Point-of-care testing for HIV and TB integration of services
Date
2016
Authors
Gous, Natasha
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Abstract
The United Nations Programme on HIV/AIDS (UNAIDS) have recently released
challenging new Human Immunodeficiency Virus (HIV) treatment targets to be achieved
globally by 2020; all of which require concentrated efforts in scaling up laboratory testing
capacity for HIV diagnosis, treatment initiation and treatment monitoring. The Global
Tuberculosis (TB) Strategy have also put forth a list of ambitious goals which include
reducing the number of deaths due to TB by 95% and the number of new TB cases by
90%.
In South Africa, which has the highest national prevalence of HIV described globally and
ranks fifth in the world in terms of TB incident cases, further integration of HIV and TB
services will be needed to achieve these targets. A major challenge to successful
integration of these programs however, will be the ability to diagnose and monitor the
progress of both infections, a process that in South Africa, is hampered by lack of access
to laboratory testing. Although public pathology laboratory service providers, such as the
National Health Laboratory Service (NHLS), are responding to increasing testing
demands by scaling up centralised laboratory capacity, limitations such as the need for
expertise, infrastructure, space, cold-chain, maintenance, logistics and cost, are
challenging full implementation and scale up.
Many international organisations believe that one of the ways to successfully achieve the
global HIV ‘90-90-90’ and TB targets, will be through the development and scaling up of
innovative, simpler and more affordable technology approaches such as Point-of-Care
testing (POCT), a view shared by the South African National Department of Health
(NDoH). POCT refers to testing that is performed near or at the site of the patient with the
result leading to a possible or immediate change in patient management or outcome and
holds promise as a strategy to extend laboratory testing capacity. Prior to large-scale POC
implementation efforts can begin, defining the difficulties and potential solutions which are
likely to arise, particularly in high disease burden clinical settings need to be addressed.
The main objective of this study was to investigate the feasibility, performance and
operational considerations of multidisciplinary POCT in South Africa, including the
development of a best practice framework to guide implementation efforts. This was
achieved by performing a clinical needs assessment and engaging with government,
evaluating POC technologies for HIV and TB diagnosis and/or monitoring and developing
a framework for how to implement POCT in the field including quality, site and training
requirements. The operational requirements for healthcare workers to perform multiple
POCT in the South African clinical setting, was also determined. The assays required
were based on the South African National Treatment guidelines in the period of review
(2011-2014).
In July 2013, the South African NDoH called a meeting with various stakeholders to
provide the context for POCT in South Africa and strong emphasis was placed on HIV and
TB and how POCT could expand on existing laboratory infrastructure for these diseases.
Outcomes from this meeting prompted a thorough literature review on the challenges
likely to be faced by large-scale POC implementation efforts.
One of the key issues highlighted was the lack of evaluation data on numerous HIV and
TB POC technologies available and/or in the pipeline. Even though viral load (VL) testing
has been available in South Africa since 2004, the global treatment guidelines (World
Health Organization) now recommend a VL test for HIV antiretroviral treatment (ART)
monitoring and there are talks around the possibilities of a ‘test and treat’ strategy. In light
of this, two potential POC plasma-based VL technologies available at the time were
evaluated in the laboratory. The Liat™ HIV-1 Plasma Quant (IQuum Inc, MA, USA; now
Roche Molecular, Branchburg, MJ, USA) and the Xpert® HIV-1 VL (Cepheid, Sunnyvale,
CA) assays both demonstrated good performance and were proven to be interchangeable
with existing in-country high-throughput VL laboratory platforms. Both however, require
centrifugation to obtain the plasma sample and thus may be more suited to a district level
facility as opposed to a ‘true’ POC environment. In light of these operational challenges,
two further blood-based POC VL platforms were also evaluated, the Liat™ HIV-1 Blood
Quant VL assay (IQuum, Inc) and the Alere™ q HIV-1/2 assay (Alere Technologies
GmbH, Jena, Germany). Both assays identified more patients as treatment failures at the
1000 copies/ml treatment failure threshold (WHO and South African treatment guideline
recommended threshold) compared to plasma VL, due to their total nucleic acid extraction
protocols. Thus, if either were implemented at POC, one could expect a significant upward
misclassification, increasing the number of HIV-positive patients requiring follow up VL
testing and programmatic costs. Application therefore, could be niched VL testing; utilising
a blood-based POC VL assay in maternity wards to diagnose HIV in new-borns; plasmabased
POCT for mothers to reduce risk of transmission.
POCT may not be the only solution to increasing access to laboratory testing services,
and thus alternative strategies for improving access were also investigated. Dried blood
spots (DBS) and PrimeStore media (a sample transport media; Longhorn Vaccines and
Diagnostics, San Antonio, TX, USA) were shown to be as valuable as plasma VL for
detecting HIV-positive patients failing ART at the 1000 copies/ml threshold and both solve
logistical issues around sample transport and maintaining sample integrity for centralized
testing.
For TB diagnosis, the Xpert® MTB/RIF assay (Cepheid, Sunnyvale, CA) was evaluated to
determine its appropriate placement within the South African setting. Although Xpert®
MTB/RIF proved superior in performance to smear microscopy, it was originally modelled
as too costly for POC placement in South Africa and was implemented into smear
microscopy centres nationally. Subsequently, the complexity of the analyser maintenance
and power issues has reinforced the original decision. Further potential POC TB
technologies are in the development pipeline, but only one other was available for
evaluation, namely the EasyNAT® detection kit (Ustar Biotechnologies, Hangzou, China).
Initial laboratory evaluation results look promising but the technology is still a long way
from clinical evaluation due to its laborious procedure.
A further challenge identified for POCT is the lack of documented implementation science
to ensure quality-assured multi-disciplinary POCT in the field. To address this, three key
components of a quality testing framework were developed to ensure best practice for
POCT; a clinic site readiness assessment tool, a POC training module and a quality
monitoring program. The clinic site assessment checklist was developed to determine site
readiness for POC placement. The POC training module included standard operating
procedures, quick reference and workflow charts and a practical training component which
was developed specifically with the non-laboratory trained user in mind. Both these
components have been adopted and modified for use by the NHLS National Priority
Program (NPP).
Certain POC assays already have External Quality Assessment (EQA) material, while
others had to be developed. For quality management of HIV VL technologies, a
standardized plasma panel was developed to ensure molecular VL platforms are ‘fit-forpurpose’
(verification, a requirement of the laboratory accreditation process). This panel,
termed SAVQA, is being manufactured and supplied to aid POC assay developers in
assessing their product for the South African market, and will also be further developed for
use by healthcare workers at POC.
Due to the hurdles encountered with the biosafety regulations for transporting TB external
quality assessment (EQA) material, a quality assessment program using dried culture
spots (DCS) was also developed for TB diagnostic technologies consisting of two
components; a verification and an EQA program. The DCS technology has become a
global product and as of 2015 is being supplied to 20 different countries. DCS were
successfully shown to be suitable for use at POC by non-laboratory trained staff. The
versatility of the material has been confirmed by its expansion to other molecular TB
diagnostic tests, most notably the Hain Genotype MTBDrplus assay for TB drug
susceptibility testing (Hain LifeScience GmbH, Nehren, Germany). This work has been
acknowledged through the Research and Development team involved in the development
of the DCS program, winning three awards: the NHLS Top Award for Innovation 2013, the
Gauteng Accelerator Program (GAP) Biosciences Award in 2014 and a special Social
Impact award for Africa Innovations held in Morocco in 2015.
Incorporating the quality components developed above, a clinical evaluation of nurse
operated multidisciplinary POCT was performed. Although multiple POCT could be
performed as accurately as laboratory testing on venepuncture specimens, it required
dedicated staff and dramatically increased POC staff duties. It was further shown that
multiple POCT could be accurately performed by a nurse on a single finger slice in order
to obtain adequate blood volume to perform up to four POC tests, and that finger stick VL
testing was also feasible by nurses at POC. Patients were also more willing to have up to
three finger sticks performed than to have a single venepuncture specimen taken. The
process of using finger sticks was further ratified by demonstrating that a single finger
stick can provide up to 150μl of blood, which is sufficient to perform an array of POC tests.
In spite of the feasibility of nurse based POCT, limitations of current technologies using
finger stick were also realised, such as the performance of the Liat™ Quant blood assay
which generated increased VL misclassification at the 1000 copies/ml treatment failure
threshold (70% misclassification). This would impact programmatic costs, but this
technology may have value as a diagnostic tool in key populations.
The work described shows that multi-disciplinary POCT within a South African setting is
achievable with appropriate clinic infrastructure, dedicated staff, training and stringent
quality monitoring measures in place. The HIV and TB POC technologies evaluated were
found to be as accurate as laboratory-based testing however, few meet the criteria of a
‘true’ POC device and thus further research and development is required. Based on South
Africa’s testing needs, a tiered hybrid model which expands on centralized laboratory
capacity through incorporating POCT into very remote, hard-to-reach areas and
innovations around linkage to care efforts, may help meet ’90-90-90’ targets but will
require costing/modelling and future assessments of the impact and outcome of the
intervention. Much of this work presented contributed towards the development of a draft
National POCT policy document in support of the national strategic plan for POCT for the
management of HIV and TB in South Africa.
Description
A thesis submitted to the Faculty of Health Sciences, university of the
Witwatersrand, Johannesburg, in fulfilment of the requirements for the
Degree of
Doctor of Philosophy
Johannesburg, 2015