Математическая модель прогноза скорости фиброза печени у больных с хроническим гепатитом С на основе комбинаций геномных маркеров

Aim of study. To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, NOS3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC).Subjects and methods: 118 patients with CHC were divided into «fast» and «slow» (fibrosis rate progression ≥0,13 and 0,13 fibrosis units/yr; n =64 and n =54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10.Results. A allele (p =0,012) and genotype AA (p =0,024) of AGT G-6T gene, as well as T allele (p =0,013) and MT+TT genotypes (p =0,005) of AGT 235 M/T gene were significantly more common in «fast fibrosers» than in «slow fibrosers». Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p =0,02). Our analysis showed a protective effect of TT genotype of ITGA2 807 C/T on fibrosis progression rate (p =0,03). There was a trend (p 0,15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI -675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical model for prediction of liver fibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R =0,39, p =0,000).Conclusion: Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC. Обоснование. В настоящее время большое внимание уделяется поиску генетических факторов, объясняющих течение хронического гепатита С (ХГС).Цель исследования: оценить прогностическую значимость носительства комбинаций аллельных вариантов генов IL 1b, IL 6, IL 10, TNF α, HFE, TGF b, ATR1, NOS3, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI на прогрессирование фиброза печени при ХГС.Материалы и методы: 118 пациентов с ХГС разделены на группы с быстрым и медленным (скорость фиброза ≥0,13 и 0,13 ед. фиброза/год; n =64 и n =54, соответственно) фиброзом. Выполнено определение полиморфизма. Статистическую обработку результатов проводили с использованием пакетов программ Statistica 10.Результаты. У больных с быстрым фиброзом в сравнении с группой с медленным чаще встречались аллель А (р =0,012) и мутантный генотип АА (р =0,024) гена AGT G-6T, также в данной группе чаще выявляли аллель Т (р =0,013) и генотип МТ+ТТ гена AGT 235 M/T (р =0,005). Больные с генотипом ТТ гена CYBA 242 C/T имели более высокую скорость фиброза по сравнению с больными с генотипом СС+СТ (р =0,02). В ходе анализа выявлено протективное влияние гомозиготы ТТ гена ITGA2 807 C/T на темпы фиброза (р =0,03). Наблюдались тенденции к различию по встречаемости аллелей и генотипов полиморфных маркеров TGFb +915 G/С, FXIII 103 G/T, PAI -675 5G/4G между двумя группами. Для остальных генов достоверных отличий не обнаружено. В дальнейшем построена математическая модель, учитывающая протективное и профиброгенное влияние генов, в также влияние генотипа вируса. Выявлена корреляция между суммой баллов в этой модели и темпом прогрессирования фиброза в печени (R =0,39, p =0,000).Заключение: предложенная математическая модель может прогнозировать течение болезни

Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4.5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial

Background: Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4.5 h after symptom onset. Methods: We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4.5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0.9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0-1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0-1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. Findings: Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89-89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1.47, 95% CI 0.93 to 2.32; p=0.10). The difference in the rate of favourable outcome at day 90 was 9.5% (95% CI -1.7 to 20.7) and the lower limit did not cross the margin of non-inferiority (p(non-inferiority) <0.0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0.087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0.32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0.044). Interpretation Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4.5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary. Copyright (C) Elsevier Ltd. All rights reserved

Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial

Background: Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset. Methods: We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0–1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0–1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. Findings: Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89–89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32; p=0·10). The difference in the rate of favourable outcome at day 90 was 9·5% (95% CI –1·7 to 20·7) and the lower limit did not cross the margin of non-inferiority (pnon-inferiority &lt;0·0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0·087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0·32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0·044). Interpretation: Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4·5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary. Funding: The Russian Academy of Sciences. © 2021 Elsevier Lt