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

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