ABSTRACT
Historically SARS-CoV-2 secondary attack rates (SAR) have been based on PCR positivity on screening symptomatic contacts, this misses transmission events and identifies only symptomatic contacts who are PCR positive at the time of sampling. We used serology to detect the relative transmissibility of Alpha Variant of Concern (VOC) to non-VOC SARS-CoV-2 to calculate household secondary attack rates. We identified index patients diagnosed with Alpha and non-VOC SARS-CoV-2 across two London Hospitals between November 2020 and January 2021 during a prolonged and well adhered national lockdown. We completed a household seroprevalence survey and found that 61.8% of non-VOC exposed household contacts were seropositive compared to 82.1% of Alpha exposed household contacts. The odds of infection doubled with exposure to an index diagnosed with Alpha. There was evidence of transmission events in almost all households. Our data strongly support that estimates of SAR should include serological data to improve accuracy and understanding.
ABSTRACT
Background: Globally rifampicin-resistant tuberculosis disease affects around 460 000 people each year. Current recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. MethodsTB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24 week regimens containing bedaquiline and pretomanid to treat rifampicin resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin resistant pulmonary tuberculosis and requiring a new course of therapy are eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients are randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also include moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment is administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study is equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome is the percentage of unfavourable outcomes at 72 weeks post randomisation. This is a composite of early treatment discontinuation, treatment failure, recurrence, lost to follow up and death. The study is conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DiscussionTB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel regimens that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to end of recruitment and additionally, the planned final analysis at 72 weeks after end of recruitment. Trial registrationClinicaltrials.gov registration number NCT02589782
Subject(s)
HIV Infections , Tuberculosis, Multidrug-Resistant , Tuberculosis , COVID-19ABSTRACT
Background: Trials of BCG to prevent COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of BCG’s beneficial non-specific effects come largely from data on mortality in infants, and from in vitro and animal studies. We assess all-cause mortality following a large BCG re-vaccination trial in Malawi. Methods: A population-based double-blind randomised trial comparing BCG re-vaccination vs placebo to prevent tuberculosis and leprosy was initiated in Karonga District, Malawi, in 1986-9, in individuals aged 3 months to 75 years. Active follow-up was carried out in northern areas of the district in 1991-94 and in a southern area in 2002-2018 covering 15.8% (7389 individuals) and 12.0% (5616 individuals) of the trial population respectively. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality rates. Findings: There was no difference in mortality rate between the BCG and placebo group in either follow-up, overall or by age group. Mortality rates in the northern areas were 6.6/1000 person years at risk (pyar), 95% confidence interval 5.5-7.8, and 7.0/1000pyar (5.9-8.2) for those who received BCG and placebo, respectively. In the southern area they were 6.3/1000 pyar, (5.5-7.1), and 5.9/1000 pyar, (5.2-6.8), respectively. Interpretation: We found no evidence of any beneficial effect of BCG re-vaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, may obscure any benefits. Funding Statement: The original trial was funded by primarily by the British Leprosy Relief Association (LEPRA), with assistance from the International Federation of Anti-Leprosy Organizations (ILEP), and the Immunology of Leprosy component of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (IMMLEP/TDR), with support of the Malawian Ministry of Health. The later follow-up was funded by The Wellcome Trust There was no specific funding for this analysis.Declaration of Interests: We declare no competing interests.Ethics Approval Statement: The trial protocol was approved in 1985 by the Health Sciences Research Committee of the Malawi Ministry of Health, the Standing Committee on Research in Human Subjects of WHO, and the Ethics Committee of the London School of Hygiene & Tropical Medicine. Follow-up of the population has been approved in the context of other studies by the Health Sciences Research Committee of the Malawi Ministry of Health and the Ethics Committee of the London School of Hygiene & Tropical Medicine.