1. The TB paradox Massimo Galli L.Sacco Hospital, University of Milano, Italy

2. The MDR TB challenge • Multidrug-resistant (MDR) tuberculosis (TB), or TB caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, represents a major threat to global TB control. • Comprising more than 5% of all TB cases annually worldwide, resistant strains require treatment duration of 2 years on average with expensive and toxic second-line anti-TB drugs. • Cure rates are far lower and mortality far higher than for drug-susceptible TB, particularly if patients are coinfected with HIV.

3. The MDR TB challenge in Africa • In a 2000 WHO report on Africa, the overall level of initial resistance varied from 6.3% to 24.8%, and the level of MDR TB from 1% to 5.3% • However, the data available for West Africa are not extensive and up to date

4. Dr Enya and Coworkers (abstract 149) will present an important cross-sectional study performed in HIV-infected patients in Lagos, Nigeria, showing a high prevalence of MDR –TB and supporting the need of urgent intervenctions

5. TB-associated IRIS • TB is the second more common IRIS-associated disease, accounting for 20% of reported IRIS cases in unselected studies of patients starting ART and is the commonest in resource-limited settings • TB-associated IRIS may present in two ways: -‘ paradoxical’ worsening of symptoms of known disease - ’unmasking’ of occult M.tuberculosis infection

6. The immunopathogenesis of unmasking TB-IRIS • The immunopathogenesis of unmasking TB-IRIS is poorly understood • In a recent case-control study performed in South Africa Haddow et al1foundhigher pre-ART levels of IFN-γ and CRP than in controls, consisting with preexisting subclinical TB • In a case-control study performed in Phnom Penh, Oliver et al2 found higher levels of IL-18, and only marginally higher levels of CXCL10 in unmasking TB than in controls, suggesting that adaptive immune responses predominate in this condition 1AIDS 2011; 25: 1163-74; 2JID 2010; 202. 1728-37

7. Dr Azzoni and Coworkers(abstract 2702)will present a cross-sectional cohort study performed in Johannesburg, addressed to investigate the signaling pathways involved in unmasking TB pathogenesis

8. The TB paradox • In recent times several studies have been addressed to assess the advantage of early ART in HIV patients with TB • The concerns about paradoxical TB-IRIS may represent a barrier to early treatment, in particular in patients with very low CD4 cell counts

9. Incidence of immune reconstitution disease stratified by previous diagnosis of tuberculosis M.Mülleret al.; LancetInfectDis 2010;10: 251–61

10. Two very important studies aimed to assess the incidence, risk factors, severity and outcomes of paradoxical TB relative to timing of ART initiation will be presented by dr Laureillard, on behalf of the CAMELIA trial study group (abstract 3020) and by dr Naidoo on behalf of the SAPiT study team (abstract 3258)

11. Thanks for the attention…