Tuberculosis prevalence after 4 years of population-wide systematic TB symptom screening and universal testing and treatment for HIV in the HPTN 071 (PopART) community-randomised trial in Zambia and South Africa: a cross-sectional survey (TREATS)

Background Tuberculosis (TB) prevalence remains persistently high in many settings, with new or expanded interventions required to achieve substantial reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART) community-randomised trial randomised 14 communities to receive the “PopART” intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7 communities to receive standard-of-care (arm C). The intervention was delivered door-to-door by community HIV care providers (CHiPs) and included universal HIV testing, facilitated linkage to HIV care at government health clinics, and systematic TB symptom screening. The Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the impact of delivering the PopART intervention on TB outcomes, in communities with high HIV and TB prevalence. Methods and findings The study population of the HPTN 071 (PopART) trial included individuals aged ≥15 years living in 21 urban and peri-urban communities in Zambia and South Africa, with a total population of approximately 1 million and an adult HIV prevalence of around 15% at the time of the trial. Two sputum samples for TB testing were provided to CHiPs by individuals who reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight loss ≥1.5 kg in the last month, or current night sweats) or that a household member was currently on TB treatment. Antiretroviral therapy (ART) was offered universally at clinics in arm A and according to local guidelines in arms B and C. The TREATS study was conducted in the same 21 communities as the HPTN 071 (PopART) trial between 2017 and 2022, and TB prevalence was a co-primary endpoint of the TREATS study. The primary comparison was between the PopART intervention (arms A and B combined) and the standard-of-care (arm C). During 2019 to 2021, a TB prevalence survey was conducted among randomly selected individuals aged ≥15 years (approximately 1,750 per community in arms A and B, approximately 3,500 in arm C). Participants were screened on TB symptoms and chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for individuals who screened positive. Sputum eligibility was determined by the presence of a cough for ≥2 weeks, or ≥2 of 5 “TB suggestive” symptoms (cough, weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was compared between trial arms using standard methods for cluster-randomised trials, with adjustment for age, sex, and HIV status, and multiple imputation was used for missing data on prevalent TB. Among 83,092 individuals who were eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing, and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence was 0.92% (457/49,556). The geometric means of 7 community-level prevalence estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with no evidence of a difference comparing arms A and B combined with arm C (adjusted prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB prevalence was higher among people living with HIV than HIV–negative individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54, 3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African communities. The primary limitations are that the study was powered to detect only large reductions in TB prevalence in the intervention arm compared with standard-of-care, and the between-community variation in TB prevalence was larger than anticipated. Conclusions There was no evidence that the PopART intervention reduced TB prevalence. Systematic screening for TB that is based on symptom screening alone may not be sufficient to achieve a large reduction in TB prevalence over a period of several years. Including chest X-ray screening alongside TB symptom screening could substantially increase the sensitivity of systematic screening for TB. Trial registration The TREATS study was registered with ClinicalTrials.gov Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013

Macrosocial determinants of population health in the context of globalization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55738/1/florey_globalization_2007.pd

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Treatment of Neuromyelitis Optica: Current Debate

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that largely affects optic nerves and spinal cord. Recent studies have identified an elevation of serum anti-aquaporin 4 antibody as a hallmark of NMO. Typical cases of NMO significantly differ from multiple sclerosis (MS) in immunological markers, histopathology, and responses to therapy. In fact, plasma exchange may be more efficacious for NMO than MS, whereas interferon-ß is recommended for MS but not for NMO. An emerging idea that pathogenesis of NMO may involve an interaction of the newly identified helper T cell subset, Th17, with B cells offers potential targets of therapy