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Tuberculosis Then, Now, and Tomorrow: The End TB Strategy

Jonathan Golub, PhD, MPH Johns Hopkins University

Tuberculosis Mortality Then and Now

! “If the importance of a disease for mankind is measured from the number of fatalities which are due to it, then tuberculosis must be considered much more important than those most feared infectious diseases, plague, cholera, and the like. Statistics have shown that one-seventh of all humans die of tuberculosis...” (Robert Koch, 1882)

b Deaths from TB among HIV-positive people are officially classified as deaths caused by HIV/AIDS in the International Classification of Diseases 2

! Caused by Mycobacterium tuberculosis, primarily affecting the lungs

! Transmitted through the air with humans the primary reservoir

! Latent TB infection persists for decades and can reactivate long after it is acquired

! Treatment of TB disease requires combination therapy

Tuberculosis Basics

! Preventive therapy is available for latently infected persons

! A vaccine is available: BCG (Bacillus Calmette– Guérin) ! Efficacy is limited primarily to infants

Tuberculosis Basics

! Two-stage process ! Initial infection with M. tuberculosis ! Progression from infection to disease

Epidemiology of TB Fundamentals

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Infection vs. Disease

Section A

Risk of TB Infection, Disease among Exposed Individuals

Impact of HIV on Risk of TB among Infected Individuals

TB Burden

Section B

TB type Estimated number of cases Estimated number of deaths

All forms of TB 9.6 million

(9.1–10 million) (IR = 133/100,000)

1.5 million* (1.18–1.85 million)

*1.1 million among HIV-negative

HIV-associated TB 1.2 million (12%) (1.1–1.3 million)

330,000 (270,000–390,000)

Multidrug-resistant TB 480,000

(360,000–600,000) 190,000

(120,000–260,000)

The Global Burden of TB—2014

2Source: WHO Global Tuberculosis Report 2015.

Source: WHO Global Tuberculosis Report 2015. 3

Source: WHO Global Tuberculosis Report 2015. 4

Source: WHO Global Tuberculosis Report 2015. 5

Source: WHO Global Tuberculosis Report 2015. 6

Source: WHO Global Tuberculosis Report 2015. 7

Source: WHO Global Tuberculosis Report 2015. 8

Source: WHO Global Tuberculosis Report 2015. 9

32% of TB patients in African region are co- infected with HIV

74% of all HIV/TB co- infected patients live in African region

A New 22?

Source: WHO. 10

The Three HBC Lists—Each with 30 Countries That Will Be Used by WHO 2016–2020

Epidemiologic Basis for TB Control

Section C

! Traditional ! Detection and treatment of cases ! Treatment of latent infection ! Vaccination

! World Health Organization Strategies for TB Control, 1974–1991 ! Passive case detection and treatment ! BCG vaccination of all children at birth ! Evaluation of children who are contacts of cases, with limited use of preventive

therapy

Epidemiologic Basis for Tuberculosis Control

Control Strategies for TB

! Failure to apply biomedical tools broadly ! Weaknesses in health systems

! Inadequacies of existing tools ! Smear detection of cases: ~50% ! Adherence to regimens is very poor ! BCG vaccine does not prevent adult TB

! Changing epidemiological situation ! HIV epidemic ! MDR

! Lack of understanding of best epidemiologic approaches

Tools to Control Tuberculosis—Why Wasn’t TB Eliminated Years Ago?

! Resolution WHA 44.8

! To intensify collaboration with Member States in strengthening NTPs in order to improve case finding and treatment and attain a global target of: 1. Curing 85% of sputum smear–positive patients by 2020 and 2. Detecting 70% of such cases by 2000

44th World Health Assembly (1991)

! Directly observed therapy ! Supervision of all doses of TB medication by a health team member

! Directly observed therapy, short course ! WHO policy for TB control, with programmatic imperatives to strengthen TB control

efforts

DOT vs. DOTS

! Governmental commitment to TB control

! System for registration and follow-up of TB cases

! Reliable supply of TB drugs

! Microbiologic confirmation of TB diagnosis

! Supervision of at least the initial phase of TB therapy

What Is DOTS?

! Established in 2000

! A global movement to accelerate social and political action to stop the spread of TB

! A network of international organizations, countries, donors (public and private sector), governmental and non-governmental organizations and individuals

! Partnership secretariat is housed in WHO

The Global Partnership to Stop TB

Vision A TB-free world

Goal To dramatically reduce the global burden of TB by 2015 in line with the Millennium Development Goals (MDGs) and the Stop TB Partnership targets

Objective Achieve universal access to high-quality care for all people with TB

Objective Reduce the human suffering and socioeconomic burden associated with TB

Objective Protect vulnerable populations from TB, TB/HIV, and drug-resistant TB

Objective Support development of new tools and enable their timely and effective use

Objective Protect and promote human rights in TB prevention, care, and control

Target MDG, Target 6.C: Halt and begin to reverse the incidence of TB by 2015

Target Targets linked to the MDGs and endorsed by the Stop TB Partnership: • 2015: Reduce prevalence of and deaths due to TB by 50% compared with a baseline of 1990 • 2050: Eliminate TB as a public health problem (defined as <1 case per 1 million population per year)

The Stop TB Strategy at a Glance (2006–2015)

9By 2005 at least 70% of people with infectious TB will be diagnosed and at least 85% cured

Stopping TB Now, The Stop TB Partnership

! The Global Plan ! 10-year perspective on the road to 2050 ! Response to country needs for long-term planning ! Outlines financial requirements for sustainability ! A pathway towards the Partnership’s targets for 2015 and goal for 2050 ! A plan with credibility will serve a key advocacy role

What Is the Global Plan?

! Process for developing the Second Global Plan to Stop TB (2006–2015) was: ! Coordinated by Stop TB Partnership secretariat ! Informed by feedback from the first Global Plan ! Guided by the Steering Committee ! Driven by the need to achieve 2015 targets ! Dependent on contributions of the seven Stop TB Partnership working groups ! Based on developing projections of the expected impact and costs of interventions

needed to achieve 2015 targets

Process for Developing the Second Global Plan

! WHO-recommended Stop TB Strategy 1. Pursuing quality DOTS expansion and enhancement

• Political commitment • Case detection through bacteriology • Standardized treatment, with supervision and patient support • Effective drug supply system • Monitoring system and impact evaluation

WHO-Recommended Stop TB Strategy

! Additional components ... 2. Addressing TB/HIV and MDR-TB 3. Contributing to health system strengthening 4. Engaging all care providers 5. Empowering patients and communities 6. Enabling and promoting research

WHO-Recommended Stop TB Strategy (cont.)

! DOTS enhanced ! Expand DOTS, improve quality and effectiveness ! Community care, public-private or public-public mix (PPM), practical approach to

lung health (PAL) ! New labs for culture and drug susceptibility testing (DST)

DOTS

! DOTS-Plus ! Drug susceptibility testing (new and retreatment) ! Treatment (new) or retreatment (previous) MDR-TB

! TB-HIV ! Integration of services: HIV testing for TB patients, with antiretroviral therapy

(ART) and/or co-trimoxazole (CPT) + TB treatment ! The 3 I’s

• Isoniazid preventive therapy for HIV+ patients • Intensified case finding in HIV+ patients in care • Infection control in institutions and clinics

DOTS-Plus and TB-HIV Strategies

Global Plan to Stop TB 2011– 2015

! Launched in Johannesburg, 13 October 2010

! Revised Stop TB Strategy and Global Plan 1. Pursue high-quality DOTS expansion 2. Address TB-HIV, MDR-TB, and needs of the

poor and vulnerable 3. Contribute to health system strengthening 4. Engage all care providers 5. Empower people with TB and communities 6. Enable and promote research

Global Plan to Stop TB 2011–2015

Source: WHO Global Tuberculosis Report 2015. 19

! Five priorities for action ! Reaching the “missed” cases (3 million not in the system) ! Address MDR-TB as crisis ! Accelerate response to TB/HIV ! Increase financing to close resource gaps ! Intensify research and ensure rapid uptake of innovations

Challenges: Priorities for Action 2015

20Source: WHO Global TB Programme.

67th World Health Assembly, Geneva, May 2014

Sixty-seventh World Health Assembly agenda item 12.1: Global strategy and targets for tuberculosis prevention, care and control after 2015. 21

End TB Strategy 2016–2035

! Vision ! A world free of TB ! Zero TB deaths ! Zero TB disease ! Zero TB suffering

! Goal ! End of the Global TB

epidemic

End TB: Vision, Goal, Targets, Milestones

22Source: WHO Global TB Programme.

1. Integrated, patient-centered care and prevention A. Early diagnosis of tuberculosis, including universal drug-susceptibility testing and

systematic screening of contacts and high-risk groups B. Treatment of all people with tuberculosis (including drug-resistant tuberculosis)

and patient support C. Collaborative tuberculosis/HIV activities and management of co-morbidities D. Preventive treatment of persons at high risk and vaccination against tuberculosis

The End TB Strategy—Components

23Source: WHO Global TB Programme.

2. Bold policies and supportive systems A. Political commitment with adequate resources for tuberculosis care and prevention B. Engagement of communities, civil society organizations, and public and private

care providers C. Universal health coverage policy; regulatory frameworks for case notification, vital

registration, quality and rational use of medicines, and infection control D. Social protection, poverty alleviation, and actions on other determinants of

tuberculosis

The End TB Strategy—Components (cont.)

24Source: WHO Global TB Programme.

3. Intensified research and innovation A. Discovery, development, and rapid uptake of new tools, interventions, and

strategies B. Research to optimize implementation and impact and to promote innovations

The End TB Strategy—Components (cont.)

25Source: WHO Global TB Programme.

Desired Decline in Global TB Incidence Rates to Reach the 2035 Targets

Source: WHO Global TB Programme. 26

Desired Decline in Global TB Incidence Rates to Reach the 2035 Targets

Source: WHO Global TB Programme. 27

A Platform for Controlling HIV-Related TB

Section D

! Find the TB that is there ! Prevalent TB is common in PLHIV

! Treat the TB that is found ! Treatment is challenging ! Treatment for M/XDR-TB* is abysmal

! Prevent the TB that hasn’t occurred yet ! Preventive therapy works but isn’t used enough ! Infection control is essential ! Control susceptibility (antiretrovirals)

A Platform for Controlling HIV-Related TB

2*Multidrug and extensively drug-resistant tuberculosis

Find TB

3.3 Million Cases Undetected

! Passive case finding ! Patient-initiated ! Current DOTS model

! Enhanced case finding ! Patient initiated—but following a provider-initiated information campaign

! Active/intensified case finding ! Provider-initiated ! An attempt to detect all cases of a disease in a specific time period or geographic

location

Case Finding Strategies for Tuberculosis

A community randomized trial of two interventions delivered to ~1,200,000 people while strengthening the existing health

systems

! Total population: 962,655 ! Six communities per arm (24 in total)

! ECF (school, ACSM, sputum collection points) ! Household interaction TB patients

! Primary endpoint ! Prevalence of culture+ve TB ! Pop. level (80,000 participants)

• ECF vs. no ECF • Hhd (HH) vs. no HH

! Secondary endpoint ! Community level: TB transmission

• Cohort of school children ! Household level: TB outcomes, TB incidence, HIV incidence

ZAMSTAR: Three-Year Intervention

8Source: Consortium to Respond Effectively to the AIDS/TB Epidemic.

Risk Rate Ratios for Intervention Effect at the Community Level, Comparing Communities with Intervention to Those Without

Source: Consortium to Respond Effectively to the AIDS/TB Epidemic. 9

Source: Dr. E. L. Corbett. (2010). 10

Yield of Active Case Finding by Two Methods in Harare, Zimbabwe

! Detection of cases ! Van = 255/5466 ! D2D = 137/4711

• aRR 1.48 (1.11-1.96)

! Prevalence after six rounds ! Baseline 6.5/1000 ! F/U 3.7/1000

• aRR 0.59 (0.40-0.89)

Source: Corbett et al. (2010 epub). Lancet. 11

Pop. screened/

study type (No.

papers)

Weighted mean NNS (range)

(No. studies)

Risk group screen Low incidence Moderate incidence Medium incidence High incidence

HIV clinic/cohort (N=58)

171 (10.3-390.3) (N=5)

215 (22.7-315.1) (N=4)

37 (1.07-120) (N=20)

58 (2.8-124.2) (N=28)*

Sx screen only vs. other

NNS=64 vs. NNS=42

CXR screen vs. no CXR screen

NNS=46 vs. NNS=48

Cx in diagnosis vs. no cx

NNS=14 vs. NNS=52

Pregnancy/gyn. clinic (N=15)

914 (17.5-3847) (N=5)*

—— 49 (6-143)

(N=5) 36 (4.7-50)

(N=4)

Diabetes (N=10) 57 (27.6-70.6)

(N=3) 2222 (N=1)

28 (24.3-37.0) (N=2)

45 (16.5-53.4) (N=3)

Drug users (N=7) 118 (76.0-149.5)

(N=4) 5

(N=1)* 20 (7.2-19.9)

(N=2) ——

VCT (N=5) —— —— 72 (20.3-119.5)

(N=3) 15 (7.1-17.1)

(N=2)

12*Category includes at least one study that found 0 cases of TB, not included in NNS calculation

Pop. screened/

study type (No.

papers)

Weighted mean NNS (range)

(No. studies)

Risk group screen Low incidence Moderate incidence Medium incidence High incidence

Prisons (N=38) 2341 (18.4-2944.4)

(N=17)* 184 (18.8-190.2)

(N=9) 67 (6.6-152.2)

(N=6) 197 (17.2-221.7)

(N=6)

Contact-tracing (all) (N=145)

206 (2.1-1770) (N=67)*

42 (5.1-354.6) (N=18)

86 (6.5-567) (N=22)*

33 (3-209.3) (N=22)

Contact tracing: households (N=71)

116 (4-337) (N=15)*

42 (8-355) (N=13)

84 (7-568) (N=23)

35 (3-210) (N=20)

Sx screen only vs. other

NNS=124 vs. NNS=32

CXR in screen vs. other NNS=34 vs. NNS=94

Cx in diagnosis vs. other

NNS=92 vs. NNS=51

13*Category includes at least one study that found 0 cases of TB, not included in NNS calculation

! Recommendation 1: household contacts and other close contacts should be systematically screened for active TB

! Recommendation 2: people living with HIV should be systematically screened for active TB at each visit to a health facility

Strong Recommendations

Prevent TB

Section E

! Intensified TB case finding (ICF)

! Isoniazid preventive therapy (IPT)

! Infection control (IC)

The Tree I’s

! Intensified case finding ! HIV-associated TB must be detected early to prevent transmission and mortality

! Isoniazid preventive therapy ! People living with HIV are at great risk for reactivation of latent TB, so the best

strategy is to prevent TB before it can develop

! Infection control ! HIV-infected patients are particularly prone to contacting people with TB in

hospitals and other health care settings

The “3 I’s” Strategy

Impact of ART on Risk of Tuberculosis: A Meta-analysis

Source: Suthar, A. B., et al. (2012). PLoS Medicine. 4

Effects of ART Timing on Death in CAMELIA and on Death or AIDS in Patients with CD4<50 in STRIDE and SAPIT

Sources: Blanc, F. X., et al. (2011). N Engl J Med, 365, 1471–1481; Havlir, D. V., et al. (2011). N Engl J Med, 365, 1482–1491; Abdool-Karim, S., et al. (2011). N Engl J Med, 365, 1492–1501. 5

! We cannot treat our way out of the HIV epidemic with ARVs

! We cannot treat our way out of the TB epidemic with TB treatment

! NEED for TB prevention in HIV-infected!

TB Prevention in HIV-Infected Patients

Treatment of LTBI* in HIV+

*Latent TB infection **Tuberculin skin test Image source: Woldehanna and Volmink. (2006). Cochrane Review.

! Review of 11 randomized trials including, 8,130 HIV+ participants

! Overall reduction in TB of 36%

! Reduction of 62% in people with a positive TST**

! One death averted for every 30 HIV+, TST+ treated

Exposure category Person-years TB cases Incidence rate (per 100 PYs) (95% CI)

Incidence rate ratio (95% CI)

Adjusted hazard ratio* (95% CI)

Naïve 3,865 155 4.01 (3.40–4.68) REF REF

HAART only 11,627 221 1.90 (1.66–2.17) 0.48 (0.39–0.59) 0.41 (0.31–0.54)

Isoniazid only 395 5 1.27 (0.41–2.95) 0.32 (0.10–0.76) 0.57 (0.18–1.82)

Both 1,253 10 0.80 (0.38–1.47) 0.20 (0.09–0.91) 0.24 (0.11–0.53)

TOTAL 17,140 391 2.28 (2.06–2.52)

IPT and HAART: Brazil (~75% on HAART)

8 *Adjusted for age, sex, CD4, prior history of TB, urban/rural Source: Golub, J. E., et al. (2007). AIDS, 21, 1441.

Exposure category Person-years TB cases Incidence rate (per 100 PYs) (95% CI)

Incidence rate ratio (95% CI)

Adjusted hazard ratio* (95% CI)

Naïve 2815 200 7.1 (6.2-8.2) REF REF

HAART only 952 44 4.6 (3.4-6.2) 0.65 (0.46-0.91) 0.36 (0.25-0.51)

INH only 427 22 5.2 (3.4-7.8) 0.73 (0.44-1.13) 0.87 (0.55-1.36)

Both 93 1 1.1 (0.2-7.6) 0.15 (0.004-0.85) 0.11 (0.02-0.78)

TOTAL 4287 267 6.2 (5.5-7.0)

TB Rates by ARV and INH Treatment Status: Johannesburg, South Africa (~25% on ART)

9 *Adjusted for age, sex, CD4, prior history of TB, urban/rural Source: Golub, J. E., Pronyk, P., et al. (2009). AIDS.

TEMPRANO: Immediate vs. Deferred ART Initiation and IPT Delivery for African Patients

Source: TEMPRANO ANRS 12136 Study Group. (2015, August 27). N Engl J Med, 373, 9, 808–822. Epub 2015 July 20. 10

Deferred ART

Deferred ART+ IPT

Early ART+ IPT Early ART

A Trial of Mass Isoniazid Preventive Therapy for Tuberculosis Control

Source: Churchyard, G. J., et al. (2014, January 23). N Engl J Med, 370, 4, 301–310. 11

! To compare the effectiveness of isoniazid preventive therapy (IPT) given on a community-wide basis ...

! ... and compare it to the current standard of TB care among gold miners in South Africa

Aim

Thibela TB: Durability of IPT Effect at Individual Level

Source: Fielding et al. (2012). CROI. 16

Source: Golub et al. (2014). CID. 17

Months from IPT initiation

IPT treatment completed (n=1330)

IPT treatment not completed (n=203)

TB/py IR/100 py (95% CI) TB/py IR/100 py (95% CI)

0-6 months 1/655 0.15 (0.004, 0.85) 0/99 0

7-12 months 4/653 0.61 (0.17, 1.57) 3/97 3.1 (0.64,8.77)

13-18 months 6/647 0.93 (0.34, 2.02) 2/95 2.1 (0.25,7.40)

19-24 months 3/643 0.47 (0.10, 1.36) 1/93 1.1 (0.03,5.85)

Provision of Isoniazid Preventive Therapy (IPT) to People Living with HIV, 2005–2014

Source: WHO Global Tuberculosis Report 2015. 18

Why Is IPT Not Being Implemented/Scaled Up in HIV Infected?

! Concerns/beliefs 1. Concerns regarding r/o active TB

in HIV-infected 2. Fear of creating INH resistance 3. Focus on active cases and

treatment 4. IPT is not needed if you’re on ART 5. IPT is too toxic 6. IPT is too complicated and costly 7. IPT adherence is poor

! Evidence 1. Algorithms exist (being tested);

one drug not “awful” 2. Meta-analysis OR: 1.45 (0.85-2.47) 3. Ignoring reservoir of infected… 4. HAART reduces TB risk 50%; IPT

adds ~1% 5. Long-term IPT adverse events

unclear 6. Operational research required 7. Can be improved (shorter

regimens)

Tools and Strategies for Reducing the Global Burden of TB

! Improved diagnostics (increased case finding) ! Simpler tests ! Find prevalent cases

! Improved therapy (treatment completion) ! Shorter duration regimens ! Compatibility with ARVs ! Effective for MDR/XDR TB

! Preventive therapy ! For high-risk populations, broad use essential

! Reduced susceptibility ! Antiretroviral therapy

! Community-level interventions ! Novel approaches at population level

21 TB infection

TB disease