A new more effective tuberculosis screening test for HIV victims

March 05, 2008

World Health Organization (WHO) figures show that each year an estimated 9 million new cases of tuberculosis (TB) arise in the world. The growth of this disease remains particularly strong in Africa owing to a high proportion of HIV patients (nearly 13% compared with less than 1% in Asian countries for example). This region of the world is experiencing accelerating advance of a deadly combination of AIDS and TB, developed because the virus weakens the immune system of TB-infected individuals. A person infected by HIV who is also contaminated with Koch's bacillus bears a greater risk of developing active TB than a non HIV-infected individual. Latent TB infection diagnosis has for several decades been founded on a positive response to the tuberculin skin test (TST). However, TST's reliability is limited in highly TB-endemic geographical settings because the presence in the environment of mycobacteria similar to that which causes TB plus the BCG vaccination people receive in early infancy can skew the results. Moreover, in HIV-carrying patients, the sensitivity of the test is drastically reduced owing to their inability to develop an allergic reaction, the very basis of the skin test. TB is a strong contributing factor to HIV mortality, therefore it is of crucial importance to be able to diagnosis latent infection early in order to adopt an appropriate treatment and prevent the development of the full disease.

The development of new IGRA3 tests is based on in vitro measurement of T-cells secretion of interferon- when challenged with antigens specific to Mycobacterium tuberculosis, the bacterium causing tuberculosis. Such assays now provide a means of getting round the drawbacks of the tuberculin skin test (TST). Yet, although these new screening methods are more effective than TST in a situation of low TB endemicity, their validity in populations subject to high risk of latent TB infection still has to be clearly established. Results recently published of an investigation conducted in Senegal, coordinated by IRD in conjunction with other scientific institutions,1 yield important information on the comparative efficiency of the immunological method and the standard TST. The research team set up two cohorts of patients living in the Dakar area: the first one made up of HIV-infected individuals but with no detected TB; the second consisting of TB patients and people from the treatment centre who had been in contact with them during a given period.

For the first cohort, 285 adults newly infected by HIV and showing no clinical or radiological sign of TB were selected at the Fann National University Hospital Centre (Dakar) between 2003 and 2004. An ELISPOT test and a TST were performed for each patient at the beginning of the study. The TST indicated that 21% (53/247) of them had a TB infection at the moment of the test. However, this proportion reached 51% (125/247) with the ELISPOT test. It appears therefore that the latter is more sensitive than the TST whatever the stage of development of the disease. Nevertheless the ability to respond to the ELISPOT test decreases with the decrease in CD4 lymphocyte count, which appears to indicate the limits of this type of test in severely immunosuppressed individuals, as advanced-stage HIV infected patients can be.

In parallel, a cohort of 243 TB patients was followed up for 2 years. The objective this time was to determine the ability of the ELISPOT test to predict, among people living in contact with these individuals, those who run the greatest risk of developing the disease. Between January 2004 and March 2005, 3072 contacts were identified for the whole set of TB patients. Preliminary results showed the sensitivity of the two tests to be comparable with this cohort, although ELISPOT is doted with a better specificity since it is not influenced by recent BCG vaccination.

The data gathered from the studies must now be analysed in greater detail in order to determine if the new tests based on measurement of the immune response to M. tuberculosis-specific antigens can serve as a reliable diagnostic method for TB infection in geographical areas where the disease is endemic and BCG coverage is strong. Such investigations should also found out if in the future these tests could be used as markers of the development of the disease within a given population.
Grégory Fléchet - DIC

1. This research work, coordinated by IRD was conducted in the context of the AFTBVAC project (Development of a Tuberculosis Vaccine in Africa), jointly with research scientists from: the British Medical Research Council; University of Oxford; Institut Pasteur, Brussels; Laboratoire de Bactériologie et Virologie, Hôpital Le Dantec (Senegal); Service de Maladies infectieuses, Service de Pneumologie, Centre Hospitalier National de Fann (Dakar).

2. The measurement test of the release of interferon- (IFN-) by the T cells stimulated by antigens specific to the tuberculosis pathogen (Mycobacterium tuberculosis). The number of T cells secreting IFN- is determined by counting the spots on a membrane covering the wells of an ELISA plate. Each spot represents a T cell secreting IFN-.

3. These tests are named with the generic term IGRA (Interferon- Release Assays). The commercially available versions are QuantiFERON-TB-Gold and T-SPOT TB.

Institut de recherche pour le développement

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