1. Challenges of HIV-TB Coinfection Sinata Koulla Shiro (MD) ANRS Satellite Meeting, IAC 2012 Washington DC, 23 July 2012

2. OUTLINE Context ◦ HIV-TB Global Epidemiology Challenges ◦ Diagnosis ◦ Combining HIV/TB Treatment WHO TB/HIV collaborative Programme TB/HIV programme integration ◦ The three I’s (Intensified TB case finding, IPT and early ART, TB Infection Control) Research Perspectves

3. TB/HIV Global Epidemiology 3  HIV has greatly contributed to resurgence and increased incidence of TB worldwide  14 million people are co-infected with TB and HIV worldwide  In some regions in Africa 75% of TB patients are co-infected with HIV  TB is the most common cause of death among AIDS patients worldwide  TB causes at least 11% of AIDS death and possibly as many as 50% in some countries  MDR-Tuberculosis among HIV patients can cause nosocomial infections  Rifampicine resistance is also found among HIV infected patients with tuberculosis

4. TB/HIV Global Epidemioloy Hiv testing of TB Patients now standard practice in many countries 2.1 million/6.2million(34%) of notified TB patients knew their HIV status in 2010 10 Times greater than 3.7% in 2003

5. TB/HIV Global Epidemiology Over 75% in 68 countries including 22 in Africa knew their status The coverage of HIV test was highest in Africa (80%) as compared to Europe (59%) 23% of TB patients tested + at global level 44% in Africa tested + HIV Testing for TB Patients By Country

6. Global TB/HIV Epidemiology Prevalence rates ranged from 8% in Congo to over 50% in South Africa, Botswana, Zambia,Malawi, Uganda Prevalence rate was up to 82% in Swaziland

7. Impact of HIV on TB 7  Increases rate of TB re-activation and progression  PLWHiv have 20 to 30 times higher life time risk of developing active TB compared with people without HIV  Increases TB morbidity  Increases TB mortality (5-14 fold)  Alters clinical manifestations of TB  Creates diagnostic challenges  Complicates treatment

8. 8 Incidence of TB after seroconversion among South African Adults, 1991-1997 Incidence For 100 Patient-years RR* HIV-negative 0.80Ref HIV-positive Time since seroconversion < 1 yr 1.622.02 1-2 yrs 2.002.50 2-3 yrs 3.614.50 Sonnenberg, JID 2005 * Relative risks HIV+ versus HIV-, all significantly superior to 1 The risk of tuberculosis increases rapidly after HIV primary infection

9. Impact of TB on HIV 9  TB infection activates T-cells, indirectly supporting HIV replication  Active TB is associated with Increased HIV-1 viral load Rate of progression to AIDS Mortality  HIV viral load decreases with successful TB therapy  TB therapy when combined with ARV has potential for drug-drug interactions and side effects

10. Treament Outcomes of TB Patients according to HIV status

11. challenges

12. Other Diagnosis challenges 12  Culture Specific but ensuring access to high sputum not available Xpert MTB/RIF Assay: Specific, major breakthrough, more sensitive than AFB on Sptum smear but limited access 1 st report on negative results of Mtbc culture positives  Empiric anti-TB treatment may be warranted in many circumstances

13. Sensitivity (with 95% confidence intervals) of Xpert MTB/RIF for diagnosing human immunodeficiency virus–associated tuberculosis during screening of patients before antiretroviral therapy, stratified by CD4 cell count and sputum smear status. Lawn S D et al. Clin Infect Dis. 2012;54:1071-1079 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please email:journals.permissions@oup.com. Challenge: 42% and 28% of culture + tested Xpert – respectively in 1 or 2 samples Sensitivity lower in less advanced HIV Patients How to address implication of false negative results of Xpert MTB/RIF

14. Earlier ART in context of TB/HIV: Why is it still challenging in real practice? Major cause of early mortality in patients using ART in RLS (TB as a priority population for earlier ART) ART significant reduce the occurrence of TB disease, but in RLS the need to treat both diseases at same time is very common … TB still an important condition, even in patients using ART and higher CD4 cell count –

15. 15 ART rapidly decreases the incidence of TB ART rapidly decreases the incidence of TB Lawn, AIDS 2006 Temps sous ARV Incidence per 100 patient-years of tuberculosis under ARTs inSouth Africa

17. Incidence and risks factors of paradoxical tuberculosis-associated IRIS in HIV-infected adults enrolled in the CAMELIA clinical trial ANRS 1295/CIPRA KH001 D. Laureillard, O. Marcy, Y. Madec, S. Chan, L. Borand, N. Prak, C. Kim, K.K. Lak, C. Hak, B. Dim, E. Nerrienet, T. Sok, A.E. Goldfeld, F.X. Blanc 6 th IAS Conference, Rome, 20 July 2011

18. 18 Study profile 661 HIV-infected adults enrolled in Camelia trial 64 patients were excluded: - 16 non tuberculous mycobacteria - 37 deaths before ART initiation - 2 withdrawal before ART initiation - 9 without follow-up after start of ART 597 patients enrolled in this analysis 155 developed paradoxical TB-IRIS 442 did not develop paradoxical TB-IRIS

19. 19 Conclusions High frequency (26%) of paradoxical TB-IRIS in HIV-infected patients with advanced immunodeficiency Double the risk of developing TB-IRIS (HR 2.23) when ART initiated at 2 weeks Median time of TB-IRIS occurrence: 2 weeks, irrespective of early or late ART initiation Low mortality directly related to TB-IRIS: 6/155 (3.9%) in accordance with published data During the first weeks following ART initiation, clinicians should be vigilant to recognize signs of TB-IRIS (lymph nodes, fever, abdominal pain…). However TB-IRIS should not be a barrier against early ART initiation in severely immunosuppressed patients.

20. Overlapping Side Effect Profiles of ARV and Anti-TB drugs 20

21. 21 La résistance aux anti-TB est un problème Définition –« Multirésistance » (MDR-TB) = résistance à au moins RMP et INH –« Ultrarésistance » (XDR-TB) = résistance à RPM et INH, et fluroroquinolones et au moins un antiTB injectable de 2 ème ligne (Kanamycine, amikacine, capreomycine) * Fréquence 2000-2004 (MMWR 2006 ) –Mondiale, sur 17690 souches : 20% MDR, 2% XDR-TB –en Afrique : 23% MDR, 1% XDR Epidémie de XDR-TB en Afrique du Sud (Ghandi, Lancet 2006) –1539 souches, 544 M tuberculosis, 41% MDR-TB –53 patients XDR +, VIH+ 100% sur ceux testés, létalité 98% * Définition WHO Global Task Force on XDR-TB, Octobre 2006

22. WHO guidelines recommend 12 collaborative TB/HIV activities A. Establish and Strengthen Mechanisms for delivering integrated TB/HIV services TB/HIV coordinating body Determine HIV prevalence in TB patients and TB prevalence among PLWH Joint TB/HIV planning Monitoring and evaluation 2012 B. Reduce Burden of TB among PLWH and Initiate early ART (Three I’s for HIV/TB) Intensified TB case finding (ICF) TB preventive therapy (IPT) and early ART TB infection control (IC) C. Reduce Burden of HIV in presumptive and diagnosed TB patients HIV testing and counselling HIV prevention HIV/AIDS care and support Co-trimoxazole Prophylaxis (CTXp) Antiretroviral therapy (ART) 2004

23. Integration of TB-HIV Services Establishing the mechanisms for collaboration 1. TB/HIV coordinating bodies 2. HIV surveillance among TB patient 3. TB/HIV joint planning 4. TB/HIV monitoring and evaluation Health Systems Community involvement Decentralization

24. 24 Challenges of the three I’s IPT among HIV + patients Proven efficacy –9 randomized studies ( 4 in Africa) –Risk to active TB decreased by 2 fold (méta-anlayse: Bucher, AIDS 1999 ) Recommanded by WHO since 1993… –INH 5 mg/Kg/j 6 mois –After ruling out active TB Low IPT completion rates Questions on durability of INH protection Fear of resistance Questions on adherence support to achieve high rates : Implication of major changes among care providers (Johnson, AIDS 2001)(Quigley, AIDS 2001)

25. Challenges of the three I’s :Intensified TB case finding through simplified clinical algorithm Four symptom-based screening HX of current cough (>15days) Fever Weight loss Night sweats Will permit identification of patients elligible for IPT

26. Tuberculosis (TB) screening questionnaire (modified from [11]). Howard A A, El-Sadr W M Clin Infect Dis. 2010;50:S238-S244 © 2010 by the Infectious Diseases Society of America

27. Early initiation of ART: Coverage of ART among TB-HIV Patients