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

Structure of the Presentation

• Background Epidemiology

• Collaborative Framework for Care

• Challenges for Care

• Conclusion

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

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]

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]

India and China [2012]

India

• 63 million DM

• 2.2 million TB per annum

China

• 92 million DM

• 1.0 million TB per annum

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

The global increase in DM

• 2012 371 million with DM

• 2030 552 million with DM

[Diabetes Atlas: International Diabetes Federation, 2012]

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

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

Recognised in Roman times that DM increases risk of TB

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

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

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

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

Expert Meeting convened in November 2009

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

Collaborative Framework for Care

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

Collaborative Framework for Care and Control of TB

and Diabetes

Launched in August 2011

The recommendations

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

Three challenges for care

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

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

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

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

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

Back of the TB Treatment card used in India

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

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

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

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

Ways forward: i) programme integrationTB Clinic Diabetes Clinic

Peripheral clinic needs integrated DM / TB facilities

ii) better screening tools

TUBERCULOSISSputum smear microscopy

Xpert MTB/RIF

DIABETES MELLITUSFasting blood glucose

Glycated haemoglobin

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

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

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

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]

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]

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

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

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]

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

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

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