1. The Ethiopian TB HAART study: Find out the timing for ART when CD4< 200cells/µL Anything new?
Wondwossen Amogne, Abiy H/ wold, Getent Yimer, Eyasu Makonnen, Alemayehu Worku, Anders Sonnerborg, Lars Lindquist, Eleni Aklillu, Getachew Aderaye

2. Acknowledgements SIDA/SAREC EDCTP AAU, School of Medicine
Addis Ababa Regional Health Bureau
Patients who voluntarily participated

3. Competing risks in timing of ART during TB/HIV
Early (< 2 wks)
Benefits:
↓ risk of OIs
↓ mortality
Risks:
↑ adverse effects
↑ incidence of IRD
↑ D-D interaction
↑ Pill burden
Late (> 8 weeks)
Benefits:
↓ risk of IRD
Risks:
↑ incidence of OIs
↑ mortality

4. What is new about this study?
EFV based ART, one wk after initial anti-TB
- ↓ all cause mortality at CD4 strata < 50 cells/mm3.
- ↑ risk of TB-IRIS but not cause of mortality
- ↑ risk of DILI but no significant Effect on treatment d/c.
≈ Effect on CD4 increase vs. Arm 2/3.
- Does not affect smear conversion rate.
- Rif – EFV interaction
= CYP 2B6*6 among Ethiopians (31.5%)
= Concomitant administration ↓ EFV clearance by %% ( Eur J Clin Pharmacol; published on line 23 Nov 2011)

5. Hypothesis
Primary: Initiation of EFV based HAART one week after anti-TB will reduce overall mortality at 24 weeks compared to four and eight weeks. Secondary: At 24 wks of treatment (anti-TB & ART), there won’t be significant difference in new ADI, TB-IRIS, DILI, CD4 increase and TB- treatment outcome among patients who start ART one wk after anti-TB as compared to 4 and 8 wks.

6. Study design.

7. Results

8. Study Population Screened= 600 Enrolled=474 171 patients 158 patients
Not Enrolled=126
HIV –ve= 19(21.6%)
CD4> 200=25 (28.4%)
TB excluded= 15(17%)
Impaired LFT= 20(22.7%)
Pregnancy= 9(10.2%)
Enrolled without random=38 (30.2%)
Screened= 600
Enrolled=474
171 patients
Week 1(arm 1)
158 patients
Week 4(arm 2)
145 patients
Week 8 (arm 3)
Anti-TB days before ART (median+IQR)= 7(7-8)
Anti-TB days before ART(median+IQR)=28(25-30)
Anti-TB days before ART (median + IQR)= 56( 56-60)
PTB+ve=30(17.5%)
PTB-ve= 79(46.2%)
Diss TB= 17(9.9%)
EPTB= 45(26.3%)
PTB+ve= 28(17.7%)
PTB-ve= 66 (41.8%)
Diss TB= 14( 8.9%)
EPTB= 50 (31.6%)
PTB+ve= 41(28.3%)
PTB-ve= 64 (44.1%)
Diss TB= 15( 3.4%)
EPTB= 35 (24.1%) 8 8 8

9. Baseline Characteristics of the Patients
Variable
Arm 1
Arm 2
Arm 3
P-value
Age(mean+sd)
0.035
Male sex # (%)
96 (56.1%)
85(53.8%)
59(40.7%)
0.015
BMI Kgs/m2(mean+ sd)
0.9
CD4 ( mean,95% CI)
75.5( )
89.8( )
90.2( )
0.014
Lg HIV RNA (mean+sd)
4.9+1
4.9+ 1
0.95
Karno score(mean+sd)
88+ 13
0.031
HBsAg +ve # (%)
17(9.9%)
14(8.9%)
10(6.9%)
0.6
HCV Ab +ve # (%)
4(2.4%)
4(2.6%)
0.16
Lost to follow up #(%)
26(15.2%)
22(13.9%)
18(12.4%)
0.8
TST (mean + sd)
5 + 8
0.63
Initial regimen # (%)
d4T/3TC/EFV
CBV/EFV
TDF/3TC/EFV
43 (25.2%)
53(31%)
62(36.3%)
60 (38%)
42(26.6%)
46(29.1%)
33(22.8%)
45(31%)
49(33.8%)
0.03 (df=10)

10. Types of Tuberculosis

11. Primary End point (ITT)
X2Log rank=1.7,df=2, P- value= 0.4
Arm 1
Arm 2
Arm 3
Person wks
2813
3848
2836
IR (ITT)
7/1000
5/1000
4.6/1000
95% CI
IR= incidence rate

12. Mortality compared at CD4 strata of < 50 and >50.
All cause mortality IR
Arm 1
Arm 2
Arm 3
CD4< 50
(95% CI)
9.5/1000
( )
8.9/1000
( )
9.6/1000
( )
CD4> 50
6.2/1000
( )
3.7/1000
( )
2.5/1000
(1-6)
IRR
1.52
2.43
( )
3.87
( )
P-value
0.34
0.09
0.019

13. Factors associated with Mortality (Cox-proportional hazards model)
Variables HR
95% CI
AHR
Baseline CD4 1
0.98-1
CD4 < 50
2.26
1.2
Karnofsky score
0.96-1
Male Sex
Age
1-1.04
Diss TB
2.5
1.8
Other than Arm 1
0.7
0.8

14. Secondary endpoints TB-IRIS Drug Induced Liver Injury
X2Logrank=19.7,df=2, P-value= 0.001
Drug Induced Liver Injury
X2Logrank=2.5,df= 2,, P-value= 0.2

15. ART timing- Effect on CD4 count
Arm 1
Arm 2
Arm 3
P- value
CD4(0)
Median +IQR 67
(36-107) 76
(46-133) 82
(48-134)
0.017
CD4 (12) 80
(31-136) 89
(39-201)
102
(62-187)
0.041
CD4 (24)
Median+ IQR 17
(-17-77)
( ) 12
( )
0.059

16. Week 8-Sputum smear conversion
PTB +ve
Converted
Def
Exp
MDR
Per wks
IR conv
95% CI
Arm 1 30 20 5 4 1
240
8.3%
Arm 2 28 24 3
224
10.7%
Arm 3 41 37
328
11.3%
Total 99 81 11 2

17. Conclusion CAMELIA STRIDE SAPIT TB HAART Setting Cambodia Multi SA
Ethiopia
Study design (Integrated)
2 arms
3 arms
Enrollment
Smear +, CD4 < 200
Clinical TB
CD4< 250
Smear +
CD4 < 500
CD4 < 200
Median CD4 + IQR ( when ART)
25(10-56)
77(36-145)
150(77-254)
75(42-125)
Primary end point
Survival
Survival/AIDS
AIDS/Death
Death
ART timing (wks/days)
Mean + sd/ Median + IQR
2 wks + 4 days
vs.
8 wks + 4 days
10 days (7-12)
70 days(66-75)
21 days(15-29) vs.
97 days (77-126)
7 days( 7-8)
28 days (28-30)
56 days(56-60)
Result
Early > Late
Early >Late
(CD4<50)
Early < Late
(CD4 < 50)

18. What is new about this study?
EFV based ART, one wk after initial anti-TB
- ↓ all cause mortality at CD4 strata < 50 cells/mm3.
- ↑ risk of TB-IRIS but not cause of mortality
- ↑ risk of DILI but no significant Effect on treatment d/c.
≈ Effect on CD4 increase vs. Arm 2/3.
- Does not affect smear conversion rate.
- Rif – EFV interaction
= CYP 2B6*6 among Ethiopians (31.5%)
= Concomitant administration ↓ EFV clearance by %% ( Eur J Clin Pharmacol; published on line 23 Nov 2011)

19. Thank you.