Over the past 5 years, increased donor, governmental, and corporate investment for the diagnosis, treatment, prevention, and control of tuberculosis have led to substantial advancement in the development of new diagnostics, drugs, and vaccines.1, 2 Accelerated drug development is leading to a new portfolio of promising drugs against tuberculosis and regimens for drug-susceptible and drug-resistant disease, some of which are now under evaluation; however, discovery of tuberculosis biomarkers has lagged behind. Over the past decade both human and Mycobacterium tuberculosis biomarker studies have focused on three specific areas of research: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. The non-specific markers of inflammation such as C-reactive protein, when considered in isolation, do not have sufficient predictive values for clinical use.
Biomarkers are objective characteristics that indicate a normal or pathogenic biological process, or a pharmacological response to a therapeutic intervention or vaccination.3 Thus they can provide information about disease status, risk of progression, likelihood of response to treatment or of drug toxicity, and protective immunity after vaccination (panel 1). Biomarkers can be the basis for surrogate endpoints in a clinical trial, replacing typical clinical endpoints that describe how a patient feels, functions, or survives. The biomarker-endpoint association can be shown by trials of antiretroviral therapy in which a biomarker (plasma HIV RNA) forms the basis of a surrogate endpoint (eg, the proportion of patients with undetectable plasma HIV RNA by week 48). The value of such an endpoint lies in its use for the prediction of clinically meaningful events (eg, opportunistic infection or mortality) in short trials with few patients, thus accelerating clinical research.
The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. This proposed highest level of certainty is indicated for month 2 sputum culture status and interferon γ release (table). Prediction of outcomes in natural history (non-interventional) studies confers an intermediate level of certainty. The simple detection of a treatment effect not yet related to a clinical outcome has the lowest level of certainty, because it depends solely on biological plausibility for its interpretation. Biomarkers inevitably overlap with diagnostics, which, by contrast, inform present rather than future health status. Some biomarkers can have a dual role (eg, plasma HIV RNA, which can be used to both diagnose HIV-1 infection and monitor its treatment), whereas others cannot (eg, HIV antibody). In some situations, markers that have confirmed prognostic value when used to assess disease extent before treatment initiation can nonetheless fail as surrogate endpoints when used after treatment has started; they therefore cannot capture the effects of treatment. One such situation is quantitative detection of M tuberculosis DNA in sputum, which correlates with bacterial burden at the time of tuberculosis diagnosis, but, like the acid fast smear, cannot distinguish live from dead bacteria as treatment progresses.68
Key messages
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Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade; current research is focused on three areas: the cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination
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Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas
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The qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis remains very challenging
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The validation of a putative surrogate endpoint in tuberculosis remains extremely challenging, and for biomarkers that are non-culture based, requires the establishment of well characterised biobanks with biospecimens from patients who have had adequate follow-up to quantify recurrent disease
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Accelerated tuberculosis biomarker research and development is anticipated with several funding agencies increasing investment into tuberculosis biomarker research
Several candidate biomarkers derived from M tuberculosis or human inflammatory immune responses have been studied over the past decade (table), describing the reactivation of latent tuberculosis infection, its durable eradication (relapse-free cure) in patients with active disease, and the induction of protective immune responses by vaccination.69, 70 With the exception of month 2 culture status, the size of these studies falls far short of research needs. Many older, non-specific markers of inflammation, when used alone, can have insufficient predictive value for clinical use in tuberculosis, although a combination of the biomarkers highlighted in the table has a theoretical potential to help assessment of clinical cure, or risk of relapse or reactivation. For example, high levels of neopterin (a non-specific marker of macrophage activation) that persist despite appropriate tuberculosis treatment are associated with increased risk of relapse or reactivation, but only in people without concomitant HIV-1 infection or other complicating medical conditions.42 Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas since this subject was last reviewed in this journal.71 In this Series paper we discuss this progress.