Comparative performance of emerging rapid diagnostics in HIV-infected individuals

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1 Comparative performance of emerging rapid diagnostics in HIV-infected individuals Maunank Shah M.D. Johns Hopkins University Clinical Diagnostics Research Consortium

2 Background Emerging diagnostics may allow rapid diagnosis of TB Urinary LAM assays Xpert MTB/Rif Urinary LAM assays and Xpert MTB/Rif are promising, but have imperfect sensitivity in HIV-infected individuals

3 Emerging Tools: Xpert MTB/RIF Test performance: (sputum) Sensitivity (pulm TB): (single sample) Smear-positive: 95-98% Smear-negative: 55-77% HIV-infected: ~80% Specificity: 94-99% Rifampin Resistance: Sensitivity: ~97-100% Specificity: ~98-100% Boehme et al. Rapid Molecular Detection of TB and Rifampin Resistance. NEJM Sep 2010 Theron et al. Evaluation of Xpert for Diagnosis of PTB in a high HIV prevalence setting. AJRCC 2011

4 Antigen Detection: Lipoarabinomannan Urinary antigen Detection ELISA: Sensitivity in HIV patients 60-85% Higher sensitivity in pts with low CD4 High sensitivity with disseminated disease or mycobacteremia Specificity % Lateral Flow Formats Point-of-care, low cost Sensitivity similar to ELISA in HIV patients with low CD4 counts Specificity high with grade 2 cut-off (>95%)

5 Background New diagnostic algorithms are likely to utilize combinations of rapid diagnostic tests. To date, new technologies have been evaluated independently The yield of combinations of emerging rapid TB diagnostics is unclear Urinary LAM assays Xpert MTB/Rif

6 Yield of Combinations of tests in HIV-infected patients? Smear-Microscopy Smear-Microscopy (20-40%) (20-40%) Xpert Urine LAM Tuberculosis (~80%) (35-85%) Not TB

7 Comparative-performance of emerging diagnostics substudy Substudy nested within Feasibility of LF-LAM study in Uganda What is the sensitivity/specificity of combinations of emerging TB diagnostics? What is the incremental yield of novel algorithms for diagnosis of HIV-associated TB?

8 Comparative-effectiveness study Parent Study Population Adult HIV-infected individuals with TB symptoms Parent Study Diagnostics: Chest Xray Urine LF-LAM Urine LAM-ELISA 2 Sputums: FM, ZN, LJ, MGIT 1 Blood for mycobacterial culture Stored sputum (frozen)

9 Comparative-effectiveness study Conducted Xpert MTB/Rif testing on individuals with and without TB from parent study Study population: blinded to Urine LAM results Culture Confirmed TB: (sensitivity) Selected 101 consecutive enrollees with culture positive TB (any culture positivity) Not TB: (specificity) 107 individuals without clinical or microbiologic evidence of TB at 2 months No positive sputum or blood cultures (LJ or MGIT) Alive at 2 months and improved without TB therapy

10 Study Population Confirmed TB Not TB N Male (%) Female (%) 61 (60%) 40 (40%) 73 (68%) 34 (32%) Age Median (IQR) 32 [26-37] 35 (27-39) CD4 Median (IQR) 60 (IQR ) 275 (IQR ) Hospitalized 84 (83%) 38 (35%)

11 Study Results: Comparative performance of individual tests

12 Study Results: Sensitivity Confirmed TB LAM (grade 2) LAM-ELISA Xpert N Pulmonary TB alone P TB and mycobacteremia Mycobacteremia for MTB alone (58%) 38 (38%) 4 (4%) 50 (50%)* 61 (61%)* 78 (77%)* Smear Microscopy (%): 1 ZN 2 ZN 1 FM 2 FM 25 (25%) 31 (31%) 35 (35%) 43 (43%) P=0.001 P=0.371 p<0.001 P<0.001 P<0.001 P<0.001 Sputum Culture 1 sputum LJ 2 sputums LJ 65 (64%) 82 (82%) P<0.001 P<0.001 P= sputum MGIT 2 sputum MGIT 79 (78%) 95 (94%) Mycobacterial Blood Culture 42 (42%) P<0.001 P=0.117 P<0.001 P<0.001 P<0.001 P<0.001 p<0.001 comparing Xpert to LAM-ELISA or LAM; p<0.001 comparing LAM-ELISA to LAM

13 Study Results TB LF-LAM (grade 2) LAM-ELISA Xpert N (50%) 61(61%) 78(77%) FM Smear-positive FM Smear-negative CD4 Count CD4 <50 CD CD CD4 >200 Hospitalized Outpatient 43 (43%) 58 (57%) 46 (46%) 16 (16%) 18 (18%) 21 (21%) 84 (84%) 17 (17%) 24 (56%) 26 (45%) 30 (65%)** 12 (75%) 4 (22%) 4 (19%) 48 (57%) 2 (12%) 25 (58%) 36 (62%) 37 (80%)** 14 (88%) 6 (33%) 4 (21%) 55 (65%) 6 (35%) 42 (98%)* 36 (62%)* 34 (74%) 13 (81%) 16 (89%) 15 (71%) 64 (76%) 14 (82%) Mycobacteremia alone 4 (4%) 4(100%) 4 (100%) 1 (25%) *p<0.001 ** p<0.001 p<0.001 Bold represents comparisons in which there was a significant difference (p<0.05) between diagnostic tests

14 Specificity: Negative results in those without TB Overall LF-LAM (Grade 2) LAM-ELISA Xpert N (97%) 105 (98%) 105 (98%) CD4 Count CD4 <50 CD CD CD4 > (18%) 9 (8%) 16 (15%) 63 (59%) 18 (95%) 9 (100%) 15 (94%) 62 (98%) 18 (95%) 9 (100%) 16 (100%) 62 (98%) 19 (100%) 9 (100%) 16 (100%) 61 (97%) There was no difference in specificity of urinary LAM assays and Xpert MTB/RIF among individuals without TB

15 Study Results: Performance of combinations of diagnostic tests

16 Combinations of diagnostic tests Smear Xpert LF-LAM Smear + LF-LAM LAM-ELISA Smear Confirmed Tuberculosis 43% 77% 68% 78% 50% Xpert + LF-LAM 87% Smear + LF-LAM (grade 2) Sensitivity (95% CI) 68% (58-77) Smear alone (43%) LF-LAM alone (50%) p<0.001 p<0.001 LAM-ELISA (61%) p=0.185 Xpert alone (77%) p=0.150 LJ Culture (82%) p=0.024 MGIT culture (94%) p<0.001 Specificity (95% CI) 97% (92-99) Smear + LAM-ELISA 78% (69-86) <0.001 <0.001 < % (93-99) Xpert +LF-LAM 87% (79-93) <0.001 <0.001 < % (89-98)

17 Sensitivity of Combinations of Diagnostic Tests among HIV-infected individuals with TB 2 Sputa FM and MGIT with Blood Culture 2 Sputa FM and MGIT 2 Sputa FM and LJ Xpert MTB/RIF and urine LAM-ELISA Xpert MTB/Rif and urine LF-LAM (grade 2) FM and urine LF-LAM and Xpert MTB/RIF FM and urine LAM-ELISA FM and urine LF-LAM (grade 2) Incremental gain with test combinations Stand alone 1 sputa Xpert MTB/RIF alone Urine LF-LAM alone (grade 1) Urine LAM-ELISA alone Urine LF-LAM alone (grade 2) 2 Sputa FM alone Conventional diagnostics 2 Sputa ZN alone Urinary LAM testing Xpert MTB/RIF 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Sensitivity of diagnostic testing

18 Emerging TB diagnostic algorithms Rapid Algorithms using combinations of tests: Sputum Smear + Urinary LAM assays (68% [58-77%]) Xpert + Urinary LAM assays (87% [79-93%]) No significant difference in sensitivity of diagnostic combination among different CD4 strata No significant difference btwn inpatient (88%) vs outpt (82%) Two-Step Algorithms (time and resource considerations) Sputum Smear + Urinary LAM if negative Xpert or Culture Urinary LAM + Xpert if negative Culture

19 Conclusions In HIV infected patients with TB, no single rapid diagnostic modality is perfect The combination of urinary LAM testing and sputum Xpert MTB/RIF had improved diagnostic sensitivity and was superior to either test alone Urinary LAM testing plus Xpert MTB/RIF may rapidly identify ~90% of HIV-associated TB Stepwise algorithms with initial testing with urinary LAM and microscopy, with selective usage of Xpert MTB/RIF could be considered

20 Acknowledgements Susan Dorman Yuka Manabe Richard Chaisson Derek Armstrong Molly Holshouser Susan Weir Moses Joloba Willy Ssengooba Gerald Mboowa Francis Mumbowa