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

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

TB HIV Treatment Integration

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.

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.

Is IRIS infrequent or insignificant?

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

Study Population:

Ambulatory TB smear +ve, HIV +ve (CD4 count < 500 cells/mm3) 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: 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

IRIS OutcomesResolved=18

Initiated ART164 (76.3%)

18 IRIS Events

215 late Integrated-treatment arm

214 early Integrated-treatment arm

Initiated ART198 (92.5%)

43 IRIS Events

IRIS OutcomesDied=2Resolved=38Not resolved=1Resolved with sequelae=2

213 sequential treatment arm

Initiated ART139 (65.3%)

19 IRIS Events

IRIS OutcomesResolved=16Not resolved=1Resolved with sequelae=1Unknown=1

VariableDeveloped IRIS

(N=80)Did not develop

IRIS (N=562)p-value

Age in years (mean ± SD) 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

CD4 cells/mm3, median (IQR) 91 (36-177) 155 (78-261) <0.0001

Log10 HIV RNA, copies/ml, mean± SD 5.5±0.7 5.0±0.9 <0.0001

Baseline characteristics of study participants

Incidence Rate / 100 P-Yr p values

Arm Early Integ Late Integ Sequential Early vs lateEarly vs

sequentialLate vs

sequential

All patients

19.5 7.5 8.1 <0.001 <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

IRIS incidence in each study arm in the SAPiT trial

Kaplan-Meier estimates of cumulative probability of IRIS in the 3 SAPIT treatment arms

Months after randomization

0 3 6 9 12 15 18

Early integrated- treatment arm

214 40/156* 42/145 42/141 42/138 43/131 43/123

Late integrated- treatment arm

215 6/188 14/167 16/153 17/143 17/139 18/130

Sequential- treatment arm

213 0/196 1/179 6/152 14/130 15/121 19/114

*number of patients with IRIS/number of patients in follow up

Early integrated- treatment arm

Late integrated- treatment arm

Sequential- treatment arm

Pro

bab

ility

of

IRIS

Early Integrated vs Sequential arm p < 0.001

Early Integrated vs late Integrated arm p < 0.001

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Severity of immune reconstitution inflammatory syndrome

Study armEarly-

integrated am Late-integrated

arm Sequential

arm p-

value

Number of patients with IRIS

43 18 19

Patients hospitalized for IRIS, %(n)

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

When is IRIS most severe?

Respiratory symptoms

Pulmonary infiltrates

Hepatosplenomegaly

Skin lesions and herpes zoster

Cervical lymphadenopathy

Neurological signs/ symptoms

Thoracic lymphadenopathy

Pleural effusions

Abdominal pain

Fever

0 10 20 30 40 50 60 70 80

Series1Early integrated-treatmentLate integrated-treatmentSequential-treatment

Proportion of patients (n=80)

Clinical signs, symptoms and radiographic features of IRIS

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)