Article Published in the Author Account of

Nitika Pant Pai

Point-of-Care Diagnostics for HIV and Tuberculosis: Landscape, Pipeline, and Unmet Needs

Abstract: Early diagnosis and rapid initiation of treatment remains a key strategy to control both HIV and tuberculosis (TB). However, HIV and TB control programs have had completely contrasting successes, especially with the development and deployment of point-of-care (POC) diagnostics. Clinicians, researchers, and public health staff who work at the frontlines of HIV care and control have had access to an outstanding array of POC diagnostics at their disposal, including those used for screening, initial diagnosis, staging, treatment monitoring, and early infant diagnosis. The field has also advanced to consider over-the-counter, self-testing options for HIV and the use of multiplexed platforms that allow for simultaneous detection of infections associated with HIV. In sharp contrast to HIV, suboptimal and delayed diagnosis of TB has perpetuated the epidemic in many high-burden countries. Although the TB diagnostics pipeline is substantially better today than it was even five years ago, absence of a simple POC test continues to be a gaping hole in the pipeline. In this review, we compare the POC diagnostics landscape and pipelines for these two important infectious diseases, and highlight gaps and unmet needs.



Low-cost, point-of-care (POC) tests have completely transformed the management of several major infectious diseases (e.g., malaria and HIV) (Yager et al., 2008), especially in resource-limited settings where healthcare infrastructure is weak, and access to quality and timely medical care is a challenge. These tests offer rapid results at the point-of-care, allowing for rapid initiation of appropriate therapy, and/or establishment of linkages to care (Peeling and Mabey, 2010). Most importantly, POC tests can be simple enough to be used at the primary care level and in remote settings with no laboratory infrastructure. POC tests are often more cost-effective for the healthcare delivery system (Peeling and Mabey, 2010), and can potentially empower patients to self-test in the privacy of their homes and make informed decisions.

The synergistic epidemics of HIV and tuberculosis (TB) have had a huge adverse impact on many populations, especially in high prevalence, resource-limited settings such as sub-Saharan Africa and Asia (Lawn and Churchyard, 2009). Early diagnosis and rapid initiation of treatment remains a key strategy to control both infections. However, HIV and TB control programs have had completely contrasting successes, especially with the development and deployment of POC diagnostics (Denkinger and Pai, 2011). Indeed, there are many lessons to be learnt by comparing the POC diagnostics landscapes and pipelines for these two important infectious diseases.

HIV Diagnostics: Current Landscape and Pipeline

Clinicians, researchers, and public health staff who work at the frontlines of HIV care and control have had access to an outstanding array of POC diagnostics at their disposal (Table 1), although uptake of these tests has varied across countries. POC tests for HIV include those used for screening, initial diagnosis, disease staging, treatment monitoring, and early infant diagnosis. The field has also advanced with the development of over-the-counter (OTC) self-testing options for HIV, and multiplexed platforms that allow for simultaneous detection of infections associated with HIV, such as hepatitis B and C, and syphilis (e.g., Multiplo®, MedMira Inc., Nova Scotia, Canada). An excellent survey of the current HIV diagnostics landscape has been published recently (Murtagh, 2011).

For initial screening and diagnosis, simple, accurate, whole-blood, finger-stick, and oral mucosal fluid-based rapid tests are widely popular and have been successfully scaled-up via voluntary counseling and testing (VCT) programs in many countries, supported by agencies such as PEPFAR, UNITAID, and the Global Fund to Fight AIDS, TB, and Malaria. Dozens of inexpensive POC HIV tests are available commercially, and quality-assured kits can be procured via the World Health Organization (WHO) prequalification program for diagnostics (World Health Organization, 2011f).

A recent evaluation of all FDA-approved rapid HIV tests on finger stick specimens documented their high accuracy (sensitivity and specificity exceed 99%) in controlled laboratory settings (Delaney et al., 2011). Rapid oral mucosal fluid tests have comparable accuracy to blood tests (Pai et al., 2012). While the vast majority of rapid HIV tests are based on antibody detection, the most recent fourth generation immunoassays simultaneously detect HIV p24 antigen as well as antibodies to HIV-1 and HIV-2 in serum, plasma, and whole blood.

Although confirmatory testing is required for all first line screening tests, even oral fluid rapid HIV tests have been found to have high accuracy in high risk populations such as sexually transmitted disease (STD) clinic attendees, and unregistered pregnant women that present at the time of delivery (Pai et al., 2007; Pant Pai et al., 2007). In addition to high diagnostic accuracy, these POC tests have also been shown to have clinical impact in resource-limited settings (Pai et al., 2008; Pai and Klein, 2009). For example, use of a simple oral-fluid test in a labor ward was successful in reducing mother-to-child HIV transmission in a rural hospital in India (Pai et al., 2008; Pai and Klein, 2009). In fact, oral fluid based HIV rapid tests may be simple enough to be potentially useful for home-based HIV self-testing (Pai and Klein, 2008), as shown in a recent study in Africa (Choko et al., 2011).

Over-the-counter (OTC) versions of oral mucosal fluid-based tests are now available (e.g., Aware Oral OTC, Calypte Biomedical Corporation, Portland, OR, USA). Although self-testing is a promising approach to expand HIV screening programs, several issues related to self-testing are unresolved, and the ideal public health strategy that can safely and effectively offer this option is yet to be determined. With the impending FDA approval of an OTC oral HIV test, some of these logistical issues may get addressed, although infrastructural and logistical barriers for linking self-testers to follow-up care will require work (Pai and Klein, 2008).

Murtagh, 2011 (reproduced with permission from UNITAID).

Figure 1. The CD4 POC test pipeline. Source: Murtagh, 2011 (reproduced with permission from UNITAID).

For disease staging and for making decisions about anti-retroviral therapy (ART) initiation or monitoring, there are qualitative and quantitative CD4 POC tests that are now available (Figure 1 shows the pipeline). These are a significant advance over the traditional, expensive, laboratory-based, flow cytometry assays (Boyle et al., 2011; Murtagh, 2011). Efforts are also underway to develop more affordable (and disposable) POC tests for CD4 counts and several such technologies are expected to reach the market within the next few years (Figure 2) (Murtagh, 2011).

Lastly, HIV diagnostics have benefited from the growing momentum towards simple, multiplexed tests that can diagnose multiple infectious diseases at the point-of-care. There are now POC options available for multiplexed detection of HIV, hepatitis B and C, and syphilis (Figure 2). Although evidence on their test performance in real world settings is limited, they offer promise of simultaneous detection of several infections, with greater convenience for patients and providers. The convergence of fields such as nanotechnology, microfluidics, proteomics, and genomics has inspired the development of novel platforms, including POC and nucleic acid amplification tests (NAATs), which enable the detection of multiple biomarkers at the point of care. Also, integration of smartphone technology with such novel platforms might lead to the development of novel testing platforms that can also use mobile telephones for delivering results quickly and efficiently.

HIV Diagnostics: Gaps and Needs

MedMira Inc., NS, Canada (reproduced with permission).

Figure 2. Point-of-care tests that can simultaneously detect HIV and hepatitis B and C (Multiplo®, MedMira Inc, NS, Canada). Source: MedMira Inc., NS, Canada (reproduced with permission).

A key gap has been lack of simple, affordable POC options for early infant diagnosis and for viral load determination (Murtagh, 2011; Usdin et al., 2010). While conventional NAATs are accurate and commercially available for early infant diagnosis and viral load, they are expensive and require sophisticated laboratory infrastructure that is not available in many resource-limited settings. Thus, most ART programs in resource-limited settings have no access to these technologies. This leads to treatment failure, impacting quality of clinical management. Viral load testing that could be conducted at the POC will reduce the need for laboratory infrastructure and lower the cost for ART programs (Murtagh, 2011). Resistance assays that are currently prohibitively expensive and run only as part of clinical studies will have tremendous potential in expediting linkages to care if offered at POC. Although there are currently no POC viral load assays that are commercially available, there are several technologies in development (Figure 3 shows the pipeline) (Murtagh, 2011).

For epidemiological and surveillance purposes, there is a felt need for an accurate, inexpensive, and easy-to-use kit that can be used to estimate HIV incidence at the population level (Incidence Assay Critical Path Working Group, 2011). A recent report by the Incidence Assay Critical Path Working Group outlines the challenges in developing such an assay, and the work that is ongoing to overcome the challenges (Incidence Assay Critical Path Working Group, 2011).

Murtagh, 2011 (reproduced with permission from UNITAID).

Figure 3. Pipeline for viral load and early infant diagnosis platforms. Source: Murtagh, 2011 (reproduced with permission from UNITAID).

Lastly, although the HIV diagnostics portfolio is impressive, there remains a concern about inadequate uptake of good tests and insufficient scale-up in many settings. An unacceptably large proportion of HIV patients (50-70%) continue to be unaware of their status in developing country settings, posing a problem for timely detection of HIV infection. Early detection and initiation of ART hinges on knowledge of serostatus, which is the key step in bringing people to treatment and care. Thus, efforts that are currently being made to link POC tests with more efficient, decentralized counseling and treatment services may have an impact. For example, research is now ongoing to combine oral fluid OTC HIV tests and mobile-phone based counseling into comprehensive HIV self-testing strategies that can be used to scale-up testing in underserved areas where trained counselors may not be available, and to overcome stigma and logistical challenges associated with conventional voluntary counseling and testing approaches (Pai and Klein, 2008). These approaches if carefully planned may leverage the growing interest in mHealth and mobile telemedicine, and further build on the phenomenal growth of mobile telephony in many developing countries and emerging economies (Estrin and Sim, 2010).

TB Diagnostics: Current Landscape and Pipeline

World Health Organization, 2011b (reproduced with permission from WHO).

Figure 4. The TB diagnostics pipeline in 2011. Source: World Health Organization, 2011b (reproduced with permission from WHO).

In sharp contrast to HIV, suboptimal and delayed diagnosis of TB continues to perpetuate the epidemic in many high-burden countries, especially those with a high prevalence of HIV infection (Wallis et al., 2010). The need for an instrument-free, laboratory-free, POC test for TB has been articulated by many groups, including patient advocates and civil society (Batz et al., 2011; Lemaire and Casenghi, 2010; Weyer et al., 2011). Although the TB diagnostics pipeline is substantially better in 2011 than it was even 5-10 years ago, absence of a dipstick type of POC test continues to be a gaping hole in the pipeline (Figure 4 shows the current pipeline) (World Health Organization, 2011b). Table 2 summarizes the diagnostic options for TB that can potentially be used at the point-of-care.

Sputum smear microscopy, in principle, can be done at the point-of-care in a primary care setting, provided a basic microscopy facility and a trained technician are available (Steingart et al., 2007). Unfortunately, smear microscopy is an insensitive technique and misses nearly half of all TB cases. To compensate for this, at least two sputum smears need to be stained and read, and this makes the test difficult to implement as a genuine POC test. On the positive side, smear microscopy is inexpensive, and a trained microscopist can identify several disease conditions (e.g., malaria, filariasis, urinary tract infections). Conventional, direct Ziehl-Neelsen microscopy can be optimized using LED fluorescence microscopy, and by using two spot sputum smears to ensure same-day diagnosis. Indeed, these approaches are now endorsed by the World Health Organization (WHO) (World Health Organization, 2011a; World Health Organization, 2011e).

The recent WHO endorsement of Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA), an automated, cartridge-based nucleic acid amplification test (NAAT), has greatly stimulated resurgent interest in using molecular tests for rapid diagnosis of active TB and drug-resistance (World Health Organization, 2011c). While the Xpert MTB/RIF assay is accurate and can potentially be used outside of a laboratory setting by a minimally trained health worker, it falls short of meeting the ideal POC requirements on two important grounds: at current prices, it is expensive and unaffordable in many settings, and it requires sophisticated equipment that cannot be deployed at the community level (Pai, 2011b). Also, the pricing of Xpert MTB/RIF assay in the private sector in developing countries is substantially higher than the pricing for the public sector, imposing additional barriers for scale-up.

For decades, researchers and the industry had pinned their hopes on serological antibody-detection methods for POC test development. Indeed, dozens of serological rapid (lateral flow assays) and ELISA tests got commercialized, even though no international guideline recommended their use. Today, these tests are on the market in at least 17 of the 22 highest tuberculosis burden countries, and millions of patients in the private sector undergo serological testing (Grenier et al., 2012). Unfortunately, TB serological tests are neither accurate nor cost-effective (Dowdy et al., 2011; Steingart et al., 2011), prompting the WHO to issue a strong negative recommendation against their use (World Health Organization, 2011d). The WHO policy, announced on July 20, 2011, states that, since the “the harms/risks [of commercial serodiagnostic tests] far outweigh any potential benefits (strong recommendation) …these tests should not be used in individuals suspected of active pulmonary or extra-pulmonary TB, irrespective of their HIV status” (World Health Organization, 2011d).

It is important to clarify three points regarding this WHO recommendation. Firstly, the WHO policy encourages research to develop new serological tests for TB based on antigen/antibody biomarkers. The negative recommendation only applies to existing commercial tests. Secondly, the WHO policy does not include commercially available blood-based tests (interferon-gamma release assays) for latent TB infection. It only applies to antibody-based (serological) tests for active TB. Thirdly, the WHO policy does not call for a ban on the technology platforms used for antibody or antigen detection (ELISA or rapid immunochromatography). They are excellent for many diseases, just not currently for TB.

The failure of antibody-based approaches spurred interest in antigen-detection methods (Flores et al., 2011). While many candidate antigens have been evaluated, urine lipoarabinomannan (LAM) detection assay was the first and, to date, the only antigen detection test to be commercialized, based on promising results from early studies (Boehme et al., 2005). Unfortunately, subsequent research showed that the urine LAM ELISA assay had suboptimal accuracy for routine clinical use in unselected patients (Minion et al., 2011; Peter et al., 2010).

Alere Inc., Waltham, MA, USA (reproduced with permission).

Figure 5. Point-of-care strip test for TB using LAM antigen detection. Source: Alere Inc., Waltham, MA, USA (reproduced with permission).

Two recent studies have evaluated the Determine® TB-LAM (Alere Inc., Waltham, MA, USA), a low-cost, POC version of the urine LAM test (Figure 5), in HIV-infected persons in South Africa (Lawn et al., 2011; Peter et al., 2011). Consistent with previous studies, the overall sensitivity of Determine® TB-LAM was low in patients with culture-confirmed TB. However, these studies showed that a combination of POC LAM test and sputum smears may offer value in screening for TB among severely immune-compromised HIV-infected patients (e.g., CD4 counts <50), a subgroup of high-risk patients for whom diagnostic delays can be fatal (Lawn et al., 2011; Peter et al., 2011). Further research is necessary to assess the clinical impact of using this POC LAM test and its role in improving case management (Denkinger and Pai, 2011). Because the Determine® TB-LAM test may have value only in those with low CD4 counts, the test must be evaluated as part of an algorithm which includes, ideally, HIV and CD4 testing at the point-of-care.

TB Diagnostics: Gaps and Needs

Tests such as Xpert MTB/RIF and Determine® TB-LAM are not the ideal POC tests that are desperately needed for TB control. But they have shown us a glimpse of what the future holds, and give us hope that an ideal POC TB test may be within reach. Clearly, if we want to replicate the successes achieved in HIV diagnostics, renewed efforts must be made to develop laboratory-free, POC tests for all forms of active TB, regardless of HIV status or CD4 counts. Mathematical models suggest that such POC tests can have a huge impact on TB case detection rates as well as TB incidence (Abu-Raddad et al., 2009; Dowdy et al., 2008; Keeler et al., 2006).

The target product profile for such an ideal TB POC test has been recently published (Table 3) (Batz et al., 2011). However, because of insufficient progress in biomarker research and because of lack of strong industry interest in TB, progress has been much slower than anticipated. In fact, efforts are being made to develop incentive prize models for successful POC tests for TB (Wilson and Palriwala, 2011). Incentive prizes are large cash rewards for achievement of specified objectives, and can be an approach to spur development of novel health technologies (e.g., diagnostics) for diseases of poverty and neglected diseases (Wilson and Palriwala, 2011). While two prizes have been proposed for POC TB tests, neither has been successfully launched (Wilson and Palriwala, 2011).

While a simple, dipstick type of POC test for TB might not be ready in the near future, the landscape is looking more promising for a more decentralized, field-friendly, affordable molecular test, which can be used at the point-of-care to reduce diagnostic delays (Figure 6) (Niemz et al., 2011). These include hand-held or portable platforms, based on DNA chips and/or disposable cartridges (Figure 7). Many of the technologies under development are capable of detecting many different infectious diseases, and that makes them very attractive for scale-up. For example, a platform that can detect TB, drug-resistant TB, as well as HIV viral loads could be very helpful in a clinic setting.

Bridging the Chasm Between HIV and TB Control

Madhukar Pai; Hojoon Sohn; Molbio Diagnostics Private Limited, India; and Epistem Ltd., Manchester, UK (reproduced with permission).

Figure 6. Progress towards decentralized, affordable, field-friendly POC NAATs for TB. Source: Madhukar Pai; Hojoon Sohn; Molbio Diagnostics Private Limited, India; and Epistem Ltd., Manchester, UK (reproduced with permission).

While TB is an ancient disease, the HIV epidemic has been a problem for only 30 years. Yet, a comparison of the HIV and TB diagnostics landscapes clearly suggests that research & development (R&D) in TB has greatly lagged behind HIV, and there may be several explanations for this big gap (Harrington, 2010). Patients, providers, and activists have played a major role in pushing for innovations in HIV diagnosis and treatment and in lobbying for price reductions and generic products. Funders, researchers, industry, and governments have responded to this pressure by supporting R&D efforts on all fronts (drugs, diagnostics, and vaccines). Because the HIV epidemic historically began as a disease of the developed world, much of activism generated in the West helped translate the R&D into products that ultimately benefited the developing world. Private pharmaceutical industry has played a big role in developing products in part because HIV is now a chronic disease that requires lifelong management and this ensures a large market. These factors partly explain the interest of pharma and biotech industries in enhancing and expanding on the ever growing HIV diagnostics and antiretroviral drugs portfolio.

In contrast, advocacy for R&D in TB has been weak, and private industry and donor interest has been low (Harrington, 2010). The revised Global Plan to Stop TB 2011-2015 estimates that at least US$9.8 billion is needed in TB R&D over the next 5 years to reach the targets of 50% reduction in TB prevalence and mortality by 2015 (World Health Organization, 2010). But according to analyses by Treatment Action Group (TAG) and Stop TB Partnership (STP), TB research globally remains grossly underfunded — the total funding gap for the next five years (2011-2015) is estimated at US$6.4 billion (64%). A 2011 funding analysis report by TAG and STP showed significant funding declines in basic science research on TB, which dropped 27% and 29% to $126.6 million and $78 million, respectively (Treatment Action Group & Stop TB Partnership, 2011). This is worrisome because progress in the area of POC test development will require major investments in biomarker and basic research.

Figure 9.

Figure 7. Portable or handheld NAATs have the potential to be used at the point-of-care, and can be used to diagnose several infectious diseases. Source: (Left) TrueLab NAAT technology by Molbio Diagnostics Private Ltd., India (reproduced with permission) and (Right) Genedrive technology by Epistem Ltd., Manchester, UK (reproduced with permission).

Given the flat-lined funding trends and lack of strong industry interest in TB, the attention is now shifting to Brazil, Russia, India, China, and South Africa (BRICS) and the leadership they can provide in the context of the global economic slowdown. There is a lot of excitement over the potential of BRICS in the development of affordable health-care technologies (Frew et al., 2008). This is especially true for diseases of poverty, such as TB, that may not be of great interest to rich countries or to industry, which do not see a market to justify investments (Engel et al., 2012). Although these countries have a large TB burden, they also have the technical resources and intellectual capital to invest in solutions and are capable of addressing the funding gap by infusing more resources into R&D for diseases such as TB (Small and Pai, 2010). Countries like China and India have a strong and growing biotechnology industry, and these countries may support the next wave of innovations in drugs, vaccines, and diagnostics (Frew et al., 2008). There is also potential for philanthropic initiatives from high-net-worth individuals and companies in these growing economies. A recent conference in India highlighted its potential in taking the lead on TB diagnostics innovations (Engel et al., 2012; Pai, 2011a).

The Stop TB Partnership and WHO have set 2015 as the deadline for developing a simple POC test for TB (World Health Organization, 2011b). Clearly, this goal will not be met without the greater engagement of industry, funders, governments, and researchers. Most importantly, the lessons from the response to the HIV epidemic must be used to step up the intensity of advocacy efforts to demand better tools for TB care and control, and to raise the level of ambition. The battle against TB cannot be won with century-old, antiquated tools.

Acknowledgments

Both authors are recipients of the CIHR New Investigator Award from the Canadian Institutes of Health Research (CIHR), and the Canadian Rising Stars in Global Health Award from Grand Challenges Canada.

Disclosures

The authors report no conflicts of interest.

Corresponding Author

Madhukar Pai, M.D., Ph.D., Associate Professor, McGill University, Department of Epidemiology & Biostatistics, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 13(68):35-45, January 2012. Copyright © Discovery Medicine. All rights reserved.]

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