Clinical trials

TB is the single biggest infectious cause of death (1.5 million died in 2018), killing more HIV-positive people than any other disease, and is arguably the most important poverty-related disease in the world. TB's estimated incidence in Africa has been declining over recent years but progress is slow and plateauing. To avert stagnation, truly innovative and ambitious technologies are needed, especially those that improve case finding and time-to-diagnosis as, in mathematical models based on the TB care cascade framework, interventions that accomplish this will have the most impact on disrupting population-level transmission, including when deployed at facilities where patients are readily accessible. Critically, these interventions (triage tests) must promote access to confirmatory testing (e.g., Xpert MTB/RIF Ultra) by enabling patients to be referred rapidly and efficiently during the same visit. The investigators will optimise and evaluate a technology that, aside from the investigators early case-controlled study to show feasibility, is hitherto not meaningfully investigated for TB. This gap is alarming given, on one hand, the enormity of the TB epidemic and the need for a triage test and, on the other hand, promising proofs-of-concept that demonstrate high diagnostic accuracy of cough audio classifier for respiratory diseases such as pneumonia, asthma. pertussis, croup, and COPD. In some cases, these classification systems are CE-marked, awaiting FDA-approval, and subject to late-stage clinical trials. This demonstrates the promise of the underlying technological principle. CAGE-TB's innovation is further enhanced by: applying advanced machine learning methods that the team have specifically developed for TB patient cough audio analysis, use of mixed methods research - drawing from health economics, implementation science, and medical anthropology - to inform product design and assess barriers and facilitators to implementation, and uniquely for a TB diagnostic test, its potential deployment as a pure mHealth (smartphone-based) innovation that mitigates many barriers that typically jeopardise TPP criteria fulfilment.

The diverse microbial communities in different parts of the human body (microbiome) are important for health but understudied in pulmonary tuberculosis (TB), which is the single biggest infectious cause of death in the world. The investigators will study the site-of-disease microbiome (in the lung bronchoalveolar space) in TB cases to investigate how, before TB treatment, metabolic compounds made by microbes affect host biomarkers important for TB control. The investigators will ask this question again at the end-of-treatment and one year later. Specifically, the investigators will sample the lung at the active TB hotspot identified by imaging and compare this to a non-involved lung segment usually in the opposite lung. The investigators will compare the lung microbiome to other sites in the body (i.e. oral cavity, nasopharynx, supraglottis, and gut). A small amount of blood (\~15 ml) will be collected to assess peripheral immunological correlates of the host microbiome. Protected specimen brushings of the lung will be used to explore transcriptomic signatures and how these relate to the lung microbiome. The investigators will also apply these questions to the same number of controls (healthy patients and patients with an alternative diagnoses). This will lay the foundation for clinical trials to evaluate if specific bacteria have diagnostic (e.g., PCR) or therapeutic potential (e.g., antibiotics, prebiotics, probiotics, vaccines) where targeting the microbiome could improve clinical outcomes.

Novel strategies are needed to engage men in Sub Saharan Africa (SSA) with HIV testing, treatment and prevention services to drive the epidemic towards elimination. Suboptimal engagement with HIV prevention by men increases their risk of HIV acquisition, and is an important driver of new HIV infections in women. HIV self-testing (HIVST) addresses several key facility-based access barriers and HIVST distribution through leveraging male peer networks for HIV prevention is feasible, acceptable and effective in SSA. The objective of this project is to use an implementation science approach to establish the impact of HIVST distribution through male social networks, with phone-based support and improved risk perception, on PrEP (Pre-Exposure Prophylaxis) uptake among men in Eastern Zimbabwe. The project will leverage infrastructure and data associated with 20-year programme of HIV surveillance and behavioural research in a well-characterized population cohort hosted by the Manicaland Centre for Public Health Research, Zimbabwe. The study will utilise a cluster randomised design of 44 clusters (22 Intervention:22 control) comprising on average 81 men in each cluster (total N = 3591) followed for 6 months (giving \>80% power to detect a difference in PrEP initiation among men of 2% versus 8.5%). In intervention clusters the investigators will identify initial distributors who will receive an HIVST kit for personal use and HIVST kits to distribute to local peers. These peers can subsequently become distributors, allowing the intervention to propagate through peer networks. A toll-free helpline will provide pre- and post-test support and an SMS (Short Message Service) -based risk assessment will expedite PrEP initiation at the clinic. The study team will conduct a performance (process) evaluation of the intervention. to assess implementation fidelity, causal mechanisms underlying trial effectiveness including how characteristics of peer networks affect outcomes. Results of the study will be used to quantify the population level impacts and cost-effectiveness of male peer to peer HIVST distribution strategies on the uptake of PrEP in HIV hyper-endemic settings using a fully calibrated individual-based mathematical model. The envisaged long-term impact of this research is the development of a generalizable, multicomponent male peer-based HIVST and PrEP uptake model for settings where HIV incidence is high.