Modern Directed Antiviral Covid-19 Therapy: Results of Multicenter Clinical Effectiveness and Safety Study of Fixed Nirmatrelvir+Ritonavir Combination

The article presents the data from an open, two-stage, multicenter study on the efficacy and safety evaluation of a combined drug (a fixed combination of nirmatrelvir 300 mg, and ritonavir 100 mg) in the complex therapy in COVID-19 patients. The aim of the study was to assess the safety, tolerability and pharmacokinetic parameters of the fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg in healthy volunteers, the efficacy and safety assessment of the drug in the combination therapy compared with the standard therapy in COVID-19 patients. Material and methods. An open two-stage multicenter clinical study to assess the main pharmacokinetic parameters, safety, and efficacy against COVID-19 of the drug nirmatrelvir 300 mg and ritonavir 100 mg combination (Skyvira((R)) PROMOMED RUS LLC, Russia) in the adult population, included 2 stages. At stage 1, safety, tolerability and pharmacokinetic parameters were evaluated in healthy volunteers (over 18 years of age) in order to confirm their comparability with the literature data known for a set of active substances. Phase 2 assessed efficacy and safety in COVID-19 patients. As a part of the second stage, the study involved 264 patients (men and women aged 18 to 80 years), who had been divided into two groups. The first group patients (n=132) received the study drugs (nirmatrelvir 300 mg and ritonavir 100 mg) - 1 tablet twice a day with an interval of 12 +/- 2 hours for 5 days in combination with pathogenetic and symptomatic therapy. The second group patients (n=132) received standard therapy in accordance with the approved Temporary Guidelines for the Prevention and Treatment of Novel Coronavirus Infection (Version 15 dated February 22, 2022). Results. During the study, none of the patients from the (nirmatrelvir + ritonavir) group experienced a transition of the COVID-19 course to a heavier severity level, in contrast to the patients in the standard therapy group. The study participants included patients with comorbidities (68% of the general population), with risk factors for COVID-19 progression to a heavier severity level and the risk of hospitalization (75% of the general population). There were no cases of COVID-19 progression to a heavier severity level in the study drug group. By the 6th day, in the nirmatrelvir + ritonavir group, the proportion of the patients who had achieved a complete recovery was twice more and amounted to 35.61% (p=0.0001), and the proportion of the patients with a negative RNA analysis to SARS-CoV-2 was 20% higher than in the comparison group, and amounted to 82.58% (p=0.0001). The fixed nirmatrelvir + ritonavir combination therapy has a favorable safety profile comparable to the standard therapy. The identified adverse reactions were transient in nature and did not require discontinuation of therapy or changes in the treatment regimen. Conclusion. The fixed nirmatrelvir + ritonavir combination has a favorable safety profile in COVID-19 patients, comparable to the standard therapy. The data obtained demonstrate a clinical and pharmacoeconomic feasibility of including the fixed (nirmatrelvir + ritonavir) combination in the COVID-19 treatment regimen.

Modern Directed Antiviral Covid-19 Therapy: Results of Multicenter Clinical Effectiveness and Safety Study of Fixed Nirmatrelvir+Ritonavir Combination

The article presents the data from an open, two-stage, multicenter study on the efficacy and safety evaluation of a combined drug (a fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg) in the complex therapy in COVID-19 patients. The aim of the study was to assess the safety, tolerability and pharmacokinetic parameters of the fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg in healthy volunteers, the efficacy and safety assessment of the drug in the combination therapy compared with the standard therapy in COVID-19 patients. Material and methods. An open two-stage multicenter clinical study to assess the main pharmacokinetic parameters, safety, and efficacy against COVID-19 of the drug nirmatrelvir 300 mg and ritonavir 100 mg combination (Skyvira PROMOMED RUS LLC, Russia) in the adult population, included 2 stages. At stage 1, safety, tolerability and pharmacokinetic parameters were evaluated in healthy volunteers (over 18 years of age) in order to confirm their comparability with the literature data known for a set of active substances. Phase 2 assessed efficacy and safety in COVID-19 patients. As a part of the second stage, the study involved 264 patients (men and women aged 18 to 80 years), who had been divided into two groups. The first group patients (n=132) received the study drugs (nirmatrelvir 300 mg and ritonavir 100 mg) - 1 tablet twice a day with an interval of 12+/-2 hours for 5 days in combination with pathogenetic and symptomatic therapy. The second group patients (n=132) received standard therapy in accordance with the approved Temporary Guidelines for the Prevention and Treatment of Novel Coronavirus Infection (Version 15 dated February 22, 2022). Results. During the study, none of the patients from the (nirmatrelvir + ritonavir) group experienced a transition of the COVID-19 course to a heavier severity level, in contrast to the patients in the standard therapy group. The study participants included patients with comorbidities (68% of the general population), with risk factors for COVID-19 progression to a heavier severity level and the risk of hospitalization (75% of the general population). There were no cases of COVID-19 progression Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

CONCLUSION OF EXPERTS. NEW POSSIBILITIES OF ETIOTROPIC THERAPY OF CORONAVIRUS INFECTION.

In conclusion, topical aspects of the etiotropic therapy of a new coronavirus infection and the prospects for the use of SKYVIRA 1 , which is a Russian-made combined drug in the form of tablets based on INN nirmatrelvir + ritonavir, are presented. Target. Determination of the place of medicines based on the INN nirmatrelvir + ritonavir in the etiotropic therapy of patients with a new coronavirus infection, depending on the severity of the course and the timing of the visit to the doctor. Determination of the paradigm for further studies of drugs based on nirmatrelvir. Copyright © 2022, Dynasty Publishing House. All rights reserved.

EFFECTIVENESS AND SAFETY OF FAVIPIRAVIR INFUSION IN PATIENTS HOSPITALIZED WITH COVID-19

Research in the development of new therapeutic agents with a wide spectrum of the antiviral activity and a low ability to develop resistance remains the main dimension in combating the global threat to public health. The need for a parenteral form of favipiravir was dictated by the necessity to increase the efficacy of therapy in COVID-19 inpatients. This dosage form has expanded the possibilities of drug therapy in the inpatients, for whom a therapeutic effect acceleration and a high safety profile of the drugs used are especially important. The aim of the article is the evaluation of the efficacy and safety of a medicinal product containing favipiravir for the parenteral administration against the background of pathogenetic and symptomatic therapy, in comparison with standard therapy in hospitalized COVID-19 patients. Materials and methods. An open, randomized, multicenter comparative study was conducted in 6 research centers in the Russian Federation to evaluate the efficacy and safety of favipiravir, a lyophilisate for the preparation of a concentrate for the infusion solution administrated to the patients hospitalized with COVID-19. Screening procedures and randomization were completed in 217 patients, 209 of which had completed the study in accordance with the protocol. Results. Between the study groups, statistically significant differences have been found out, making it possible to consider the hypothesis of the drug Areplivir (favipiravir) superiority for the parenteral administration over the standard therapy, which included favipiravir (p. o.) and remdesivir. A comparative analysis has shown that a course of therapy with the parenteral favipiravir drug leads to a significant improvement in the condition of patients with COVID-19, significant benefits in terms of the speed and frequency of improvement in the clinical status of patients, as well as a reduction in the hospital stay length. It has been proven that therapy with a drug containing favipiravir for the parenteral administration does not adversely affect the parameters of clinical and biochemical blood tests, urinalysis, coagulograms, vital signs and ECG, which indicates the therapy safety. The study drug is characterized by a high safety profile and tolerability. Conclusion. The versatility and resistance to mutations of RNA-dependent RNA polymerase make it possible to consider it as the main target for combating the most common RNA viruses that cause ARVI, that determines the need further studies of favipiravir to expand the range of its indications.

Inpatient care for urological patients in a pandemic of the coronavirus disease-covid-19 infection

Since the first cases of coronavirus disease were detected in Wuhan (Hubei Province, China) in December 2019, the spread distribution of COVID-19 has expanded so much that the World Health Organization declared COVID-19 a pandemic. The most common symptoms of corona-virus infection are fever (85-90%), cough (65-70%), general weakness (35-40%), shortness of breath or feeling short of breath (15-20%);less common symptoms such as myalgia, headaches, sore throat and chills (10-15%). Currently, cases of infection are recorded in almost all countries of the world, there is a daily increase in the number of infected by an average of 100,000, and the death toll by average estimates is over 3,000,000. At present time, the “leading” position in the number of cases of COVID-19 detected belongs to the United States, in which over the entire observation period, more than 32,000,000 thousand cases were recorded. Another badly affected region is Europe, in which more than 43,000,000 thousand cases were recorded. The rapid growth in the number of newly diagnosed cases of COVID-19 dictates the need to search for optimal ways of providing medical care. It is obvious that inpatient practice carrying high risk of infection for patients as well as for medical stuff. Moreover, postoperative mortality rate in infected patients may be as high as 20%. Since the pandemic onset many authors and societies have provided recommendations on how the risk of infection during inpatient practice should be reduced. This article discusses the options for providing inpatient care to urological patients in a pandemic of the coronary viral infection COVID-19.

Acute kidney injury in COVID-19: clinical and morphological comparisons based on autopsy data

Severe Acute Respiratory Syndrome (SARS-CoV-2) has spread rapidly throughout the world, causing high morbidity and mortality. Analysis of clinical and autopsy data may allow to understand this disease. The results of pulmonary and renal autopsies in 37 deceased patients from COVID-19 are presented. Materials and methods. An autopsy was performed in Moscow in 37 deceased patients aged from 28 to 94 years. The microscopic features of the lungs and kidneys were examined using hematoxylin and eosin staining. Results. Important findings include diffuse alveolar injury, pulmonary thrombosis and microangiopathy, as well as acute kidney injury in all cases, varying in severity. Conclusions. We report the presence of acute kidney injury in all cases, which requires correction of renal function in patients with SARS-CoV-2, with control of serum creatinine levels, urine volume, proteinuria and hematuria. Тяжелый острый респираторный синдром (SARS-CoV-2) быстро распространился по всему миру, вызвав высокую заболеваемость и смертность. Анализ клинических данных и данных аутопсии может помочь нам разобраться в данной болезни. Мы представляем результаты легочной и почечной аутопсии у 37 умерших от COVID-19 пациентов. Материалы и методы. В Москве произведена аутопсия 37 умершим пациентам в возрасте от 28 до 94 лет. Были исследованы микроскопические особенности легких и почек с помощью окрашивания гематоксилином и эозином. Результаты. Важные результаты включают диффузное альвеолярное повреждение, тромбоз и микроангиопатию в легких, а также острое повреждение почек во всех случаях различной степени тяжести. Выводы. Мы сообщаем о наличии острого повреждения почек во всех исследуемых случаях, что требует коррекции функции почек у больных SARS-CоV-2 с контролем уровня креатинина в плазме крови, объема мочи, наличия протеинурии и гематурии.

Characteristics of covid-19 and possibilities of early causal therapy. Results of favipiravir use in clinical practice

Objective. Тo evaluate the efficacy and safety of favipiravir (Areplivir) in patients with coronavirus disease 2019 (COVID-19) and compare it with recommended standard therapy. Patients and methods. Two hundred men and women aged between 18 and 80 years with COVID-19 were randomized into this study. The experimental group included patients who received favipiravir, whereas the control group comprised patients who received causal therapy in accordance with the latest version of the temporary methodical recommendations of the Ministry of Health of Russia ‘Prevention, diagnosis, and treatment of coronavirus infection (COVID-19).’ The efficacy and safety of therapy were evaluated by assessing clinical improvement using the WHO Ordinal Scale for Clinical Improvement, clinical and laboratory parameters, findings of chest computed tomography (CT), and elimination of SARS-CoV-2. We also analyzed the frequency and type of adverse events, need for invasive and non-invasive ventilation, and death rates. Results. Our analysis has demonstrated significant benefits of favipiravir over standard therapy in terms of the time to clinical improvement (in the experimental group it was 4 days shorter on average), time to recovery, frequency of recovery after 10 days (44% of patients from the experimental group and 10% of patients from the control group had no clinical signs of the disease at this time-point), and frequency of virus elimination by day 10 of therapy. Treatment with favipiravir was associated with a significant improvement in the lung condition (according to CT), normalization of laboratory parameters, and saturation level. Favipiravir has demonstrated a good safety profile similar to that of standard therapy. There was no difference in the frequency of adverse events between the experimental and control groups. Conclusion. The use of favipiravir for the treatment of SARS-CoV-2 infection reduced the time to clinical improvement by 4 days on average compared to standard therapy, ensured improvement of the lung condition (according to CT scans), and facilitated virus elimination in more than 90% of patients, thereby promoting faster recovery. Favipiravir had a good safety profile and was well tolerated by patients. This treatment regimen was shown to be effective, sufficient, and clinically reasonable to achieve good outcomes. Timely initiation of therapy with favipiravir (Areplivir) improves disease prognosis and reduces the global socioeconomic burden of the current pandemic. © 2020, Dynasty Publishing House. All rights reserved.

[Acute kidney injury in COVID-19: clinical and morphological comparisons based on autopsy data]

Severe Acute Respiratory Syndrome (SARS-CoV-2) has spread rapidly throughout the world, causing high morbidity and mortality. Analysis of clinical and autopsy data may allow to understand this disease. The results of pulmonary and renal autopsies in 37 deceased patients from COVID-19 are presented. MATERIALS AND METHODS: An autopsy was performed in Moscow in 37 deceased patients aged from 28 to 94 years. The microscopic features of the lungs and kidneys were examined using hematoxylin and eosin staining. RESULTS: Important findings include diffuse alveolar injury, pulmonary thrombosis and microangiopathy, as well as acute kidney injury in all cases, varying in severity. CONCLUSIONS: We report the presence of acute kidney injury in all cases, which requires correction of renal function in patients with SARS-CoV-2, with control of serum creatinine levels, urine volume, proteinuria and hematuria.

Оказание стационарной помощи пациентам урологического профиля в условиях пандемии коронаровирусной инфекции covid-19

Objective. Since the first cases of Coronavirus Disease were detected in Wuhan (Hubei Province, China) in December 2019, the spread distribution of COVID-19 has expanded so much that the World Health Organization declared COVID-19 a pandemic. Materials. Currently, cases of infection are recorded in almost all countries of the world, there is a daily increase in the number of infected by an average of 100 000, and the death toll by average estimates is over 115 000. At present time, the «leading» position in the number of cases of COVID-19 detected belongs to the United States, in which over the entire observation period, more than 500 000 cases were recorded. In Spain, Italy, France and Germany the total number of cases exceeded 526 000 people in less than a month. The rapid growth in the number of newly diagnosed cases of COVID-19 dictates the need for search for optimal ways of providing medical care. Clinical practice and results. This article discusses the options for providing inpatient care to urological patients in a pandemic of the coronary viral infection COVID-19. Clinical practice is described and a list of urological diseases is presented, the surgical treatment of which is possible in a pandemic. Intraoperative measures have been developed to reduce the risk of viral contamination during laparoscopic and robot-assisted operations. The routing and scope of work with patients suffering from acute urological diseases are described in detail: renal colic, acute obstructive pyelonephritis, macrohematuria, acute urinary retention. Conclusion. The principles of the organization of work of the urological department and precautions in identifying patients with COVID- 19 have been developed. Введение. С момента выявления первых случаев коронаровирусной инфекции (КВИ) в городе Ухань (провинция Хубэй, КНР) в декабре 2019 года география распространения COVID-19 расширилась настолько, что Всемирная Организация Здравоохранения присвоила вспышке статус пандемии. Материалы и методы. В настоящее время случаи инфекции зафиксированы практически во всех странах мира, отмечается ежедневный прирост числа инфицированных в среднем на 100 000 человек, а количество погибших по средним подсчетам составляет свыше 115 000 человек. В настоящее время «лидирующие» позиции по числу выявленных случаев КВИ принадлежат США, где за весь период наблюдения зафиксировано свыше 526 000 заболевших. В Испании, Италии, Франции и Германии меньше, чем за месяц, суммарное число заболевших превысило 570 000 человек. Молниеносный рост числа вновь выявленных случаев заболевания КВИ предопределяет поиск оптимальных путей оказания медицинской помощи. Клиническая практика и результаты. В статье рассмотрены варианты оказания стационарной помощи пациентам урологического профиля в условиях пандемии коронавирусной инфекции COVID-19. Описана клиническая практика и представлен список урологических заболеваний, оперативное лечение которых возможно в условиях пандемии. Разработаны интраоперационные меры для снижения риска вирусной контаминации при выполнении лапароскопических и робот-ассистированных операций. Подробно описана маршрутизация и объем работы с пациентами, страдающими острыми урологическими заболеваниями: почечная колика, острый обструктивный пиелонефрит, макрогематурия, острая задержка мочи. Выводы. Авторами были разработаны принципы организации работы урологического отделения и меры предосторожности при выявлении больных с COVID-19.

Inpatient care for urological patients in a pandemic of the coronavirus disease infection COVID-19

Objective. Since the first cases of Coronavirus Disease were detected in Wuhan (Hubei Province, China) in December 2019, the spread distribution of COVID-19 has expanded so much that the World Health Organization declared COVID-19 a pandemic. Materials. Currently, cases of infection are recorded in almost all countries of the world, there is a daily increase in the number of infected by an average of 100 000, and the death toll by average estimates is over 115 000. At present time, the «leading» position in the number of cases of COVID-19 detected belongs to the United States, in which over the entire observation period, more than 500 000 cases were recorded. In Spain, Italy, France and Germany the total number of cases exceeded 526 000 people in less than a month. The rapid growth in the number of newly diagnosed cases of COVID-19 dictates the need for search for optimal ways of providing medical care. Clinical practice and results. This article discusses the options for providing inpatient care to urological patients in a pandemic of the coronary viral infection COVID-19. Clinical practice is described and a list of urological diseases is presented, the surgical treatment of which is possible in a pandemic. Intraoperative measures have been developed to reduce the risk of viral contamination during laparoscopic and robot-assisted operations. The routing and scope of work with patients suffering from acute urological diseases are described in detail: renal colic, acute obstructive pyelonephritis, macrohematuria, acute urinary retention. Conclusion. The principles of the organization of work of the urological department and precautions in identifying patients with COVID- 19 have been developed. Введение. С момента выявления первых случаев коронаровирусной инфекции (КВИ) в городе Ухань (провинция Хубэй, КНР) в декабре 2019 года география распространения COVID-19 расширилась настолько, что Всемирная Организация Здравоохранения присвоила вспышке статус пандемии. Материалы и методы. В настоящее время случаи инфекции зафиксированы практически во всех странах мира, отмечается ежедневный прирост числа инфицированных в среднем на 100 000 человек, а количество погибших по средним подсчетам составляет свыше 115 000 человек. В настоящее время «лидирующие» позиции по числу выявленных случаев КВИ принадлежат США, где за весь период наблюдения зафиксировано свыше 526 000 заболевших. В Испании, Италии, Франции и Германии меньше, чем за месяц, суммарное число заболевших превысило 570 000 человек. Молниеносный рост числа вновь выявленных случаев заболевания КВИ предопределяет поиск оптимальных путей оказания медицинской помощи. Клиническая практика и результаты. В статье рассмотрены варианты оказания стационарной помощи пациентам урологического профиля в условиях пандемии коронавирусной инфекции COVID-19. Описана клиническая практика и представлен список урологических заболеваний, оперативное лечение которых возможно в условиях пандемии. Разработаны интраоперационные меры для сниженРя риска вирусной контаминации при выполнении лапароскопических и робот-ассистированных операций. Подробно описана маршрутизация и объем работы с пациентами, страдающими острыми урологическими заболеваниями: почечная колика, острый обструктивный пиелонефрит, макрогематурия, острая задержка мочи. Выводы. Авторами были разработаны принципы организации работы урологического отделения и меры предосторожности при выявлении больных с COVID-19.