Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Efficacy of Approved Versus Unapproved Vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Randomized Blinded Clinical Trials.

Background: Five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca, and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Zifivax, Medicago, Clover, and Cansino, but they are not approved in high-income countries. This meta-analysis compared the efficacy of US Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved and -unapproved vaccines in randomized clinical trials (RCTs). Methods: A systematic review of trial registries identified RCTs of SARS-CoV-2 vaccines. Risk of bias was assessed using the Cochrane tool (RoB 2). In the meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method). Results: Twenty-two RCTs were identified and 1 was excluded for high-risk of bias. Ten RCTs evaluated 5 approved vaccines and 11 RCTs evaluated 9 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% confidence interval [CI], 68%-92%) for approved vaccines versus 72% (95% CI, 66%-77%) for unapproved vaccines, with no significant difference between vaccine types (P = .12). Prevention of severe SARS-CoV-2 infection was 94% (95% CI, 75%-98%) for approved vaccines versus 86% (95% CI, 76%-92%) for unapproved vaccines (P = .33). The risk of serious adverse events was similar between vaccine types (P = .12). Conclusions: This meta-analysis of 21 RCTs in 390 459 participants showed no significant difference in efficacy between the FDA/EMA-approved and -unapproved vaccines for symptomatic or severe infection. Differences in study design, endpoint definitions, variants, and infection prevalence may have influenced results. New patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly.

Global COVID-19 Vaccine Inequity: Failures in the First Year of Distribution and Potential Solutions for the Future

Within the first year of distribution of vaccines against COVID-19, high-income countries (HICs) have achieved vaccination rates of 75-80%, whilst low-income countries (LICs) vaccinated <10%. This disparity in access has been one of the greatest failures of international cooperation during the SARS-CoV-2 pandemic. Global COVID-19 vaccine inequity affects us all, with ongoing risk of new variants emerging until global herd immunity is strengthened. The current model of global vaccine distribution is based on financial competition for limited vaccine supplies, resulting in HICs getting first access to vaccines, with LICs being forced to rely on voluntary donations through schemes like COVAX. Pharmaceutical companies own the intellectual property (IP) rights for COVID-19 vaccines, allowing them to control manufacturing, distribution, and pricing. However, the pharmaceutical industry did not develop these vaccines alone, with billions of dollars of public funding being instrumental in their discovery and development. Solutions to enable global equitable access already exist. The next step in scale up of manufacture and distribution worldwide is equitable knowledge sharing and technology transfer. The World Health Organization centralized technology transfer hub would facilitate international cooperation. Investments made into developing this infrastructure benefit the COVID-19 response whilst promoting future pandemic preparedness. Whilst globally there is majority support for waivers of IP to facilitate this next step, key opponents blocking this move include the UK and other European countries which host large domestic pharmaceutical industries. A nationalistic approach is not effective during a global pandemic. International cooperation is essential to achieve global goals against COVID-19.

Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

[This retracts the article DOI: 10.1093/ofid/ofab358.]

Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

Ivermectin is an antiparasitic drug being investigated for repurposing against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ivermectin showed in vitro activity against SARS-COV-2, but only at high concentrations. This meta-analysis investigated ivermectin in 23 randomized clinical trials (3349 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv, and trial registries. The primary meta-analysis was carried out by excluding studies at a high risk of bias. Ivermectin did not show a statistically significant effect on survival (risk ratio [RR], 0.90; 95% CI, 0.57 to 1.42; P = .66) or hospitalizations (RR, 0.63; 95% CI, 0.36 to 1.11; P = .11). Ivermectin displayed a borderline significant effect on duration of hospitalization in comparison with standard of care (mean difference, -1.14 days; 95% CI, -2.27 to -0.00; P = .05). There was no significant effect of ivermectin on time to clinical recovery (mean difference, -0.57 days; 95% CI, -1.31 to 0.17; P = .13) or binary clinical recovery (RR, 1.19; 95% CI, 0.94 to 1.50; P = .15). Currently, the World Health Organization recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.

Ivermectin for the prevention of COVID-19: addressing potential bias and medical fraud.

BACKGROUND: Ivermectin is an antiparasitic drug being investigated in clinical trials for the prevention of COVID-19. However, there are concerns about the quality of some of these trials. OBJECTIVES: To conduct a meta-analysis with randomized controlled trials of ivermectin for the prevention of COVID-19, while controlling for the quality of data. The primary outcome was RT-PCR-confirmed COVID-19 infection. The secondary outcome was rate of symptomatic COVID-19 infection. METHODS: We conducted a subgroup analysis based on the quality of randomized controlled trials evaluating ivermectin for the prevention of COVID-19. Quality was assessed using the Cochrane risk of bias measures (RoB 2) and additional checks on raw data, where possible. RESULTS: Four studies were included in the meta-analysis. One was rated as being potentially fraudulent, two as having a high risk of bias and one as having some concerns for bias. Ivermectin did not have a significant effect on preventing RT-PCR-confirmed COVID-19 infection. Ivermectin had a significant effect on preventing symptomatic COVID-19 infection in one trial with some concerns of bias, but this result was based on post hoc analysis of a multi-arm study. CONCLUSIONS: In this meta-analysis, the use of ivermectin was not associated with the prevention of RT-PCR-confirmed or symptomatic COVID-19. The currently available randomized trials evaluating ivermectin for the prevention of COVID-19 are insufficient and of poor quality.

Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud.

Ivermectin has become a controversial potential medicine for coronavirus disease 2019. Some early studies suggested clinical benefits in treatment of infection. However, the body of evidence includes studies of varying quality. Furthermore, some trials have now been identified as potentially fraudulent. We present a subgroup meta-analysis to assess the effects of stratifying by trial quality on the overall results. The stratification is based on the Cochrane Risk of Bias measures and raw data analysis where possible. The results suggest that the significant effect of ivermectin on survival was dependent on largely poor-quality studies. According to the potentially fraudulent study (risk ratio [RR], 0.08; 95% CI, 0.02-0.35), ivermectin improved survival ~12 times more in comparison with low-risk studies (RR, 0.96; 95% CI, 0.56-1.66). This highlights the need for rigorous quality assessments, for authors to share patient-level data, and for efforts to avoid publication bias for registered studies. These steps are vital to facilitate accurate conclusions on clinical treatments.

Whose voices should shape global health education? Curriculum codesign and codelivery by people with direct expertise and lived experience.

There are contrasting opinions of what global health (GH) curricula should contain and limited discussion on whose voices should shape it. In GH education, those with first-hand expertise of living and working in the contexts discussed in GH classrooms are often absent when designing curricula. To address this, we developed a new model of curriculum codesign called Virtual Roundtable for Collaborative Education Design (ViRCoED). This paper describes the rationale and outputs of the ViRCoED approach in designing a new section of the Global Health Bachelor of Science (BSc) curriculum at Imperial College London, with a focus on healthcare in the Syrian conflict. The team, importantly, involved partners with lived and/or professional experience of the conflict as well as alumni of the course and educators in all stages of design and delivery through to marking and project evaluation. The project experimented with disrupting power dynamics and extending ownership of the curriculum beyond traditional faculty by codesigning and codelivering module contents together with colleagues with direct expertise and experience of the Syrian context. An authentic approach was applied to assessment design using real-time syndromic healthcare data from the Aleppo and Idlib Governorates. We discuss the challenges involved in our collaborative partnership and describe how it may have enhanced the validity of our curriculum with students engaging in a richer representation of key health issues in the conflict. We observed an enhanced self-reflexivity in the students' approach to quantitative data and its complex interpretation. The dialogic nature of this collaborative design was also a formative process for partners and an opportunity for GH educators to reflect on their own positionality. The project aims to challenge current standards and structures in GH curriculum development and gesture towards a GH education sector eventually led by those with lived experience and expertise to significantly enhance the validity of GH education.

Symptomatic, biochemical and radiographic recovery in patients with COVID-19.

BACKGROUND: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described. METHODS: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness. RESULTS: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge. CONCLUSIONS: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19.

Missing clinical trial data: the evidence gap in primary data for potential COVID-19 drugs.

BACKGROUND: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of overall clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in this data by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications to quantify the number of trials missing results for drugs potentially being repurposed for COVID-19. METHODS: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. RESULTS: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. Tabular results were available on ClinicalTrials.gov for 1172 (31.2%) completed trials. A further 1066 (28.4%) had published results in the academic literature, but did not report results on ClinicalTrials.gov . Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). CONCLUSIONS: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause unnecessary additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

A review of the safety of favipiravir - a potential treatment in the COVID-19 pandemic?

BACKGROUND: Repurposing broad-spectrum antivirals is an immediate treatment opportunity for 2019 coronavirus disease (COVID-19). Favipiravir is an antiviral previously indicated for influenza and Ebola, which has shown some promise in early trials for treatment of COVID-19. We aim to review existing favipiravir safety evidence, which is vital to informing the potential future use of favipiravir in COVID-19. METHODS: A search was conducted across EMBASE and MEDLINE databases, supplemented by relevant grey-literature and ClinicalTrials.gov. All studies assessing the use of favipiravir in humans by 27 March 2020 were considered for inclusion. Further analysis of available safety data from phase 2 and 3 studies was undertaken. Data extracted were adverse events (AEs) grade 1-4, serious AEs and discontinuation for AEs. Specific AEs of interest highlighted in early-phase studies, including gastrointestinal AEs and hyperuricaemia, were also examined. RESULTS: Twenty-nine studies were identified as potential sources of evidence of the clinical safety of favipiravir. Six were phase 2 and 3 studies reporting relevant safety data for statistical comparison, representing a total of 4299 participants, an estimated 175 person-years-of-follow-up (PYFU). Comparator drugs were oseltamivir, umifenovir, lopinavir/ritonavir or placebo. Study follow-up was between 5 and 21 days. The proportions of grade 1-4 AEs on favipiravir was 28.2% vs 28.4% (P = n.s.) in the comparison arms. The proportion of discontinuations due to AEs on favipiravir was 1.1% vs 1.2% (P = n.s.) in the comparison arms. For serious AEs the proportion was 0.4% in both arms (P = n.s.). There were significantly fewer gastrointestinal AEs occurring on favipiravir vs comparators [8.7% vs 11.5%; P = 0.003]. Favipiravir showed significantly more uric acid elevations than comparators [5.8% vs 1.3%; P<0.0001]. CONCLUSIONS: Favipiravir demonstrates a favourable safety profile regarding total and serious AEs. However, safety concerns remain: hyperuricaemia, teratogenicity and QTc prolongation have not yet been adequately studied. Favipiravir may be safe and tolerable in short-term use, but more evidence is needed to assess the longer-term effects of treatment. Given the limitations of the evidence and unresolved safety concerns, caution is warranted in the widespread use of favipiravir against pandemic COVID-19.