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

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

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

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 29.%% ( Eur J Clin Pharmacol; published on line 23 Nov 2011)

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.

Study design.

Results

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

Baseline Characteristics of the Patients Variable Arm 1 Arm 2 Arm 3 P-value Age(mean+sd) 36.8 + 9.8 36.3+ 8.9 34.1 + 9.5 0.035 Male sex # (%) 96 (56.1%) 85(53.8%) 59(40.7%) 0.015 BMI Kgs/m2(mean+ sd) 18.8 + 2.9 18.7 + 3 18.6 + 3 0.9 CD4 ( mean,95% CI) 75.5(68.1-83) 89.8(81.3-98.3) 90.2(81.7-98.6) 0.014 Lg HIV RNA (mean+sd) 4.9+1 4.9+ 1 4.9 + 1 0.95 Karno score(mean+sd) 84 + 15 85 + 14 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) 3.6 + 6.4 5 + 8 3 + 6.3 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)

Types of Tuberculosis

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 4.9-11.4 3.1-8.4 2.7-7.9 IR= incidence rate

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 (5.1-17.6) 8.9/1000 (4.4-17.8) 9.6/1000 (4.8-19.3) CD4> 50 6.2/1000 (3.5-11.3) 3.7/1000 (1.8-7.3) 2.5/1000 (1-6) IRR 1.52 0.6-3.95 2.43 (0.8-7.43) 3.87 (1.12-15.02) P-value 0.34 0.09 0.019

Factors associated with Mortality (Cox-proportional hazards model) Variables HR 95% CI AHR Baseline CD4 1 0.98-1 CD4 < 50 2.26 1.3-3.94 1.2 0.5-2.9 Karnofsky score 0.96-1 Male Sex 0.6-1.7 Age 1-1.04 Diss TB 2.5 0.8-7.6 1.8 0.5-5.4 Other than Arm 1 0.7 0.3-1.4 0.8 0.3-1.6

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

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) (-55-55.5) 12 (-46.5-60) 0.059

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% 5.3-12.9 Arm 2 28 24 3 224 10.7% 7.1-15.98 Arm 3 41 37 328 11.3% 8.1-15.6 Total 99 81 11 2

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)

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 29.%% ( Eur J Clin Pharmacol; published on line 23 Nov 2011)

Thank you.