Tuberculosis (TB) remains the main cause of death in people living with HIV (PLHIV). Indeed, PLHIV have a 20-30% greater risk of developing TB compared to HIV-uninfected subjects and have lower TB treatment success rates. In 2014, among the 9.6 million incident cases of TB reported worldwide, 12% occurred in PLHIV and 0.4 million deaths from HIV-associated TB were recorded.Mycobacterium tuberculosis is the main etiological agent for TB. For a majority of individuals, the immune response upon infection by M. tuberculosis is sufficient to prevent the development of disease, but insufficient to clear the bacteria. This leads to the persistence of viable M. tuberculosis in diverse cells with no resulting clinical manifestations, an entity known as latent tuberculosis infection (LTBI). The resulting reservoir of M. tuberculosis is vast, and an estimated one third of the world population is concerned. For subjects with LTBI, the life-time risk of reactivation and progression to TB lies between 5 and 10%. However, if co-infected with HIV, the risk is much greater and reaches 10% per year. According to a Cochrane review in 2010, the screening and treatment of LTBI in PLHIV reduces this risk by 30-60%. This prevention strategy is therefore widely recommended. However, the implementation of LTBI screening and treatment into standard HIV-care has been limited. In this work, three different approaches have been used to understand and address this issue, focusing on a low TB-incidence and high-income setting.The first approach was to assess the implementation of LTBI screening in HIV-care across Belgium and identify its barriers as perceived by the caregivers on the field. Raising awareness to this issue was an indirect objective of the study. A multi-choice questionnaire was sent to 55 physicians working in a Belgian AIDS reference center or satellite clinic. A response rate of 62% was obtained. Only 20% of participants performed LTBI screening on all their patients and notable variations in the screening methods used were observed. A large majority of participants were in favor of targeting LTBI screening to HIV-infected patients at highest risk of TB rather than a systematic screening of all PLHIV. These results have been communicated to the Belgian LTBI working group, currently updating the national LTBI screening guidelines. Indeed, targeting screening to those at highest risk of TB is an attractive strategy in low-TB incidence countries and is already recommended in the United Kingdom. However, to date, no score assessing the risk of TB in PLHIV has been validated. Among the barriers to LTBI screening identified by the participants of this first study, the most frequently reported were lack of sensitivity of screening tools, risk associated to polypharmacy and toxicity of treatment. Improving the sensitivity of LTBI screening was the cornerstone of the second approach. The available screening tools for LTBI are the tuberculin skin test (TST) and two Interferon-gamma release assays (IGRAs): the QuantiFERON-TB Gold-IT (QFT-GIT) and the T-SPOT.TB®. All three lack sensitivity in PLHIV. Various strategies to discover superior LTBI screening tools are therefore being explored, including the development of IGRAs in response to alternative M. tuberculosis antigens to those used in the QFT-GIT or T-SPOT.TB®. A potential candidate is the native Heparin-Binding Haemagglutin (nHBHA), a methylated M. tuberculosis protein regarded as a latency-associated antigen. An in-house IGRA based on nHBHA (nHBHA-IGRA) has been shown to be a promising LTBI screening tool both in immunocompetent adults and in hemodialysed patients. The contribution of this nHBHA-IGRA to the detection of M. tuberculosis in PLHIV was therefore investigated. Treatment-naïve HIV-infected subjects were recruited from 4 Brussels-based hospitals. Subjects underwent screening for latent TB using the nHBHA-IGRA in parallel to the classical method consisting of medical history, chest X-ray, TST and QFT-GIT. Prospective clinical and biological follow-up ensued, with repeated testing with nHBHA-IGRA. Among 48 candidates enrolled for screening, 9 were diagnosed with LTBI by combining the TST and QFT-GIT results (3 TST+/QFT-GIT+, 1 TST+/QFT-GIT- and 5 TST-/QFT-GIT+). All 3 TST+/QFT-GIT+ patients, the TST+/QFT-GIT- patient as well an additional 3 subjects screened positive with the nHBHA-IGRA. These 3 additional patients had known M. tuberculosis exposure risks compatible with LTBI. During follow-up (median 14 months) no case of TB was reported and nHBHA-IGRA results remained globally constant. Multiplex analysis confirmed IFN- as the best read-out for the assay. From this study, we concluded that the nHBHA-IGRA appears complementary to the QFT-GIT for the screening of LTBI in PLHIV and the combination of the two tests may increase the sensitivity of screening. A large-scale study is however necessary to determine whether combining nHBHA-IGRA and QFT-GIT offers sufficient sensitivity to dismiss TST, as suggested by our results. In the same study, a group of HIV-infected adults with clinical suspicion of active TB were also recruited and tested with nHBHA-IGRA. Contrary to results in HIV-uninfected subjects, the nHBHA-IGRA could not discriminate between LTBI and active TB in PLHIV. This is an important caveat as HIV-infected subjects may present subclinical TB.A different angle was used for the third approach to the problem of LTBI in PLHIV. Systemic immune activation (SIA) is one of the principal driving forces in the natural course of HIV-infection. Despite long-term viral suppression by combination antiretroviral treatment (cART), a low-level SIA persists and is associated with an early-onset of age-associated disorders such as cardiovascular disease, dementia and osteoporosis. Causes of SIA in PLHIV are multiple and certain chronic infections appear to be implicated. A recent study in South Africa found that LTBI in PLHIV was associated with an increase in circulating activated CD8+ T-cells. If LTBI should contribute to the persistence of SIA, its screening and treatment could have an additional benefit on the clinical outcome of PLHIV. To investigate this theory, the expression of T-cell activation markers (CD38 and HLADR) as well as the level of plasmatic markers of immune activation (IL-6, sCD14, D-Dimers) were compared between subjects presenting active TB, subjects with LTBI and M. tuberculosis-free persons, with and without HIV-infection. In accordance with previous studies, active TB was associated with higher levels of SIA biomarkers in both HIV-infected and -uninfected groups. Among the HIV-uninfected subjects, no significant difference in biomarker level was found between those presenting LTBI and those with no evidence of M. tuberculosis. The effect of LTBI on activation biomarkers in the HIV-infected groups remained inconclusive because of the small number of individuals in the HIV+/LTBI group. Further investigation is therefore warranted. Interestingly, it was found that plasmatic markers may have a greater sensitivity for the detection of M. tuberculosis-associated SIA than the T-cell activation markers, an important result for future studies.Overall, LTBI in PLHIV is a challenging topic, in particular because of the lack of a gold-standard for the diagnosis of LTBI. Despite suboptimal tools, the evident clinical impact of LTBI screening and treatment in PLHIV on TB incidence justifies its implementation in standard HIV-care. In low TB-incidence countries, who, when and how to screen for LTBI in PLHIV remains unclear. This work offers an overview on the subject with particular focus on possible measures for improvement in the field. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/241270 |
| Date | 13 December 2016 |
| Creators | Wyndham-Thomas, Chloe |
| Contributors | Mascart, Françoise, Van Vooren, Jean-Paul, Casimir, Georges, Denis, Olivier, Hougardy, Jean-Michel, Levy, Jack, Moutschen, Michel, Carcelain, Guislaine G. |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté de Médecine – Médecine, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | 1 v. (217 p.), No full-text files |
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