A Comparative Study of Antiretroviral (Lopinavir/Ritonavir) and Remdesivir Used in the Pandemic in Iraq on the Clinical Outcome in Patients with SARS-CoV-2.

The SARS-CoV-2 virus, which emerged in December 2019, has infected millions worldwide and caused many deaths. Due to its high mortality rate, several studies assessed the effectiveness of different drugs against COVID-19, mainly in reducing the hospitalization rate among the elderly and compromised patients. Lopinavir-ritonavir combination and remdesivir were among the medications used to treat COVID-19. Due to considerable differences in the effectiveness and clinical outcomes of the two treatments, this study aimed to compare the clinical outcomes between COVID-19 patients treated with antiretrovirals (lopinavir-ritonavir) and remdesivir. A total of 33 patients on lopinavir-ritonavir and 35 on remdesivir were selected for this study. A retrospective comparative analysis was conducted based on demographic characteristics, hospital stay, laboratory parameters of C-reactive protein (CRP) and plasma blood oxygen saturation (SPO2), clinical treatment, and a clinical outcome assessment extracted from hospital archive data. Both treatments improved patient outcomes, yet there was a significant difference between lopinavir-ritonavir and remdesivir groups in platelet count, CRP, SPO2, and monocyte results, with remdesivir showing better clinical outcomes. No significant difference was reported in white blood cells, lymphopenia, and lactate dehydrogenase between the two treatments. It is still necessary to conduct further research to determine how effective the two treatments are in treating severe COVID-19 cases due to the limited number of available studies and the inconsistency in research methods and measurements.

Risk Factors for the Prescription of Ineffective Antiviral Candidates for COVID-19 During the Early Pandemic Period in Korea.

BACKGROUND: Although the evidence of treatment for coronavirus disease 2019 (COVID-19) changed rapidly, little is known about the patterns of potential pharmacological treatment during the early period of the COVID-19 pandemic in Korea and the risk factors for ineffective prescription. METHODS: Using claims data from the Korean National Health Insurance System, this retrospective cohort study included admission episodes for COVID-19 from February to December 2020. Ineffective antiviral prescriptions for COVID-19 were defined as lopinavir/ritonavir (LPN/r) and hydroxychloroquine (HCQ) prescribed after July 2020, according to the revised National Institute of Health COVID-19 treatment guidelines. Factors associated with ineffective prescriptions, including patient and hospital factors, were identified by multivariate logistic regression analysis. RESULTS: Of the 15,723 COVID-19 admission episodes from February to June 2020, 4,183 (26.6%) included prescriptions of LPN/r, and 3,312 (21.1%) included prescriptions of HCQ. Of the 48,843 admission episodes from July to December 2020, after the guidelines were revised, 2,258 (4.6%) and 182 (0.4%) included prescriptions of ineffective LPN/r and HCQ, respectively. Patient factors independently associated with ineffective antiviral prescription were older age (adjusted odds ratio [aOR] per 10-year increase, 1.17; 95% confidence interval [CI], 1.14-1.20) and severe condition with an oxygen requirement (aOR, 2.49; 95% CI, 2.24-2.77). The prescription of ineffective antiviral drugs was highly prevalent in primary and nursing hospitals (aOR, 40.58; 95% CI, 31.97-51.50), public sector hospitals (aOR, 15.61; 95% CI, 12.76-19.09), and regions in which these drugs were highly prescribed before July 2020 (aOR, 10.65; 95% CI, 8.26-13.74). CONCLUSION: Ineffective antiviral agents were prescribed to a substantial number of patients during the first year of the COVID-19 pandemic in Korea. Treatment with these ineffective drugs tended to be prolonged in severely ill patients and in primary and public hospitals.

Therapeutic Potential of Targeting the Cytochrome P450 Enzymes Using Lopinavir/Ritonavir in Colorectal Cancer: A Study in Monolayers, Spheroids and In Vivo Models.

Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC.

Systemic Review and Meta-Analysis to Evaluate Therapeutic Effectiveness of Interferon Beta-1b in Hospitalized COVID-19 Patients.

The COVID-19 pandemic has caused havoc in the health sector. Inflammatory cytokines play an important role in the disease condition. Existing evidence has provided certain insights into the repurposing of the drugs. This meta-analysis and systematic review aimed to explore the efficacy of the administration of interferon beta-1b (IFN ß-1b) and standard care versus only standard care as the therapeutic agent for managing COVID-19 patients who are severely ill. The search was conducted in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Scopus, and Google Scholar, which were published during the period January 1, 2020, to February 16, 2023. All the included three studies were independently assessed for eligibility. The modified data extraction form of Cochrane were used. The quality of the three included studies was assessed using the Cochrane risk of bias tool. GradePro software was used to summarize the quality grading of the primary outcome measures. The time taken for clinical improvement was (MD: -3.28 days; 95% CI: -5.65, -0.91; P value = 0.007) when treated with IFN ß-1b. The duration of hospital stays (MD: -2.43 days; 95% CI: -4.45, -0.30; P value = 0.03), and need for intensive care unit (ICU) admission (RR: 0.71; 95% CI: 0.52, 0.97; P value = 0.03) was statistically significant. Interferon beta-1b is proven to reduce the duration of hospital stay, and the improved clinical status may become a cornerstone of COVID-19 treatment.

Clinical outcomes after the introduction of dolutegravir for second-line antiretroviral therapy in South Africa: a retrospective cohort study.

Background: Dolutegravir is now recommended for second-line anti-retroviral therapy (ART) in low- and middle-income countries. We compared outcomes with dolutegravir (DTG) versus the previous lopinavir/ritonavir (LPV/r) regimen in South Africa. Methods: We used routinely collected, de-identified data from 59 South African clinics. We included people living with HIV aged ≥ 15 years with virologic failure (two consecutive viral loads ≥1000 copies/mL) on first-line tenofovir disoproxil fumarate (TDF)-based ART and switched to second-line ART. We used modified Poisson regression models to compare outcomes of 12-month retention-in-care and viral suppression (<50 copies/ml) after switching to second-line regimens of zidovudine (AZT), emtricitabine/lamivudine (XTC), DTG and TDF/XTC/DTG and AZT/XTC/LPV/r. Findings: Of 1214 participants, 729 (60.0%) were female, median age was 36 years (interquartile range 30 to 42), 689 (56.8%) were switched to AZT/XTC/LPV/r, 217 (17.9%) to AZT/XTC/DTG and 308 (25.4%) to TDF/XTC/DTG. Retention-in-care was higher with AZT/XTC/DTG (85.7%, adjusted risk ratio (aRR) 1.14, 95% confidence interval (CI) 1.03 to 1.27; adjusted risk difference (aRD) 10.89%, 95%CI 2.01 to 19.78) but not different with TDF/XTC/DTG (76.9%, aRR 1.01, 95%CI 0.94 to 1.10; aRD 1.04%, 95%CI -5.03 to 7.12) compared to AZT/XTC/LPV/r (75.2%). Retention-in-care with TDF/XTC/DTG was not statistically significantly different from AZT/XTC/DTG (aRR 0.89, 95%CI 0.78 to 1.01; aRD -9.85%, 95%CI -20.33 to 0.63). Of 799 participants who were retained-in-care with a 12-month viral load, viral suppression was higher with AZT/XTC/DTG (59.3%, aRR 1.25, 95%CI 1.06 to 1.47; aRD 11.57%, 95%CI 2.37 to 20.76) and TDF/XTC/DTG (60.7%, aRR 1.30, 95%CI 1.14 to 1.48; aRD 14.16%, 95%CI 7.14 to 21.18) than with the AZT/XTC/LPV/r regimen (46.7%). Interpretation: DTG-based second-line regimens were associated with similar or better retention-in-care and better viral suppression than the LPV/r-based regimen. TDF/XTC/DTG had similar viral suppression compared to AZT/XTC/DTG. Funding: Bill & Melinda Gates Foundation, Africa Oxford Initiative.

Adverse pregnancy outcomes associated with antiretroviral therapy initiated before pregnancy and during pregnancy: a retrospective study in Hubei province, China.

Background: Antiretroviral therapy (ART) initiation before pregnancy was reported to have an increased risk of adverse pregnancy outcomes (APOs) than ART initiation during pregnancy. However, the risks of APOs associated with different ART regimens initiated before or during pregnancy remain unknown. Methods: Pregnant women living with HIV (PWLHIV) from Hubei Province, China, were retrospectively enrolled between January 1, 2004, and December 31, 2021. The trends of ART initiation time and application of different ART regimens were evaluated over time, separately. Using no ART exposure before and during pregnancy as control, the risks of APOs associated with protease inhibitor (PI) based regimens and non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens initiated before pregnancy were analyzed; and the risks of APOs associated with PI-based regimens, NNRTIs based regimens and zidovudine (AZT) monotherapy initiated during pregnancy were analyzed. APOs, including low birthweight (LBW), stillbirth, preterm birth (PTB) and early miscarriage, were reviewed. Results: Among 781 PWLHIV including 1,010 pregnancies, 522 pregnancies (51.7%) were exposed to ART before or during pregnancy. Of them, the proportion of ART initiation before pregnancy per year increased from around 20% in the early period to more than 60% after 2019. Efavirenz (EFV)-nucleoside reverse transcriptase inhibitors (NRTIs) (32.2%), LPV/r-NRTIs (31.2%), and nevirapine (NVP)-NRTIs (27.4%) were the most commonly used regimens, and the proportion of LPV/r-NRTIs used per year has increased to around 50.0% in recent years. LPV/r-NRTIs was associated with higher risks of LBW whether initiated before pregnancy [adjusted OR (aOR) = 2.59, 95%CI 1.04-6.45, p = 0.041] or during pregnancy (aOR = 2.19, 95%CI 1.03-4.67, p = 0.041), compared with no exposure to ART before and during pregnancy. However, no matter initiated before or during pregnancy, LPV/r-NRTIs had no significantly increased risks of stillbirth, PTB and early miscarriage, and EFV /NVP-NRTIs and AZT monotherapy had no significantly increased risks of LBW, stillbirth, PTB and early miscarriage when compared with no exposure to ART before and during pregnancy. Conclusion: Our data suggests that LPV/r-NRTIs has been widely used among PWLHIV in recent years. However, the potential risk of LBW should be continuously monitored among PWLHIV whether LPV/r-NRTIs is initiated before or during pregnancy.

A Practical Approach in Refining Binary Outcome for Treatment Effect of COVID-19 According to Geographical Diversity.

The recent COVID-19 pandemic has drawn attention to health and economics worldwide. Initially, diseases only ravage local populations, while a pandemic could aggravate global economic burdens. Lopinavir/Ritonavir is an anti-HIV drug that was used on small scale patients during SARS, but its effectiveness for COVID-19 treatment is still unclear. Previous studies or meta-analysis have retrieved clinical data of subgroup analysis to evaluate the efficacy and safety of Lopinavir/Ritonavir for the treatment of COVID-19 in a few affected regions. However, geographical diversity and small number of studies bias correction were not achieved in such subgroup analysis of published meta-analysis. The present study demonstrates a practical approach in refining the binary outcome for COVID-19 treatment of Lopinavir/Ritonavir according to geographical location diversity and small number of studies (less than or equal to five) for subgroup analysis. After performing practical approach, the risk of adverse event with LPV/RTV for treatment of COVID-19 becomes nonsignificant compared to previous meta-analysis. Furthermore, we also notice heterogeneity of random effect of meta-analysis may be declined after proposed adjustment. In conclusion, proposed practical approach is recommend for performing a subgroup analysis to avoid concentration in a single geographical location and small number of studies bias.

Drug-drug interactions of ritonavir-boosted SARS-CoV-2 protease inhibitors in solid organ transplant recipients: experience from the initial use of lopinavir-ritonavir.

OBJECTIVES: To review the drug-drug interactions between tacrolimus and lopinavir/ritonavir in 23 patients who received solid organ transplant during the first wave of COVID-19 and to determine the efficacy as well as safety of prednisone monotherapy. METHODS: Observational study performed between March and June 2020 in solid organ transplant recipients admitted with an established diagnosis of SARS-CoV-2 infection who received lopinavir/ritonavir (≥2 doses). Once lopinavir/ritonavir therapy was initiated, calcineurin inhibitor treatment was temporarily switched to prednisone monotherapy (15-20 mg/d) to avoid drug-drug interactions and toxicity. After lopinavir/ritonavir treatment completion, immunosuppressive treatment was restarted with reduced doses of prednisone-tacrolimus (target minimum blood concentration -C0- approximately 5 ng/mL). Patients were observed for 3 months to confirm the absence of rejection. RESULTS: The median time from discontinuation of tacrolimus to initiation of lopinavir/ritonavir was 14 hours (interquartile range [IQR], 12-15) and from discontinuation of lopinavir/ritonavir to resumption of tacrolimus 58 hours (IQR, 47-81). The duration of lopinavir/ritonavir treatment was 7 days (IQR, 5-7). Nine of the 21 (42.8%) patients on tacrolimus treatment had C0 above the cutoff point after lopinavir/ritonavir initiation, despite having been substituted with prednisone before lopinavir/ritonavir initiation. Three patients had very high concentrations (>40 ng/mL) and developed toxicity. No episodes of acute rejection were diagnosed. DISCUSSION: We did not observe toxicity in patients for whom tacrolimus was discontinued 24 hours before starting lopinavir/ritonavir and reintroduced at half dose 48 to 72 hours after lopinavir/ritonavir discontinuation. Prednisone monotherapy during lopinavir/ritonavir therapy was safe with no episodes of acute rejection. Experience with lopinavir/ritonavir may be applicable to the use of nirmatrelvir/ritonavir, but larger multicentre studies are needed to confirm these findings.

Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China.

Background: Antiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children. Methods: From January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2-4 adverse events and abnormal laboratory test results. Results: A total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5-10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3-4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5-6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p < 0.05). The risk factors of virologic failure in ART-naïve children were clinic setting in rural hospitals (aHR = 2.251, 1.108-4.575), annual missed dose times >5 days of LPV intake (aHR = 1.889, 1.004-3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299-5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238-0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2-4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children. Conclusion: Our research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality. Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5-9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49-0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed. Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials. Systematic Review Registration: [https://clinicaltrials.gov/ct2/show/NCT04351724, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT], identifier [NCT04351724, EUDRACT-NR: 2020-001302-30].

Favipiravir Experience in COVID-19 Patients at a Tertiary Center Intensive Care Unit.

Objectives: The aim of this study was to compare intensive care unit (ICU) and overall hospital mortality in patients treated with favipiravir and lopinavir-ritonavir for COVID-19. Methods: Data were collected retrospectively between March 10 and May 10, 2020, from patients' records admitted to ICU due to COVID-19. Laboratory data, clinical characteristics, ICU and hospital mortality, ICU and hospital length of stay were compared in patients treated with favipiravir and lopinavir-ritonavir. Results: A total of 100 patients' data were investigated. Favipiravir was used as the treatment for 85% of patients, with the rest treated with lopinavir-ritonavir. Clinical and laboratory data of both antiviral treatment groups were similar. Length of hospital stay was 16 (9-24) days with favipiravir and 8.5 (5-12.5) days with lopinavir-ritonavir (p=0.002). Length of ICU stay for favipiravir and lopinavir-ritonavir groups were 8 (5-15) days and 4 (3-9) days, respectively (p=0.011). ICU mortality was 65.9% for the favipiravir and 80% for lopinavir-ritonavir (p=0.002). Hospital mortality for favipiravir and lopinavir-ritonavir was 67.1% and 80%, respectively (p=0.001). Conclusion: The mortality in patients treated with favipiravir was less than patients treated with lopinavir-ritonavir. Favipiravir needs more attention and trials for its effect to be confirmed.

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

Evaluación del perfil de seguridad del medicamento lopinavir/ritonavir (Lpv/r) en los pacientes sospechosos o confirmados por COVID-19 / Evaluation of the safety profile of the drug lopinavir/ritonavir (Lpv/r) in suspected or confirmed COVID-19 patients

Introducción: El nuevo SARS-CoV-2, es el agente causal de la enfermedad COVID-19. La Organización Mundial de la Salud (OMS) ha referenciado el uso del lopinavir/ritonavir (Lpv/r), es un inhibidor de la proteasa del virus de inmunodeficiencia humana adquirida (VIH-1). El estudio clínico de Cao et al., identificó que el uso de Lpv/r no se asociaron con un mayor número de eventos adversos en comparación con el tratamiento estándar.Materiales y métodos: Estudio retrospectivo de farmacovigilancia en una cohorte en pacientes sospechosos o confirmados de COVID-19 en un hospital de tercer Nivel de la Ciudad de México en el periodo 01 abril 2020 al 30 julio 2020. Resultados: El tratamiento de Lpv/r incluyó 140 pacientes, de los cuales 91 pacientes completaron el tratamiento, mientras que 50 pacientes no terminaron el esquema. Los principales motivos de la suspensión del esquema del medicamento fueron: alta por mejoría (11 casos), defunciones (10 casos) y por inicio de ruxolitinib (9 casos). Además, se identificaron 8 reacciones adversas al medicamento, de las cuales 5 son reacciones asociadas a los trastornos gastrointestinales (diarreas) y las otras 3 reacciones asociadas a trastornos hepatobiliares (hipertransaminasemia).Conclusión: El perfil de seguridad del medicamento Lpv/r demostró una coherencia con las observaciones de estudios previos en relación en los eventos adversos presentados de tipo gastrointestinales y hepáticos, estos últimos se encuentran relacionados a interacción fármaco-fármaco, por lo que sugerimos un seguimiento farmacoterapéutico para identificar las interacciones y las reacciones adversas durante el uso Lpv/r. (AU)

Abstract: The new SARS-CoV-2 is the causal agent for COVID-19. The World Health Organization (WHO) referenced the use of lopinavir/ritonavir (Lpv/r), which is a protease inhibitor of human inmunodeficiency virus (HIV-1). The Clinical trial by Cao et al. identified that the use of Lpv/r has not been associated with any increase of adverse drug reactions within compared to the standard of care.Materials and methods: Pharmacovigilance retrospective study of patients suspected or confirmed with COVID-19 in a 3rd level hospital in Mexico City from April, 01 2020 to July, 30 2020.Results: Lopinavir/ritonavir treatment was prescribed 140 patients from which 91 patients completed the treatment, while 50 patients did not completed the treatment. The cause suspensions were: patient discharge for improvement (11 cases), deaths (10 cases) and start of ruxolitinib (9 cases). In addition, were identify 8 adverse drug reaction from which 5 were associated to gastrointestinal disorders (diarrhea) and 3 hepatobiliary disorders (hypertransaminasemia).Conclusion: The safety profile of the Lpv/r demonstrated consistency with the observations of previous studies in relation to gastrointestinal and hepatic adverse events, which were related to drug-drug interaction, so we suggest a pharmacotherapeutic monitoring to identify them as well as adverse drug reactions due to Lpv/r. (AU)

Influence of traditional Chinese medicines on the in vivo metabolism of lopinavir/ritonavir based on UHPLC-MS/MS analysis.

A fast, reliable, and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019, namely, Lianhua Qingwen granules, Huoxiang Zhengqi capsules, Jinhua Qinggan granules, Shufeng Jiedu capsules, and Angong Niuhuang pills, on the pharmacokinetics of lopinavir/ritonavir in rats. Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard (IS). Separation was performed on an Agilent ZORBAX eclipse plus C18 (2.1 mm × 50 mm, 1.8 µm) column using acetonitrile and water containing 0.1% formic acid as the mobile phase for gradient elution. The flow rate was 0.4 mL/min and the injection volume was 2 µL. Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir, m/z 721.3→296.1 for ritonavir, and m/z 705.4→168.1 for the IS. The method showed good linearity in the concentration range of 25-2500 ng/mL (r=0.9981) for lopinavir and 5-500 ng/mL (r=0.9984) for ritonavir. The intra-day and inter-day precision and accuracy were both within ±15%. Items, such as dilution reliability and residual effect, were also within the acceptable limits. The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats. The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5- to 2-fold relative to that in the control group. Similarly, the pharmacokinetic parameters of lopinavir were altered. Overall, the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.

Optimal Drug Regimen and Combined Drug Therapy and Its Efficacy in the Treatment of COVID-19: A Within-Host Modeling Study.

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon (INF) and Lopinavir/Ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and viral load. Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection.

Predictive factors of six-week mortality in critically ill patients with SARS-CoV-2: A multicenter prospective study.

OBJECTIVE: The objective of the study is to identify the risk factors associated with mortality at six weeks, especially by analyzing the role of antivirals and munomodulators. DESIGN: Prospective descriptive multicenter cohort study. SETTING: 26 Intensive care units (ICU) from Andalusian region in Spain. PATIENTS OR PARTICIPANTS: Consecutive critically ill patients with confirmed SARS-CoV-2 infection were included from March 8 to May 30. INTERVENTIONS: None. VARIABLES: Variables analyzed were demographic, severity scores and clinical condition. Support therapy, drug and mortality were analyzed. An univariate followed by multivariate Cox regression with propensity score analysis was applied. RESULTS: 495 patients were enrolled, but 73 of them were excluded for incomplete data. Thus, 422 patients were included in the final analysis. Median age was 63 years and 305 (72.3%) were men. ICU mortality: 144/422 34%; 14 days mortality: 81/422 (19.2%); 28 days mortality: 121/422 (28.7%); 6-week mortality 152/422 36.5%. By multivariable Cox proportional analysis, factors independently associated with 42-day mortality were age, APACHE II score, SOFA score at ICU admission >6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission <6.5%, and thrombocytopenia whereas the use of lopinavir/ritonavir was a protective factor. CONCLUSION: Age, APACHE II, SOFA>value of 6 points, along with vasopressor requirements or renal replacement therapy have been identified as predictor factors of mortality at six weeks. Administration of corticosteroids showed no benefits in mortality, as did treatment with tocilizumab. Lopinavir/ritonavir administration is identified as a protective factor.

Pharmacological treatment of COVID-19: an opinion paper / Tratamiento farmacológico del COVID-19: un documento de opinión

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation. (AU)

La precocidad y la eficacia de las vacunas desarrolladas hasta ahora frente al COVID-19, ha sido el avance más significativo y salvador frente a la pandemia. El desarrollo vacunal no ha impedido, durante todo el periodo de la pandemia, la búsqueda constante de remedios terapéuticos, tanto entre los medicamentos ya existentes y con indicaciones diversas, como en el desarrollo de nuevos fármacos. Sobre estos nuevos fármacos, sobre las novedades en la inmunoterapia y sobre lo aprendido de los moduladores de la respuesta inmune ya conocidos y que se han mostrado eficaces frente al virus, el Comité Científico del COVID-19 del Ilustre Colegio de Médicos de Madrid ha querido ofrecer una aproximación precoz, simplificada y critica que pueda ayudar a comprender la situación actual. (AU)

Predictive factors of six-week mortality in critically ill patients with SARS-CoV-2: A multicenter prospective study / Factores predictivos de la mortalidad a las seis semanas en pacientes críticos con SARS-CoV-2: estudio multicéntrico prospectivo

Objective: The objective of the study is to identify the risk factors associated with mortality at six weeks, especially by analyzing the role of antivirals and munomodulators. Design: Prospective descriptive multicenter cohort study. Setting: 26 Intensive care units (ICU) from Andalusian region in Spain. Patients or participants: Consecutive critically ill patients with confirmed SARS-CoV-2 infection were included from March 8 to May 30. Interventions: None. Variables: Variables analyzed were demographic, severity scores and clinical condition. Support therapy, drug and mortality were analyzed. An univariate followed by multivariate Cox regression with propensity score analysis was applied. Results: 495 patients were enrolled, but 73 of them were excluded for incomplete data. Thus, 422 patients were included in the final analysis. Median age was 63 years and 305 (72.3%) were men. ICU mortality: 144/422 34%; 14 days mortality: 81/422 (19.2%); 28 days mortality: 121/422 (28.7%); 6-week mortality 152/422 36.5%. By multivariable Cox proportional analysis, factors independently associated with 42-day mortality were age, APACHE II score, SOFA score at ICU admission >6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission <6.5%, and thrombocytopenia whereas the use of lopinavir/ritonavir was a protective factor. Conclusion: Age, APACHE II, SOFA>value of 6 points, along with vasopressor requirements or renal replacement therapy have been identified as predictor factors of mortality at six weeks. Administration of corticosteroids showed no benefits in mortality, as did treatment with tocilizumab. Lopinavir/ritonavir administration is identified as a protective factor (AU)

Objetivo: Identificar los factores de riesgo asociados con la mortalidad a las seis semanas. Diseño: Estudio prospectivo multicéntrico. Ámbito: Se incluyeron a 26 pacientes de la Unidad de Cuidados Intensivos (UCI) de Andalucía. Pacientes o participantes: Pacientes ingresados en UCI por neumonía grave por SARS-CoV-2 del 8 de marzo al 30 de mayo de 2020. Intervenciones: Ninguna. Variables de interés principales: Características demográficas, clínicas y escalas de gravedad. Se analizaron tratamientos de soporte, fármacos y la mortalidad. Resultados: Se incluyeron 495 pacientes, 73 fueron excluidos por incompletos y 422 pacientes se incorporaron en el análisis final. La mediana de edad fue de 63 años, 305 (72,3%) eran hombres. La mortalidad en la UCI fue: 144/422 34%; mortalidad a los 14 días: 81/422 (19,2%); mortalidad a los 28 días: 121/422 (28,7%); mortalidad a las seis semanas 152/422 36,5%. Los factores asociados con la mortalidad a los 42 días fueron la edad, APACHE II, SOFA > 6 y LDH al ingreso > 470 U/L, uso de vasopresores, necesidad de técnicas de reemplazo de la función renal, porcentaje de linfocitos a las 72 horas del ingreso en UCI < 6,5%, y trombocitopenia, mientras que el uso de lopinavir/ritonavir fue identificado como un factor protector. Conclusiones: La edad, gravedad y fracaso orgánico junto con la necesidad de terapias de soporte fueron identificadas como factores predictores de mortalidad a las seis semanas. La administración de corticoesteroides a dosis altas no mostró beneficios en la mortalidad, al igual que el tratamiento con tocilizumab, lopinavir/ritonavir se identificaron como un factor protector (AU)

Effect of HIV aspartyl protease inhibitors on experimental infection with a cystogenic Me49 strain of Toxoplasma gondii.

Toxoplasmosis is a zoonotic disease of major significant perspectives in public health and veterinary medicine. So far, the available drugs control only the active infection, once the parasite encysts in the tissues, they lose their efficacy. Cytokines; IFN-γ and IL-10, play a critical role in the modulation of toxoplasmic encephalitis and neuro-inflammation in chronic toxoplasmosis. Antiretroviral protease inhibitors applied in the treatment of acquired immunodeficiency syndrome, revealed activity against multiple parasites. Aluvia (lopinavir/ritonavir) (L/R); an aspartyl protease inhibitor, had efficiently treated T. gondii RH strain infection. We investigated the potential activity of L/R against experimental T. gondii infection with a cystogenic Me49 strain in mice, considering the role of IFN-γ and IL-10 in the neuropathology versus pyrimethamine-sulfadiazine combination therapy. Three aluvia regimens were applied; starting on the day of infection (acute phase), 2-week PI (early chronic phase) and eight weeks PI (late chronic phase). L/R reduced the brain-tissue cyst burden significantly in all treatment regimens. It impaired the parasite infectivity markedly in the late chronic phase. Ultrastructural changes were detected in Toxoplasma cyst membrane and wall, bradyzoite membrane and nuclear envelope. The signs of bradyzoite paraptosis and cytoplasmic lipid droplets were observed. L/R had significantly reduced the brain-homogenate levels of IFN-γ and IL-10 in its three regimens however, they could not reach the normal level in chronic phases. Cerebral hypercellularity, perivascular inflammatory response, lymphoplasmacytic infiltrates and glial cellular reaction were ameliorated by L/R treatment. Herein, L/R was proved to possess promising preventive and therapeutic perspectives in chronic cerebral toxoplasmosis.

Characteristics and outcomes of patients with COVID-19 and liver injury: a retrospective analysis and a multicenter experience.

Background and aims. Patients with COVID-19 frequently present abnormal elevated liver function tests of unknown clinical significance. We aimed to investigate the characteristics and factors influencing outcome in patients with confirmed SARS-CoV-2 infection and liver injury on admission.Methods. This is a retrospective observational study of patients hospitalized in two COVID units in Romania. Relevant data on clinical and laboratory parameters and medication administered during the admission were analyzed to identify predictors of a negative outcome. Patients with confirmed COVID-19 and liver function tests (LFTs) above the upper limit of normal were included in the analysis.Results. From 1,207 patients, we identified 134 patients (11%) with abnormal LFTs during hospitalization. The majority of patients had mildly elevated levels and a predominantly cholestatic pattern of liver injury. Patients who received lopinavir/ritonavir were more likely to have increased ALAT levels (p<0.0001). Sixteen patients had pre-existing chronic liver disease, and they were more likely to suffer from severe COVID-19 (p=0.009) and have a negative outcome (p<0.001), but on multivariate analysis, only the severity of COVID-19 was predictive of death (OR 69.9; 95% CI 6.4-761.4).Conclusions. Mild liver injury is relatively common in COVID-19 and possibly influenced by medication. Patients with chronic liver disease are at high risk for negative outcome, but the severity of the infection is the only predictor of death.