Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.

Clade I-Associated Mpox Cases Associated with Sexual Contact, the Democratic Republic of the Congo.

We report a cluster of clade I monkeypox virus infections linked to sexual contact in the Democratic Republic of the Congo. Case investigations resulted in 5 reverse transcription PCR-confirmed infections; genome sequencing suggest they belonged to the same transmission chain. This finding demonstrates that mpox transmission through sexual contact extends beyond clade IIb.

Clinical course and management of COVID-19 in the era of widespread population immunity.

The clinical implications of COVID-19 have changed since SARS-CoV-2 first emerged in humans. The current high levels of population immunity, due to prior infection and/or vaccination, have been associated with a vastly decreased overall risk of severe disease. Some people, particularly those with immunocompromising conditions, remain at risk for severe outcomes. Through the course of the pandemic, variants with somewhat different symptom profiles from the original SARS-CoV-2 virus have emerged. The management of COVID-19 has also changed since 2020, with the increasing availability of evidence-based treatments in two main classes: antivirals and immunomodulators. Selecting the appropriate treatment(s) for patients with COVID-19 requires a deep understanding of the evidence and an awareness of the limitations of applying data that have been largely based on immune-naive populations to patients today who most likely have vaccine-derived and/or infection-derived immunity. In this Review, we provide a summary of the clinical manifestations and approaches to caring for adult patients with COVID-19 in the era of vaccine availability and the dominance of the Omicron subvariants, with a focus on the management of COVID-19 in different patient groups, including immunocompromised, pregnant, vaccinated and unvaccinated patients.

Non-pharmaceutical interventions for COVID-19: a systematic review on environmental control measures.

The purpose of this review was to identify the effectiveness of environmental control (EC) non-pharmaceutical interventions (NPIs) in reducing transmission of SARS-CoV-2 through conducting a systematic review. EC NPIs considered in this review are room ventilation, air filtration/cleaning, room occupancy, surface disinfection, barrier devices, [Formula: see text] monitoring and one-way-systems. Systematic searches of databases from Web of Science, Medline, EMBASE, preprint servers MedRxiv and BioRxiv were conducted in order to identify studies reported between 1 January 2020 and 1 December 2022. All articles reporting on the effectiveness of ventilation, air filtration/cleaning, room occupancy, surface disinfection, barrier devices, [Formula: see text] monitoring and one-way systems in reducing transmission of SARS-CoV-2 were retrieved and screened. In total, 13 971 articles were identified for screening. The initial title and abstract screening identified 1328 articles for full text review. Overall, 19 references provided evidence for the effectiveness of NPIs: 12 reported on ventilation, 4 on air cleaning devices, 5 on surface disinfection, 6 on room occupancy and 1 on screens/barriers. No studies were found that considered the effectiveness of [Formula: see text] monitoring or the implementation of one-way systems. Many of these studies were assessed to have critical risk of bias in at least one domain, largely due to confounding factors that could have affected the measured outcomes. As a result, there is low confidence in the findings. Evidence suggests that EC NPIs of ventilation, air cleaning devices and reduction in room-occupancy may have a role in reducing transmission in certain settings. However, the evidence was usually of low or very low quality and certainty, and hence the level of confidence ascribed to this conclusion is low. Based on the evidence found, it was not possible to draw any specific conclusions regarding the effectiveness of surface disinfection and the use of barrier devices. From these results, we further conclude that community agreed standards for well-designed epidemiological studies with low risk of bias are needed. Implementation of such standards would enable more confident assessment in the future of the effectiveness of EC NPIs in reducing transmission of SARS-CoV-2 and other pathogens in real-world settings. This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.

Emergence of mpox in the post-smallpox era-a narrative review on mpox epidemiology.

BACKGROUND: The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic. OBJECTIVES: This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak. SOURCES: We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023. CONTENT: The emergence of human mpox is intertwined with the eradication of smallpox and the cessation of the global smallpox vaccination campaign. The first human clade I and II monkeypox virus (MPXV) infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its re-emergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox. IMPLICATIONS: The changing epidemiology of mpox demonstrates how neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox.

Standard of care for viral haemorrhagic fevers (VHFs): a systematic review of clinical management guidelines for high-priority VHFs.

The Sudan virus disease outbreak in Uganda in 2022 showed our vulnerability to viral haemorrhagic fevers (VHFs). Although there are regular outbreaks of VHFs with high morbidity and mortality, which disproportionally affect low-income settings, our understanding of how to treat them remains inadequate. In this systematic review, we aim to explore the availability, scope, standardisation, and quality of clinical management guidelines for VHFs. We identified 32 guidelines, 25 (78%) of which were low quality and did not have supporting evidence and eight (25%) of which had been produced or updated in the past 3 years. Guidance on supportive care and therapeutics had little detail and was sometimes contradictory. Guidelines based on uncertain evidence are a risk to patients, an ethical challenge for clinicians, and a challenge to implementing trials due to heterogeneous standards of care. We recommend a standard living guideline framework to improve the quality, scope, and applicability of guidelines. Furthermore, investments into trials should aim to identify optimal treatment strategies for VHFs and prioritise affordable and scalable interventions to improve outcomes globally.

Estimating the global impact of coronavirus disease 2019 on people living with HIV.

PURPOSE OF REVIEW: The COVID-19 pandemic and public health response have directly and indirectly affected broader health outcomes, especially for those with existing chronic conditions, including HIV. We examine our current understanding of the global impact of COVID-19 on people with HIV (PWH). RECENT FINDINGS: The interaction between COVID-19 and HIV is complex, making it challenging to estimate its true impact on PWH. Evidence to date does not suggest that HIV confers a higher risk of acquiring SARS-CoV-2. However, once acquired, HIV increases the risk of severe COVID-19 and mortality, particularly in immunosuppressed viraemic individuals and in the context of traditional COVID-19 risk factors, including disparities in social determinants of health. In addition, COVID-19 vaccines may be less effective in the context of HIV infection with additional doses needed. The consequences of disruption of access to essential prevention and treatment services because of the pandemic are becoming evident and will likely adversely affect outcomes, risking decades of progress. SUMMARY: Given the increased mortality risk and reduced vaccine effectiveness seen in PWH, specific prevention and support measures are needed, including prioritization of vaccination and boosters, funding to mitigate the impact of pandemic and enabling integrated healthcare delivery during pandemics will be critical.

Mpox virus and transmission through sexual contact: Defining the research agenda.

In a Policy Forum piece, Dr. Nicola Low and colleagues define the research agenda for Mpox virus and transmission through sexual contact.

An evaluation of global Chikungunya clinical management guidelines: A systematic review.

Background: Chikungunya virus (CHIKV) has expanded its geographical reach in recent decades and is an emerging global health threat. CHIKV can cause significant morbidity and lead to chronic, debilitating arthritis/arthralgia in up to 40% of infected individuals. Prevention, early identification, and clinical management are key for improving outcomes. The aim of this review is to evaluate the quality, availability, inclusivity, and scope of evidence-based clinical management guidelines (CMG) for CHIKV globally. Methods: We conducted a systematic review. Six databases were searched from Jan 1, 1989, to 14 Oct 2021 and grey literature until Sept 16, 2021, for CHIKV guidelines providing supportive care and treatment recommendations. Quality was assessed using the appraisal of Guidelines for Research and Evaluation tool. Findings are presented in a narrative synthesis. PROSPERO registration: CRD42020167361. Findings: 28 CMGs were included; 54% (15/28) were produced more than 5 years ago, and most were of low-quality (median score 2 out of 7 (range 1-7)). There were variations in the CMGs' guidance on the management of different at-risk populations, long-term sequelae, and the prevention of disease transmission. While 54% (15/28) of CMGs recommended hospitalisation for severe cases, only 39% (11/28) provided guidance for severe disease management. Further, 46% (13/28) advocated for steroids in the chronic phase, but 18% (5/28) advised against its use. Interpretation: There was a lack of high-quality CMGs that provided supportive care and treatment guidance, which may impact patient care and outcomes. It is essential that existing guidelines are updated and adapted to provide detailed evidence-based treatment guidelines for different at-risk populations. This study also highlights a need for more research into the management of the acute and chronic phases of CHIKV infection to inform evidence-based care. Funding: The UK Foreign, Commonwealth and Development Office, Wellcome Trust [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135].

Competing health risks associated with the COVID-19 pandemic and early response: A scoping review.

BACKGROUND: COVID-19 has rapidly emerged as a global public health threat with infections recorded in nearly every country. Responses to COVID-19 have varied in intensity and breadth, but generally have included domestic and international travel limitations, closure of non-essential businesses, and repurposing of health services. While these interventions have focused on testing, treatment, and mitigation of COVID-19, there have been reports of interruptions to diagnostic, prevention, and treatment services for other public health threats. OBJECTIVES: We conducted a scoping review to characterize the early impact of COVID-19 on HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition. METHODS: A scoping literature review was completed using searches of PubMed and preprint servers (medRxiv/bioRxiv) from November 1st, 2019 to October 31st, 2020, using Medical Subject Headings (MeSH) terms related to SARS-CoV-2 or COVID-19 and HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition. Empiric studies reporting original data collection or mathematical models were included, and available data synthesized by region. Studies were excluded if they were not written in English. RESULTS: A total of 1604 published papers and 205 preprints were retrieved in the search. Overall, 8.0% (129/1604) of published studies and 10.2% (21/205) of preprints met the inclusion criteria and were included in this review: 7.3% (68/931) on HIV, 7.1% (24/339) on tuberculosis, 11.6% (26/224) on malaria, 7.8% (19/183) on sexual and reproductive health, and 9.8% (13/132) on malnutrition. Thematic results were similar across competing health risks, with substantial indirect effects of the COVID-19 pandemic and response on diagnostic, prevention, and treatment services for HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition. DISCUSSION: COVID-19 emerged in the context of existing public health threats that result in millions of deaths every year. Thus, effectively responding to COVID-19 while minimizing the negative impacts of COVID-19 necessitates innovation and integration of existing programs that are often siloed across health systems. Inequities have been a consistent driver of existing health threats; COVID-19 has worsened disparities, reinforcing the need for programs that address structural risks. The data reviewed here suggest that effective strengthening of health systems should include investment and planning focused on ensuring the continuity of care for both rapidly emergent and existing public health threats.

Availability, scope and quality of monkeypox clinical management guidelines globally: a systematic review.

BACKGROUND: Monkeypox (MPX) is an important human Orthopoxvirus infection. There has been an increase in MPX cases and outbreaks in endemic and non-endemic regions in recent decades. We appraised the availability, scope, quality and inclusivity of clinical management guidelines for MPX globally. METHODS: For this systematic review, we searched six databases from inception until 14 October 2021, augmented by a grey literature search until 17 May 2022. MPX guidelines providing treatment and supportive care recommendations were included, with no exclusions for language. Two reviewers assessed the guidelines. Quality was assessed using the Appraisal of Guidelines for Research and Evaluation II tool. RESULTS: Of 2026 records screened, 14 guidelines were included. Overall, most guidelines were of low-quality with a median score of 2 out of 7 (range: 1-7), lacked detail and covered a narrow range of topics. Most guidelines focused on adults, five (36%) provided some advice for children, three (21%) for pregnant women and three (21%) for people living with HIV. Treatment guidance was mostly limited to advice on antivirals; seven guidelines advised cidofovir (four specified for severe MPX only); 29% (4/14) tecovirimat, and 7% (1/14) brincidofovir. Only one guideline provided recommendations on supportive care and treatment of complications. All guidelines recommended vaccination as post-exposure prophylaxis (PEP). Three guidelines advised on vaccinia immune globulin as PEP for severe cases in people with immunosuppression. CONCLUSION: Our results highlight a lack of evidence-based clinical management guidelines for MPX globally. There is a clear and urgent need for research into treatment and prophylaxis including for different risk populations. The current outbreak provides an opportunity to accelerate this research through coordinated high-quality studies. New evidence should be incorporated into globally accessible guidelines, to benefit patient and epidemic outcomes. A 'living guideline' framework is recommended. PROSPERO REGISTRATION NUMBER: CRD42020167361.

Association between women's authorship and women's editorship in infectious diseases journals: a cross-sectional study.

BACKGROUND: Gender inequity is still pervasive in academic medicine, including journal publishing. We aimed to ascertain the proportion of women among first and last authors and editors in infectious diseases journals and assess the association between women's editorship and women's authorship while controlling for a journal's impact factor. METHODS: In this cross-sectional study, we randomly selected 40 infectious diseases journals (ten from each 2020 impact factor quartile), 20 obstetrics and gynaecology journals (five from each 2020 impact factor quartile), and 20 cardiology journals (five from each 2020 impact factor quartile) that were indexed in Journal Citation Reports, had an impact factor, had retrievable first and last author names, and had the name of more than one editor listed. We retrieved the names of the first and last authors of all citable articles published by the journals in 2018 and 2019 that counted towards their 2020 impact factor and collected the names of all the journals' editors-in-chief, deputy editors, section editors, and associate editors for the years 2018 and 2019. We used genderize.io to predict the gender of each first author, last author, and editor. The outcomes of interest were the proportions of women first authors and women last authors. We assessed the association between women's editorship and women's authorship by fitting quasi-Poisson regression models comprising the variables: the proportion of women last authors or women first authors; the proportion of women editors; the presence of a woman editor-in-chief; and journal 2020 impact factor. FINDINGS: We found 11 027 citable infectious diseases articles, of which 167 (1·5%) had an indeterminable first author gender, 155 (1·4%) had an indeterminable last author gender, and seven (0·1%) had no authors indexed. 5350 (49·3%) of 10 853 first authors whose gender could be determined were predicted to be women and 5503 (50·7%) were predicted to be men. Women accounted for 3788 (34·9%) of 10 865 last authors whose gender could be determined and men accounted for 7077 (65·1%). Of 577 infectious diseases journal editors, 190 (32·9%) were predicted to be women and 387 (67·1%) were predicted to be men. Of the 40 infectious diseases journals, 13 (32·5%) had a woman as editor-in-chief. For infectious diseases journals, the proportion of women editors had a significant effect on women's first authorship (incidence rate ratio 1·32, 95% CI 1·06-1·63; p=0·012) and women's last authorship (1·92, 1·45-2·55; p<0·0001). The presence of a woman editor-in-chief, the proportion of women last or first authors, and the journal's impact factor exerted no effect in these analyses. INTERPRETATION: The proportion of women editors appears to influence the proportion of women last and first authors in the analysed infectious diseases journals. These findings might help to explain gender disparities observed in publishing in academic medicine and suggest a need for revised policies towards increasing women's representation among editors. FUNDING: The European Society of Clinical Microbiology and Infectious Diseases.

A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors.

The number of occupants in a space influences the risk of far-field airborne transmission of SARS-CoV-2 because the likelihood of having infectious and susceptible people both correlate with the number of occupants. This paper explores the relationship between occupancy and the probability of infection, and how this affects an individual person and a population of people. Mass-balance and dose-response models determine far-field transmission risks for an individual person and a population of people after sub-dividing a large reference space into 10 identical comparator spaces. For a single infected person, the dose received by an individual person in the comparator space is 10 times higher because the equivalent ventilation rate per infected person is lower when the per capita ventilation rate is preserved. However, accounting for population dispersion, such as the community prevalence of the virus, the probability of an infected person being present and uncertainty in their viral load, shows the transmission probability increases with occupancy and the reference space has a higher transmission risk. Also, far-field transmission is likely to be a rare event that requires a high emission rate, and there are a set of Goldilocks conditions that are just right when equivalent ventilation is effective at mitigating against transmission. These conditions depend on the viral load, because when they are very high or low, equivalent ventilation has little effect on transmission risk. Nevertheless, resilient buildings should deliver the equivalent ventilation rate required by standards as minimum.