the camelia trial cambodian early vs. late introduction of antiretrovirals anrs 1295/12160 - cipra...
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The CAMELIA trialCAMbodian Early vs. Late Introduction of Antiretrovirals
ANRS 1295/12160 - CIPRA KH001/10425 trial
22nd July 2010Late Breaker Session B-1, XVIII IAS Conference, Vienna, Austria
F.X. Blanc, T. Sok, D. Laureillard, L. Borand, C. Rekacewicz, E. Nerrienet,Y.Madec, O. Marcy, S. Chan, N. Prak, C. Kim, K.K. Lak, C. Hak, B. Dim,
C.I. Sin, S. Sun, B. Guillard, B. Sar, S. Vong, M. Fernandez, L. Fox,J.F. Delfraissy, A.E. Goldfeld.
START TB TREATMENT AND HAART SIMULTANEOUSLY
START TB TREATMENT FIRST AND DELAY HAART
PROS PROS
Lower risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm3)
Avoid overlapping side effectsAvoid PK interactionsLower pill burdenLower risk of IRIS
CONS CONS
Overlapping side effectsPK interactionsHigher pill burdenRisk of immune reconstitution disease
Higher risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm3 )
Adapted from J Acquir Immune Defic Syndr 2007; 46: S9-S18.
HAART in TB-HIV: Early or late?
2003: CD4 < 200/mm3:
- Start TB treatment.
- Start ART as soon as TB treatment is tolerated (between 2 weeks and 2 months)
- Efavirenz-containing regimens
2010: - Start ART in all HIV-infected individuals with active TB, irrespective of the CD4 cell count. Strong recommendation, low
quality of evidence.
- Start TB treatment first, followed by ART as soon as possible afterwards (and within the first eight weeks). Strong recommendation, moderate quality of evidence.
- Use efavirenz as the preferred NNRTI in patients starting ART while on TB treatment. Strong recommendation, high quality of evidence.
WHO recommendations
CAMELIA study design (2003-2004)
- Prospective, randomized, open-label, two-armed trial with no placebo
- Designed as a superiority trial to answer the question of the best timing for the introduction of HAART in severely immunosuppressed (CD4 ≤ 200/mm3) HIV-infected adult patients with newly diagnosed TB in Cambodia
- 2 arms: late introduction of ART (reference arm: 8 weeks) vs. early (2 weeks) introduction of the same HAART
- Primary endpoint: survival at the end of the trial (intent-to-treat analysis)
ANRS 1295/12160 - CIPRA KH001/10425 study
CAMELIA strategy
Switch D4T to AZT
ANRS 1295/12160 - CIPRA KH001/10425 study
- 2 sponsors: French ANRS and U.S. NIH/DAIDS (CIPRA)
- Partnership with Cambodian Health Committee
- 5 study sites (rural and urban) in Cambodia
- 661 patients were AFB+ at inclusion (pulmonary or extra-
pulmonary TB) with CD4 ≤ 200/mm3
- 1st patient enrolled on January 31st 2006
- 6 DSMB meetings
- Last patient enrolled on May 27th 2009
- End of the study: May 2010
CAMELIA key points
ANRS 1295/12160 - CIPRA KH001/10425 study
661 patients randomized
282culture +
M.tb
38culture -
332 randomized tothe EARLY arm
329 randomized to the LATE arm
778 patients screened
12NTM
294culture +
M.tb
31culture -
4NTM
117 patients not enrolled due to:- CD4>200 (n=78)- LFT impairment (n=24)- pregnancy (n=3)- TB treatment >1month (n=2)- CD4 >200 & LFT impairment (n=2)- death before randomization (n=2)- pregnancy & LFT impairment (n=1)- no CD4 at enrolment (n=1)- high bilirubine (n=1)- delay in blood sampling (n=1)- CD4>200 & pregnancy (n=1)- ART history & LFT impairment (n=1)
CAMELIA recruitment
M.Tb: Mycobacterium tuberculosis; NTM: nontuberculous mycobacteria
ANRS 1295/12160 - CIPRA KH001/10425 study
Early arm (N=332) Late arm (N=329) p
Gender Male Female
215 (64.8)117 (35.2)
210 (63.8)119 (36.2)
0.80
Age, years Median (IQR) 35 (30 – 41) 36 (30 – 42)
0.38
BMI, kg/m2
Median (IQR) 16.7 (15.3 – 18.3) 16.8 (15.2 – 18.6)0.90
Karnofsky score ≥80 50-70 ≤40
43 (13.0)259 (78.0)
30 (9.0)
44 (13.4)251 (76.3)34 (10.3)
0.83
CD4, cells/mm3
Median (IQR) 25 (11 – 56) 25 (10 – 55)0.61
Viral load, log copies/mL Median (IQR) 5.60 (5.20 – 6.02) 5.66 (5.25 – 6.00)
0.25
Patient characteristics at enrollment
ANRS 1295/12160 - CIPRA KH001/10425 study
Early arm (N=320)
Late arm (N=325)
p
Location of TB Pulmonary Pulmonary & extra-pulmonary Extra-pulmonary
221 (69.1) 71 (22.2) 28 (8.7)
222 (68.3) 73 (22.5) 30 (9.2)
0.97
Drug resistance None Isoniazid (INH) monoresistance Streptomycin monoresistance Rifampin monoresistance INH polydrug resistance Multidrug resistant (MDR) No DST Missing
217 (67.8) 23 (7.2) 17 (5.3) 3 (0.9) 16 (5.0) 6 (1.9) 37 (11.6) 1 (0.3)
240 (73.8) 10 (3.1) 10 (3.1) 4 (1.2) 24 (7.4) 7 (2.2) 30 (9.2) -
0.10
Characteristics of tuberculosis
ANRS 1295/12160 - CIPRA KH001/10425 study
N Deaths Follow-up time* Mortality rate** (95% CI) p
Early arm 332 59 712.4 8.28 (6.42 – 10.69)0.002
Late arm 329 90 653.7 13.77 (11.20 – 16.93)
* expressed in person-years** per 100 person-years
12 patients (1.8%) lost to follow-up.8,955 protocol visits, <2% missed visits.
SIGNIFICANT REDUCTION OF MORTALITY IN THE EARLY ARM
ANRS 1295/12160 - CIPRA KH001/10425 study
0.60
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Pro
bab
ility
of su
rviv
al (
%)
0 50 100 150 200 250Time from TB treatment initiation (weeks)
Early arm Late arm
Log-rank p-value: p=0.0042
Survival probability (95% CI)
Early arm Late arm Log-rank p-value
Week 50 86.1 (81.8 – 89.4) 80.7 (76.0 – 84.6) 0.07
Week 100 82.6 (78.0 – 86.4) 73.0 (67.7 – 77.6) 0.006
Week150 82.0 (77.2 – 85.9) 70.2 (64.5 – 75.2) 0.002
Kaplan-Meier survival curves
ANRS 1295/12160 - CIPRA KH001/10425 study
Multivariate analysis
Adjusted HR (95% CI)*
p
Arm Early Late
11.52 (1.12 – 2.05)
0.007
BMI ≤1616-1717-18.5>18.5
1.68 (1.07 – 2.63)0.93 (0.53 – 1.60)11.11 (0.66 – 1.87)
0.01
Karnofsky score ≥8050-70≤40
11.78 (0.97 – 3.26)4.96 (2.42 – 10.16)
<0.001
TB identification and location*
Pulmonary Extra-pulmonaryPulm. and extra-pulm.NTM
11.19 (0.68 – 2.07)2.26 (1.62 – 3.16)2.84 (1.13 – 7.13)
<0.001
Drug resistance No**YesYes, MDR
10.98 (0.63 – 1.51)8.02 (4.00 – 16.07)
<0.001
* Also adjusted for site and CD4 level at baseline (stratification factors)
Factors independently associated with mortality
Cox proportional hazard modelANRS 1295/12160 - CIPRA KH001/10425
study
N PR/IRIS Follow-up time* Incidence** (95% CI) p
Early arm 332 110 2 728.5 4.03 (3.34 – 4.86)<0.0001
Late arm 329 48 3 333.5 1.44 (1.09 – 1.91)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
TB
-re
latd
PR
/IR
IS p
roba
bili
ty (
%)
Time aftre TB treatment initiation (weeks)
Early arm Late arm
IRIS significantly more frequent in the early arm
ANRS 1295/12160 - CIPRA KH001/10425 study
* expressed in person-months** per 100 person-months
Time after TB treatment initiation (weeks)
W26 W50 W78 W102 W126 W150
Early arm Undetectable VL VL > 250 copies/mL Not available
259 (90.2)25 (8.7)3 (1.1)
264 (95.6)9 (3.3)3 (1.1)
184 (93.0)6 (3.0)8 (4.0)
173 (93.5)7 (3.8)5 (2.7)
142 (93.4)6 (4.0)4 (2.6)
111 (95.7)3 (2.6)2 (1.7)
Late arm Undetectable VL VL > 250 copies/mL Not available
241 (88.3)25 (9.2)7 (2.5)
237 (95.6)9 (3.6)2 (0.8)
145 (91.8)8 (5.1)5 (3.1)
143 (92.9)5 (3.2)9 (3.9)
126 (96.2)3 (2.3)2 (1.5)
96 (96.0)1 (1.0)3 (3.0)
p 0.80 0.82 0.34 0.81 0.64 0.63
Plasma viral load (VL) measured by real time PCR for HIV-1 RNA plasmatic quantification (ANRS kit).
>95% undetectable viral load at week 50
ANRS 1295/12160 - CIPRA KH001/10425 study
W26 W50 W78 W102 W126 W150
Early N Median (IQR)
28365
(26 – 125)
273118
(67 – 191)
189169
(101 – 270)
180194
(134 – 299)
148210
(128 – 324)
115230
(152 – 321)
Late N Median (IQR)
26559
(14 – 111)
247112
(53 – 175)
153165
(88 – 243)
148177
(106 – 285)
129187
(119 – 288)
97201
(127 – 322)
p 0.11 0.22 0.81 0.19 0.57 0.51
Median CD4 increase at week 50: 114/mm3
Week 0: median CD4+ cell count was 25/mm3
ANRS 1295/12160 - CIPRA KH001/10425 study
CD4 increase from baseline
1. Mortality was reduced by 34% when HAART was initiated 2 weeks vs. 8 weeks after onset of TB treatment.
2. Irrespective of study arm, HAART has been extremely successful, as evidenced by >95% of patients with undetectable viral load.
3. Despite extremely low CD4+ cell count at inclusion, patients enrolled in this pivotal strategic trial have been extremely adherent.
4. HAART initiation 2 weeks after onset of TB treatment could potentially save 150,000 of the 450,000 annual HIV-TB deaths.
CONCLUSIONS
ANRS 1295/12160 - CIPRA KH001/10425 study
Sponsors: ANRS and NIH/DAIDSCambodian Health CommitteeInstitut Pasteur du CambodgeMédecins Sans Frontières – BelgiumCambodian Ministry of HealthCambodian National TB Program (CENAT)Cambodian National AIDS Program (NCHADS)
Study sites: Khmer-Soviet Friendship Hospital (Phnom Penh), Donkeo Provincial Hospital (Takeo), Calmette Hospital (Phnom Penh), Svay Rieng Provincial Hospital and Siem Reap Referral Hospital Investigators, nurses, technicians, monitors, social workers…Members of the DSMB and the Scientific Advisory Board
And especially all the patients and PLWHA representatives who joined us in this challenge.
ACKNOWLEDGEMENTS
ANRS 1295/12160 - CIPRA KH001/10425 study