Randomized clinical trial to determine efficacy and safety of antiretroviral therapy one week after tuberculosis therapy in patients with CD4 counts <

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Randomized clinical trial to determine efficacy and safety of antiretroviral therapy one week after tuberculosis therapy in patients with CD4 counts < 200 cells /µL. Wondwossen Amogne, Abiy H/ wold, Getent Yimer, Eyasu Makonnen, Alemayehu Worku, Anders Sonnerborg, Lars Lindquist, Eleni Aklillu, Getachew Aderaye 1

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 2

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. 4

Results 5

Study Population Enrolled=474 Anti-TB days before ART(median+IQR)=28(25-30) 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 PTB+ve= 28(17.7%) PTB-ve= 66 (41.8%) Diss TB= 14( 8.9%) EPTB= 50 (31.6%) Anti-TB days before ART (median + IQR)= 56( 56-60) 158 patients Week 4(arm 2) 145 patients Week 8 (arm 3) 171 patients Week 1(arm 1) Anti-TB days before ART (median+IQR)= 7(7-8) PTB+ve=30(17.5%) PTB-ve= 79(46.2%) Diss TB= 17(9.9%) EPTB= 45(26.3%) PTB+ve= 41(28.3%) PTB-ve= 64 (44.1%) Diss TB= 15( 3.4%) EPTB= 35 (24.1%) 6

Baseline Characteristics of the Patients VariableArm 1Arm 2Arm 3P-value Age(mean+sd) Male sex # (%)96 (56.1%)85(53.8%)59(40.7%)0.015 BMI Kgs/m 2 (mean+ sd) CD4 ( mean,95% CI)75.5( )89.8( )90.2( )0.014 Lg HIV RNA (mean+sd) Karno score(mean+sd) HBsAg +ve # (%)17(9.9%)14(8.9%)10(6.9%)0.6 HCV Ab +ve # (%)4(2.4%)4(2.6%)00.16 Lost to follow up #(%)26(15.2%)22(13.9%)18(12.4%)0.8 TST (mean + sd) Initial regimen # (%) -d4T/3TC/EFV CBV/EFV TDF/3TC/EFV (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) X 2 Log rank=1.7,df=2, P- value= 0.4 Arm 1Arm 2Arm 3 Person wks IR (ITT) 7/10005/ / % CI

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

Factors associated with Mortality (Cox-proportional hazards model) VariablesHR95% CIAHR95% CI Baseline CD CD4 < Karnofsky score Male Sex Age Diss TB Other than Arm

Secondary endpoints TB-IRIS X 2 Logrank=19.7,df=2, P-value= Drug Induced Liver Injury X 2 Logrank=2.5,df= 2,, P-value=

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

Week 8-Sputum smear conversion PTB +veConvertedDefExpMDRPer wksIR conv95% CI Arm % Arm % Arm % Total

Conclusion CAMELIASTRIDESAPITTB HAART SettingCambodiaMultiSAEthiopia Study design (Integrated)2 arms 3 arms EnrollmentSmear +, CD4 < 200 Clinical TB CD4< 250 Smear + CD4 < 500 Clinical TB CD4 < 200 Median CD4 + IQR ( when ART)25(10-56)77(36-145)150( ) 75(42-125) Primary end pointSurvivalSurvival/AIDSAIDS/DeathDeath ART timing (wks/days) Mean + sd/ Median + IQR 2 wks + 4 days vs. 8 wks + 4 days 10 days (7-12) vs. 70 days(66-75) 21 days(15- 29) vs. 97 days ( ) 7 days( 7-8) vs. 28 days (28-30) vs. 56 days (56-60) ResultEarly > Late (CD4<50) Early < Late (CD4<50) Early < Late (CD4 < 50) 15

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.