FIOCRUZ

Model of management and interventions for TB control: The Brazilian Experience

Prf. Margareth Dalcolmo, MD, PhD FIOCRUZ MoH

New Delhi, India - June 2013 TB in India: Challenges and Opportunities MSF Internal Workshop Agenda

Declaration of conflict of interest

Principal investigator in Brazil of Phase III Clinical Study with Bedaquiline TMC 207 Janssen

Member of TB MoH Steering Committee

Member of implementation group for the rapid molecular test Gene Xpert for TB diagnostic - MoH / FAP / Bill & Melinda Gates Foundation Member of WHO Task Force Group for introduction of new TB Treatments

Brazil: factsheets
Surface: 8.514.877 km (5th largest country) States: 27 Borders: Argentina, Bolivia, Colombia, French Guyana, Guyana, Paraguay, Peru, Suriname, Uruguay and Venezuela Population (2011): 193.917.083 inhab. (5th largest) Urban population: 84,0% GNP (2012): - Total: US$ 2.2 trillons USD (7th) - Per capita: US$ 11.670 (68rd) - Minimun wage: US$ 339 Social indicators - HDI (2012): 0.73 (85th) - Life expectancy: 73.8 years (102nd) - Child mortality (2010): 19,3/ thousand (106th) - Years of study: 7.2 years (last in South Amrica) Brazilian Health System universal access, free of change (Right of all, duty of the State Federal Constitution)

Highest MDR-TB rates > 10% among new cases > 50% among treated cases

MDRTB: 500.000 casos

XDRTB: 50.000 casos

New cases
14.2 14.2 13.7 13.2 12.3 Estonia Kazakhstan Russia (Tomsk) Uzbekistan Russia (Ivanovo)

Previously treated cases 58.1 56.4 53.3 Russia (Ivanovo) Kazakhstan Lithuania

KZN

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2005. All rights reserved

Countries with XDR TB confirmed cases

Russian Federation

Republic of Korea

South Africa

Netherlands

Lithuania

Peru

Romania

Slovenia

Islamic Republic of Iran

China, Hong Kong SAR

Czech Republic

Bangladesh

Azerbaijan

Argentina

Germany

Ecuador

Armenia

Georgia

Estonia

Canada

Ireland

France

Latvia Japan Brazil Israel Chile Italy

Thailand Portugal Sweden Norway Mexico Poland Spain

USA UK

Based on information provided to WHO Stop TB Department May 2009

TB in Brazil: factsheets and context

70 thousand new TB cases reported in 2012 4,6 thousand deaths in 2010 17th country in burden of disease (one of 22 high burden countries) 111th country in TB incidence rate 4th cause of death among infectious disease TB is a compulsory reported disease

Treatment is fully provided by government and free of charge. Procurement is a federal responsability
Standardized drugs not available in private sector. No conflict between public and private sector

TB in Brazil: Guidelines
Since the introducton of short-course regimen RHZ, in 1980 at countrywide level, all revisions and recommendations are made and published with the agreement with MoH and medical societies. Drug procurement is a federal level responsability

. Treatment is fully provided by government and free of charge first line as well as second line
Standardized drugs not available in private sector. No conflict between public and private sector DOT adopted as a national policy in different modalities Quality control of all drugs regularly done

TB incidence rate. Brazil, 1990-2012.*

Per 100 thousand inhab.

Decrease = 30,2% (average 1,4% per year)

70 60 50 40 30 20 10 0
36.1 51.8

Year

Source: MS/Sinan and IBGE. *preliminary data

Epidemiological Antecedents
Consistent decrease of incidence and mortality rates since mid 90s
Stability of operational indicators as cure and default rates in undesirable levels One fourth of TB patients are enrolled in the Unified Register for government social support programs (Cadastro nico) 14% of TB cases are beneficiaries of Bolsa Famlia

TB mortality rate. Brazil, 2000 - 2010

Per 100.000 inhab.

5
4
3.3 3.1

3
2 1 0 2000 2001

3.0

2.8

2.8

2.6

2.6

2.5

2.6

2.5

2.4

2002

2003

2004

2005
Year

2006

2007

2008

2009

2010

Source: MS/Sinan and IBGE.

TB cure and default rates. Brazil, 2001- 2011

%

100 90 80 70 60 50 40 30 20 10 0

70.4

70.4

72.4

73.0

74.7

74.6

74.6

74.5

74.3

73.4

71.6

10.8

9.8

9.5

9.3

9.3

9.2

10.3

10.4

11.2

10.5

9.8

2001

2002

2003

2004

2005 cura

2006

2007

2008

2009

2010

2011

abandono

Year

Source: MS/Sinan and IBGE. *preliminary data

Vulnerable Populations (RR comparing with general population)

Afrodescendent population: 1,5 times*

Indigenous population: 3 times* Prisoners: 28 times* PLHA: 35 times* Homeless: 67 times**

* Source: MS/Sinan and IBGE ** Source: Adorno 2010

Relationship between family income (in minimum wages per capita) and TB ocurrence. Brazil, 2008
MW <1/4 SM MW 1/4 a 1/2 SM MW 1/2 a 1 SM MW 1 a 2 SM MW 2 a 3 SM

1.00

1.00 0.76

0.74

0.76
0.59

0.10
Family income (per capita)

Source: PNAD, 2008. Minimum Wage = R$678 (US$339)

OR tuberculosis

Thinking about TB control in Brazil

According to Styblos rule, to control TB it would be enough to detect 70% of BK+ cases and cure, at least, 85% of them. Several respected researches have questioned this rule, pointing that in different scenarios this two programmatic indicators won`t push down incidence trend until reaches <1/100 thousand inhab And several other have establish the relationship between social economic variables and tuberculosis So what should we do?...

Brazilian Social Protection System

Based on three pillars:
National Health System (SUS) Social Security (National Social Insurance Institute - INSS) National Social Assistance Policy (SUAS) Brazilian social security system covers the entire population against all basic social risks under the ILO Social Security (Minimum Standards) Convention (No. 102), 1952.

Social Security (INSS)

Contributory and requires compulsory affiliation (except for retirement) The social insurance system covers individuals in old age, those with disabilities and survivors. In addition, it provides maternity coverage, involuntary unemployment protection and others INSS survey on infectious diseases that most cause insurance for been away from work in 2012: Tuberculosis has been the disease among infectious ones that most causes payment of sickness benefits granted to formal workers by social security: 12,997 cases, representing 31.4% of the number of sickness benefits by DIP

Social Assistence Policy (SUAS)

A non-contributory public policy to provide cash benefits and services to populations living in poverty, in need, or in a condition of social vulnerability Social assistance is responsible for ensuring the following securities: income, shelter, coexistence, autonomy and the survival of circumstantial risks Currently, there are 19.5 million households (around 80 millions people) enrolled in Unified Register for government social support program (Cadnico)

Cadnico (Unified Registry): key features

Instrument to collect data to identify and characterize the poor families in Brazil Target population: families with per capita income of 12 minimum wage (US$170.00) up to three minimum wages (US$1,015.00) Purpose: identifying the characteristics of poor families and their individual members through the Social Identification Number (NIS); producing socioeconomic diagnosis of low-income families in Brazil, serving as an input for public policies in all levels of government Types of information about families enrolled: characteristics of household, family composition, civil identification, educational level, employment status, labor market situation of each family member, income and total household spending Transparency and control: auditing by crossing administrative databases of the federal government; biennial review of the socioeconomic situation of families registered; control by outside agencies and social control agencies

Bolsa Famlia Programme (BFP)

Conditional cash transfer policy focused on poor and extremely poor families Immediate relief from poverty Poor families per capita monthly incomes range from US$ 35 to US$ 70; the extremely poor families per capita monthly income is below US$ 35 (based on World Bank US$1,25/day) Conditionalities as a tool for achieving familie`s commitment with attendance to health and education services and enforcing the supply of services for the poor population Funding of financial benefits: Federal Government budget. Number of beneficiaries of BFP: 13,3 millions Fiscal Impact of BFP: 0,46% of GDP - US$ 10 billion

Bolsa Famlia Programme Social Outcomes

Reduction in income inequality
21% of the reduction achieved in income inequality was due to BFP (2004-2006). Soares et alii, 2006. Extreme poverty BFP explains 18% of the reduction in the poverty gap Soares and Satyro, 2009. In 2009, 4.3 million out of 12.4 million beneficiary families have crossed the extreme poverty line (US$35 per capita monthly) by receiving the financial benefits Senarc, 2010.

Bolsa Famlia Programme Health Outcomes Impacts on health Increase of child immunization rates (15-25%, according to the vaccine).
Beneficiary pregnant women have 1.5 as many pre-natal doctor attendances as non-beneficiaries with the same social and economic profile Probability of being born full term is 14.1% higher for children in families that receive the benefit
Source: (Bolsa Familia Impact Evaluation Research, 2010)

Political Commitment

Brazilian federal budget (US$) for TB, 2000-2012*

US$ $ 90,000,000.00 $ 80,000,000.00 $ 70,000,000.00 $ 60,000,000.00 $ 50,000,000.00 $ 40,000,000.00 $ 30,000,000.00 $ 20,000,000.00 $ 10,000,000.00 $ 0.00

Source: NTP Brazil

Improvement of social indicators in Brazil in recent years

Over the last few years, there was a significative reduction of the population living under conditions of poverty. Poverty in Brazil decreased 67% and 35 million people left the poverty line since 2004 This outcome was the result of the economic growth and political decisions Highlights: the increase of the number of jobs and it s formalizations, the real valuation of the minimum wage, the extention and consolidation of conditioned income transfers programs (Bolsa Famlia, Benefcio de Prestao Continuada) and credit expantion However, in spite of this recognized effort, 16,2 million people still live under conditions of extreme poverty

Policies in the Ministry of Health & advances

Participation at National Health Council

(the highest health forum in country)

Recommendation # 003 of March 17th 2011 National Health Council

"It is recommended that the Ministry of Health: joined with other areas of the Federal Government, with the participation and support of social movements, the National Congress and institutions from other sectors, the creation and maintenance of social benefits for people with tuberculosis, so as to increase treatment adherence and reduce abandon rates. "

Resolution # 444 of the National Health Council, July 6th, 2011

Decided: (...) 11. Develop actions and strategies that consider the needs of impoverished communities, the afrodescendent population, the homeless people, prisoners and indigenous population and people living with HIV/AIDS in order to improve TB control among these populations. 12. To establish an intersectoral committee with the participation of civil society, to develop joint actions in order to address social determinants related to TB, especially those who have direct relationship with poverty and poor access. () I ratify the National Health Council resolution # 444 of July 6th, 2011. Alexandre Rocha Santos Padilha Minister of Health

Important achievements of 2012

1. Creation of the Parliamentary Front against TB, at the National Congress, to promote the discussion on TB control in the Brazilian parliament 2. Supply of social incentives for TB patients by 85% of States and municipalities (food packages, travel vouchers, free of charge to community restaurants) 3. Research funding and development in social protection and TB in partnership with universities (UFBA, UFES, UFRJ, UNB, Fiocruz)

4. Creation of the special committee at the National Congress to study and produce reports in diseases of poverty
5. Linkage between TB information system (Sinan-TB) and the Unified Register for government social support programs (Cadnico)

Social Determinants
Linkage between Sinan (2011) x Cadnico: Out of 73.833 TB new cases 25.1% live in poverty 13.9% (10,278) of new TB cases receive Bolsa Famlia

First general outcomes and TB impact

Among cases beneficiaries of BF only 17.8 had more than eight years of education
And only 36.1% had any kind of work in the previous year before enrollment in Cadastro nico For those who worked the amount received during this period (one year) had a median of US$900 (min US$1 and max of US$21,000) Cure rate in cases recipients of BF was 6% greater than in the all other cases

Source: MS/Sinan and Cad.nico

Treatment outcome of TB new cases acording to receipt of benefit. Brazil, 2011*

% 90
77.7 71.8

80
70 60 50 40 30 20

10
0 Cure BF
Source: MS/Sinan and Cad.nico

7.7

9.5
3.8

9.2

Default Defoult Not BF

Death

TB new cases under DOTS according to receipt of benefit. Brazil, 2011*

% 50 49 48
49.5

47
46 45 44 43 42 41 BF Not BF
44.1

Source: MS/Sinan and Cad.nico

In conclusion: Next steps in social determinants

To evaluate the impact of Bolsa Famlia Programme in TB treatment outcome To uphold the special committee for study in diseases of poverty, at the National Congress
To increase research partnership in social protection and TB

To strengthen the intersectoral actions both at state and municipality levels

Social income transfer for TB patients living under social vulnerability linked to adherence to the treatment.

Rationale of changes of TB guidelines done in Brazil in 2009

Justification

MoH, Medical societies, nurse council, and civil society Systematic revision

TB Treatment System in Brazil Changes done in 2009

Retreatment post cure or abandon All cases with culture and DST 2RHZE/4RH

Treatment only in references FAILURE

Failed or TBXDR individualized regimen with 5 drugs

2RHZE/4RH Culture, ID & DST at end of 2nd month when smear

Pediatric regimen 2RHZ/4RH Dispersible tablets Until FDCs 4 For meningitis 2RHZE/7RH + steroids

6SZELvf/TZ AM alternative to SM 18 - 24 mo duration

CM ETH CLZ PAS

TB Brazil

National Guidelines 2010

Failed MDR or TBXDR

Individual regimen with 5 drugs Failure and MDR regimen

6 S Z E Lvf / TZ
AM alternative to SM 18 - 24 months duration

Capreomyicin Ethionamide Clofazimine PAS +1

Example of Brazil
Developing and implementing a full platform for DR-TB program management with a comprehensive patient follow-up module integrated with a secondline drug management system On line
Helio Fraga MDR-TB Clinic

DR-TB Diagnosis and Information

Suspected cases in primary health facilities or hospitals
Culture and drug susceptibility test Confirmed or probable cases Regional DR-TB Reference Center Case Reporting System Case validation National Reference Level for DR-TB control (MoH)

DR-TB Treatment and information

Case validation in the system by Central Level (MoH) Quantity medicines calculated by the system for each case Shipment to Regional Reference Center (3 months stock +1 month buffer) Case treatment Quarterly Follow-up Reporting to the system

DR TB reference units in Brazil: 132 em 2013

DR-TB Multidisciplinary Teams integrated within one system:

Medical doctors: clinical and treatment perspective

Nurses: operational and case management perspective Social assistant: patient support perspective / adherence Health Community Agent: link with community / adherence perspective Pharmacist: Drug Management / Supply perspective Laboratory: lab results perspective

Enhanced TB Strategy Post-2015 Targets (draft) : 75% reduction of deaths

(and 40% reduction in incidence by 2025)

Innovative TB Care
Rapid diagnosis of TB including universal drug-susceptibility testing ; systematic screening of contacts and high-risk groups Treatment of all forms of TB including drug -resistant TB with patient support Collaborative TB/HIV activities and management of comorbidities Preventive treatment for highrisk groups and vaccination of children

Bold policies and supportive systems

Government stewardship , commitment, and adequate resources for TB care and control with monitoring and evaluation Engagement of communities , civil society organizations, and all public and private care providers

Intensified Research

Discovery, development and rapid uptake of new diagnostics, drugs and vaccines

Regulatory framework for vital registration, case notification, drug quality and rational use, and infection control
Universal Health Coverage, social protection and other measures to address social determinants of TB

Operational research to optimize implementation and adopt innovations

Advances in TB treatment Where are we ?

After 40 y post Rifampin .....

Guidelines, clinical studies, new drugs perspectives

Approved drugs for TB in 70 years

1940-9 SM, PAS

1950-9
1960-9

INH, PZA, CS, ETH

CM, EMB, RIF

1970-9
1980-9 1990-9 2000-9 Rifabutina, Ciprofloxacin* Rifapentine Momentum

*not approved for TB

TB drugs: state of the art for clinical use 2012

Drug Class Producer Status

Rifapentine Rifamycin Sanofi-Aventis Fase 3 Moxifloxacin Fluoroquinolone Bayer/GA Fase 3 Gatifloxacin Fluoroquinolone BMS Fase 3 TMC-207 Diarylquinolone Janssen Fase 2b OPC-67683 Imidazooxazole Otsuka Fase 2b PA-824 Imidazooxazine GATB Fase 2a SQ-109 Ethylene Diamine Sequella Fase 1 PNU-100480 Oxazolidinone Pfizer Fase 1 AZD-5847 Oxazolidinone AstraZeneca Fase 1

How we are participating in research studies in Brazil ?

BASIC RESEARCH

New roots to isoniazid and ethambutol

NITROIMIDAZOLIC and OXAZOLIDINONES

DESCOBERTA NOVO FRMACO

PRE CLINICAL EVALUATION

EBA studies
CLINICA FASE I

DIARYLQUINOLIN

CLINICA FASE II

Rifapentin / Moxifloxacin
CLINICA FASE III

FLUOROQUINOLONES

Bedaquilin

REGISTRO

Post marketing study Phase IV Terizidon

ACESSO AO PACIENTE

In conclusion: Next steps in social determinants

To evaluate the impact of Bolsa Famlia Programme in TB treatment outcome To uphold the special committee for study in diseases of poverty, at the National Congress
To increase research partnership in social protection and TB

To strengthen the intersectoral actions both at state and municipality levels

Social income transfer for TB patients living under social vulnerability linked to adherence to the treatment.

In conclusion: Next steps in TB control

To implemment rapid molecular diagnostic using Gene X-pert in all municipalities with > 200 cases / year

To provide culture , ID and DST to ALL retreatment cases

To go on with transference of tecnology for FDC production (Lupin and Farmanguinhos)

To implement farmacovigilance in all reference units

To assure more civil society participation To obtain the part of the second line drugs through GDF To start compassionate use for Bedaquiline for XDR cases

Acknowledgements FIOCRUZ - Brazil and Ministry of Health

Dr Draurio Barreira NTP Coordinator and staff

Dr. Joel Keravec and Project MSH - Brazil

WHO/Stop TB Department - Task Force Expert Group