TB fast track: effect of a point-of-care TB test-and-treat algorithm on early mortality in people with HIV accessing ART

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

Treatment for HIV (antiretroviral therapy, or ART), has greatly reduced death rates among people with HIV worldwide. However in low-resource settings, death rates continue to be high even for people taking ART, particularly in the first few months on treatment. Tuberculosis (TB) is the most important cause of these early deaths, and people who are due to start ART are recommended to be screened for TB first. However, TB is hard to diagnose because the tests which are most widely available do not work well for people with HIV. As a result, people with HIV may have to go through lots of tests for TB, which delays the start of TB treatment; it also delays the start of ART. Both of these delays increase the risk that the patient dies.
We propose a study to try to reduce this high death rate. In 20 primary care clinics in South Africa, we will enrol people with advanced HIV who have come to start ART to our study. In 10 of the clinics (intervention), selected at random, we will use simple, inexpensive tests (a new urine test for TB, weight and height, and a blood test for anaemia) which can be done on site with immediate results, to identify those patients who are at highest risk of having TB, and of dying early. People who are high risk will start TB treatment straight away, then ART as soon as possible afterwards; people who are low TB risk will start ART straight away. People with medium TB risk will be given antibiotics while a chest X-ray and sputum (spit) test for TB are done, and will come back after a week to decide if they should start TB treatment followed by ART, or just start ART. At the other 10 (control) clinics, patients will be looked after in the normal way, following national guidelines. We will follow all patients up for 6 months. We will compare the death rate at 6 months in the 10 intervention clinics, using our new approach, to death rates in the 10 control clinics, using the routine approach. If our new approach reduces the death rate, clinics throughout low resource settings could use this low-cost strategy to save lives among people with HIV.

Technical Summary

Background: Early mortality remains high among adults with HIV accessing antiretroviral therapy (ART) in resource-constrained settings, with tuberculosis (TB) a leading cause of death. 20% people accessing ART in South Africa have undiagnosed TB. However, due to insensitivity of sputum microscopy, and a complex diagnostic pathway for smear-negative TB, the time to TB diagnosis is protracted, delaying both TB treatment (among those diagnosed with TB) and ART (among all investigated, whether or not TB is diagnosed). We hypothesise that a care pathway using point-of-care technology to rapidly identify individuals presenting for ART at high risk of TB and ensure they start TB treatment, then ART, will markedly reduce early mortality.
Objective: To compare 6-month mortality among patients with HIV disease and CD4 150 cells/?l referred to start ART between intervention clinics implementing a point-of-care algorithm to identify individuals with a high probability of active TB, and facilitate rapid initiation of TB treatment, followed by ART; vs. control clinics delivering standard of care management according to South African TB/HIV care guidelines.
Methods: This is a cluster-randomised trial, randomising 20 primary health clinics in Gauteng and Limpopo provinces, South Africa. ART-eligible patients (CD4 150, ambulant, no recent TB treatment) at intervention clinics will be assessed using simple point-of-care assays. Patients with any of: positive urine lipoarabinomannan (LAM), haemoglobin (Hb) 10, body mass index (BMI) 18.5 will be considered high probability TB, and start TB treatment immediately, then ART. Asymptomatic patients with negative LAM, Hb 10, BMI 18.5 will be low probability and will start ART. Others ( medium probability ) will be investigated for smear-negative TB as per South African guidelines with review after one week to re-categorise into high or low probability. In control clinics we will recruit similar patients and obtain permission for follow-up; management will be as per national guidelines. The primary outcome is mortality at 6 months after recruitment; secondary outcomes include severe morbidity, measured by duration of hospitalisation. Diagnostic cost per TB case detected, and cost per DALY, will be estimated. We estimate mortality conservatively at 25/100 person years in the control arm; with 10 clusters per arm, 175 patients per cluster, and 95% ascertainment of vital status at 6 months, using between-cluster coefficients of variation of 0.2 and 0.25, there will be 91% and 85% power to assess 40% reduction in mortality, respectively.
Significance: This strategy may result in a major reduction in mortality for people with HIV.

Publications

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Grant AD (2016) CROI 2016 presentation

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Mukora R (2018) Cost of point-of-care lateral flow urine lipoarabinomannan antigen testing in HIV-positive adults in South Africa. in The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

 
Guideline Title The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV
Description Citation in WHO LF-LAM guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/
 
Description Member of WHO guideline development group
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
URL http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/
 
Description Proposed change to ICD-11: at their request we have submitted a proposal to revise the classification of HIV-associated causes of death to Dr Robert Jakob of the the Joint Task Force on ICD-11.
Geographic Reach Multiple continents/international 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Workshop presentation on CROI education day on Pragmatic Trials
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.croiwebcasts.org/console/player/37026?mediaType=audio&&crd_fl=1&ssmsrq=1521074094858&ctms...
 
Description Prevalence of TB at autopsy in South Africa
Amount $599,127 (USD)
Funding ID OPP1083118 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2013 
End 01/2016
 
Description Young investigator award
Amount $2,000 (USD)
Organisation Conference on Retroviruses and Opportunistic Infections (CROI) 
Sector Charity/Non Profit
Country United States
Start 02/2015 
End 02/2015
 
Title TB Fast Track autopsy data 
Description Autopsy data from TB Fast Track research participants 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact not yet known 
URL http://datacompass.lshtm.ac.uk/243/
 
Title TB Fast Track cost data 
Description Data used in the TB Fast Track cost analysis 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Not aware of impact to date 
URL https://datacompass.lshtm.ac.uk/
 
Title TB Fast Track main study database 
Description Data used in the analysis of the main results of the TB Fast Track trial. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Data are being used in further analyses. 
URL https://datacompass.lshtm.ac.uk/
 
Title TB Fast Track 
Description The intervention is a management strategy for people with HIV and CD4<150, in primary care clinics in South Africa, who are not currently taking ART or TB treatment. The intervention uses point of care tests (urine LAM, haemoglobin and BMI) to assign probability of TB. Patients assigned high probability start TB treatment immediately followed by ART after two weeks. The aim is to reduce mortality as measured after 6 months. The strategy is currently being tested in a cluster-randomised trial funded by Global Health Trials. 
Type Health and Social Care Services
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Trial is in progress 
URL http://www.controlled-trials.com/ISRCTN35344604
 
Description CROI 2016 press briefing 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I gave a press briefing concerning my CROI 2016 conference presentation, discussing the primary outcome of the study, to invited journalists. This led to several press items being published.
Year(s) Of Engagement Activity 2016
 
Description Conference presentation (Blizard) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk stimulated a number of interesting questions from a range of participants

Several audience members wanted to discuss the study strategy after the talk.
Year(s) Of Engagement Activity 2014
 
Description Conference presentation (SATB 2014) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk resulted in several questions about the study

The talk has helped to raise awareness of the study among the South African TB community
Year(s) Of Engagement Activity 2014
URL http://www.tbconference.co.za/
 
Description Department of health briefing, Cape Town 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact We met with Dr Yogan Pillay, Deputy Director - General: HIV/AIDS, TB and Maternal, Child and Womens Health in the National Department of Health, South Africa, in order to give him a private briefing of the results of the TB Fast Track trial, since the trial results are of direct relevance to his department.
Year(s) Of Engagement Activity 2015
 
Description Empirical TB treatment symposium (Union TB conference) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Symposium at the Union TB meeting in which lead researchers of all current and recent trials of empirical TB treatment presented their studies. Talk was followed by a lively discussion about trials of empirical TB treatment

Following from this talk, I have been asked by WHO TB department to take part in a symposium on empirical TB treatment at the US HIV conference 2015. In addition, we are in discussion with WHO TB department about how the results of this trial may feed into WHO guidelines.
Year(s) Of Engagement Activity 2014
 
Description Feedback on TB Fast Track 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Feedback of study results to Sekhukhkune Department of Health, South Africa. Discussion focussed on how best to diagnose TB among HIV+ patients.
Year(s) Of Engagement Activity 2016
 
Description Feedback on TB Fast Track 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Discussion of study results with Limpopo provincial ethics committee, South Africa. Study team was requested to provide further feedback to clinicians in the study area.
Year(s) Of Engagement Activity 2016
 
Description Feedback on TB Fast Track 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Presentation of study results to Tshwane Department of Health, South Africa. Discussion focussed on need to initiate antiretroviral therapy promptly.
Year(s) Of Engagement Activity 2016
 
Description Global Health Lecture Series (LSHTM) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Students were keen to ask questions about the intervention strategy

Several students contacted me after the talk to find out more and to ask if they could contribute to the project. Two students subsequently undertook MSc projects within the larger project.
Year(s) Of Engagement Activity 2014
 
Description HIV research meeting, Mortimer Market 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Presentation of the trial at the HIV research meeting, Mortimer Market centre. Increased knowledge of TB and empirical TB treatment
Year(s) Of Engagement Activity 2015
 
Description International AIDS conference: CDC symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of TB Fast Track results at a CDC symposium: A Survival Guide for Advanced HIV Disease: Increasing Access to and Knowledge of Life-Saving Interventions.
Year(s) Of Engagement Activity 2016
URL http://programme.aids2016.org/Programme/Session/1048
 
Description International AIDS conference: TB Fast Track symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Presentation of TB Fast Track results in a symposium on TB diagnosis among people with HIV. Attended by policy makers from WHO, Stop TB, UNAIDS, South African department of health, funders, implementers, researchers. Following from the presentation, Alison Grant was interviewed by a South African television news channel, and was invited to join a WHO guideline group.
Year(s) Of Engagement Activity 2016
URL http://programme.aids2016.org/Programme/Session/955
 
Description Meeting for clinics and district TB/HIV coordinators 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Around 50 clinic staff and district / regional HIV/TB coordinators attended a progress update meeting with questions afterwards.

Increased interest in and understanding of the study. Clinic staff were interested to know how they could promote participation in the study at their clinic.
Year(s) Of Engagement Activity 2013
 
Description Presentation at HIV academic meeting (St Mary's) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Talk was followed by lively discussion of study strategy.

After my talk other researchers were interested to share experience around patient engagement in HIV care
Year(s) Of Engagement Activity 2014
 
Description Presentation at South Africa TB Think Tank meeting on TB mortality 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Invited presentations at a meeting aiming to better understand TB mortality in South Africa. Specific objectives were, using a health systems approach, to understand what is known currently, the current existing gaps, and to identify possible root causes for TB mortality.
Year(s) Of Engagement Activity 2020
 
Description TB Fast Track results presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of TB Fast Track study results to Southern African HIV clinicians society meeting. Discussion focussed on importance of prompt ART initiation and importance of mixed infections as cause of death amongst these patients.
Year(s) Of Engagement Activity 2016
 
Description TV interview (Durban) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Alison Grant interviewed by TV team for Africa News Network 7 about TB in South Africa and its importance as a cause of death.
Year(s) Of Engagement Activity 2016
 
Description Union conference: WHO symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Presentation of TB Fast Track results at WHO-organised symposium "Enough is enough - Time to end preventable mortality among people living with HIV!"
Year(s) Of Engagement Activity 2016
URL http://liverpool.worldlunghealth.org/programme/symposia