Search

Background and Aims: The 12-week regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (OPrD) has shown high efficacy and tolerability in clinical trials for the treatment of chronic hepatitis C virus (HCV). The shorter 8-week regimen has been recently incorporated into clinical guidelines and on-label indications, but real-world evidence on its use is limited. Given this knowledge gap, the AMETHYST study aimed to evaluate the effectiveness of the 8- and 12-week regimens of OPrD in treatment-naive patients with HCV with mild to moderate liver fibrosis in Romanian clinical practice., Methods: This was a secondary data collection study analyzing data from a 1-year Patient Support Program in HCV in Romania. Patients received OPrD treatment for 8 or 12 weeks. The effectiveness endpoint was sustained virologic response 12 weeks post-treatment (SVR12)., Results: A total of 1,835 treatment-naive patients with HCV with mild or moderate fibrosis were included in the study. Of these, 426 and 1,375 completed the 8-week and 12-week regimens, respectively. SVR12 was 98.1% in the 8-week treatment group and 98.7% in the 12-week treatment group., Conclusion: The study provides real-world evidence that 8-week and 12-week treatment regimens of OPrD are highly effective in treatment-naive patients with HCV with mild to moderate liver fibrosis.

Currently, there is no specific antiviral treatment for COVID-19. However, drugs previously developed to treat other viral infections are being tested to verify if they might also be effective against SARS-CoV-2, the virus that causes COVID-19. Twenty years ago, the F.D.A. approved Lopinavir/ritonavir (LPV/r) to treat HIV infection. LPV and ritonavir were initially purposed to inhibit 3-chymotrypsin-like protease (3CL pro ) of SARS-CoV and MERS-CoV and preliminary promising data on its efficacy for treating people infected with those viruses were available. Therefore, due to the high genetic similarities among those viruses and SARS-CoV-2, early during COVID-19 pandemic LPV/r was also proposed as one emergency treatment. We reviewed data from the literature about LPV/r treatment and SARS-CoV-2 infection, mainly focused on the efficacy and safety of this drugs for COVID-19 treatment. We can conclude that although up to date no clear benefit has been observed with the LPV/r treatment beyond standard care, its efficacy against SARS-COV-2 infection deserves further evaluations, particularly during the very early phase of the disease., Competing Interests: Conflicts of interest All authors disclose that they have no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r., Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir., Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03., Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC) 0-48 , AUC 0-inf and maximum concentration (C max ) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir C max , the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC 0-48 and AUC 0-inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity., Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C max . Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS., Gov Identifier: NCT03147378, date of registration: May 10 2017.

Interferon Beta-1a (IFN-β1-a), an immunomodulatory mediator with antiviral effects, has shown in vivo and in vitro activities especially on coronavirus including SARS-CoV-2. COVID-19 defined as the disease caused by infection with SARS-CoV-2. The virus has been illustrated inhibits the production of IFN-β1-a from inflammatory cells. We conducted a retrospective study of all adult confirmed COVID-19 hospitalized patients who received combination of three doses of 12 million international units of IFN-β1-a and Lopinavir 400 mg and Ritonavir 100 mg every 12 h (case group) for 14 days besides standard care and age- and sex- matched COVID-19 patients with receiving lopinavir/ritonavir (control group) at Masih Daneshvari Hospital as a designated hospital for COVID-19 between Feb 19 and Apr 30, 2020. Multivariate analysis was done to determine the impact of IFN-β1-a on outcome and all-cause mortality. 152 cases in IFN-β1-a group and 304 cases as control group were included. IFN-β1-a group stayed at hospital longer and required noninvasive ventilation more than control group (13 vs. 6 days, p = 0.001) and (34% vs. 24%, p = 0.04), respectively. During treatment, 57 (12.5%) patients died. The death rate in case and control groups was 11% and 13% respectively. In multivariate analysis, not receiving IFN-β1-a (HR 5.12, 95% CI: 2.77-9.45), comorbidity (HR 2.28, 95% CI: 1.13-4.60) and noninvasive ventilation (HR 2.77, 95% CI: 1.56-4.93) remained significantly associated with all-cause mortality. In this study, risk of death decreased by using IFN-β1-a in COVID-19 patients. More clinical study will be necessary to measure efficacy of IFN-β1-a in COVID-19 treatment., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV., Design: IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858)., Methods: IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented., Results: Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect., Conclusions: Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis., Competing Interests: The authors have declared that no competing interests exist.

In the ANRS 12174 trial, HIV-exposed uninfected African neonates who received lopinavir-ritonavir (LPV/r) prophylaxis for 1 year exhibited slower growth from birth to week 50 compared with those receiving lamivudine (3TC). We assessed whether this difference in growth persisted over time, and was accompanied by differences in neuropsychological and clinical outcomes. Between February 2017 and February 2018, we conducted a cross-sectional clinical evaluation among former trial participants who completed the 50-week follow-up and who were not HIV-infected. In addition to clinical examination, neuropsychological outcomes were assessed using the tests Kaufman-ABCII, Test of Variables of Attention, Movement Assessment Battery for Children and the Strengths and Difficulties questionnaire, parent version. Of 1101 eligible children, aged 5-7 years, 553 could be traced and analysed (274 in the LPV/r and 279 in the 3TC groups). Growth, clinical and neuropsychological outcomes did not differ between treatment groups. At school age, children exposed to LPV/r and 3TC at birth for 1 year had comparable growth and neuropsychological outcomes without evidence of long-term side-effects of LPV/r. It provides reassuring data on clinical outcomes for all HIV-infected children treated with this antiretroviral drug in early life.

Many drugs that have been proposed for treatment of coronavirus disease 2019 (COVID-19) are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here, we explored the potential effects on cardiac electrophysiology of four drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PKs) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both PK and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that women with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared with diseased men or healthy individuals of either sex. Statistical analysis of population simulations revealed the molecular factors that make certain women with heart failure especially susceptible to arrhythmias. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies., (© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential., Methods: Real-world COVID-19 data based on a retrospective study., Results: Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6-6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders., Conclusions: Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Treatment options for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) are limited with no clarity on efficacy and safety profiles. We performed a systematic review and meta-analysis of studies on patients ≥18 years reporting data on therapeutic interventions in SARS-CoV-2. Primary outcome was all-cause mortality and secondary outcomes were rates of mechanical ventilation, viral clearance, adverse events, discharge, and progression to severe disease. Pooled rates and odds ratios (OR) were calculated. Twenty-nine studies with 5207 patients were included. Pooled all-cause mortality in intervention arm was 12.8% (95% confidence interval [CI]: 8.1%-17.4%). Mortality was significantly higher for studies using hydroxychloroquine (HCQ) for intervention (OR: 1.36; 95% CI: 0.97-1.89). Adverse events were also higher in HCQ subgroup (OR: 3.88; 95% CI: 1.60-9.45). There was no difference in other secondary outcomes. There is a need for well-designed randomized clinical trials for further investigation of every therapeutic intervention for further insight into different therapeutic options., (© 2020 Wiley Periodicals LLC.)

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin., (Copyright © 2020 Elsevier B.V. All rights reserved.)

To evaluate the predictive effect of T-lymphoid subsets on the conversion of common covid-19 to severe. The laboratory data were collected retrospectively from common covid-19 patients in the First People's Hospital of Zaoyang, Hubei Province, China and the Third People's Hospital of Kunming, Yunnan Province, China, between January 20, 2020 and March 15, 2020 and divided into training set and validation set. Univariate and multivariate logistic regression was performed to investigate the risk factors for the conversion of common covid-19 to severe in the training set, the prediction model was established and verified externally in the validation set. 60 (14.71%) of 408 patients with common covid-19 became severe in 6-10 days after diagnosis. Univariate and multiple logistic regression analysis revealed that lactate (P = 0.042, OR = 1097.983, 95% CI 1.303, 924,798.262) and CD8 + T cells (P = 0.010, OR = 0.903, 95% CI 0.835, 0.975) were independent risk factors for general type patients to turn to severe type. The area under ROC curve of lactate and CD8 + T cells was 0.754 (0.581, 0.928) and 0.842 (0.713, 0.970), respectively. The actual observation value was highly consistent with the prediction model value in curve fitting. The established prediction model was verified in 78 COVID-19 patients in the verification set, the area under the ROC curve was 0.906 (0.861, 0.981), and the calibration curve was consistent. CD8 + T cells, as an independent risk factor, could predict the transition from common covid-19 to severe.

Source Citation: RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396:1345-52. 33031764.

Objectives: We aimed to compare the antiviral effect of hydroxychloroquine (HCQ) and lopinavir/ritonavir (LPV/r) in patients with COVID-19., Methods: Nationwide retrospective case-control study was conducted to compare the effect of HCQ and LPV/r on viral shedding duration among patients with mild-to-moderate COVID-19 using the reimbursement data of National Health Insurance Service. After propensity score matching (PSM), multivariate analysis was conducted to determine statistically significant risk factors associated with prolonged viral shedding., Results: Overall, 4197 patients with mild-to-moderate COVID-19 were included. Patients were categorized into three groups: LPV/r (n = 1268), HCQ (n = 801), and standard care without HCQ or LPV/r (controls, n = 2128). The median viral shedding duration was 23 (IQR 17-32), 23 (IQR 16-32), and 18 (IQR 12-25) days in the LPV/r, HCQ, and control groups, respectively. Even after PSM, the viral shedding duration was not significantly different between LPV/r and HCQ groups: 23 (IQR, 17-32) days versus 23 (IQR, 16-32) days. On multivariate analysis, old age, malignancy, steroid use, and concomitant pneumonia were statistically significant risk factors for prolonged viral shedding., Conclusion: The viral shedding duration was similar between HCQ and LPV/r treatment groups. There was no benefit in improving viral clearance compared to the control group., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Because of the limited treatment options available, oral lopinavir/ritonavir (LPR) was used for treating coronavirus disease (COVID-19) in pediatric patients. This study aimed to assess the efficacy and safety of LPR in COVID-19 pediatric patients with mild symptoms., Patients and Methods: This retrospective multicenter analysis included hospitalized children with mild COVID-19 who received LPR at one of 13 hospitals in China from January 1, 2020, to June 1, 2020. Patients treated with LPR were matched with patients not treated with LPR (1:4) according to age, sex, and length of symptom onset and hospitalization. Descriptive statistics and non-parametric tests were applied to compare differences between groups. Kaplan-Meier probability curves and Cox regression models were used to analyze nasal swab turning negative time (recovery time) and hospital discharge days., Results: In total, 23 patients treated with LPR were matched with 92 untreated controls. The median age of patients was 6 years, and 56.52% of them were male. All patients were discharged from the hospital after being cured. The treatment group had a longer nasal swab turning negative time (hazard ratio [HR] 5.33; 95% CI: 1.94-14.67; p = 0.001) than the control group. LPR treatment was also associated with a longer hospitalization time (HR 2.01; 95% CI: 1.24-3.29; p = 0.005). After adjusting for the influence of LPR treatment, adverse drug reaction events were associated with a longer nasopharyngeal swab negative time (HR 4.67; 95% CI 1.35-16.11; p = 0.015)., Conclusions: For children with mild COVID-19, LPR is inferior to conventional treatment in reducing virus shedding time and hospitalization duration and is associated with increased adverse reactions.

Purpose: To provide the latest evidence on the efficacy and safety of lopinavir/ritonavir compared to other treatment options for COVID-19., Methods: We searched PubMed, Cochran Library, Embase, Scopus, and Web of Science for the relevant records up to April 2021. Moreover, we scanned MedRxiv, Google Scholar, and clinical registry databases to identify additional records. We have used the Newcastle-Ottawa Scale and Cochrane risk of bias tools to assess the quality of studies. This Meta-analysis was conducted using RevMan software (version 5.3)., Results: Fourteen studies were included. No significant difference was observed between lopinavir/ritonavir and non-antiviral treatment groups in terms of negative rate of PCR (polymerase chain reaction) on day 7 (risk ratio [RR]: 0.83; 95% CI: 0.63 to 1.09; P=0.17), and day 14 (RR: 0.93; 95% CI: 0.81 to 1.05; P=0.25), PCR negative conversion time (mean difference [MD]: 1.09; 95% CI: -0.10 to 2.29; P=0.07), secondary outcomes, and adverse events (P>0.05). There was no significant difference between lopinavir/ritonavir and chloroquine as well as lopinavir/ritonavir and hydroxychloroquine regarding the efficacy outcomes (P>0.05). However, lopinavir/ritonavir showed better efficacy than arbidol for the same outcomes (P<0.05). Lopinavir/ritonavir plus arbidol was effective compared to arbidol alone in terms of the negative rate of PCR on day 7 (P=0.02). However, this difference was not significant regarding other efficacy outcomes (P>0.05)., Conclusion: Lopinavir/ritonavir has no more treatment effects than other therapeutic agents used herein in COVID-19 patients.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Aims of the Study: Hydroxychloroquine and lopinavir/ritonavir have been used as experimental therapies to treat COVID-19 during the first wave of the pandemic. Randomised controlled trials have recently shown that there are no meaningful benefits of these two therapies in hospitalised patients. Uncertainty remains regarding the potential harmful impact of these therapies as very early treatments and their burden to the health care system. The present study investigated the length of hospital stay (LOS), mortality, and costs of hydroxychloroquine, lopinavir/ritonavir or their combination in comparison with standard of care among patients hospitalised for coronavirus disease 2019 (COVID-19)., Methods: This retrospective observational cohort study took place in the Geneva University Hospitals, Geneva, Switzerland (n = 840) between 26 February and 31 May 2020. Demographics, treatment regimens, comorbidities, the modified National Early Warning Score (mNEWS) on admission, and contraindications to COVID-19 treatment options were assessed. Outcomes included LOS, in-hospital mortality, and drug and LOS costs., Results: After successful propensity score matching, patients treated with (1) hydroxychloroquine, (2) lopinavir/ritonavir or (3) their combination had on average 3.75 additional hospitalisation days (95% confidence interval [CI] 1.37&ndash;6.12, p = 0.002), 1.23 additional hospitalisation days (95% CI &minus;1.24 &ndash; 3.51, p = 0.319), and 4.19 additional hospitalisation days (95% CI 1.52&ndash;5.31, p &lt;0.001), respectively, compared with patients treated with the standard of care. Neither experimental therapy was significantly associated with mortality. These additional hospital days amounted to 1010.77 additional days for hydroxychloroquine and hydroxychloroquine combined with lopinavir/ritonavir, resulting in an additional cost of US$ 2,492,214 (95%CI US$ 916,839&ndash;3,450,619)., Conclusions: Prescribing experimental therapies for COVID-19 was not associated with a reduced LOS and might have increased the pressure put on healthcare systems.

We report the case of a man affected by cystic fibrosis who developed a severe SARS-CoV-2 related pneumonia in March 2020. In addition to lopinavir/ritonavir and hydroxychloroquine, he was treated with two doses of tocilizumab, displaying a significant clinical improvement. This is the first case described in the literature of an adult patient affected by cystic fibrosis who received tocilizumab for COVID-19, with documented total recovery, also assessed by a spirometry.

Background/aims: This study aimed to evaluate the real-life efficacy and tolerability of direct-acting antiviral treatments for patients with chronic hepatitis C (CHC) with/without cirrhosis in the Turkish population., Material and Methods: A total of 4,352 patients with CHC from 36 different institutions in Turkey were enrolled. They received ledipasvir (LDV) and sofosbuvir (SOF)±ribavirin (RBV) orombitasvir/paritaprevir/ritonavir±dasabuvir (PrOD)±RBV for 12 or 24 weeks. Sustained virologic response (SVR) rates, factors affecting SVR, safety profile, and hepatocellular cancer (HCC) occurrence were analyzed., Results: SVR12 was achieved in 92.8% of the patients (4,040/4,352) according to intention-to-treat and in 98.3% of the patients (4,040/4,108) according to per-protocol analysis. The SVR12 rates were similar between the treatment regimens (97.2%-100%) and genotypes (95.6%-100%). Patients achieving SVR showed a significant decrease in the mean serum alanine transaminase (ALT) levels (50.90±54.60 U/L to 17.00±14.50 U/L) and model for end-stage liver disease (MELD) scores (7.51±4.54 to 7.32±3.40) (p<0.05). Of the patients, 2 were diagnosed with HCC during the treatment and 14 were diagnosed with HCC 37.0±16.0 weeks post-treatment. Higher initial MELD score (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.22-2.38; p=0.023]), higher hepatitis C virus (HCV) RNA levels (OR: 1.44, 95% CI: 1.31-2.28; p=0.038), and higher serum ALT levels (OR: 1.38, 95% CI: 1.21-1.83; p=0.042) were associated with poor SVR12. The most common adverse events were fatigue (12.6%), pruritis (7.3%), increased serum ALT (4.7%) and bilirubin (3.8%) levels, and anemia (3.1%)., Conclusion: LDV/SOF or PrOD±RBV were effective and tolerable treatments for patients with CHC and with or without advanced liver disease before and after liver transplantation. Although HCV eradication improves the liver function, there is a risk of developing HCC.

The Sub-Saharan countries, particularly South Africa has the largest number of people living with HIV, accompanied by the largest antiretroviral treatment (ART) programme in the world. The Highly Active Antiretroviral Treatment (HAART) is the most effective regimen against HIV/AIDS and has improved the lifespan and quality of life of HIV positive patients. HAART has also led to a decrease in the incidence of AIDS defining cancers (ADCs) while there is an increased incidence of the non-AIDS Defining Cancers (NADCs), such as lung cancer in the HAART era. The association between lung tumourigenesis and the use of HAART components such as the dual protease inhibitor (PI) lopinavir/ritonavir (LPV/r) is poorly understood. Using cell and molecular biological approaches, this study aimed at elucidating the effects of LPV/r on the regulation of the cell cycle related genes in normal (MRC-5) and adenocarcinoma (A549) lung cells. Initially, the nuclear integrity of these cells in response to LPV/r was determined using DAPI staining. The effect of LPV/r on cell cycle genes was evaluated through the use of a RT2 PCR gene array of 84 genes related to the cell cycle signaling pathway. The PCR array data was validated by Real-Time Quantification PCR (RT-qPCR). Ingenuity Pathway Analysis (IPA) bio-informatics tool was employed to disclose the molecular mechanism/s observed at cellular and gene expression levels. Loss of nuclear integrity and the upregulation of the p53 DNA damage response (DDR) pathway was revealed by DAPI staining, differential gene expression and IPA core analysis. Furthermore, MAD2L2 and AURKB which also play a role in the DDR pathway were shown to be differentially expressed. The activation of the CASP3 gene in response to LPV/r in A549 cells was also observed. The findings of this study suggest genotoxic properties of LPV/r in healthy normal lung fibroblasts cells and anti-tumour properties in the A549 cells., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A previous report on 814 patients who were coronavirus disease 2019 (COVID-19) positive provided preliminary therapeutic efficacy evidence with interferon-α2b (IFN-α2b) in Cuba, from March 11 to April 14, 2020. This study re-evaluates the effectiveness of IFN-α2b during the period from March 11 to June 17, 2020. Patients received a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN-α2b. The primary endpoint was the proportion of patients discharged from the hospital; the secondary endpoint was the case fatality rate, and several outcomes related to time variables were also evaluated. From March 11 to June 17, 2,295 patients had been confirmed to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive in Cuba, 2,165 were treated with Heberon ® Alpha R, and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with the non-IFN-treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. Benefits of IFN were significantly supported by time variables analyzed. This second report confirmed our preliminary evidence about the therapeutic effectiveness of IFN-α2b in SARS-CoV-2 infection and postulated Heberon Alpha R as the main component within antiviral drugs used in the Cuban protocol COVID-19.

Background: The role of the antiviral therapy in treatment of COVID-19 is still a matter to be investigated. Also efficacy and safety of antiviral regimens were not compared according severity of the disease. In this study the efficacy and safety of hydroxychloroquine plus atazanavir/ritonavir was compared in patients with moderate and severe COVID-19., Methods: We prospectively evaluated the clinical outcomes of 213 patients with COVID-19 during the hospitalization course and up to 56 days after the hospital discharge. The disease was categorized to moderate and severe based on the severity of pneumonia and peripheral oxygen saturation (SpO2). The patients received the national treatment protocol containing hydroxychloroquine (400 mg BD in first day and then 200 mg BD) plus atazanavir/ritonavir (300/100 mg daily) for 7 days. Main outcomes included discharge rates at day 7, 14 and 28, 28-day mortality, rate of intensive care unit (ICU) admission and intubation, length of hospital and ICU stay and incidence of adverse events., Results: The mean (SD) age of patients was 60(14) years and 53% were male. According to WHO definition, 51.64% and 48.36% of the patients had moderate (SpO2 ≥ 90%) and severe disease (SpO2 < 90%) at baseline, respectively. The discharge rate of the moderate group was significantly higher than the severe group at day 7, 14 and 28 (HR = 0.49; 95% CI: 0.35-0.69, p = < 0.001 at day 7, HR = 0.48; 95% CI: 0.35-0.66, p = < 0.001 at day 14 and HR = 0.49; 95% CI: 0.36-0.67, p = < 0.001at day 28). The 28-day mortality of the severe group was six times higher than the moderate group (HR = 6.00; 95% CI: 2.50-14.44), p = < 0.001). The need of admission in ICU for the severe group and the moderate group was 37.86% and 18.18% of the patients. Length of hospital stay was significantly shorter in the moderate group in comparison with the severe group (5 ± 4 vs. 8 ± 6 days, p < 0.001). Patients in the moderate group experienced the serious adverse events and complications less than the severe group. The discharged patients were followed up to 56 days after discharge. Some of the patients complained of symptoms such as exertional dyspnea, weakness and new-onset hair loss., Conclusion: Our study did not support the use of hydroxychloroquine plus atazanavir/ritonavir in patients who had SpO 2  < 90% at the time of hospital admission. SpO2 was the only predictor of clinical outcomes (duration of hospital stay, discharge from the hospital and mortality) in patients treated with hydroxychloroquine plus atazanavir/ritonavir.

The pediatric adherence to antiretroviral therapy is critical to therapeutic success. Ritonavir, a protease inhibitor drug, is commercially available as an oral solution containing a high amount of ethanol and propylene glycol, contraindicated in children younger than 4 years. Moreover, this medicine presents a bitter taste, which is limiting for the adherence to treatment. This study aims to develop ritonavir nanoparticles followed by polymeric coating for sensory characteristics improvement. The nanoparticles were coated with Eudragit ® L 100-55 and characterized. A human sensory panel evaluated the proposed formulations regarding its bitter taste. The formulation showed nanotechnological features, with 130 and 134 nm for ritonavir nanoparticles and ritonavir coated nanoparticles, respectively. The pH, zeta potential, drug content and encapsulation efficiency results were suitable for oral administration. The coated nanoparticles were capable of decreasing the drug bitter taste as shown in the sensory analysis. The ritonavir incorporation in nanoparticles, followed by polymer coating can be a reasonable strategy to obtain alcohol free taste-masked medicines, which are promising for pediatric therapy.

Background: There is no identified pharmacological therapy for COVID-19 patients, where potential therapeutic strategies are underway to determine effective therapy under such unprecedented pandemic. Therefore, combination therapies may have the potential of alleviating the patient's outcome. This study aimed at comparing the efficacy of two different combination regimens in improving outcomes of patients infected by novel coronavirus (COVID-19)., Methods: This is a single centered, retrospective, observational study of 60 laboratory-confirmed COVID-19 positive inpatients (≥18 years old) at two wards of the Baqiyatallah Hospital, Tehran, Iran. Patient's data including clinical and laboratory parameters were recorded. According to the drug regimen, the patients were divided into two groups; group I who received regimen I consisting azithromycin, prednisolone, naproxen, and lopinavir/ritonavir and group II who received regimen II including meropenem, levofloxacin, vancomycin, hydroxychloroquine, and oseltamivir., Results: The oxygen saturation (SpO2) and temperature were positively changed in patients receiving regimen I compared to regimen II (P = 0.013 and P = 0.012, respectively). The serum level of C-reactive protein (CRP) changed positively in group I (P < 0.001). Although there was a significant difference in platelets between both groups (75.44 vs 51.62, P < 0.001), their change did not clinically differ between two groups. The findings indicated a significant difference of the average length of stay in hospitals (ALOS) between two groups, where the patients under regimen I showed a shorter ALOS (6.97 vs 9.93, P = 0.001)., Conclusion: This study revealed the beneficial effect of the short-term use of low-dose prednisolone in combination with azithromycin, naproxen and lopinavir/ritonavir (regimen I), in decreasing ALOS compared to regimen II. Since there is still lack of evidence for safety of this regimen, further investigation in our ongoing follow-up to deal with COVID-19 pneumonia is underway. Graphical abstract.

The number of people infected with severe acute respiratory syndrome coronavirus 2 is increasing globally, and some patients have a fatal clinical course. In light of this situation, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. While clinical studies and basic research on a treatment for COVID-19 are ongoing around the world, no treatment has yet been proven to be effective. Several clinical studies have demonstrated the efficacy of chloroquine phosphate and nafamostat mesylate with COVID-19. Here, we report the case of a Japanese patient with COVID-19 with severe respiratory failure who improved following the administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate. Hence, hydroxychloroquine with nafamostat mesylate might be a treatment option for severe COVID-19., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients., Methods: This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100 mg/100 mg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated., Results: The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital., Conclusion: Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.

The outbreak of coronavirus disease 2019 (COVID-19) has involved more than 159 countries and more than 5 million people worldwide. A 40-year-old man with a history of rheumatoid arthritis treated with prednisolone, Disease-Modifying Anti-Rheumatic Drugs (DMARDs), and biologic agents was admitted with chief complaints of fever, chills, malaise, myalgia, and dyspnea. Chest computed tomography showed bilateral subsegmental atelectasis and diffuse ground-glass opacities in both lungs inducing the suspicion of COVID-19 infection. The oro-nasopharynx swab sample for COVID-19 polymerase chain reaction was positive. In addition to supportive care, lopinavir/ritonavir 400/100 mg twice daily and oseltamivir (75 mg) twice daily were started in combination with a starting dose of hydroxychloroquine (400 mg). The methotrexate dose was decreased, and the dose of prednisolone was increased to 30 mg for 10 days. Azathioprine and adalimumab were continued at previous doses. The use of biologic agents and DMARDs in rheumatic patients is a serious challenge in the COVID-19 pandemic. In conclusion, during the COVID-19 pandemic, due to the key roles of cytokines in the promotion of the disease, the rheumatic patients may benefit from continuing their previous treatment, which may have protective effects.

We present here the case of a 62-year-old man, who was referred to the emergency department with fever and cough for 3 days. He underwent liver transplantation 4 years earlier due to HCV and NASH-related cirrhosis with hepatocellular carcinoma. At admission he was in reduced general conditions. Nasopharyngeal smear specimen resulted positive for SARS-CoV-2 infection. Pulmonary low-dose CT-scan revealed bilateral subpleural ground-glass infiltrates. O2 saturation was 93%. A treatment with lopinavir/ritonavir and hydroxychloroquine twice daily was started. The patient received also cefepime and remained in isolation. Seven days later imaging showed a progression of the pulmonary infiltrates. Cefepime was replaced by meropenem. During the following 3 days the fever resolved, and the general conditions of the patient significantly improved. Consequently, treatment with lopinavir/ritonavir and hydroxychloroquine was stopped. The evolution of SARS-CoV-2 interstitial pneumonia in this immunosuppressed patient was moderate to severe and liver injury was not clinically significant. Despite its limitations, this case report confirm that the liver may be only mildly affected during SARS-CoV-2 infection, also in liver transplanted patients. Further studies are needed to assess whether the outcome of SARS-CoV-2 infection is worse in immunosuppressed patients than in the general population., (Copyright © 2020. Published by Elsevier Masson SAS.)

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

GSK2838232 is a novel, potent HIV-1 maturation inhibitor for use in regimen-based combination antiretroviral therapy from a once-daily oral dose boosted with a pharmacoenhancer (ritonavir or cobicistat). This phase 1 study in healthy participants was conducted in 2 parts. Part 1 (n = 14) assessed the relative bioavailability of single doses of a 200-mg GSK2838232 tablet and capsule formulation boosted with 100 mg ritonavir in fed and fasted (tablet-only) subjects. Part 2 (n = 10) assessed the pharmacokinetics of repeated 500-mg once-daily doses of GSK2838232 without a pharmacoenhancing boosting agent. In part 1, GSK2838232 demonstrated comparable bioavailability following a single dose of 200 mg GSK2838232 as capsule and tablet formulations in combination with ritonavir (RTV) under fed conditions, with lower intrasubject variability observed for the tablet formulation. In part 2, following administration of 500 mg GSK2838232 once daily for 11 days under fed conditions, C max , AUC 0-τ , and Cτ showed a small degree of accumulation (1.2- to 1.3-fold) of GSK2838232. The median t max was approximately 4 hours on both day 1 and day 11 when given with food. The mean t ½ was approximately 23 hours on day 11. Steady-state concentrations were achieved by day 3 with a geometric mean steady-state Cτ on day 11 of 28 ng/mL. The tablet formulation was generally well tolerated as a single 200-mg dose with RTV under fed and fasted conditions and following administration of multiple daily doses (11 days) of 500 mg unboosted., (© 2020, The American College of Clinical Pharmacology.)

Background: Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and meta-analysis to assess the efficacy of various treatment modalities in nCOV-2019 patients., Methods: A literature search was conducted before 29 June 2020 in PubMed, Google Scholar and Cochrane library databases. A fixed-effect model was applied if I 2  < 50%, else results were combined using random-effect model. Risk ratio (RR) or standardized mean difference (SMD) along with 95% confidence interval (95% CI) was used to pool the results. Between-study heterogeneity was explored using influence and sensitivity analyses, and publication bias was assessed using funnel plots. Entire statistical analysis was conducted in R version 3.6.2., Results: Fifty studies involving 15 in vitro and 35 clinical studies including 9170 nCOV-2019 patients were included. Lopinavir-ritonavir was significantly associated with shorter mean time to clinical recovery (SMD -0.32; 95% CI -0.57 to -0.06), remdesivir was significantly associated with better overall clinical recovery (RR 1.17; 95% CI 1.07 to 1.29), and tocilizumab was associated with less all-cause mortality (RR 0.38; 95% CI 0.16 to 0.93). Hydroxychloroquine was associated with longer time to clinical recovery and less overall clinical recovery. It additionally had higher all-cause mortality and more total adverse events., Conclusion: Our meta-analysis suggests that except in vitro studies, no treatment has shown overall favourable outcomes in nCOV-2019 patients. Lopinavir-ritonavir, remdesivir and tocilizumab may have some benefits, while hydroxychloroquine administration may cause harm in nCOV-2019 patients. Results from upcoming large clinical trials may further clarify role of these drugs., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Rationale: Reversible splenial lesion syndrome (RESLES) is a recently identified clinico-radiological syndrome, the etiology is miscellaneous. Atrial septal defect (ASD) as an underlying etiology for RESLES has not been reported. We first report a rare case of RESLES associated with ASD. The clinical, radiological, and ultrasonic profiles were presented and the pathophysiological mechanism was analyzed., Patient Concerns: A 23-year-old man presented with headache, drowsiness, occasional paraphasia, and paroxysmal dry cough. Brain magnetic resonance imaging (MRI) on admission showed an ovoid isolated lesion in the splenium of corpus callosum, which exhibited hyperintensity on diffusion-weighted imaging and hypointensity on apparent diffusion coefficient, and completely disappeared on the follow-up MRI 14 days later. ASD was found by transthoracic echocardiography, Right-to-left shunts were detected on color Doppler of transesophageal echocardiography, and microemboli were captured by transcranial Doppler ultrasound., Diagnoses: According to his clinical history and imaging results, we confirmed the diagnosis of RESLES associated with ASD., Interventions: The patient was treated by oral aspirin and lopidogrel sulfate to inhibit platelet aggregation. In addition, oral nimodipine to suppress vasoconstriction., Outcomes: After 14 days treatment, all the symptoms presenting on admission resolved completely. Subsequently, a repair surgery of ASD under thoracoscopy was successfully performed., Lessons: To our knowledge, this is the first reported case of ASD may be an underlying etiology for RESLES and need require an etiotropic treatment.

What Is Known and Objective: Acquired long QT syndrome secondary to drug-induced QT prolongation and torsades de pointes has been reported for antiviral drugs. However, no studies have reported an association between corrected QT (QTc) prolongation and antiviral therapy in patients with novel coronavirus disease (COVID-19)., Case Description: We present two cases from our institution in which patients with COVID-19 experienced QTc prolongation during treatment with antiviral therapy. Lopinavir/ritonavir, together with gender and drug-drug interactions, may have contributed to the induction of QTc prolongation in those patients., What Is New and Conclusion: Co-administration of QT-prolonging medications and drugs interfering with the metabolism of those medications must be considered in patients with COVID-19. Careful analysis of electrocardiograms for QTc duration should be performed at baseline and during antiviral therapy to identify individuals at high risk of arrhythmias., (© 2020 John Wiley & Sons Ltd.)

Introduction: We investigated the potential hepatotoxicity of lopinavir/ritonavir recently used in the treatment of Severe Acute Respiratory Syndrome Coronavirus., Methods: This is a retrospective cohort of critical patients in a teaching hospital: 12 treated with lopinavir/ritonavir and 30 in the standard-of-care group., Results: Elevation occurred more frequently in patients treated with lopinavir/ritonavir (33% vs 6.7%)., Discussion: Caution is advised regarding the use of lopinavir/ritonavir in the most severe cases of Severe Acute Respiratory Syndrome Coronavirus.

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR = 11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR = 1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR = 4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.

Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.

Interferons (IFNs) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, a recent report of ACE2, the host factor mediating SARS-Cov-2 infection, identifying it as interferon-stimulated raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study of 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or computed tomography (CT) scan improvement, whereas late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir alone or together were associated with reduced mortality and accelerated recovery in comparison with treatment with lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 could induce favorable clinical responses., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000-8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir., Objectives: To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir., Patients and Methods: Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored., Results: Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928-32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394-32 735)., Conclusions: In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)