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Tuberculosis in women, infants, children and adolescents – key data, gaps and opportunities Steve Tuberculosis in women, infants, children and adolescents – key data, gaps and opportunities Steve Graham Centre for International Child Health University of Melbourne International Union Against Tuberculosis and Lung Disease (The Union) The Burnet Institute, Melbourne

Are we making progress? Are we making progress?

3 month old twins in Da Nang 3 month old twins in Da Nang

Include the needs of children and adolescents in research, policy development and clinical practices Include the needs of children and adolescents in research, policy development and clinical practices

Proportion of new and relapse TB that were children in 2015 Estimated 1 million Proportion of new and relapse TB that were children in 2015 Estimated 1 million cases of child TB in 2015 - 10. 7% of global caseload - and 210, 000 TB-related deaths in children, 41, 000 of these HIV-infected Child TB represented 6. 3% of all TB notified by NTPs by WHO

Gap in surveillance Incident (new) TB cases Under-diagnosed Under-reported TB case notifications known to Gap in surveillance Incident (new) TB cases Under-diagnosed Under-reported TB case notifications known to the NTP Gap

Reported TB by age in Western Pacific region countries WHO Global TB Report 2016 Reported TB by age in Western Pacific region countries WHO Global TB Report 2016 Philippines Cambodia Wide variability in detection and reporting Papua New Guinea Viet Nam

The challenges of MDR TB in children It is estimated that 25, 000 children The challenges of MDR TB in children It is estimated that 25, 000 children developed MDR TB in 2014 although >90% not detected and treated Dodd PJ, Sismanidis C, Seddon JA. Lancet Infect. Dis 2016 Likely to be as prevalent in children as in adults Often a clinical diagnosis based on contact history Important role for Xpert and Xpert Ultra Treatment outcomes more favorable than for adults Use of injectables causing permanent sensorineural deafness Lack of combination child-friendly formulations Large drug burden if HIV co-infected Children excluded from access to new drugs

Recent mortality estimates for TB in children Jenkins HE, et al. Lancet Infect Dis Recent mortality estimates for TB in children Jenkins HE, et al. Lancet Infect Dis 2016; Dodd P, et al. Lancet Glob Health 2017 An estimated 239, 000 (95% UI: 194, 000 -298, 000) children <15 years died from TB in 2015 Of these, 39, 000 (17%, 95%UI: 23, 000 -73, 000) were HIV co-infected – 31, 000 (79%) in African region 80% of TB-related deaths in children were in young children < 5 years More than 70% in WHO South-East Asian and African Regions More than 96% of deaths occurred in children not receiving treatment Case fatality rate for: - TB in children not receiving treatment: 22% higher in young children < 5 years than 5 -14 years: 44% v 15% - TB in children receiving treatment was 0. 9% - HIV-infected children with TB treatment before ART: 14% - HIV-infected children with TB treatment and ART: : 3. 4%

The global burden of TB in women • 3. 5 million TB cases in The global burden of TB in women • 3. 5 million TB cases in women in 2015 or 34% of total burden • 350, 000 deaths due to TB in HIV-negative women and 140, 000 deaths in HIV-positive women • Prevalence surveys show that case detection rates are higher in women than men • Estimated 216, 000 TB cases in pregnant women annually but did not account for increased risk in pregnancy Sugarman J, et al. Lancet Glob Health 2014

TB in Pregnancy In many high TB burden countries, 10 -20% of girls aged TB in Pregnancy In many high TB burden countries, 10 -20% of girls aged 1519 years give birth each year. Late pregnancy is associated with substantial immunological changes which may increase the risk of TB Pregnancy-related TB tends to present perinatally – last trimester or early post-natal period TB/HIV in pregnancy is associated with negative outcomes for both mother and infant Gupta A, et al. Clin Infect Dis 2007; Mathad J, Gupta A. Clin Infect Dis 2012 UK study found a significantly higher risk of TB in pregnancy and postpartum (up to 6 months) women compared to the same women outside of pregnancy and postpartum period: IRR 1. 95 (95% CI: 1. 24 -3. 07) Zenner D, et al. AJRCCM 2011

TB in adolescents Few data reported specifically on the burden of TB or TB/HIV TB in adolescents Few data reported specifically on the burden of TB or TB/HIV in adolescents – WHO definition: 10 -19 years Under-detection: Study of 5, 004 adolescents (12 -18 years) in Western Kenya: prevalence of confirmed TB – 320/100, 000 prevalence of all PTB – 680/100, 000 compared to case notification rate – 101/100, 000 Nduba V, et al. Int J Infect Dis 2015

Who and where adolescents? “Child” under 15 “Child” 0 -12 “Adult” aged 15+ “Adolescent” Who and where adolescents? “Child” under 15 “Child” 0 -12 “Adult” aged 15+ “Adolescent” aged 13 -18 “Young adult” aged 19– 24 Age groups for reporting to WHO by TB type are 0 -14 years and 15 -24 years No global estimates for the adolescent age group (10 -19 years) “Young child” aged 0 -5 “Older child” aged 5– 9 “Young adolescent” aged 10– 14 “Older adolescent” aged 15– 19 “Young adult” aged 20– 24

Age-related burden of TB in the pre-HIV era Average annual case rate (per 100, Age-related burden of TB in the pre-HIV era Average annual case rate (per 100, 000) 400 300 200 100 0 0 5 10 15 20 25 30 35 Age (years) Comstock GW, et al. Am J Epidemiol 1974; 99: 131 -8 40

Numbers of TB in children and adolescents, South Africa 2012 Smith J, Moyo S, Numbers of TB in children and adolescents, South Africa 2012 Smith J, Moyo S, Day C. South African Health Review 2013/14

Adolescents as a proportion of populations u 10% u 15% u 10% u 20% Adolescents as a proportion of populations u 10% u 15% u 10% u 20% u 15% u 20% u 25%

Challenges for adolescents with TB and TB/HIV • Access to diagnosis • Appropriate health Challenges for adolescents with TB and TB/HIV • Access to diagnosis • Appropriate health service: child or adult • Treatment duration, support and adherence • Stigma of TB and TB/HIV • School and tertiary training attendance • Very limited data on disease burden, treatment outcomes and tolerance – including MDR TB • Co-morbidities e. g. diabetes, smoking, chronic lung disease

TB in the context of maternal, child and adolescent health Graham SM, et al. TB in the context of maternal, child and adolescent health Graham SM, et al. Lancet 2014 TB is an increasingly important cause of morbidity and mortality due to a treatable and preventable infectious disease in infants and young children globally as other infectious causes become less prevalent Presents in young children as pneumonia, meningitis and malnutrition Increased risk of TB in HIV-exposed and HIV-infected children Pregnancy-related TB – impacts maternal, birth and infant outcomes Orphans due to TB – estimated to be around 9 million globally Catastrophic economic costs of TB – families living with TB TB in adolescents – uncertain burden and specific management issues – including in adolescents living with HIV

Risk of TB disease following infection by age Adapted from Marais B, et al. Risk of TB disease following infection by age Adapted from Marais B, et al. Int J Tuberc Lung Dis 2004

Clinical challenges are the diagnostic challenges • Young age • Acute severe pneumonia • Clinical challenges are the diagnostic challenges • Young age • Acute severe pneumonia • HIV-infected • Malnourished • MDR TB

Evolution of global TB strategies The State and Society END TB STRATEGY TB Programme, Evolution of global TB strategies The State and Society END TB STRATEGY TB Programme, STOP TB STRATEGY Providers and Patients DOTS TB Programmes & Care PATIENT-CENTRED CARE AND PREVENTION BOLD POLICIES AND SUPPORTIVE SYSTEMS INTENSIFIED RESEARCH AND INNOVATION Health Systems and Services Community Social and Development Services

Rapid development of diagnostics History Bacteriology Tuberculin Skin Test Chest X-ray 1882 1890 1896 Rapid development of diagnostics History Bacteriology Tuberculin Skin Test Chest X-ray 1882 1890 1896

Diagnostic yield with Xpert (and culture) for pulmonary TB is lower in children compared Diagnostic yield with Xpert (and culture) for pulmonary TB is lower in children compared to adults Most (>50%) child TB cases will still require clinical diagnosis Xpert cannot be used to rule out TB Xpert needs implementation research to inform optimal usage in children Particularly useful for children with presumptive MDR TB

Experience of Xpert yield for presumptive TB in children in programmatic conditions • Diagnostic Experience of Xpert yield for presumptive TB in children in programmatic conditions • Diagnostic yield twice as high as smear microscopy in Indian children with presumptive TB • 12970 presumptive with 1, 107 (8. 5%) TB diagnosed • Of these, 143 (13%) with Rif resistance Combined data: Raizada N, et al. PLo. S ONE 2014 and 2016 • Lower sensitivity (42%) from Xpert in outpatients versus inpatients and from presumptive cases from contact screening Togun T, et al. IJTLD 2015; Detjen AK, et al Lancet Resp Med 2015

Xpert Ultra Compared to current Xpert MTB/RIF: • Increased sensitivity: level of detection 14 Xpert Ultra Compared to current Xpert MTB/RIF: • Increased sensitivity: level of detection 14 cfu/ml versus 114 cfu/ml • Improve detection of rifampicin resistance • Turnaround time 90 minutes Endorsed by WHO on World TB Day 2017

Job aides Job aides

Free on-line training Free on-line training

Introduction of the new FDCs in 2016 o Rifampicin 75 mg + Isoniazid 50 Introduction of the new FDCs in 2016 o Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150 mg (twomonth intensive phase) o Rifampicin 75 mg + Isoniazid 50 mg (four-month continuation phase) • Product attributes: Correct, WHOrecommended doses, Dispersible in liquid, Palatable fruit flavors • The average treatment costs is $15. 54 through the Global Drug Facility (GDF) • First introduced in PNG and Kenya 28

Opportunities for prevention of TB in HIV-infected and HIV-uninfected children Graham SM. Exp Opin Opportunities for prevention of TB in HIV-infected and HIV-uninfected children Graham SM. Exp Opin Resp Dis 2017 • Political will: Role of prevention increasingly recognized within broader strategies such as End TB strategy, Global Plan to Stop TB, NTP strategic plans • WHO LTBI Taskforce: Revision of WHO LTBI management guidelines to include guidelines for LMICs • Shorter, simpler, safer regimens with improved adherence and equal effectiveness to 6 H or 9 H • Evidence emerging from TB endemic settings of integrated, community or family-based approaches for greater reach and improved uptake • Evidence of cost-benefit important and potentially compelling 29

Available data on numbers of eligible child contacts that were started on preventive therapy Available data on numbers of eligible child contacts that were started on preventive therapy in 2015 Only 9 of 30 high burden countries reported data

Global Plan to End TB 2016 -2020 Includes End TB goals for 2025………. • Global Plan to End TB 2016 -2020 Includes End TB goals for 2025………. • 90% or more of children who have been exposed to TB receive preventive therapy • 90% or more of people in close contact with all people diagnosed with TB should be evaluated for TB A “top ten” indicator for monitoring implementation of the End TB Strategy 90% or more of children aged <5 years who are household contacts of TB cases started on treatment for LTBI

PILLAR 1 Test and treat infection Ideal test for infection Point-of-care with high degree PILLAR 1 Test and treat infection Ideal test for infection Point-of-care with high degree of accuracy Distinguishes between infection and disease Blood-based biomarker with immediate result Applicable at primary care or household level Tebruegge M, et al. AJRCCM 2015

Treatment options recommended for LTBI include: 6 H, or 9 H, or 3 HP Treatment options recommended for LTBI include: 6 H, or 9 H, or 3 HP weekly rifapentine plus isoniazid, or 3 RH (Strong recommendation, moderate to high quality of evidence).

Cascade of care: need for M & E tools for contact management • Numbers Cascade of care: need for M & E tools for contact management • Numbers screened • Numbers (%) diagnosed with TB • Numbers (%) eligible for preventive therapy • Numbers (%) received preventive therapy • Numbers (%) completed preventive therapy • Numbers (%) developed TB

Community awareness – and support health worker! 12, 750 posters 554, 400 leaflets Community awareness – and support health worker! 12, 750 posters 554, 400 leaflets

Management of MDR TB contacts • Current guidelines are not specific for treatment of Management of MDR TB contacts • Current guidelines are not specific for treatment of infection • Observational studies suggest that preventive therapy regimen that is determined by drug susceptibility of index case is effective • Randomised placebo-controlled trials of levofloxacin for MDR contacts started in 2016 in South Africa and Viet Nam

Benefit outweighs harm with reasonable confidence • Consequences of developing MDR TB – – Benefit outweighs harm with reasonable confidence • Consequences of developing MDR TB – – Mortality Sequelae – permanent deafness, chronic lung disease Cost to health service Cost to families • Major (but unwarranted) concerns – Safety – Propogation of resistance

Summary of gaps • Accurate epidemiological data remain critical challenges – improving but very Summary of gaps • Accurate epidemiological data remain critical challenges – improving but very limited for MDR TB, adolescents and pregnancy-related TB • Improved diagnostics for disease and infection a research priority • Needs for PK and safety studies and child friendly preparations for second line and “third-line” drugs • Contact screening is an important activity for active case finding and prevention - universal recommendation but wide policy-practice gap • Prevention of MDR TB in contacts compelling • Data of cost effectiveness of preventive therapy for DS and DR TB are critically important and potentially highly compelling • Models of effective community-based or family–integrated delivery

Summary of opportunities • Greater emphasis than previously on TB in children and prevention Summary of opportunities • Greater emphasis than previously on TB in children and prevention within End TB Strategy • Increasing awareness of TB in context of child mortality and in integrated approaches to maternal and child health • Development and roll out of appropriate dosage, child friendly medications has increased focus on TB in young children • • • Targets set for contact screening and preventive therapy Shorter, safer regimens for treatment of infection Prevention of MDR TB in contacts is compelling M & E developing for contact management with reporting Increasing implementation of household contact screening and management under programmatic conditions • Huge scope for operational/implementation research

Thank you “ There are many contributions which the pediatrician can make to a Thank you “ There are many contributions which the pediatrician can make to a TB control program. First the negativism about tuberculosis so prevalent in pediatrics must be overcome…” Edith Lincoln, 1961 Donald PR. Edith Lincoln, an American Pioneer of Childhood Tuberculosis. Pediatr Infect Dis J 2013