1. www.ias2011.org HIV and TB Alberto Matteelli WHO collaborative centre for TB/HIV co-infection Department of Infectious Diseases Brescia University Hospital, Brescia, Italy HIV and Co-Infections: HCV, Malaria, TB and Beyond

2. www.ias2011.org Outline of the presentation 1.Rationale for TB/HIV collaborative activities 2.Impact of HAART on TB/HIV co- infection 3.Treatment of co-infected patients 4.Collision between MDR-TB and TB/HIV co-infection

3. www.ias2011.org Estimated number of cases Estimated number of deaths HIV-associated TB 1.1 million (12%) (range: 1.0–1.2 million) 380,000 (range: 320,000–450,000) 0–24 25–49 50–99 100–299 300 and higher No estimate available The Global Burden of TB -2009 TB is responsible for one in four AIDS deaths People living with HIV have an estimated 20 to 30 times greater risk of developing active TB than people without HIV infection.

4. www.ias2011.org Countries with the highest number of deaths from HIV-associated TB Time to act - Save a million lives by 2015 Prevent and treat tuberculosis among people living with HIV. WHO 2011

5. www.ias2011.org A. Establish the mechanism for integrated TB& HIV services  Set up coordinating bodies for effective TB/HIV activities at all levels  Conduct surveillance of HIV prevalence among TB cases  Carry out joint TB/HIV planning  Conduct monitoring and evaluation B. Decrease burden of TB among PLHIV (the "3 Is")  Establish Intensified TB case finding and ensure quality TB treatment  Introduce TB prevention with IPT or ART  Ensure TB Infection control in health care and congregate settings C. Decrease burden of HIV among TB patients  Provide HIV testing and counselling to TB suspects & TB patients  Introduce HIV prevention methods for TB suspects & TB patients  Provide CPT for TB patients living with HIV  Ensure HIV prevention; treatment & care for TB patients with HIV  Introduce ARVs to TB patients living with HIV TB/HIV collaborative activities: a 12 points package

6. www.ias2011.org 2011 WHO Recommendations on collaborative TB/HIV activities "The 3 Is" 1.Infection control 2.Isoniazid preventive therapy (IPT) 3.Intensified TB case- finding

7. www.ias2011.org Reducing TB burden among PLWHA Isoniazid preventive therapy Infection control Intensified case finding Adapted from WHO; 2009 The 3 Is Antiretroviral therapy The 4 th I

8. www.ias2011.org

9. Variable Adjusted Relative Hazard (95%CI) P-value HAART after TB Dx0.45 (0.26-0.79)0.005 CD4 < 200 (Time- 200 – 349 dependent)350 – 499 ≥ 500 1 0.46 (0.27-0.79) 0.47 (0.26-0.85) 0.32 (0.17-0.61) 0.005 0.01 < 0.001 SexMale Female 1 1.03 (0.67-1.60)0.89 Age < 30 30-39 40-49 ≥ 50 1 0.85 (0.41-1.79) 0.80 (0.38-1.69) 0.26 (0.09-0.75) 0.67 0.56 0.01 Golub et al., AIDS 2008; 22:2527 Recurrent TB and ART in HIV-infected patients in Rio de Janeiro N=1042 – recurrences in 8.9%

10. www.ias2011.org Impact of HAART on MDR-TB spread and outcome During the 90s’, in the pre-HAART era, several MDR-TB outbreaks and high mortality reported among PLWHA in U.S. and Europe Large outbreaks virtually disappeared after 1996 in these settings In 2006 XDR-TB emerging as a global threat from outbreaks among PLWHA in South Africa, at a time where HAART coverage was marginal

11. www.ias2011.org Unmasking TB by HAART During the three months following start of ART there is a spike of TB incidence Somi G, et al. Rome IAS Conference, 2011 Data from >100,000 PLWHA under programme conditions in Tanzania (2004 – 2009)

12. www.ias2011.org Changes in TB incidence during 3 years of HAART in Europe and North America with regression curve fitted (number of cases per 1000 person-years of follow-up) Girardi E, Clin Infect Dis 2005, 41: 1772 Incidence at steady state 150 per 100,000 PYFU, which is 10-fold higher than in HIV negative population

13. www.ias2011.org ART in HIV / TB patients HR for mortality 0.45 (0.26 – 0.79) in patients starting ART during TB therapy regardless of CD4 Trial stopped by the ethical committee Abdool Karim SS, N Engl J Med 2010; 362:697-706

14. www.ias2011.org CONCLUSION: Mortality was reduced by 34% when HAART was initiated 2 weeks vs 8 weeks after onset of TB treatment Early (2 weeks) vs. late (8 weeks) initiation of HAART: the CAMELIA study (Blanc et al). Kaplan-Meier Survival curve

15. www.ias2011.org Timing of ART in HIV / TB patients WHO recommendation Start TB treatment first, followed by ART as soon as possible after starting TB treatment irrespective of CD4 cell count (strong recommendation – Moderate quality of evidence) WHO, 2010: ART guidelines

16. www.ias2011.org ART in TB patients by Region, 2008 Region started on ART AFR30% AMR67% EMR55% EUR29% SEAR35% WPR28%

17. www.ias2011.org Operationalising ART in TB patients Rapid HIV diagnosis Rapid CD4 determination (or identificatioon of surrogate markers – BMI,Hb, clinical or radiological signs) Avalability of ART (often requires referral and loss during referral or delay) Instruct on how to identify and manage IRIS Improve communications between HIV and TB services

18. www.ias2011.org Timing of ART during TB therapy TrialSites and patients Study design and endpoint Overall results Results in CD4<50 ACTG 5221 STRIDE study (1) Multicentre in 4 continents (majority in Africa). TB suspect or confirmed <250 CD4 Immediate (2 w) Vs. early (8 w) Death+AIDS events at W48 13.0% Vs.16.1% P=0.45 15.5% Vs. 26.6% P=0.02 SAPiT continuatio n phase (2) One centre in South Africa Smear+PTB <500 CD4 Early (1-4 w) Vs. late (8-12 w) Death+AIDS events at W48 6.9 Vs. 7.8 /100 p-y P=0.73 8.5 Vs. 26.3 /100 p-y P=0.06 (1) Havlir D, et al. Abs 38, 18° CROI, Boston 2011 (2) Abdool Karim S, et al. Abs 39LB, 18° CROI, Boston 2011 The Camelia study: the median of the CD4 cellc count of enrolled patients was 25 cells STRIDE and SAPiT trials: for CD4> 50 there was no trend towards decreased death/AIDS events

19. www.ias2011.org Treatment strategies for TB/HIV co-infected patients First choice: standard TB regimen + 2NRTI + Efavirenz Is a first line option for HIV treatment In the most widely used first line drug in resource limited settings Allows for standard TB therapy Allows for once a day therapy with minimal pill burden (Atripla) Clinical trials available from South Africa and Thailand

20. www.ias2011.org Effect of RFM on Serum Concentrations of PIs and NNRTI PI Saquinavir Ritonavir Indinavir Nelfinavir Amprenavir Lopinavir/ritonavir Atazanavir  80%  35%  90%  82%  81%  75% not done NNRTI Nevirapine Efavirenz  37-58%  13-26% What if efavirenz cannot be used ?

21. www.ias2011.org Rifabutin can be used with LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR, DARUNAVIR, TIPRANAVIR always with RITONAVIR boosting Rifabutin and HIV drugs of the PI class RIFABUTIN acceptable substitute for rifampicin, in standard TB regimens but: - not widely available - requires loose drugs

22. www.ias2011.org Rifabutin doses: still debated 9/10 patients and 5/5 patients with low C max values (<30  g/ml) Selection of rifa-R MTB Boulanger C, CID 2009 Khaci H, JAC 2009 Naiker S, 18° ICAAR, 2011 AUC significantly reduced compared to the standard in 16 TB/HIV patients in South Africa. AUC reverted by 150 mg daily during LPV/r treatment Ritonavir increases rifabutin levels significantly, requiring a dose reduction to 150 mg every other day (DHHS) This recommendation is derived from PK studies in healthy volunteers

23. www.ias2011.org Drug Interactions: Rifampicin and other HIV drugs NNRTIs –Rifampicin decreases Etravirin exposure “significantly”. Combination not recommended CCR5 Inhibitors –Rifampicin reduces maraviroc exposure by 63%. Maraviroc doses could theoretically be doubled but no clinical experience Integrase inhibitors –Rifampicin reduces raltegravir exposure by 40-60%. Raltegravir 800 mg BID suggested, but optimal concentration range of this drug is unknown

24. www.ias2011.org The perfect storm Areas of collision between MDR and TB/HIV epidemics already existent: –- South Africa –- Eastern Europe –- Central Asia

25. www.ias2011.org Outcomes of Treatment for MDR TB in the South African DOTS-Plus Program, 2002-2004 OutcomeHIV + (N=327) HIV – /unknown (N=875) P value Successful Rx38.5%49.3%<0.001 Failed4.3%11.4%<0.001 Defaulted21.4%22.6%0.65 Died35.8%16.7%<0.001 Farley, van der Walt, et al., IUATLD World Conference, 2007

26. www.ias2011.org Early diagnosis crucial for MDR- TB among PLWHA Diagnostic capacity for MDR-TB inadequate in most countries (7% world-wide). We need; –- high quality culture and 1st and 2nd line DST –- molecular tests –- Cepheid Xpert MTB/RIF HIV testing does not affect test performance Rachow A, PLoS-ONE 2011; 6: e20458

27. www.ias2011.org Key messages HAART expansion key to reduce the burden of HIV- associated TB Improve communications between TB and HIV service to operationalise dual treatment Actively promote the introduction of rifabutin in resource limited settings after defining appropriate doses Invest massively in TB lab platform. Widen acces to high quality culture or molecular tests. Use them preferentially for PLWHA who are TB suspect

28. www.ias2011.org THE ITALIAN GOVERNMENT STILL OWES 260 MILLION EUROS TO THE GLOBAL FUND AND NEVER PLEDGED FOR 2011 - 2013 ITALY: KEEP THE PROMISE, NOW! FUND THE FUND, NOW! AIDS, TUBERCOLOSIS AND MALARIA WILL NOT WAIT!