SMA-TB: study protocol for the phase 2b randomized double-blind, placebo-controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetylsalicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen.

BACKGROUND: The duration and regimen of tuberculosis (TB) treatment is currently based predominantly on whether the M. tuberculosis (Mtb) strain is drug-sensitive (DS) or multidrug-resistant (MDR) with doses adjusted by patients' weight only. The systematic stratification of patients for personalized treatment does not exist for TB. As each TB case is different, individualized treatment regimens should be applied to obtain better outcomes. In this scenario, novel therapeutic approaches are urgently needed to (1) improve outcomes and (2) shorten treatment duration, and host-directed therapies (HDT) might be the best solution. Within HDT, repurposed drugs represent a shortcut in drug development and can be implemented at the short term. As hyperinflammation is associated with worse outcomes, HDT with an anti-inflammatory effect might improve outcomes by reducing tissue damage and thus the risk of permanent sequelae. METHODS: SMA-TB is a multicentre randomized, phase IIB, placebo-controlled, three-arm, double-blinded clinical trial (CT) that has been designed in the context of the EC-funded SMA-TB Project ( www.smatb.eu ) in which we propose to use 2 common non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) and ibuprofen (Ibu), as an HDT for use as adjunct therapy added to, and compared with, the standard of care (SoC) World Health Organization (WHO)-recommended TB regimen in TB patients. A total of 354 South African and Georgian adults diagnosed with confirmed pulmonary TB will be randomized into SoC TB treatment + placebo, SoC + acetylsalicylic acid or SoC + ibuprofen. DISCUSSION: SMA-TB will provide proof of concept of the HDT as a co-adjuvant treatment and identify the suitability of the intervention for different population groups (different epidemiological settings and drug susceptibility) in the reduction of tissue damage and risk of bad outcomes for TB patients. This regimen potentially will be more effective and targeted: organ saving, reducing tissue damage and thereby decreasing the length of treatment and sequelae, increasing cure rates and pathogen clearance and decreasing transmission rates. It will result in better clinical practice, care management and increased well-being of TB patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT04575519. Registered on October 5, 2020.

The management of polypharmacy in people living with HIV.

Antiretroviral therapy (ART) has modified the prognosis of HIV which has evolved into a chronic condition. People living with HIV (PLWH) are living longer presenting an increased number of comorbidities leading to polypharmacy. Literature on the prevalence, associated factors, drug-drug interactions (DDIs), effects on ART-outcomes, geriatric conditions, and nutritional status together with health-interventions aimed to reduce it is presented in this review. A literature search was conducted on the MEDLINE database for all relevant English- and Spanish-language studies since 2006. Studies providing data of interest were identified and ordered in groups: (i) prevalence and associated factors (n = 37), (ii) DDIs (n = 19), (iii) Effects on ART-outcomes (n = 12), (iv) Effects on health conditions (n = 13), and (V) Health-interventions to assess and/or reduce it (n = 9). Polypharmacy occurs in 9-91% of PLWH (2.6-19.5% affected by severe polypharmacy). Main factors associated with polypharmacy are older age, a higher number of comorbidities, frailty, deteriorated renal function, and previous hospitalizations. DDIs were present in 19.15-84% of cases (1.3-12.2% for the most severe types). Mainly involved non-ART drugs were antihypertensives, statins, antithrombotic agents, corticosteroids, divalent cations, and antiacids. Polypharmacy can affect ART selection, adherence, and outcomes and has been related to some geriatric conditions such as falls, frailty, and poor nutritional status. Potentially prescribing issues are present in up to 87.9% of cases according to the STOPP-START and Beers criteria and some pharmacist-led interventions have been shown to reduce it. Considering these findings, polypharmacy should be considered a clinical concern in this population and treatment-optimization programs are needed to reduce its burden.

Cost-effectiveness analysis of the daily HIV pre-exposure prophylaxis in men who have sex with men in Barcelona.

INTRODUCTION: Pre-Exposure Prophylaxis (PrEP) for HIV prevention has been implemented in several countries. Previous literature has shown that its cost-effectiveness (and, under some specifications, cost-saving character) is dependent on the reduction in price due to generics, the time-horizon and its effectiveness. The intervention has never been studied in Catalonia after the approval of the PrEP, a territory with extensive implementation. METHODS: Economic evaluation of the implementation of HIV pre-exposition prophylaxis using administrative data from Men who have Sex with Men (MSM) who receive the treatment (at the generic price) compared with non-implementation. A deterministic compartmental model and a social perspective with a micro-costing approach over the time horizon 2022-2062 are used. A baseline 86% effectiveness of PrEP is assumed. RESULTS: Daily oral PrEP is found to be cost-saving: discounted savings in costs are attained after 16 years, and after 40 years they reach 81 million euros. In terms of health indicators, 10,322 additional discounted QALYs are generated by the intervention. Results are sensitive to sexual behavioral patterns among MSM, the price of PrEP (reduced if offered on-demand), its effectiveness and the discount rate. CONCLUSIONS: The use and promotion of PrEP in Catalonia is predicted to result in substantial health and monetary benefits because of reductions in HIV infections. Short-term investments in the promotion of PrEP will result in important cost-savings in the long term.

Successful long-term treatment of paediatric ulcerative colitis with vedolizumab: a case report.

Biologics are recommended to treat paediatric ulcerative colitis (UC) that is chronically active or steroid-dependent despite aminosalicylic acids (5-ASA) and thiopurine treatments. Anti-tumour necrosis factor inhibitors (Anti-TNF inhibitors) are the agents of choice and vedolizumab could be considered as second-line biologic therapy.In the current case, we aim to describe a successful long-term treatment with vedolizumab in a 9-year-old boy with severe UC and primary non-response to infliximab. Concomitant azathioprine was used, and steroid refractoriness was also detected. Drug and anti-drug antibody levels were negative after infliximab induction so a switch to a 6-week-induction vedolizumab regimen followed by a maintenance regimen as a monotherapy was decided. The clinical response and tolerability to vedolizumab allowed long-term disease remission. Vedolizumab is currently non-authorised to treat paediatric patients and there is limited data on long-term treatments to date. This case contributes to the literature by adding evidence on the long-term efficacy and safety of vedolizumab in paediatric UC.

Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0-27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0-10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0-50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.

Risk factors for nosocomial bloodstream infections in COVID-19 affected patients: protocol for a case-control study.

BACKGROUND: Nosocomial bloodstream infection (nBSI) is an important clinical concern among COVID-19 hospitalised patients. It can cause sepsis and septic shock leading to high morbidity, mortality, and the emergence of antibiotic resistance. The aim of this case-control study is to identify the risk factors associated with the nBSI development in COVID-19 hospitalised patients and its incidence. METHODS AND ANALYSIS: A retrospective case-control study will be performed. Cases will include nBSI episodes of adult patients (≥18 years) admitted to Hospital Universitari Germans Trias i Pujol, Barcelona, Spain, from April to December 2020 with a diagnosis of SARS-CoV-2 pneumonia. Patients transferred from other hospitals will be excluded. Controls will include hospitalisation episodes of COVID-19 patients without nBSI. We will recruit a minimum of 74 nBSI episodes (cases) and 74 controls (according to sample size calculation). We will collect data on sociodemographics, clinical status at admission, hospital admission, in-hospital mortality, and exposure data (use of antivirals, glucocorticoids or immunomodulatory agents, length of hospitalisation, and use of medical devices such as intravenous catheters). A bivariate and a subsequent multivariate regression analysis will be performed to assess the independent effect of the associated risk factors after adjusting for confounders. The nBSI incidence rate will be estimated according to the number of nBSI episodes in admitted COVID-19 patients among the total person-month of follow-up. ETHICS AND DISSEMINATION: The protocol of this study was approved by the Ethical Committee for Drug Investigation of the Hospital Universitari Germans Trias i Pujol. The results of this case-control study will be published in a peer reviewed journal.

Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen.

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC50 below 25 µM or 102 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

Treatment Adherence and Clinical Outcomes of Patients with Inflammatory Bowel Disease on Biological Agents During the SARS-CoV-2 Pandemic.

BACKGROUND: The outbreak of COVID19 evolved rapidly into a global pandemic, forcing hospitals, including inflammatory bowel disease (IBD) referral units, to change their practices to ensure quality of care. AIMS: To describe the clinical outcomes and the fulfilment of the treatment schedule of patients with IBD treated with biological agents in a single-center of a red-zone of the pandemic, and to report the patients' perceptions about COVID-19 and the measures adopted at our center. METHODS: Therapeutic adherence and clinical outcomes were collected for all patients undergoing treatment with intravenous biologicals and subcutaneous biologicals at our center. A telephone survey was also performed to assess these patients' perceptions of the COVID pandemic and the related measures adopted at their IBD unit. RESULTS: A total of 234 patients were included (117 on intravenous and 117 on subcutaneous biologicals). Only 10% of patients postponed intravenous infusions intentionally and 5% postponed the collection of subcutaneous biologicals at the hospital pharmacy. Only five confirmed COVID-19 cases were registered (2.1%), all of them of mild severity. One hundred and fifty-five patients participated in the survey (77 on intravenous and 78 on subcutaneous drugs). Fear of going to the hospital was the most common reason for postponing biological administrations. Among those on combination therapy, only 7% admitted to have withdrawn immunosuppressants. CONCLUSIONS: Adherence to intravenous and subcutaneous biological therapies during the pandemic was high in a single-center cohort of IBD patients even though the cumulative incidence of confirmed COVID-19 was low.

Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial.

BACKGROUND: No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19. METHODS: Multicenter open-label, randomized, controlled trial conducted in Catalonia, Spain, between 17 March and 26 May 2020. Patients recently diagnosed with <5-day of symptom onset were assigned to receive HCQ (800 mg on day 1 followed by 400 mg once daily for 6 days) or usual care. Outcomes were reduction of viral load in nasopharyngeal swabs up to 7 days after treatment start, disease progression up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. RESULTS: A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD, 12.6), mean viral load at baseline was 7.90 log10 copies/mL (SD, 1.82), and median time from symptom onset to randomization was 3 days. No differences were found in the mean reduction of viral load at day 3 (-1.41 vs -1.41 log10 copies/mL in the control and intervention arm, respectively) or at day 7 (-3.37 vs -3.44). Treatment did not reduce risk of hospitalization (7.1% control vs 5.9% intervention) nor shorten the time to complete resolution of symptoms (12 days, control vs 10 days, intervention). No relevant adverse events were reported. CONCLUSIONS: In patients with mild COVID-19, no benefit was observed with HCQ beyond the usual care.

A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19.

BACKGROUND: Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. METHODS: We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. RESULTS: The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. CONCLUSIONS: Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.).