CURRENT ISSUES IN TB (& HIV)
Marc Lipman
8 September 2011
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
HIV prevalence in new active TB cases, 2007
WHO, 2009
Areas we will cover
• Latency• Screening • Treatment of LTBI
• When to start ART• IRIS
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 NilHIV : 2-5% HIV : 40% progressors
HIV : 5% lifetime risk HIV : 3-14%/year
Glynn AIDS 2008;22:1859
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
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
What is clinical latency?
The spectrum of tuberculosis
Barry CE. Nat Rev Micro 2009;7:845
The spectrum of tuberculosis
Barry CE. Nat Rev Micro 2009;7:845
The typical, atypical CXR of TB/HIV
The spectrum of tuberculosis
Barry CE. Nat Rev Micro 2009;7:845
Clinical states of TB to consider
• Active TB
• Sub-clinical TB
• Latent TB infection
• (BCG vaccinated)
• (Treated TB)
WHO three “’I’s” strategy
• Intensified case finding
• Infection control
• Isoniazid preventative therapy
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
Clinical states of TB to consider
• Active TB
• Sub-clinical TB
• Latent TB infection
• (BCG vaccinated)
• (Treated TB)
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
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
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?
Clinical states of TB to consider
• Active TB
• Sub-clinical TB
• Latent TB infection
• (BCG vaccinated)
• (Treated TB)
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
Symptoms & CRP at diagnosis in active TB in the UK
HIV+ (n=42) HIV- (n=101)No cough 45% 36%
No fever 17% 46%*
No sweats 19% 48%**
No weight loss 21% 45%***
No fever, sweats
& weight loss
7% 33%****
Normal CRP 7% 18%
No fever, sweats & weight loss plus normal CRP
2% 13%
* p=0.008; **p=0.001; ***p=0.02; ****p=0.003 Breen. IJTLD 2008;12:44
Symptoms & CRP at diagnosis in active TB in the UK
HIV+ (n=42) HIV- (n=101)No cough 45% 36%
No fever 17% 46%*
No sweats 19% 48%**
No weight loss 21% 45%***
No fever, sweats
& weight loss
7% 33%****
Normal CRP 7% 18%
No fever, sweats & weight loss plus normal CRP
2% 13%
* p=0.008; **p=0.001; ***p=0.02; ****p=0.003 Breen. IJTLD 2008;12:44
Cavity
Parenchymal bandTree in bud
Nodules
Bronchial thickening
Consolidation
Ground glass
Tree in bud
Clinical states of TB to consider
• Active TB
• Sub-clinical TB
• Latent TB infection
• (BCG vaccinated)
• (Treated TB)
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
UK (BHIVA) approach to LTBI
Balance risk of active TB developing
vs
Risk of drug induced hepatotoxicity*
* Serious hepatotox estimated as 0.3%
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
BHIVA recommendation:When to give LTBI treatment in UK HIV
Sub-Saharan
Africa
Medium TB incidence country
Low TB incidence country
Blood IGRA + + +
Blood CD4 count
Any <500 <350
Duration of ART use
<24 months <24 months <6 months
TB assessment summary
• Clinical history (incl PMH)
• Examination
• CXR
• (TST/IGRA)
• Sputum (x1-3)– Smear & culture– Nucleic acid amplification
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
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 survivalMartinson NEJM 2011;365:11
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!
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
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
Timing of HAART
2 weeks vs 8-12 weeks will be answered by:
SAPIT follow up; STRIDE; CAMELIA
Karim S NEJM 2010
BHIVA recommendation: to start HAART
Blood CD4 count
(cells/μL)
Recommendation
<100 As soon as practical
100-350 As soon as practical, but can wait till after 2 months TB treatment (if drug interactions, adherence or toxicity a problem)
>350 At physician’s discretion
BHIVA TB/HIV Guidelines 2010
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
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
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