1. #AIDS2016 | @AIDS_conference Intensified TB case-finding among PLHIV: diagnostic yield of Xpert MTB/RIF, Determine TB-LAM and liquid culture Fred Semitala, MBChB, M.Med, MPH Makerere University, College of Health Sciences

2. #AIDS2016 | @AIDS_conference HIV & TB TB - leading cause of HIV deaths (1 in 3) worldwide Intensified case finding (ICF) is recommended to reduce TB burden among PLHIV WHO. Global TB Report, 2015 WHO. 3I’s Guidelines, 2011

3. #AIDS2016 | @AIDS_conference Screen for TB: WHO symptom screen Cough, fever, night sweats, weight loss Test for TB: Xpert MTB/RIF 1 st line confirmatory test for PLHIV ICF algorithm for PLHIV Active TB: Initiate TB treatment Screen-positive Xpert-positive Lawn, et al. Plos MED, 2011 Abed Al-Darraji, et al. PLoS ONE, 2013 LaCourse, et al. JAIDS, 2016 Sensitivity 43-58%

4. #AIDS2016 | @AIDS_conference Options for novel ICF algorithm Increased speed: Determine TB-LAM LAM, an MTb cell wall antigen Recommended as an “add-on test” for patients with advanced HIV and/or severe illness Increased sensitivity: Culture Gold standard for pulmonary TB diagnosis Unprocessed urine $ 3.5- 4 per strip Results in 25 min WHO. Urine LAM, 2015 + =

5. #AIDS2016 | @AIDS_conference Study Objectives and Design Objectives In the context of ICF, to compare the current TB testing strategy (Xpert MTB/RIF) to TB testing strategies inclusive of urine LAM and/or a single liquid culture Diagnostic accuracy Time-to-diagnosis Design Prospective study among consecutive HIV-infected adults who screened positive for TB by symptoms

6. #AIDS2016 | @AIDS_conference Design overview Participants: Adults with CD4 count ≤350 cells/μL initiating ART who screened positive for TB by symptoms Setting: Mulago HIV/AIDS Clinic (Kampala, Uganda) (7/2013 – 5/2016) Procedures: Sputum x 1 for Xpert and x 2 for MGIT culture Urine x 1 for Determine TB-LAM (if CD4 count ≤ 200 cells/μL; Grade 2 cut-point) TB testing algorithms: Individual tests (Xpert, LAM, MGIT-1) Test combinations Active TB definition: ≥1 positive sputum MGIT culture

7. #AIDS2016 | @AIDS_conference Patient flow diagram Patients screened for TB N=963 Screen positive N= 843 (87%) Screen negative, N=120 No TB N=731 (88%) TB N=112 (13%)

8. #AIDS2016 | @AIDS_conference Demographics and clinical characteristics Characteristic, N (%)Total (N=843) Age (years) † 33 (27-40) Female 264 (55%) CD4 count (cells/µL) † 223 (97-295) CD4 count ≤ 200 cells/µL 563 (58%) Culture-positive TB* 112 (13%) Legend: † Median (IQR); *At least 1 of 2 MGIT cultures.

9. #AIDS2016 | @AIDS_conference Diagnostic accuracy of individual tests Test Sensitivity, n/N (%) Specificity, n/N (%) Urine LAM (CD4 count ≤200 cells/µL) † 18/85 (21%)274/276 (99%) Xpert MTB/RIF69/112 (62%)727/731 (99%) MGIT-1*88/112 (79%)731/731 (100%) Legend: † If CD4 count ≤200 cells/uL; * MGIT-1 – culture result from the 1 st sputum specimen.

10. #AIDS2016 | @AIDS_conference Diagnostic accuracy of test combinations Test Combination Sensitivity n/N (%) Specificity n/N (%) Xpert + LAM73/112 (65%)723/731 (99%) LAM + MGIT-192/112 (82%)727/731 (99%) Xpert + MGIT-198/112 (88%)727/731 (99%) Xpert + LAM + MGIT-199/112 (88%)723/731 (99%)

11. #AIDS2016 | @AIDS_conference Case detection yield and days-to- diagnosis TB testing strategy % TB cases detected (N=112) Median days to TB diagnosis (IQR) LAM21%0 (0-0) Xpert62%0 (0-0) Xpert + LAM65%0 (0-0) MGIT-179%12 (9-16) LAM + MGIT-182%10 (6-15) Xpert + MGIT-188%0 (0-9) Xpert + LAM + MGIT-188%0 (0-8)

12. #AIDS2016 | @AIDS_conference Conclusions TB prevalence is high among PLHIV initiating ART who screen positive by symptoms The current TB testing strategy for ICF – Xpert alone – misses nearly 40% of all culture-positive TB cases Addition of urine LAM did not significantly increase diagnostic yield beyond that of Xpert alone In the context of ICF, any TB testing strategy not including MGIT misses at least 1/3 of all TB cases More sensitive rapid tests are needed and are likely to have the highest impact in context of ICF

13. #AIDS2016 | @AIDS_conference Acknowledgments UCSF Adithya Cattamanchi Christina Yoon Makerere University Moses R. Kamya Elly Atuhumuza Alfred Andama Lucy Asege Sandra Mwebe Jane Katende Martha Nakaye Johns Hopkins University David Dowdy Derek Armstrong Funding sources: NIAID K23 UCSF-GIVI CFAR NIAID/PEPFAR UCSF Nina Ireland Program in Lung Health NIH-FIC

14. #AIDS2016 | @AIDS_conference

18. Performance of TB testing strategies (relative to Xpert MTB/RIF alone) TB testing strategy Difference in sensitivity, % (95% CI) Difference in specificity, % (95% CI) LAM-40% (-53 to -28)-1% (-2 to 1) MGIT-1+17% (5 to 29)1% (0 to 1) Xpert + LAM+4% (-9 to 16)-1% (-1 to 0) LAM + MGIT-1+21% (9 to 32)0% (-1 to -1) Xpert + MGIT-1+26% (15 to 37)0% (-1 to -1) Xpert + LAM + MGIT-1+27% (16 to 38)-1% (-1 to 0)