Influence of the COVID-19 Pandemic on Medical Management and on Healthcare Delivery of Immune-Mediated Rheumatic and Musculoskeletal Diseases during the First Pandemic Period February to July 2020: A Systematic Review.

(1) Background and Objectives: The COVID-19 pandemic influenced the management of patients with immune-mediated rheumatic and musculoskeletal diseases (imRMDs) in various ways. The goal of our systematic review was to determine the influence of the first period of the COVID-19 pandemic (February 2020 to July 2020) on the management of imRMDs regarding the availability of drugs, adherence to therapy and therapy changes and on healthcare delivery. (2) Materials and Methods: We conducted a systematic literature search of PubMed, Cochrane and Embase databases (carried out 20-26 October 2021), including studies with adult patients, on the influence of the COVID-19 pandemic on the management of imRMDs. There were no restrictions regarding to study design except for systematic reviews and case reports that were excluded as well as articles on the disease outcomes in case of SARS-CoV-2 infection. Two reviewers screened the studies for inclusion, and in case of disagreement, a consensus was reached after discussion. (3) Results: A total of 5969 potentially relevant studies were found, and after title, abstract and full-text screening, 34 studies were included with data from 182,746 patients and 2018 rheumatologists. The non-availability of drugs (the impossibility or increased difficulty to obtain a drug), e.g., hydroxychloroquine and tocilizumab, was frequent (in 16-69% of patients). Further, medication non-adherence was reported among patients with different imRMDs and between different drugs in 4-46% of patients. Changes to preexisting medication were reported in up to 33% of patients (e.g., reducing the dose of steroids or the cessation of biological disease-modifying anti-rheumatic drugs). Physical in-office consultations and laboratory testing decreased, and therefore, newly implemented remote consultations (particularly telemedicine) increased greatly, with an increase of up to 80%. (4) Conclusions: The COVID-19 pandemic influenced the management of imRMDs, especially at the beginning. The influences were wide-ranging, affecting the availability of pharmacies, adherence to medication or medication changes, avoidance of doctor visits and laboratory testing. Remote and telehealth consultations were newly implemented. These new forms of healthcare delivery should be spread and implemented worldwide to routine clinical practice to be ready for future pandemics. Every healthcare service provider treating patients with imRMDs should check with his IT provider how these new forms of visits can be used and how they are offered in daily clinical practice. Therefore, this is not only a digitalization topic but also an organization theme for hospitals or outpatient clinics.

Interpreting hydroxychloroquine blood levels for medication non-adherence: a pharmacokinetic study.

OBJECTIVE: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients. METHODS: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses. RESULTS: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements. CONCLUSIONS: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.

Burden of disease and real-world treatment patterns of patients with systemic lupus erythematosus in the Australian OPAL dataset.

OBJECTIVE: To describe the demographics, disease burden and real-world management of patients with systemic lupus erythematosus (SLE) in Australian community practice. METHODS: Patients with a physician diagnosis of SLE and at least 1 visit between 1 January 2009 and 31 March 2021 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 112 Australian rheumatologists. Demographics, basic clinical features and prescribed medications were described, with medication combinations used as a surrogate of disease severity. RESULTS: Of 5133 patients with a diagnosis of lupus, 4260 (83%) had SLE. Of these SLE patients, almost 90% of patients were female, with a median age of 49 years [IQR 37-61] at first-recorded visit. Of the 2285 SLE patients whose most recent visit was between 1 January 2019 and 31 March 2021, 52.5% had mild disease, 29.9% had moderate-severe disease and 7.4% had very severe disease. Visit frequency increased with disease severity. Most patients (85.8%) were treated with hydroxychloroquine, typically prescribed as first line-of-therapy. CONCLUSION: In this large real-world Australian cohort of patients with SLE, a substantial burden of disease was identified, with a significant proportion (almost one-third of patients) considered to have moderate to severe disease based on medication use. This study provides a greater understanding of the path from symptom onset to treatment and the heterogeneous presentation of patients with SLE who are treated in community practice in Australia. Key messages • Most published studies describing patients with SLE are derived from specialist lupus centres, typically in the hospital setting, therefore little is known about the characteristics of patients with SLE who are receiving routine care in community clinics. • The OPAL dataset is a large collection of clinical data from the electronic medical records of rheumatologists predominantly practising in private community clinics, which is where the majority (73-80%) of adult rheumatology services are conducted in Australia [1-3] . Since data from community care has not been widely available for SLE research, this study contributes important insight into this large and under-reported patient population. • To improve access to care and effective treatments, and reduce the burden of SLE in Australia, a greater understanding of the characteristics and unmet needs of patients with SLE managed in the community setting is required.

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients.

BACKGROUND: Maintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19. METHODS: Using claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020. RESULTS: Up to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters. CONCLUSION: Maintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.

Emerging Therapies for COVID-19: The Value of Information From More Clinical Trials.

OBJECTIVES: The COVID-19 pandemic necessitates time-sensitive policy and implementation decisions regarding new therapies in the face of uncertainty. This study aimed to quantify consequences of approving therapies or pursuing further research: immediate approval, use only in research, approval with research (eg, emergency use authorization), or reject. METHODS: Using a cohort state-transition model for hospitalized patients with COVID-19, we estimated quality-adjusted life-years (QALYs) and costs associated with the following interventions: hydroxychloroquine, remdesivir, casirivimab-imdevimab, dexamethasone, baricitinib-remdesivir, tocilizumab, lopinavir-ritonavir, interferon beta-1a, and usual care. We used the model outcomes to conduct cost-effectiveness and value of information analyses from a US healthcare perspective and a lifetime horizon. RESULTS: Assuming a $100 000-per-QALY willingness-to-pay threshold, only remdesivir, casirivimab-imdevimab, dexamethasone, baricitinib-remdesivir, and tocilizumab were (cost-) effective (incremental net health benefit 0.252, 0.164, 0.545, 0.668, and 0.524 QALYs and incremental net monetary benefit $25 249, $16 375, $54 526, $66 826, and $52 378). Our value of information analyses suggest that most value can be obtained if these 5 therapies are approved for immediate use rather than requiring additional randomized controlled trials (RCTs) (net value $20.6 billion, $13.4 billion, $7.4 billion, $54.6 billion, and $7.1 billion), hydroxychloroquine (net value $198 million) is only used in further RCTs if seeking to demonstrate decremental cost-effectiveness and otherwise rejected, and interferon beta-1a and lopinavir-ritonavir are rejected (ie, neither approved nor additional RCTs). CONCLUSIONS: Estimating the real-time value of collecting additional evidence during the pandemic can inform policy makers and clinicians about the optimal moment to implement therapies and whether to perform further research.

Assessment of Recovery Time, Worsening, and Death among Inpatients and Outpatients with COVID-19, Treated with Hydroxychloroquine or Chloroquine plus Azithromycin Combination in Burkina Faso.

OBJECTIVES: Our study aimed to assess the statistical relationship between the use of chloroquine phosphate or hydroxychloroquine plus azithromycin (CQ/HCQ + AZ) and virological recovery, disease worsening, and death among out- and inpatients with COVID-19 in Burkina Faso. METHODS AND DESIGNS: This was a retrospective observational study that compared outcomes in terms of time to recovery, worsening, and death in patients who received CQ/HCQ + AZ and those who did not using a multivariable Cox or Poisson model before and after propensity matching. RESULTS: Of the 863 patients included in the study, about 50% (432/863) were home-based follow-up patients and 50% were inpatients. Of these, 83.3% (746/863) received at least 1 dose of CQ/HCQ + AZ and 13.7% (118/863) did not. There were no significant differences in associated time to recovery for patients receiving any CQ/HCQ + AZ (adjusted HR 1.44; 95% CI 0.76-2.71). Similarly, there was no significant association between CQ/HCQ + AZ use and worsening (adjusted IRR 0.80; 95% CI 0.50-1.50). However, compared with the untreated group, the treated group had a lower risk of death (adjusted HR 0.20; 95% CI 0.10-0.44). CONCLUSIONS: The study provided valuable additional information on the use of CQ/HCQ in patients with COVID-19 and did not show any harmful outcomes of CQ/HCQ + AZ treatment.

Predictors of Initial Hydroxychloroquine Receipt Among Medicaid Beneficiaries With Incident Systemic Lupus Erythematosus.

OBJECTIVE: Although hydroxychloroquine/chloroquine (HCQ/CQ) form the cornerstone of systemic lupus erythematosus (SLE) treatment, not all patients receive this, which may contribute to disparities in outcomes. The present study was undertaken to investigate factors associated with first dispensing of HCQ/CQ. METHODS: Using Medicaid insurance claims from 2000 to 2010, we identified individuals ages 18-65 years with incident SLE (≥3 SLE International Classification of Diseases, Ninth Revision codes separated by ≥30 days without prior SLE codes or HCQ/CQ use for 24 months). The primary outcome was first dispensing of HCQ/CQ within 24 months of the first SLE code. We used Cox proportional hazards regression models to examine the association between sociodemographic factors, comorbidities, health care utilization, and medication use and HCQ/CQ dispensing within 24 months of diagnosis. RESULTS: We identified 9,560 Medicaid beneficiaries with incident SLE; 41% received HCQ (n = 3,949) or CQ (n = 14) within 24 months of diagnosis. Younger patients were more likely to receive HCQ/CQ. Black, Asian, Hispanic, and American Indian/Alaska Native individuals were more likely to receive HCQ/CQ than White individuals. Alcohol and nicotine use, chronic pain, diabetes mellitus, and end-stage renal disease were associated with lower dispensing. Appointments and preventive care services were associated with higher rates, and more hospitalizations with lower rates. CONCLUSION: Only 41% of Medicaid beneficiaries with SLE received HCQ/CQ within 24 months of diagnosis. Greater outpatient and preventive care increased receipt. All non-White race/ethnicities had higher rates of first dispensing. Time to initial HCQ/CQ dispensing may not explain racial/ethnic disparities in adverse outcomes, highlighting the need to consider other care quality-related issues and medication adherence challenges.

Outpatient prescription patterns of COVID-19 drugs in the metropolitan area of Mexico City.

BACKGROUND: We aimed to describe the use of drugs with apparent efficacy in ambulatory patients with confirmed COVID-19 and the relationship of Google Trends searches with prescriptions and the total number of COVID-19 cases in Mexico City. METHODS: Between March 2020 and February 2021, we surveyed 350 patients confirmed to have COVID-19 across 3 hospitals in Mexico City for their ambulatory prescriptions. We analysed the correlation between prescription patterns of 4 drugs with apparent efficacy against COVID-19, Google Trends searches for these drugs, and the overall number of confirmed COVID-19 cases in Mexico City. RESULTS: We included 350 patients, of whom 59% were women with a median age of 38 years (interquartile range, 29-51), and 72% had a bachelor's degree or higher. There were ambulatory medical prescriptions in 172 (49%) patients, and self-prescriptions were reported in 99 (28%) patients. The prescription rate was high for hydroxychloroquine/azithromycin (19%) and dexamethasone (25%). There was a decrease in the prescription of hydroxychloroquine (P < 0.001) and a strong positive correlation between hydroxychloroquine (r = 0.66; 95% confidence interval, 0.11-0.90; P = 0.02) prescription and online searches for hydroxychloroquine. There was a strong positive correlation between online searches for azithromycin, dexamethasone, ivermectin, and vitamin D and the number of confirmed COVID-19 cases. CONCLUSIONS: During the COVID-19 pandemic, there was a high proportion of prescriptions for hydroxychloroquine/azithromycin and dexamethasone despite their unproven efficacy. Analysis of Google Trends showed a strong correlation between the overall number of confirmed COVID-19 cases and searches for such drugs, suggesting a higher rate of prescriptions. Analysis of online searches could thus help to actively survey public health behaviours in the future.

Acesso da população a medicamentos durante a pandemia do novo coronavírus / Access of the population to medicines during the pandemic of the new coronavirus / Acceso de la poblacióna medicamentos durante la pandemia del nuevo coronavirus

Introdução:Em 2020 a Organização Mundial da Saúde declarou a pandemia do novo coronavírus. Diante desse cenário vários estudos começaram a ser realizados em busca de uma terapia eficaz para o manejo clínico dos pacientes. A Cloroquina e a Hidroxicloroquina foram os primeiros medicamentos testados. A divulgação dos resultados iniciais fez aumentar a procura desses medicamentos em farmácias e drogarias. Objetivo:Avaliar o acesso da população a medicamentos na pandemia e o uso das "promessas terapêuticas":Cloroquina, Hidroxicloroquina e Ivermectina para prevenção e tratamento da COVID-19. Metodologia:Trata-se de um estudo descritivo exploratório de abordagem quantitativa, não probabilístico e por conveniência. A coleta de dados foi realizada online,via Google Formulários. Participaram 1.754 pessoas, resultando em 1.748 questionários válidos. A amostra foi distribuída em 3 grupos, de acordo com a pergunta de nº 11 do formulário de pesquisa: "Você já teve COVID-19?". Resultados:Dos 1.748 respondentes, 200 (11,4%) pertenciam ao grupo que "teve COVID-19", 1.041 (59,6%) ao grupo que não teve a doença, e 507 (29%) responderam não saber se foram infectados. No que diz respeito ao acesso a medicamentos na pandemia, 55,2% do total da amostra relatou não ter sido afetado, e 29% disseram ter tido o acesso afetado de alguma forma. Em relação ao uso das "promessas terapêuticas", 61% dos respondentes disse não ter feito uso com finalidade de prevenção, e sim para tratamento, já 52,6% da população do estudo disse que não fez uso de jeito nenhum, e 46,2% relatou que fez uso dos medicamentos mencionados para tratar a COVID-19. Conclusões:Constatou-se que a explosão na busca por medicamentos durante a pandemia não afetou o acesso da população. Além disso, a Cloroquina e a Hidroxicloroquina, não foram amplamente utilizadas para prevenção da doença (AU).

Introduction:In 2020the World Health Organization declared the new coronavirus pandemic. In view of this scenario, several studies began to be carried out in search of an effective therapy for the clinical management of patients. The release of initial results has increased demand for Chloroquine and Hydroxychloroquine in pharmacies and drugstores. Objective: To assess the population's access to medicines in the pandemic and the use of "therapeutic promises": Chloroquine, Hydroxychloroquine and Ivermectin for the prevention and treatment of COVID-19. Methodology:Exploratory descriptive study with a quantitative approach, non-probabilistic and for convenience. Data collection was performed online, via Google Forms. 1,754 people participated, resulting in 1,748 valid questionnaires. The sample was divided into 3 groups, according to question #11 of the survey form: "Have you ever had COVID-19?". Results:Of the 1,748 respondents, 200 (11.4%) belonged to the group that "had COVID-19", 1,041 (59.6%) to the group that did not have the disease, and 507 (29%) answered not knowing if they were infected. With regard to access to medicines in the pandemic, 55.2% of the total sample reported not being affected, and 29% said their access was affected in some way. Regarding the use of "therapeutic promises", 61% of respondents said they did not use it for prevention purposes, but for treatment, while 52.6% of the study population said they did not use it at all, and 46, 2% used the medications mentioned to treat COVID-19. Conclusions:It wasfound that the explosion in the search for medicines during the pandemic did not affect the population's access. Furthermore, Chloroquine and Hydroxychloroquine have not been widely used for disease prevention (AU).

Introducción:En 2020, la Organización Mundial de la Salud declaró la nueva pandemia de coronavirus. Ante este escenario, se comenzaron a realizar varios estudios en busca de una terapia eficaz para el manejo clínico de lospacientes. La publicación de los resultados iniciales ha aumentado la demanda de cloroquina e hidroxicloroquina en farmacias y droguerías. Objetivo:Evaluar el acceso de la población a medicamentos en la pandemia y el uso de "promesas terapéuticas": cloroquina, hidroxicloroquina e ivermectina para la prevención y tratamiento de COVID-19. Metodología:Se trata de un estudio descriptivo exploratorio con enfoque cuantitativo, no probabilístico y por conveniencia. La recopilación de datos se realizó en línea, a través de Google Forms. Participaron 1.754 personas, resultando 1.748 cuestionarios válidos. La muestra se dividió en 3 grupos, de acuerdo con la pregunta # 11 del formulario de la encuesta: "¿Alguna vez ha tenido COVID-19?". Resultados: De los 1.748 encuestados, 200 (11,4%) pertenecían al grupo que "tenía COVID-19", 1.041 (59,6%) al grupo que no tenía la enfermedad y 507 (29%) respondieron sin saber si estaban infectados. Con respecto al acceso a medicamentos en la pandemia, el 55,2% del total de la muestra informó no estar afectado y el 29% dijo que su acceso se vio afectado de alguna manera. Con respecto al uso de "promesas terapéuticas", el 61% de los encuestados dijo que no lo usaba con fines de prevención, sino de tratamiento, mientras que el 52,6% de la población del estudio dijo que no lo usaba en absoluto, y el 46,2% informó que utilizaron los medicamentos mencionados para tratar COVID-19. Conclusiones: Se encontró que la explosión en la búsqueda de medicamentos durante la pandemia no afectó el acceso de la población. Además, la cloroquina y la hidroxicloroquina no se han utilizado ampliamente para la prevención de enfermedades (AU).

Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial.

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost-utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (-£11.80; 95% confidence interval (CI) -£15.60 to -£8.00) and marginally fewer QALYs (-0.0052; 95% CI -0.0057 to -0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.

Guía de práctica clínica para el tratamiento farmacológico de nefritis lúpica / Clinical practice guideline for the pharmacological treatment of lupus nephritis

La nefritis lúpica (NL) es un tipo de glomerulonefritis que se desarrolla como consecuencia del lupus eritematoso sistémico (LES), una enfermedad autoinmune sistémica de presentación clínica variable (1, 2). La NL se clasifica histológicamente en seis clases(I-VI) (3), las cuales poseen diferentes manifestaciones clínicas y expresan diferentes grados de gravedad del daño renal (1). En este documento no se abordará a pacientes con clase VI pues solo son tributarios a terapia de reemplazo renal. La NL se presenta aproximadamente en el 50 a 60% de las personas con LES, en quienes es una de las principales causas de morbimortalidad puesto que progresa a falla renal o muerte (1, 2). En suma, la prevalencia, gravedad y mortalidad de la NL son mayores en hispanos, afroamericanos, y asiáticos (4). El tratamiento farmacológico de la NL consta de las fases de inducción y mantenimiento (1). Entre los fármacos principalmente utilizados durante estas fases, se encuentran los antimaláricos, glucocorticoides (GC), inmunosupresores como micofenolato mofetilo (MMF) y ciclofosfamida (CYC) endovenosa, entre otros (1, 2). Sin embargo, la incidencia de respuesta renal completa suele ser baja (~20 a 30%) (1, 5, 6), y tanto las recaídas como los eventos adversos pueden ser frecuentes con estas terapias (1). Por ello, actualmente se ha propuesto el uso de diferentes dosis de dichos fármacos y otros inmunosupresores ya sea solos o en combinación. La evaluación de los beneficios y daños de estos fármacos permitirá conocer cuáles son las opciones más eficaces y seguras que logren inducir la remisión de la enfermedad, prevenir las recaídas, prevenir la progresión a falla renal y disminuir la mortalidad de los adultos con diagnóstico reciente de NL. Por ello, el Seguro Social de Salud (EsSalud) priorizó la realización de la presente guía de práctica clínica (GPC) para establecer lineamientos basados en evidencia con el fin de gestionar de la mejor manera los procesos y procedimientos asistenciales de la presente condición. Esta GPC fue realizada por la Dirección de Guías de Práctica Clínica, Farmacovigilancia y Tecnovigilancia del Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) de EsSalud.

Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer.

Hydroxychloroquine (HCQ) is being tested in a number of human clinical trials to determine the role of autophagy in response to standard anticancer therapies. However, HCQ pharmacodynamic (PD) responses are difficult to assess in patients, and preclinical studies in mouse models are equivocal with regard to HCQ exposure and inhibition of autophagy. Here, pharmacokinetic (PK) assessment of HCQ in non-tumor-bearing mice after intraperitoneal dosing established 60 mg/kg as the human equivalent dose of HCQ in mice. Autophagy inhibition, cell proliferation, and cell death were assessed in two-dimensional (2D) cell culture and three-dimensional tumor organoids in breast cancer. Mice challenged with breast cancer xenografts were then treated with 60 mg/kg HCQ via intraperitoneal dosing, and subsequent PK and PD responses were assessed. Although autophagic flux was significantly inhibited in cells irrespective of autophagy-dependence status, autophagy-dependent tumors had decreased cell proliferation and increased cell death at earlier time points compared with autophagy-independent tumors. Overall, this study shows that 2D cell culture, three-dimensional tumor organoids, and in vivo studies produce similar results, and in vitro studies can be used as surrogates to recapitulate in vivo antitumor responses of HCQ. SIGNIFICANCE STATEMENT: Autophagy-dependent tumors but not autophagy-independent tumors have decreased cell proliferation and increased cell death after single-agent hydroxychloroquine treatment. However, hydroxychloroquine causes decreased autophagic flux regardless of autophagy status, suggesting its clinical efficacy in the context of autophagy inhibition.

Assessment of clinical outcomes in renal transplant recipients with COVID-19.

The coronavirus disease 2019 (COVID-19) has affected more than a hundred million individuals and caused more than three million deaths worldwide. Specific risk groups were defined for increased risk of mortality and morbidity in COVID-19, and renal transplant recipients are at a significantly increased risk regarding outcomes due to their immunosuppressed conditions. This study evaluated the general characteristics of kidney transplant recipients with COVID-19 infection. Among 1257 transplant cases, 56 had COVID-19 infection, and 23 (41%) were hospitalized during the 9-month study period. Among all COVID-19 cases, 58% were male with a mean age of 45.5 (±13.2, 19-71) years, and the most frequent comorbidities were hypertension (70.9%) and diabetes (23.6%). Hospitalized patients were older (p = 0.03) and had higher rates of hypertension (p = 0.008), diabetes (p = 0.002), and ischemic heart disease (p = 0.03). Therapeutic management included antimetabolite withdrawal and prednisolone increase in 71%, calcineurin inhibitor withdrawal in 8% and decrease in 58%, hydroxychloroquine in 17%, tocilizumab in 3%, and antivirals in 67% of patients. Acute kidney injury and respiratory failure developed in 34% and 85%, respectively. The mortality rate was 23%. These results emphasized that the COVID-19 infection in renal transplant recipients significantly increases the risk of morbidity and mortality. Therefore, these patients should be intervened earlier and monitored closely to prevent poor outcomes.

Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: An interrupted time series analysis.

BACKGROUND: We assessed the impact of the coronavirus disease 2019 (COVID-19) epidemic in India on the consumption of antibiotics and hydroxychloroquine (HCQ) in the private sector in 2020 compared to the expected level of use had the epidemic not occurred. METHODS AND FINDINGS: We performed interrupted time series (ITS) analyses of sales volumes reported in standard units (i.e., doses), collected at regular monthly intervals from January 2018 to December 2020 and obtained from IQVIA, India. As children are less prone to develop symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a predominant increase in non-child-appropriate formulation (non-CAF) sales. COVID-19-attributable changes in the level and trend of monthly sales of total antibiotics, azithromycin, and HCQ were estimated, accounting for seasonality and lockdown period where appropriate. A total of 16,290 million doses of antibiotics were sold in India in 2020, which is slightly less than the amount in 2018 and 2019. However, the proportion of non-CAF antibiotics increased from 72.5% (95% CI: 71.8% to 73.1%) in 2019 to 76.8% (95% CI: 76.2% to 77.5%) in 2020. Our ITS analyses estimated that COVID-19 likely contributed to 216.4 million (95% CI: 68.0 to 364.8 million; P = 0.008) excess doses of non-CAF antibiotics and 38.0 million (95% CI: 26.4 to 49.2 million; P < 0.001) excess doses of non-CAF azithromycin (equivalent to a minimum of 6.2 million azithromycin treatment courses) between June and September 2020, i.e., until the peak of the first epidemic wave, after which a negative change in trend was identified. In March 2020, we estimated a COVID-19-attributable change in level of +11.1 million doses (95% CI: 9.2 to 13.0 million; P < 0.001) for HCQ sales, whereas a weak negative change in monthly trend was found for this drug. Study limitations include the lack of coverage of the public healthcare sector, the inability to distinguish antibiotic and HCQ sales in inpatient versus outpatient care, and the suboptimal number of pre- and post-epidemic data points, which could have prevented an accurate adjustment for seasonal trends despite the robustness of our statistical approaches. CONCLUSIONS: A significant increase in non-CAF antibiotic sales, and particularly azithromycin, occurred during the peak phase of the first COVID-19 epidemic wave in India, indicating the need for urgent antibiotic stewardship measures.

Hydroxychloroquine availability during COVID-19 crisis and its effect on patient anxiety.

OBJECTIVE: To report the results of a survey exploring the experience of patients with SLE facing hydroxychloroquine (HCQ) shortage that occurred during the early phases of the COVID-19 pandemic. METHODS: A survey was designed by Lupus Europe's patient advisory network and distributed through its social media, newsflash and members' network. People with lupus were asked about their last HCQ purchases and their level of anxiety (on a 0-10 scale) with regard to not being able to have access to HCQ, once in April 2020 (first wave) and after 11 August (second wave). The results were compared. RESULTS: 2075 patients responded during the first wave; 1001 (48.2%) could get HCQ from the first place they asked, 230 (11.1%) could get the drug by going to more than one pharmacy, 498 (24.0%) obtained HCQ later from their usual pharmacy and 126 (6.1%) from other sources. 188 (9.1%) could not get any; 32 (1.5%) did not respond to this question. All countries showed significant improvement in HCQ availability during the second wave. 562 (27.4%) patients reported an extremely high level of anxiety in wave 1 and 162 (10.3%) patients in wave 2; 589 (28.7%) and 268 (17.1%) patients reported a high level of anxiety in wave 1 and wave 2, respectively. CONCLUSIONS: The HCQ shortage had a significant impact on patients with SLE and has been responsible for psychological consequences including anxiety. Indeed, despite an objective improvement in drug availability, the event is leaving significant traces in patients' mind and behaviours.

Assessment and management of asymptomatic COVID-19 infection: A systematic review.

BACKGROUND: COVID-19 can be asymptomatic in a substantial proportion of patients. The assessment and management of these patients constitute a key element to stop dissemination. AIM: To describe the assessment and treatment of asymptomatic infection in patients with a confirmed diagnosis of COVID-19. METHODS: We searched five databases and search engines for preprints/preproofs, up to August 22, 2020. We included cohort, cross-sectional, and case series studies, reporting the assessment and management of asymptomatic individuals. We extracted data on total discharges with negative PCR, length of hospitalization, treatment, and number of patients who remained asymptomatic. A random-effects model with inverse variance method was used to calculate the pooled prevalence. RESULTS: 41 studies (nine cross-sectional studies, five retrospective studies and 27 reports/case series; 647 asymptomatic individuals), were included, of which 47% were male (233/501). The age of patients was between 1month and 73 years. In patients who became symptomatic, length of hospitalization mean was 13.6 days (SD 6.4). Studies used lopinavir/ritonavir, hydroxychloroquine plus ritonavir/lopinavir, hydroxychloroquine with and without azithromycin, ribavirin plus interferon and interferon alfa. The proportion of individuals who remained asymptomatic was 91% (463/588 patients; 95%CI: 78.3%-98.7%); and asymptomatic individuals discharged with negative PCR was 86% (102/124 individuals; 95%CI: 58.4%-100%). CONCLUSIONS: There is no standard treatment for asymptomatic COVID-19 individuals. There are no studies of adequate design to make this decision. It has been shown that most asymptomatic individuals who were followed have recovered, but this cannot be attributed to standard treatment.

The efficacy, safety and cost-effectiveness of hydroxychloroquine, sulfasalazine, methotrexate triple therapy in preventing relapse among patients with rheumatoid arthritis achieving clinical remission or low disease activity: the study protocol of a randomized controlled clinical Trial (ESCoRT study).

BACKGROUND: Tumor necrosis factor α inhibitors (TNFi) is effective for rheumatoid arthritis (RA) patients who fail to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Because of high cost, the discontinuation is common but often lead to disease relapse. The study aims to investigate, if the combination therapy of csDMARDs is more effective in reducing disease relapse than methotrexate (MTX) monotherapy, and more cost-effective than continuing TNFi and MTX. METHODS: It will be a two-stage trial. In the first stage, all RA patients who failed to csDMARDs treatment [disease activity score 28 (DAS28)-CRP > 3.2] will receive MTX plus TNFi for no more than 12 weeks. Patients achieving DAS28-CRP < 3.2 during the first stage will be randomized into three groups at 1:1:1 ratio: (A) add hydroxychloroquine (HCQ) and sulfasalazine (SSZ) for the first 12 weeks and then remove TNFi but continue other treatments for the next 48 weeks; (B) maintain TNFi + MTX for 60 weeks; and (C) maintain TNFi + MTX for the first 12 weeks and then remove TNFi but continue MTX monotherapy for the next 48 weeks. The primary outcome will be disease relapse (DAS28-CRP increases by at least 0.6 and > 3.2). Secondary outcomes will include the incremental cost per reducing 1 case of relapse; patient reported intolerance to the treatment; adverse events; change of mean disease activity measured by DAS28, clinical disease activity index (CDAI) and simplified disease activity index (SDAI); the proportion of modified Sharp score increase < 0.3; ultrasound-detected remission in hands; Health Assessment Questionnaire Disability Index (HAQ-DI) and health related quality of life [the five-level EuroQol-5D (EQ-5D-5L) and short form-6D (SF-6D)]. DISCUSSION: The aim of this trail will be to seek effective treatment options of preventing relapse of RA. The results of the current study may provide an instructive recommendation for more economical application of TNFi treatment in RA. Trial registration NCT, NCT02320630. Registered on 16 December 2014. https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=3&cx=-jg9qo2 .

The Era of the Coronavirus Disease 2019 Pandemic: A Review on Dynamics, Clinical Symptoms and Complications, Diagnosis, and Treatment.

Coronavirus disease 2019 (COVID-19) displays a broad spectrum of clinical presentations ranging from lack of symptoms to severe multiorgan system complications and death. Various laboratory assays have been employed in the diagnosis of COVID-19, including: nucleic acid-based tests; antigen tests; and serum testing for anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies. The disease can also be diagnosed based on suggestive clinical features and radiological findings. Until now, remdesivir is the only medication approved for the treatment of COVID-19 by the U.S. Food and Drug Administration (FDA); however, it is anticipated that several anti-SARS-CoV-2 monoclonal antibodies will gain soon approval. Other methods of treatment include supportive care directed toward treating the symptoms. Nevertheless, many studies have recently emerged, showing controversial preliminary results with the off-label medication hydroxychloroquine. Given that all results are still preliminary, including those seen by remdesivir, additional evidence and research are required to identify effective medications that are broadly effective and well tolerated. Importantly, two RNA-based vaccines have recently gained approval from Pfizer and Moderna, with many others still in clinical trials. This article reviews various aspects of COVID-19, including its epidemiology; its evolution and mutational spectrum; and its clinical dynamics, symptoms and complications, diagnosis, and treatment.

Real-World Evidence for Assessing Pharmaceutical Treatments in the Context of COVID-19.

The emergence and global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an urgent need for evidence on medical interventions and outcomes of the resulting disease, coronavirus disease 2019 (COVID-19). Although many randomized controlled trials (RCTs) evaluating treatments and vaccines for COVID-19 are already in progress, the number of clinical questions of interest greatly outpaces the available resources to conduct RCTs. Therefore, there is growing interest in whether nonrandomized real-world evidence (RWE) can be used to supplement RCT evidence and aid in clinical decision making, but concerns about nonrandomized RWE have been highlighted by a proliferation of RWE studies on medications and COVID-19 outcomes with widely varying conclusions. The objective of this paper is to review some clinical questions of interest, potential data types, challenges, and merits of RWE in COVID-19, resulting in recommendations for nonrandomized RWE designs and analyses based on established RWE principles.