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.

22 nd 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 PROS

Lower risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm 3 )

CONS

Overlapping side effects PK interactions Higher pill burden Risk of immune reconstitution disease

START TB TREATMENT FIRST AND DELAY HAART PROS

Avoid overlapping side effects Avoid PK interactions Lower pill burden Lower risk of IRIS

CONS

Higher risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm 3 ) Adapted from

J Acquir Immune Defic Syndr

2007; 46: S9-S18 .

WHO recommendations

2003

: CD4 < 200/mm 3 : - 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.

of evidence.

Strong recommendation, low quality

-

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.

evidence.

Strong recommendation, high quality of

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/mm 3 ) HIV-infected adult patients with newly diagnosed TB in Cambodia - 2 arms:

vs. early

late

introduction of ART (reference arm:

(2 weeks) 8 weeks

introduction of the same HAART ) - Primary endpoint: treat analysis)

survival

at the end of the trial (intent-to-

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/mm 3 - 1 st patient enrolled on January 31 st 2006 - 6 DSMB meetings - Last patient enrolled on May 27 th 2009 - End of the study: May 2010

ANRS 1295/12160 - CIPRA KH001/10425 study

CAMELIA recruitment

778 patients screened

661 patients randomized 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)

332 randomized to the EARLY arm 329 randomized to the LATE arm

282 culture +

M.tb

38 culture 12 NTM 294 culture +

M.tb

31 culture 4 NTM

M.Tb

:

Mycobacterium tuberculosis;

NTM: nontuberculous mycobacteria

ANRS 1295/12160 - CIPRA KH001/10425 study

Patient characteristics at enrollment

Gender

Male Female

Age, years

Median (IQR)

BMI, kg/m 2

Median (IQR)

Karnofsky score

≥80 50-70 ≤40

CD4, cells/mm 3 Median (IQR) Viral load, log copies/mL

Median (IQR) Early arm (N=332) 215 (64.8) 117 (35.2) 35 (30 – 41) 16.7 (15.3 – 18.3) 43 (13.0) 259 (78.0) 30 (9.0)

25 (11 – 56)

5.60 (5.20 – 6.02) Late arm (N=329)

p

0.80

210 (63.8) 119 (36.2) 0.38

36 (30 – 42) 0.90

16.8 (15.2 – 18.6) 0.83

44 (13.4) 251 (76.3) 34 (10.3)

0.61

25 (10 – 55)

5.66 (5.25 – 6.00) 0.25

ANRS 1295/12160 - CIPRA KH001/10425 study

Characteristics of tuberculosis

Location of TB

Pulmonary Pulmonary & extra-pulmonary Extra-pulmonary Early arm (N=320) 221 (69.1) 71 (22.2) 28 (8.7) Late arm (N=325) 222 (68.3) 73 (22.5) 30 (9.2)

p

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) 0.10

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

Early arm

Late arm N

332

329 Deaths * expressed in person-years ** per 100 person-years

59

90 Follow-up time*

712.4

653.7

Mortality rate** (95% CI)

8.28 (6.42 – 10.69)

13.77 (11.20 – 16.93)

p

0.002

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

0.60

0 Survival probability (95% CI) Week 50 Week 100 Week150 Log-rank p-value: p=0.0042

50 100 150 200 Time from TB treatment initiation (weeks) Early arm Late arm Early arm 250 Late arm 86.1 (81.8 82.6 (78.0 82.0 (77.2 – 89.4) – 86.4) – 85.9) 80.7 (76.0 – 84.6) 73.0 (67.7 – 77.6) 70.2 (64.5 – 75.2) Log-rank

p

-value 0.07

0.006

0.002

ANRS 1295/12160 - CIPRA KH001/10425 study

Factors independently associated with mortality

Arm BMI Karnofsky score TB identification and location*

Early

Late ≤16

16-17 17-18.5

>18.5

≥80 50-70

≤40

Pulmonary Extra-pulmonary

Pulm. and extra-pulm.

NTM Drug resistance

No** Yes

Yes, MDR

Cox proportional hazard model * Also adjusted for site and CD4 level at baseline (stratification factors) Adjusted HR (95% CI)* 1

1.52 (1.12 – 2.05) 1.68 (1.07 – 2.63)

0.93 (0.53 – 1.60) 1 1.11 (0.66 – 1.87) 1 1.78 (0.97 – 3.26)

4.96 (2.42 – 10.16)

1 1.19 (0.68 – 2.07)

2.26 (1.62 – 3.16) 2.84 (1.13 – 7.13)

1 0.98 (0.63 – 1.51)

8.02 (4.00 – 16.07)

0.007

0.01

<0.001

<0.001

<0.001

ANRS 1295/12160 - CIPRA KH001/10425 study

IRIS significantly more frequent in the early arm

N PR/IRIS Follow-up time* Incidence** (95% CI)

p

Early arm

Late arm

332

329 * expressed in person-months ** per 100 person-months 0.35

0.30

0.25

0.20

110

48

2 728.5

3 333.5

4.03 (3.34

1.44 (1.09

– 4.86)

– 1.91) <0.0001

0.15

0.10

0.05

0.00

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 Time aftre TB treatment initiation (weeks) Early arm Late arm

ANRS 1295/12160 - CIPRA KH001/10425 study

>95% undetectable viral load at week 50

Early arm Undetectable VL VL > 250 copies/mL Not available Late arm Undetectable VL VL > 250 copies/mL Not available

p

W26 259 (90.2) 25 (8.7) 3 (1.1) W50 264 (95.6) 9 (3.3) 3 (1.1) W78 184 (93.0) 6 (3.0) 8 (4.0) W102 W126 173 (93.5) 7 (3.8) 5 (2.7) 142 (93.4) 6 (4.0) 4 (2.6) 241 (88.3) 25 (9.2) 7 (2.5) 0.80

237 (95.6) 9 (3.6) 2 (0.8) 0.82

145 (91.8) 8 (5.1) 5 (3.1) 0.34

143 (92.9) 5 (3.2) 9 (3.9) 0.81

126 (96.2) 3 (2.3) 2 (1.5) 0.64

W150 111 (95.7) 3 (2.6) 2 (1.7) 96 (96.0) 1 (1.0) 3 (3.0) 0.63

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

Early N Median (IQR) Late N Median (IQR)

p

W26 W50 W78 W102 W126 W150 283 65 (26 – 125) 273 118 (67 – 191) 189 169 (101 – 270) 180 194 (134 – 299) 148 210 (128 – 324) 115 230 (152 – 321) 265 59 (14 – 111) 0.11

247 112 (53 – 175) 0.22

153 165 (88 – 243) 0.81

148 177 (106 – 285) 0.19

129 187 (119 – 288) 0.57

97 201 (127 – 322) 0.51

Week 0: median CD4+ cell count was 25/mm 3

Median CD4 increase at week 50: 114/mm 3 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 HIV TB 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