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World Journal of Transplantation 2018年第5期8卷 156-166页

作者： Petra E de Ruiter Yashna Gadjradj Robert J de Knegt Herold J Metselaar Jan NM Ijzermans Luc JW van der Laan Department of Surgery Erasmus MC-University Medical Center Department of Gastroenterology and Hepatology Erasmus MC-University Medical Center

AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and *** The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) *** Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP *** Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

关键词： Immunosuppressant Hepatitis C daclatasvir Asunaprevir Liver Transplantation

抗丙肝新药daclatasvir dihydrochloride的合成

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中国新药杂志 2013年第22期22卷 2679-2682页

作者：宋宝慧姜迪杜杨南京理工大学化工学院南京210014 江苏省医疗器械检验所南京210012

目的:合成抗丙肝新药daclatasvir dihydrochloride,并对其工艺进行改进。方法:以联苯为原料经傅克酰基化,亲核取代,环合,酸化脱保护和亲核取代反应制得daclatasvir dihydrochloride。结果:目标产物结构经1H-NMR和MS确证,整个工艺总收率... 详细信息

目的:合成抗丙肝新药daclatasvir dihydrochloride,并对其工艺进行改进。方法:以联苯为原料经傅克酰基化,亲核取代,环合,酸化脱保护和亲核取代反应制得daclatasvir dihydrochloride。结果:目标产物结构经1H-NMR和MS确证,整个工艺总收率为23.9%。结论:本路线操作简便、成本较低、条件温和、步骤少,适合工业化生产。

关键词：丙肝病毒 daclatasvir dihydrochloride 合成

Efficacy and safety of generic daclatasvir +sofosbuvir ± ribavirin in treatment of genotype 3infected hepatitis C patients - a real life experience from Pakistan

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Hepatoma Research 2018年第11期4卷 32-38页

作者： Muhammad Umar Tayyab Saeed Akhter Junaid Sadiq Samar Saleem Shoaib Khokhar Centre for Liver and Digestive Diseases Holy Family HospitalRawalpindi Medical College and Allied HospitalsRawalpindi46300Pakistan Tehsil Headquarter Hospital Murree47150Pakistan

Aim: Genotype 3 is the most prevalent genotype in Pakistan. Despite a revolution in the treatment of Hepatitis C, genotype 3 is still thought to be difficult to treat genotype. The price of patent direct acting antivirals was thought to a great limiting factor especially for low income countries. In Pakistan low cost generics of daclatasvir and sofosbuvir are easily available for treatment. The aim of our study is to provide real life local data to determine their efficacy and safety. Methods: This open-label, non-randomized, uncontrolled study was carried out at Center for Liver and Digestive Diseases, Holyfamily Hospital, Rawalpindi. We enrolled patients from March 2016 through March 2018 who were 18 years or older having chronic hepatitis C infection with detectable polymerase chain reaction (PCR), regardless of whether they were treatment na?ve or have experienced Interferon in the past. The patients were offered generic sofosbuvir 400 mg and daclatasvir 60 mg once daily with or without ribavirin for a period of 12 to 24 weeks. Follow-up PCRs were performed at 4th week of treatment, end of treatment and 12 weeks post treatment. All those patients were included in the study that had at least one follow-up PCR during or after the course of treatment. Results: A total of 102 patients were enrolled in the study with a mean age of 48.11 ± 12.70 including 63% males and 37% females. All patients were genotype 3. On 4th week follow up, 31/36 (86.11%) patients had quantitative PCR negative. Out of 102 patients 78 patients had follow up PCR at the completion of therapy with an end of treatment response of about 96.1%. Thirty patients had a follow up at 12 weeks post treatment with a SVR12 of 83.33% (25/30) amongst which treatment Na?ve had a response rate of 84% (21/25), treatment experience 80%(4/5), non-cirrhotics 85.71% (12/14), cirrhotics 81.25% (13/16) and decompensated chronic liver disease patients have a SVR12 of about 83.33% (10/12) respectively. The combina

关键词： daclatasvir sofosbuvir genotype 3 hepatitis C

Hepatitis C virus genotype 3: Meta-analysis on sustained virologic response rates with currently available treatment options

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World Journal of Gastroenterology 2016年第22期22卷 5285-5292页

作者： Javier Ampuero K Rajender Reddy Manuel Romero-Gomez Inter-Centre Unit of Digestive Diseases and CIBERehd Virgen Macarena Virgen del Rocio University Hospitals University of Sevilla 41018 Sevilla Spain Instituto de Biomedicina de Sevilla 41018 Sevilla Spain Division of Gastroenterology and Hepatology Department of Medicine University of Pennsylvania Philadelphia PA 19107 United States

AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort ***:(1) PEG-INF-based therapy including sofosbuvir(SOF) + RBV for 12 wk vs SOF + RBV 24 wk;(2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and(3) the role of RBV in SOF + daclatasvir(DCV) and SOF + ledipasvir(LDV) combinations. This metaanalysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype ***: A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV(24 wk) has achieved higher SVR rates than shorter durations(12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. CONCLUSION: Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.

关键词： Hepatitis C Genotype 3 Sofosbuvir daclatasvir Ledipasvir

Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12

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World Journal of Gastroenterology 2016年第35期22卷 8050-8059页

作者： Christoph R Werner Julia M Schwarz Daniel P Egetemeyr Robert Beck Nisar P Malek Ulrich M Lauer Christoph P Berg Department of Gastroenterology Hepatology and Infectiology University Hospital Tübingen Institute of Medical Virology University Hospital Tübingen

AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral(DAA) treatment with respect to sustained virological response(SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this *** Two hundred and sixty patients treated with SOF combination partners PR(n = 51), R(n = 10), SMV(n = 30), DCV(n = 81), LDV(n = 73), or 3D(n = 15).144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were postliver transplantation patients. 194/260 had HCV GT1, 44/260 HCV *** Two hundred and forty/256(93.7%) patients achieved SVR12(m ITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/n L, 88% post-liver transplantation, 95% for GT1 a, 93% for GT1 b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10(P < 0.0001), liver cirrhosis(P = 0.005) at baseline. In Interferonfree treatment GT3 had significantly lower SVR rates than GT1(P = 0.016). Side effects were mild. CONCLUSION Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into "real-world". Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/n L and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.

关键词： Sofosbuvir Simeprevir Ledipasvir Hepatitis C Liver transplant Sustained virological response Liver cirrhosis Side effects Resistance daclatasvir

New treatments for chronic hepatitis C:an overview for paediatricians

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World Journal of Gastroenterology 2014年第43期20卷 15965-15974页

作者： Daniele Serranti Giuseppe Indolfi Massimo Resti Department of Health Sciences University of Florence Paediatric and Liver Unit Meyer Children’s University Hospital of Florence

Pegylated interferon (IFN) α-2a or 2b in combination with ribavirin for children aged 3 years and older is the standard treatment for paediatric chronic hepatitis C. This treatment regimen was developed firstly in adults. In recent years, a number of direct-acting antiviral agents (DAAs) are under development for treatment of chronic hepatitis C virus (HCV) infection. These agents block viral replication inhibiting directly one of the several steps of HCV lifecycle. DAAs are classified into several categories based on their molecular target: HCV NS3/4A protease inhibitors, HCV NS5B polymerase inhibitors and HCV NS5A inhibitors. Other promising compounds are cyclophilin A inhibitors, mi-RNA122 and IFN-λ. Several new drugs associations will be developed in the near future starting from the actual standard of care. IFN-based and IFN-free regimens are being studied in adults. In this constantly evolving scenario new drug regimens targeted and suitable for children would be possible in the next future. Especially for children, it is crucial to identify the right combination of drugs with the highest potency, barrier to resistance and the best safety profile.

关键词： Hepatitis C virus Children Treatment Interferon Ribavirin daclatasvir Sofosbuvir Efficacy Safety

Impact of interferon-free antivirus therapy on lipid profiles in patients with chronic hepatitis C genotype 1b

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World Journal of Gastroenterology 2017年第13期23卷 2355-2364页

作者： Daisuke Endo Kenichi Satoh Noritomo Shimada Atsushi Hokari Yoshio Aizawa Department of Gastroenterology and Hepatology Internal Medicine of Jikei University Katsushika Medical Center Department of Gastroenterology and Hepatology Internal Medicine of Otakanomori Hospital

AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b(HCV1b) *** Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1 b infection, and changes in serum lipids of those who achieved sustained virologic response(SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir(DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir(SOF + LDV). SVR was achieved in 121(85.8%) of 141 patients treated with DCV + ASV and 132(97.8%) of 135 patients treated with SOF + LDV. In the two patient groups(DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were *** Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDVSVR group than in the DCV + ASV-SVR group(P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol(DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of *** Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol.

关键词： Chronic hepatitis C daclatasvir Asunaprevir Sofosbuvir Ledipasvir Total cholesterol Low-density lipoprotein cholesterol

Hepatitis C virus NS5A inhibitors and drug resistance mutations

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World Journal of Gastroenterology 2014年第11期20卷 2902-2912页

作者： Shingo Nakamoto Tatsuo Kanda Shuang Wu Hiroshi Shirasawa Osamu Yokosuka Department of Molecular Virology Graduate School of MedicineChiba UniversityChiba 260-8677Japan Department of Gastroenterology and Nephrology Graduate School of MedicineChiba UniversityChiba 260-8677Japan

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HCV-infected patients. “First generation” HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

关键词： ACH-3102 Direct-acting antiviral agents daclatasvir Hepatitis C virus Ledipasvir

Effectiveness and safety of generic and brand direct acting antivirals for treatment of chronic hepatitis C

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World Journal of Clinical Cases 2022年第34期10卷 12566-12577页

作者： Maheeba Abdulla Aysha Mohamed Al Ghareeb Hamed Ali Hasan Yusuf Husain Nafeesa Mohammed Jehad Al Qamish Department of Internal Medicine Salmaniya Medical ComplexArabian Gulf UniversityManama 2904Bahrain Department of Internal Medicine Salmaniya Medical ComplexManama 2904Bahrain Internal Medicine Department Ibn AlNafees HospitalManama 3302Bahrain

BACKGROUND Direct acting antivirals(DAAs)are a very effective treatment for hepatitis C virus(HCV).However,brand DAAs are *** licensing of cheaper generic DAAs may address this issue,but there is a lack of clinical studies comparing the efficacy of generic vs brand DAA *** To compare the efficacy and safety of generic against brand DAAs for chronic hepatitis C treatment in *** This was a retrospective observational study involving 289 patients with chronic HCV infection during 2016 to *** were 149 patients who were treated with brand DAAs,while 140 patients were treated with generic *** used DAAs were Ombitasvir/Paritaprevir/Ritonavir±Dasabuvir±Ribavirin,and Sofosbuvir/daclatasvir±*** at 12 wk post treatment was the main outcome *** Overall,87 patients(30.1%)had cirrhosis and 68.2%had genotype 1 HCV *** 12 wk post treatment,SVR was achieved by 271(93.8%)of the *** patients who were treated with generic medications,134(95.7%)achieved SVR at 12 wk post treatment,compared to 137(91.9%)among those treated with brand medications(P=0.19).Having cirrhosis[odds ratio(OR):9.41,95%confidence interval(CI):2.47–35.84]and having HCV genotype 3(OR:3.56,95%CI:1.03–12.38)were significant independent predictors of not achieving *** transaminase,gamma-glutamyl transpeptidase,and total bilirubin levels decreased significantly following therapy with both generic and brand *** Generic and brand DAAs demonstrate comparable effectiveness in the treatment of chronic hepatitis C *** are safe and equally effective in improving biochemical markers of hepatic inflammation.

关键词： Hepatitis C virus Direct acting antivirals Generic Brand Sofosbuvir Ombitasvir Ledipasvir daclatasvir Paritaprevir Ritonavir Dasabuvir Ribavirin Sustained virologic response

Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand?

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World Journal of Hepatology 2015年第12期7卷 1606-1616页

作者： Chrysoula Pipili Evangelos Cholongitas Division of Nephrology Royal Infirmary of Edinburgh 4th Department of Internal Medicine Medical Medical School of Aristotle University Hippokration General Hospital of Thessaloniki

The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second generation DAAs are associated with high sustained virological response rates(> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs(simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment(Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 m L/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence posttransplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.

关键词： Liver transplantation Decompensatedcirrhosis Hepatitis C New antiviral agents Sofosbuvir Simeprevir daclatasvir Recurrent hepatitis C