Transcript Slide 1

The Timing of ART initiation in TB
HIV co-infected patients:
Impact on IRIS severity
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
20 July 2011
Kogieleum Naidoo; on behalf of Nonhlanhla Yende-Zuma; Nesri
Padayatachi; Niraksha Jithoo; Gonasagrie Nair; Sheila Bamber;
Santhana Gengiah; Wafaa El-Sadr; Gerald Friedland; Salim Abdool Karim
TB HIV Treatment Integration
 Evidence based
guidelines now available
for Integrated
management of TB and
HIV
 Unanswered questions on
IRIS associated morbidity
remains an obstacle to
widespread integration of
TB and HIV care
Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting
antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:251-61.
Is IRIS infrequent or insignificant?
Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected
individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361-73.
Purpose of
study:
To determine IRIS incidence, severity, risk factors, and outcome in
a TB-HIV co-infected population randomized to ART initiation
during or after TB therapy - sub-study of the CAPRISA 003 SAPiT
Trial.
Design:
Open-label 3-arm randomized controlled trial:
• Arm 1- ART within 4 weeks of starting tuberculosis treatment
• Arm 2 - ART within 4 weeks of completing the intensive phase
of tuberculosis treatment
• Arm 3 - ART initiated after TB treatment completed
Sample
size:
642 HIV-TB co-infected patients
Ambulatory TB smear +ve, HIV +ve (CD4 count < 500 cells/mm3)
Study
Population: and on standard TB treatment regimens.
• Cotrimoxazole prophylaxis: provided to all patients
• Once daily ART: ddI + 3TC + efavirenz –integrated with TB Rx
• Protocol Definition of IRIS:
New onset or worsening symptoms, signs or radiographic
features temporally related to ART treatment initiation;
together with a CD4+ increase, viral load decrease and
upon exclusion of confirmed TB or ART treatment failure,
toxicity, non-compliance, or new concurrent opportunistic
infections.
 in accordance with other published case definitions
 Cases were retrospectively assessed & found to have
met the 2008 IRIS definition(INSHI) of one major or two
minor clinical criteria
IRIS Evaluation
• IRIS evaluated using standardized set of criteria at every
clinical visit
• Diagnosis of IRIS verified by an independent trained
clinician
• IRIS severity measured by number of IRIS associated:
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deaths;
life-threatening events;
hospitalizations and duration of hospitalization
events warranting steroid use; and
IRIS events that did not resolve or resolved with sequelae at
study exit
SAPiT trial:
Randomization, and follow-up of study participants with
suspected IRIS
642 Randomized
214 early Integratedtreatment arm
215 late Integratedtreatment arm
213 sequential treatment
arm
Initiated ART
198 (92.5%)
Initiated ART
164 (76.3%)
Initiated ART
139 (65.3%)
43 IRIS Events
18 IRIS Events
19 IRIS Events
IRIS Outcomes
Died=2
Resolved=38
Not resolved=1
Resolved with sequelae=2
IRIS Outcomes
Resolved=18
IRIS Outcomes
Resolved=16
Not resolved=1
Resolved with sequelae=1
Unknown=1
Baseline characteristics of study
participants
Variable
Developed IRIS Did not develop
p-value
(N=80)
IRIS (N=562)
34.3±6.4
34.2±8.5
0.97
Males, % (n)
49 (39)
280 (50)
0.91
BMI (kg/h2) <18.5, % (n)
13 (10)
13 (72)
1.00
91 (36-177)
155 (78-261)
<0.0001
5.5±0.7
5.0±0.9
<0.0001
Age in years (mean ± SD)
CD4 cells/mm3, median (IQR)
Log10 HIV RNA, copies/ml, mean± SD
IRIS incidence in each study arm in the SAPiT trial
p values
Incidence Rate / 100 P-Yr
Arm
All
patients
Early Integ
Late Integ
Sequential
Early vs late
19.5
7.5
8.1
<0.001
Early vs
Late vs
sequential sequential
<0.001
0.86
IRIS Incidence stratified by CD4+ cell count (cells/mm3)
<50
45.5
9.7
19.7
0.004
0.05
0.19
≥50
15.3
7.1
5.6
0.01
0.003
0.53
Kaplan-Meier estimates of cumulative
probability of IRIS in the 3 SAPIT treatment arms
0.35
Early Integrated vs Sequential
arm p < 0.001
Probability of IRIS
0.30
0.25
Early integrated- treatment arm
0.20
Early Integrated
vs late Integrated
arm p < 0.001
0.15
Late integrated- treatment arm
0.10
Sequential- treatment arm
0.05
0.00
Months after
randomization
Early integratedtreatment arm
Late integratedtreatment arm
Sequentialtreatment arm
0
3
6
9
12
15
18
214
40/156*
42/145
42/141
42/138
43/131
43/123
215
6/188
14/167
16/153
17/143
17/139
18/130
213
0/196
1/179
6/152
14/130
15/121
19/114
*number of patients with IRIS/number of patients in follow up
When is IRIS most severe?
Severity of immune reconstitution inflammatory syndrome
Study arm
Number of patients
with IRIS
Earlyintegrated am
Late-integrated Sequential
parm
arm
value
43
18
19
41.9 (18)
22.2 (4)
5.3(1)
0.01
Patients who received
steroids for IRIS,% (n)
9.3 (4)
5.6 (1)
15.8 (3)
0.69
IRIS associated
deaths, % (n)
4.7(2)
0
0
1.00
Patients hospitalized
for IRIS, %(n)
Clinical signs, symptoms and radiographic
features of IRIS
Fever
Abdominal pain
Pleural effusions
Early integrated-treatment
Late integrated-treatment
Sequential-treatment
Thoracic lymphadenopathy
Neurological signs/ symptoms
Cervical lymphadenopathy
Skin lesions and herpes zoster
Hepatosplenomegaly
Pulmonary infiltrates
Respiratory symptoms
0
10
20
30
40
50
60
Proportion of patients (n=80)
70
80
Conclusion
• Initiation of ART early during TB treatment
 > 2-fold higher risk of IRIS in study patients, however in patients with
CD4< 50, there was a five- fold higher IRIS risk
 greater proportion of IRIS being severe cases
 More frequent hospitalization
• Low IRIS associated mortality
• Low rate of steroid use
• IRIS occurred at all CD4 strata
• Respiratory signs and symptoms accounted for most
clinical presentations of IRIS
Recommendation
 Patients with CD4+ counts <50 cells/mm3:
 Early ART initiation as soon as possible after TB treatment
initiation – with close clinical observation for IRIS
 Patients with CD4 counts ≥ 50 cells/mm3:
 ART initiation can be deferred to start of the continuation phase
of TB treatment to avoid IRIS associated morbidity
 Decision on early or late initiation: use clinical judgment,
consider capacity to manage IRIS & toxicities
Acknowledgements
• The patients in the study
• President’s Emergency Plan for AIDS Relief (PEPfAR)
• Global Fund & Enhancing Care Initiative
• eThekwini Metro & staff of Prince Cyril Zulu clinic
• CAPRISA SAPiT Team & Community Support Group
• The SAPiT Safety Monitoring Committee
• KwaZulu-Natal Provincial Department of Health
• KwaZulu-Natal, Yale & Columbia Universities
• CAPRISA was established by the Comprehensive
International Program of Research on AIDS of the US
National Institutes of Health (grant# AI51794)