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The New England Journal of Medicine May 2020No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.
METHODS
We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao) to the fraction of inspired oxygen (Fio) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
RESULTS
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.
CONCLUSIONS
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
Topics: Adult; Aged; Antiviral Agents; Betacoronavirus; COVID-19; COVID-19 Testing; Clinical Laboratory Techniques; Coronavirus Infections; Cytochrome P-450 CYP3A Inhibitors; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Intention to Treat Analysis; Lopinavir; Male; Middle Aged; Pandemics; Patient Acuity; Pneumonia, Viral; Proportional Hazards Models; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; SARS-CoV-2; Time-to-Treatment; Treatment Failure; Viral Load
PubMed: 32187464
DOI: 10.1056/NEJMoa2001282 -
Nature Communications Sep 2023Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral...
Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China.
Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.
Topics: Humans; Nevirapine; Cohort Studies; Lopinavir; Retrospective Studies; Benzoxazines; Acquired Immunodeficiency Syndrome; China
PubMed: 37660054
DOI: 10.1038/s41467-023-41051-w -
Pharmacogenomics Apr 2021Lopinavir and ritonavir are substrates of permeability glycoprotein encoded by The efficacy and safety of these drugs is unknown in COVID-19 patients affected by... (Review)
Review
Lopinavir and ritonavir are substrates of permeability glycoprotein encoded by The efficacy and safety of these drugs is unknown in COVID-19 patients affected by genetic variability. Patients carrying one or two copies of the C3435T were predictively considered as risk phenotypes. It was predicted that risk phenotypes due to carrying either one or two copies of C3435T were highly prevalent in Europe (76.8%; 95% CI: 75-78), followed by America (67%; 95% CI: 65-69), Asia (63.5%; 95% CI: 62-65) and Africa (41.4%; 95% CI: 37-46), respectively. It is hypothesized that a considerable proportion of COVID-19 patients treated with lopinavir/ritonavir inheriting C3435T genetic polymorphism may be predisposed to either therapeutic failure or toxicity.
Topics: ATP Binding Cassette Transporter, Subfamily B; COVID-19; Humans; Lopinavir; Polymorphism, Single Nucleotide; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33759544
DOI: 10.2217/pgs-2020-0096 -
Journal of Pharmacy & Pharmaceutical... 2021To provide the latest evidence on the efficacy and safety of lopinavir/ritonavir compared to other treatment options for COVID-19. (Meta-Analysis)
Meta-Analysis
PURPOSE
To provide the latest evidence on the efficacy and safety of lopinavir/ritonavir compared to other treatment options for COVID-19.
METHODS
We searched PubMed, Cochran Library, Embase, Scopus, and Web of Science for the relevant records up to April 2021. Moreover, we scanned MedRxiv, Google Scholar, and clinical registry databases to identify additional records. We have used the Newcastle-Ottawa Scale and Cochrane risk of bias tools to assess the quality of studies. This Meta-analysis was conducted using RevMan software (version 5.3).
RESULTS
Fourteen studies were included. No significant difference was observed between lopinavir/ritonavir and non-antiviral treatment groups in terms of negative rate of PCR (polymerase chain reaction) on day 7 (risk ratio [RR]: 0.83; 95% CI: 0.63 to 1.09; P=0.17), and day 14 (RR: 0.93; 95% CI: 0.81 to 1.05; P=0.25), PCR negative conversion time (mean difference [MD]: 1.09; 95% CI: -0.10 to 2.29; P=0.07), secondary outcomes, and adverse events (P>0.05). There was no significant difference between lopinavir/ritonavir and chloroquine as well as lopinavir/ritonavir and hydroxychloroquine regarding the efficacy outcomes (P>0.05). However, lopinavir/ritonavir showed better efficacy than arbidol for the same outcomes (P<0.05). Lopinavir/ritonavir plus arbidol was effective compared to arbidol alone in terms of the negative rate of PCR on day 7 (P=0.02). However, this difference was not significant regarding other efficacy outcomes (P>0.05).
CONCLUSION
Lopinavir/ritonavir has no more treatment effects than other therapeutic agents used herein in COVID-19 patients.
Topics: COVID-19; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Hydroxychloroquine; Lopinavir; Randomized Controlled Trials as Topic; Retrospective Studies; Ritonavir; COVID-19 Drug Treatment
PubMed: 34048671
DOI: 10.18433/jpps31668 -
The Korean Journal of Internal Medicine Mar 2021The efficacies of lopinavir-ritonavir or hydroxychloroquine remain to be determined in patients with coronavirus disease 2019 (COVID-19). To compare the virological and... (Comparative Study)
Comparative Study
BACKGROUND/AIMS
The efficacies of lopinavir-ritonavir or hydroxychloroquine remain to be determined in patients with coronavirus disease 2019 (COVID-19). To compare the virological and clinical responses to lopinavir-ritonavir and hydroxychloroquine treatment in COVID-19 patients.
METHODS
This retrospective cohort study included patients with COVID-19 treated with lopinavir-ritonavir or hydroxychloroquine at a single center in Korea from February 17 to March 31, 2020. Patients treated with lopinavir-ritonavir and hydroxychloroquine concurrently and those treated with lopinavir-ritonavir or hydroxychloroquine for less than 7 days were excluded. Time to negative conversion of viral RNA, time to clinical improvement, and safety outcomes were assessed after 6 weeks of follow-up.
RESULTS
Of 65 patients (mean age, 64.3 years; 25 men [38.5%]), 31 were treated with lopinavir-ritonavir and 34 were treated with hydroxychloroquine. The median duration of symptoms before treatment was 7 days and 26 patients (40%) required oxygen support at baseline. Patients treated with lopinavir-ritonavir had a significantly shorter time to negative conversion of viral RNA than those treated with hydroxychloroquine (median, 21 days vs. 28 days). Treatment with lopinavir-ritonavir (adjusted hazard ratio [aHR], 2.28; 95% confidence interval [CI], 1.24 to 4.21) and younger age (aHR, 2.64; 95% CI 1.43 to 4.87) was associated with negative conversion of viral RNA. There was no significant difference in time to clinical improvement between lopinavir-ritonavir- and hydroxychloroquine-treated patients (median, 18 days vs. 21 days). Lymphopenia and hyperbilirubinemia were more frequent in lopinavir-ritonavir-treated patients compared with hydroxychloroquine-treated patients.
CONCLUSION
Lopinavir-ritonavir was associated with more rapid viral clearance than hydroxychloroquine in mild to moderate COVID-19, despite comparable clinical responses. These findings should be confirmed in randomized, controlled trials.
Topics: Aged; Aged, 80 and over; Antiviral Agents; COVID-19; Drug Combinations; Female; Humans; Hydroxychloroquine; Lopinavir; Male; Middle Aged; Retrospective Studies; Ritonavir; SARS-CoV-2; Time Factors; Treatment Outcome; Viral Load; COVID-19 Drug Treatment
PubMed: 32536150
DOI: 10.3904/kjim.2020.224 -
Cardiovascular Drugs and Therapy Jun 2021Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage... (Review)
Review
Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.
Topics: Anticoagulants; Drug Interactions; Drug Therapy, Combination; Heart Diseases; Humans; Hypolipidemic Agents; Lopinavir; Platelet Aggregation Inhibitors; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32918656
DOI: 10.1007/s10557-020-07070-1 -
The Journal of Antimicrobial... Jan 2021Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with... (Observational Study)
Observational Study
BACKGROUND
Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection.
OBJECTIVES
To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir.
METHODS
This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines.
RESULTS
Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration.
CONCLUSIONS
Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.
Topics: Antiviral Agents; COVID-19; Cohort Studies; Darunavir; Drug Therapy, Combination; Electrocardiography; France; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; SARS-CoV-2; Severity of Illness Index; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33221868
DOI: 10.1093/jac/dkaa441 -
European Journal of Clinical... May 2022The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and... (Review)
Review
PURPOSE
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s).
METHOD
Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials.
RESULTS
Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed.
CONCLUSION
In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.
Topics: Antiviral Agents; Chloroquine; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxychloroquine; Ivermectin; Lopinavir; Reproducibility of Results; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35088108
DOI: 10.1007/s00228-021-03270-2 -
SLAS Discovery : Advancing Life... Dec 2020In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei Province, China. The pathogen has been identified as a novel... (Review)
Review
In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei Province, China. The pathogen has been identified as a novel enveloped RNA beta-coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus SARS-CoV-2 is associated with a disease characterized by severe atypical pneumonia known as coronavirus 2019 (COVID-19). Typical symptoms of this disease include cough, fever, malaise, shortness of breath, gastrointestinal symptoms, anosmia, and, in severe cases, pneumonia. The high-risk group of COVID-19 patients includes people over the age of 60 years as well as people with existing cardiovascular disease and/or diabetes mellitus. Epidemiological investigations have suggested that the outbreak was associated with a live animal market in Wuhan. Within the first few months of the outbreak, cases were growing exponentially all over the world. The unabated spread of this deadly and highly infectious virus is a health emergency for all nations in the world and has led to the World Health Organization (WHO) declaring a pandemic on March 11, 2020. In this report, we consolidate and review the available clinically and preclinically relevant results emanating from in vitro animal models and clinical studies of drugs approved for emergency use as a treatment for COVID-19, including remdesivir, hydroxychloroquine, and lopinavir-ritonavir combinations. These compounds have been frequently touted as top candidates to treat COVID-19, but recent clinical reports suggest mixed outcomes on their efficacies within the current clinical protocol frameworks.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hydroxychloroquine; Lopinavir; Ritonavir; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32942923
DOI: 10.1177/2472555220958385 -
Turkish Journal of Medical Sciences Aug 2021SARS-CoV-2, a ribonucleic acid coronavirus, rapidly spread worldwide within a short timeframe. Although different antiviral, antiinflammatory, and immunomodulatory drugs... (Comparative Study)
Comparative Study
BACKGROUND/AIM
SARS-CoV-2, a ribonucleic acid coronavirus, rapidly spread worldwide within a short timeframe. Although different antiviral, antiinflammatory, and immunomodulatory drugs are used, current evidence is insufficient as to which drug is more efficient. Our study compared favipiravir and lopinavir/ritonavir (LPV/RTV) therapies in inpatient care for coronavirus disease 2019 (COVID-19) pneumonia.
MATERIALS AND METHODS
Demographic data, test results, treatments, and latest status of patients receiving inpatient COVID-19 pneumonia therapy were recorded. The initial favipiravir and LPV/RTV receiving groups were compared regarding the need for intensive care units (ICU) and mortality. Logistic regression analysis was performed by including variables showing significant differences as a result of paired comparisons into the model.
RESULTS
Of the 204 patients with COVID-19 pneumonia, 59 (28.9%), 131 (64.2%), and 14 were administered LPV/RTV, favipiravir, and favipiravir with LPV/RTV, respectively. No difference was found in age, sex, presence of comorbidity, and tocilizumab, systemic corticosteroid, and plasma therapy use between patients administered with these three different treatment regimens. The mean mortality age of the patients was 71 ± 14.3 years, which was substantially greater than that of the survivors (54.2 ± 15.5 years). Compared with patients administered with LPV/RTV, ICU admission and mortality rates were lower in patients administered with favipiravir. CK-MB, AST, CRP, LDH, and creatinine levels were higher, whereas lymphocyte counts were lower in patients who died. Age, AST, CRP, LDH, and neutrophil counts were higher in patients needing ICU, and eosinophil and lymphocyte counts were significantly lower. Logistic regression analysis showed that favipiravir use independently decreased mortality (p = 0.006).
CONCLUSION
The use of favipiravir was more effective than LPV/RTV in reducing mortality in hospitalized patients with COVID-19.
Topics: Aged; Amides; Antiviral Agents; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrazines; Retrospective Studies; Ritonavir; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33726482
DOI: 10.3906/sag-2012-189