The intersection between diabetes and tuberculosis: a perspective from Africa HIV and Diabetes Naomi (Dinky) Levitt Division of Endocrinology and Diabetes , University of Cape Town, Chronic Diseases Initiative for Africa Potsdam June 2016 Naomi (Dinky) Levitt University of Cape Town Chronic Diseases Initiative for Africa Multimorbidity workshop London June 2018

Trends in the prevalence of diabetes WHO Global report on diabetes 2016

Prevalence of diabetes in older people in Africa Overall prevalence 13·7% OGTT 23·9% FBG 10·9% We did a systematic review of the prevalence of type 2 diabetes in studies reported from 2000 to 2015, and extracted and synthesized data from 49 separate data involving 16 086 individuals met the inclusion criteria. The overall prevalence of diabetes was 13·7% and was higher in studies based on the oral glucose tolerance test 23·9%, than fasting blood glucose criteria (10·9%, and in urban than in rural settings (19·7% vs 7·9%) Mahmoud, et al. Lancet Diabetes & endocrinology 4.1 (2016): 72-84.

10.4 million cases worldwide Estimated TB incidence rates, 2016 for countries with more than 100, 000 incident cases 10.4 million cases worldwide 140 cases/100,000 population Global Tuberculosis Report WHO 2017

Associations between TB and DM macrophage function is altered: range from decreased phagocytic and chemotactic activity to polarization toward alternativelactivated macrophages Neutrophil function is compromised with reduced chemotaxis and phagocytosis as well as reduced anti-microbial activity Alters Th1 and Th17 frequency and pro-inflamatory cytokines Diabetes is associated with increased risk of: Relapse : RR 3.89 (95% CI, 2.43-6.23) Death: RR 1.89 (95% CI, 1.52 to 2.36) uncorrected RR 4.95 (95% CI, 2.69 to 9.10) adjusted Baker et al 2011 BMC medicine, 9(1), p.81.

Median prevalence of diabetes in patients with TB by region Workneh et al 2017PLOS ONE 12(4): e0175925.

Associations between TB and DM macrophage function is altered: range from decreased phagocytic and chemotactic activity to polarization toward alternativelactivated macrophages Neutrophil function is compromised with reduced chemotaxis and phagocytosis as well as reduced anti-microbial activity Alters Th1 and Th17 frequency and pro-inflamatory cytokines Diabetes is associated with increased risk of TB: Prospective studies: 3.59 (CI 2.3-5.7) fold Retrospective studies: 1.55 (CI 1.4-1.7) fold Case control: 2.09 (CI 1.7-2.6) fold Al-Rifai et al 2017 PLOS ONE 12(11): e0187967.

Associations between TB and DM macrophage function is altered: range from decreased phagocytic and chemotactic activity to polarization toward alternativelactivated macrophages Neutrophil function is compromised with reduced chemotaxis and phagocytosis as well as reduced anti-microbial activity Alters Th1 and Th17 frequency and pro-inflamatory cytokines increased risk of TB Diabetes is associated with increased risk of TB: DM blood test: 3.10–fold (95% CI 2.02–4.74) DM medical records: 1.60-fold (95% CI 1.18–2.17) DM self-reported: 1.95-fold (95% CI 0.90–4.25) Al-Rifai et al 2017 PLOS ONE 12(11): e0187967.

How to screen for diabetes in people with TB? . How to screen for diabetes in people with TB?

Prevalence of hyperglycaemia and duration of TB treatment  Decreasing trend in hyperglycaemia in patients with tuberculosis undergoing tuberculosis treatment. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Tropical Medicine & International Health: 15; 1300-1314, 2010

Prevalence of diabetes by diagnostic test: OGTT, FBG, HbA1c Diagnosis based on: Non-TB % (95% CI) TB p-value (chi-square)   Any test 10.1 (7.6 – 13.2) 12.6 (9.7 – 16.1) 0.246 FPG 3.9 (2.4 – 6.2) 4.4 (2.8 - 6.9) 0.752 OGTT 3.5 (2.1 – 5.8) 3.1 (1.7 – 5.3) 0.704 HbA1c 6.2 (4.3 – 8.9) 10.2 (7.7 – 13. 6) 0.032 Oni et al Eur Respir J 2017; 50: 1700004

Prevalence of diabetes by diagnostic test: OGTT, FBG, HbA1c Diagnosis based on: Overall % (95% CI) Non-TB TB p-value (chi-square)   Any test 11.3 (9.3 – 13.6) 10.1 (7.6 – 13.2) 12.6 (9.7 – 16.1) 0.246 FPG 4.1 (3.0 – 5.7) 3.9 (2.4 – 6.2) 4.4 (2.8 - 6.9) 0.752 OGTT 3.3 (2.3 – 4.8) 3.5 (2.1 – 5.8) 3.1 (1.7 – 5.3) 0.704 HbA1c 8.2 (6.5 – 10.2) 6.2 (4.3 – 8.9) 10.2 (7.7 – 13. 6) 0.032 Diabetes associated with TB: Unaffected by HIV (OR 2.4, 95% CI 1.3–4.3; p=0.005) HIV-1-infected individuals (OR 2.4, 95% CI 1.1–5.2; p=0.030)  14% population attributable risk fraction.   Oni et al Eur Respir J 2017; 50: 1700004

Forest plot adjusted odds ratios of active tuberculosis DM vs no DM At diagnosis of PTB Bailey S et al Trop Med and Int Health22; 261–268 2017

Forest plot adjusted odds ratios of active tuberculosis DM vs no DM At diagnosis of PTB 5 months on treatment of PTB Bailey S et al Trop Med and Int Health22; 261–268 2017

Proportion of patients with multimorbidity Multimorbidity: prevalence 22.6% 94% had 2 conditions 5% had 3 conditions Proportion of patients with multimorbidity among 32 474 patients who attended the clinic and received any prescription; and the distribution of morbidities among patients with prescriptions for at least one of HPT, DM, HIV/ART, and TB. Key: HPT Hypertension; DM Diabetes; HIV/ART HIV infected patients on antiretroviral therapy; TB Tuberculosis; MM Multimorbidity. Oni et al. BMC Infectious Diseases (2015) 15:20

Healthcare Provider Perspective Health System Perspective Effect of chronic disease morbidities on: Susceptibility and risk of HIV/TB (incl. role of shared risk factors) Diagnosis and clinical manifestation of TB Diagnosis and clinical manifestation of NCDs Complications and treatment outcomes of HIV/TB/NCDs Biological Interaction Effect of multiple chronic disease morbidities on: Patient workload (incl. impact of poverty) Treatment load Resilience and capacity Patient prioritization of morbidities Patient Perspective Health provider capacity to deal with high patient load and complexity Health provider role delineation Healthcare Provider Perspective Patients and Families Community Partners Health Care team Policy environment -How to integrate these perspectives to influence chronic care delivery -Incorporating disease interaction complexity, patient and provider priorities into patient engagement with the health system Health System Perspective MICRO MESO MACRO Oni, et al T BMC public health, 14(1), p.575

Healthcare Provider Perspective Health System Perspective Effect of chronic disease morbidities on: Susceptibility and risk of HIV/TB (incl. role of shared risk factors*) Diagnosis and clinical manifestation of TB Diagnosis and clinical manifestation of NCDs Complications and treatment outcomes of HIV/TB/NCDs Biological Interaction Effect of multiple chronic disease morbidities on: Patient workload (incl. impact of poverty) Treatment load Resilience and capacity Patient prioritization of morbidities Patient Perspective Health provider capacity to deal with high patient load and complexity Health provider role delineation Healthcare Provider Perspective Patients and Families Community Partners Health Care team Policy environment -How to integrate these perspectives to influence chronic care delivery -Incorporating disease interaction complexity, patient and provider priorities into patient engagement with the health system Health System Perspective MICRO MESO MACRO

Healthcare Provider Perspective Health System Perspective Effect of chronic disease morbidities on: Susceptibility and risk of HIV/TB (incl. role of shared risk factors*) Diagnosis and clinical manifestation of TB Diagnosis and clinical manifestation of NCDs Complications and treatment outcomes of HIV/TB/NCDs Biological Interaction Effect of multiple chronic disease morbidities on: Patient workload (incl. impact of poverty) Treatment load Resilience and capacity Patient prioritization of morbidities Patient Perspective Health provider capacity to deal with high patient load and complexity Health provider role delineation Healthcare Provider Perspective Patients and Families Community Partners Health Care team Policy environment -How to integrate these perspectives to influence chronic care delivery -Incorporating disease interaction complexity, patient and provider priorities into patient engagement with the health system Health System Perspective MICRO MESO MACRO