The CAMELIA trial CAMbodian Early vs. Late Introduction of Antiretrovirals ANRS 1295/12160 - CIPRA...

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


- 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


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


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


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


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


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


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


* 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


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


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


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


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