Short summary

Tuberculosis (TB) remains the major cause of morbidity and mortality among patients with HIV. Sub-optimal diagnostics contributes to poor patient outcome and there is an urgent need to identify non-sputum-based rapid diagnostic tests. We aim to identify point-of-care strategies that can improve TB case detection and clinical outcomes among patients with advanced HIV in Ghana including: the implementation and evaluation of the urine-based point-of-care LF-LAM test; the description of point-of-care ultrasound; the description of the epidemiology of HIV-associated TB; and the the foundation of an HIV-cohort and biobank for evaluation of new diagnostic and prognostic markers.

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Rationale

Background
Tuberculosis (TB) is a common cause of hospitalization, morbidity and mortality among HIV-infected people that disproportionately affects low resource countries. In Sub-Saharan Africa, autopsy studies have found a mean TB prevalence of 40% among HIV-infected patients, and almost half of the cases were undiagnosed with TB in life. To improve TB case detection, new diagnostic tools and strategies for systematic screening of people living with HIV is a key component of the World Health Organizations'(WHO) "End TB strategy". Non-sputum-based TB diagnostic tests, that can be performed at the point-of-care at low cost are highly desired and could serve to narrow the diagnostic gap and ensure timely treatment. 

The TB diagnostic test lateral flow lipoarabinomannan (LF-LAM) is a urine-based test that detects lipoarabinomannan antigen in the urine as a marker of active TB. We previously evaluated LF-LAM test among HIV-infected patients in Ghana. Our study formed part of the evidence base for WHO to endorse use of the LF-LAM for detection of active TB among patients with advanced HIV in 2015. A clinical trial from 2016 was the first to demonstrate that LAM-guided anti-tuberculous treatment could reduce early mortality among HIV-infected inpatients. Very recently another trial found that LF-LAM leads to earlier and increased TB diagnosis and found indications of survival benefit in some high-risk subgroups of patients with HIV, although underpowered. These trials support introduction of LF-LAM test as part of national TB programmes, but uptake has been slow. 

Rationale and innovation

Our project proposes a multi-center cluster randomized controlled trial of LF-LAM implementation in Ghana using a stepped wedge design which allows implementation under 'real-world' conditions. The project is unique and comes timely to guide implementation and scale-up of LF-LAM. To augment the possible impact of LF-LAM test we will make use of an implementation framework which includes clinical audit. Attention to how LF-LAM is accepted and utilized in daily practice, is essential to maximize the potential impact of the test. We expect that LF-LAM will lead to earlier diagnosis of TB in a high proportion of HIV positive patients with low CD4 cell count. We expect that our findings will assist to guide implementation of LF-LAM in a wider context and augment the potential impact of the LF-LAM on patient related outcomes. 

In a sub-study, we will evaluate ultrasound of the heart, lungs and abdomen as a point-of-care tool to assess HIV-infected individuals for TB. Over time, focused ultrasound has increasingly turned into an essential point-of-care tool for clinical decision making. Focused ultrasound protocols are available for assessment of extra-pulmonary TB diagnosis as well as for improved management of patients admitted with respiratory distress. Evaluation of the patients with focused ultrasound will contribute evidence on the potential of ultrasound as a clinical tool in management of TB among patients with HIV. 

From the clinical and para-clinical data collected, we will be able to describe characteristics of a vulnerable HIV-infected population, the prevalence of TB and predictors associated with poor outcomes. We will describe the prevalence of MDR-TB which is a national and international priority and be able to delineate the molecular epidemiology of M. tuberculosis complex strains. 

We will describe the epidemiology of HIV/TB co-infected patients enrolled taking advantage of access to advanced molecular analysis of samples. The cohort established as part of our project is expected to be continued as a unique Ghanaian HIV cohort with data warehouse and biobank. This will secure future analysis of new diagnostic and prognostic markers, which will facilitate adoption of new promising tests into treatment guidelines with the aim to improve patient prognosis.

Problem statement

The overall aim of the study is to identify point-of-care strategies that can improve TB diagnosis and clinical outcomes of patients with advanced HIV-infection. Our overall objectives include the implementation of the point-of-care LF-LAM test among three HIV-clinics and the evaluation of test uptake among clinicians; the description of point-of-care ultrasound of heart, lungs and abdomen in a subpopulation and the evaluation of its TB diagnostic value in a routine care setting; and lastly the description of the epidemiology of HIV-associated TB including the foundation of an ongoing HIV-cohort and biobank for evaluation of new diagnostic and prognostic markers. 

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Description of the cohort

690 participants from the three hospital HIV-clinics in greater Accra area, Ghana will be enrolled over 80 weeks with a minimum of 8 weeks follow-up. 

Study inclusion criteria: HIV-positive; 18 years and above; able to give informed consent; admitted at the research site; CD4-cell-count ?200 cells/?L or seriously ill regardless of CD4-cell-count defined by WHO (respiratory rate > 30/min, temperature > 39°C, heart rate > 120/min and unable to walk unaided); a positive WHO TB symptom screening (current cough, fever, weight loss, and night sweats).

Study exclusion criteria: current anti-tuberculous treatment; earlier participation in the same study.

Data and biological material

Patient conscent forms are collected. We will use a standardized pre-tested questionnaire to systematically record socio-demographical characteristics, clinical and paraclinical data, co-morbidities, HIV related treatment at inclusion and overall survival outcomes after 8 weeks. In the same paper file the test ordinations by the treating physician and test results will be noted.  Patient data will be stored safely and locked-in as paper file raw data at the research sites and digitally in a register database in REDCap at OPEN.

Urine for LF-LAM testing will be collected from included patients in the intervention phase at all three research sites as a spot sample and after 8 weeks follow up.

For patients at Fevers unit, Korle-Bu Teaching Hospital included in the HIV-cohort with biobank we will collect venous blood (20 ml), urine (50 ml), and sputum samples at baseline and after 8 weeks follow up.  

For the patients starting anti-tuberculous treatment at Fevers Unit, Korle-Bu Teaching Hospital included in the HIV-cohort we will collect dried capillary blood spot on filter paper day 0, 3 and 14, when possible. 

For the first 100 patients included at Fevers unit, Korle-Bu Teaching Hospital an ultrasound examination will be performed and the pre-tested examination protocol will generate pictures and snaps for storage via REDCap at OPEN. 

Collaborating researchers and departments

Main PhD student Supervisor and co-investigator:

Department of Infectious Diseases, Odense University Hospital, University of Southern Denmark

• Professor Isik Somuncu Johansen, MD, DMSc, Professor, Head of research

Supervisors and co-investigators:

Department of Clinical Research, Research Unit of Infectious Diseases, Odense University Hospital, University of Southern Denmark

• Dr. Stephanie Bjerrum, MD, PhD, MPH 

Dean at School of Medicine and Dentistry, Ghana University

• Professor Margaret Lartey, MD, MSc, MPH, Professor

Department of Epidemiology and Disease Control, University of Ghana

• Dr. Ernest Kenu, MD, PhD, MPH

Department of Clinical Research, Research Unit of Infectious Diseases, University of Southern Denmark, and Department of Infectious Diseases, Rigshospitalet

• Professor Åse Bengaard Andersen, MD, DMSc, Professor

Co-investigators:

Fevers unit, Korle Bu Teaching hospital

• Dr. Vincent Ganu, MD 

Department of Internal Medicine, Lekma Hospital

• Dr. Joseph Oliver-Commey, MD

Head of ART/HIV center, Tema General Hospital

• Dr. Akosua Osei Manu, MD, MPH

Collaborators:

Fevers Unit, Korle Bu Teaching hospital

• Dr. Peter Puplampu, MD

Assistant Medical Director, Tema General Hospital

• Dr. Agustine Kwashie, MD

National TB Control Programme, Ghana Health Service

• Dr. Yaw Adusi-Poku, MD, Programme Manager

Respiratory medicine department, Odense University Hospital

• Dr. Christian B. Laursen, MD, PhD, Associate Professor