ANRS 1295/12160 - CIPRA KH001/10425 trial
The CAMELIA trial
CAMbodian Early vs. Late Introduction of Antiretrovirals
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.
22nd July 2010
Late Breaker Session B-1, XVIII IAS Conference, Vienna, Austria
HAART in TB-HIV: Early or late?
START TB TREATMENT AND
HAART SIMULTANEOUSLY
START TB TREATMENT
FIRST AND DELAY HAART
PROS
PROS
Lower risk of HIV disease Avoid overlapping side effects
progression or death in advanced Avoid PK interactions
patients (CD4 < 50 cells/mm3)
Lower pill burden
Lower risk of IRIS
CONS
CONS
Overlapping side effects
PK interactions
Higher pill burden
Risk 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.
WHO recommendations
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.
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-totreat analysis)
ANRS 1295/12160 - CIPRA KH001/10425 study
CAMELIA strategy
Switch D4T to AZT
ANRS 1295/12160 - CIPRA KH001/10425 study
CAMELIA key points
- 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
ANRS 1295/12160 - CIPRA KH001/10425 study
CAMELIA recruitment
778 patients screened
661 patients randomized
332 randomized to
the EARLY arm
282
38
culture + culture M.tb
12
NTM
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)
329 randomized to
the LATE arm
294
31
culture + culture M.tb
4
NTM
M.Tb: Mycobacterium tuberculosis; NTM: nontuberculous mycobacteria
ANRS 1295/12160 - CIPRA KH001/10425 study
Patient characteristics at enrollment
Early arm (N=332)
Gender
Male
Female
Age, years
Median (IQR)
BMI, kg/m2
Median (IQR)
Karnofsky score
≥80
50-70
≤40
CD4, cells/mm3
Median (IQR)
Viral load, log copies/mL
Median (IQR)
Late arm (N=329)
p
0.80
215 (64.8)
117 (35.2)
210 (63.8)
119 (36.2)
0.38
35 (30 – 41)
36 (30 – 42)
0.90
16.7 (15.3 – 18.3)
16.8 (15.2 – 18.6)
0.83
43 (13.0)
259 (78.0)
30 (9.0)
44 (13.4)
251 (76.3)
34 (10.3)
0.61
25 (11 – 56)
25 (10 – 55)
0.25
5.60 (5.20 – 6.02)
5.66 (5.25 – 6.00)
ANRS 1295/12160 - CIPRA KH001/10425 study
Characteristics of tuberculosis
Early arm
(N=320)
Location of TB
Pulmonary
Pulmonary & extra-pulmonary
Extra-pulmonary
Drug resistance
None
Isoniazid (INH) monoresistance
Streptomycin monoresistance
Rifampin monoresistance
INH polydrug resistance
Multidrug resistant (MDR)
No DST
Missing
Late arm
(N=325)
p
0.97
221 (69.1)
71 (22.2)
28 (8.7)
222 (68.3)
73 (22.5)
30 (9.2)
0.10
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)
ANRS 1295/12160 - CIPRA KH001/10425 study
SIGNIFICANT REDUCTION OF MORTALITY
IN THE EARLY ARM
N
Deaths
Follow-up time*
Mortality rate** (95% CI)
Early arm
332
59
712.4
8.28 (6.42 – 10.69)
Late arm
329
90
653.7
13.77 (11.20 – 16.93)
p
0.002
* expressed in person-years
** per 100 person-years
12 patients (1.8%) lost to follow-up.
8,955 protocol visits, <2% missed visits.
ANRS 1295/12160 - CIPRA KH001/10425 study
Kaplan-Meier survival curves
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
Log-rank p-value: p=0.0042
0.60
0
50
100
150
200
Time from TB treatment initiation (weeks)
Early arm
250
Late arm
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
ANRS 1295/12160 - CIPRA KH001/10425 study
Factors independently associated with mortality
Multivariate analysis
Adjusted HR (95% CI)*
p
Arm
Early
Late
1
1.52 (1.12 – 2.05)
0.007
BMI
≤16
16-17
17-18.5
>18.5
1.68 (1.07 – 2.63)
0.93 (0.53 – 1.60)
1
1.11 (0.66 – 1.87)
0.01
Karnofsky score
≥80
50-70
≤40
1
1.78 (0.97 – 3.26)
4.96 (2.42 – 10.16)
<0.001
TB identification
and location*
Pulmonary
Extra-pulmonary
Pulm. and extra-pulm.
NTM
1
1.19 (0.68 – 2.07)
2.26 (1.62 – 3.16)
2.84 (1.13 – 7.13)
<0.001
Drug resistance
No**
Yes
Yes, MDR
1
0.98 (0.63 – 1.51)
8.02 (4.00 – 16.07)
<0.001
Cox proportional hazard model
* Also adjusted for site and CD4 level at baseline (stratification factors)
ANRS 1295/12160 - CIPRA KH001/10425 study
IRIS significantly more frequent in the early arm
N
PR/IRIS Follow-up time*
Incidence** (95% CI)
Early arm
332
110
2 728.5
4.03 (3.34 – 4.86)
Late arm
329
48
3 333.5
1.44 (1.09 – 1.91)
p
<0.0001
* expressed in person-months
** per 100 person-months
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
0.00
Time
aftre
TBTBtreatment
initiation
(weeks)
Time
after
treatment initiation
(weeks)
Early arm
Late arm
ANRS 1295/12160 - CIPRA KH001/10425 study
>95% undetectable viral load at week 50
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)
0.80
0.82
0.34
0.81
0.64
0.63
p
Plasma viral load (VL) measured by real time PCR for
HIV-1 RNA plasmatic quantification (ANRS kit).
ANRS 1295/12160 - CIPRA KH001/10425 study
CD4 increase from baseline
W26
W50
W78
W102
W126
W150
Early
N
Median
(IQR)
283
65
(26 – 125)
273
118
(67 – 191)
189
169
(101 – 270)
180
194
(134 – 299)
148
210
(128 – 324)
115
230
(152 – 321)
Late
N
Median
(IQR)
265
59
(14 – 111)
247
112
(53 – 175)
153
165
(88 – 243)
148
177
(106 – 285)
129
187
(119 – 288)
97
201
(127 – 322)
0.11
0.22
0.81
0.19
0.57
0.51
p
Week 0: median CD4+ cell count was 25/mm3
Median CD4 increase at week 50: 114/mm3
ANRS 1295/12160 - CIPRA KH001/10425 study
CONCLUSIONS
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 HIVTB deaths.
ANRS 1295/12160 - CIPRA KH001/10425 study
ACKNOWLEDGEMENTS
Sponsors: ANRS and NIH/DAIDS
Cambodian Health Committee
Institut Pasteur du Cambodge
Médecins Sans Frontières – Belgium
Cambodian Ministry of Health
Cambodian 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.
ANRS 1295/12160 - CIPRA KH001/10425 study