Background: Lopinavir/Ritonavir is an oral combination agent being used to treat Human Immunodeficiency Virus. It was demonstrated to have clinical and in vitro activity against coronaviruses. There are no specific anti viral preparation or biologic agents currently recommended to treat Severe Acute Respiratory Syndrome Corona Virus 2(SARS-CoV-2) infection. There are no in-vitro studies published as well, for Lopinavir/ritonavir against SARS- CoV-2. However, recent case series and cohort studies showed earlier clinical improvement and shorter duration of viral shedding were noted especially if the combination drug is administered early in the course of the disease. Objective: The objective of this review is to search, retrieve, appraise and summarize existing studies and clinical trials regarding the efficacy and safety of Lopinavir/Ritonavir combination in the treatment of SARS Cov-2 infection. The evidenced based recommendations may be used as a guide by clinicians and practitioners in their current practice. Methods: Electronic databases were searched for evidences (Medline, CENTRAL, ISRCTN registry, ClinicalTrial. gov and Chinese Clinical Trial Registry) and articles were selected based on a pre-defined criteria according to population, intervention, outcome and study designs. Results: Two randomized controlled trials were included in this review. Lopinavir/ritonavir treatment did not significantly accelerate clinical improvement, reduce mortality, or shoten the viral RNA detectability in patients with serious COVID-19. Conclusion There is little evidence to conclude on the effectiveness of lopinavir/ritonavir in patients with COVID-19. More high-quality randomized controlled trials are needed.
Lopinavir ; Ritonavir ; COVID-19

A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of lopinavir and ritonavir in human plasma. Analytes were separated from plasma by a combination of alkalinized protein precipitation and liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a Agilent ZORBAX Eclipse XDB-C18 column with the mobile phase consisted of methanol-0.1% formic acid in water (80:20). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 629.6 --> 155.2, m/z 721.4 --> 268.2, and m/z 515.2 --> 276.2 for lopinavir, ritonavir and telmisartan (internal standard), respectively. The method showed a good linearity in a concentration range of 62.5 - 10000 ng mL(-1) for lopinavir, and 12.5 - 2000 ng mL(-1) for ritonavir. The lower limits of quantification were 15 pg mL(-1) and 8 pg mL(-1) for lopinavir and ritonavir, respectively. The intra- and inter-day precision was less than 15% and the absolute recovery was above 75%. This method was selective and rapid, sensitive for investigating blood drug concentrations in clinics.
Chromatography, Liquid ; methods ; HIV Infections ; blood ; Humans ; Lopinavir ; blood ; Ritonavir ; blood ; Sensitivity and Specificity ; Tandem Mass Spectrometry ; methods

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occasioned worldwide alarm. Globally, the number of reported confirmed cases has exceeded 84.3 million as of this writing (January 2, 2021). Since there are no targeted therapies for COVID-19, the current focus is the repurposing of drugs approved for other uses. In some clinical trials, antiviral drugs such as remdesivir (Grein et al., 2020), lopinavir/ritonavir (LPV/r) (Cao et al., 2020), chloroquine (Gao et al., 2020), hydroxychloroquine (Gautret et al., 2020), arbidol (Wang et al., 2020), and favipiravir (Cai et al., 2020b) have shown efficacy in COVID-19 patients. LPV/r combined with arbidol, which is the basic regimen in some regional hospitals in China including Zhejiiang Province, has shown antiviral effects in COVID-19 patients (Guo et al., 2020; Xu et al., 2020). A retrospective cohort study also reported that this combination therapy showed better efficacy than LPV/r alone for the treatment of COVID-19 patients (Deng et al., 2020).
Animals ; COVID-19/drug therapy* ; Drug Interactions ; Drug Therapy, Combination ; Female ; Indoles/pharmacokinetics* ; Lopinavir/pharmacokinetics* ; Male ; Rats ; Retrospective Studies ; Ritonavir/pharmacokinetics* ; SARS-CoV-2

BACKGROUND: The combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has been the first choice nucleoside reverse transcriptase inhibitor (NRTI) according to many reliable antiretroviral treatment (ART) guidelines because of its high efficacy. However, TDF-related renal toxicity reported in Western countries is a challenging issue regarding clinical use. We conducted this study to evaluate the incidence and characteristics of an acute increase in serum creatinine (Cr) level > 1.5 mg/dL among TDF/FTC-based highly active antiretroviral treatment (HAART)-treated patients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 205 HIV-infected patients treated with TDF/FTC-containing regimens between 1 February 2010 and 30 April 2014. Three groups of TDF/FTC + ritonavir-boosted protease inhibitor (PI/r), TDF/FTC + non-nucleoside reverse transcriptase inhibitor (NNRTI), and TDF/FTC + integrase strand transfer inhibitor (INSTI), and three PI/r subgroups of TDF/FTC + lopinavir (LPV)/r, TDF/FTC + atazanavir (ATV)/r, TDF/FTC + darunavir (DRV)/r were evaluated. RESULTS: A total 136 patients (91 in the TDF/FTC + PI/r group, 20 in the TDF/FTC + NNRTI group and 25 in the TDF/FTC + INSTI group) were included in the statistical analysis. Four cases (4.9%; all in the TDF/FTC + PI/r group) among 136 patients showed an acute increase in serum Cr more than 1.5 mg/dL, so the overall incidence was 2.8 cases per 100 patient-years. One case was a patient treated with TDF/FTC + LPV/r, and the others were treated with TDF/FTC + ATV/r. No case of an acute increase in serum Cr was observed in the TDF/FTC + DRV/r group. The incidence of serum Cr increase more than 1.5 mg/dL in TDF/FTC + PI/r group was 4.0 cases per 100 patient-years. CONCLUSION: Although only a small number of patients were evaluated retrospectively from a single center, the TDF/FTC + PI/r regimen may have been related with relatively higher tendency of increment of serum Cr level. These findings reinforce the importance of close follow-ups of HIV-infected patients treated with the TDF/FTC + PI/r regimens.
Anti-Retroviral Agents ; Antiretroviral Therapy, Highly Active* ; Atazanavir Sulfate ; Creatinine* ; Darunavir ; Emtricitabine ; Follow-Up Studies ; HIV ; Humans ; Incidence* ; Integrases ; Lopinavir ; Medical Records ; Protease Inhibitors ; Retrospective Studies ; RNA-Directed DNA Polymerase ; Tenofovir

Adult ; Aged ; Antiviral Agents ; administration & dosage ; Betacoronavirus ; Coronavirus Infections ; drug therapy ; Drug Therapy, Combination ; Humans ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Middle Aged ; Pandemics ; Pneumonia, Viral ; drug therapy ; Randomized Controlled Trials as Topic ; Ribavirin ; administration & dosage ; Ritonavir ; administration & dosage

OBJECTIVE: To establish a clinically applicable model of rapid identification of adverse drug reaction program (RiADP) for risk management and decision-making of clinical drug use. METHODS: Based on the theory of disproportion analysis, frequency method and Bayes method, a clinically applicable RiADP model in R language background was established, and the parameters of the model were interpreted by MedDRA coding. Based on the actual monitoring data of FDA, the model was validated by the assessing hepatotoxicity of lopinavir/ritonavir (LPV/r). RESULTS: The established RiADP model included four parameters: standard value of adverse drug reaction signal information, empirical Bayesian geometric mean value, ratio of reporting ratio and number of adverse drug reaction cases. Through the application of R language parameter package "phViD", the model parameters could be output quickly. After being encoded by MedDRA, it was converted into clinical terms to form a clinical interpretation report of adverse drug reactions. In addition, the evaluation results of LPV/r hepatotoxicity by the model were matched with the results reported in latest literature, which also proved the reliability of the model results. CONCLUSIONS In this study, a rapid identification method of adverse reactions based on post marketing drug monitoring data was established in R language environment, which is capable of sending rapid warning of adverse reactions of target drugs in public health emergencies, and providing intuitive evidence for risk management and decision-making of clinical drugs.
Databases, Pharmaceutical ; Decision Making, Computer-Assisted ; Drug Monitoring ; Drug-Related Side Effects and Adverse Reactions ; HIV Protease Inhibitors ; adverse effects ; pharmacology ; Humans ; Liver ; drug effects ; Lopinavir ; adverse effects ; toxicity ; Models, Statistical ; Reproducibility of Results ; Software ; standards

The aim of this study was to evaluate the safety of an antiviral regimen of protease inhibitors combined with Arbidol (umifenovir) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients. The genomic sequence of SARS-CoV-2 is highly homologous to that of SARS-CoV (Zhou et al., 2020). Previously published basic and clinical research on anti-SARS-CoV treatment found that lopinavir/ritonavir (LPV/r) could improve the prognosis of SARS patients (Chan et al., 2003; Chu et al., 2004). Darunavir (DRV) is another protease inhibitor that blocks the binding of SARS-CoV-2 to human angiotensin-converting enzyme 2 (Omotuyi et al., 2020). The broad-spectrum antiviral drug Arbidol (umifenovir) also shows in vitro anti-SARS-CoV activity (Khamitov et al., 2008).
Adult ; COVID-19/drug therapy* ; China ; Darunavir ; Drug Combinations ; Female ; Humans ; Indoles/therapeutic use* ; Lipid Metabolism ; Lopinavir ; Male ; Middle Aged ; Protease Inhibitors/therapeutic use* ; Retrospective Studies ; Ritonavir ; SARS-CoV-2/genetics*

BACKGROUNDIn the era of highly active antiretroviral therapy (HAART), the use of antiretrovirals as post-exposure prophylaxis (PEP) was the most important strategy for preventing occupational exposure to blood or fluids containing human immunodeficiency virus (HIV). The objective of this study was to retrospectively evaluate the tolerability, safety, and side effects of a HAART regimen containing three antiretroviral drugs, consisting of zidovudine, lamivudine, and lopinavir/ritonavir, in healthcare personnel (HCP) who experienced occupational exposure to HIV.

METHODSThe tolerability, safety, and side effects in 26 HCPs who experienced PEP and in 27 HIV/AIDS patients with HAART regimen, AZT+3TC+Lpv/r, were evaluated between January 2010 and December 2012.

RESULTSThe most frequent clinical side effect was fatigue (in 23 cases, 88.5%), and gastroenterological symptoms were the second most common side effects in HCP with PEP. Liver dysfunction was found in 10 cases (38.5%), while drug rash was found in 18 cases (69.2%) after PEP. The prevalence of side effects in HCPs who experienced PEP was higher than that in HIV/AIDS patients P < 0.05. One nurse (3.8%) experienced severe gastrointestinal symptoms, which led to withdrawal of PEP. No HIV infection was found during 6-month follow-up period.

CONCLUSIONHCPs who received occupational PEP with triple-drug regimen, AZT+3TC+Lpv/r, experienced different side effects, and the tolerability and safety of PEP regimen were good in this cohort.

Adult ; Anti-HIV Agents ; adverse effects ; therapeutic use ; Antiretroviral Therapy, Highly Active ; adverse effects ; Female ; HIV Infections ; drug therapy ; prevention & control ; Humans ; Lamivudine ; adverse effects ; therapeutic use ; Lopinavir ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Post-Exposure Prophylaxis ; Retrospective Studies ; Ritonavir ; adverse effects ; therapeutic use ; Zidovudine ; adverse effects ; therapeutic use

The severe acute respiratory syndrome (SARS) pandemic caught the world by surprise in 2003 and spread rapidly within a relatively short period of time. Hence, randomised placebo-controlled clinical trials on the treatment of SARS were not possible. Our understanding was obtained from observational, cohort studies, case series and reports. Nevertheless, such information is useful in providing clinical management guidelines and directing future research in case SARS recurs. Early in the pandemic, a combination of ribavirin and corticosteroids was adopted as the standard treatment in Hong Kong, Canada and elsewhere because of the apparent good results of the first few patients. Subsequent reports showed that ribavirin was associated with a high rate of toxicity and lacked in vitro antiviral effect on SARS-coronavirus (SAR-CoV). The timing and dosage regimens of steroid in the treatment of SARS are controversial. Pulse methylprednisolone 250 to 500 mg/day for 3 to 6 days has been reported to have some efficacy in a subset of patients with "critical SARS", i.e., critically ill SARS patients with deteriorating radiographic consolidation, increasing oxygen requirement with PaO2 <10 kPa or SpO2 <90% on air, and respiratory distress (rate of 30/min). Prolonged therapy with high-dose steroids, in the absence of an effective antimicrobial agent, could predispose patients to complications such as disseminated fungal infection, and avascular necrosis. Kaletra (400 mg ritonavir and 100 mg lopinavir), a protease inhibitor used in the treatment of human immunodeficiency virus infection, may be considered for early treatment of SARS patients, preferably in a randomised double-blind placebo-controlled clinical trial setting. Interferon (IFN) is not recommended as standard therapy in SARS. However, there are enough data on in vitro activity of IFN preparations and a few clinical studies for these products to support a controlled trial if SARS recurs. Many other experimental treatments have been tried in an uncontrolled manner, and they should not be recommended as standard therapy.
Adrenal Cortex Hormones ; pharmacology ; therapeutic use ; Antiviral Agents ; pharmacology ; therapeutic use ; Clinical Competence ; Disease Outbreaks ; prevention & control ; Global Health ; Humans ; Immunoglobulins ; pharmacology ; therapeutic use ; Immunologic Factors ; pharmacology ; therapeutic use ; Interferons ; pharmacology ; therapeutic use ; Lopinavir ; Practice Guidelines as Topic ; Protease Inhibitors ; pharmacology ; therapeutic use ; Pyrimidinones ; pharmacology ; therapeutic use ; Ribavirin ; pharmacology ; therapeutic use ; SARS Virus ; drug effects ; Severe Acute Respiratory Syndrome ; drug therapy ; epidemiology

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).
Administration, Inhalation ; Adult ; China ; Coronavirus Infections ; diagnosis ; drug therapy ; mortality ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Follow-Up Studies ; Humans ; Integrative Medicine ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnosis ; drug therapy ; mortality ; Risk Assessment ; Severe Acute Respiratory Syndrome ; diagnosis ; drug therapy ; mortality ; Severity of Illness Index ; Survival Rate