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Correlates for disease progression and prognosis during concurrent HIV/TB infection

Open ArchivePublished:April 24, 2007DOI:https://doi.org/10.1016/j.ijid.2007.02.001

      Summary

      Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are both life-threatening pathogens in their own right, but their synergic effects on the immune system during co-infection markedly enhance their effect on the host. This review focuses on the bidirectional interaction between HIV and Mtb and discusses the relevance of sputum smear examination, CD4+ counts, viral load at baseline and after initiation of anti-retroviral therapy, as well as additional existing and new potential immune correlates of disease progression and prognosis. These markers include β2-microglobulin, neopterin, tumor necrosis factor receptor II (TNFRII), CD8+/CD38+, soluble urokinase plasminogen activator receptor (suPAR) and CXCL10 (or IP-10).

      Keywords

      Synergistic effect of concurrent HIV and TB infection

      The influence of concurrent human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb) infection on disease progression of both individual diseases has been clearly established during the past years. Mtb infection represents the leading cause of mortality in HIV-infected patients,
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      Risk for developing tuberculosis among anergic patients infected with HIV.
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      This escalates to well over 10%
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      Risk for developing tuberculosis among anergic patients infected with HIV.
      with an annual rate between 7% and 10%, when there is concurrent HIV infection.
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      Interference with the ability of dendritic cells to direct the adaptive immune response

      Key concepts in the immunologic interplay of Mtb and HIV infection are summarized in Figure 1. LTBI is a dynamic state between mycobacterium and host immunity. Infected macrophages and dendritic cells (DCs) process and present mycobacterial and viral antigens to CD4+ and CD8+ T-cells and other lymphocyte subsets like regulatory T-cells, γδ and natural killer (NK) cells. Processed peptides together with macrophage/DC-derived interleukin (IL)-12 favor T helper cell 1 (Th1) differentiation and secretion of interferon- γ (IFN-γ), IL-2 and tumor necrosis factor-α (TNF-α), which are believed to be protective.
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      Host innate and Th1 responses and the bacterial factors that control mycobacterium tuberculosis infection.
      Although DCs are seen as crucial in the production of an effective adaptive immune response due to their ability to carry antigens to lymphoid tissue where interactions with CD4+ T-cells occur,
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      it has been reported that DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-dependent uptake of HIV facilitates T-cell transinfection.
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      DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T Cells.
      Mycobacteria also shed molecules interacting with DCs and macrophages through DC-SIGN and this has been shown to stimulate secretion of the anti-inflammatory cytokine IL-10, thereby suppressing DC function and maturation.
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      • Schaible U.E.
      A dangerous liaison between two major killers: mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN.
      This could have severe consequences in the case of concurrent HIV and Mtb infection as the conjugated effect of the two pathogens will supposedly increase not only DC-dependent T-cell transinfection but also minimize the ability of the host to respond adequately to pathogens, thereby enhancing their survival and dissemination.
      Figure thumbnail gr1
      Figure 1Key concepts of immunopathogenesis of latent TB. In brief, cytokines drive the interaction between CD4+ T-cells and infected macrophages. Stable latent TB infection requires dominance of Th1 over Th2 for effective containment of the infection within granulomas. HIV infection results in T-cell depletion but also in a switch from Th1 to Th2 dominance, thus enabling progression to active disease. The uptake of HIV through DC-SIGN enables transinfection of CD4+ T-cells and leads to both functional defects and loss of CD4+ cells that are required for an effective immune response against Mtb. DC, dendritic cell; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; Th, T helper cell; Treg, regulatory T-cell; TGF, transforming growth factor; DC-SIGN, DC-specific intercellular adhesion molecule-3-grabbing nonintegrin; Mtb, Mycobacterium tuberculosis.
      Substantial evidence exists that DCs can influence the immune response and outcome of infections although the mechanisms are not fully understood. Several types of DCs have been described in humans and include the following: the myeloid DCs (DC1) that elicit the Th1 response in the presence of IL-12, and the plasmacytoid DCs (DC2) that elicit a Th2 response when IL-4 is present.
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      Dendritic cell regulation of TH1-TH2 development.
      It has been shown that the presence of IL-10 and the absence of IL-12 may lead to Th2 polarization by default.
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      Dendritic cell subsets and the regulation of Th1/Th2 responses.
      This may be one of the means by which Mtb-infected DCs shift the Th-cell balance from the required Th1 response to a more deleterious Th2 type response.

      Cytokine dysregulation drives immunopathology during concurrent HIV and Mtb infection

      TNF-α and IFN-γ are key cytokines in granuloma formation that contain TB infection; however, pro-inflammatory cytokines and especially TNF-α will, in excess, lead to severe tissue destruction and caseating necrosis.
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      Miliary tuberculosis: new insights into and old disease.
      The sustained containment of stable LTBI is based on the balance between protective responses (pro-inflammatory) and suppressive responses (anti-inflammatory) to limit immunopathology. The dominant Th1 cell activation is under the regulation of other T-cell subsets. Polarized Th2 sets secrete IL-4, IL-10 and IL-13 and thereby inhibit the Th1-mediated pro-inflammatory and tissue-destructive response. CD4+CD25+ regulatory T-cells favor Th2 skewing by augmenting suppressive reactions and promoting negative feedback on Th1 cells.
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      Regulatory T cells are expanded in blood and disease sites in tuberculosis patients.
      Secretion of IL-4 in active TB patients has always been looked at as an indicator of Th2 cell activity.
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      Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease.
      There is evidence that increased IL-4 secretion enhances TNF-α toxicity and fibrosis
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      Pulmonary tuberculosis in BALB/c mice with non-functional IL-4 genes: changes in the inflammatory effects of TNF-α and in the regulation of fibrosis.
      and promotes TNF-α-mediated apoptosis in Mtb activated lymphocytes. IL-4 is therefore involved in the immunopathology of TB infection
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      IL-4 Influences apoptosis of mycobacterium-reactive lymphocytes in the presence of TNF-α.
      and its presence has been associated with the extent of tuberculosis disease.
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      Increased IL-4 production in response to virulent mycobacterium tuberculosis in tuberculosis patients with advanced disease.
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      In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis.
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      High levels of mRNA encoding IL-4 in unstimulated peripheral blood mononuclear cells from tuberculosis patients revealed by quantitative nested reverse transcriptase-polymerase chain reaction; correlations with serum IgE levels.
      In the case of concurrent HIV and Mtb infection the IL-4/TNF-α interaction could exacerbate the situation, as the depletion of T-cells would make the host vulnerable to HIV progression. The discovery of IL-4δ2, an IL-4 splice variant and IL-4 antagonist, has brought new insight into the concept of immune regulation and problems with its assessment. Commonly used immunoassays for IL-4 do not differentiate between IL-4 and its splice variant, and it is now clear that IL-4 levels have to be interpreted together with IL-4δ2 expression levels. Recent studies have shown increased expression of IL-4δ2 in individuals with LTBI, unlike active TB patients who have low expression of IL-4δ2 and increased IL-4 expression.
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      High levels of mRNA encoding IL-4 in unstimulated peripheral blood mononuclear cells from tuberculosis patients revealed by quantitative nested reverse transcriptase-polymerase chain reaction; correlations with serum IgE levels.
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      Healthy individuals that control a latent infection with mycobacterium tuberculosis express high levels of Th1 cytokines and the IL-4 antagonist IL-4delta2.
      It has also been reported that TB patients have greater levels of mRNA for both cytokines when compared to healthy controls, and that only IL-4δ2 levels increase in parallel with IFN-γ after anti-TB treatment.
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      In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis.
      Investigations of concurrent HIV and Mtb infections have led to the concept that Mtb-induced T-cell turnover speeds up the progression of asymptomatic HIV infection to AIDS by triggering viral replication
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      Effect of mycobacterium tuberculosis on HIV replication: role of immune activation.
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      Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung.
      and inducing programmed cell death in T-lymphocytes through TNF-α-dependent pathways.
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      Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung.
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      Tumor necrosis factor (TNF)-α and TNF receptors in viral pathogenesis.
      The subsequent increase in viral load leads to altered immune cell function,
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      Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging.
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      Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals.
      further T-cell infection and depletion.
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      Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection.
      The subsequent weakening of cellular immunity and loss of pro-inflammatory cytokine production leads to granuloma disintegration,
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      • Snider Jr., D.E.
      Tuberculosis in patients with human immunodeficiency virus infection.
      or the inability to form granulomas,
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      Disseminated tuberculosis in interferon gamma gene-disrupted mice.
      and ultimately to HIV-associated active TB and even death.
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      Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection.
      • Dheda K.
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      • Lipman M.C.
      Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy.
      In individuals with LTBI the progressive depletion of CD4+ T-cells caused by HIV activity increases the likelihood of Mtb reactivation and disease.
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      Immune response during HIV and tuberculosis co-infection.
      HIV infection has also been shown to negatively impact on TB recurrence and treatment failure.
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      HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers.
      • Dylewski J.
      • Thibert L.
      Failure of tuberculosis chemotherapy in human immunodeficiency virus-infected patient.
      It is the underlying cause of the paradoxical reaction
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      • et al.
      Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection.
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      and presumed to increase the likelihood for developing TB drug resistance.
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      • Rodriguez P.
      • Moreno C.
      • Garrigo M.
      • Coll P.
      • et al.
      Acquired drug resistance in mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis.

      Tuberculosis immune reconstitution inflammatory syndrome (TB IRIS)

      TB IRIS is recognized in two different clinical situations. Unrecognized active TB may be unmasked early after initiation of highly active antiretroviral therapy (HAART) when the development of abscesses containing acid-fast bacilli enables diagnosis.
      • Colebunders R.
      • John L.
      • Huyst V.
      • Kambugu A.
      • Scano F.
      • Lynent L.
      Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources.
      Alternatively, a known TB patient on anti-TB treatment may develop worsening of the clinical picture after the introduction of HAART.
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      • Bekker L.D.
      • Miller R.F.
      Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals.
      TB IRIS usually develops within 2–8 weeks of initiation of HAART,
      • French M.A.
      • Price P.
      • Stone S.F.
      Immune restoration disease after antiretroviral therapy.
      although much later presentations have been described.
      • Lawn S.D.
      • Bekker L.D.
      • Miller R.F.
      Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals.
      A universally accepted clinical definition has not been established but a combination of the development of new symptoms, new clinical signs, new radiological findings, and special investigations may be needed to secure this diagnosis. Symptoms developing after the onset of HAART include fever, feeling acutely unwell, and increased cough or dyspnea. The development of new clinical signs may involve lymph node enlargement, occurrence of skin lesions or development of subcutaneous or muscle abscesses. Radiological signs include new or enlarging mediastinal lymph nodes (or abdominal nodes as seen by ultrasound or computed tomography) and increased pulmonary infiltrates or appearance of pleural effusions.
      • Colebunders R.
      • John L.
      • Huyst V.
      • Kambugu A.
      • Scano F.
      • Lynent L.
      Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources.
      • Lawn S.D.
      • Bekker L.D.
      • Miller R.F.
      Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals.
      An increase in the size of a tuberculin skin test reaction, a drop in viral load and an increase in CD4+ counts are characteristic results from special investigations associated with IRIS.
      • Lawn S.D.
      • Bekker L.D.
      • Miller R.F.
      Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals.
      Further research is needed to enable the establishment of reliable diagnostic criteria and algorithms.
      The risk for development of TB IRIS is higher in patients receiving treatment for TB and antiretroviral treatment simultaneously,
      • Breen R.A.
      • Smith C.J.
      • Bettinson H.
      • Dart S.
      • Bannister B.
      • Johnson M.A.
      • et al.
      Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection.
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      and higher in patients with disseminated TB.
      • Breen R.A.
      • Smith C.J.
      • Bettinson H.
      • Dart S.
      • Bannister B.
      • Johnson M.A.
      • et al.
      Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection.
      The immunopathology of TB IRIS is based on restoration of mycobacteria-specific T-cells after induction of antiretroviral therapy. Clinical presentation of IRIS corresponds to restoration of delayed type hypersensitivity as measured by skin test responses to purified protein derivative (PPD),
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      and enhancement of PPD-specific Th1 cyto- and chemokine production (IL-2, IL-12, IFN-γ, CXCL10/IP-10 (IFN-γ-inducible protein-10) and CXCL9/MIG (monokine induced by γ-interferon)) with no antagonizing Th2 response.
      • Bourgarit A.
      • Carcelain G.
      • Martinez V.
      • Lascoux C.
      • Delcey V.
      • Gicquel B.
      • et al.
      Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients.
      The Th1 cytokine burst coincides with a peak in other non-specific pro-inflammatory mediators (TNF-α, IL-6, IL-1β, CCL5/RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted) and CCL2/MCP-1 (monocyte chemotactic protein-1)).
      • Bourgarit A.
      • Carcelain G.
      • Martinez V.
      • Lascoux C.
      • Delcey V.
      • Gicquel B.
      • et al.
      Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients.
      • Morlese J.F.
      • Orkin C.M.
      • Abbas R.
      • Burton C.
      • Qazi N.A.
      • Nelson M.R.
      • et al.
      Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection.
      IRIS has not been shown to negatively influence treatment outcome (treatment failure, increase in mycobacterial and viral load or mortality) of HIV-infected TB patients as long as it is managed without interrupting HIV/TB treatment.
      • Dheda K.
      • Lampe F.
      • Johnson M.A.
      • Lipman M.C.
      Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy.
      Identifying surrogate markers for IRIS would be clinically useful as a confident diagnosis of this syndrome is needed to rule out other possible etiologies, such as opportunistic infections.

      Development of anti-TB drug resistance

      Drug-resistant Mtb refers to isolates that withstand anti-TB agents (any one of isoniazid, rifampin, pyrazinamide, or ethambutol) and the term ‘multidrug-resistant’ (MDR) is used when the isolate is resistant to at least isoniazid and rifampin. HIV-infected persons appear to be at increased risk for the development of drug resistance,
      • March F.
      • Garriga X.
      • Rodriguez P.
      • Moreno C.
      • Garrigo M.
      • Coll P.
      • et al.
      Acquired drug resistance in mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis.
      • Bradford W.Z.
      • Martin J.N.
      • Reingold A.L.
      • Schecter G.F.
      • Hopewell P.C.
      • Small P.M.
      The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA.
      although the mechanisms are not clear. The pharmacokinetic interaction between antiretroviral and anti-TB drugs that induces drug malabsorption may impair treatment responses
      • Di Perri G.
      • Aguilar Marucco D.
      • Mondo A.
      • Gonzalez de Requena D.
      • Audagnotto S.
      • Gobbi F.
      • et al.
      Drug–drug interactions and tolerance in combining antituberculosis and antiretroviral therapy.
      and lead to acquired drug resistance
      • March F.
      • Garriga X.
      • Rodriguez P.
      • Moreno C.
      • Garrigo M.
      • Coll P.
      • et al.
      Acquired drug resistance in mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis.
      • Sahai J.
      • Gallicano K.
      • Swick L.
      • Tailor S.
      • Garber G.
      • Seguin I.
      • et al.
      Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection.
      and drug tolerance
      • Di Perri G.
      • Aguilar Marucco D.
      • Mondo A.
      • Gonzalez de Requena D.
      • Audagnotto S.
      • Gobbi F.
      • et al.
      Drug–drug interactions and tolerance in combining antituberculosis and antiretroviral therapy.
      in HIV positive TB patients. Patel et al. have advocated that clinicians should seriously consider introducing routine checks of anti-mycobacterial drug levels in HIV positive TB patients.
      • Patel K.B.
      • Belmonte R.
      • Crowe H.M.
      Drug malabsorption and resistant tuberculosis in HIV-infected patients.
      The introduction of routine drug level measurements in TB patients, regardless of HIV status, could potentially be of great use in the fight against the development of TB drug resistance in general, but the economic feasibility in developing countries, where the overwhelming majority of patients are found, is questionable. Traditional identification of drug-resistant TB is based on failed sputum smear conversion and on culture with drug sensitivity testing, a time-consuming endeavor, also not readily available in resource-limited settings. Thus, there is a need for simple, quick and inexpensive tests to determine TB treatment efficacy, especially in the context of HIV co-infection. One approach could be to identify immune surrogate markers associated with drug resistance. Recently, in the search for such markers, Nunes et al.
      • Nunes E.A.
      • De Capitani E.M.
      • Coelho E.
      • Joaquim O.A.
      • Figueiredo I.R.
      • Cossa A.M.
      • et al.
      Patterns of anti-tuberculosis drug resistance among HIV-infected patients in Maputo, Mozambique, 2002–2003.
      screened HIV positive TB patients with drug-sensitive and MDR TB, with chest X-rays, hemoglobin levels, and total lymphocyte and CD4+ counts. No association with anti-TB drug resistance was found. However, the search for useful markers has not been exhausted.

      Markers for TB treatment response in HIV-infected patients

      The control of active TB infection in HIV positive patients in newly industrialized countries depends on the implementation of new treatment strategies based on existing ones against TB and HIV individually. In order to efficiently optimize the treatment of TB in this setting and to overcome the problems that limit the implementation of therapy today (what to treat first and the timing of treatment initiation), it is crucial to identify new independent immune signatures for each pathogen (immune correlates of Mtb clearance or persistence and correlates of immune reconstitution and viral load). The identified markers could then be integrated in a model to stratify patients on a risk scale. Most recently, Brahmbhatt et al.
      • Brahmbhatt S.
      • Black G.F.
      • Carroll N.M.
      • Beyers N.
      • Salker F.
      • Kidd M.
      • et al.
      Immune markers measured before treatment predict outcome of intensive phase tuberculosis therapy.
      and Veenstra et al.
      • Veenstra H.
      • Baumann R.
      • Carroll N.M.
      • Lukey P.T.
      • Kidd M.
      • Beyers N.
      • et al.
      Changes in leukocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+ natural killer T cells in fast treatment responders.
      demonstrated that immune parameters could be integrated in algorithm models for the early prediction of month 2 sputum sterilization in HIV-uninfected active TB patients. In the light of these preliminary reports, we screened the literature, selected and discussed some of many potential host immunological candidate markers that could be combined in such models, and investigated prospectively in a search for predictors of TB treatment outcome in HIV patients. For our literature search via Medline, we focused on markers that have been reported within the context of TB treatment response in HIV-infected but also HIV-uninfected individuals (Table 1).
      Table 1Markers of disease progression and treatment response in HIV and Mtb infection. The effect of markers discussed in this review are summarized
      Immune markersMtb-specific value of marker
      Prognosis associated with TB.
      HIV-specific value of marker
      Prognosis associated with HIV.
      Associated prognosis during therapy (anti-TB
      Prognosis associated with TB.
      or ARV
      Prognosis associated with HIV.
      )
      Reference number(s)
      Microbiological and Mtb-specific markers
      PositiveNegative
       Sputum culture/smear after 8 weeks of treatmentPresence of active MtbPoor response to therapy/poor outcome
      Prognosis associated with TB.
      Good response
      Prognosis associated with TB.
      • Combs D.L.
      • O’Brien R.J.
      • Geiter L.J.
      USPHS Tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, acceptability.
      IncreaseUnchanged
       TTP during treatmentPresence of active Mtb, bacterial burdenRemission
      Prognosis associated with TB.
      Poor response to therapy/poor outcome
      Prognosis associated with TB.

      Hanna BA, Walters SB, Heller PA, et al. Time to culture detection of mycobacterium tuberculosis as a possible index of patient progress and outcome. Abstract D-44. Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, September 17–20, 1995.

      Hanna BA, Walters SB, Kodsi SE, Stitt DT, Tierno PM, Tick LJ. Detection of mycobacterium tuberculosis directly from patient specimens with the Mycobacterial Growth Indicator tube: a new rapid method. Abstract C-112. Presented at the meeting of the American Society of Microbiology, Las Vegas, Nevada, USA, May 23–27, 1994.

      • Epstein M.D.
      • Schluger N.W.
      • Davidow A.L.
      • Bonk S.
      • Rom W.N.
      • Hanna B.
      Time to detection of mycobacterium tuberculosis in sputum culture correlates with outcome in patients receiving treatment for pulmonary tuberculosis.
      Mtb-specific IFN-γ release assaysMtb-specific immune competenceRemission
      Prognosis associated with TB.
      ,
      Subject to some controversy.
      Poor response to therapy/poor outcome
      Prognosis associated with TB.
      ,
      Subject to some controversy.
      • Lee J.Y.
      • Choi H.J.
      • Park I.N.
      • Hong S.B.
      • Oh Y.M.
      • Lim C.M.
      • et al.
      Comparison of two commercial interferon-γ assays for diagnosing mycobacterium tuberculosis infection.
      • Pai M.
      • Riley L.
      • Colford J.J.
      Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review.
      • Brock I.
      • Ruhwald M.
      • Lundgren B.
      • Westh H.
      • Mathiesen L.R.
      • Ravn P.
      Latent tuberculosis in HIV positive, diagnosed by the M. tuberculosis specific interferon-γ test.
      • Piana F.
      • Codecasa L.R.
      • Cavallerio P.
      • Ferrarese M.
      • Migliori G.B.
      • Barbarano L.
      • et al.
      Use of a T-cell-based test for detection of tuberculosis infection among immunocompromised patients.
      • Carrara S.
      • Vincenti D.
      • Petrosillo N.
      • Amicosante M.
      • Girardi E.
      • Goletti D.
      Use of a T cell-based assay for monitoring efficacy of antituberculosis therapy.
      • Pathan A.A.
      • Wilkinson K.A.
      • Klenerman P.
      • McShane H.
      • Davidson R.N.
      • Pasvol G.
      • et al.
      Direct ex vivo analysis of antigen-specific IFN-γ-secreting CD4 T cells in mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment.
      • Ulrichs T.
      • Anding R.
      • Kaufmann S.H.
      • Munk M.E.
      Numbers of IFN-γ-producing cells against ESAT-6 increase in tuberculosis patients during chemotherapy.
      LTBI
      Persistence/Active disease
      HIV-specific markers
      IncreaseDecrease
       CD4+ countImmune competenceHIV infection stagingResponse to TB treatment
      Prognosis associated with TB.
      /ARV
      Prognosis associated with HIV.
      Poor outcome
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Wolday D.
      • Hailu B.
      • Girma M.
      • Hailu E.
      • Sanders E.
      • Fontanet A.L.
      • et al.
      Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians.
      • Ghani A.C.
      • de Wolf F.
      • Ferguson N.M.
      • Donnelly C.A.
      • Coutinho R.
      • Miedema F.
      • et al.
      Surrogate markers for disease progression in treated HIV infection.
      • Martin D.J.
      • Sim J.G.
      • Sole G.J.
      • Rymer L.
      • Shalekoff S.
      • van Niekerk A.B.
      • et al.
      CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis.
      • Chene G.
      • Binquet C.
      • Moreau J.F.
      • Neau D.
      • Pellegrin I.
      • Malvy D.
      • et al.
      Changes in CD4+ cell count and the risk of opportunistic infection or death after highly active antiretroviral treatment. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine.
      • Dragsted U.B.
      • Mocroft A.
      • Vella S.
      • Viard J.P.
      • Hansen A.B.
      • Panos G.
      • et al.
      Predictors of immunological failure after initial response to highly active antiretroviral therapy in HIV-1-infected adults: a EuroSIDA study.
      • Silveira J.M.
      • Sassi R.A.
      • de Oliveira Netto I.C.
      • Hetzel J.L.
      Prevalence of and factors related to tuberculosis in seropositive human immunodeficiency virus patients at a reference center for treatment of human immunodeficiency virus in the southern region of the state of Rio Grande do Sul, Brazil.
       ViremiaHIV loadPoor response to therapy/poor outcome
      Prognosis associated with HIV.
      Remission
      Prognosis associated with HIV.
      • Kaplan J.E.
      • Hanson D.L.
      • Jones J.L.
      • Dworkin M.S.
      Adult and Adolescent Spectrum of HIV Disease Project Investigators
      Viral load as an independent risk factor for opportunistic infection.
      • Swindells S.
      • Evans S.
      • Zackin R.
      • Goldman M.
      • Haubrich R.
      • Filler S.G.
      • et al.
      Predictive value of HIV-1 viral load on risk for opportunistic infection.
      Non-specific host markers of inflammation
      IncreaseDecrease
       β2-MicroglobulinHost inflammatory responseHost inflammatory responsePoor outcome
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Vitiello A.
      • Potter T.A.
      • Sherman L.A.
      The role of beta 2-microglobulin in peptide binding by class I molecules.
      • Berko D.
      • Carmi Y.
      • Cafri G.
      • Ben-Zaken S.
      • Sheikhet H.M.
      • Tzehoval E.
      • et al.
      Membrane-anchored beta 2-microglobulin stabilizes a highly receptive state of MHC class I molecules.
      • Bhalla R.B.
      • Safai B.
      • Mertelsmann R.
      • Schwartz M.K.
      Abnormally high concentrations of beta 2 microglobulin in acquired immunodeficiency syndrome (AIDS) patients.
      • Fahey J.L.
      • Taylor J.M.
      • Detels R.
      • Hofmann B.
      • Melmed R.
      • Nishanian P.
      • et al.
      The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1.
      • Wanchu A.
      • Arora S.
      • Bhatnagar A.
      • Sud A.
      • Bambery P.
      • Singh S.
      Decline in beta-2 microglobulin levels after anti-tubercular therapy in tubercular patients with HIV infection.
      • Phillips A.N.
      • Sabin C.A.
      • Elford J.
      • Bofill M.
      • Timms A.
      • Janossy G.
      • et al.
      Serum β2-microglobulin at HIV-1 seroconversion as a predictor of severe immunodeficiency during 10 years of follow-up.
      • Zangerle R.
      • Steinhuber S.
      • Sarcletti M.
      • Dierich M.P.
      • Wachter H.
      • Fuchs D.
      • et al.
      Serum HIV-1 RNA levels compared to soluble markers of immune activation to predict disease progression in HIV-1-infected individuals.
       NeopterinHost inflammatory responseHost inflammatory responsePoor outcome
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      Remission
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Huber C.
      • Batchelor J.R.
      • Fuchs D.
      • Hausen A.
      • Lang A.
      • Niederwieser D.
      • et al.
      Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma.
      • Tozkoparan E.
      • Deniz O.
      • Cakir E.
      • Yaman H.
      • Ciftci F.
      • Gumus S.
      • et al.
      The diagnostic value of serum, pleural fluid and urine neopterin measurements in tuberculosis pleurisy.
      • Immanuel C.
      • Victor L.
      • Chelvi K.S.
      • Padmapriyadarsini C.
      • Rehman F.
      • Iliayas S.
      • et al.
      Serum neopterin levels in HIV infected patients with and without tuberculosis.
      • Mildvan D.
      • Spritzler J.
      • Grossberg S.E.
      • Fahey J.L.
      • Johnston D.M.
      • Schock B.R.
      • et al.
      Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection.
       sTNFRIIHost inflammatory responseHost inflammatory responsePoor outcome
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      Remission
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Balcewicz-Sablinska M.K.
      • Keane J.
      • Kornfeld H.
      • Remold H.G.
      Pathogenic mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-α.
      • Juffermans N.P.
      • Verbon A.
      • van Deventer S.J.
      • van Deutekom H.
      • Speelman P.
      • van der Poll T.
      Tumor necrosis factor and interleukin-1 inhibitors as markers of disease activity of tuberculosis.
      • Nokta M.
      • Rossero R.
      • Loesch K.
      • Pollard R.B.
      Kinetics of tumor necrosis factor alpha and soluble TNFRII in HIV-infected patients treated with a triple combination of stavudine, didanosine, and hydroxyurea.
      • Hsieh S.M.
      • Hung C.C.
      • Chen M.Y.
      • Sheng W.H.
      • Chang S.C.
      Dynamics of plasma cytokine levels in patients with advanced HIV infection and active tuberculosis: implications for early recognition of patients with poor response to anti-tuberculosis treatment.
      • Lawn S.D.
      • Rudolph D.
      • Wiktor S.
      • Coulibaly D.
      • Ackah A.
      • Lal R.B.
      Tuberculosis (TB) and HIV infection are independently associated with elevated serum concentrations of tumour necrosis factor receptor type 1 and beta-2-microglobulin, respectively.
       CD8+/CD38+ T-cellsHost inflammatory responseHost inflammatory responsePoor outcome
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      Remission

      Hanna BA, Walters SB, Heller PA, et al. Time to culture detection of mycobacterium tuberculosis as a possible index of patient progress and outcome. Abstract D-44. Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, September 17–20, 1995.

      • Hamblin T.J.
      CD38: what is it there for?.
      • de Martino M.
      • Rossi M.E.
      • Azzari C.
      • Gelli M.G.
      • Galli L.
      • Vierucci A.
      Different meaning of CD38 molecule expression on CD4+ and CD8+ cells of children perinatally infected with human immunodeficiency virus type 1 infection surviving longer than five years.
      • Beran O.
      • Holub M.
      • Spala J.
      • Kalanin J.
      • Stankova M.
      CD38 expression on CD8+ T cells in human immunodeficiency virus 1-positive adults treated with HAART.
      • Vigano A.
      • Saresella M.
      • Villa M.L.
      • Ferrante P.
      • Clerici M.
      CD38+CD8+ T cells as a marker of poor response to therapy in HIV-infected individuals.
      • Sherman G.G.
      • Scott L.E.
      • Galpin J.S.
      • Kuhn L.
      • Tiemessen C.T.
      • Simmank K.
      • et al.
      CD38 expression on CD8(+) T cells as a prognostic marker in vertically HIV-infected pediatric patients.
      • Mocroft A.
      • Bofill M.
      • Lipman M.
      • Medina E.
      • Borthwick N.
      • Timms A.
      • et al.
      CD8+,CD38+ lymphocyte percent: a useful immunological marker for monitoring HIV-1-infected patients.
      • Rodrigues D.S.
      • Medeiros E.A.
      • Weckx L.Y.
      • Bonnez W.
      • Salomao R.
      • Kallas E.G.
      Immunophenotypic characterization of peripheral T lymphocytes in mycobacterium tuberculosis infection and disease.
       suPARHost inflammatory responseHost inflammatory responsePoor outcome Mtb persistence and predictor of survival
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      Remission
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Ge Y.
      • Elghetany M.T.
      Urokinase plasminogen activator receptor (CD87): something old, something new.
      • Huai Q.
      • Mazar A.P.
      • Kuo A.
      • Parry G.C.
      • Shaw D.E.
      • Callahan J.
      • et al.
      Structure of human urokinase plasminogen activator in complex with its receptor.
      • Blasi F.
      • Carmeliet P.
      uPAR: a versatile signalling orchestrator.
      • Ostrowski S.R.
      • Ullum H.
      • Goka B.Q.
      • Hoyer-Hansen G.
      • Obeng-Adjei G.
      • Pedersen B.K.
      • et al.
      Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome.
      • Rijneveld A.W.
      • Levi M.
      • Florquin S.
      • Speelman P.
      • Carmeliet P.
      • van Der Poll T.
      Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia.
      • Sun H.
      • Ringdahl U.
      • Homeister J.W.
      • Fay W.P.
      • Engleberg N.C.
      • Yang A.Y.
      • et al.
      Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.
      • Eugen-Olsen J.
      • Gustafson P.
      • Sidenius N.
      • Fischer T.K.
      • Parner J.
      • Aaby P.
      • et al.
      The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau.
      • Ostrowski S.R.
      • Piironen T.
      • Hoyer-Hansen G.
      • Gerstoft J.
      • Pedersen B.K.
      • Ullum H.
      High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients.
      • Alfano M.
      • Sidenius N.
      • Panzeri B.
      • et al.
      Urokinase–urokinase receptor interaction mediated an inhibitory signal for HIV-1 replication.
      • Sidenius N.
      • Sier C.F.
      • Ullum H.
      • Pedersen B.K.
      • Lepri A.C.
      • Blasi F.
      • et al.
      Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection.
       CXCL10/IP-10Host inflammatory responseHost inflammatory responsePoor outcome Mtb reactivation
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      TB treatment, ARV response
      Prognosis associated with TB.
      ,
      Prognosis associated with HIV.
      • Gangur V.
      • Simons F.E.
      • Hayglass K.T.
      Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN-gamma over IL-4 responses.
      • Ferrero E.
      • Biswas P.
      • Vettoretto K.
      • Ferrarini M.
      • Uguccioni M.
      • Piali L.
      • et al.
      Macrophages exposed to mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: focus on gammadelta cells.
      • Azzurri A.
      • Sow O.Y.
      • Amedei A.
      • Bah B.
      • Diallo S.
      • Peri G.
      • et al.
      IFN-γ-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in mycobacterium tuberculosis infection.
      • Juffermans N.P.
      • Verbon A.
      • van Deventer S.J.
      • van Deutekom H.
      • Belisle J.T.
      • Ellis M.E.
      • et al.
      Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan.
      • Reinhart T.A.
      Chemokine induction by HIV-1: recruitment to the cause.
      • Stylianou E.
      • Aukrust P.
      • Bendtzen K.
      • et al.
      Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART) — possible immunosuppressive role of IFN-alpha in HIV infection.
      • Relucio K.I.
      • Beernink H.T.
      • Chen D.
      • Israelski D.M.
      • Kim R.
      • Holodniy M.
      Proteomic analysis of serum cytokine levels in response to highly active antiretroviral therapy (HAART).
      Mtb, Mycobacterium tuberculosis; ARV, antiretroviral; TTP, time to positivity; IFN-γ, interferon-γ; TB, tuberculosis; LTBI, latent TB infection; sTNFRII, soluble TNF-α receptor II; suPAR, soluble urokinase plasminogen activator receptor; IP-10, IFN-γ-inducible protein-10.
      a Prognosis associated with TB.
      b Prognosis associated with HIV.
      * Subject to some controversy.
      Currently, sputum smear status after the intensive phase of fixed dose anti-TB drug regimens in the case of TB,
      • Enarson D.E.
      • Rieder H.L.
      • Arnadottir T.
      • Trebucq A.
      Management of tuberculosis: a guide for low income countries.
      and CD4+ count and viral load in the case of HIV infection, are the surrogate markers most used for assessing treatment response and disease progression in these two infections.

      Mtb-specific markers

      Microbiological markers: sputum smear and culture

      Continuous monitoring of bacterial activity during the course of anti-TB chemotherapy through sputum smear is very useful in the assessment of treatment efficacy.
      • Combs D.L.
      • O’Brien R.J.
      • Geiter L.J.
      USPHS Tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, acceptability.
      However, the use of sputum status for the assessment of TB treatment response has important limitations as a substantial proportion of HIV positive TB cases have a negative sputum smear at diagnosis.
      • Colebunders R.
      • Bastian I.
      A review of the diagnosis and treatment of smear-negative pulmonary tuberculosis.
      • Hargreaves N.J.
      • Kadzakumanja O.
      • Phiri S.
      • Nyangulu D.S.
      • Salaniponi F.M.
      • Harries A.D.
      • et al.
      What causes smear-negative pulmonary tuberculosis in Malawi, an area of high HIV seroprevalence?.
      Although sputum culture is more sensitive than smear, it can take several weeks to obtain results of sputum cultures.
      • Kapoor S.C.
      The difficult diagnosis.
      Additionally, this is of no benefit in HIV patients where extrapulmonary TB frequently occurs. Cultures are also expensive and are often not available in resource constraint settings. Thus the identification of immune correlates of TB clearance and the development of more rapid methods for assessment of sterilization is the challenge we face today.

      Time to positivity (TTP)

      With the development of culture-based TB diagnosis, a parameter has emerged with important potential in the assessment of patient progress during therapy: time to detection (TTD), also known as time to positivity (TTP). TTP represents the time to detectable growth of Mtb in culture. Hanna et al.

      Hanna BA, Walters SB, Heller PA, et al. Time to culture detection of mycobacterium tuberculosis as a possible index of patient progress and outcome. Abstract D-44. Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, September 17–20, 1995.

      Hanna BA, Walters SB, Kodsi SE, Stitt DT, Tierno PM, Tick LJ. Detection of mycobacterium tuberculosis directly from patient specimens with the Mycobacterial Growth Indicator tube: a new rapid method. Abstract C-112. Presented at the meeting of the American Society of Microbiology, Las Vegas, Nevada, USA, May 23–27, 1994.

      were amongst the first to observe that TTP of Mtb increased in samples of patients receiving anti-TB therapy and that no change in TTP correlated with poor response to therapy. Further evidence of the potential use of TTP as an early indicator of treatment effectiveness comes from the study by Epstein et al.
      • Epstein M.D.
      • Schluger N.W.
      • Davidow A.L.
      • Bonk S.
      • Rom W.N.
      • Hanna B.
      Time to detection of mycobacterium tuberculosis in sputum culture correlates with outcome in patients receiving treatment for pulmonary tuberculosis.
      who showed that TTP of Mtb in sputum culture correlates with the response to anti-TB therapy. Further studies are needed to investigate the value of TTP as a biomarker of TB treatment outcome in both HIV-infected and uninfected patients; the same disadvantages as those of other culture methods may operate in concurrent HIV infection.

      Mtb-specific cytokine release assays for diagnosis and response to treatment

      Accurate diagnosis of TB and monitoring the efficacy of anti-TB treatment are both crucial for the control of the TB epidemic. Until recently, the tuberculin skin test (TST) was the only diagnostic test for latent tuberculosis infection. The development of new in vitro diagnostic tests such as QuantiFERON-TB in tube (QFT-IT) and enzyme-linked immunospot (ELISPOT) that are rapid, more sensitive,
      • Lee J.Y.
      • Choi H.J.
      • Park I.N.
      • Hong S.B.
      • Oh Y.M.
      • Lim C.M.
      • et al.
      Comparison of two commercial interferon-γ assays for diagnosing mycobacterium tuberculosis infection.
      • Pai M.
      • Riley L.
      • Colford J.J.
      Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review.
      and more specific for Mtb
      • Pai M.
      • Riley L.
      • Colford J.J.
      Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review.
      by minimizing cross-reactive responses due to BCG vaccination or infection with non-tuberculous mycobacteria,
      • Pai M.
      • Riley L.
      • Colford J.J.
      Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review.
      have surely added great value to the diagnosis of LTBI, both in HIV negative and non-immunocompromised HIV positive individuals.
      • Brock I.
      • Ruhwald M.
      • Lundgren B.
      • Westh H.
      • Mathiesen L.R.
      • Ravn P.
      Latent tuberculosis in HIV positive, diagnosed by the M. tuberculosis specific interferon-γ test.
      Additionally, a recent study by Piana et al. reported that the ELISPOT-based T-SPOT.TB from OxfordImmunotec (UK) maintains its sensitivity and performance in diagnosing latent Mtb infection in tuberculin skin test (TST) anergic and immunocompromised individuals.
      • Piana F.
      • Codecasa L.R.
      • Cavallerio P.
      • Ferrarese M.
      • Migliori G.B.
      • Barbarano L.
      • et al.
      Use of a T-cell-based test for detection of tuberculosis infection among immunocompromised patients.
      These methods rely on IFN-γ production by T-cells in overnight whole blood (QuantiFERON tests) or peripheral blood mononuclear cell (PBMC) culture (ELISPOT and T-SPOT.TB) with stimulation by Mtb-specific antigens (ESAT-6 (early secretory antigenic target-6) and CFP-10 (culture filtrate protein-10)). Although the usefulness of these tests lies mainly in the diagnosis of LTBI, studies have shown that these assays could be useful to monitor the efficacy of anti-TB therapy. However the interpretation and usefulness of these tests in this setting remain controversial. Whereas some researchers have reported reduced T-cell IFN-γ responses after 2–3 months of effective treatment,
      • Carrara S.
      • Vincenti D.
      • Petrosillo N.
      • Amicosante M.
      • Girardi E.
      • Goletti D.
      Use of a T cell-based assay for monitoring efficacy of antituberculosis therapy.
      • Pathan A.A.
      • Wilkinson K.A.
      • Klenerman P.
      • McShane H.
      • Davidson R.N.
      • Pasvol G.
      • et al.
      Direct ex vivo analysis of antigen-specific IFN-γ-secreting CD4 T cells in mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment.
      others have reported an increase in IFN-γ production
      • Ulrichs T.
      • Anding R.
      • Kaufmann S.H.
      • Munk M.E.
      Numbers of IFN-γ-producing cells against ESAT-6 increase in tuberculosis patients during chemotherapy.
      and more research is needed to define the role of these tests during concurrent infection with HIV.

      Markers of HIV disease severity as possible markers for TB disease progression and treatment response

      CD4+ cell count

      The CD4+ T-cell count is a valuable surrogate marker for response to antiretroviral treatment and a risk factor for progression of LTBI to active TB in HIV positive patients.
      • Wolday D.
      • Hailu B.
      • Girma M.
      • Hailu E.
      • Sanders E.
      • Fontanet A.L.
      • et al.
      Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians.
      It is mainly used to establish the immunosuppressive state of patients, for HIV treatment initiation and to monitor immune recovery.
      • Wolday D.
      • Hailu B.
      • Girma M.
      • Hailu E.
      • Sanders E.
      • Fontanet A.L.
      • et al.
      Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians.
      • Ghani A.C.
      • de Wolf F.
      • Ferguson N.M.
      • Donnelly C.A.
      • Coutinho R.
      • Miedema F.
      • et al.
      Surrogate markers for disease progression in treated HIV infection.
      • Martin D.J.
      • Sim J.G.
      • Sole G.J.
      • Rymer L.
      • Shalekoff S.
      • van Niekerk A.B.
      • et al.
      CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis.
      Low baseline CD4+ counts are not only predictive of the progression of asymptomatic HIV infection to AIDS but also constitute a risk factor for opportunistic infections such as TB.
      • Wolday D.
      • Hailu B.
      • Girma M.
      • Hailu E.
      • Sanders E.
      • Fontanet A.L.
      • et al.
      Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians.
      • Chene G.
      • Binquet C.
      • Moreau J.F.
      • Neau D.
      • Pellegrin I.
      • Malvy D.
      • et al.
      Changes in CD4+ cell count and the risk of opportunistic infection or death after highly active antiretroviral treatment. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine.
      • Dragsted U.B.
      • Mocroft A.
      • Vella S.
      • Viard J.P.
      • Hansen A.B.
      • Panos G.
      • et al.
      Predictors of immunological failure after initial response to highly active antiretroviral therapy in HIV-1-infected adults: a EuroSIDA study.
      In addition, a retrospective analysis of an HIV-infected cohort from Brazil found a mean CD4+ count of 203 in pulmonary TB cases and 180 in patients with extrapulmonary TB.
      • Silveira J.M.
      • Sassi R.A.
      • de Oliveira Netto I.C.
      • Hetzel J.L.
      Prevalence of and factors related to tuberculosis in seropositive human immunodeficiency virus patients at a reference center for treatment of human immunodeficiency virus in the southern region of the state of Rio Grande do Sul, Brazil.
      Anti-TB therapy has been shown to significantly increase CD4+ counts in both HIV positive and negative TB patients.
      • Martin D.J.
      • Sim J.G.
      • Sole G.J.
      • Rymer L.
      • Shalekoff S.
      • van Niekerk A.B.
      • et al.
      CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis.

      Viremia

      High HIV viral load is considered to be a risk factor associated with development and progression of asymptomatic HIV infection to AIDS and infection with opportunistic pathogens, independently of the CD4+ cell count.
      • Kaplan J.E.
      • Hanson D.L.
      • Jones J.L.
      • Dworkin M.S.
      Adult and Adolescent Spectrum of HIV Disease Project Investigators
      Viral load as an independent risk factor for opportunistic infection.
      • Swindells S.
      • Evans S.
      • Zackin R.
      • Goldman M.
      • Haubrich R.
      • Filler S.G.
      • et al.
      Predictive value of HIV-1 viral load on risk for opportunistic infection.
      Low CD4+ counts with high levels of viremia have been reported to precede the progression to active TB in a cohort study of HIV-infected individual in Ethiopia.
      • Wolday D.
      • Hailu B.
      • Girma M.
      • Hailu E.
      • Sanders E.
      • Fontanet A.L.
      • et al.
      Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians.
      The initiation of anti-TB treatment in these Ethiopian subjects did not initiate a decline in viral load, implying a poor prognosis. Viral load represents a critical factor in the control of disease progression in HIV positive people with LTBI and should be assessed independently of CD4+ count in order to anticipate the course of events, such as the rate of CD4+ cell number decline, development of active TB and progression to AIDS. However, economic realities in developing countries preclude the routine use of this test. Thus, it has become crucial to identify correlates of HIV disease severity by more cost effective means.

      Non-specific host biomarkers for TB disease progression and response to treatment

      In the following section, we will discuss candidate markers for disease progression in HIV-infected people with LTBI or for treatment response in active TB that have been described in the literature. Although the measurement of some of these markers may not currently be cost-effective in resource-poor settings, the identification of suitable and accurate markers would constitute a first and important step in the development of such tests, as refinement for field site use could achieve this goal. One problem with all these tests is that they are not specific for TB and this may pose significant problems for all inflammatory and immune markers in a chronic condition that by its very nature predisposes the host to multiple and often concurrent opportunistic infections and non-infectious complications. Nevertheless, in the absence of specific markers, these analytes may provide important clinical information.

      β2-Microglobulin

      β2-Microglobulin (β2M) is a component of the class I major histocompatibility (MHC class I)-molecule which is present on almost all nucleated host cells. β2M is essential for binding of MHC class I molecules to cytosolic pathogen peptides and its efficient transport to the cell surface for presentation to CD8+ T-cells.
      • Vitiello A.
      • Potter T.A.
      • Sherman L.A.
      The role of beta 2-microglobulin in peptide binding by class I molecules.
      • Berko D.
      • Carmi Y.
      • Cafri G.
      • Ben-Zaken S.
      • Sheikhet H.M.
      • Tzehoval E.
      • et al.
      Membrane-anchored beta 2-microglobulin stabilizes a highly receptive state of MHC class I molecules.
      β2M was one of the first immune markers to be found elevated
      • Bhalla R.B.
      • Safai B.
      • Mertelsmann R.
      • Schwartz M.K.
      Abnormally high concentrations of beta 2 microglobulin in acquired immunodeficiency syndrome (AIDS) patients.
      and of prognostic value
      • Fahey J.L.
      • Taylor J.M.
      • Detels R.
      • Hofmann B.
      • Melmed R.
      • Nishanian P.
      • et al.
      The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1.
      among HIV-infected individuals. Wanchu et al. have demonstrated that HIV positive patients with concomitant active TB infection have higher concentrations of β2M than HIV-infected individuals without any opportunistic infection and healthy controls.
      • Wanchu A.
      • Arora S.
      • Bhatnagar A.
      • Sud A.
      • Bambery P.
      • Singh S.
      Decline in beta-2 microglobulin levels after anti-tubercular therapy in tubercular patients with HIV infection.
      Initiation of anti-TB therapy often results in a significant decrease in β2M levels.
      • Wanchu A.
      • Arora S.
      • Bhatnagar A.
      • Sud A.
      • Bambery P.
      • Singh S.
      Decline in beta-2 microglobulin levels after anti-tubercular therapy in tubercular patients with HIV infection.
      An increase in β2M serum levels has been associated with AIDS development and death,
      • Phillips A.N.
      • Sabin C.A.
      • Elford J.
      • Bofill M.
      • Timms A.
      • Janossy G.
      • et al.
      Serum β2-microglobulin at HIV-1 seroconversion as a predictor of severe immunodeficiency during 10 years of follow-up.
      • Zangerle R.
      • Steinhuber S.
      • Sarcletti M.
      • Dierich M.P.
      • Wachter H.
      • Fuchs D.
      • et al.
      Serum HIV-1 RNA levels compared to soluble markers of immune activation to predict disease progression in HIV-1-infected individuals.
      and higher concentrations are found in patients with early progression to AIDS.
      • Phillips A.N.
      • Sabin C.A.
      • Elford J.
      • Bofill M.
      • Timms A.
      • Janossy G.
      • et al.
      Serum β2-microglobulin at HIV-1 seroconversion as a predictor of severe immunodeficiency during 10 years of follow-up.

      Neopterin

      Neopterin is produced by activated macrophages in response to lymphocyte-derived IFN-γ.
      • Huber C.
      • Batchelor J.R.
      • Fuchs D.
      • Hausen A.
      • Lang A.
      • Niederwieser D.
      • et al.
      Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma.
      As enhanced levels of neopterin reflect the activity of cell-mediated immune responses, its measurement in human fluids could be a useful tool for monitoring diseases associated with the activation of cell-mediated immune responses.
      • Tozkoparan E.
      • Deniz O.
      • Cakir E.
      • Yaman H.
      • Ciftci F.
      • Gumus S.
      • et al.
      The diagnostic value of serum, pleural fluid and urine neopterin measurements in tuberculosis pleurisy.
      Comparing three groups of patients (HIV positive asymptomatic patients with and without TB and HIV negative patients with TB), Immanuel et al. demonstrated that serum neopterin was initially significantly elevated in TB patients irrespective of their HIV status.
      • Immanuel C.
      • Victor L.
      • Chelvi K.S.
      • Padmapriyadarsini C.
      • Rehman F.
      • Iliayas S.
      • et al.
      Serum neopterin levels in HIV infected patients with and without tuberculosis.
      In HIV patients with active TB, neopterin levels were even higher compared to the other two groups and inversely correlated to CD4+ count both before and after TB treatment. Even though anti-TB therapy induced a reduction in neopterin concentration, steady high levels of neopterin in HIV-infected or HIV/TB concurrently-infected patients were associated with HIV disease progression and adverse outcome.
      • Immanuel C.
      • Victor L.
      • Chelvi K.S.
      • Padmapriyadarsini C.
      • Rehman F.
      • Iliayas S.
      • et al.
      Serum neopterin levels in HIV infected patients with and without tuberculosis.
      More recently Mildvan et al. showed that the risk for an HIV-infected person to develop clinically active TB could be determined six months prior to the dramatic decline in CD4+ T-cell count and increase in viremia by measurement of this marker.
      • Mildvan D.
      • Spritzler J.
      • Grossberg S.E.
      • Fahey J.L.
      • Johnston D.M.
      • Schock B.R.
      • et al.
      Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection.

      TNF-α and its soluble receptor II (sTNFRII)

      Infection by an intracellular pathogen may induce TNF-α-dependent apoptosis in infected cells as a defensive mechanism by limiting the growth of intracellular pathogens. It has been demonstrated by Balcewicz-Sablinska et al.
      • Balcewicz-Sablinska M.K.
      • Keane J.
      • Kornfeld H.
      • Remold H.G.
      Pathogenic mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-α.
      that virulent Mtb interferes with host macrophage apoptosis by inducing inactivation of the cytokine TNF-α through the release of sTNFRII and formation of inactive TNF-α–TNFRII complex. Additionally, the levels of sTNFRII together with other soluble receptors such as sTNFRI, and IL-1ra have been reported to be elevated in active TB patients and down-modulated by anti-TB therapy suggesting their potential use as markers of disease activity and in the assessment of therapy.
      • Juffermans N.P.
      • Verbon A.
      • van Deventer S.J.
      • van Deutekom H.
      • Speelman P.
      • van der Poll T.
      Tumor necrosis factor and interleukin-1 inhibitors as markers of disease activity of tuberculosis.
      In HIV-infected patients undergoing triple-therapy (stavudine, didanosine, and hydroxyurea), Nokta et al.
      • Nokta M.
      • Rossero R.
      • Loesch K.
      • Pollard R.B.
      Kinetics of tumor necrosis factor alpha and soluble TNFRII in HIV-infected patients treated with a triple combination of stavudine, didanosine, and hydroxyurea.
      showed an association between sTNFRII levels and HIV viremia. After the first week of therapy they observed a decline in viral titer and a drop in TNF-α and sTNFRII levels. In HIV positive patients with active TB, increased circulating TNF-α has been linked to HIV activity
      • Hsieh S.M.
      • Hung C.C.
      • Chen M.Y.
      • Sheng W.H.
      • Chang S.C.
      Dynamics of plasma cytokine levels in patients with advanced HIV infection and active tuberculosis: implications for early recognition of patients with poor response to anti-tuberculosis treatment.
      and its persistence during TB treatment associated with ongoing viral replication.
      • Lawn S.D.
      • Rudolph D.
      • Wiktor S.
      • Coulibaly D.
      • Ackah A.
      • Lal R.B.
      Tuberculosis (TB) and HIV infection are independently associated with elevated serum concentrations of tumour necrosis factor receptor type 1 and beta-2-microglobulin, respectively.

      CD8+/CD38+ T-cells

      CD38 is a glycoprotein expressed by monocytes and involved in transduction of their activation and proliferation.

      Hanna BA, Walters SB, Heller PA, et al. Time to culture detection of mycobacterium tuberculosis as a possible index of patient progress and outcome. Abstract D-44. Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, September 17–20, 1995.

      • Hamblin T.J.
      CD38: what is it there for?.
      The level of CD38 expression on CD8+ T-cells has been reported to have prognostic value for disease progression to AIDS in HIV-infected adults and children.
      • de Martino M.
      • Rossi M.E.
      • Azzari C.
      • Gelli M.G.
      • Galli L.
      • Vierucci A.
      Different meaning of CD38 molecule expression on CD4+ and CD8+ cells of children perinatally infected with human immunodeficiency virus type 1 infection surviving longer than five years.
      • Beran O.
      • Holub M.
      • Spala J.
      • Kalanin J.
      • Stankova M.
      CD38 expression on CD8+ T cells in human immunodeficiency virus 1-positive adults treated with HAART.
      • Vigano A.
      • Saresella M.
      • Villa M.L.
      • Ferrante P.
      • Clerici M.
      CD38+CD8+ T cells as a marker of poor response to therapy in HIV-infected individuals.
      In children, elevated expression of CD38 on CD8+ T-cells was found to positively correlate with plasma viral load and to negatively correlate with CD4+ T-cell count.
      • de Martino M.
      • Rossi M.E.
      • Azzari C.
      • Gelli M.G.
      • Galli L.
      • Vierucci A.
      Different meaning of CD38 molecule expression on CD4+ and CD8+ cells of children perinatally infected with human immunodeficiency virus type 1 infection surviving longer than five years.
      • Sherman G.G.
      • Scott L.E.
      • Galpin J.S.
      • Kuhn L.
      • Tiemessen C.T.
      • Simmank K.
      • et al.
      CD38 expression on CD8(+) T cells as a prognostic marker in vertically HIV-infected pediatric patients.
      Adults studies have shown that high CD38 expression is a strong predictor of disease progression to AIDS and death.
      • Beran O.
      • Holub M.
      • Spala J.
      • Kalanin J.
      • Stankova M.
      CD38 expression on CD8+ T cells in human immunodeficiency virus 1-positive adults treated with HAART.
      • Vigano A.
      • Saresella M.
      • Villa M.L.
      • Ferrante P.
      • Clerici M.
      CD38+CD8+ T cells as a marker of poor response to therapy in HIV-infected individuals.
      Mocroft et al. showed that a 10% increase in CD8+/CD38+ T-cells resulted in an 88% increase in the risk of AIDS development.
      • Mocroft A.
      • Bofill M.
      • Lipman M.
      • Medina E.
      • Borthwick N.
      • Timms A.
      • et al.
      CD8+,CD38+ lymphocyte percent: a useful immunological marker for monitoring HIV-1-infected patients.
      Additionally CD8+/CD38+ T-cell numbers have been associated with a poor response to therapy in HIV-infected individuals.
      • Vigano A.
      • Saresella M.
      • Villa M.L.
      • Ferrante P.
      • Clerici M.
      CD38+CD8+ T cells as a marker of poor response to therapy in HIV-infected individuals.
      Increased CD38 expression on T-cells has also been reported in active TB patients and has been shown to return to baseline after successful anti-TB chemotherapy.
      • Rodrigues D.S.
      • Medeiros E.A.
      • Weckx L.Y.
      • Bonnez W.
      • Salomao R.
      • Kallas E.G.
      Immunophenotypic characterization of peripheral T lymphocytes in mycobacterium tuberculosis infection and disease.
      These findings point to CD38 as a candidate biomarker for the progression of disease and for treatment response in concurrent HIV/TB infection. However, studies of differential CD38 expression profiles in people with different TB and HIV infection status are needed to develop clinically useful approaches using this marker.

      Soluble urokinase plasminogen activator receptor (suPAR)

      Different cell types, including neutrophils, phagocytes, activated T-cells, endothelial cells and tumor cells, express the urokinase plasminogen activator receptor (uPAR).
      • Ge Y.
      • Elghetany M.T.
      Urokinase plasminogen activator receptor (CD87): something old, something new.
      uPAR, like the soluble form of the receptor, suPAR, is a flexible molecule,
      • Huai Q.
      • Mazar A.P.
      • Kuo A.
      • Parry G.C.
      • Shaw D.E.
      • Callahan J.
      • et al.
      Structure of human urokinase plasminogen activator in complex with its receptor.
      enabling it to interact with several ligands and engage in numerous immunological activities including chemokinesis, cell migration, differentiation, chemokine receptor regulation, and plasminogen activation.
      • Blasi F.
      • Carmeliet P.
      uPAR: a versatile signalling orchestrator.
      In recent years, it has become evident that elevated suPAR levels are prognostic of a poor outcome in infectious diseases including malaria,
      • Ostrowski S.R.
      • Ullum H.
      • Goka B.Q.
      • Hoyer-Hansen G.
      • Obeng-Adjei G.
      • Pedersen B.K.
      • et al.
      Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome.
      pneumococcal pneumonia,
      • Rijneveld A.W.
      • Levi M.
      • Florquin S.
      • Speelman P.
      • Carmeliet P.
      • van Der Poll T.
      Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia.
      streptococcal infection,
      • Sun H.
      • Ringdahl U.
      • Homeister J.W.
      • Fay W.P.
      • Engleberg N.C.
      • Yang A.Y.
      • et al.
      Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.
      active TB
      • Eugen-Olsen J.
      • Gustafson P.
      • Sidenius N.
      • Fischer T.K.
      • Parner J.
      • Aaby P.
      • et al.
      The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau.
      and HIV.
      • Ostrowski S.R.
      • Piironen T.
      • Hoyer-Hansen G.
      • Gerstoft J.
      • Pedersen B.K.
      • Ullum H.
      High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients.
      The prognostic value of suPAR in HIV-1 infection is similar in strength to, and independent of, CD4+ count and viral load.
      • Ostrowski S.R.
      • Piironen T.
      • Hoyer-Hansen G.
      • Gerstoft J.
      • Pedersen B.K.
      • Ullum H.
      High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients.
      The uPAR ligand, urokinase, mediates a negative signal on the late stages of the HIV-1 lifecycle in vitro through binding to cell-bound uPAR, and the scavenging of urokinase by suPAR may partly explain the strong prognostic value of suPAR in HIV-infection.
      • Alfano M.
      • Sidenius N.
      • Panzeri B.
      • et al.
      Urokinase–urokinase receptor interaction mediated an inhibitory signal for HIV-1 replication.
      There is strong support of suPAR as a marker in HIV infection.
      • Ostrowski S.R.
      • Piironen T.
      • Hoyer-Hansen G.
      • Gerstoft J.
      • Pedersen B.K.
      • Ullum H.
      High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients.
      • Sidenius N.
      • Sier C.F.
      • Ullum H.
      • Pedersen B.K.
      • Lepri A.C.
      • Blasi F.
      • et al.
      Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection.
      Ostrowski et al.
      • Ostrowski S.R.
      • Piironen T.
      • Hoyer-Hansen G.
      • Gerstoft J.
      • Pedersen B.K.
      • Ullum H.
      High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients.
      and Sidenius et al.
      • Sidenius N.
      • Sier C.F.
      • Ullum H.
      • Pedersen B.K.
      • Lepri A.C.
      • Blasi F.
      • et al.
      Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection.
      showed that plasma concentrations of different forms of suPAR are positively associated with immune activation and independent predictors of mortality in HIV patients. As suPAR significantly predicts CD4+ T-cell decline (unpublished observation), combined suPAR and CD4+ T-cell count measurement in HIV-infected individuals can aid in clinical decisions on when to test viral load and when to initiate antiretroviral therapy. However, the lack of a commercially available assay allowing comparisons of data from at different study sites hampers the comprehensive evaluation of the prognostic potential of this marker and the effects of race and co-infection on expression levels. Several studies are now ongoing using the suPARnostic assay (launched August 2006), which has been developed for clinical use in HIV-1 infection. These studies will determine whether suPAR is a serious candidate marker for disease progression in HIV, TB, and co-infected patients.

      CXCL10/IP-10

      IFN-γ-inducible protein-10 (IP-10 or CXCL10) is an activated T-cell and monocyte chemotactic factor involved in delayed-type hypersensitivity.
      • Gangur V.
      • Simons F.E.
      • Hayglass K.T.
      Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN-gamma over IL-4 responses.
      CXCL10 has been found in vivo in lymph nodes and in lung tuberculous granulomas.
      • Ferrero E.
      • Biswas P.
      • Vettoretto K.
      • Ferrarini M.
      • Uguccioni M.
      • Piali L.
      • et al.
      Macrophages exposed to mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: focus on gammadelta cells.
      Studies have correlated serum CXCL10 levels with TB infection; serum levels of CXCL10 were higher in patients with active TB than in household and community controls at diagnosis (p < 0.0001), and increased after reactivation of a latent infection.
      • Azzurri A.
      • Sow O.Y.
      • Amedei A.
      • Bah B.
      • Diallo S.
      • Peri G.
      • et al.
      IFN-γ-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in mycobacterium tuberculosis infection.
      Others have found elevated CXCL10 concentrations during active TB, with higher levels in patients with fever and anorexia.
      • Juffermans N.P.
      • Verbon A.
      • van Deventer S.J.
      • van Deutekom H.
      • Belisle J.T.
      • Ellis M.E.
      • et al.
      Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan.
      CXCL10 also has potential as a marker for TB treatment efficacy. Cured patients showed significant reductions in serum CXCL-10 at two months and at the end of treatment (p < 0.0001) in one study, whereas non-cured patients showed no reduction in CXCL10 levels.
      • Azzurri A.
      • Sow O.Y.
      • Amedei A.
      • Bah B.
      • Diallo S.
      • Peri G.
      • et al.
      IFN-γ-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in mycobacterium tuberculosis infection.
      CXCL10 is induced by HIV in vitro,
      • Reinhart T.A.
      Chemokine induction by HIV-1: recruitment to the cause.
      and both symptomatic and asymptomatic HIV patients have been found to have elevated plasma levels of this marker. HAART has been shown to induce a significant decrease in plasma levels of CXCL10, which correlate negatively with CD4+ T-cell counts.
      • Stylianou E.
      • Aukrust P.
      • Bendtzen K.
      • et al.
      Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART) — possible immunosuppressive role of IFN-alpha in HIV infection.
      • Relucio K.I.
      • Beernink H.T.
      • Chen D.
      • Israelski D.M.
      • Kim R.
      • Holodniy M.
      Proteomic analysis of serum cytokine levels in response to highly active antiretroviral therapy (HAART).
      In a population of patients with active TB, serum CXCL10 levels were higher in HIV positive patients than in HIV negative patients.
      • Juffermans N.P.
      • Verbon A.
      • van Deventer S.J.
      • van Deutekom H.
      • Belisle J.T.
      • Ellis M.E.
      • et al.
      Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan.

      Biomarkers — beyond disease progression and prognosis

      Reliable biomarkers for different TB disease states would contribute significantly to clinical management and to clinical trials of new TB drugs. Markers for progression to active TB in latently infected HIV positive individuals would allow timely interventions. Additionally, the current clinical management of TB treatment, where the response to therapy in individuals is monitored by sputum smear conversion after 8 and 26 weeks of treatment, would certainly benefit from appropriate biomarkers that are measured early during the course of treatment, especially in the context of concurrent HIV infection. Identification of patients with a high risk for poor outcome before the start of treatment or during early treatment would allow the health care system to focus their resources on increased surveillance of such high-risk patients and possibly on intensified treatment regimens.
      The efficacy of TB treatment regimes is currently assessed by recurrence rates within 2 or 5 years of treatment completion and this is not conducive to the development of new TB drugs. Trials simply take too long and are therefore too costly in a market with challenging profit margins. Surrogate markers for treatment response would allow the early identification of ineffective drugs and would therefore shorten the duration of trials. This is of particular importance as at least 90% of new drugs entering clinical testing fail to reach the markets.
      • Moore A.
      The big and small of drug discovery. Biotech versus pharma: advantages and drawbacks in drug development.
      Clearly, the potential markers discussed above still fall far short of clinically valuable indicators of disease progression, individual treatment responses or treatment regimen efficacies, as they lack both sensitivity and specificity. More research emphasis needs to be put on the development of surrogate markers of treatment response. In our attempts to find useful surrogate markers for evaluation in people with differential outcomes of infection and treatment we often rely on our limited understanding of the nature of protective responses. It is however likely that better markers do exist that have escaped our attention, and new technologies should be applied more extensively in this field. New multiplex assays, such as the Luminex X-map technology, which enables the simultaneous measurement of up to 200 plasma proteins, may become important tools in the ongoing search for biomarkers. Proteomic,
      • Agranoff D.
      • Fernandez-Reyes D.
      • Papadopoulos M.C.
      • Rojas S.A.
      • Herbster M.
      • Loosemore A.
      • et al.
      Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum.
      metabonomic
      • Shockcor J.
      • Holmes E.
      Metabonomic applications in toxicity screening and disease diagnosis.
      and differential gene expression analysis have opened the door to the discovery of hitherto unknown markers of disease outcomes.
      • Crockford D.J.
      • Lindon J.C.
      • Cloarec O.
      • Plumb R.S.
      • Bruce S.J.
      • Zirah S.
      • et al.
      Statistical search space reduction and two-dimensional data display approaches for UPLC-MS in biomarker discovery and pathway analysis.
      • Holmes E.
      • Cloarec O.
      • Nicholson J.K.
      Probing latent biomarker signatures and in vivo pathway activity in experimental disease states via statistical total correlation spectroscopy (STOCSY) of biofluids: Application to HgCl2 toxicity.
      Additionally, the use of weighted algorithms and calculated risk scores should be investigated and these could include combinations of markers rather that an over-optimistic reliance on single analytes to predict a particular clinical course.
      In conclusion, there are currently no reliable single surrogate markers for disease progression or treatment response although combinations of known markers have not been sufficiently evaluated. The first challenge in this field is to find new markers for inclusion into such predictive models, but an equally challenging task will be the development of new detection methods that will enable measurement of these markers on a large scale in resource-poor settings.

      Acknowledgments

      Thanks to Teri Robert (Department of Biomedical Sciences University of Stellenbosch Medical School) for critical reading of the manuscript. We are grateful to the European and Developing Countries Clinical Trials Partnership (EDTCP) and La Direction Générale des Bourses et Stages du Gabon (DGBS-Gabon) for their support.
      Conflict of interest: No conflict of interest to declare.

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