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Background/Aims: Recent data indicate the presence of liver enzyme abnormalities in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the clinical features and treatment outcomes of COVID-19 patients with abnormal liver enzymes. Methods: We performed a retrospective, multicenter study of 874 COVID-19 patients admitted to five tertiary hospitals from February 20 to April 14, 2020. Data on clinical features, laboratory parameters, medications, and treatment outcomes were collected until April 30, 2020, and compared between patients with normal and abnormal aminotransferases. Results: Abnormal aminotransferase levels were observed in 362 patients (41.1%), of which 94 out of 130 (72.3%) and 268 out of 744 (36.0%) belonged to the severe and non-severe COVID- 19 categories, respectively. The odds ratios (95% confidence interval) for male patients, patients with a higher body mass index, patients with severe COVID-19 status, and patients with lower platelet counts were 1.500 (1.029 to 2.184, p=0.035), 1.097 (1.012 to 1.189, p=0.024), 2.377 (1.458 to 3.875, p=0.001), and 0.995 (0.993 to 0.998, p>0.001), respectively, indicating an independent association of these variables with elevated aminotransferase levels. Lopinavir/ ritonavir and antibiotic use increased the odds ratio of abnormal aminotransferase levels after admission (1.832 and 2.646, respectively, both p

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemic of Corona Virus Disease 2019 (COVID-19). Few patients infected with SARS-CoV-2 develop acute respiratory distress syndrome, leading to a high rate of admission to intensive care units and ultimately death in severe cases [Chen et al., 2020; Huang et al., 2020]. No antiviral treatment has been proven to be effective in SARS-CoV-2 infection. Optimized supportive care remains the mainstay of therapy for it. The Lopinavir/ ritonavir combination is one of the repurposed drugs currently used in the treatment of COVID-19. They are protease inhibitors used for treating the HIV infection. The protease is considered key enzyme in coronavirus polyprotein processing [Sanders et al. 2020]. In-vitro study by Kang et al observed significant antiviral activity of combination of lopinavir/ritonavir against SARS-CoV-2 [Kang et al., 2020]. However, the current use of lopinavir/ritonavir is mainly based on the experience of use of lopinavir/ritonavir in SARS and MERS. The aim of this systematic review is to find out the efficacy and safety outcomes in COVID-19 patients treated with lopinavir/ ritonavir combination. Study identification Two investigators will independently searched the following databases: PubMed, medrxiv.org, biorxib.org, mediterranee-infection.com/pre-prints-ihu, Google Scholar and CNKI. The search terms will be: (Lopinavir AND Ritonavir) AND (COVID-19 OR coronavirus OR SARS-CoV-2). There will be no language and time restriction to include the published articles. Selection criteria All randomized clinical studies evaluating the efficacy and/or safety of Lopinavir/ritonavir on COVID-19 patients will be included. The studies will be considered irrespective dose and duration of lopinavir/ritonavir and its comparator interventions (placebo, supportive care or any other treatment modalities). Risk of bias assessment of included studies Two investigators will assess the methodological quality of the included studies as per “risk of bias assessment tool for the randomized controlled clinical trials (ROB-II)” [Sterne et al., 2019]. Data extraction The following data will be extracted in a Microsoft Excel sheet, 2016: first author, publication year, study design, study site, baseline data of study population in treatment arms, efficacy and safety data. Efficacy and safety outcomes The efficacy outcome variables will be virological cure, radiological improvement and mortality between patients who received lopinavir/ritonavir and comparator interventions at the end of the study period. The safety outcomes will be adverse events between lopinavir/ritonavir and comparator interventions at the end of the study period. The subgroup analyses of efficacy and safety outcomes will be performed based on the type of control interventions. Data synthesis All outcomes will be summarized as risk ratio (RR) with 95% CI and will be pooled using the Mantle-Hanzle method using the fixed effect or random model. The heterogeneity will be assessed using I2 test. The publication bias will be assessed visually through a ‘funnel plot’. The meta-analysis will be performed through ‘Review manager software version 5.3’. References: 1.Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395(10223):507-13. 2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497-506. [Erratum in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID: PMC7159299]. 3.Kang CK, Seong MW, Choi SJ, Kim TS, ChoePG, Song SH, et al. In vitro activity of lopinavir/ritonavir and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 at concentrations achievable by usual doses. Korean J Intern Med 2020. doi: 10.3904/kjim.2020.157. 4.Sanders JM, MonogueML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020. doi: 10.1001/jama.2020.6019. Sterne JAC, Savović J, Page MJ, ElbersRG, BlencoweNS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.

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.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

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.

Background: Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals. WHO has named the novel coronavirus disease as COVID-19. Objective: We have conducted this review to focus on the studies that assessed the treatment efficacy and safety of Coronavirus (COVID-19) to describe its relation with the clinical outcomes of patients. Method: PubMed, was searched for studies on the clinical evaluation of selected currently used treatments for COVID-19. we included six studies about therapeutic activity of chloroquine/hydroxychloroquine, two case series about oseltamivir and three studies about lopinavir/ritonavir Results: some of studies have been demonstrated and approved for a wider use hydroxychloroquine for COVID-19, others concluded that there was insufficient evidence to offer any recommendation on the routine use of these drug in patients admitted to the intensive care unit (ICU). Other treatments have insufficient evidence to recommend the use (lopinavir-Ritonavir or oseltamivir) for COVID-19 outside of research studies. Conclusion: In order to determine their efficacy and safety for COVID-19, more adequately powered randomized clinical trials are required. Ideally, these studies should be double-blinded and conducted in a range of settings. Keywords: Covid-19, hydroxychloroquine, Azithromycin, Oseltamivir, lopinavir-Ritonavir

INTRODUCTION: Antiretroviral and anti-tuberculosis (TB) drugs are often co-administered in people living with HIV (PLWH). Early initiation of antiretroviral therapy (ART) during TB treatment improves survival in patients with advanced HIV disease. However, safety concerns related to clinically significant changes in drug exposure resulting from drug-drug interactions; development of overlapping toxicities and specific challenges related to co-administration during pregnancy represent barriers to successful combined treatment for HIV and TB. AREAS COVERED: Pharmacokinetic interactions of different classes of ART when combined with anti-TB drugs used for sensitive-, drug-resistant (DR) and latent TB are discussed. Overlapping drug toxicities, implications of immune reconstitution inflammatory syndrome (IRIS), safety in pregnancy and research gaps are also explored. EXPERT OPINION: New antiretroviral and anti-tuberculosis drugs have been recently introduced and international guidelines updated. A number of effective molecules and clinical data are now available to build treatment regimens for PLWH with latent or active TB. Adopting a systematic approach that also takes into account the need for individualized variations based on the available evidence is the key to successfully integrate ART and TB treatment and improve treatment outcomes.

Background Liver injury has been documented independently in novel coronavirus disease 2019 (COVID-19) patients and patients treated with lopinavir-ritonavir. Objective to investigate the drug-induced liver injury associated with lopinavir-ritonavir among the patients with COVID-19. Methods We conducted a disproportionality analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) between 2020Q1 and 2021Q1 to evaluate the association between lopinavir-ritonavir and risk of drug-induced liver injury (or severe drug-induced liver injury) and calculated their reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results A total of 3,425 cases of drug-induced liver injury were reported in 19,782 patients with COVID-19. The ROR for drug-induced liver injury was 2.99 (2.59–3.46), 3.16 (2.68–3.73), and 5.39 (4.63–6.26) when comparing lopinavir-ritonavir with all other drugs, hydroxychloroquine/chloroquine only, and remdesivir, respectively. For severe drug-induced liver injury, RORs for lopinavir-ritonavir provided evidence of an association compared with all other drugs (3.98; 3.15–5.05), compared with hydroxychloroquine/chloroquine only (5.33; 4.09–6.94), and compared with remdesivir (3.85; 3.03–4.89). Conclusions In the FAERS, we observed a disproportional signal for drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19.

Background: In the absence of SARS-CoV-2 specific antiviral treatments, various repurposed pharmaceutical approaches are under investigation for the treatment of COVID-19. Antiviral drugs considered for this condition include atazanavir, remdesivir, lopinavir-ritonavir, and favipiravir. Whilst the combination of lopinavir and ritonavir has been previously linked to prolongation of the QTc interval on the ECG and risk of torsades de pointes arrhythmia, less is known in this regard about atazanavir, remdesivir, and favipiravir. Unwanted abnormalities of drug-induced QTc prolongation by diverse drugs are commonly mediated by a single cardiac anti-target, the hERG potassium channel. This computational modeling study was undertaken in order to explore the ability of these five drugs to interact with known determinants of drug binding to the hERG channel pore.Methods: Atazanavir, remdesivir, ritonavir, lopinavir and favipiravir were docked to in silico models of the pore domain of hERG, derived from cryo-EM structures of hERG and the closely related EAG channel.Results: Atazanavir was readily accommodated in the open hERG channel pore in proximity to the S6 Y652 and F656 residues, consistent with published experimental data implicating these aromatic residues in atazanavir binding to the channel. Lopinavir, ritonavir, and remdesivir were also accommodated in the open channel, making contacts in a model-dependent fashion with S6 aromatic residues and with residues at the base of the selectivity filter/pore helix. The ability of remdesivir (at 30 μM) to inhibit the channel was confirmed using patch-clamp recording. None of these four drugs could be accommodated in the closed channel structure. Favipiravir, a much smaller molecule, was able to fit within the closed channel and could adopt multiple binding poses in the open channel, but with few simultaneous interactions with key binding residues. Only favipiravir and remdesivir showed the potential to interact with lateral pockets below the selectivity filter of the channel.Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets. Favipiravir's small size and relatively paucity of simultaneous interactions may confer reduced hERG liability compared to the other drugs. Experimental structure-function studies are now warranted to validate these observations.

Covid-19 infection caused by the novel coronavirus SARS-COV-2 continues to be a major global health challenge. Till date, no drug has been approved for the treatment of this infection. A number of medications have been proposed and there are ongoing clinical trials around the world to find a suitable treatment. A recent randomised control trial compared lopinavir/ritonavir with standard care among 199 patients with severe Covid-19 infection and concluded that there was no significant reduction in mortality rate with lopinavir/ritonavir. However, there are a few important lessons which may be learnt from the study apart from the statistical reduction in mortality rate. There was a numerical reduction in mortality rate, less intensive care unit stay and less complications in the lopinavir-ritonavir group. This article points out some of those important lessons with some suggestions for future clinical trials.

Clinical outcomes of COVID‐19 vary considerably between patients. Little was known about the clinical course and optimal management of immunosuppressed patients infected with SARS‐CoV‐2. We report a kidney transplant recipient with COVID‐19 who presented with pneumonitis and acute kidney injury (AKI). She improved after reduction of immunosuppressive treatment and had two consecutive negative reverse transcription polymerase chain reaction (RT‐PCR) tests. Her respiratory tract samples turned positive again afterwards, and she was treated with lopinavir‐ritonavir. She had satisfactory virological and clinical response after a prolonged disease course. This case illustrates the risk of relapse or persisting shedding of SARS‐CoV‐2 in immunosuppressed patients, the important role of viral load monitoring in management, the challenges in balancing the risks of COVID‐19 progression and transplant rejection, and the pharmacokinetic interaction between immunosuppressive and antiviral medications., SUMMARY AT A GLANCE A kidney transplant recipient with COVID‐19, who had a prolonged, apparently relapsing course of SARS‐CoV‐2 infection is described. This case illustrates the need for vigilance during recovery from COVID‐19 in transplant recipients, and some of the challenges with managing immunosuppression and using novel unapproved anti‐viral therapies.

Background On June 30, 2020, the WHO reported over 10 millions of COVID-19 cases worldwide with over half a million deaths. In severe cases the disease progresses into an Acute Respiratory Distress Syndrome (ARDS), which in turn depends on an overproduction of cytokines (IL-6, TNFα, IL-12, IL-8, CCL-2 and IL1) that causes alveolar and vascular lung damage. Clearly, it is essential to find an immunological treatment that controls the “cytokine storm”. In the meantime, however, it is essential to have effective antiviral and anti-inflammatory drugs available immediately. Pharmacologic therapy for COVID-19 Hydroxychloroquine or chloroquine have been widely adopted worldwide for the treatment of SARS-CoV-2 pneumonia. However, the choice of this treatment was based on low quality of evidence, i.e. retrospective, non-randomized controlled studies. Recently, four large Randomized Controlled Trials (RCTs) have been performed in record time delivering reliable data: (1) the National Institutes of Health (NIH) RCT included 60 hospitals participating all over the world and showed the efficacy of remdesivir in reducing the recovery time in hospitalized adults with COVID-19 pneumonia; (2) three large RCTs already completed, for hydroxychloroquine, dexamethasone and Lopinavir and Ritonavir respectively. These trials were done under the umbrella of the 'Recovery' project, headed by the University of Oxford. The project includes 176 participating hospitals in the UK and was set up to verify the efficacy of some of the treatments used for COVID-19. These three ‘Recovery’ RCTs concluded definitely: (a) that treatment with hydroxychloroquine provides no benefits in patients hospitalized with COVID-19; (b) that treatment with dexamethasone reduced deaths by one-third in COVID-19 patients that were mechanically ventilated, and by one-fifth in patients receiving oxygen only; (c) that the combination of Lopinavir and Ritonavir is not effective in reducing mortality in COVID-19 hospitalized patients. Conclusions The results of these four large RCTs have provided sound indications to doctors for the treatment of patients with COVID-19 and prompted the correction of many institutional provisions and guidelines on COVID-19 treatments (i.e. FDA, NIH, UK Health Service, etc.). Even though a definitive treatment for COVID-19 has not yet been found, large RCTs stand as the Gold Standards for COVID-19 therapy and offer a solid scientific base on which to base treatment decisions.

Purpose: A number of research articles has been published evaluating safety and efficacy of drugs against COVID-19. This study was undertaken to collate and review the information regarding common proposed anti- viral drugs for easy reference. Methods: The literature was search was done using terms like severe acute respiratory syndrome or SARS-CoV-2 or 2019-nCoV or SARS-CoV or COVID-19 in combination with drugs or treatment or pharmaco-therapy using PubMed and google scholar to identify relevant articles. Results: Despite showing good early results, hydroxychloroquine and lopinavir-ritonavir has not shown clinical benefit in randomized controlled trials. However lopinavir in combination with other drugs specially interferon is being investigated. Remdesivir has shown positive effect in terms of clinical improvement and continued to being investigated alone or in combination with other drugs. Favipiravir has shown mixed results and more data from adequately powered study is needed to prove its efficacy. Conclusions: Many drugs which showed positive effect in initial studies could not replicate the same benefit in large randomized controlled trials. There is need to evaluate efficacy and safety of drugs based on high quality evidence before allowing it to be used in general population.

Background: Coronavirus disease 2019 (COVID-19) has affected over 145 million infected people and 3 million deaths worldwide. There has been limited data to recommend either for or against use of antiviral regimens in mild COVID-19 patients. This study aimed to compare clinical outcomes between mild COVID-19 patients receiving antiviral drugs and those without. Method: Thai patients diagnosed with COVID-19 at field hospital affiliated to Thammasat University Hospital, Thailand were evaluated between January 1, 2020 and April 13, 2021. Patients’ data, clinical presentation, past medical history, laboratory results, and treatment outcomes were extensively reviewed. Results: Five hundred patients with positive tests were included in the study. The mean age was 35.9 years; 46% males. There were 225 (45%), 207 (41.4%), 44 (8.8%), 18 (3.6%), 6 (1.2%) patients with asymptomatic, mild, moderate, severe, and critical COVID-19, respectively. Of 207 mild COVID-19 patients, 9 (4.3%) received lopinavir/ritonavir or darunavir/ritonavir, 17 (8.2%) received favipiravir, while 175 (84.5%) had only supportive care. Mild COVID-19 patients receiving antiviral treatment had longer median length of hospital stay [13 days (IQR 11–14) vs. 10 days (IQR 8–12), p < 0.001] than patients having only supportive treatment. Antiviral drug use was significantly associated with longer hospital stay (>10 days) in mild COVID-19 patients (OR 5.52; 95%CI 2.12–14.40, p < 0.001). Adverse drug reactions such as diarrhea, abdominal pain, and hepatitis were also demonstrated in our COVID-19 patients with antiviral treatments. Majority of patients (97.6%) recovered without any complications and were discharged home. Two deaths were caused by acute respiratory distress syndrome from severe COVID-19 pneumonia. Conclusion: Antiviral treatment could not provide superior clinical outcomes to supportive care in mild COVID-19 patients. Mild COVID-19 patients receiving antiviral medication had longer length of hospital stay than those without. Standard supportive care and regular monitoring of disease progression might be keys for successful management of mild COVID-19.

Drug design is a long and costly process taking many stages; start with target identification passing through target validation, lead identification, and candidate optimization of pre-clinical and clinical trials. Drug design types depend on screening of a large number of molecules to distinguish and can select the most effective drug with high pharmaceutical effect. Ligand and Structure Based Drug Design are the two types of drug design. The drug takes journey when administered into the body through several ways (oral, inhalation, Intravenous (IV), Intramuscular (IM)) to deliver its target site. Twenty years ago, Computational strategies applied to understand particular target molecules with hits achieving lead target and that helps in lead Identification and Optimization stages of drug design and development. Screening, molecular modification and rational drug design are the three approaches to search for a modern drug. Bioinformatics plays a vital role in the discovery of drug as Bioinformatics includes both the programmed preparing of huge amounts of existing information and the creation of modern sorts of data resource. Both required in case the information is to be changed into data and utilized to assist in drug discovery. This work will discuss what is the meaning of drug design? What are the stages of drug design? What are the drug design types? Computer- Aided Drug Design (CAAD), Approaches in the search for a new drug, What is the journey of drug to deliver its target site? What are the methods of drug delivery? And will discuss the recommended antiviral therapy in the management of COVID-19.

The COVID-19 pandemic is an unprecedented situation with physicians awaiting information on therapeutic advances to an extent hardly ever seen in medical history. In the context of this medical crisis, we here exemplify the rapidity by which dissemination of scientific data impacts real-life medical

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7., Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P

Background COVID-19 infection is the most serious global public health crisis of the century. With no approved treatments against it, investigational treatments are being used despite limited safety data. Besides being at higher risk of complications of COVID-19 infection, patients with underlying cardiovascular disease are more likely to develop cardiac-related side effects of treatment. We present a case of sinus arrest with junctional escape related to lopinavir–ritonavir. Case summary A 67-year-old man, with underlying stable ischaemic heart disease, acquired COVID-19 infection. He had a prolonged duration of fever and cough. He subsequently developed acute respiratory distress and required intensive care unit (ICU) care. Given his severe infection, he was started on lopinavir–ritonavir. Hydroxychloroquine was not used as he had a prolonged QTc interval. During observation in the ICU, the patient developed recurrent episodes of sinus arrest with junctional escape. Initial concerns were of myocarditis, but he had no ST-segment changes on ECG, with mild elevations of highly sensitive troponin I and a normal transthoracic echocardiogram. A multidisciplinary team discussion involving the intensivist, infectious disease physicians, and cardiologist; the decision was made to stop treatment with lopinavir–ritonavir. Within 48 h, the bradyarrhythmia resolved. The patient did not require transvenous and permanent pacemaker insertion. Conclusion Current efficacy and safety evidence of lopinavir–ritonavir as a treatment in COVID-19 patients is limited. Although uncommonly reported, those with underlying cardiovascular disease are at increased risk of bradyarrhythmia-related adverse effects of lopinavir–ritonavir. When initiating investigational therapies, especially in patients with cardiovascular conditions, adequate counselling and close monitoring are required.

Background Treatments for coronavirus disease 2019 (COVID-19) are limited by suboptimal efficacy. Methods From January 30, 2020 to March 23, 2020, we conducted a non-randomised controlled trial, in which all adult patients with laboratory-confirmed COVID-19 were assigned to three groups non-randomly and given supportive treatments: Group A, Lopinavir-Ritonavir; Group B,Huashi Baidu Formula(a Chinese medicineformula made by the China Academy of Chinese Medical Sciences to treatCOVID-19, which is now in the clinical trial period) and Lopinavir-Ritonavir; and Group C, Huashi Baidu Formula. The use of antibiotics, antiviruses, and corticosteroids was permitted in Group A and B. Traditional Chinese medicine injections were permitted in Group C. The primary outcomes were clinical remission time (interval from admission to the first time the patient tested negatively for novel coronavirus or an obvious improvement was observed from chest CT) and clinical remission rate (number of patients whose clinical time was within 16 days/total number of patients) Results A total of 60 adult patients with COVID-19 were enrolled at sites in Wuhan, China, and the sample size of each group was 20. In Groups A, B and C, the clinical remission rates were95.0%(19/20), 100.0%(20/20) and 100.0%(20/20), respectively. Compared with Groups A and B, the clinical remission time of Group C was significantly shorter (5.9 days vs. 10.8 days, P < 0.050; 5.9 days vs. 9.7 days, P < 0.050). There was no significant difference among Groups A, B, and C in terms of the time taken to be released from quarantine. The clinical biochemical indicators and safety indexes showed no significant differences among the three groups. Conclusions Our findings suggest that Lopinavir-Ritonavir has some efficacy in the treatment of COVID-19, and the Huashi Baidu Formula might enhance this effect to an extent. In addition, superiority was displayed in the treatment of COVID-19 through a combination of the Huashi Baidu Formula and traditional Chinese medicine injection. In future, well-designed prospective double-blinded randomised control trials are required to confirm our findings.

The coronavirus disease (COVID-19) pandemic has led to a global struggle to cope with the sheer numbers of infected persons, many of whom require intensive care support or eventually succumb to the illness. The outbreak is managed by a combination of disease containment via public health measures and supportive care for those who are affected. To date, there is no specific anti-COVID-19 treatment. However, the urgency to identify treatments that could turn the tide has led to the emergence of several investigational drugs as potential candidates to improve outcome, especially in the severe to critically ill. While many of these adjunctive drugs are being investigated in clinical trials, professional bodies have attempted to clarify the setting where the use of these drugs may be considered as off-label or compassionate use. This review summarizes the clinical evidence of investigational adjunctive treatments used in COVID-19 patients as well as the recommendations of their use from guidelines issued by international and national organizations in healthcare.

Background: We would like to raise awareness about the toxicities related to the added excipients present in the oral solution of Liponavir/ritonavir in particular alcohol and propylene glycol. Case presentation: In this case report, we describe an 18 month-old child with a newly diagnosed HIV infection on antiretroviral therapy (ART). She developed shortly after starting the ART unsteady gait and imbalance. Conclusions: The excipient-excipient interaction in Lopinavir/ritonavir may contribute to major toxicities not only in premature neonates and infants; but also in older children specifically from Asian ethnicity. Keywords: HIV, Lopinavir-ritonavir, Unsteady gait

The severe acute respiratory syndrome coronavirus 2 pandemic has resulted in the development of various therapeutics to treat and prevent major complications related to the virus; pregnant patients are vulnerable to acquiring severe acute respiratory syndrome coronavirus 2 because of frequent contact with the healthcare setting. Despite the publication of a plethora of case series and randomized control trials of severe acute respiratory syndrome coronavirus 2 therapeutics, few have addressed treatment in the pregnant population. To date, there has been no published review of therapeutic options in the treatment of pregnant patients with severe acute respiratory syndrome coronavirus 2 infection. Here, we provide a review of available treatments for severe acute respiratory syndrome coronavirus 2, various trials with inclusion and exclusion of the pregnant patients, and potential side effects of each treatment in the pregnant patient.

COVID-19 has grown into a global pandemic that has strained healthcare throughout the world. There is a sense of urgency in finding a cure for this deadly virus. In this study, we reviewed the empiric options used in common practice for COVID-19, based on the literature available online, with an emphasis on human experiences with these treatments on severe acute respiratory syndrome-associated coronavirus (SARS-COV-1) and other viruses. Convalescent blood products are the most promising potential treatment for use in COVID-19. The use of chloroquine or hydroxychloroquine (HCQ), remdesivir, and tocilizumab are some of the other promising potential therapies; however, they are yet to be tested in randomized clinical trials (RCTs). The use of lopinavir-ritonavir did not prove beneficial in a large RCT. The use of corticosteroids should be avoided in COVID-19 pneumonia unless used for other indications, based on the suggestion of harm in patients with SARS-COV-1 and Middle Eastern Respiratory Syndrome (MERS) infection. The reviews of this paper are available via the supplemental material section.

Background: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens. Methods: Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with

The efficacy and safety of a combination regimen including either efavirenz or lopinavir–ritonavir was examined in a cohort of 65 patients positive for human immunodeficiency virus-1 (HIV-1). Both the efavirenz (n = 33, 18 anti-retroviral naive) and lopinavir–ritonavir (n = 32, 15 naive) regimens achieved significant changes from baseline CD4 cell counts and HIV RNA levels after 108 weeks (p < 0.01). Despite diminished immunological and virological parameters at study entry, the lopinavir– ritonavir group showed greater virological effects than the efavirenz group after 108 weeks (median change 3.3 log10, interquartile range (IQR) 2.2–3.8 log10 vs. 2.4 log10, IQR 0.9–3.3 log10, respectively, p 0.004). Use of lopinavir–ritonavir, in contrast to use of efavirenz, was associated with significant hypertriglyceridaemia.

We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3–6.48) and the median CD4 cell count was 219 cells/mm3 (range 1–836). During a median follow-up of 272 days (range 92–635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had ≥6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured ≥6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.