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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