New WHO algorithm to prevent TB deaths in seriously ill patients with HIV Yohhei Hamada TB/HIV and Community Engagement

Seriously Ill Patients Defined as patients with one or more of the following danger signs: Unable to walk unaided Respiratory rate over 30/min Fever of more than 39oC Pulse rate of over 120/min

Challenges in early diagnosis Low sputum bacillary load Unable to provide sufficient and high quality sputum specimens High rates of extrapulmonary TB

New tools to expedite TB diagnosis and treatment Xpert MTB/RIF Lateral flow urine lipoarabinomannan assay (LF-LAM) Presumptive TB treatment (http://apps.who.int/iris/bitstream/10665/112472/1/9789241506335_eng.pdf) (http://www.who.int/tb/areas-of-work/laboratory/policy_statement_lam_web.pdf) (http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf)

Xpert MTR/RIF Automated and rapid assay (less than 2 hours) Higher sensitivity than microscopy (79% for PLHIV)

Xpert MTR/RIF Should be used as the initial diagnostic test in PLHIV to diagnose pulmonary TB and TB meningitis May be used rather than conventional tests for testing other extrapulmonary specimens (lymph nodes and other tissues)

Lateral flow urine lipoarabinomannan assay (LF-LAM) Urine-based point of care test Results available in 25 minutes

Diagnostic characteristics of LF-LAM Pooled sensitivity Pooled specificity By CD4 count (5 studies) <=100 56% 90% <=200 49% >200 15% 96% By health care setting Inpatients (6 studies) 54% Outpatients (3 studies) 21% 97% Sensitivity is higher with lower CD4 and higher severity of illness

LF-LAM associated with reduced deaths in HIV-positive inpatients suspected of having TB Treatment given by trained nurses based on the positive LF-LAM

Lateral flow urine lipoarabinomannan assay (LF-LAM) LF-LAM may be only used to assist in the diagnosis of active TB in HIV positive adults and children (both in-and out-patients), presumed to have TB who: 1) have a CD4 cell count<= 100 or 2) are seriously ill, regardless of CD4 cell count LF-LAM should not be used as a screening test for TB Detailed recommendations are available at: http://apps.who.int/iris/bitstream/10665/193633/1/9789241509633_eng.pdf

Presumptive TB treatment Operational definition Initiation of TB treatment for PLHIV in peripheral facilities based exclusively on clinical suspicion for “seriously ill patients” with respiratory distress based on the judgment of the clinician.

Presumptive TB treatment Systematic review of presumptive TB treatment: 8 electronic databases up to March 2015. 2563 citations and 4 ongoing trials. Identified one RCT (REMEMBER); but the study did not meet the operational definition of presumptive TB treatment.

This does not meet the operational definition of presumptive treatment ACTG A5274 - REMEMBER trial Multi-country RCT: Empirical TB tx vs IPT Population: PLHIV with CD4<50 cells/mm2 without evidence of active TB No evidence of reduced mortality as a result of presumptive TB treatment in PLHIV with CD4<50 in whom TB had been ruled out by extensive investigations and was not suspected. This does not meet the operational definition of presumptive treatment GLOBAL TB PROGRAMME

This does not meet the operational definition of presumptive treatment TB FAST TRACK Trial Design: Cluster RCT Population: Ambulatory PLHIV with CD4≤150 Intervention group: Provide TB treatment for subjects with high TB probability (any of Hb <10g/dl, BMI ≤18.5 or a positive LF-LAM) No reduction in mortality This does not meet the operational definition of presumptive treatment GLOBAL TB PROGRAMME

44% reduction in 8-week mortality among inpatients Presumptive TB treatment associated with reduced deaths in PLHIV who are seriously ill and presumed to have TB

Presumptive TB treatment In peripheral settings where TB investigations are not available, clinical assessment and judgment should be used to provide presumptive TB treatment for select individuals who are seriously ill

Xpert MTB/RIF-negative7 or no test available HIV-positive or unknown and Seriously ill, suspected of having TB and danger signs Immediate referral to a higher level facility Immediate referral not possible Xpert MTB/RIF Parenteral antibiotics for treatment of bacterial infections Consider treatment for Pneumocystis pneumonia Chest X-ray if available Xpert MTB/RIF-positive Xpert MTB/RIF-negative7 or no test available LF-LAM may be used to assist in the diagnosis of active TB

Xpert MTB/RIF-negative7 or no test available Clinical worsening or no improvement after 3-5 days Improvement after 3-5 days Start presumptive TB treatment ART Co-trimoxazole preventive therapy Further investigations for TB and other diseases Complete the course of parenteral antibiotics TB unlikely Reassess for other HIV-related diseases ART assessment Isoniazid preventive therapy Co-trimoxazole preventive therapy Complete the course of parenteral antibiotics

Conclusions New WHO algorithm is likely to minimize delay in TB treatment initiation and prevent early mortality Consider presumptive TB treatment among PLHIV who are seriously ill and presumed to have TB Adopt rapid TB diagnostic tools (i.e. Xpert MTB/RIF and LF-LAM) to ensure early diagnosis of TB