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Timing of HAART and TB Treatment

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  • 1. Timing of Highly Active Antiretroviral Therapy (HAART) Initiation during Tuberculosis (TB) Treatment and Early HIV-RNA and CD4-T Lymphocyte Responses Simbarashe Takuva 1, Mhairi Maskew 1, Daniel Westreich 2, Ian Sanne 1,3, Lynne McNamara 1 1 Clinical HIV Research Unit, Department of Medicine, University of the Witwatersrand, South Africa. 2 Duke Global Health Institute and Obstetrics & Gynecology, Duke University, NC, USA. 3 Right to Care, Johannesburg, South Africa. Table 2 : Relative Risk (RR) and 95% confidence intervals (95%CI) of study outcomes according to timing of HAART Statistical analysis : ABSTRACT OBJECTIVE during TB treatment •modified Poisson regression models with robust error variance to estimate the adjusted relative risk and 95% CIs for the study Timing (days) Total (N) Events, n (%) Crude RR (95% CI) Adjusted RR (95% CI) Background: Concern over drug-drug interactions may result in •we examined whether the different timing of HAART outcomes. 3 Failure to achieve CD4 increase ≥ 50 cell/mm by 6 months * delayed initiation of HAART among patients receiving TB therapy. initiation during TB treatment has an impact on early < 14 172 76 (44.2%) 1.02 (0.85-1.23) 1.02 (0.85-1.22) We examined the effect of initiating HAART on CD4 and viral viral and immune responses to first-line HAART. •analyses were repeated after stratifying according to the response to HAART at different time periods during TB therapy. degree of immunosuppression at initiation of HAART (CD4 15–60 463 189 (40.8%) 0.91 (0.79-1.04) 1.00 (0.86-1.15) Methods: Cohort data analysis for 1499 HIV-TB co-infected <50cells/mm3 vs CD4 ≥ 50cells/mm3). > 60 575 260 (45.2%) 1 1 ‡ patients classified according to timing of HAART after the Failure to suppress viral load (< 400 copies/ml) by 6 months initiation of TB therapy: < 14 days after initiation of TB therapy; METHODS •sensitivity analyses to examine impact of potential selection < 14 171 21 (12.8%) 1.04 (0.65-1.67) 0.98 (0.59-1.63) 15-60 days; or ≥60 days. We used multivariate modified Poisson bias due to missing outcome data : two assumptions a) all regression models to estimate the relative risk (RR) for failure to deaths and LTFU were failure events and, b) only death was a 15–60 474 49 (10.3%) 0.96 (0.68-1.36) 0.96 (0.66-1.41) increase CD4 by ≥ 50cells/mm3, suppress virus by 6months and •cohort data for 1499 HIV-infected patients initiating failure event and LTFU events were random. > 60 566 64 (11.3%) 1 1 also viral rebound at 12 months. HAART at the Themba Lethu Clinic (TLC), Johannesburg, Viral rebound at 12 months (> 400 copies/ml) ¥ Results: In adjusted regression models, CD4 and viral responses South Africa, between April 2004 – March 2009. •ethical approval granted by University of the Witwatersrand < 14 111 4 (3.6%) 1.17 (0.40-3.43) 1.14 (0.39-3.34) showed no significant differences according to timing of HAART •most patients are initiated on EFV-3TC-d4T and TB Human Research Ethics Committee (Medical). 15–60 333 18 (5.4%) 1.50 (0.52-4.34) 1.43 (0.50-4.12) initiation (failure to increase CD4 by 6 months, <14 days vs >60 days: RR 1.02 (95%CI 0.85-1.22), 15-60 days vs >60 days: RR 1.00 treatment is Rifampicin based. > 60 379 16 (4.2%) 1 1 (95%CI 0.86-1.15); failure to suppress virus by 6 months, <14 * adjusted for CD4 count, employment status, BMI and age at initiation of HAART; ‡ adjusted for CD4 days vs >60 days: RR 0.98 (95%CI 0.59-1.63), 15-60 days vs >60 Eligibility criteria : RESULTS count, ALT, employment status, gender and age at initiation of HAART; ¥ adjusted for age at initiation of HAART. days: RR 0.96 (95%CI 0.66-1.41) and viral rebound at 12 months, 14 days vs >60 days: RR 1.43 (95%CI 0.50-4.12), 15-60 days vs •age ≥ 18 years Table 3 : Analysis restricted to patients with CD4 count < 50 cells/mm3 at baseline >60 days: RR 1.14 (95%CI 0.39-3.34). Similar estimates were Table 1 : Characteristics of study cohort at baseline and end of follow-up by timing of found when analysis was restricted to patients with severe •CD4 ≤ 350 cells/mm3 Failure to achieve CD4 Failure to suppress viral Viral rebound at 12 months HAART initiation during TB treatment increase ≥ 50 cell/mm3 load < 400copies/ml > 400 copies/ml immunosuppression. Timing (days) •first-line HAART Adjusted RR (95% CI) Adjusted RR (95% CI) Adjusted RR (95% CI) Conclusion: Among patients in our cohort who initiated HAART, early stage TB therapy did not compromise early immune and •pregnant women u Baseline characteristic Total, n (%) 0-14 days 219 (14.6%) 14 - 60 days 579 (38.6%) 60 days 701 (46.8%) < 14 0.93 (0.66-1.31) 0.74 (0.39-1.41) 1.11 (0.22-5.54) viral responses among those who remained in the cohort. were excluded Male, n (%) 110 (50.2%) 254 (43.9%) 294 (41.9%) 15–60 0.93 (0.67-1.30) 0.72 (0.39-1.34) 1.88 (0.43-8.25) Figure 1: Pulmonary TB Figure 2: Acid Fast Bacilli Concern over drug-drug interactions should not be a reason to > 60 1 1 1 Employed, n (%) 86 (39.3%) 213 (36.8%) 260 (37.1%) delay HAART during TB therapy. Exposure categories : Black, n (%) 205 (93.6%) 560 (96.7%) 666 (95%) •in both sensitivity analyses, the adjusted RR estimates were slightly lower for Timing of HAART during TB therapy - Age, years; median (IQR) 36 (31-42) 35 (31-41) 36 (31-41) both outcomes compared to those of the main analysis. within 14 days ; between 15-60 days and at least 60 days. WHO stage IV, n (%) 57 (26.1%) 123 (21.2%) 146 (21.3%) BACKGROUND EFV-3TC-d4T, n (%) 202 (92.2%) 536 (92.6%) 619 (88.3%) Study outcomes : CONCLUSIONS Pulmonary TB, n (%) 210 (95.9%) 553 (95.5%) 664 (94.7%)•treatment of HIV-TB co-infected patients is complicated. 1. failure to gain a defined CD4 response of ≥50 cells/mm3 CD4 count; median (IQR) 45 (14-108) 42 (18-89) 70 (30-126) •these results suggest that concurrent use of TB drugs (containing 600mg by 6 months after HAART initiation. Hb, g/dl; median (IQR) 10.2 (8.5-11.5) 10 (8.8-11.4) 11 (9.6-12.3) Rifampicin) and HAART (containing Efavirenz standard 600mg dose) does not•concerns over pharmacokinetic drug interactions, drug intolerance, co-toxicity and variable drug absorption. 2. failure to achieve viral suppression (<400 copies/ml) by 6 BMI, kg/m2; median (IQR) 20 (17.5-22.4) 19.6 (17.6-22) 20.4 (18.3-23.2) jeopardize viral and immune responses to HAART. months after initiation of HAART. Status by end of follow-up •our findings further add weight to recent recommendations that HAART can safely•concurrent use of efavirenz and rifampicin may result in treatment failure and poor clinical outcomes. 3. viral rebound at 12 months after initiation of HAART Lost to follow-up (LTFU) 33 (15.1%) 71 (12.3%) 96 (13.7%) be initiated earlier and should not be delayed in patients with TB. (>400 copies/ml). Died 21 (9.6%) 53 (9.2%) 47 (6.7%)•deferring HAART among patients with TB may •left truncation may have potentially biased our results; our inferences are result in faster HIV disease progression and an increased •baseline characteristics of patients who had a missing outcome conditional, based on the patient having survived from initiation of TB therapy the risk of mortality from both infections. •followed up until an event, competing risk (death or laboratory measurement compared to those who had a until the time of initiation of HAART. LTFU), or cut-off on 31 March 2010. measurement available were generally similar. •by the end of the 12 month follow-up period, proportions of Presented at the 18th Conference on Retroviruses & Opportunistic Infections Contact : Dr Simbarashe Takuva (CROI), 27February – 02March, 2011 , Boston, MA. Division of Epidemiology & Biostatistics patients who died or were LTFU did not differ by exposure Clinical HIV Research Unit (CHRU) category. Acknowledgements : Grant numbers - USAID grant number: 674-A-00-08-00007-00 and Johannesburg, South Africa CIPRA grant number: IU19AI53217-01 Email : stakuva@witshealth.co.za