1. Diabetes Mellitus and Tuberculosis: current status and implications for tuberculosis control __________________________ Anthony D Harries “The Union” Paris, France

2. Global Burden of DM and TB Diabetes Mellitus: 2008 250 million people living with DM 6 million new cases each year 3.5 million people died of DM during the year [World Diabetes Foundation 2009] Tuberculosis: 2009 14.0 million people living with TB 9.4 million new cases each year 1.7 million people died of TB during the year [WHO- Global TB Control 2010]

3. Global Distribution of DM and TB Diabetes Mellitus: 2008 South East Asia 20% Western Pacific 23% Africa5% 70% in LIC and MIC [World Diabetes Foundation 2009] Tuberculosis: 2009 South East Asia 35% Western Pacific 20% Africa 30% 95% in LIC and MIC [WHO- Global TB Control 2010]

4. The global increase in DM 2010285 million with DM 2030440 million with DM [Diabetes Atlas: International Diabetes federation, 2009]

5. M.tuberculosis bacteria 2.0 billion people carry this bacteria in their bodies TUBERCULOSIS Life-time risk of active TB = 5-15% THE TUBERCLE BACILLUS

6. Risk of active TB increased in… HIV/AIDS Other causes of immune suppression (steroids) Silicosis Malnutrition Smoke from domestic stoves and cigarettes Diabetes mellitus

7. Recognised in Roman times that DM increases risk of TB

8. Jeon CY, Murray MB. Diabetes Mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Medicine 2008; 5: e152 Search of PubMed and EMBASE databases: studies reporting age-adjusted quantitative estimate of association between DM and active TB 13 observational studies [3 cohort; 8 case-control; 2 other]

9. RESULTS 1,786,212 participants with 17,698 TB cases DM associated with increased risk of TB [ Cohort studies = RR 3.1, 95% CI 2.3 – 4.3] [Case control studies = OR 1.2 – 7.8] Higher risks in young people and communities with high background TB incidence

10. Other global studies on DM increasing the risk of TB Stevenson et al (Chronic Illn, 2007): –Medline search for studies after 1995 –Increased RR or OR of 1.5 – 7.8 –Risk higher in younger people

11. India [Stevenson et al BMC Public Health 2007] Epidemiological model constructed based on 21M adults with DM and 900,000 new TB cases in 2000 DM accounted for: 15% PTB (7% - 23%) : 20% smear+ve PTB (8% - 42%) Urban areas more affected than rural areas Diabetes mellitus makes substantial contribution to burden of new TB in India

12. Diabetes Mellitus increases the risk of TB by a factor of 2 - 3 Dooley and Chaisson, Lancet Infectious Diseases, 2009 Ruslami et al, Tropical Medicine & International Health, 2010 Goldhaber-Fiebert et al, International Journal Epidemiology 2011

13. Is this biologically plausible? YES:- Animal models – diabetic mice have impaired CMI and have higher M.TB loads than normal mice Patients with DM have low levels of IFN- gamma, reduced white cell killing activity DM impairs innate and immune responses to TB

14. Diabetes Mellitus associated with: Pulmonary microangiopathy Renal failure Micronutrient Deficiency ALSO:- Increased risk of TB

15. Association between DM and TB Not in doubt Biologically plausible BUT previous studies have limitations:- Most are from industrialised countries Almost none from Africa Many are health facility-based and are secondary analyses of routine data sources Many critical unanswered questions

16. Expert Meeting convened in November 2009 (WHO, Union, WDF, IDF, Academia, Ministries of Health)

17. Objectives of Meeting 1.Discuss an updated systematic review conducted by Harvard University between May – Aug 2009, and identify knowledge gaps 2.Develop a prioritised research agenda 3.Decide on policy recommendations

18. 1. Updated systematic review: focus on issues related to TB control PUBMED, EMBASE, Bibliographies, Conference proceedings from IUATLD in 2007 and 2008

19. 1.Linkage between DM and TB Strong evidence from 16 age-adjusted studies (summary OR = 2.2) Some evidence that poor DM control increases risk of TB (HbA1c >7% = RR 2.56) [USA,UK, Canada, Mexico, Russia, India, Taiwan, South Korea, Indonesia] Knowledge gaps: –Little evidence from low-income countries, especially Africa –Need more data on the effect of DM control on risk of TB

20. 2. Diagnosis of TB and DM Two main problems:- In patients with TB, DM is not suspected or recognised In patients with DM, TB may present differently and may not be diagnosed

21. (2.1.) Is DM under-diagnosed in TB patients? Tanzania – 506 consecutive PTB patients 9 known to have DM Other patients given a 75G OGTT – 11 had sustained high blood glucose levels = DM DM missed in over half the patients Mugusi et al, Tubercle 1990

22. (2.2.) Does TB present differently in patients with DM? Most consistent difference is “infiltrates more common in lower lung fields” –Turkey [Bacakoglu et al, 2001] –Saudi Arabia [Shaikh et al, 2003] –Pakistan [Jabbar et al 2006] –Taiwan [Wang et al, 2008]

23. TYPICAL CHEST X-RAY ATYPICAL CHEST X-RAY

24. 3. Effect of DM on treatment outcomes of TB DM associated with:- –possible delay in sputum culture conversion –increased risk of death –increased risk of recurrent TB BUT many limitations to these studies

25. 3.1. Delay in sputum culture conversion at 2-3 months 8 studies comparing DM with non-DM Relative risks from 0.8 – 3.2 Five of eight studies had RR > 2

26. Risk of remaining sputum culture positive after 2-3 months of treatment for DM patients with TB versus non-DM patients with TB

27. 3.2. Increased risk of death 23 studies comparing risk of death in DM and non-DM patients Pooled RR = 1.85 (95% CI, 1.5 – 2.3) 4 studies adjusted for age /other confounders: pooled OR = 4.95 (95% CI, 2.7 – 9.1)

28. Risk of death for DM patients with TB compared to non-DM patients with TB

29. Adjusted odds of death for diabetic patients with TB compared to non-diabetic patients with TB [adjusted for age and other confounders]

30. 3.3. Increased risk of recurrent TB 5 studies assessed risk of relapse or drug- resistant recurrent TB For Relapse, pooled RR = 3.89 (95% CI, 2.1 – 7.5) For drug-resistant recurrent disease, there was no evidence of any association (pooled OR = 1.24, 95% CI 0.7 – 2.2)

31. Population with DM Relapse/ Total Population without DM Relapse/ Total Risk of TB relapse for DM patients with TB compared to non-DM patients with TB

32. Why an increased risk of adverse outcomes? Drug-drug interactions between oral hypoglycaemic drugs and rifampicin (decreased RF concentrations and poor glycaemic control) DM is a risk factor for hepatic toxicity with TB drugs Immune-suppressive effects of DM

33. 4. Preventing TB in DM Two observational studies in 1958 and 1969 showing that isoniazid prophylaxis in DM patients reduces risk of TB Knowledge gaps: –Very poorly conducted studies and therefore evidence base still weak

34. Summary: DM-TB is “similar” to HIV-TB HIV-TB Increased TB cases More difficult to diagnose TB cases Increased death Increased recurrent TB DM-TB Increased TB cases More difficult to diagnose TB cases Increased death Increased recurrent TB Int J Tuberc Lung Dis 2011; 6 September epub ahead of print

35. Proportion of TB burden attributable to some major risk factors in high TB burden countries Relative risk for active TB disease Weighted prevalence (adults 22 HBCs) Population Attributable Fraction (adults) HIV infection 20.6/26.7*0.8% 16% Malnutrition 3.2**16.7% 27% Diabetes 3.15.4% 10% Alcohol use (>40g / d) 2.98.1% 13% Active smoking 2.026% 21% Indoor Air Pollution 1.471.2% 22% Sources: Lönnroth K, Castro K, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, Raviglione M. Tuberculosis control 2010 – 2050: cure, care and social change. Lancet 2010 DOI:10.1016/s0140-6736(10)60483-7.

36. 2. Prioritised research agenda Tropical Medicine & International Health 2010; 15: 659-663

37. Highly prioritised Research: Bi-directional screening: active TB in DM patients and DM in TB patients Treatment outcomes in DM patients (focus on mortality and strategies to reduce mortality Use of the “DOTS” model to manage DM POC diagnostic and monitoring tests for DM (glycosylated haemoglobin HbA 1c )

38. 3. Policy Recommendations

39. Collaborative Framework for Care and Control of TB and Diabetes

40. The recommendations http://www.who.int/tb/publications/2011/en/index.htmlDocument available at:

41. Summary: Diabetes and Tuberculosis Rapidly growing pandemic of diabetes This could threaten tuberculosis control by:- increasing the number of cases increasing the case fatality increasing the risk of relapse after treatment We have a framework for action and now need to implement