Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).

A living WHO guideline on drugs for covid-19

Updates: This is the fourteenth version (thirteenth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline. Clinical question: What is the role of drugs in the treatment of patients with covid-19? Context: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics. What is new?: The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19. About this guideline: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.

Drug treatments for covid-19: living systematic review and network meta-analysis

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 3 December 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 1 December 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration; 265 (57.2%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 fewer to 7 fewer, moderate certainty), interleukin-6 receptor antagonists when given with corticosteroids (23 fewer per 1000, 36 fewer to 7 fewer, moderate certainty), and Janus kinase inhibitors (44 fewer per 1000, 64 fewer to 20 fewer, high certainty). Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir (36 fewer per 1000, 41 fewer to 26 fewer, moderate certainty) and molnupiravir (19 fewer per 1000, 29 fewer to 5 fewer, moderate certainty). Remdesivir may reduce hospital admission (29 fewer per 1000, 40 fewer to 6 fewer, low certainty). Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution (3.3 days fewer, 4.8 fewer to 1.6 fewer, moderate certainty); several others showed a possible benefit. Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty). CONCLUSION: Corticosteroids, interleukin-6 receptor antagonists, and Janus kinase inhibitors probably reduce mortality and confer other important benefits in patients with severe covid-19. Molnupiravir and nirmatrelvir/ritonavir probably reduce admission to hospital in patients with non-severe covid-19. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fifth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness and safety of dual agent antiplatelet therapy combining clopidogrel and aspirin to prevent recurrent thrombotic and bleeding events compared with aspirin alone in patients with acute minor ischaemic stroke or transient ischaemic attack (TIA). DESIGN: Systematic review and meta-analysis of randomised, placebo controlled trials. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Library, ClinicalTrials.gov, WHO website, PsycINFO, and grey literature up to 4 July 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: Two reviewers independently screened potentially eligible studies according to predefined selection criteria and assessed the risk of bias using a modified version of the Cochrane risk of bias tool. A third team member reviewed all final decisions, and the team resolved disagreements through discussion. When reports omitted data that were considered important, clarification and additional information was sought from the authors. The analysis was conducted in RevMan 5.3 and MAGICapp based on GRADE methodology. RESULTS: Three eligible trials involving 10 447 participants were identified. Compared with aspirin alone, dual antiplatelet therapy with clopidogrel and aspirin that was started within 24 hours of symptom onset reduced the risk of non-fatal recurrent stroke (relative risk 0.70, 95% confidence interval 0.61 to 0.80, I2=0%, absolute risk reduction 1.9%, high quality evidence), without apparent impact on all cause mortality (1.27, 0.73 to 2.23, I2=0%, moderate quality evidence) but with a likely increase in moderate or severe extracranial bleeding (1.71, 0.92 to 3.20, I2=32%, absolute risk increase 0.2%, moderate quality evidence). Most stroke events, and the separation in incidence curves between dual and single therapy arms, occurred within 10 days of randomisation; any benefit after 21 days is extremely unlikely. CONCLUSIONS: Dual antiplatelet therapy with clopidogrel and aspirin given within 24 hours after high risk TIA or minor ischaemic stroke reduces subsequent stroke by about 20 in 1000 population, with a possible increase in moderate to severe bleeding of 2 per 1000 population. Discontinuation of dual antiplatelet therapy within 21 days, and possibly as early as 10 days, of initiation is likely to maximise benefit and minimise harms.

Antiretroviral resistance testing in HIV-positive people.

BACKGROUND: Resistance to antiretroviral therapy (ART) among people living with human immunodeficiency virus (HIV) compromises treatment effectiveness, often leading to virological failure and mortality. Antiretroviral drug resistance tests may be used at the time of initiation of therapy, or when treatment failure occurs, to inform the choice of ART regimen. Resistance tests (genotypic or phenotypic) are widely used in high-income countries, but not in resource-limited settings. This systematic review summarizes the relative merits of resistance testing in treatment-naive and treatment-exposed people living with HIV. OBJECTIVES: To evaluate the effectiveness of antiretroviral resistance testing (genotypic or phenotypic) in reducing mortality and morbidity in HIV-positive people. SEARCH METHODS: We attempted to identify all relevant studies, regardless of language or publication status, through searches of electronic databases and conference proceedings up to 26 January 2018. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov to 26 January 2018. We searched Latin American and Caribbean Health Sciences Literature (LILACS) and the Web of Science for publications from 1996 to 26 January 2018. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and observational studies that compared resistance testing to no resistance testing in people with HIV irrespective of their exposure to ART.Primary outcomes of interest were mortality and virological failure. Secondary outcomes were change in mean CD4-T-lymphocyte count, clinical progression to AIDS, development of a second or new opportunistic infection, change in viral load, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed each reference for prespecified inclusion criteria. Two review authors then independently extracted data from each included study using a standardized data extraction form. We analysed data on an intention-to-treat basis using a random-effects model. We performed subgroup analyses for the type of resistance test used (phenotypic or genotypic), use of expert advice to interpret resistance tests, and age (children and adolescents versus adults). We followed standard Cochrane methodological procedures. MAIN RESULTS: Eleven RCTs (published between 1999 and 2006), which included 2531 participants, met our inclusion criteria. All of these trials exclusively enrolled patients who had previous exposure to ART. We found no observational studies. Length of follow-up time, study settings, and types of resistance testing varied greatly. Follow-up ranged from 12 to 150 weeks. All studies were conducted in Europe, USA, or South America. Seven studies used genotypic testing, two used phenotypic testing, and two used both phenotypic and genotypic testing. Only one study was funded by a manufacturer of resistance tests.Resistance testing made little or no difference in mortality (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.36 to 2.22; 5 trials, 1140 participants; moderate-certainty evidence), and may have slightly reduced the number of people with virological failure (OR 0.70, 95% CI 0.56 to 0.87; 10 trials, 1728 participants; low-certainty evidence); and probably made little or no difference in change in CD4 cell count (mean difference (MD) -1.00 cells/mm³, 95% CI -12.49 to 10.50; 7 trials, 1349 participants; moderate-certainty evidence) or progression to AIDS (OR 0.64, 95% CI 0.31 to 1.29; 3 trials, 809 participants; moderate-certainty evidence). Resistance testing made little or no difference in adverse events (OR 0.89, 95% CI 0.51 to 1.55; 4 trials, 808 participants; low-certainty evidence) and probably reduced viral load (MD -0.23, 95% CI -0.35 to -0.11; 10 trials, 1837 participants; moderate-certainty evidence). No studies reported on development of new opportunistic infections or quality of life. We found no statistically significant heterogeneity for any outcomes, and the I² statistic value ranged from 0 to 25%. We found no subgroup effects for types of resistance testing (genotypic versus phenotypic), the addition of expert advice to interpretation of resistance tests, or age. Results for mortality were consistent when we compared studies at high or unclear risk of bias versus studies at low risk of bias. AUTHORS' CONCLUSIONS: Resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted 12 or more years ago. We found no evidence in treatment-naive people. Resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS. The trials included very few participants from low- and middle-income countries.

Increasing HIV subtype diversity and its clinical implications in a sentinel North American population.

BACKGROUND: HIV-1 is a highly diverse virus; subtypes may exhibit differences in rates of transmission, disease progression, neurotoxicity, antiretroviral treatment failure profiles and accuracy of viral load measurements. To date, the HIV epidemic in Canada and the rest of the developed world has been largely due to subtype B; however, shifts in subtype epidemiology could have significant implications. OBJECTIVE: To determine whether there has been an increase in HIV subtype diversity in southern Alberta, Canada. METHODS: All 2358 patients receiving any HIV care between December 31, 2001 and December 31, 2010 were included in a retrospective analysis of subtype prevalence and incidence. In an indexed analysis, subtype trends from 1994 to 2010 were also evaluated. RESULTS: Between 2001 and 2010, the prevalence of non-B HIV subtypes in patients with a known subtype increased from 7% to 24%. In 2010, the most prevalent non-B subtypes were C (65%), A (11%), CRF02_AG (9.7%), CRF01_AE (4.9%), D (3.9%), G (2.9%) and CRF06_cpx (1.5%). In the indexed analysis, there was an overall proportional increase in non-B subtypes of 2.3% per year. The year-over-year increase in the prevalence of patients infected with a nonsubtype B virus increased from 13% from 1995 to 2002 to 27% from 2003 to 2010 (P=0.01). Incident non-B subtype cases increased from 9.6% to 32.4% over these time periods. CONCLUSIONS: This recent and dramatic shift in HIV strain diversity in Canada is unprecedented and may have important public health, research and clinical consequences.

HISTORIQUE: Le VIH-1 est un virus très hétérogène, dont les sous-types peuvent différer sur le plan du taux de transmission, de l'évolution de la maladie, de la neurotoxicité, des profils d'échec de traitement antirétroviral et de la précision des mesures de la charge virale. Jusqu'à présent, l'épidémie de VIH au Canada et dans le reste du monde industrialisé est en grande partie attribuable au sous-type B, mais des changements dans l'épidémiologie des sous-types pourraient avoir des conséquences considérables. OBJECTIF: Déterminer si la diversité des sous-types de VIH a augmenté dans le sud de l'Alberta, au Canada. MÉTHODOLOGIE: Les 2 358 patients qui avaient reçu des soins du VIH entre le 31 décembre 2001 et le 31 décembre 2010 ont participé à une étude rétrospective de la prévalence et de l'incidence des sous-types. Dans une analyse indexée, les tendances de sous-types ont également été évaluées entre 1994 et 2010. RÉSULTATS: Entre 2001 et 2010, la prévalence des sous-types de VIH non-B chez les patients dont le sous-type est connu est passée de 7 % à 24 %. En 2010, les sous-types non-B les plus prévalents étaient les sous-types C (65 %), A (11 %), CRF02_AG (9,7 %), CRF01_AE (4,9 %), D (3,9 %), G (2,9 %) et CRF06_cpx (1,5 %). Dans l'analyse indexée, on constatait une augmentation proportionnelle globale des sous-types non-B de 2,3 % par année. L'augmentation de la prévalence de patients infectés par un virus de sous-type non-B a augmenté d'une année à l'autre, passant de 13 % de 1995 à 2002 à 27 % de 2003 à 2010 (P=0,01). Les nouveaux cas de sous-types non-B sont passés de 9,6 % à 32,4 % pendant ces périodes. CONCLUSIONS: Ces changements récents et marqués de la diver-sité des souches de VIH au Canada sont sans précédent et pourraient avoir des conséquences importantes en matière de santé publique, de recherche et de clinique.