TB and HIV
Treatment and Screening
Santino Capocci
Incidence
•
Expressed as x/100PY (sometimes /1000 or 100 000)
•
Cape Town Township 1.6/100PY
• England 1915 - 1.2/100PY
• 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
• Newham - 0.108
• Russia - 0.106
• Brazil - 0.045
• London - 0.0413
• Spain 0.017
• UK (National) 0.012
• US (National) 0.0041
•
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
Country
Active TB
prev
Lawn 2010-11
SA
17.3%
Oni 2008-10
SA
Mtei 2001-3
Tanz
Shah 2005-6
Rate
Propn with
subclinical of
symptoms
infn
18%
75%
8.5%
56%
15%
29-50%
37%*
Ethiopia
7%
16%
-
Swaminathan
India
-
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
100-350
As 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
Italy
CD4
TST+
TST-
SA
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
2.0
Antonucci 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
Badri. Lancet 2002;359:2059
•
•
Low blood CD4 count
Not on ART
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%
BHIVA 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
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 ART
Grant, AIDS 2009: 23 2507
CD4
Relative risk
increase
<50
10.65
50-199
3.4
200-349
1.77
350-499
1.84
Origin
Incidence
(/100PY)
Incidence if Incidence if
CD4 <50
CD4 >500
sSA
0.845
5.11
0.45
MI
0.375
1.19
0.05
LI
0.189
1.06
0.03
Origin
Incidence
(/100PY)
Incidence if Incidence if
CD4 <50
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
Active TB 142
6160
4168
TST
TST +
390
TST 3778
No TST
1850
LTBI Rx
144
No TB
No Rx
246
16 TB
(6.5%)
10 TB
(0.26%)
30 TB
Role of Isoniazid Preventative Therapy
•
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
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 ART
Churchyard, AIDS 2003:, 17:20632070
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 1026
Girardi 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%
Golub AIDS 2007 21 1441
CD4<100: 10.7/ 100PY TB
Golub AIDS 2009 23 631
Martinson et al 2011, NEJM 365:11-20
•
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
•
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
BHIVA 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
• 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