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Page 1: TB and Diabetes

The double burden of diabetes mellitus and tuberculosis:

interactions and challenges for care__________________________

Anthony D Harries“The Union”, Paris, France

London School of Hygiene and Tropical Medicine

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Structure of the Presentation

• Background Epidemiology

• Collaborative Framework for Care

• Challenges for Care

• Conclusion

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Non-communicable and communicable disease

Diabetes Mellitus (DM)• Disease of antiquity• Three main types:-

– Type 1– Type 2– Gestational DM

• Diagnosis: Blood glucose

• Treatment: diet, drugs, insulin for life

Tuberculosis (TB)• Disease of antiquity• Three main types:-

– Site of disease– Bacterially confirmed – Drug sensitive / resistant

• Diagnosis: Smear for AFB

• Treatment: 6 months of drugs

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Global Burden of DM and TBDiabetes Mellitus: 2012

• 371 million people living with DM

• 10 million new cases per annum

• 4.8 million people died of DM during the year

[IDF Diabetes Atlas 2012]

Tuberculosis: 2012

• 12.0 million people living with TB

• 8.6 million new cases in the year

• 1.3 million people died of TB during the year

[WHO- Global TB Control 2013]

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Global Distribution of DM and TBDiabetes Mellitus: 2012

• South East Asia 19%

• Western Pacific 36%

• Africa 4%

80% in LIC and MIC

[IDF Diabetes Atlas 2012]

Tuberculosis: 2012

• South East Asia 40%

• Western Pacific 19%

• Africa 27%

95% in LIC and MIC

[WHO- Global TB Control 2013]

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India and China [2012]

India

• 63 million DM

• 2.2 million TB per annum

China

• 92 million DM

• 1.0 million TB per annum

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Not diagnosed or notifiedDiabetes Mellitus 2012

• 371 M with DM

• 187 M (50%) undiagnosed

IDF Diabetes Atlas 2012

Tuberculosis 2012

• 8.6 M with TB

• 3.0 M (35%) not notified to NTPs

WHO Global Report 2013

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The global increase in DM

• 2012 371 million with DM

• 2030 552 million with DM

[Diabetes Atlas: International Diabetes Federation, 2012]

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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

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Risk of active TB increased in…

• Extremes of age (infants and elderly)• HIV/AIDS• Other causes of immune suppression (steroids)• Silicosis• Malnutrition• Smoke from domestic stoves or cigarettes• Alcohol and substance abuse• Diabetes mellitus

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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

Some evidence that poor DM control increases TB risk (HbA1c >7% = RR 2.56) [USA,UK, Canada, Mexico, Russia, India, Taiwan, South Korea, Indonesia]

Stevenson et al, Chronic Illness 2007 Jeon and Murray, PLoS Medicine 2008

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Is this biologically plausible?

YES:-

• Animal models – diabetic mice have impaired cell mediated immunity and have higher M.TB loads than normal mice

• Patients with DM have impaired immunity and poor lung defences against M.TB

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WHO estimates for 2012PAF of DM for adult TB No. adults with TB and DM

World 8.3% 1,042,000

South-East Asia 7.6% 423,000

Western Pacific 9.1% 238,000

Africa 5.0% 194,000

Europe 8.5% 94,000

Eastern Mediterranean 9.4% 51,000

The Americas 9.6% 41,000

PAF = population attributable fraction Lonnroth, Lancet Diabetes Endocrinol 2014

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WHO estimates for 2012PAF of DM for adult TB No. adults with TB and DM

India 8.6% 302,000

China 9.6% 156,000

South Africa 8.3% 70,000

Indonesia 5.6% 48,000

Pakistan 6.8% 43,000

Bangladesh 5.5% 36,000

Philippines 6.0% 29,000

PAF = population attributable fractionLonnroth, Lancet Diabetes Endocrinol 2014

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Expert Meeting convened in November 2009

(WHO, Union, WDF, IDF, Academia, Ministries of Health)

Collaborative Framework for Care

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Rationale for a Framework

• Evidence of interaction between DM and TB• Need for guidance on collaborative activities• Evidence weak to support specific guidance• Thus, Provisional Framework• Launched in 2011

• To be reviewed and revised by 2015

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Collaborative Framework for Care and Control of TB

and Diabetes

Launched in August 2011

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The recommendations

http://www.who.int/tb/publications/2011/en/index.html Document available at:

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Three challenges for care

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1. Bi-directional screening

• Screening TB patients for Diabetes (DM) [DM may not be recognised clinically]

• Screening DM patients for active TB [TB may present differently]

Jeon CY et al, TMIH 2010; 15: 1300-1314

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Bi-Directional Screening of TB and Diabetes

Mellitus

China and India

World Diabetes Foundation Support

• National Stakeholders Meeting

• Training for implementers

• Implementation of screening

• Review of activities and data

• National Stakeholders Meeting

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Screen TB patients for DM

Is there is a known diagnosis of DM?

No known diagnosis - screen first with RBG

If RBG ≥ 6.1 mmol/l, screen with FBG

If FBG ≥ 7.0 mmol/l, then diagnose DM and refer to DM care

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Screening TB patients for DM in India

 Indicator TOTAL

Number of patients with TB registered and enrolled 8269

Number (%) with known diagnosis of DM 682 (8)

Number needing to be screened with RBG 7587

Number (%) actually screened with RBG 7467 (98)

Number with RBG >110 mg/dl and needing to be screened with FBG 2838

Number (%) screened with FBG 2703 (95)

Number (%) with FBG ≥ 126 mg/dl (newly diagnosed with DM) 402 (5)

Number (%) with known and newly diagnosed DM 1084 (13)

Number (%) with known / newly diagnosed DM referred to DM care 1033 (95)

India TB-DM study group TMIH 2013: 18: 636-45

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Screening TB patients for DM in

India • directive from India TB Programme to screen TB patients for DM and link them to diabetes care

• directive from India NCD programme to use glucometers to screen TB patients for DM

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Back of the TB Treatment card used in India

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Simple parameters added for routine recording in quarterly TB reports

• Number of TB patients registered

• Number of TB patients screened for DM

• Number of TB patients diagnosed with DM

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Screen DM patients for TB

Screen once a quarter when DM patients come to clinic

Ask: “Has TB been diagnosed during the quarter”

If no, screen for positive symptoms of TB

Refer those with positive symptoms for TB diagnosis and care

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DM patients Q2-2012

Number seen in the quarter 12237

Number diagnosed with TB in the quarter from elsewhere 74

Screened for TB symptoms in the DM clinic in the quarter 6393 (52%)

Positive TB symptom screen 135 (2%)

Referred for TB investigations 128 (95%)

Diagnosed with a new episode of TB 11

Total number with new TB and TB from elsewhere 85

Known to have started or to be on anti-TB Treatment 80

TB cases per 100,000 DM patients seen per quarter 695

Screening of DM Patients for TB in India

India DM-TB study group TMIH 2013; 18: 646-654

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Challenges in screening DM patients for TB

• Diabetes doctors not interested – extra work

• No structured recording systems in DM clinics

• No cohort analysis or public health approach

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Ways forward: i) programme integrationTB Clinic Diabetes Clinic

Peripheral clinic needs integrated DM / TB facilities

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ii) better screening tools

TUBERCULOSISSputum smear microscopy

Xpert MTB/RIF

DIABETES MELLITUSFasting blood glucose

Glycated haemoglobin

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iii) cohort analysis for DM for case burden and treatment outcomes

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2. DM and TB treatment outcomes

• Previous studies in TB patients show that DM is associated with:-– possible delay in sputum culture conversion– increased risk of death– increased risk of recurrent TB

• BUT many limitations to these studies

Baker MA et al, BMC Medicine 2011; 9: 81

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

8 studies: RR 0.8 – 3.2

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

23 studies: Pooled RR 1.85 [1.5-2.4]

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Weights are from random effects analysis

Summary

Heterogeneity I-squared = 0% (0,79)

Wada, 2000

Singla, 2006

Zhang, 2009

Study

Mboussa, 2003

Maalej, 2009

Japan

Saudi Arabia

China

Country

Congo

Tunisia

7/61 (11%)

2/130 (2%)

33/165 (20%)

6/17 (35%)

4/55 (7%)

4/284 (1%)

3/367 (1%)

9/170 (5%)

9/77 (12%)

1/82 (1%)

3.89 (2.43, 6.23)

8.15 (2.46, 26.97)

1.88 (0.32, 11.14)

3.78 (1.87, 7.65)

RR (95% CI)

3.02 (1.24, 7.35)

5.96 (0.68, 51.95)

3.89 (2.43, 6.23)

8.15 (2.46, 26.97)

1.88 (0.32, 11.14)

3.78 (1.87, 7.65)

RR (95% CI)

3.02 (1.24, 7.35)

5.96 (0.68, 51.95)

1.3 1 3.89 15 60

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

5 Studies: Pooled RR 3.89 [2.4 – 6.2]

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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 liver toxicity with TB drugs

• Immune-suppressive effects of DM

• Possible exposure to TB in DM clinics

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But many questions….

• DM control and TB treatment outcomes• 6-months anti-TB treatment – adequate?• Timing of death in DM-TB patients• Reasons for death • Strategies to prevent death• Recurrent TB – reactivation or re-infection?• Integration of DM and TB care

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3. 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

Pfaffenberg et al, 1958 [Germany]

Lesnichii et al, 1969 [Russia]

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Summary: DM-TB is “similar” to HIV-TB

HIV-TB• Increased TB cases• More difficult to

diagnose TB cases• Increased death• Increased recurrent TB• Increased failure

DM-TB• Increased TB cases• More difficult to

diagnose TB cases• Increased death• Increased recurrent TB• Increased failure

Harries AD et al, Int J Tuberc Lung Dis 2011; 15: 1436 - 1444

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Need to tackle the upstream issues

HIV prevention/control• Behaviour• Condoms• Male circumcision• Early use of ART• ART as HIV prevention

DM prevention/control:• Healthy diets• Exercise• Obesity• Early detection of

impaired glucose tolerance

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Summary:Diabetes and Tuberculosis

• Rapidly growing pandemic of diabetes

• This could threaten tuberculosis control by:- increasing the number of cases

increasing case fatality increasing the risk of failure or relapse

• Global framework for collaborative activities exists but we need country-level action