1. The effect of tuberculosis treatment on virologic and immunologic response to combination antiretroviral therapy among South African children Heidi M. Soeters, Shobna Sawry, Harry Moultrie, Annelies Van Rie 44 th Union World Conference – Abstract OP-186-02 November 2, 2013

2. Introduction

3. In 2010, World Health Organization (WHO) guidelines recommended that HIV-infected infants and children start combination antiretroviral therapy (cART) as soon as TB treatment is tolerated 1 Little is known about the effect of receiving TB treatment at time of cART initiation on response to cART in young children 1. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access - 2010 revision. Geneva, 2010.

4. Introduction The few studies that have assessed the effect of concomitant TB treatment on virologic or CD4 cell response to pediatric cART found that children receiving TB treatment at cART initiation may experience: Lower rates of virologic suppression 2-4 Similar CD4 cell reconstitution 2,4-6 Similar proportion of severe immunodeficiency 7 2.Frohoff C, et al. PLoS One 2011; 6:e17273. 3.Zanoni BC, et al. AIDS 2011; 25:49-55. 4.Reitz C, et al. JID 2010; 201:1121-31. 5.van Dijk JH, et al. PLoS One 2013; 8:e55111. 6.Zanoni BC, et al. PLoS One 2012; 7:e33611. 7.Fatti G, et al. JAIDS 2011; 58:e60-7.

5. Study Aim Evaluate the effect of receiving TB treatment at the time of cART initiation on short- and long-term virologic and immunologic response to cART among children aged 0-8 years

6. Research Methods

7. Secondary analysis of data from the TB HIV IRIS and Nutrition in Kids (THINK) cohort study Study population cART-naive children aged 0-8 years presented at Harriet Shezi outpatient pediatric HIV clinic or the Paediatric Wards of Chris Hani Baragwanath Hospital in Soweto, South Africa eligible for cART Enrolled September 2009 to March 2012 Follow-up: 24 months or until August 2013

8. Research Methods 2 groups: children on TB treatment at the time of cART initiation children who are TB-free at the time of cART initiation cART regimen prescribed according to age and weight >3 years and >10 kilograms: Efavirenz-based cART <3 years or <10 kilograms: LPV/r-based cART ­Super-boosted LPV/r if on TB treatment Eligible for inclusion in this secondary analysis if have at least 1 follow-up HIV RNA and/or CD4% LPV/r, lopinavir/ritonavir

9. Research Methods Study outcomes: Virologic suppression: first documented HIV RNA <50 copies/mL after cART initiation Virologic rebound: among those that suppressed, first documented HIV RNA >1000 copies/mL Median increase in CD4% from cART initiation Median CD4% Proportion with severe immunodeficiency* *Defined according to World Health Organization age-specific classifications: CD4% 5 years. 5

10. Results

11. 246 children enrolled in the THINK study and initiated cART 199 children had ≥1 follow-up HIV RNA and/or CD4% 92 (46%) children were receiving TB treatment 107 (54%) were not receiving TB treatment at cART initiation

12. Results: Baseline Characteristics

13. Results: Virologic Suppression Median time to HIV RNA <50 copies/mL 6.2 months in both groups aHR 1.20 (0.69, 2.08) aHR 1.36 (0.94, 1.96) aHR 1.23 (0.82, 1.84)

14. Results: Virologic Rebound aHR 1.53 (0.71, 3.30)

15. Results: CD4% Response Children on TB treatment had lower CD4% in the first 12 months, after which they caught up to children who were not on TB treatment Those receiving TB treatment had a similar median increase in CD4% 3 months (7.2% vs. 6.5%) 6 months (9.9% vs. 9.6%) 12 months (14.2% vs. 11.9%) 24 months (14.5% vs. 14.2%), all P ≥0.06

16. Results: Immunodeficiency At almost all time points, a higher proportion of children on TB treatment had severe age-specific immunodeficiency

17. cART Regimen Stratified Results No significant effect of TB treatment among children on efavirenz-based cART Among children on LPV/r-based regimens, those on TB treatment tended to have: Increased time to suppression (9.5 vs. 6.8 months) Increased virologic rebound (29% vs. 20%) Hazard of rebound (aHR 2.34, 95% CI 0.80, 6.83) Lower CD4% at 3, 6, 12 months Higher proportion of severe immunodeficiency at 6, 12, 24 months

18. Conclusions

19. Summary of Findings Despite having more advanced disease at baseline, children receiving TB treatment at cART initiation did not have a substantially different response to cART Both groups had similar rates of virologic suppression, virologic rebound, and CD4% increase Children on TB treatment remained more vulnerable ­lower CD4% and a higher prevalence of severe immunodeficiency throughout the first 2 years of cART Combination of TB treatment and super-boosted LPV/r-based cART may result in suboptimal response to cART in younger children

20. Acknowledgements National Institutes of Health (NIH) Funding for this study was granted by the United States NIH Award 1 R01 HD058972-01 PEPFAR/WRHI for core infrastructure The USAID’s Wits RHI PEPFAR Project provided partial funding for staff, equipment and technical support at the Harriet Shezi Children's Clinic. REDCap Study data were collected and managed using the REDCap electronic data capture system hosted at University of North Carolina – Chapel Hill [NIH grant 1UL1TR001111-01]. THINK study staff Participants and caregivers Joe Eron, Sonia Napravnik, Alan Brookhart

21. Thank you! Questions?