CURRENT ISSUES IN TB (& HIV)

1. CURRENT ISSUES IN TB (& HIV) Marc Lipman 8 September 2011

2. Headlines • 9 million new cases of active TB each year • 12% HIV co-infected • 80% from sub-Saharan Africa or SE Asia • TB rate increased 2-3x in high HIV sSA • TB/HIV morbidity and economic cost huge but unknown • TB responsible for 25% of all HIV-related deaths

3. HIV prevalence in new active TB cases, 2007 WHO, 2009

4. Areas we will cover • Latency • Screening • Treatment of LTBI • When to start ART • IRIS

5. NATURAL HISTORY OF TB & WHY HIV IS SUCH A PROBLEM Exposure 70% no infection 30% infection Early Containment progressors (60-95%) (1-2 years) Late Nil HIV : 2-5% HIV : 40% progressors HIV : 5% lifetime riskHIV : 3-14%/year Glynn AIDS 2008;22:1859

6. Risk factors for active TB/HIV • Injecting drug users vs MSM • Heterosexuals vs MSM • From TB endemic country • ? Reported previous TB • Advanced clinical stage of disease • Low blood CD4 count • Not on ART Badri. Lancet 2002;359:2059 Girardi. CID 2005;41:1772 Seyler. AJCCRM 2005;172:123

7. What history tells us • TB cannot be controlled if there is uncontrolled HIV infection • ART is associated with ~60-90%  in active TB • Possible  in active TB during initial 3 months of ART • Developing world: 10,000 – 23,000/100,000 • Developed world: 1300 - 1700 /100,000 • Need to develop strategies to screen for TB pre ART

8. What is clinical latency?

9. The spectrum of tuberculosis Barry CE. Nat Rev Micro 2009;7:845

10. The spectrum of tuberculosis Barry CE. Nat Rev Micro 2009;7:845

11. The typical, atypical CXR of TB/HIV

12. The spectrum of tuberculosis Barry CE. Nat Rev Micro 2009;7:845

13. Clinical states of TB to consider • Active TB • Sub-clinical TB • Latent TB infection • (BCG vaccinated) • (Treated TB)

14. WHO three “’I’s” strategy • Intensified case finding • Infection control • Isoniazid preventative therapy

15. What is the aim of screening? High TB burden countries • Active TB disease • Subclinical TB disease • Latent TB infection Low TB burden countries • Latent TB infection • Active TB disease • Subclinical TB disease

16. Clinical states of TB to consider • Active TB • Sub-clinical TB • Latent TB infection • (BCG vaccinated) • (Treated TB)

17. Undiagnosed culture positive PTB in HIV infection • Durban, South Africa • ART roll-out programme, 825 adults (median blood CD4 100) • Single sputum sample for MTB smear & culture • 158 (19%) MTB culture+ (91% smear -) • 48% no cough • 22% no symptoms at all Bassett CID 2010;51:823

18. Nucleic acid amplification in sub-clinical TB diagnosis • South African, Adult ART roll out, CD4 171 • 2 sputums requested (468/515 at least 1) • XpertTB MTB/RIF (Boehme NEJM 2010) • Compare to culture & smear • MTB cultured from 81/468 (17.3%) • Xpert – sens 73%, spec 99% • Smear – sens 28%, spec 100% • Xpert achieved results using single sample & detected RIF resistance in 4 Lawn PLoS Med 2011;8:e1001067

19. Undiagnosed active TB in HIV • How does this occur? • Reactivation? Rapid progression? New infection? • Can symptom questionnaires pick out these subjects ie how many really have no symptoms? • Are CXR/other tests helpful? • What do we do once we have detected them? • Can TB treatment duration be shortened in this population?

20. Clinical states of TB to consider • Active TB • Sub-clinical TB • Latent TB infection • (BCG vaccinated) • (Treated TB)

21. Screening for active TB in TB endemic, high HIV areas • Cambodia, Thailand, Vietnam • Prospective screening questionnaire and sputum (3), stool, urine, blood +/- LN aspirate • 267 (15%) of 1748 diagnosed with TB • Cough (2 or 3 weeks in last 4): sens 22-33% • Any cough + any fever or night sweats (≥3 weeks) in last 4 weeks: sens 93%, spec 36% • In such pts, 2 negative sputum smears, normal CXR, and CD4≥350 – ruled out active TB Cain NEJM 2010;362:707

22. Symptoms & CRP at diagnosis in active TB in the UK * p=0.008; **p=0.001; ***p=0.02; ****p=0.003 Breen. IJTLD 2008;12:44

23. Symptoms & CRP at diagnosis in active TB in the UK * p=0.008; **p=0.001; ***p=0.02; ****p=0.003 Breen. IJTLD 2008;12:44

25. Bronchial thickening Parenchymal band Tree in bud Cavity Consolidation Nodules Ground glass

26. Tree in bud

27. Clinical states of TB to consider • Active TB • Sub-clinical TB • Latent TB infection • (BCG vaccinated) • (Treated TB)

28. Can we refine screening in low prevalence areas? • USA & Canada study, NA-ACCORD • reporting not active screening • 1995 – 2009; 41% previously on ARV • Endpoint: TB diagnosed after starting ART • Follow up median 4.7 years • Increase in TB rates for at least 6 months of ART • at 3/12 = 215/100,000. Background rate = 5/100,000 • Associated risk (ie who is best screened) • Blood CD4<200, high HIV load, non-Whites, history of IDU Sterling JID 2011;204;893

29. UK (BHIVA) approach to LTBI Balance risk of active TB developing vs Risk of drug induced hepatotoxicity* * Serious hepatotox estimated as 0.3%

30. UK (BHIVA) approach to LTBI • Use data from available low incidence countries • UK CHIC* • Swiss HIV cohort study** • Risk based on • Country of origin • Blood CD4 count • Use & duration of use of ART • Blood IGRA result *AIDS 2009;23:2507 **CID 2007;44:94

31. BHIVA recommendation:When to give LTBI treatment in UK HIV

32. TB assessment summary • Clinical history (incl PMH) • Examination • CXR • (TST/IGRA) • Sputum (x1-3) • Smear & culture • Nucleic acid amplification

33. Isoniazid preventative therapy • Botswana • IPT 6/12 vs 36/12 (+/- ART) • TB INH 6: 34/989 (3.4%) [1.26%/yr] • TB INH 36: 20/1006 (2.0%) [0.72%/yr], p=0.047! • Effect limited to TST+ subjects • ?increased mortality in TST- on INH 36 • Possible additional benefit of ART Samandari Lancet 2011;377:1588

34. Other preventative therapies • South Africa – HIV+ TST+ N= 1148, CD4 484 • Randomised • INH 300mg 6/12 • INH 300mg continuous (up to 6 years) • Rifapentine 900mg + INH 900mg weekly 12/52 • Rifampin 600mg + INH 900mg twice weekly 12/52 • TB incidence: 3.6% vs 2.7% vs 3.1 vs 2.9% • No difference in survival Martinson NEJM 2011;365:11

35. Summary • HIV has altered our understanding of TB and human host interaction • TB control = HIV control = TB control = …. • Management strategies are location and person specific (implications for healthcare planning and resource use) • There is a lot going on in TB/HIV!

36. Problems with HAART + anti-TB Rx EARLY con-comitant use = • drug-drug interactions • additive adverse effects • high pill burden • reduced patient adherence • immune reconstitution disease DELAY con-comitant use = • high risk of major opportunistic infection & death Velasco JAIDS 2009;50:148. Westreich AIDS 2009; 23:707

37. Active TB: when to start HAART • South African study • Adults, Smear+ PTB, CD4<500 • Integrated (<4/52 & >4/52) n = 429 vs Sequential n = 213 TB & HAART • Primary end point - death 56% in Int group • IRIS - Int 12.4% vs Seq 3.8% (no deaths) • Severe AE Int 30 vs Seq 32 per 100 py Abdool Karim. NEJM 2010;362:697-706

38. Timing of HAART Karim S NEJM 2010 2 weeks vs 8-12 weeks will be answered by: SAPIT follow up; STRIDE; CAMELIA

39. BHIVA recommendation: to start HAART BHIVA TB/HIV Guidelines 2010

40. TB/HIV treatment in UK practice Little difference in adverse events with different ARVS Good virological response with all ARVS No effect of TB on response to HAART No effect of HIV on TB outcome Breen JID 2006;193:1437

41. NICE HIV & TB CRG 2010 • Blood CD4 <200 – TST & IGRA • Either positive – ASSESS FOR ACTIVE TB & CONSIDER TREATMENT FOR LTBI • Blood CD4 200-500 – IGRA OR TST/IGRA • Either positive – ASSESS FOR ACTIVE TB & CONSIDER TREATMENT FOR LTBI • Blood CD4 >500 – CONSIDER AS IMMUNCOMPETENT ADULT NO DISTINCTION BETWEEN IGRA TEST TYPES