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Objectives: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation.Trial Design: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial.Participants: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations.Intervention and Comparator: The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan.Main Outcome: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm.Randomisation: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home).Blinding (masking): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment.Numbers To Be Randomised (sample Size): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively.Trial Status: This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites.Trial Registration: The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27).Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). [ABSTRACT FROM AUTHOR]

Background. Efavirenz (EFV) is a highly active antiretroviral drug, use of which is associated with frequent (although transient) neurosensorial adverse reactions. Whether the use of EFV is associated with the risk of depression or suicide remains controversial. Methods. ALIZE-ANRS (Agence Nationale de Recherches sur le SIDA et les Hépatites Virales) 099 was a 48-week randomized trial involving virologically suppressed, human immunodeficiency virus (HIV)-infected patients that compared the maintenance of a treatment regimen that contained protease inhibitors (177 subjects) with a switch to a once-daily combination of EFV, didanosine, and emtricitabine (178 subjects).We used the trial's adverse events reporting system and a self-administered Center for Epidemiologic Studies-Depression Scale questionnaire to assess depressive disorders. Determinants were studied using a multivariate proportional hazards model adjusted for antiretroviral treatment, sex, age, HIV risk factor, history of depression, hepatic disorder, alcohol abuse, and HIV-related or non-HIV-related events. Results. Thirty cases of depressive disorder (26 cases of depression and 4 suicide attempts) occurred during treatment in 27 patients (12 patients [7%] and 15 patients [8%] in the protease inhibitor-based and EFV-based treatment arms, respectively; P = .56). In the proportional hazards model, only age (hazard ratio, 1.6 per 10 years younger; 95% confidence interval, 1.0-2.6) and a history of depressive disorder (hazard ratio, 5.0; 95% confidence interval, 2.1-12.0) were associated with a risk of depressive disorders. The proportion of depressive patients (24%), as determined on the basis of the Center for Epidemiologic Studies-Depression Scale data, was stable during the follow-up period, without difference between treatment groups. Patients with a history of depressive disorder were more frequently depressed (53%) than were those without such history (22%; P = .03). Conclusions. The frequency of depressive disorders was high in this population, but the disorders were not related to EFV treatment. Younger age and a history of depression are important determinants for depression and should be considered for early detection and case management. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1)-infected persons frequently have increased numbers of T cells bearing the γδ T cell receptor for antigen (γδ TCR). HIV-1–seropositive patients with < 100 CD4+ cells/rum3 were selected and divided into 9 AIDS-defining illness groups. The percentages of CD4+,CD8+, or double-negative CD4-CDS- (DN) T cells (most of the latter expressing the γδ TCR) for 8 symptomatic groups were compared with those for a reference group of asymptomatic HIV-1–infected patients. DN T cells were increased only in patients with disseminated Mycobacterium avium-intracellulare complex (MAC) infection, toxoplasmosis, or Kaposi's sarcoma. Multivariate logistic regression analysis revealed that the percentage of DN T cells was a better predictor of MAC infection than was the percentage of CD4+ T cells. The increased percentage of DN T cells might have important implications for the understanding of γδ T cell physiology and for the early diagnosis and management of MAC infections in AIDS patients. [ABSTRACT FROM PUBLISHER]

AbstractCentralized statistical monitoring (CSM) detects clinical trial centers in which the distribution of a variable is atypical compared to its distribution in other centers. Most proposed CSM methods concern quantitative variables. Here we propose a new hierarchical Bayesian beta-binomial (HBBB) method for categorical variables and report the results of a simulation study assessing the performance of the method and of an application study using a real database to assess its usefulness. In the simulation study, sensitivity exceeded 90% when the sample size in the atypical center (N a ) was ≥ 20 and the difference in the proportion of events between the atypical center and the other centers (δ ) was ≥ 0.4; when N a was ≥ 40 and δ ≥ 0.3; and when N a was ≥ 150 and δ≥ 0.2. Specificity exceeded 90% when N a was ≥ 150 in all scenarios, and remained between 75% and 90% when N a was lower. In the application study, the method detected two centers in which N a was 50 and 200, and δ was 0.12 and 0.04, respectively. The performance of the HBBB method was similar to that proposed by competing approach. The modeling is easy and specificity is good in many scenarios with a limited sample size. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast., Methods: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies., Results: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies., Conclusions: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.).

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Background: We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1)., Methods: A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL., Results: At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8)., Conclusions: Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression.

Risk factors associated with the occurrence of protease inhibitor (PI)-related severe and serious adverse drug reactions (SADRs) were analyzed in a prospective cohort of 1155 patients who initiated PI-containing therapy. During a total follow-up of 2037 patient-years, 169 SADRs were reported, yielding a rate of 8 incidents per 100 patient-years (95% confidence interval [CI], 6.8-8.6). The most frequent SADRs were elevated transaminase levels (in 49 events); renal colic (27); abnormal hematological findings (23); and metabolic (18), neuromuscular (7), pancreatic (6), cutaneous (6), cardiovascular (5), and psychiatric disorders (5). Among baseline characteristics, plasma human immunodeficiency virus RNA levels of >or=5 log(10) copies/mL (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2), elevated aspartate aminotransferase levels (HR, 1.1 for each 20 IU of elevation; 95% CI, 1.1-1.2), creatinine clearance levels of <70 mL/min (HR, 2.1; 95% CI, 1.2-3.7), test results positive for hepatitis C virus antibodies or hepatitis B surface antigenemia (HR, 2.6; 95% CI, 1.8-3.7), and receipt of indinavir (HR, 1.7; 95% CI, 1.2-2.4) were independently predictive of a SADR. SADRs were frequent in the first 4 months after initiation of highly active antiretroviral therapy but continued to occur after that time period.

The role of nucleoside analogues (NAs) in lipodystrophy (LD) syndrome in human immunodeficiency virus (HIV)-infected patients remains controversial. We studied the prevalence of LD in previously untreated patients randomized to receive different NA combinations (in the ALBI-ANRS 070 trial) for 6 months. At month 30 of follow-up, 37 (31%) of 120 patients had >/=1 morphologic change, and 21 (57%) of 37 had isolated peripheral lipoatrophy; corresponding values for the patients who received only NAs throughout follow-up were 20 (30%) of 66 and 14 (67%) of 21, respectively. In multivariate analysis, factors associated with presence of LD at month 30 were initial assignment to the group receiving stavudine and didanosine (odds ratio [OR], 6.7; P=.02), age (OR for being 10 years older, 3.6; P=.002), and HIV RNA level at month 30 (OR, 0.4; P=.007). No difference was observed in cholesterol and glucose levels as a function of any pattern of antiretroviral exposure. Exposure to stavudine and didanosine was associated with LD syndrome (predominantly lipoatrophy).