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Shahin Merat - One of the best experts on this subject based on the ideXlab platform.
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sofosbuvir and Daclatasvir for the treatment of covid 19 outpatients a double blind randomized controlled trial
Journal of Antimicrobial Chemotherapy, 2021Co-Authors: Fatemeh Roozbeh, Andrew Hill, Hannah Wentzel, Shahin Merat, Majid Saeedi, Reza Alizadehnavaei, Akbar Hedayatizadehomran, Jacob Levi, Amir ShamshirianAbstract:Introduction: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and Daclatasvir versus standard care for outpatients with mild COVID-19 infection. Methods: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/Daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. Results: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/Daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/Daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/Daclatasvir arm and 16 in the control arm; P < 0.001. Conclusions: In this study, sofosbuvir/Daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/Daclatasvir arm, this was not statistically significant. Sofosbuvir/Daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.
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sofosbuvir Daclatasvir regimens for the treatment of covid 19 an individual patient data meta analysis
Journal of Antimicrobial Chemotherapy, 2021Co-Authors: Bryony Simmons, Hannah Wentzel, Gholamali Eslami, Anahita Sadeghi, Hamideh Abbaspour Kasgari, Shahin Merat, Sara Mobarak, Ali Ali Asgari, Hafez Fakheri, Andrew HillAbstract:Background The combination of sofosbuvir and Daclatasvir has a well-established safety profile and improves clinical outcomes in HCV patients. In silico and in vitro studies suggest that sofosbuvir/Daclatasvir may show antiviral activity against SARS-CoV-2. Methods Three clinical trials comparing sofosbuvir/Daclatasvir-based regimens with a comparator in hospitalized COVID-19 patients were combined in a meta-analysis. The primary outcomes measured were clinical recovery within 14 days of randomization, time to clinical recovery and all-cause mortality. A two-step approach was used to analyse individual-level patient data. The individual trial statistics were pooled using the random-effects inverse-variance model. Results Our search identified eight studies of which three met the inclusion criteria (n = 176 patients); two studies were randomized and one was non-randomized. Baseline characteristics were similar across treatment arms. Clinical recovery within 14 days of randomization was higher in the sofosbuvir/Daclatasvir arms compared with control arms [risk ratio = 1.34 (95% CI = 1.05-1.71), P = 0.020]. Sofosbuvir/Daclatasvir improves time to clinical recovery [HR = 2.04 (95% CI = 1.25-3.32), P = 0.004]. The pooled risk of all-cause mortality was significantly lower in the sofosbuvir/Daclatasvir arms compared with control arms [risk ratio = 0.31 (95% CI = 0.12-0.78), P = 0.013]. Conclusions Available evidence suggests that sofosbuvir/Daclatasvir improves survival and clinical recovery in patients with moderate to severe COVID-19. However, the sample size for analysis was relatively small, one of the trials was not randomized and the designs were not standardized. These results need to be confirmed in larger randomized controlled trials.
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Evaluation of the efficacy of sofosbuvir plus Daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial.
Journal of Antimicrobial Chemotherapy, 2020Co-Authors: Hamideh Abbaspour Kasgari, Siavash Moradi, Amir Mohammad Shabani, Farhang Babamahmoodi, Ali Reza Davoudi Badabi, Lotfollah Davoudi, Ahmad Alikhani, Akbar Hedayatizadeh‑omran, Majid Saeedi, Shahin MeratAbstract:Background New therapeutic options are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). Repurposing existing pharmaceuticals provides an immediate treatment opportunity. We assessed the efficacy of sofosbuvir and Daclatasvir with ribavirin for treating patients with COVID-19. Methods This was a single-centre, randomized controlled trial in adults with moderate COVID-19 admitted to the Ghaem Shahr Razi Hospital in Mazandaran Province, Iran. Patients were randomly assigned to 400 mg sofosbuvir, 60 mg Daclatasvir and 1200 mg ribavirin (intervention group) or to standard care (control group). The primary endpoint of this study was length of hospital stay. This study is registered by IRCT.ir under the ID: IRCT20200328046886N1. Results Between 20 March 2020 and 8 April 2020, 48 patients were recruited; 24 patients were randomly assigned to the intervention group and 24 to the control group. The median duration of hospital stay was 6 days in both groups (P = 0.398). The number of ICU admissions in the sofosbuvir/Daclatasvir/ribavirin group was not significantly lower than the control group (0 versus 4, P = 0.109). There was no difference in the number of deaths between the groups (0 versus 3, P = 0.234). The cumulative incidence of recovery was higher in the sofosbuvir/Daclatasvir/ribavirin arm (Gray's P = 0.033). Conclusions This randomized trial was too small to make definitive conclusions. There were trends in favour of the sofosbuvir/Daclatasvir/ribavirin arm for recovery and lower death rates. However, there was an imbalance in the baseline characteristics between the arms. Larger randomized trials should be conducted to investigate this treatment further.
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sd1000 high sustained viral response rate in 1361 patients with hepatitis c genotypes 1 2 3 and 4 using a low cost fixed dose combination tablet of generic sofosbuvir and Daclatasvir a multicenter phase iii clinical trial
Clinical Infectious Diseases, 2020Co-Authors: Shahin MeratAbstract:BACKGROUND The combination of sofosbuvir and Daclatasvir is a potent, pangenotypic regimen suitable for mass-scale hepatitis C treatment, especially in resource-limited countries where newer, expensive combinations are not available. This combination has been widely tested on genotype 4. However, Phase III trials of this combination in other genotypes have been cost prohibitive. With the introduction of generic, low-cost sofosbuvir and Daclatasvir, large-scale studies in resource-limited countries are now possible. METHODS Sofosbuvir at 400 mg and Daclatasvir at 60 mg were coformulated into a fixed-dose combination (FDC) tablet (Sovodak, Rojan Pharma, Tehran, Iran). Patients from 46 centers were dosed for 12 or 24 weeks with or without ribavirin, in line with existing guidelines. Responses to treatment were evaluated 12 weeks after the end of treatment (for a sustained virological response at Week 12; SVR12). RESULTS There were 1361 patients recruited. Overall, the patients were 21% female, with a mean age of 50 years; 39% were cirrhotic; 22% were treatment-experienced; 47% were genotype 1, 41% were genotype 3, and 2% were other genotypes. The genotype was not known in 10% of the patients. The intention-to-treat and per-protocol SVR12 rates were 94.7% and 98.8%, respectively. The safety profile was unremarkable, treatment was well tolerated, and compliance with the single-tablet regimen was excellent. CONCLUSIONS The treatment with FDC of sofosbuvir and Daclatasvir achieved high SVR12 rates, equivalent to those seen in Phase III trials of other pangenotypic options, and has been conducted at a similar scale in a representative, real-world population at a cost of under $100 per patient, which makes this combination suitable for elimination protocols in resource-limited countries. CLINICAL TRIALS REGISTRATION NCT03200184.
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erratum to sd1000 high sustained viral response rate in 1361 patients with hepatitis c genotypes 1 2 3 and 4 using a low cost fixed dose combination tablet of generic sofosbuvir and Daclatasvir a multicenter phase iii clinical trial
Clinical Infectious Diseases, 2020Co-Authors: Shahin Merat, Amir Houshang Sharifi, Hossein Poustchi, Eskandar Hajiani, Abdolsamad Gharavi, Jalal Karimi, Fariborz Mansourghanaei, Mohammad Reza Fattahi, Lida Ahmadi, Mohammadhossein SomiAbstract:BACKGROUND The combination of sofosbuvir and Daclatasvir is a potent, pangenotypic regimen suitable for mass-scale hepatitis C treatment, especially in resource-limited countries where newer, expensive combinations are not available. This combination has been widely tested on genotype 4. However, Phase III trials of this combination in other genotypes have been cost prohibitive. With the introduction of generic, low-cost sofosbuvir and Daclatasvir, large-scale studies in resource-limited countries are now possible. METHODS Sofosbuvir at 400 mg and Daclatasvir at 60 mg were coformulated into a fixed-dose combination (FDC) tablet (Sovodak, Rojan Pharma, Tehran, Iran). Patients from 46 centers were dosed for 12 or 24 weeks with or without ribavirin, in line with existing guidelines. Responses to treatment were evaluated 12 weeks after the end of treatment (for a sustained virological response at Week 12; SVR12). RESULTS There were 1361 patients recruited. Overall, the patients were 21% female, with a mean age of 50 years; 39% were cirrhotic; 22% were treatment-experienced; 47% were genotype 1, 41% were genotype 3, and 2% were other genotypes. The genotype was not known in 10% of the patients. The intention-to-treat and per-protocol SVR12 rates were 94.7% and 98.8%, respectively. The safety profile was unremarkable, treatment was well tolerated, and compliance with the single-tablet regimen was excellent. CONCLUSIONS The treatment with FDC of sofosbuvir and Daclatasvir achieved high SVR12 rates, equivalent to those seen in Phase III trials of other pangenotypic options, and has been conducted at a similar scale in a representative, real-world population at a cost of under $100 per patient, which makes this combination suitable for elimination protocols in resource-limited countries. CLINICAL TRIALS REGISTRATION NCT03200184.
Michio Imamura - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Daclatasvir plus asunaprevir therapy for chronic hepatitis c patients with renal dysfunction
Journal of Medical Virology, 2017Co-Authors: Yuki Nakamura, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Kana Daijo, Yuji Teraoka, Fumi Honda, Takashi Nakahara, Yuko NagaokiAbstract:Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of Daclatasvir plus asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m2) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m2). Plasma concentrations of Daclatasvir and asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of Daclatasvir and asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665–671, 2017. © 2016 Wiley Periodicals, Inc.
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safety and efficacy of dual therapy with Daclatasvir and asunaprevir for older patients with chronic hepatitis c
Journal of Gastroenterology, 2017Co-Authors: Reona Morio, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Yuki Kimura, Masataka TsugeAbstract:Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with Daclatasvir plus asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR. Older patients have a virological response and tolerance of Daclatasvir plus asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.
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Real-world efficacy and safety of Daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients.
Journal of Gastroenterology and Hepatology, 2017Co-Authors: Kei Morio, Yoshiiku Kawakami, Michio Imamura, Masataka Tsuge, Reona Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Akira HiramatsuAbstract:Background and Aims Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. Methods A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of Daclatasvir and asunaprevir combination therapy. Plasma concentrations of Daclatasvir and asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. Result Plasma asunaprevir concentration was significantly higher, and Daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. Conclusion Patients with compensated liver cirrhosis have similar virological response and tolerance for Daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis.
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the practical management of chronic hepatitis c infection in japan dual therapy of Daclatasvir asunaprevir
Expert Review of Gastroenterology & Hepatology, 2017Co-Authors: Nelson C Hayes, Michio Imamura, Kazuaki ChayamaAbstract:ABSTRACTIntroduction: Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus Daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein.Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and Daclatasvir therapy focused primarily on Japan. A literature search using the keywords ‘asunaprevir,’ ‘Daclatasvir,’ ‘interferon-free therapy,’ and ‘direct-acting antiviral drugs’ was initially used to select relevant literature for inclusion in the review.Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus Daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patie...
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Characteristics of propensity score-matched patient treated with PEG-IFN plus RBV or Daclatasvir plus asunaprevir.
2017Co-Authors: Yuko Nagaoki, Michio Imamura, Hiroshi Aikata, Reona Morio, Yuki Nakamura, Kana Daijo, Yuji Teraoka, Fumi Honda, Masahiro Hatooka, Kei MorioAbstract:Characteristics of propensity score-matched patient treated with PEG-IFN plus RBV or Daclatasvir plus asunaprevir.
Kei Morio - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of dual therapy with Daclatasvir and asunaprevir for older patients with chronic hepatitis c
Journal of Gastroenterology, 2017Co-Authors: Reona Morio, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Yuki Kimura, Masataka TsugeAbstract:Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with Daclatasvir plus asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR. Older patients have a virological response and tolerance of Daclatasvir plus asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.
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efficacy and safety of Daclatasvir plus asunaprevir therapy for chronic hepatitis c patients with renal dysfunction
Journal of Medical Virology, 2017Co-Authors: Yuki Nakamura, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Kana Daijo, Yuji Teraoka, Fumi Honda, Takashi Nakahara, Yuko NagaokiAbstract:Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of Daclatasvir plus asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m2) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m2). Plasma concentrations of Daclatasvir and asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of Daclatasvir and asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665–671, 2017. © 2016 Wiley Periodicals, Inc.
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Real-world efficacy and safety of Daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients.
Journal of Gastroenterology and Hepatology, 2017Co-Authors: Kei Morio, Yoshiiku Kawakami, Michio Imamura, Masataka Tsuge, Reona Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Akira HiramatsuAbstract:Background and Aims Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. Methods A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of Daclatasvir and asunaprevir combination therapy. Plasma concentrations of Daclatasvir and asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. Result Plasma asunaprevir concentration was significantly higher, and Daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. Conclusion Patients with compensated liver cirrhosis have similar virological response and tolerance for Daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis.
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Characteristics of propensity score-matched patient treated with PEG-IFN plus RBV or Daclatasvir plus asunaprevir.
2017Co-Authors: Yuko Nagaoki, Michio Imamura, Hiroshi Aikata, Reona Morio, Yuki Nakamura, Kana Daijo, Yuji Teraoka, Fumi Honda, Masahiro Hatooka, Kei MorioAbstract:Characteristics of propensity score-matched patient treated with PEG-IFN plus RBV or Daclatasvir plus asunaprevir.
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Cumulative hepatocellular carcinoma (HCC) development.
2017Co-Authors: Yuko Nagaoki, Michio Imamura, Hiroshi Aikata, Reona Morio, Yuki Nakamura, Kana Daijo, Yuji Teraoka, Fumi Honda, Masahiro Hatooka, Kei MorioAbstract:Patients who achieved viral eradication by peg-interferon and ribavirin (PEG-IFN/RBV) or Daclatasvir plus asunaprevir (DCV/ASV) therapies were analyzed.
Kazuaki Chayama - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of clinical trial patients treated for chronic hcv infection with Daclatasvir based regimens
Liver International, 2018Co-Authors: Rajender K Reddy, Joji Toyota, Kazuaki Chayama, Hiromitsu Kumada, Paul J. Thuluvath, Stanislas Pol, Eric Lawitz, James M Levin, Adrian Gadano, W GhesquiereAbstract:Background & aims Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of Daclatasvir-based regimens administered during clinical studies. Methods Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analyzing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. Results Between 24-February-2012 and 17-July-2015, this study enrolled and began following 1503 recipients of Daclatasvir-based regimens (follow-up cut-off, 13-October-2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n=9) or after (n=3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions SVR12 was durable in 99% of recipients of Daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders. This article is protected by copyright. All rights reserved.
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Daclatasvir asunaprevir beclabuvir fixed dose combination in japanese patients with hcv genotype 1 infection
Journal of Gastroenterology, 2017Co-Authors: Joji Toyota, Fumitaka Suzuki, Yoshiyasu Karino, Fusao Ikeda, Akio Ido, Katsuaki Tanaka, Koichi Takaguchi, Atsushi Naganuma, Eiichi Tomita, Kazuaki ChayamaAbstract:Background DCV-TRIO, a fixed-dose combination of Daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.
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the practical management of chronic hepatitis c infection in japan dual therapy of Daclatasvir asunaprevir
Expert Review of Gastroenterology & Hepatology, 2017Co-Authors: Nelson C Hayes, Michio Imamura, Kazuaki ChayamaAbstract:ABSTRACTIntroduction: Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus Daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein.Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and Daclatasvir therapy focused primarily on Japan. A literature search using the keywords ‘asunaprevir,’ ‘Daclatasvir,’ ‘interferon-free therapy,’ and ‘direct-acting antiviral drugs’ was initially used to select relevant literature for inclusion in the review.Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus Daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patie...
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randomized comparison of Daclatasvir asunaprevir versus telaprevir peginterferon ribavirin in japanese hepatitis c virus patients
Journal of Gastroenterology and Hepatology, 2016Co-Authors: Hiromitsu Kumada, Fumitaka Suzuki, Joji Toyota, Kazuaki Chayama, Yoshiyuki Suzuki, Yoshiyasu Karino, Yoshiiku Kawakami, Shigetoshi Fujiyama, Takayoshi Ito, Yoshito ItohAbstract:Background and Aim Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of Daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. Methods Treatment-naive patients (20–70 years; baseline viral load, ≥100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either Daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20–75 years; baseline viral load, ≥100,000 IU/mL) received Daclatasvir plus asunaprevir. Results In treatment-naive patients, sustained virologic response at post-treatment week 12 in Daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of Daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving Daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). Conclusion Marked differences were observed in the efficacy and safety profile of Daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.
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a randomized trial of Daclatasvir with peginterferon alfa 2b and ribavirin for hcv genotype 1 infection
Antiviral Therapy, 2014Co-Authors: Fumitaka Suzuki, Fiona Mcphee, Joji Toyota, Kenji Ikeda, Kazuaki Chayama, Satoshi Mochida, Norio Hayashi, Hiroki Ishikawa, Hidetaka Miyagoshi, Eric HughesAbstract:BACKGROUND Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic HCV genotype 1 infection. METHODS In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily Daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same Daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA<15 IU/ml at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48. RESULTS Sustained virological response 24 weeks post-treatment (SVR24) was achieved by 66.7%, 90.0% and 62.5% of treatment-naive patients in the Daclatasvir 10 mg, 60 mg and placebo groups, respectively. Prior non-responders had more frequent virological failure; 22.2% and 33.3% of Daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite and malaise were the most common adverse events; two Daclatasvir recipients discontinued due to adverse events. CONCLUSIONS Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior non-responders.
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Daclatasvir and sofosbuvir with ribavirin for 24 weeks in chronic hepatitis c genotype 3 infected patients with cirrhosis a phase iii study ally 3c
Antiviral Therapy, 2018Co-Authors: Fred Poordad, Fiona Mcphee, Wayne Ghesquiere, Stephen D. Shafran, Alnoor Ramji, Mitchell L Shiffman, Alexander Wong, Gregory D Huhn, Florence Wong, Rong YangAbstract:BACKGROUND Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks. METHODS This was a single-arm, Phase III study of Daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection. The primary end point was sustained virological response at post-treatment week 12 (SVR12); the primary objective was to demonstrate statistical superiority to historical SVR12 data for 12 weeks' Daclatasvir+sofosbuvir without ribavirin in genotype-3-infected patients with cirrhosis (95% CI lower bound >79.0%). RESULTS A total of 78 patients were treated (54 treatment-naive, 24 treatment-experienced including 8 with prior sofosbuvir exposure). SVR12 was achieved by 87% (68/78; 95% CI 77.7, 93.7%) of patients in the primary analysis of central laboratory data. One additional patient achieved SVR12 by local testing resulting in an overall SVR12 rate of 88% (95% CI 79.2, 94.6%) and the lower bound of the 95% CI above the historical threshold. SVR12 rates were 93% (50/54) for treatment-naive and 79% (19/24) for treatment-experienced patients. Of the nine non-SVR12 patients, four were lost to follow-up, two relapsed (both sofosbuvir-experienced), two had end-of-treatment virological failure and one discontinued early. There were no unexpected safety signals; only one patient discontinued for an adverse event. CONCLUSIONS Daclatasvir+sofosbuvir+ribavirin for 24 weeks was well tolerated and efficacious in HCV genotype-3-infected patients with compensated cirrhosis, with SVR12 outcomes comparable to previously reported outcomes in patients treated with this regimen for 12-16 weeks. ClinicalTrials.gov ID NCT02673489.
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Daclatasvir and sofosbuvir with ribavirin for 24 weeks in chronic hepatitis c genotype 3 infected patients with cirrhosis a phase iii study ally 3c
Antiviral Therapy, 2018Co-Authors: Fred Poordad, Fiona Mcphee, Wayne Ghesquiere, Stephen D. Shafran, Alnoor Ramji, Mitchell L Shiffman, Alexander Wong, Gregory D Huhn, Florence Wong, Rong YangAbstract:BackgroundOptimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients...
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ns5a sequence heterogeneity and mechanisms of Daclatasvir resistance in hepatitis c virus genotype 4 infection
The Journal of Infectious Diseases, 2016Co-Authors: Nannan Zhou, Joseph Ueland, Dennis Hernandez, Xiaoyan Yang, K Sims, Philip D Yin, Fiona McpheeAbstract:Background. Daclatasvir is an NS5A inhibitor approved for treatment of infection due to hepatitis C virus (HCV) genotypes (GTs) 1–4. To support Daclatasvir use in HCV genotype 4 infection, we examined a diverse genotype 4–infected population for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with Daclatasvir resistance (positions 28, 30, 31, or 93), and their effects on Daclatasvir activity in vitro and clinically. Methods. We performed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 sequences from the European HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons. Results. The clinical trial patients represented 14 genotype 4 subtypes; most prevalent were genotype 4a (55%) and genotype 4d (27%). Daclatasvir 50% effective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic clusters were ≤0.080 nM. Most baseline sequences had ≥1 NS5A polymorphism at residues associated with Daclatasvir resistance; however, only 3 patients (1.6%) had polymorphisms conferring ≥1000-fold Daclatasvir resistance in vitro. Among 46 patients enrolled in Daclatasvir trials, all 20 with baseline resistance polymorphisms achieved a sustained virologic response. Conclusions. Circulating genotype 4 subtypes are genetically diverse. Polymorphisms conferring high-level Daclatasvir resistance in vitro are uncommon before therapy, and clinical data suggest that genotype 4 subtype and baseline polymorphisms have minimal impact on responses to Daclatasvir-containing regimens.
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In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir
Infectious Diseases and Therapy, 2014Co-Authors: Jacques Friborg, Nannan Zhou, Zhou Han, Xiaoyan Yang, Paul Falk, Patricia Mendez, Fiona McpheeAbstract:Introduction Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1–6 in vitro, and asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6. This study evaluates potential options for the re-treatment of HCV genotype 1b-infected patients who have failed combination therapy with Daclatasvir plus asunaprevir.
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a randomized trial of Daclatasvir with peginterferon alfa 2b and ribavirin for hcv genotype 1 infection
Antiviral Therapy, 2014Co-Authors: Fumitaka Suzuki, Fiona Mcphee, Joji Toyota, Kenji Ikeda, Kazuaki Chayama, Satoshi Mochida, Norio Hayashi, Hiroki Ishikawa, Hidetaka Miyagoshi, Eric HughesAbstract:BACKGROUND Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic HCV genotype 1 infection. METHODS In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily Daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same Daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA<15 IU/ml at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48. RESULTS Sustained virological response 24 weeks post-treatment (SVR24) was achieved by 66.7%, 90.0% and 62.5% of treatment-naive patients in the Daclatasvir 10 mg, 60 mg and placebo groups, respectively. Prior non-responders had more frequent virological failure; 22.2% and 33.3% of Daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite and malaise were the most common adverse events; two Daclatasvir recipients discontinued due to adverse events. CONCLUSIONS Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior non-responders.
