Expert Review of Molecular Diagnostics

ISSN: 1473-7159 (Print) 1744-8352 (Online) Journal homepage: http://www.tandfonline.com/loi/iero20

Robust, reliable and resilient: designing molecular tuberculosis tests for microscopy centers in developing countries Claudia M Denkinger, Sandra V Kik & Madhukar Pai To cite this article: Claudia M Denkinger, Sandra V Kik & Madhukar Pai (2013) Robust, reliable and resilient: designing molecular tuberculosis tests for microscopy centers in developing countries, Expert Review of Molecular Diagnostics, 13:8, 763-767, DOI: 10.1586/14737159.2013.850034 To link to this article: http://dx.doi.org/10.1586/14737159.2013.850034

Published online: 09 Jan 2014.

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Date: 29 June 2017, At: 20:25

Editorial

Robust, reliable and resilient: designing molecular tuberculosis tests for microscopy centers in developing countries Expert Rev. Mol. Diagn. 13(8), 763–767 (2013)

Claudia M Denkinger McGill International TB Centre & Department of Epidemiology & Biostatistics, McGill University, 1020 Pine Ave West, Montreal, QC H3A 1A2, Canada

Sandra V Kik McGill International TB Centre & Department of Epidemiology & Biostatistics, McGill University, 1020 Pine Ave West, Montreal, QC H3A 1A2, Canada

Madhukar Pai Author for correspondence: McGill International TB Centre & Department of Epidemiology & Biostatistics, McGill University, 1020 Pine Ave West, Montreal, QC H3A 1A2, Canada Tel.: +1 514 398 5422 Fax: +1 514 398 4503 [email protected]

“Microscopy centers should be the ideal place for the implementation of a novel molecular assay that is more sensitive than smear microscopy and has a faster turnaround time to support more rapid initiation of anti-TB therapy in an already established infrastructure.” Nucleic acid amplification tests (NAATs) for the diagnosis of tuberculosis (TB) have been in clinical use for almost two decades. Yet, for the most part, because of high cost and stringent infrastructure requirements, their use has been limited to reference laboratories in high-income countries. Widely held as the biggest recent advance in TB diagnosis, the Xpert MTB/RIF assay (Cepheid Inc., Sunnyvale, CA, USA) entered the market in 2009, and was endorsed by the WHO in 2010 [1]. Since then, over 3 million test cartridges have been used worldwide, with South Africa alone accounting for over half of this volume [101]. Unlike conventional PCR-based assays, the Xpert MTB/RIF assay is an automated, cartridge-based nested PCR designed for use in district and subdistrict level laboratories [2]. With no requirement for manual DNA extraction, clean rooms or stringent quality assurance for prevention of amplicon contamination, this technology is the first TB NAAT that can be deployed outside of the high-level or reference laboratory [3]. These features, combined with high accuracy [4], strong WHO policy endorsement [1], and subsidized

instrument and cartridge prices for highburden countries [102], has made Xpert MTB/RIF the first NAAT that is actively being scaled up in high-burden countries for TB diagnosis as well as rapid detection of drug resistance [1,101]. Although Xpert MTB/RIF is a potentially game-changing technology, it has its limitations. First, the implementation of this test at the district level still means limited access to many patients who may not reach that tier of the healthcare system [5]. Even if they do, access may occur after several weeks or months of diagnostic delay, during which TB transmission may occur. Furthermore, since the most important goal of point-of-care (POC) testing is to make a treatment decision in the same clinical encounter or visit [6], Xpert MTB/RIF may be less helpful for decentralized POC testing programs at lower levels of the healthcare system (e.g., primary care) where patients with TB symptoms initially seek care. Another important concern with the implementation of the Xpert MTB/RIF technology is its high overall cost for national TB programs in low-income countries [7], especially for decentralized deployment of the test [8]. A more affordable molecular POC test at the primary care level will greatly

KEYWORDS: microscopy centers • molecular diagnostics • point-of-care testing • test development • tuberculosis

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10.1586/14737159.2013.850034

Ó 2013 Informa UK Ltd

ISSN 1473-7159

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read every year by trained microscopy technicians [103]. These microscopy centers are linked to decentralized treatment units where first-line TB drugs are available and TB treatment can be initiated and monitored by community-based directly observed therapy providers. Because microscopy centers are usually embedded in or attached to primary health centers, they are closer to patients than district or subdistrict level hospitals and laboratories. This, in turn, suggests that TB can be diagnosed earlier at the microscopy center level. Therefore, these centers should be the ideal place for the implementation of a C D novel molecular assay that is more sensitive than smear microscopy and has a faster turnaround time to support more rapid initiation of anti-TB therapy in an already established infrastructure. The big issue then is: are the so-called POC NAATs for TB deployable in peripheral microscopy centers? Are they designed for such settings? For example, can they survive the high temperature and frequent power outages that are likely in such settings? Will manual sample processing and DNA extraction prove to be too big a hurdle for basic laboratories? To summarize the current state of Figure 1. Examples of peripheral TB microscopy centers in India (B & C), Uganda (A) and Kenya (D). peripheral microscopy centers, we recently Reproduced with permission from M Pai (McGill University, Montreal, QC, Canada), conducted a survey of microscopy centers M Bonnet (Epicentre, Paris, France), L David and A Cattamanchi (University of California, in 22 highest TB burden countries [12]. San Francisco, CA, USA). We surveyed multiple respondents from each country and asked them to complete help to reduce diagnostic delays and curb TB transmission in a simple questionnaire, keeping in mind a typical, peripheral the community [9]. Inspired by the success of Xpert MTB/RIF, microscopy center. The results of the survey are summarized a variety of newer, ‘fast-follower’ NAATs are now entering the in FIGURE 2, which highlights scarcity of infrastructure (e.g., tempermarket and claim to be ‘POC NAATs’, that is, intended for ature control, uninterrupted power), lack of basic equipment (e.g., more decentralized settings than the Xpert MTB/RIF biosafety hood, centrifuge) and limited skills at the level of assay [10,11]. If they are designed for POC use, then, at the very peripheral microscopy centers in all high-burden countries, least, they should be deployable in peripheral microscopy cen- although BRICS (i.e., Brazil, Russia, India, China and South ters where currently the majority of initial TB testing takes Africa) countries fare better than the others. place by use of sputum smear microscopy. These are usually On the positive side, our survey showed that all high-burden primary health centers with attached small laboratories with countries have successfully established direct Ziehl–Neelsen technicians trained to do microscopy, and often staffed by microscopy with external quality assurance. Also, mobile phones physicians or nurses who can initiate TB treatment. Thus, these seem to be widely available, opening the possibility of mobile health centers are a level higher than health posts or outpatient health interventions to recall patients with positive results, notifyclinics that have no attached laboratories and are unlikely to be ing cases to TB control programs and being of use for supply staffed by physicians. chain management and quality assurance [13]. National TB programs in high-burden countries are heavily reliWhile the Xpert MTB/RIF technology was clearly not designed ant on microscopy centers and thousands of such centers have been for the kind of laboratories shown in FIGURES 1 & 2, it is unclear established for smear microscopy TB testing (FIGURE 1). For example, whether fast-follower NAATs can actually be implemented in such India alone has over 13,000 designated microscopy centers in the settings either. For example, all the so-called POC NAATs, besides public sector, where over 15 million sputum smears are stained and Xpert MTB/RIF, that are currently on the market still require A

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Non-BRICS

Russia

Brazil

South Africa

China

India

Thailand

Indonesia

Philippines

Vietnam

Pakistan

Nigeria

Cambodia

Bangladesh

Kenya

Tanzania

Uganda

Myanmar

Afghanistan

Ethiopia

Mozambique

Zimbabwe

Congo

Country

Yes/present

Power

Water

Maybe

N95

Pipetting

No/not present

Mobile

ZN

FM

Current testing

QA Internet established

Communication Computer Landline

Unsure/question not answered

PCR tests

Hood

Skills

Available equipment RefrigeWater Incubator Centrifuge Pipettes rator bath

Figure 2. Characteristics of peripheral microscopy centers in 22 high tuberculosis burden countries. Questions related to environmental conditions (is temperature or humidity not a concern?); infrastructure (is stable power supply, clean water supply present?); presence of equipment (are N95 respirator, micropipettes, refrigerator, incubator, centrifuge, hot water bath or biosafety hood present?) and skills (Are staff able to operate a micropipette or computer or perform a PCR test?); and the presence of means of communication (is landline, mobile network or internet present?). Additional questions asked about whether QA measures were established and which smear methods were currently used. Countries are sorted by increasing purchasing power parity. BRICS countries are Brazil, Russia, India, China and South Africa. FM: Fluorescence microscopy; QA: Quality assurance; ZN: Ziehl–Neelsen. Reproduced with permission from [12].

BRICS

Environment Infrastructure

TempeHumidity rature

Designing molecular TB tests for developing countries

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• Maintenance of the instrument should be inexpensive, easily

Box 1. Critical requirements for any sputum-based NAAT that is intended for point-of-care TB testing use at the level of peripheral microscopy centers in high-burden countries.

Training requirements

Accuracy

• As with microscopy and Xpert MTB/RIF, periodic, short dura-

• The assay should be more sensitive than sputum smear

microscopy and ideally at least as sensitive as the Xpert MTB/RIF assay for the detection of pulmonary TB. • It should be at least as specific as smear microscopy and Xpert MTB/RIF for the detection of pulmonary TB. • The added ability to detect drug resistance is desirable and can be an add-on (reflex) test, if it is not integrated into the initial detection cartridge. • Turnaround time should allow for same-day treatment initiation (

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