Developing and evaluating next generation diagnostic strategies to Improve HIV testing among infants in resource limited settings (DETECT)

Early initiation of Antiretroviral Therapy (ART) treatment reduces mortality and morbidity in HIV Infected children therefore timely diagnosis of HIV infection in infants is key to reducing mortality and long-term morbidity.  Early Infant HIV diagnosis (EID) is a challenge in children aged less than 18 months due to the presence of maternal antibodies which prevents the use of standard antibody based HIV testing. Currently, therefore, HIV status requires confirmation by Polymerase chain reaction (PCR). Although highly sensitive and specific, PCR requires expensive reagents, equipment and complex assays which must be conducted in specialised laboratories. Such facilities are scarce in Sub-Saharan Africa (SSA) ( Malawi only has seven), causing long delays in diagnosis. For example, in Malawi, diagnostic turn-around of 2-3 months together with transport and logistical challenges contribute to a 33% loss to follow-up by the age of 24 months.

Early initiation of Antiretroviral Therapy (ART) treatment reduces mortality and morbidity in HIV Infected children therefore timely diagnosis of HIV infection in infants is key to reducing mortality and long-term morbidity. Early Infant HIV diagnosis (EID) is a challenge in children aged less than 18 months due to the presence of maternal antibodies which prevents the use of standard antibody based HIV testing. Currently, therefore, HIV status requires confirmation by Polymerase chain reaction (PCR). Although highly sensitive and specific, PCR requires expensive reagents, equipment and complex assays which must be conducted in specialised laboratories. Such facilities are scarce in Sub-Saharan Africa (SSA) ( Malawi only has seven), causing long delays in diagnosis. For example, in Malawi, diagnostic turn-around of 2-3 months together with transport and logistical challenges contribute to a 33% loss to follow-up by the age of 24 months.
A fast, accurate, inexpensive HIV test that can be carried out in local health care centres and mobile clinics; that avoids costs and adverse out comes of unnecessary ARV exposure in HIV negative infants and unacceptably high loss to follow up among HIV positive infants is desperately needed.
Two WHO pre-qualified point-of care tests have been evaluated in Sub-Saharan Africa (SSA), including Malawi. Although early data suggests that these tests will have a positive impact on early infant HIV diagnosis and treatment, they still have limitations due to; high equipment and running costs, processing specifications, numbers of samples that can be processed in a reasonable turnaround time and assay sensitivity.
The aim of this project is to develop a rapid, portable, battery powered, easy-to-use, inexpensive, sensitive and specific HIV diagnostic test that can be conducted at mobile health clinics across the country.
We will develop an HIV loop mediated amplification assay (LAMP) which is very rapid, (likely around 30 minutes), highly sensitive (>98%) and also specific (>99%) as it uses 4-6 specific primers targeting different parts of the HIV genome. LAMP requires simple equipment, in the form of a heat block and staff need only minimal training to run and interpret the results, making a HIV LAMP assay ideal for rural settings. LAMP assays have been successfully developed to diagnose infectious diseases, including TB, Malaria, group B Streptococcus, Meningococcus, Streptococcus pneumoniae and Trypanosoma brucei gambiense. In fact, a TB LAMP assay has already been approved by WHO.
The 3-year project will be conducted in 2 stages as follows: (i) initial developmental phase at Great Ormond Street Institute of Child Health, London, UK; (ii) validation phase, including an assessment of performance, acceptability and cost effectiveness will be carried out at Mulanje District Hospital (MDH) in Malawi in comparison to PCR testing and the point of care Cepheid Xpert HIV-1 Qual test.
The outcomes of this project have the potential to revolutionise the way HIV is diagnosed in infants born in SSA making HIV testing accessible to those living in rural settings, and reducing loss to follow-up of these babies in desperate need of early diagnosis and ART. Upon completion of the study report, the results of the study will be submitted for publication and posted in a publicly accessible database of clinical study results.

 

Where does this project lie in the translational pathway?

T1 – Basic Research in Medecine

T2 Human / Clinical Research in Medecine

T3 Evidence into Practice

T4 Practice to Policy / Population

Human / Clinical Research in Medecine

The aim of this project is to develop a rapid, portable, battery powered, easy to use, inexpensive, sensitive and specific HIV diagnostic test (LAMP) that can be utilised within primary care and mobile health clinics across Malawi.

We aim to design and optimise an HIV LAMP assay: This will be conducted in the United Kingdom (UK) in conjunction with University College London Great Ormond Street Institute of Child Health (ICH) and Imperial College London.

 

Evidence into Practice

We will validate the HIV LAMP assay by assess sensitivity and specificity of the HIV LAMP assay within a UK laboratory: (a) on retrospective samples and; (b) on fresh blood samples collected prospectively in clinic.

Thereafter we will do a clinical study to assess the performance of the HIV LAMP assay in a rural Malawian hospital setting to assess sensitivity, specificity, cost per test, patient/carer acceptability and health worker usability.

 

Practice to Policy / Population

The expected outcome of this project is the successful transition of the developed LAMP assay for HIV diagnosis in infants into a clinical setting. This will enable rapid turn-around of results for patients allowing immediate linkage to care and initiation of ART. This will make a key contribution to the Global 90:90:90 goals for HIV control.

What are the methodological aspects of the PhD project?

The PhD project focusses on the optimisation and field testing of a novel HIV loop mediated amplification assay (LAMP) and will enable the candidate to develop key skills in

1. laboratory and health systems quality assurance methods

2. implementational research of hospital-based clinical studies.

3. how to address ethical issues pertaining to research in children, in particular 

 those related to HIV testing.

4. economic evaluation through performing cost and cost effectiveness analysis on LAMP as a POCT versus other HIV testing strategies.

 

What are the expected outputs of the PhD project?

Publications

1. Systematic review of HIV LAMP.

2.The performance (sensitivity and specificity) of HIV LAMP assay in a rural district hospital in Malawi.

3.The cost effectiveness of HIV LAMP versus current HIV testing strategies in a rural district hospital in Malawi.

4.Acceptability and usability of HIV LAMP assay by health workers in a rural district hospital in Malawi.

5.Perspective of caregivers towards HIV LAMP as a point of care tests in a rural district hospital in Malawi.

 

Impact

National and international level

Findings from this study have the potential to deliver a practice and policy ready solution addressing the challenges of HIV diagnosis and linkage to care among infants in Malawi. Findings are likely to translate rapidly to other high HIV prevalence countries in Sub Saharan Africa

 

External industry links or training opportunities available for the student

We will explore links with the EID consortium at LSHTM, UNICEF or WHO diagnostic teams will be a great experience.

Required skills/experience/aptitudes

  • This study would be ideally suited to a clinician with experience in HIV provision and working with small children and their families
  • Prior experience working in resource limited settings would be an advantage
  • Proven publication record to demonstrate ability to write
  • Excellent communication skills and organisation
  • Ability to work in both laboratory and clinical settings

 

Key publications that relate to this proposed project

1.

Serra-Casas E, Manrique P, Ding XC, Carrasco-Escobar G, Alava F, Gave A, Rodriguez H, Contreras-Mancilla J, Rosas-Aguirre A, Speybroeck N, González IJ, Rosanas-Urgell A, Gamboa D. Loop-mediated isothermal DNA amplification for asymptomatic malaria detection in challenging field settings: Technical performance and pilot implementation in the Peruvian Amazon. PLoS One. 2017 Oct 5;12(10):

 

2.

Bourke TW, McKenna JP, Coyle PV, Shields MD, Fairley DJ.  Diagnostic accuracy of loop-mediated isothermal amplification as a near-patient test for meningococcal disease in children: an observational cohort study. Lancet Infect Dis. 2015 May;15(5):552-8.

 

3.

Poerksen, Goenke; Nyirenda, Maggie; Pollock, Louisa; Blencowe, Hannah; Tembo,Paul; Chesshyre, Emily; Jefferis, Oliver; Kenny, Julia; Moons, Peter; Bunn, James; Molyneux, Elizabeth.

Comparison of previous and present World Health Organization clinical staging criteria in HIV-infected Malawian children. AIDS.  23(14):1913-1916, [10 September 2009]

 

More information about this programme and application process can be found here.

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