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The world’s largest randomised clinical trial of potential coronavirus treatments is well underway in the UK as part of the race to find a treatment.
Introduction: The 4-aminoquinolines, chloroquine, and hydroxychloroquine have been used for over 70 years for malaria and rheumatological conditions, respectively. Their broad-spectrum antiviral activity, excellent safety profile, tolerability, low cost, and ready availability made them prime repurposing therapeutic candidates at the beginning of the COVID-19 pandemic.Areas covered: Here, the authors discuss the history of hydroxychloroquine and chloroquine, the in vitro data which led to their widespread repurposing and adoption in COVID-19 and their complex pharmacokinetics. The evidence for the use of these drugs is assessed through in vivo animal experiments and the wealth of conflicting data and interpretations published during COVID-19, including the more informative results from randomized controlled trials (RCTs). The safety aspects of these drugs, in particular cardiotoxicity, are then reviewed.Expert opinion: The evidence from clinical trials in COVID-19 supports the well-established safety record of the 4-aminoquinolines at currently recommended dosage. In hospitalized patients with severe COVID-19 RCTs show clearly that the 4-aminoquinolines are not beneficial. The only treatments with proven benefit at this stage of infection are immunomodulators (dexamethasone, IL-6 receptor antagonists). No antiviral drugs have proven life-saving in late-stage COVID-19.
AbstractStudies have shown that HCV subtype 3a had likely been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV subtype 3a from the UK, North America, Australia and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV subtype 3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country and that they were more diverse than viruses from other host ancestries. We also inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America and the Australian continent. This initial spread happened during or soon after the end of the second world war. This was followed by an exponential growth in the effective population size of HCV subtype 3a worldwide and many independent transmissions between the UK, North America and Australian continent. Using both host and virus genomic information can be highly informative in studying the virus epidemic history especially in the context of chronic infections.
Strategic Treatment Optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C
ABSTRACTBackgroundThe WHO has identified the need for a better understanding of which patients can be cured with ultrashort course hepatitis C (HCV) therapyMethods202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks’ sofosbuvir/ledipasvir/ribavirin. Primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment.ResultsAll evaluable participants achieved SVR12 overall (197/197, 100%[95%CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95%CI −3.8%,+3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91%[86%-97%] (92/101) for fixed-duration vs 48%[39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall first-line SVR12 was 72%[65%-78%] (70/101) without ribavirin and 68%[61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01).ConclusionsUnsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy.RegistrationISRCTN 37915093.FundingNational Institutes of Health Research.
Background: Angiotensin I converting enzyme 2 (ACE2) is a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and differences in its expression may affect susceptibility to infection. Methods: We performed a genome-wide expression quantitative trait loci (eQTL) analysis using hepatitis C virus-infected liver tissue from 190 individuals. Results: We discovered that polymorphism in a type III interferon gene (IFNL4), which eliminates IFN-λ4 production, is associated with a two-fold increase in ACE2 RNA expression. Conversely, among genes negatively correlated with ACE2 expression, IFN-signalling pathways were highly enriched and ACE2 was downregulated after IFN-α treatment. Negative correlation was also found in the gastrointestinal tract where inflammation driven IFN-stimulated genes were negatively correlated with ACE2 expression and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of ACE2 across tissue and species. Conclusions: We conclude that ACE2 is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of IFNL4 gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions.
Ambulatory induction phase treatment of cryptococcal meningitis in HIV integrated primary care clinics, Yangon, Myanmar.
BackgroundCryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon.MethodThis retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day).ResultsSeventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies.ConclusionAmbulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.
Inter-prescriber variability in the decision to prescribe antibiotics to febrile patients attending primary care in Myanmar
Abstract Background Most antibiotic prescribing occurs in primary care. Even within the same health facility, there may be differences between prescribers in their tendency to prescribe antibiotics, which may be masked by summary data. We aimed to quantify prescriber variability in antibiotic prescription to patients with acute fever in primary care clinics in Myanmar. Methods We conducted a secondary analysis of prescribing data from 1090 patient consultations with 40 prescribing doctors from a trial investigating the effect of point-of-care C-reactive protein (CRP) tests on antibiotic prescription for acute fever. We used multilevel logistic regression models to assess inter-prescriber variability in the decision to prescribe antibiotics. Results The median odds ratio (MOR) in the unadjusted model was 1.82 (95% CI: 1.47–2.56) indicating that when two prescribers from this population are randomly selected then in half of these pairs the odds of prescription will be greater than 1.82-fold higher in one prescriber than the other. The estimated variability from this sample of prescribers corresponds to a population of prescribers where the top 25% of prescribers will prescribe antibiotics to over 41% of patients while the bottom 25% will prescribe antibiotics to less than 23% of patients. Inter-prescriber variation in antibiotic prescribing remained after adjustment for patient characteristics and CRP information (P < 0.001). Conclusions Despite sharing the same management guidelines, there was substantial inter-prescriber variation in antibiotic prescription to patients with acute fever. This variation should be considered when designing trials and stewardship programmes aiming to reduce inappropriate antibiotic prescribing.
MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Niche and local geography shape the pangenome of wastewater- and livestock-associated Enterobacteriaceae
Escherichia coli and other Enterobacteriaceae are diverse species with “open” pangenomes, where genes move intra- and interspecies via horizontal gene transfer. However, most analyses focus on clinical isolates. The pangenome dynamics of natural populations remain understudied, despite their suggested role as reservoirs for antimicrobial resistance (AMR) genes. Here, we analyze near-complete genomes for 827 Enterobacteriaceae (553 Escherichia and 274 non-Escherichia spp.) with 2292 circularized plasmids in total, collected from 19 locations (livestock farms and wastewater treatment works in the United Kingdom) within a 30-km radius at three time points over a year. We find different dynamics for chromosomal and plasmid-borne genes. Plasmids have a higher burden of AMR genes and insertion sequences, and AMR-gene-carrying plasmids show evidence of being under stronger selective pressure. Environmental niche and local geography both play a role in shaping plasmid dynamics. Our results highlight the importance of local strategies for controlling the spread of AMR.
The challenges of estimating the human global burden of disease of antimicrobial resistant bacteria.
Estimating the contribution of antimicrobial resistance (AMR) to global mortality and healthcare costs enables evaluation of interventions, informs policy decisions on resource allocation, and drives research priorities. However assembling the high quality, patient-level data required for global estimates is challenging. Capacity for accurate microbiology culture and antimicrobial susceptibility testing is woefully neglected in low and middle-income countries, and further surveillance and research on community antimicrobial usage, bias in blood culture sampling, and the contribution of co-morbidities such as diabetes is essential. International collaboration between governments, policy makers, academics, microbiologists, front-line clinicians, veterinarians, the food and agriculture industry and the public is critical to understand and tackle AMR.
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3·5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.
Non-coding variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only ∼35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream of MEF2C that cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified in MEF2C in the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5’UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.
Development and validation of an in silico decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients
Most deaths from severe falciparum malaria occur within 24 hours of presentation to hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections Bayesian pharmacokinetic-pharmacodynamic modelling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% parasites within 24 hours (PC24≥99%) for standard (2.4 mg/kg i.v. artesunate at 0 and 12 hours) and simplified (4 mg/kg i.v. artesunate at 0 hours) regimens were 65% (52.5%-74.5%) versus 44% (25%-61.5%) for adults, 62% (51.5%-74.5%) versus 39% (20.5%-58.5%) for larger children (≥20 kg) and 60% (48.5%-70%) versus 36% (20%-53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. Rapid clearance of parasites, where there is loss of ring stage sensitivity to artemisinin, in patients with severe falciparum malaria is compromised with the currently recommended and proposed simplified i.v. artesunate dosing regimens.
Awake Proning as an Adjunctive Therapy for Refractory Hypoxemia in Non-Intubated Patients with COVID-19 Acute Respiratory Failure: Guidance from an International Group of Healthcare Workers.
Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6-12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.