Point-of-care testing for HIV and TB integration of services

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.