TB and HIVTreatment and Screening

Santino Capocci

Incidence

• Expressed as x/100PY (sometimes /1000 or 100 000)

• Cape Town Township 1.6/100PY

• SAfrica - Nationally 0.948/100PY

• Lesotho - 0.64/100PY

• Ethiopia - 0.3/100PY

• Somalia - 0.285

• Bangladesh - 0.225• India - 0.168• Thailand - 0.137 • Russia - 0.106• Brazil - 0.045

• Spain 0.017• UK (National) 0.012• US (National) 0.0041

• England 1915 - 1.2/100PY

• London - 0.0413

• Newham - 0.108

• 9 million new cases of active TB each year

• 12% HIV co-infection

• 80% from sub-Saharan Africa or SE Asia

• TB rate increased 2-3x in sSA

• TB/HIV morbidity and economic cost huge but unknown

• TB responsible for 25% of all HIV-related deaths

WHO, 2011

Study CountryActive TB

prev

Rate subclinical of

infn

Propn with

symptoms

Lawn 2010-11

SA 17.3% 18% 75%

Oni 2008-10 SA 8.5% 56%Mtei 2001-3 Tanz 15% 29-50% 37%*Shah 2005-6 Ethiopia 7% 16% -Swaminatha

nIndia - 4% total -

Corbett 2001

Zimb 1.5% 41% -

SAPIT - Oct 2011

• KwaZulu-Natal (CAPRISA), open label RCT

• 642 patients with TB, CD4 <500

• ART ≤4 wks or at 2-3 months or after treatment (stopped)

• AIDS or death 6.9 vs 7.8 /100PY overall; (death 12 in seq arm)

• 8.5 vs 26.3 /100PY if CD4 <50

• IRIS: 20.1 vs 7.7/100PY

STRIDE / ACTG A5221 Oct 2011

• Open label, randomised, CD4 <250

• ART ≤2 weeks or 8-12 weeks

• Death or new ADI at 48 weeks

• 661 patients

• 16% early group vs 27% later group died or ADI if CD4<50

• IRIS 11% vs 5%

CAMELIA - Oct 2011

• CAMbodian Early versus Late Introduction of Antivirals

• 2 wk or 8 wk ART into TB treatment; CD4 <200

• 661 patients; 59/332 deaths (18%) early, 90/329 (27%) late

• 8.28 /100PY in early, 13.77 / 100PY late group

• No difference between CD4 <50 or 50-200

• IRIS rate: 3.76 early vs 1.53 / 100PY late (HR 2.5, P<0.001)

BHIVA Guidance

CD4 (cells/µL) When to start HAART

<100 As soon as practical

100-350As soon as practical, but can wait until after 2 monthsTB

treatment

>350 Physicians discretion

TB Meningitis - Török, 2011

• Randomised RCT, double blind, immediate vs deferred ART - at entry or 2 months

• 253 patients in Vietnam

• Treatment with efavirenz (800 od with Rif), zidovudine, lamivudine

• All treated with TB meds, dexamethasone, cotrimoxazole. (3 months RHZE, then 6 months RH) Followed for 12 months

Török, CID 2011;52:1374

• 127 immediately, 126 deferred

• 76 died in immediate group, 70 in deferred within 9 months

• Immediate ART not significantly associated with inc mortality (P0.31)

• High severe adverse events in both arms (89% vs 90%), but more grade 4 in immediate arm

• Conclusion - immediate ART does not improve outcome, more Gd 4 adverse events

• Supports delayed initiation of ART in HIV associated TMB

Sterling - After ART

• Review of NA-Accord data from 16 centres

• Risk of TB after starting ART - compared those at <3 months to those after 3 months

• 19% IDU, median CD4 207 prior to ART

• Risks quoted as 1.3 to 1.7/100PY

• Risk factors for TB in first 3 months were:Black, Hispanic, IDU, ART naive, CD4 <200, high HIV VL.

• 0.4% diagnosed with TB after HAART initiation.

• Risk not significantly different between 200-350 vs ≥350.

• 64% of TB patients were TST positive; 39% had had IPT.

• At 3 months, IR was 2.15/100PY vs 0.05 gen pop (50x)

• Rate 8x that of gen pop, even after 5 yrs on ART.

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

CD4

Italy SA

TST+ TST- No ART ART

Incidence (100 PY)

<200 13.3 1.31 17.5 3.4

200-350 6.54 0.27 12 1.7

≥350 2.56 0.36 3.6 2.0Antonucci JAMA1995;274:143

Badri Lancet 2002;359:2059

Screening for Latent TB

• In Southern Africa, 10-89% adults have evidence of latent tuberculosis infection

• Active TB risk is increased 2-3x within first 2 years after seroconversion and rises

Risk factors for active TB

• Injecting drug user vs MSM

• Heterosexual 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

NICE guidelines for screening

BHIVA approach to LTBI

• Balance risk of active TB developing

• vs

• Risk of drug induced hepatotoxicity* * Serious hepatotox estimated as 0.3%

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

BHIVA guidelines for screening

CHIC data

• Collaborative HIV Cohort Study Group

• Observational cohort of 27868 patients

• Risk factors for TB were: low CD4 , ethnicity, high VL

• Black African (RR 2.93)

• TB incidence decreased after starting ARTGrant, AIDS 2009: 23 2507

CD4Relative risk

increase

<50 10.65

50-199 3.4

200-349 1.77

350-499 1.84

OriginIncidence (/100PY)

Incidence if CD4 <50

Incidence if CD4 >500

sSA 0.845 5.11 0.45

MI 0.375 1.19 0.05

LI 0.189 1.06 0.03

OriginIncidence (/100PY)

Incidence if CD4 <50

Incidence if CD4 >500

sSA 0.845 5.11 0.45

MI 0.375 1.19 0.05

LI 0.189 1.06 0.03

SHCS Data 2007

• Swiss cohort data. Overall incidence was 0.2/100PY

• 69% had TSTs, 9.4% positive.

• 56 patients/6160 developed TB

• 6.5% pos TST group dev TB, 0.26% neg TST group (Pos likelihood ratio 10.7)

• NNT for IPT was 15 (8 high burden country)

Elzi CID 2007 44:94-102

6160

Active TB 142

TST -3778

TST +390

No Rx 246

No TST1850

16 TB (6.5%)

No TB

10 TB (0.26%)

4168TST

30 TB

LTBI Rx 144

• Isoniazid 6-12 months reduced risk of active TB by 34%

• TST +ve - 62%

• TST -ve - 11%

• Reduction in all cause mortality for Inh in TST+ or Inh/Rif

• Countries inc USA, Spain, sSA

• Usually benefit for 2-3 years

Role of Isoniazid Preventative Therapy

Akolo, Cochrane Review, 2010

After having TB…any role for IPT again?

• South African gold miners

• Secondary IPT prevented 55% further cases

• NNT 5 and 19 if CD4 <200 or ≥200

• No ARTChurchyard, AIDS 2003:, 17:2063-

2070

Role of ART

• 9 observational cohort studies - reduction by 67%

• ~80% (Brazil, USA, Italy)

• Most benefit in those with low CD4 counts

• Lifelong treatment (hence longterm benefit)Badri Lancet 2002 359 2059

Jones IJATLD 2000 4 1026Girardi AIDS 2000 14:13, 1985

Role of ART and IPT

• 1 Brazilian study – 76% reduction in Rio on IPT and ART.

Rates (TST+):IPT 1.6% No IPT 11.5% ART 2.8% No ART 5.5%

• 1 SA study - 2 cohorts IPT alone reduced by 27%, ART alone 64%, Combined 89%CD4<100: 10.7/ 100PY TB Golub AIDS 2007 21 1441

Golub AIDS 2009 23 631

• 4 groups, all pos TST

• Rifapentine 900mg + Isoniazid 900mg weekly

• Rifampicin 600mg + Isoniazid 900mg twice weekly

• Isoniazid 300mg od for up to 9 years

• Isoniazid 300mg od for 6 months

Martinson et al 2011, NEJM 365:11-20

• Median CD4 484

• Rates of TB:

• 3.1 R’pentine/Iso

• 2.9 R’icine/Iso

• 2.7 Isoniazid cont

• 3.6 Isoniazid 6 months

• None inferior to 6 months isoniazid.

NICE guidelines for screening

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

BHIVA guidelines for screening

•From 2000-2010, RFH treated 212 cases in total with TB/HIV co-infection

•140 not eligible for screening as presented with TB at HIV diagnosis

Summary

• Incidence of TB is lower on ART but higher than w/o HIV

• Normal X ray and no symptoms ≠ no TB in HIV

• Treat TB with ART immediately if CD4 <100, within 8 weeks if 100-350, maybe later if TBM

• Screening recommended but not rolled out

Questions?

• Not talked about:

• Limits of TSTs and IGRAs in HIV

• Use of IGRAs in detecting active disease in HIV

• Drug interactions when treating it

• IPT and ART in reducing the risk of reactivation of latent TB