UNIVERSIDADE FEDERAL DE MATO GROSSO DO SUL

PROGRAMA DE PÓS-GRADUAÇÃO EM DOENÇAS INFECCIOSAS E

PARASITÁRIAS

EVERTON FERREIRA LEMOS

AVALIAÇÃO DE ESTRATÉGIAS PARA O CONTROLE DA TUBERCULOSE NAS

PRISÕES BRASILEIRAS

CAMPO GRANDE
2019
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EVERTON FERREIRA LEMOS

AVALIAÇÃO DE ESTRATÉGIAS PARA O CONTROLE DA TUBERCULOSE NAS

PRISÕES BRASILEIRAS

Tese apresentada como requisito para a

obtenção do título de Doutor pelo Programa
de Pós-Graduação em Doenças
Infecciosas e Parasitárias da Universidade
Federal de Mato Grosso do Sul, sob
orientação da Prof Dr Julio Henrique Rosa
Croda e Co-orientação da Profª. Dra
Crhistinne Cavalheiro Maymone
Gonçalves.

CAMPO GRANDE
2019
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FOLHA DE APROVAÇÃO
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AGRADECIMENTOS

Hoje, após quatro anos de muito aprendizado, tenho muita “gratidão” a todos que
fizeram parte desta serene conquista. O ato de agradecer é sem dúvida um gesto de
humildade, pois nossas conquistas são alcanças e fortalecidas na união de grupos,
pois precisamos um do outro para podermos vencer. A nossa caminhada não é
sozinha!
Desta forma, agradeço:
À Deus e a Nossa Senhora, que com sua Luz me guiam com muita sabedoria para
trilhar o caminho com humildade, responsabilidade e resiliência.
Pai e Mãe como base, esteio e refúgio. Agradeço pelo amor e os ensinamentos
éticos, pois esta base fez de mim a pessoa que me tornei hoje, com a essência dos
seus ensinamentos. Meus queridos irmãos, avó, sobrinha e cunhado; vocês
acreditaram e apoiaram na minha escolha, hoje mais uma etapa acadêmica finaliza,
e esta vitória é dedicada também a vocês!
A minha amada, e eterna namorada Glauciely, pela força transmitida, pela paciência
e pelo Amor demonstrado em todo o caminho que já percorremos juntos, e ainda por
todo sonho e propósito de vida juntos.
Ao meu Orientador Dr Julio Croda pela confiança depositada, incentivo,
oportunidade de trabalhar em seus projetos, e por ter contribuído para meu
crescimento profissional e pessoal.
A minha Co Orientadora Dra Crhistinne Maymone, que incansavelmente contribuiu
significativamente a esta produção. Gratidão por fazer parte da minha história e do
nosso crescimento, pois apredemos juntos e crescemos juntos.
A UFMS, Faculdade de Medicina e ao Programa de Pós Graduação em Doenças
Infecciosas e Parasitárias, uma instituição pública de qualidade que depositou em
mim a confiança em cumprir as exigências acadêmicas e científicas e oportunizou
meu crescimento.
A Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), por
financiar por meio de Bolsa Social a execução deste trabalho.
Ao nosso grupo de Pesquisa, que bravamente tem enfrentado os desafios de
combater, inovar e construir o conhecimento científico em Tuberculose nas prisões
brasileira e divulgar esse conhecimento ao mundo. Em especial agradeço as minhas
amigas Enfermeiras Andrea e Dayse, pois desde 2013 estamos juntos nesta batalha.
A grande equipe do Sistema Prisional, que nos acolheram e fizeram nosso projeto
fazer parte da rotina de trabalho de cada servidor penitenciário. Em especial, alguns
nomes que gostaria de mencionar, Dr Maurício, Dra Maria de Lourdes (Chefia de
Saúde - AGEPEN), Enfª. Renata Terumi, Guiomar, Sarlete, Denise, Vagner,
Enfª.Ludmila, Maria José e Enfª Christiane, vocês nesses últimos quatro anos,
estiveram presentes em minha vida.
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Aos meus grandes amigos, que vivenciaram os meus passos desde a Graduação
até o Doutorado, sem dúvida faltariam espaço nesta tese para pontuar cada um, mas
sintam-se agradecidos. Menciono a Prof. Dra Dulce Ribas, que me Iniciou à Pesquisa
em 2009 com o Pibic - CNPQ voluntário, dedico a minha conquista de hoje de forma
muito especial, com eterna gratidão aos seus ensinamentos.
Não poderia deixar de mencionar, alguns nomes: Dras. Anamaria, Claudia Volpe,
Sandra Leone, Adriana Negri e toda equipe Hospital Dia, aprendi muito, e sou
eternamente grato, pois vocês fizeram parte da minha história. À Sandra Leone,
gratidão, pelo cuidado, carinho e oportunidade de aprendizagem, possibilitou a
capacitação na aplicação e leitura de Teste Tuberculínico, que sem dúvida fez
diferença nesta tese.
Ao Prof. Dr.Tietê, que nos permitiu profunda reflexão no conhecimento.
A consolidação deste trabalho não seria possível sem a ajuda e contribuição de
inúmeras pessoas, por isso, gostaria de expressar minha eterna gratidão e apreço a
todos que fizeram a diferença para que esse projeto se tornasse realidade.
Muito obrigado a todos.
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Tudo que um sonho precisa para ser realizado é você

acreditar que é capaz de torná-lo possível.
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RESUMO

Introdução/Objetivo: A incidência de tuberculose (TB) nas prisões é 25-50 vezes

maior do que a comunidade. É de relevância na saúde pública avaliar as estratégias
para o controle da TB nas prisões no contexto da nova estratégia da Organização
Mundial da Saúde para redução da doença e óbitos até 2035. Materiais e Métodos:
Estudo realizado utilizando duas etapas metodológicas. A primeira consistiu numa
coorte prospectiva de 2013 - 2014 de 12 prisões estaduais, nas cinco maiores
cidades de Mato Grosso do Sul, para avaliar as taxas de infecção e incidência da
doença e impacto do rastreamento anual. Na segunda etapa, utilizamos dados
secundários (SINAN, 2006-2015 e o Sistema Integrado de Gestão Operacional -
SIGO, 2005-2014) realizando modelagem matemática para simular a ocorrência da
transmissão da TB entre presos, ex-presos e a comunidade e propor melhores
estratégias de controle da doença. Resultados: Na etapa 1, de 7.221 presos nas 12
prisões, recrutamos 3.771. Após 1 ano, 1.422 participantes permaneceram
encarcerados na mesma prisão. Este subconjunto compreendeu a coorte
prospectiva em que as conversões do Teste Tuberculínico (TT) e a incidência de TB
foram avaliadas. Encontramos um risco anual de infecção latente (ILTB) de 26% (IC
95%: 23 ± 29%) e incidência de TB ativa de 1.275 (IC 95%: 760 ± 2.020) por 100.000
habitantes. Casos identificados pelo rastreio ativo eram menos susceptíveis de
serem bacilíferos do que os detectados passivamente (10% vs 51%). Não houve
redução da incidência da doença entre os indivíduos rastreados ativamente versus
aqueles não rastreados (1,27% vs. 1,69%, p = 0,95). A conversão de TT e a
incidência de TB ativa foram maiores no sexo masculino do que no feminino
mulheres (28% versus 10%, p <0,01 e 1,94% versus 0,53%, respectivamente, p =
0,18). Na etapa 2 obtivemos dados de encarceramento (n = 42.925) e os casos de
TB (n = 5.643) referentes ao período de 2007 a 2013 no estado. Foram combinadas
as bases de dados de privados de liberdade e TB e estimadas a incidência de TB, a
partir do momento de entrada e saída da prisão, usando modelos de riscos
proporcionais de Cox. Durante a prisão, as taxas de TB aumentaram de 111 casos
por 100.000 pessoas-ano na entrada para um máximo de 1.303 por 100.000
pessoas-ano, em 5,2 anos. A incidência de TB foi de 229 por 100.000 pessoas-ano,
que declinou para 42 por 100.000 pessoas-ano após 7 anos. Com esses dados, foi
elaborado um modelo comportamental de transmissão da TB e encarceramento e,
foram avaliados os efeitos de intervenções na incidência de TB, na prisão e na
comunidade. Foram identificas, através da modelagem matemática, 5 estratégias de
controle de TB nas prisões: rastreamento da TB na entrada e saída da prisão,
tratamento da ILTB com isonizada, busca melhoria de 25% na taxa de detecção de
casos passivos e campanhas anuais de detecção de casos ativos. Conclusões: A
alta taxa de encarceramento e movimento combinado com alta taxa de ILTB, tornam
as prisões reservatórios e amplificadores importantes. Apenas um rastreamento
anual não reduziu o risco de doença subsequente em doze prisões brasileiras,
provavelmente devido a uma força extremamente alta de infecção. Caso sejam
combinadas as cinco estratégias, prevê-se a diminuição da incidência de TB nas
prisões em 79,2% (IC95%: 70,2%, 95,6%) e em 40,0% (IC95%: 36,1%, 44,3%) na
população geral em 10 anos.

Palavras-chave: Prisões, tuberculose, controle, modelagem matemática.

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ABSTRACT

Introduction / Objective: The incidence of TB (TB) in prisons is 25-50 times higher

than the community. It is of public health relevance to evaluate strategies for the
control of TB in prisons in the context of the World Health Organization's new strategy
for ending tuberculosis by 2035. Materials and Methods: This study was carried out
in two stages, the first stage consisted of in a prospective 2013-2014 cohort of 12
state prisons in the five largest cities of Mato Grosso do Sul to evaluate infection and
disease rates and impact of annual screening. In the second phase, the study with
secondary data (SINAN, 2006-2015 and the Integrated Operational Management
System - SIGO, 2005-2014) made possible a mathematical modeling to simulate the
occurrence of TB transmission among prisoners, ex-prisoners and the community
and propose better strains of disease control. Results: In stage 1, of 7,221 prisoners
in 12 prisons, we recruited 3,771. After 1 year, 1,422 participants remained
incarcerated in the same prison. This subset comprised the prospective cohort in
which Tuberculin Test (TT) and TB incidence conversions were evaluated. We found
an annual risk of tuberculosis infection of 26% (95% CI: 23 ± 29%) and incidence of
active TB of 1.275 (95% CI: 760 ± 2020) per 100,000 inhabitants. Cases identified by
active screening were less likely to be positive smear microscopy than passively
detected (10% vs 51%). There was no reduction in disease incidence among actively
screened vs. untraced individuals (1.27% vs. 1.69%, p = 0.95). Conversion of TT and
incidence of active TB were higher in males than in females (28% versus 10%, p
<0.01 and 1.94% versus 0.53%, respectively, p = 0.18). In step 2 we obtained
incarceration data (n = 42,925) and cases of TB (n = 5,643) for the period from 2007
to 2013 in the state. Databases of prisoners of liberty and TB were combined and TB
incidence rates estimated from the time of entry and exit of the prison using Cox
proportional hazards models. During prison, TB rates increased from 111 cases per
100,000 person-years at entry to a maximum of 1,303 per 100,000 person-years in
5.2 years. The incidence of TB was 229 per 100,000 person-years, which declined to
42 per 100,000 person-years after 7 years. With these data, a behavioral model of
TB transmission and incarceration was elaborated and the effects of prison
interventions on the incidence of TB in prison and community were evaluated.
Conclusions: The high rate of incarceration and movement combined with high
infection rates make reservoirs and amplifiers important. Only one annual screening
did not reduce the risk of subsequent disease in twelve Brazilian prisons, probably
due to an extremely high infection force. It was evaluated through mathematical
modeling 5 strategies of TB control in prisons: TB screening at the entrance and exit
of the prison, treatment for ILTB with isonized, 25% improvement in the rate of
detection of passive cases and annual campaigns of detection of active cases. If the
five approaches are combined, the incidence of TB in prisons is expected to decrease
by 79.2% (95% CI: 70.2%, 95.6%) and 40.0% (95% CI: 36.1%, 44.3%) in the general
population in 10 years.
Keywords: Prisons, TB, control, mathematical modeling.
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LISTA DE ABREVIATURAS

4R 4 meses de terapia com rifampicina

6H 6 meses de terapia com isoniazida
DOTS Direcy Observed Treatment Strategy
Hab. Habitantes
ILTB Infecção Latente pelo Mycobacterium tubeculosis
IST Infecções Sexualmente Transmissíveis
MDR-TB TB – Multidrogaresistente
MTB / RIF Micobacterium tuberculosis/ resistência Rifampicina
OMS Organização Mundial de Saúde
PNCT Programa Nacional de Controle da Tuberculose
PPL População Privada de Liberdade
SIAPEN Sistema Integrado de Administração do Sistema Penitenciário
SIGO Sistema Integrado de Gestão Operacional
SINAN Sistema de Informação de Agravos de Notificação
SR Sintomático Respiratório
TB Tuberculose
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SUMÁRIO

1 INTRODUÇÃO......................................................................................... 11
2 REVISÃO DE LITERATURA................................................................... 13
3 OBJETIVOS............................................................................................. 23
3.1 Geral........................................................................................................ 23
3.2 Específicos............................................................................................. 23
4 MATERIAL E MÉTODOS........................................................................ 24
4.1 Linha de base da pesquisa.................................................................. 24
4.2 Condução metodológica da Etapa 1.................................................... 25
4.3 Condução metodológica da Etapa 2.................................................... 26
4.2 Aspectos éticos...................................................................................... 27
5 RESULTADOS......................................................................................... 28
5.1 Artigo 1.................................................................................................... 29
5.2 Artigo 2.................................................................................................... 40
6 DISCUSSÃO........................................................................................... 62
7 CONCLUSÃO.......................................................................................... 68
REFERÊNCIAS....................................................................................... 69
ANEXO A................................................................................................ 74
ANEXO B................................................................................................ 83
ANEXO C................................................................................................ 92
ANEXO D................................................................................................ 95
APENDICE A.....…………………………………………………………….. 101
APENDICE B.....…………………………………………………………….. 103
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1. INTRODUÇÃO

A doença tuberculose (TB) ainda se constitui como desafio na saúde pública,

ocasionando mortes prematuras e quadros incapacitantes em crianças e adultos. Embora
medidas sejam tomadas em âmbito mundial e nacional, o declíno da doença é lento e alguns
contextos persistem com elevada incidência.
A População Privada de Liberdade (PPL) compõe uma das subpopulações de alto risco
para a TB, apresenta dados preocupantes, uma vez que muitos estudos já apontam elevada
incidência de doença ativa em comparação a população geral de várias partes do mundo. Ao
analisar as características dessas PPL, tem-se a composição de uma população jovem,
pouca escolaridade, oriunda de comunidades carentes e com maior incidência de infecção
pelo HIV e encarceramento prévio.
Além das características pessoais, há também as condições em que estão expostas
dentro das prisões: celas superlotadas, mal ventiladas, más condições de higiene, nutrição
inadequada e exposição frequente ao Mycobacterium tuberculosis. Estas particularidades do
ambiente nas prisões apresentam-se como desafios para a execução das ações do programa
de controle de TB e demais implementações que promovam melhores condições de vida e
saúde.
Apesar da alta carga de TB, existem poucos dados sobre as taxas de conversão dentro
das prisões, que seriam fundamentais na avaliação da contribuição relativa de transmissão
recente nesses cenários.
Em 1991, a Organização Mundial de Saúde (OMS) lançou a estratégia Directly
Observed Treatment Short-Course (DOTS) pautada em cinco pilares: compromisso político;
detecção de casos por baciloscopia; esquema de tratamento padronizados e tratamento
diretamente observado (TDO); suprimento regular e ininterrupto dos medicamentos
padronizados e, sistema de registro e notificação. A iniciativa almejava a padronização de
medidas que colaborassem para a reversão do quadro de epidemia mundial.
No entanto, o observado tem sido um lento declínio da incidência da doença, estimado
em 2% ao ano na última década (BRASIL, 2011a; 2018). O Brasil apresenta a terceira maior
população carcerária do mundo, com mais de 700 mil encarcerados (taxa de encarceramento
de 311,1 por 100 mil habitantes), e as taxas de doença ativa entre essa população excedem
> 1.000 casos por 100.000 habitantes (DEPEN, 2018; RIBEIRO MACEDO et al., 2013).
Além da preocupação com a incidência da doença na PPL, outro aspecto tem sido
amplamente estudado, o da reintegração desta população na comunidade. A transmissão da
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doença pode se tornar um relevante problema de saúde pública, uma vez que já há evidências
de circulação das cepas M.tuberculosis em casos como esses (SACHI et al., 2015; WARREN
et al., 2018).
Frente a esta situação, justifica-se esta tese pela necessidade de identificar estratégias
efetivas para o controle da TB que possam contribuir para implementação de políticas
públicas já vigentes, como a Estratégia End TB da OMS e o Plano Nacional de combate à TB.
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2 REVISÃO DE LITERATURA

2.1 Tuberculose: epidemiologia, diagnóstico e tratamento

2.1.1 Epidemiologia

A Tubeculose (TB) é uma doença de natureza infecto-contagiosa, cujo agente

etiológico é o Mycobacterium tuberculosis e tem o homem como principal reservatório. É do
grupo de doenças de transmissão respiratória, de pessoa a pessoa principalmente através do
ar, por meio da fala, espirro, tosse e expectoração. O doente de TB pulmonar bacilífera lança
no ar gotículas, de tamanhos variados, que contém o bacilo em seu interior (BRASIL, 2011b).
Estima-se que 1/4 da população mundial esteja infectada pelo bacilo, e que
aproximadamente 2 a 3 bilhões de pessoas (cerca de 5-15%) poderão desenvolver a doença
em qualquer fase da vida. No entanto, a probabilidade de desenvolver TB é muito maior entre
as pessoas infectadas pelo HIV. Na presença ou não da referida infecção, o diagnóstico
oportuno e tratamento correto, leva a maioria das pessoas que desenvolvem a cura (WHO,
2017; 2018).
Trata-se de uma doença que afeta adultos e crianças. Dados do ano de 2016
apontaram que 90% dos casos registrados de TB eram adultos e 10% crianças, com maiores
proporções entre homens, sendo que a proporção entre o sexo masculino: feminino foi de 1,6:
1 (WHO, 2017). No ano de 2017, dos casos identificados, 5,8 milhões foram do sexo
masculino e 3,2 milhões do feminino (WHO, 2018).
A TB é problema de saúde pública em virtude do potencial incapacitante e das mortes
prematuras, considerada uma doença reemergente e negligenciada. Em 2015, a TB foi uma
das 10 maiores causas de morte por doença infecciosa em todo o mundo, ficando acima do
HIV / AIDS (WHO, 2017). Em 2017, 10,0 milhões de pessoas adoeceram por TB no mundo,
e cerca de 1,3 milhão de pessoas morreram em decorrência da doença (WHO, 2018).
WHO (2018) destaca que 30 países possuem alta carga de TB, representando 87%
dos casos no mundo. Entre os 30 países, 8 destacam-se pela concentração: Índia (27%),
China (9%), Indonésia (8%), Filipinas (6%), Paquistão (5%), Nigéria (4%), Bangladesh (4%)
e África do Sul (3%).
Em resposta às necessidades de lidar com o problema em países com alta prevalência
de TB, a OMS propôs a Estratégia Global pelo Fim da TB (End Tb – OMS) em maio de 2014,
visando a redução das mortes e a incidência da doença. As estratégias de enfrentamento
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foram organizadas em três pilares: Pilar 1 – prevenção e cuidado integrado centrados na

pessoa com TB; Pilar 2 – políticas arrojadas e sistema de apoio e o Pilar 3 – intensificação da
pesquisa e inovação, cujo objetivo é reduzir até 2035 cerca de 90% da TB no mundo (WHO,
2018).
No Brasil, dados do Boletim Epidemiológico, destacam que em 2017 foram notificados
69.569 casos novos de TB e o coeficiente de incidência foi igual a 33,5 casos/100 mil hab. As
taxas registradas entre as regiões brasileiras, mostram uma variação de 20,0 casos/100 mil
hab. no Centro-Oeste a 42,7 casos/100 mil hab. no Norte (BRASIL, 2018).
Quanto aos estados, nesse mesmo ano, os três maiores coeficientes de incidência
foram no Amazonas (74,1/100 mil hab.), no Rio de Janeiro (63,5/100 mil hab.) e em
Pernambuco (46,0/100 mil hab). Entre as capitais brasileiras, destacam-se as de maiores
incidências: Manaus (104,7/100 mil hab.), Rio de Janeiro (88,5 /100 mil hab.) e Recife
(85,5/100 mil hab.) (BRASIL, 2018).
Apesar da Região Centro-Oeste representar menor taxa de incidêncoa entre as demais
regiões, grandes oscilações são observadas entre os Estados de Mato Grosso (33,5/100 mil)
e Mato Grosso do Sul (30/100 mil) e entre as capitais Cuiabá/MT (59,5/100 mil) e Campo
Grande/MS (24/ 100 mil).
Em relação aos óbitos, no ano de 2016, foram registrados 4.426 óbitos por TB,
resultando em um coeficiente de mortalidade igual a 2,1 óbitos/100 mil hab. Os maiores
coeficientes de mortalidade, no mesmo período, foram registrados em Recife (6,4/100 mil
hab.), Belém (5,3/100 mil hab.) e Manaus (4,7/100 mil hab.) (BRASIL, 2018).

2.1.2 Diagnóstico

A TB, em relação a sua forma clínica, pode ser pulmonar ou extrapulmonar, a depender
da localização do sítio de infecção, dentro ou não dos pulmões. Desta forma, os marcadores
clínicos de sinais e sintomas podem ser variados. Na TB pulmonar, os sinais e sintomas mais
comuns incluem: tosse por mais de três semanas, expectoração, febre vespertina, sudorese
noturna, emagrecimento, astenia, hemoptise, dor nas costas e no peito (BRASIL, 2017).
Embora os sintomas sejam conhecidos, identificar precocemente os sintomáticos
respiratórios (SR) e aqueles com maior potencial de adoecimento por TB é ainda um grande
desafio (CASTRO et al., 2011), pois raramente procuram uma unidade de saúde no início dos
sintomas, sendo esses sintomas atribuídos a uma gripe mal curada, a uma bronquite tabágica
ou a outra situação clínica qualquer (CONDE et al., 2009).
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Reduzir as fontes de infecção pode quebrar a cadeia de transmissão da doença e

reduzir o problema da TB. Nesta perspectiva, o diagnóstico rápido e o tratamento oportuno
são de extrema importância no combate da doença. Para o diagnóstico, os testes disponíveis
incluem (WHO, 2017; BRASIL, 2011b; BRASIL, 2017):
A) baciloscopia de escarro: As amostras de expectoração são examinadas sob
microscopia para verificar a existências de bactérias. A pesquisa do bacilo álcool-ácido
resistente (BAAR), pelo método de Ziehl-Nielsen, é uma técnica simples e de baixo custo,
sendo a mais utilizada. Esta técnica, quando executada corretamente, permite detectar a
maioria dos casos pulmonares (BRASIL, 2017).
B) testes rápidos moleculares (TRM): O único teste rápido para diagnóstico de TB
atualmente recomendado pela OMS é o Xpert® Ensaio MTB / RIF (Cepheid, Sunnyvale USA).
Inicialmente recomendado (em 2010) para diagnóstico de TB pulmonar em adultos. Desde o
ano 2013, também tem sido recomendado para crianças e formas específicas de TB
extrapulmonares. É um teste de amplificação de ácidos nucléicos utilizado para detecção de
DNA do M. tuberculosis e triagem de cepas resistentes à rifampicina pela técnica de reação
em cadeia da polimerase (PCR) em tempo real. O tempo de execução do teste no laboratório
é de duas horas e o resultado é gerado automaticamente, informando a presença ou ausência
do complexo M. tuberculosis e indicando, nos casos positivos, a sensibilidade ou resistência
à rifampicina. Poderá ser utilizado para amostras extrapulmonares de líquor, gânglios
linfáticos e outros tecidos (BRASIL, 2017).
C) métodos por cultura: Estes são considerados padrão ouro de referência atual, mas
requer capacidade laboratorial mais desenvolvida e pode levar até 12 semanas para fornecer
o resultado. Tem elevada especificidade e sensibilidade no diagnóstico da TB, podendo
aumentar em até 20% o diagnóstico bacteriológico da doença (BRASIL, 2017).
D) radiografia de tórax: É um importante meio de diagnóstico da TB primária, no
entanto, alterações pulmonares não são demonstradas em até 15% dos casos. Deve ser
solicitada para todo o paciente com suspeita clínica de TB pulmonar, pois a TB apresenta
lesões características fundamentais para a definição do diangóstico. A radiografia auxilia no
descarte de doenças associadas na visualização da extensão da lesão nos casos com
baciloscopia positiva.
E) histopatológico: É empregado na investigação das formas extrapulmonares ou nas
formas pulmonares que se apresentam na radiografia como doença difusa, por exemplo, na
TB miliar, ou em indivíduos imunossuprimidos.
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F) Prova Tuberculínica (PT): é utilizada como uma importante avaliação de contatos

assintomáticos com pessoas doentes por TB para identificação de infecção latente (ILTB), ou
seja, quando o paciente tem o bacilo no organismo, mas não desenvolve a doença (primo-
infecção da doença). Consiste na inoculação de um derivado proteico purificado de M.
tuberculosis com a finalidade de medir a resposta imune celular a estes antígenos (BRASIL,
2017). A tuberculina usada é o PPD RT-23, aplicada por via intradérmica no terço médio da
face anterior do antebraço esquerdo, na dose de 0,1mL, que contém 2UT (unidades de
tuberculina). Após a aplicação, deve ser realizada a leitura, entre 48 a 72 horas. Durante a
leitura, deve-se medir o maior diâmetro transverso da enduração palpável com régua
milimetrada transparente e registrar o resultado em milímetros. A interpretação do resultado
e a indicação do tratamento da ILTB dependem da probabilidade de infecção latente, do risco
de adoecimento por TB, do tamanho da enduração e da idade (BRASIL, 2017).
Para viabilizar o processo de identificação de casos de TB, a aplicação de um escore
clínico decorrente do estudo “Avaliação de um escore clínico para rastreamento de suspeitos
de TB pulmonar” pode ser uma ferramenta útil na detecção precoce de casos de TB pulmonar,
principalmente em áreas com baixa prevalência de infecção por HIV (CASTRO et al., 2011).
O escore avaliado por Castro et al., (2011) apresentou alta sensibilidade (83,13% IC
77,8 - 87,6%) e apontou que ao ser utilizado por um profissional treinado, poderá gerar
informações com melhor qualidade, pois a detecção não se baseará somente no critério tosse,
conforme preconizado pela OMS e pelo Ministério da Saúde (MS). Nesta perspectiva, os
pacientes selecionados podem ser submetidos a testes de maior custo ou mais complexos,
como cultura para micobactéria, exames radiológicos do tórax, testes moleculares e/ou outros
testes (CASTRO et al., 2011; BRASIL, 2011b).

2.1.3 Tratamento

Estudos internacionais apontam o desafio do diagnóstico precoce da TB em âmbito

mundial, acarretando atrasos no início do tratamento, comprometendo a efetividade do
mesmo.
A preocupação em relação ao diagnóstico precoce se dá pela carga da doença e a
elevada possibilidade de transmissão. Portanto, deve-se intensificar as medidas de
identificação de pacientes fontes e dos fatores de riscos que causam o atraso, visando a
melhoria do controle da doença (HABIBULLAH et al., 2004; MESFIN et al., 2009; ODUSANYA
et al., 2004).
 17

O atraso no tempo para diagnóstico e para início do tratamento da TB podem estar

relacionados: ao tipo de serviço de saúde procurado pelo doente de TB, ao acolhimento
realizado ao usuário de forma inadequada, a baixa prioridade na busca por SR e ainda aos
meios diagnósticos disponíveis nos serviços de saúde (DÍEZ et al., 2005; JAMAL et al., 2007;
CÁCERES-MANRIQUE; OROZCO-VARGAS, 2008; MESFIN et al., 2009; SCATENA et al.,
2009; KUZNETSOV et al., 2014; LEMOS et al., 2014).
Desta forma, o diagnóstico precoce e o tratamento oportuno são elementos
fundamentais para o controle da TB, pois interrompem a cadeia de transmissão. A OMS
preconiza que os países devam se organizar para atingir a meta de percentual de cura de
pelo menos 85%, e de abandono menos que 5% (BRASIL, 2017).
No Brasil, dados do Ministério da Saúde, do ano de 2017, mostraram a taxa de cura
de 73,0%, que embora abaixo da meta preconizada pela OMS, foi maior quando comparada
com os anos anteriores. Em relação ao abandono, nas diferentes regiões brasileiras, as taxas
variaram entre 9,4% a 10,9%, mostrando-se 2 vezes maior que o recomendado pela OMS
(BRASIL, 2017).
O tratamento ao paciente diagnosticado com TB, baseia-se na associação de
antimicrobianos com funções específicas para eliminação do bacilo.
Os fármacos associados na fase intensiva do tratamento para adulto (dois primeiros
meses) são: rifampicina (150mg), isoniazida (75mg), pirazinamida (400mg) e etambutol
(275mg) e estão indicados para todos os casos novos de todas as formas de TB pulmonar e
extrapulmonar (exceto meningoencefalite). Já no esquema da fase de manutenção (os
últimos quatro meses de tratamento) faz-se a associação entre rifampicina e isoniazida
(BRASIL, 2011b).
Uma vez iniciado o tratamento escolhido, o mesmo não poderá ser interrompido antes
do prazo estabelecido, uma vez que as doses e tempo estabelecido promovem a cura e
diminuem as chances de resistências ao microorganismo (BRASIL, 2011b).
A não conclusão do tratamento da TB pode ser um dos fatores para aumentar o risco
de resistência do bacilo aos fármacos contra a doença, uma vez que um rigoroso tratamento
se tem mostrado eficaz no controle da mesma.
Fregona et al., (2017) analisou a prevalência e os fatores associados à TB resistente
em pacientes do Espírito Santo e encontrou uma taxa de 5% de resistência aos fármacos
rifampicina e isoniazida. Neles, apresentaram-se como fatores associados independentes
para TB resistente: história de tratamento prévio para a TB [Recidiva (OR = 7,72; IC95% 4,24–
14,05), tabagismo (OR = 3,93; IC95% 1,98 – 7,79); cultura positiva para Mycobacterium
 18

tuberculosis no momento da notificação do caso ( OR = 3,22; IC95% 1,15 – 8,99) e reingresso

após abandono (OR = 3,91; IC95% 1,81–8,43)].
Em relação a melhoria da detecção precoce e tratamento, Wang et al. (2014) analisou
a implementação do Programa de Controle da Tuberculose em um estudo longitudinal de 20
anos, na China. Identificou uma redução significativa de sua prevalência com baciloscopia
positiva, acima de 50%, resultado atribuído à implantação do DOTS. Os autores destacaram
que a implementação deste programa pode melhorar substancialmente a qualidade do
tratamento da TB.

2.2 TB em População Privada de Liberdade (PPL) no Brasil

Nas prisões, a TB constitui-se um importante problema de saúde, especialmente nos

países de alta e média endemicidade (WHO, 2018). Há um reconhecimento crescente do alto
risco nesses ambientes para os que pertencem ao sistema prisional e para a comunidade
(CONINX, et al., 2000), pois essas populações são vulneráveis, com chances até 28 vezes
maiores do que a população geral (BASU et al., 2011; WHO, 2017).
As condições das prisões influenciam nas altas taxas, tanto no que diz respeito às
inadequações dos ambientes quanto ao acesso limitado ao serviço de saúde para o
diagnóstico precoce e o tratamento adequado (DARA et al., 2015; SÁNCHEZ et al., 2013).
Inserido neste contexto destacam-se os fatores relacionados ao encarceramento,
como celas superpopulosas, mal ventiladas e com pouca iluminação solar e exposição
frequente ao M.tuberculosis (JITTIMANEE; WHITE; JITTIMANEE, 2007).
Fatores individuais e condições de vida antes do encarceramento contribuem para a
alta endemicidade da TB na PPL, como população jovem, predominantemente masculina, de
baixa escolaridade, oriunda de comunidades desfavorecidas com maior ocorrência de TB.
Também constata-se o uso de drogas, maior prevalência de infecção pelo HIV, maior
frequência de tratamento anterior para TB e antecedentes de encarceramento (CARBONE et
al., 2015; VALENÇA et al., 2015).
Em revisão sistemática, conduzida por Dianatinasab et al., (2018), foram compilados
dados disponíveis sobre a prevalência de TB entre os portadores de HIV positivos, visando
identificar novas abordagens para melhorias nos planos de prevenção da coinfecção TB /
HIV. Essa meta-análise incluiu 22 estudos publicados no período de 1992 a 2016 e identificou
que, globalmente, a prevalência combinada de TB em PPL soropositivos para HIV/AIDS foi
 19

de 32,6% (IC 95%: 27,5% a 38,2%; valor de p para heterogeneidade = 0,001). As análises
dos subgrupos por continente mostraram variações nas taxas de co-infecções, na África, 14%
(IC: 8% a 24%); América do Norte / Sul, 37% (IC: 31% a 44%); Ásia, 35% (IC: 12% a 68%); e
Europa, 25% (IC: 12% a 45%). Os achados indicaram o rastreamento da TB nessa população
como essencial para o tratamento de ambas as doenças.
Em 2014, um total de 8,4% de todos os casos de TB notificados ocorreu entre reclusos,
que representam < 0,3% da população, correspondendo a um aumento de 35,4% do
percentual de casos de TB ocorridos entre reclusos em 5 ano (2009 - 2014). As taxas de
notificação de casos de TB ente os presos foram 31,3 vezes maiores do que as da população
geral. O estudo revelou que as mulheres presas correm maior risco de contrair tuberculose.
As taxas de encarceramento entre as mulheres aumentaram mais rapidamente, e as taxas
de notificação de TB e as taxas de coinfceção por HIV foram maiores do que as taxas
correspondentes entre os homens. Uma explicação potencial é a maior taxa de TB associada
ao HIV entre mulheres presas do que entre homens (24,1% vs. 15,2%) (BOURDILLON et al.,
2017).
Em estudos referentes à TB ativa nas prisões brasileiras, evidenciou-se uma taxa
elevada nas diferentes regiões do país. Um resultado destacado é o da variação da taxa
infecção latente de TB (ILTB) nas prisões dos estados brasileiros, com valores entre 11,7% a
73,0%, mostrando que a infecção nos encarcerados do sexo masculino é maior do que a
encontrada nas mulheres encarceradas (LEMOS et al., 2009; NOGUEIRA et al., 2012;
CARBONE et al., 2015; COSTA-JUNIOR et al., 2016).
Kuhleis et al., (2012) e Valença et al., (2015) destacam que a alta taxa de TB ativa
encontrada na região Sul do país está relacionada à infecções recentes, pois observaram que
a TB foi causada, principalmente, por estirpes transmitidas nos últimos anos. Por estes
resultados recomendam que a prioridade seja dada à avaliação dos presos com mais tempo
de encarceramento, àqueles que são HIV-positivos, àqueles com sintomas e aos com história
prévia de TB.
Na região Nordeste, altas taxas de doença ativa e ILTB e foram encontradas, chegando
a 2500 casos por 100 mil e de 65% de ILTB (LEMOS et al., 2009). Na região Sudeste, nas
prisões do Espirito Santo, as taxas menores de prevalência de TB ativa foram menores que
aquelas encontradas nas demais regiões supracitadas, (830 casos/100 mil). O estudo discute
a possibilidade desta baixa prevalência estar relacionada com a subnotificação no sistema
(MOREIRA et al., 2010).
 20

Já, dados de TB na região Centro Oeste, mostram que, em prisões de Goiás, a taxa
de incidência foi muito superior do que a taxa de TB no restante do estado (de 1800 casos
por 100 mil versus 14/100 mil hab.) (COSTA-JUNIOR et al., 2016; BRASIL, 2018). Nas
prisões de Mato Grosso do Sul, embora a prevalência global de ILTB em internos
apresentarem menores taxas (25,7%) menores que em outras prisões do país; a prevalência
de TB ativa foi alta (970 casos por 100 mil), o que indica necessidade de abordar a
transmissão da TB dentro das prisões (CARBONE et al., 2015).
Uma preocupação crescente, dentro do cenário das prisões, é a TB com resistência ao
tratamento. Estudos sobre as prisões apresentaram taxas de resistência elevadas aos
medicamentos antituberculose, o que gera preocupações neste cenário
(BIADGLEGNE;ROLDLOFF;SACK, 2015; RUDDY et al., 2005). Em Mato Grosso do Sul,
estudo realizado em prisões por Cunha et al., (2018) mostrou que as taxas de resistência a
múltiplas drogas (MDR) primárias e adquiridas foram (0,3% e 1,3%, respectivamente)
estiveram abaixo das encontradas na população geral do estado (0,6% e 6,3%,
respectivamente) (MARQUES et al., 2017). Desta forma, a garantia do tratamento completo,
sem interrupção com taxa de cura pelo menos 85% vai refletir nas menores taxa de
resistência.

2.3 Estratégias para controle da TB nas prisões

A TB e outras infecções respiratórias são transmitidas de pessoa a pessoa por via

aérea, por essa razão, ambientes superpopulosos, mal ventilados e com iluminação solar
limitada, como é observado na maioria das prisões, são favoráveis à disseminação destas
doenças (CARBONE et al., 2015).
A literatura científica, bem como os manuais de recomendações das Organizações
Mundial de Saúde (WHO, 2000) e do Ministério da Saúde (BRASIL, 2011b) realizam
abordagem para o controle da TB nestes cenários. Entre as recomendações estão:
intervenções ambientais na arquitetura das prisões e o rastreamento da PPL, incluindo
exames mais sensíveis como Radiografia de Tórax e TRM.
Na perspectiva de melhorar as condições ambientais de encarceramento, foi publicado
em 2012 pelo Departamento Penitenciário Nacional, um manual que propôs soluções
arquitetônicas para a melhoria das condições de iluminação e ventilação, de forma que,
respeitando os imperativos de segurança, sejam incorporadas na construção de novas
prisões e na reforma das atuais (DEPEN, 2012). Para Urrego et al. (2015), ao analisar as
 21

características de arquitetura e ventilação estimada em três prisões de Mato Grosso do Sul,

reforçou que se houver melhoria da ventilação natural, haverá uma contribuição efetiva para
redução da TB nas prisões. Na ausência de intervenções, o risco médio projetado de infecção
foi de 78,0% durante um período de 6 meses.
Em estudo conduzido por Prasad et al., (2017) em prisões da Índia, que analisou a
disponibilidade de serviços de saúde para atenção a TB nas prisões, propõem que os serviços
de triagem, diagnóstico e tratamento de TB precisam ser fortalecidos com urgência, tendo em
vista que a Índia tem apresentado altas taxas da doença, e apenas a metade das prisões
analisadas selecionaram PPL para diagnóstico da TB na entrada.
A estratégia recomendada internacionalmente (WHO, 2017) e adotada no Brasil
consiste da triagem por busca passiva e/ou busca ativa. A busca ativa do SR deve ser
realizada permanentemente, de forma sistemática, entre os ingressos ou indivíduos já
encarcerados (rastreamento em massa) e tem sido uma estratégia recomendada
internacionalmente (BRASIL, 2011b).
Já, a busca passiva, deve ser direcionada para àqueles casos que não acessam os
serviços de saúde de forma espontânea. Para tanto, deve-se sensibilizar a PPL e demais
integrantes do sistema prisional quanto a importância de identificação precoce dos sinais e
sintomas da TB; promover educação continuada sobre a temática; promover melhoria de
acesso ao serviço de saúde e submeter o suspeito aos exames de triagem (BRASIL, 2011b).
Considerando como método de referência o rastreamento radiológico, avaliou-se o
desempenho do escore proposto pela OMS, que permitiria identificar, dentre as PPL, quais
aquelas presumidamente poderiam ser TB ativa (WHO, 2000). Ao utilizar esse escore na
prisão do RJ, os resultados mostraram um desempenho insatisfatório e ineficaz para
direcionar o rastreamento da TB. Destacando que a triagem sistemática por raio-X pode ser
considerada, pelo menos durante os estágios iniciais do programa reforçado de TB, a fim de
reduzir o impacto da TB no cenário de alta endemicidade (FOURNET et al., 2006).
Um modelo matemático, desenvolvido para as prisões no Rio de Janeiro, comparou
cinco estratégias e estimou o impacto de cada uma delas sobre a prevalência da TB num
período de 10 anos. A estratégia que se mostrou mais eficaz associava às medidas de base
(detecção passiva e tratamento de casos), o exame radiológico sistemático de ingressantes
e, anualmente, na população já encarcerada (LEGRAND et al., 2008).
Ao medir o impacto da triagem com radiografia de tórax na entrada, associada à
triagem sistemática sobre a prevalência e incidência de TB ativa de prisões do RJ, os autores
destacaram que os casos identificados por exames foram menos prováveis de serem
 22

confirmados bacteriologicamente quando comparados com os casos identificados pela

descoberta de casos passivos. Reforçaram a utilização da radiografia de tórax a ser
considerado para controlar a TB em prisões altamente endêmicas (SANCHEZ et al., 2013).
Nessa perspectiva, devem ser concentradas medidas de prevenção e controle, no
intuito de garantir um melhor controle da doença e a implantação de um programa de TB
eficaz, evitando-se dessa forma que as prisões sejam fontes de transmissão da doença para
as próprias instituições e para a comunidade em geral (WHO, 2017).
 23

3 OBJETIVOS

3.1 Geral

Avaliar estratégias para o controle da TB em prisões de Mato Grosso do Sul.

3.2 Específicos

a) Analisar o impacto do rastreamento anual com baciloscopia e cultura no que diz respeito a
incidência da doença em 12 prisões de Mato Grosso do Sul;
b) Quantificar o risco de TB para privados de liberdade de acordo com a trajetória no sistema
prisional do estado de Mato Grosso do Sul e o retorno na comunidade.
c) Avaliar através da modelagem matemática cinco estratégias para controle da TB nas
prisões e possíveis impactos na redução da incidência da doença nas prisões e na
comunidade.
 24

4 MATERIAIS E MÉTODOS

A tese está inserida em um amplo projeto detalhado no item 4.1 e dividido por etapas
de construções (Etapa 1 e Etapa 2) que exigiram métodos específicos. As etapas contemplam
dois artigos os quais apresentam seus percursos metodológicos.

4.1 Linha de base da pesquisa

A linha de base da pesquisa iniciou-se em 2013 com o “Estudo multicêntrico da

prevalência de TB e HIV na população carcerária do Estado do Mato Grosso do Sul” e serviu
como base para realização de novos estudos.
Nesse ano totalizavam 12.306 presos no estado, sendo 11.152 do sexo masculino e
1.154 do sexo feminino distribuídos entre 37 instituições penais. As de regime fechado
apresentavam um total de 9.913 internos distribuídos em 22 instituições. Doze delas foram
incluídas no estudo, totalizando 7.221 internos representando 73% do total no regime fechado
e 59% da PPL no estado. Destas, oito eram masculinas (6.552) e quatro eram femininas (669).
A amostra deste primeiro estudo foi definida por meio de um cálculo amostral, baseada
na prevalência esperada de HIV, assumindo-se 2% de prevalência com um erro de +/− 1%,
poder de 80% e erro tipo alfa de 5%. A amostra calculada foi de 3.159 internos; prevendo-se
possível perda na recusa em participar, houve um incremento de 20% sobre essa população,
perfazendo um total de 3.771 PPL. Para a realização do recrutamento, foi realizado
sorteio, utilizando a ferramenta do EpiInfo on line. Desta forma, foi ofertada a pesquisa a todos
indivíduos sorteados aleatoriamente. Após realizar os esclarecimentos da participação
voluntária, foi coletada a assinatura do Termo de Consentimento Livre e Esclarecido (TCLE).
Foi aplicado questionário padronizado, as variáveis obtidas durante a entrevista
incluíram os seguintes grupos temáticos: informações gerais, drogas, TB, infecções
sexualmente transmissíveis e exame realizados. Para os entrevistados SR foram realizados
a pesquisa de BAAR e cultura e também aplicado Teste Tuberculínico (TT), utilizando o PPD
RT23 (Staten Serum Institute, Copenhagen).
Os dados coletados foram compilados e tratados estatisticamente e estão descritos no
artigo publicado que se encontra no ANEXO A.
 25

4.2 Condução metodológica da Etapa 1

Os achados despertaram curiosidade científica quanto ao conhecimento exaustivo do

fenômeno e possíveis estratégias de mudança da realidade. Assim, foi delineado um estudo
de coorte, nos quais as mesmas 12 prisões estaduais de regime fechado das cidades de
Campo Grande, Corumbá, Dourados, Ponta Porã e Três Lagoas foram analisadas quanto ao
impacto do rastreamento anual com baciloscopia e cultura no que diz respeito a incidência da
doença
Para este estudo foi observado o grupo recrutado no estudo de linha de base
(N=3.771), bem como o grupo não recrutado no mesmo (N=3.450).
Entre o universo de linha de base, ao final de um ano, 1.442 permaneceram no estudo,
representando 58% de perda do rastreamento. Para identificação de ocorrência de casos de
TB diagnosticados pelo serviço, entre o estudo de linha de base e etapa 1, foi realizado uma
busca nos registros de prontuários dos serviços de saúde das prisões e consulta ao banco de
dados do SINAN. Estes foram denominados grupo de identificação passiva.
Para os 1.442 internos foram coletadas as assinaturas do Termo de Consentimento
Livre e Esclarecido (TCLE) (APENDICE A); a aplicação de questionário (APENDICE B) e a
realização de exames de baciloscopia, cultura e TT.
Os dados foram compilados e submetidos à análise estatística de curvas de
sobrevivência e teste log-rank para comparar as incidências cumulativas de TB e modelos de
Cox.
Esta estapa propiciou a publicação dos achados no artigo 1, intitulado “Impact of mass-
screening on tuberculosis incidence in a prospective cohort of Brazilian prisoners”; nos
resumos “Alarming of rates tuberculosis trasnmissions in brazilians prisions” (Cape Town,
South Africa, 2015) e “High incidence of tuberculosis infection and disease in twelve Brazilian
prisons” (Liverpool, United Kingdom, 2016), ambos publicados no The International Journal of
Tuberculosis and Lung Disease. Foram também publicados: o resumo “High incidence of
tuberculosis infection and disease in twelve Brazilian prisons” no Congresso Brasileiro de
Medicina Tropical (Maceió – AL, 2016), sendo premiado em 3º lugar, na categoria Doutorado,
recebendo o título de Jovem Pesquisador de 2016 da Sociedade Brasileira de Medicina
Tropical; Em 2017, o resumo “Estratégias para controle da tuberculose nas prisões do Brasil”
publicado na revista PECIBES ( UFMS) recebeu as premiações: 1º lugar no III Prêmio de Pós-
Graduação stricto sensu Dr Durval Batista Palhares (Consulpit – Humap) e o 3º lugar no I
Prêmio painel Maria Elizabeth Moraes Cavalheiros Dorval (Consulpit – Humap) (ANEXO B).
 26

4.3 Condução metodológica da Etapa 2

Para a abordagem da Etapa 2 foi conduzido um estudo de modelagem matemática,

utilizando dados secundários (SINAN, 2006-2015 e o Sistema Integrado de Gestão
Operacional – SIGO/ Sistema Integrado de Administração do Sistema Penitenciário/SIAPEN,
2005-2014) para simular a ocorrência da transmissão da TB entre PPL, ex-PPL e a
comunidade e propor melhores estratégias de controle. Isso possibilitou identificar a PPL de
2007 a 2013 do estado (n = 42.925) e os casos de TB (n = 5.643) visando estimar a incidência
de TB a partir do momento do encarceramento e o tempo de saída da prisão, bem como
avaliar as estratégias de redução de TB em prisões de Mato Grosso do Sul, por meio da
análise de impacto das intervenções nas prisões sobre a carga de TB na comunidade.
Para vincular os dois bancos de dados, foi construído um algorítmo de correspondência
de nomes no GREL, usando OpenRefine versão 2.6 ( VERBORGH et al., 2013), que combina
a impressão digital fonético e uma função de distância entre as letras, para identificar
correspondências “fuzzy” - nomes semelhantes mas não necessariamente idênticos entre
SINAN e o relatório SIGO/SIAPEN (PACHECO et al., 2008; FONSECA et al., 2010).
Aumentou-se a distância permitida entre os nomes correspondentes até alcançar uma
sensibilidade de 100% ao comparar as correspondências do algorítmo com um conjunto de
dados independentes.
O processo produziu 1.258 correspondências fuzzy entre os dois bancos de dados,
que a posteriori foram consultados por dois pesquisadores independentes. Isto permitiu a
comparação manual da data de nascimento, nome da mãe, cidade de nascimento e nome do
pai entre o SINAN e o SIGO/SIAPEN. A partir do conjunto de dados, foram encontrados 615
indivíduos corretamente pareados diagnosticados com TB durante ou após um período de
prisão.
Na sequência foram realizadas análises de sobrevivência (package “survival”) em
relação aos primeiros encarceramentos e o período de liberação após o primeiro
encarceramento, gerando duas coortes: 1) PPL que teve seu primeiro encarceramento entre
2007-2013 e 2) ex-PPL liberta do primeiro encarceramento no mesmo período. E, para a
estimativa das funções de risco foi utilizado o package “muhaz”, considerado IC 95%.
Para o gupo 1, o acompanhamento foi do início da primeira prisão, excluídos os
indivíduos no momento da liberação, morte ou no final do período do estudo. Para o grupo 2,
 27

o acompanhamento foi a data de liberação do primeiro encarceramento e exclusão no

momento do reencarceramento (se tivessem vários encarceramentos), morte ou no final do
período do estudo.
Foram realizadas análises estatísticas de regressão multivariada de Cox, avaliação
gráfica e análise dos resíduos de Schoenfeld, utilizando o R versão 3.5.0.
Esta estapa propiciou a publicação do artigo intitulado: “Evaluating strategies for control
of tuberculosis in prisons and prevention of spillover into communities: An observational and
modeling study from Brazil” na revista PLOS Medicine; bem como a publicação do resumo
intitulado “Identificação de estratégias para o controle da tuberculose em prisões brasileiras”
no Boletim da Sociedade Brasileira de Infectologia (SBI), premiado como um dos cinco
melhores trabalhos “Prêmio Manoel de Barros” (ANEXO B)

4.5 Aspectos éticos

O estudo foi aprovado pelo Comitê de Ética de Pesquisa em Seres Humanos da

Universidade Federal da Grande Dourados sob o protocolo nº 877. 294/2014 (ANEXO C). E
consentida autorização para utilização dos dados pela Agência de Admnistração Penitenciária
de Mato Grosso do Sul.
 28

5 RESULTADOS

O trabalho originou dois artigos, de acordo com os objetivos e metodologia utilizados,

que serão apresentados a seguir:

Artigo 1 - Impact of mass-screening on tuberculosis incidence in a prospective

cohort of Brazilian prisoners

Artigo 2 - Evaluating strategies for control of tuberculosis in prisons and

prevention of spillover into communities: An observational and modeling study from
Brazil
 29

Artigo 1 – Impact of mass-screening on tuberculosis incidence in a prospective cohort

of Brazilian prisoners

Dayse Sanchez Guimarães Paião1†, Everton Ferreira Lemos2†, Andrea da Silva Santos
Carbone1, Renata Viebrantz Enne Sgarbi1, Alexandre Laranjeira Junior1, Fellipe Matos da
Silva1, Letícia Marques Brandão1, Luciana Squarizi dos Santos1, Vaneli Silva Martins1,
Simone Simionatto3, Ana Rita Coimbra Motta-Castro4,5, Maurício Antônio Pompílio2, Juliana
Urrego6, Albert Icksang Ko6,7, Jason Randolph Andrews8 and Julio Croda1,5*

†Equal contributors
1Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, Brazil.
2School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
3Faculty of Ambiental and Biological Sciences,

Federal University of Grande Dourados, Dourados, Brazil.

4Department of Biochemical Pharmacy, Federal University of Mato Grosso do Sul, Campo

Grande, Brazil.
5Oswaldo Cruz Foundation, Campo Grande, Brazil.
6Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New

Haven, CT, USA.

7Oswaldo Cruz Foundation, Salvador, Brazil.
8Division of Infectious Diseases and Geographic Medicine, Stanford School of Medicine,

Palo Alto, CA, USA

Received: 9 June 2016 Accepted: 24 September 2016

Publised on line: 03 octuber 2016.

BMC Infectious Diseases

Paião, Lemos et al. BMC Infectious Diseases (2016) 16:533
DOI 10.1186/s12879-016-1868-5

1471-2334 BMC INFECTIOUS DISEASES (ONLINE) MEDICINA II B1

 30

Impact of mass-screening on tuberculosis

incidence in a prospective cohort of Brazilian
prisoners
Dayse Sanchez Guimarães Paião1†, Everton Ferreira Lemos2†, Andrea da Silva Santos Carbone1,
Renata Viebrantz Enne Sgarbi1, Alexandre Laranjeira Junior1, Fellipe Matos da Silva1, Letícia Marques Brandão1,
Luciana Squarizi dos Santos1, Vaneli Silva Martins1, Simone Simionatto3, Ana Rita Coimbra Motta-Castro4,5,
Maurício Antônio Pompílio2, Juliana Urrego6, Albert Icksang Ko6,7, Jason Randolph Andrews 8 and Julio Croda1,5*

Abstract
Background: Globally, prison inmates are a high-risk population for tuberculosis (TB), but the specific drivers of
disease and impact of mass screening interventions are poorly understood.
Methods: We performed a prospective cohort study to characterize the incidence and risk factors for tuberculosis
infection and disease in 12 Brazilian prisons, and to investigate the effect of mass screening on subsequent disease
risk. After recruiting a stratified random sample of inmates, we administered a questionnaire to ascertain symptoms and
potential risk factors for tuberculosis; performed tuberculin skin testing (TST); collected sera for HIV testing; and
obtained two sputum samples for smear microscopy and culture, from participants reporting a cough of any duration.
We repeated the questionnaire and all tests for inmates who remained incarcerated after 1 year. TST conversion was
defined as TST ≥10 mm and an induration increase of at least 6 mm in an individual with a baseline TST <10 mm.
Cox proportional hazard models were performed to identify risk factors associated with active TB. To evaluate the
impact of screening on subsequent risk of disease, we compared TB notifications over one year among individuals
randomized to screening for active TB with those not randomized to screening.
Results: Among 3,771 inmates recruited, 3,380 (89.6 %) were enrolled in the study, and 1,422 remained incarcerated
after one year. Among 1,350 inmates (94.9 %) with paired TSTs at baseline and one-year follow-up, 25. 7 % (272/1060)
converted to positive. Among those incarcerated for the year, 10 (0.7 %) had TB at baseline and 25 (1.8 %) were
diagnosed with TB over the subsequent year. Cases identified through active screening were less likely to be
smearpositive than passively detected cases (10.0 % vs 50.9 %; p < 0.01), suggesting early case detection.
However, there was no reduction in subsequent disease among individuals actively screened versus those not screened
(1.3 % vs 1.7 %; p = 0.88). Drug use during the year (AHR 3.22; 95 % CI 1.05–9.89) and knows somebody with TB were
(AHR 2.86; 95 % CI 1.01–8.10) associated with active TB during one year of follow up
Conclusions: Mass screening in twelve Brazilian prisons did not reduce risk of subsequent disease in twelve
Brazilian prisons, likely due to an extremely high force of infection. New approaches are needed to control TB in this
high-transmission setting.
Keywords: Tuberculosis, LTBI, Mass screening, Prisons, Case finding, Brazil, Cohort

* Correspondence: juliocroda@gmail.com
†
Equal contributors
1
Faculty of Health Sciences, Federal University of Grande Dourados,
Dourados, Brazil
5
Oswaldo Cruz Foundation, Campo Grande, Brazil
Full list of author information is available at the end of the article

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Background
Globally, incarcerated populations have among the highest
tuberculosis (TB) notification rates, frequently in excess of 20
times the rates of their corresponding non-incarcerated
communities [1]. Brazil has the world’s 4th largest prisoner
population, which grew by 86 % (335,410–622,202) be- tween
2007 and 2015 (http://www.prisonstudies.org/high- est-to-
lowest/prison-population-total). While TB incidence is
declining in community settings across Brazil, it has risen by
nearly 40 % among incarcerated population over the past
seven years, representing 8 % of approximately 70,000 TB
cases reported annually to the Ministry of Health [2].
Moreover, a number of cross-sectional studies have
demonstrated a high prevalence of undiagnosed TB among
prisoners in Brazil [1, 3–6].
Prisons are optimal environments for TB transmission since
they bring together individuals with high rates of tobacco,
alcohol, and drug use, and limited access to healthcare and
TB diagnostics, into crowded, poorly ven- tilated cells for
16–20 h a day [7, 8]. Determining which interventions
would be most effective and efficient in reducing the burden
of TB in such settings is difficult due to the lack of data.
The World Health Organization (WHO) and Brazil’s
Ministry of Health recommend screening for active TB upon
initial entry into prisons and then annually. Yet, to date
Brazilian prisons have not implemented mass screening
recommendations since chest x-radiography or laboratory
facilities are not available. Cross-sectional studies have
demonstrated a high yield of annual screen- ing for active
TB among prisoners on a one-time basis, but the yield of this
approach over time and impact on subsequent TB incidence
remains uncertain [1, 3, 4].
In a previous model-based analysis, we projected a modest
reduction (8.3 %) in tuberculosis infection risk following a
25 % reduction in time to TB diagnosis in 3 Brazilian prisons
[7]. We hypothesized that the annual mass screening with
smear and culture could avert even more transmission and
thereby reduce TB incidence in this setting. To address these
questions, we designed a prospective cohort study to
evaluate the impact of an- nual screening and assess TB
infection and disease rates in 12 Brazilian prisons.
Methods
Study location, population and study design
Brazil has a population of 200.4 million and 622,202 pris-
oners (incarceration rate of 311.1 per 100,000 population).
Mato Grosso do Sul state, located in Midwestern Brazil, has
a population of 2.5 million with 14,904 prisoners,
representing the highest national incarceration rate (596.2
per 100,000 population) [9]. The penal system is comprised
of “closed” and “open” subsets to segregate high and low-
risk offenders (the latter of whom are
2
allowed to leave the prison during daytime hours); 9,913
inmates in 22 penitentiaries comprise the total closed sub-
set. From January 2013 to December 2014, we conducted a
prospective cohort study in 8 male and 4 female prisons in
the cities of Campo Grande, Corumbá, Dourados, Ponta
Porã, and Três Lagoas. The study population, 7,221 inmates,
represents 59 % of the total state inmate popula- tion and 73
% of inmates in the closed subset. Of the 12 study prisons, 8
male prisons included 6,552 inmates and 4 female prisons
included 669 inmates.
Prior to the study, none of these 12 selected prisons
implemented the entrance and annual mass TB screening
recommended by WHO [10], and all TB cases were de-
tected passively by inmates seeking medical consultation
based on their symptoms; clinicians used clinical assess-
ment, smear and culture to make diagnoses. We con- ducted
a prospective study of active tuberculosis screening in the
study prisons.
Sample size calculation
Prisoners who were 18 years of age and who consented to
participate were recruited for the study. Proportional
stratified sampling was performed by using each prison as a
unit of randomization, as reported previously [8]. Screening
for tuberculosis (reported here) was per- formed alongside
parallel screening studies for HIV, Hepatitis B, Hepatitis C,
and syphilis. The sample size was calculated based on the
expected prevalence of HIV, as this was the lowest
prevalence condition for the over- all study. We assumed 2
% prevalence of HIV with an error of +/−1 %, power of 80
% and alpha-type error of 5 %. The study population is
7,221 prisoners, and the sample size was 3,159 prisoners. We
added 20 % more individuals to account for anticipated loss
due to refusal to participate, for a total of 3,771 prisoners.
Study procedures
We administered a questionnaire and tuberculin skin test
(TST) (PPD RT23, Staten Serum Institute, Copenhagen) to
all patients, and performed sputum smear microscopy and
culture for all participants reporting cough. The vari- ables
obtained during the interview included age, sex, marital
status, educational attainment, drug use over the last year,
history of sexually transmitted infections (STIs), smoking,
tuberculosis, self-reported mental illness and diabetes
mellitus, knows someone with TB and previous
incarceration. The participant’s race/ethnicity (i.e., white,
black, indigenous, Asian or mixed) was self-reported.
We scored clinical symptoms and signs according to WHO
guidelines: cough lasting for more than two weeks (2 points),
expectoration (2 points), chest pain (1 point), weight loss in the
last three months (1 point), and a recent loss of appetite (1
point). A score equal to or greater than 5 points indicate a high
probability of active disease [10–12].

One sputum sample was collected on the spot and a second
sputum sample was collected the following morning. Serum
samples of participants were initially screened with a
commercial enzyme linked immuno- sorbent assay (ELISA)
for detection of antibodies against HIV-1 and HIV-2 (Murex
HIV-1.2.0, DiaSorin, Italy). All positive and indeterminate
specimens were confirmed by Western blot assay
(Novopath HIV-I, Immunoblot, BioRad) [8]. TST positivity
was defined as an induration of ≥10 mm (≥5 mm for HIV-
infected individuals), and TST conversion was defined as
TST ≥10 mm and an in- duration increase of at least 6 mm
in an individual with a baseline TST <10 mm [10]. In HIV-
positive individuals, TST conversion was defined as an
induration increase of at least 6 mm in an individual with a
baseline TST
<5 mm. Brazilian Ministry of Health (MoH) recommends
IPT only for HIV-infected inmates with positive TST.
After one year, we returned and administered a second
questionnaire and TST, and again performed smear mi-
croscopy and culture for all participants reporting cough.
To calculate the yield of smear, individuals with positive
sputum smear and/or culture in the first and second screening
were included in the active screening group. Additionally,
we reviewed prison medical records and the National
Notifiable Disease database (Sistema de Informação de
Agravos de Notificação National, SINAN) to identify TB
cases occurring between the study initi- ation and
conclusion. TB cases identified during these period were
included in the passive screening group. All questionnaires
were entered twice into the Research Electronic Data
Capture database (REDCap, secure online database). SAS
version 9.2 (SAS Institute, Cary, NC, USA) was used to
analyze bivariable and multivariable models.
Analytic approach
Tuberculosis cases were considered “actively detected” if
they were detected by diagnostics performed during mass
screening, conducted at baseline and after one year. Cases
were considered “passively detected” if they were detected
by routine presentation for medical care between the two
mass screening rounds; there was no overlap between the
two forms of diagnosis. The “active screening” group was
the group of inmates enrolled in the study who were actively
screened at baseline and one year follow up. Cumulative
incidence of active TB was calculated using all incident
cases notified by SINAN between the two screening periods
divided by all the prisoners who remained one year in the
same prison in the two groups. We used survival curves and
log-rank test to compare the cumulative incidences of active
tu- berculosis among the group who underwent annual
screening with the group of individuals who did not undergo
annual screening. Cox proportional hazards models were
used to estimate crude (CHR) and adjusted
3
hazards ratios (AHR) for active TB. Variables were in-
cluded in the model if they reached a significance level of p
< 0.20 by log-rank test, which was then trimmed using
stepwise backward selection. Statistical significance was
determined at a p value of <0.05.
Ethical issues
All eligible participants provided written informed consent
prior to study participation. The study was approved by the
Research Ethics Committee at the Federal University of
Grande Dourados (Number 793,740). All LTBI in HIV-
positive individuals and active TB cases identified during the
screening underwent medical consultation after the test
results and were referred for free tuberculosis treat- ment or
preventive therapy.
Results
From 7,221 inmates in the 12 prisons, we enrolled 3,380
inmates for the study. The results of initial screening were
previously reported [8]. Among these, 1,422 remained
incarcerated in the same prison after 1 year (Fig. 1); this
subset comprises the prospective cohort in whom TST
conversions and TB incidence were assessed. The majority
of study participants were men (87 %) and mean age was 33
years old (SD: ±10 years, range: 18–80 years). Previous
incarceration was reported among 61 % of participants, and
45 % had less than 4 years of school- ing. We identified 18
(1.3 %) inmates with positive HIV serology. At baseline, 66
% reported at least 1 TB symp- tom as defined by the WHO
and 23 % had productive cough (Table 1). Among 1,422
inmates followed for one year, baseline latent and active TB
prevalence were 21 % (95 % CI: 19–24 %) and 0.7 % (95
% CI: 0.3–1.3 %), re-
spectively (Fig. 1).
A second TST was performed in 1,379 (97 %) inmates who
remained incarcerated at one year. Among 1,089 participants
with a negative TST at baseline, 1060 had a TST performed
at one year, and 272 (25.7 %, 95 % CI 22.7–28.9 %)
converted. TST conversion was higher in male compared to
female prisoners (28 % versus 10 %; p < 0.01), while TB
incidence was non-significantly higher (1.39 % versus 0.53
%; p = 0.68) (Table 2). No difference in TST conversion
rates was observed when comparing HIV-uninfected and
HIV-infected prisoners (26 % versus 25 %, p = 0.95).
During the first year of follow-up, active TB was diag- nosed
in 18 participants in the active screening group. All tested
negative for HIV at baseline and after 1 year. All but 1 case
occurred among male inmates, and 9 (36 %) occurred in
just one prison, the maximum-security prison in Campo
Grande. Seven cases were diagnosed at the time of the
second survey (Table 2).
While cases identified through active screening were much
less likely to be smear positive than those identified
 4

by passive case detection (10.0 % vs 50.9 %; p < 0.01), there 6-month duration of disease before diagnosis, death, or re-
was no statistical difference in the subsequent cumulative lease; it is during this window that transmission occurs.
incidence of the group that was actively screened versus While this period may be longer due to underestimation of
those not screened (1.3 % vs 1.7 %; log-rank p value = 0.88) prevalence, it nevertheless reflects a narrow window for
(Fig. 2). Drug susceptibility testing are done by con- diagnosis, in comparison with community estimates of in-
ventional broth-based culture methods using the MGIT 960 fectious duration that are often twice as long [13].
system and did not identify any case of multidrug- resistant The effective contact rate (annual risk of infection di- vided
tuberculosis. Drug use during the year (AHR 3.22; 95 % CI by prevalence) during this period is extremely high
1.05–9.89) and knows somebody with TB were (AHR 2.86; (>36/year), reflecting high rates of transmission and could
95 % CI 1.01–8.10) associated with active TB during one year represents the confluence of several factors: 1) overcrowding;
of follow up (Table 1). 2) poorly ventilated environments; 3) limited TB diagnostic
infrastructure; and 4) an inmate population with low prevalence
Discussion of latent tuberculosis infection (LTBI) upon initial
The extraordinarily high incidence of TB infection (25.7 %) incarceration, who are at higher risk for infec- tion upon
and disease (1,275 per 100,000 inmates) indicate a critical need exposure [7, 8, 14–16].
to address TB transmission inside prisons. By compar- ing TB WHO and the Brazilian Ministry of Health recom- mend
prevalence with incidence, we estimate an average screening for TB in prions at entry and annually;
 5

Table 1 Risk factors associated with incident cases of active tuberculosis (TB) among inmates from 12 Brazilian prisons during one
year of follow-up (N = 1,422)
Variables N (%) Active TB
Crude hazard ratio p-value Adjusted hazard ratio p-value
Age (mean ± SD) 32.6 ± 9.7 0.99 (0.95–1.04)a 0.821
Sex (Male) 1235 (86.8) 2.63 (0.35–19.73) 0.348
Race
White 463 (33.9) 1.0
Mixed 685 (50.2) 0.94 (0.30–2.98) 0.924
Black 170 (12.5) 3.30 (1.01–10.83) 0.048b
Indigenous 19 (1.4) -
Asian 28 (2.1) -
Reported any WHO TB symptom at baseline 934 (65.7) 2.63 (0.76–9.09) 0.126b
Reported productive cough at baseline 325 (22.9) 2.25 (0.87–5.80) 0.094b
Less than 4 year of schooling 772 (55.5) 1.63 (0.61–4.36) 0.323
Diabetes Mellitus 0 (0.0) - -
Current Smoker 730 (51.8) 2.47 (0.88–6.94) 0.085b
HIV positive 18 (1.3) - -
Drug use over the last year 739 (52.0) 3.91 (1.29–11.87) 0.016b 3.22 (1.05–9.89) 0.042
Previous incarceration 860 (60.8) 1.03 (0.40–2.66) 0.951
TST positive 290 (21.0) 1.74 (0.60–5.00) 0.306
Previous TB 92 (6.6) 3.01 (0.90–10.70) 0.074b
Knows someone with TB 607 (43.5) 3.45 (1.24–9.73) 0.018b 2.86 (1.01–8.10) 0.049
a
Per 1-year increase
b
Variables initially included in the multivariate model, which was trimmed through backward selection

however, in practice, this was not being performed in any
of the study prisons. In this study, mass screening appeared
to identify patients early in the course of disease, as reflected
by lower smear positivity rates (10.0 % vs
50.9 % by passive diagnosis); similar findings concerning
smear positivity have been demonstrated in community
settings comparing active and passive case detection [17].
However, subsequent TB incidence among screened indi-
viduals was not significantly reduced. This may be a result
of the extremely high force of infection driving new cases.

Table 2 Tuberculin skin test (TST) conversions and tuberculosis (TB) incidence in 8 male and 4 female Brazilian prisons (N = 1,422)
Variables Prisons
Male Female Total
Capacity 2,469 451 2,920
Inmate population 6,552 669 7,221
Individuals enrolled at baseline 2,861 519 3,380
Individuals followed for 1 year 1,235 187 1,422
TST-negative subjects 905 155 1,060
TST converted subjects 256 16 272
TST conversion rate, %a 28 (25–32) 10 (6–17) 26 (23–29)
Incident cases reported between screenings 17 1 18
TB cases at 1st screening 10 0 10
TB cases at 2 nd screening 7 0 7
TB incidence, %a,b 1.39 (0.81–2.22) 0.53 (0.01–2.98) 1.27 (0.76–2.02)
Abbreviations: TB tuberculosis; TST tuberculin skin test
a
Percentage and 95 % confidence interval
b
Cases identified between screenings or at second screening as a proportion of individuals followed for 1 year

Moreover, the majority (72 %) of TB diagnoses were made
passively between the two active screening points. En-
hanced screening for active TB, while valuable, may be in-
sufficient to effectively control TB in prisons [8]. Most
likely, multiple interventions will be necessary to reduce TB
transmission in prisons in resource-poor countries. Emphasis
on direct measures to reduce transmission, such as reducing
crowding and improving ventilation [7], or re- ducing
disease risk among recently infected inmates, may be needed
to control TB under these conditions.
There are two broad classes of proven interventions for
averting TB transmission: expedited diagnosis with
treatment of infectious cases, and preventive therapy for
LTBI. In Alaska (U.S.), for example, vigorous programs
for early diagnosis, treatment and isoniazid preventive
therapy (IPT) had rapid and dramatic effects on TB inci-
dence and transmission [18, 19]. Currently, the WHO
provides a conditional recommendation for LTBI screen-
ing and provision of isoniazid preventive therapy (IPT) in
prisons in high and upper middle-income countries [20],
but the Brazilian MoH does not recommend treat- ing
inmates with a positive TST. In contrast, treatment is
recommended and has been shown to be effective in
controlling the disease in other high-risk populations,
such as indigenous groups [21]. Screening for TB at the
entry and annually, with provision of IPT for infected in-
dividuals, has been effective at reducing TB incidence in
the United States [22], but there are few published data on
the use of IPT in penal institutions in resource-poor
6
countries. Our finding of low LTBI prevalence at time of
prison admission and a high rate of TST conversion after one
year suggests that annual TST screening and treat- ment of
LTBI could potentially be an effective interven- tion in this
setting [23].
Although two previous cross-sectional studies have shown
that drug use was associated with active TB in prisoners
populations [24, 25], this is the first cohort study designed
to identify individual risk factors associ- ated with active TB
inside the prisons. Drug use over the last year (AHR 3.22; 95
% CI 1.05–9.89) was associated with active TB and drug
abuse program need to imple- ment to reduce the incidence
of active TB in prisons.
Urrego et al. documented overcrowding and inad- equate
ventilation in 3 prisons included in this study [7]. In a recent
study in prisons in Chile, overcrowding was identified as a
key determinant of LTBI among contacts of active TB cases
[14]. In our study, female prisons were at 148 % (669/451)
capacity, while male prisons were at 265 % (6,552/2,469)
capacity (Table 2). The higher TST conversion rates and
active TB incidence in male prisons compared with female
prisoners may be in part due to greater overcrowding in the
former.
Our findings are subject to several limitations. We used the
TST conversion to assess tuberculosis infec- tions, which has
imperfect sensitivity and specificity, but is the primary
modality of latent tuberculosis infection testing in Brazil. To
test for active tuberculosis, we per- formed smear and culture
on two sputum specimens.

Chest radiography is not available in the prisons, which
could enhance screening sensitivity and could potentially
decrease TB transmission and incidence. While recom-
mended by Brazilian guidelines, screening for TB upon entry
into prisons is not routinely performed. TB inci- dence in the
general population of this state is <40 per 100,000, and we
have previously found LTBI prevalence of <10 % at entry to
prisons [8], suggesting entry screen- ing may have low yield
[26].
At the individual level, we found no impact of screen- ing on
subsequent TB diagnosis rates. We enrolled only half
(3,380/7,221) of the total prisoner population, and
transmission from the unscreened group may have lim- ited
any population-level transmission benefits of screening.
Achieving higher screening coverage and screening more
frequently would likely have a greater impact on subsequent
TB incidence in both the screened and non-screened
population. A caveat is that the me- dian duration of
incarceration is under 2 years in this population, meaning
that the inmate population turns over quickly between
annual screenings, potentially diminishing the impact of this
intervention. An add- itional consequence of the high
turnover rates are that loss to follow-up in prospective
cohorts of prisoners are high, as was the case in this study;
since we randomly selected inmates for screening, this was
unlikely to bias the study findings. We did not collect clinical
or demo- graphic data on the inmates who were not
enrolled in the screening group; as we randomly selected
individuals for recruitment and participation rates were
high, the risk for selection bias was low. Additionally, our
findings were from the “closed” system, where prisoners are
in- carcerated continuously, and further work is needed to
characterize risks in the “open” system, a transitional en-
vironment where prisoners are only housed at night.
Conclusions
In a network of 12 prisons in central western Brazil, TB in-
fection and disease rates were extraordinarily high. More
aggressive interventions—including more frequent screen- ing
and use of preventive therapy—may be required to re- duce
the burden of TB in this high transmission setting. Moreover,
the high TB rates found in these prisons not only represent an
institutional public health crisis, but also a threat to the control
of TB in the broader population, as supported by molecular
evidence of spillover in this com- munity [15]. The high rate
of incarceration and movement combined with extraordinary
infection rates, indicate that prisons can be important
reservoirs of TB transmission to the general population.
Urgent interventions are needed to address the unimpeded
spread of TB in Brazil’s prisons.
Abbreviations
AHR: adjusted hazard ratio; CHR: crude hazard ratio; CI: confidential interval; CXR:
Chest X radiography; ELISA: enzyme-linked immuno sorbent assay, HIV,
7
human immunodeficiency virus; IPT: isoniazid preventive therapy; LTBI: latent
tuberculosis infection; MGIT: Mycobacteria Growth Indicator Tube;
PPD: purified protein derivative; REDCap: Research Electronic Data Capture
database; SD: standard deviation; SINAN: Sistema de Informação de Agravos de
Notificação National; TB: tuberculosis; TST: tuberculin skin test;
WHO: World Health Organization
Acknowledgements
We would like to thank the students from the Federal University of Grande
Dourados and Mato Grosso do Sul who participated in the data collection for the
study. We would also like to thank the State Agency of Administration Prisons
(AGEPEN) for their full support during the study period and Sandra Maria do
Valle Leone de Oliveira for her advice in designing the study.
Funding
This study was funded and sponsored by Fundação de Apoio ao
Desenvolvimento do Ensino, Ciência e Tecnologia do Estado do Mato Grosso do
Sul (FUNDECT, grant no. 0059/2013), the Ministry of Education (PROEXT), the
Brazilian National Research Council (Ciências sem Fronteiras Program) and the
Fogarty Global Health Equity Scholars Program (NIH 1 R25 TW009338). The
funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Availability of data and materials
The data will not be shared in order to protect the participants' anonymity.
Authors’ contributions
DSGP and EFL were involved in conception, design, data collection and
analysis and drafted the manuscript. ASSC, RVES, ALJ, FMS, LMB, VSM, SS,
ARCMT, MAP were involved in data collection and analysis and drafted the
manuscript. JU were envolved in drafted the manuscript. AIK and JA were
involved in data analysis and obtaining funding for the fieldwork and review
the manuscript. JC was involved in conception, design, data analysis,
coordination of the study, obtaining funding for the fieldwork and review
the manuscript. All authors contributed in writing of the manuscript and
approved submission of the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent to publish
Not applicable.
Ethics approval and consent to participate
All eligible participants provided written informed consent prior to study
participation. The study was approved by the Research Ethics Committee at the
Federal University of Grande Dourados (CAAE: 24549414.7.0000.5160).
Author details
1
Faculty of Health Sciences, Federal University of Grande Dourados,
Dourados, Brazil. 2School of Medicine, Federal University of Mato Grosso do Sul,
Campo Grande, Brazil. 3Faculty of Ambiental and Biological Sciences, Federal
University of Grande Dourados, Dourados, Brazil. 4Department of Biochemical
Pharmacy, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
5Oswaldo Cruz Foundation, Campo Grande, Brazil.
6
Department of Epidemiology of Microbial Diseases, Yale School of Public
Health, New Haven, CT, USA. 7Oswaldo Cruz Foundation, Salvador, Brazil. 8Division
of Infectious Diseases and Geographic Medicine, Stanford School of Medicine, Palo
Alto, CA, USA.
Received: 9 June 2016 Accepted: 24 September 2016
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 40

Artigo 2 - Evaluating strategies for control of tuberculosis in prisons and prevention of spillover
into communities: An observational and modeling study from Brazil

Authors:
Tarub S. Mabud1, Maria de Lourdes Delgado Alves2, Albert I. Ko3, Sanjay Basu1, Katharine S. Walter1,Ted
Cohen3, Barun Mathema4, Caroline Colijn5, Everton Lemos6, Julio Croda6, Jason R. Andrews1

Affiliations:

1Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA,
94305, USA
2Agência Estadual de Administração do Sistema Penitenciário, Bairro Coronel Antonino, Campo Grande,
MS 79011-190, Brazil
3Department of Epidemiology of Microbial Diseases, Yale School of Public Health, 60 College Street,
New Haven, CT 06510, USA
4Department of Epidemiology, Mailman School of Public Health, Columbia University
West 168th Street, Room 707, New York, New York 10032, USA
5Department of Mathematics, Imperial College London, 180 Queen's Gate, London, SW7 2AZ, UK
6School of Medicine, Federal University of Mato Grosso do Sul, Av. Costa e Silva, Campo Grande, MS
79070-900, Brazil

Published: January 24, 2019

PLOS Medicine
1549-1676 PLOS MEDICINE (ONLINE) MEDICINA II A1

Anexo D - Informações de Suporte matemático

 41

RESEARCH ARTICLE

Evaluating strategies for control of tuberculosis in

prisons and prevention of spillover into communities: An
observational and modeling study from Brazil
Tarub S. Mabud 1, Maria de Lourdes Delgado Alves2, Albert I. Ko 3, Sanjay Basu 1, Katharine S.
Walter1, Ted Cohen 3, Barun Mathema4, Caroline Colijn 5,6,
Everton Lemos7, Julio Croda 7,8, Jason R. Andrews 1*

1 Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America, 2
Agência Estadual de Administração do Sistema Penitenciário, Campo Grande, Brazil,
3 Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United
States of America, 4 Department of Epidemiology, Columbia University Mailman School of Public Health, New York,
New York, United States of America, 5 Department of Mathematics, Imperial College London, London, United
Kingdom, 6 Department of Mathematics, Simon Fraser University, Burnaby, Canada, 7 School of Medicine, Federal
University of Mato Grosso do Sul, Campo Grande, Brazil, 8 Oswaldo Cruz Foundation, Campo Grande, Brazil
confidential data. Prison record data are available from the Agência Estadual de Administração do Sistema Penitenciário (AGEPEN:
www.agepen.ms. gov.br) for researchers who meet the criteria for access to confidential data.

OPEN ACCESS

Citation: Mabud TS, de Lourdes Delgado Alves M, Ko

AI, Basu S, WalterKS, Cohen T, et al. (2019) Evaluating
strategies for control of tuberculosis in prisons and
prevention of spillover into communities: An
observational and modeling study from Brazil. PLoS Med
16(1): e1002737. https://
doi.org/10.1371/journal.pmed.1002737

Academic Editor: John Z Metcalfe, University of

California San Francisco, UNITED STATES

Received: July 3, 2018

Accepted: December 24, 2018

Published: January 24, 2019

Copyright: © 2019 Mabud et al. This is an open access

article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.

Data Availability Statement: Tuberculosis data are

available from the Brazilian Ministry of Health’s
Sistema de Informação de Agravos de Notificação
(SINAN: http://portalsinan.saude.gov.br) for
researchers who meet the criteria for access to
 42
data to populate a compartmental model of TB transmission and incarceration to eval- uate the effects
* jandr@stanford.edu of various prison-based interventions on the incidence of TB among prison- ers and the general
population. Annual mass TB screening within Brazilian prisons would

Abstract

Background
It has been hypothesized that prisons
serve as amplifiers of general
tuberculosis (TB) epi- demics, but
there is a paucity of data on this
phenomenon and the potential
population-level effects of prison-
focused interventions. This study (1)
quantifies the TB risk for prisoners as
they traverse incarceration and
release, (2) mathematically models the
impact of prison- based interventions
on TB burden in the general population,
and (3) generalizes this model to a wide
range of epidemiological contexts.

Methods and findings

We obtained individual-level
incarceration data for all inmates (n =
42,925) and all reported TB cases (n =
5,643) in the Brazilian state of Mato
Grosso do Sul from 2007 through 2013.
We matched individuals between
prisoner and TB databases and
estimated the incidence of TB from the
time of incarceration and the time of
prison release using Cox proportional
hazards models. We identified 130 new
TB cases diagnosed during
incarceration and 170 among
individuals released from prison.
During imprisonment, TB rates
increased from 111 cases per 100,000
person-years at entry to a maximum of
1,303 per 100,000 person-years at 5.2
years. At release, TB incidence was 229
per 100,000 person-years, which
declined to 42 per 100,000 person-
years (the average TB incidence in
Brazil) after 7 years. We used these

Funding: This work was supported by the National
Institutes of Health (https://www.nih.gov/) (grant
#R01 AI30058 [JRA]; #DP2 MD010478 [JRA, SB];
#U54 MD010724 [SB]; #R25 TW009338 [AIK];
#D43 TW010540 [AIK]), the Engineering and
Physical Sciences Research Council (https://epsrc.
ukri.org/) (grant #EP/K026003/1 [CC]; #EP/
N014529/1 [CC]), the Stanford Medical Scholars
Program (http://med.stanford.edu/medscholars. html)
(TSM), and the Infectious Disease Society of America
Medical Scholars Program (http://www.
idsociety.org/Medical_Scholars_Program/) (TSM). The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript.
Competing interests: I have read the journal’s
policyand the authorsof thismanuscripthave the
following competing interests: SB receives a
stipend as a specialty consulting editor for PLOS
Medicine and serves on the journal’s editorial
board.
Abbreviations: AHR, adjusted hazard ratio; BCI,
Bayesian credible interval; IPT, isoniazid preventive
therapy; IQR, interquartile range; LMIC, low- and
middle-income country; MDR, multidrug-resistant;
SIGO, Sistema Integrado de Gestão Operacional;
SINAN, Sistema de Informação de Agravos de
Notificação; TB, tuberculosis; WHO, World Health
Organization.
43
reduce TB incidence in prisons by 47.4% (95% Bayesian credible interval [BCI], 44.4%– 52.5%)
and in the general population by 19.4% (95% BCI 17.9%–24.2%). A generalized model
demonstrates that prison-based interventions would have maximum effectiveness in reducing
community incidence in populations with a high concentration of TB in prisons and greater degrees of
mixing between ex-prisoners and community members. Study limitations include our focus on a
single Brazilian state and our retrospective use of administrative databases.
Conclusions
Our findings suggest that the prison environment, more so than the prison population itself, drives TB
incidence, and targeted interventions within prisons could have a substantial effect on the broader
TB epidemic.
Author summary
Why was this study done?
• Tuberculosis (TB) remains a leading cause of infectious disease mortality
worldwide, despite global efforts to combat it.
• Certain environments such as prisons predispose individuals to higher than normal
risk of TB.
• High-risk prison environments may sustain and amplify TB transmission in their
sur- rounding communities as individuals are incarcerated and released.
• The time course of TB risk following incarceration and release has not been well
charac- terized, and the impact of interventions conducted in prisons upon the
community TB epidemic is not known.
What did the researchers do and find?
• We used Brazilian TB and prisoner databases to quantify the TB risk for
individuals throughout incarceration and release from prison.
• We created a mathematical model to simulate prison-based TB interventions
among prisoners, ex-prisoners, and the general population in a Brazilian
community and then generalized this model to a wide range of epidemiological
contexts.
• After incarceration, the TB risk for a prisoner rises to 30 times that of a
community member, and this risk remains elevated for 7 years after release
from prison.
• A comprehensive intervention including mass screening, entry and exit screening,
improved diagnostics, and isoniazid preventive therapy conducted within Brazilian
pri- sons would reduce active TB incidence by 79% in the prisons and by 40% in the
general population.
 44

• Across global contexts, prison-based TB interventions would

have maximum effective- ness in reducing community
incidence of TB in populations with a high concentration of
disease in prisons and greater degrees of mixing between ex-
prisoners and commu- nity members.

What do these findings mean?

• The prison environment, more so than an inherently high-risk

prison population, drives TB incidence in prisons.
• Targeted interventions within prisons could substantially
impact TB epidemics in the general population.

INTRODUCTION

The World Health Organization’s (WHO) “End Tuberculosis Strategy”

targets a 90% reduc- tion in tuberculosis (TB) incidence by 2035, which
requires significant acceleration in the 2% annual decline seen at present
[1]. A major obstacle to achieving TB control in low- and mid- dle-income
countries (LMICs) is thought to be the concentration of disease in high-
burden subpopulations, which serve as reservoirs or amplifiers for TB
epidemics in the general popula- tion. This concept is supported by some
ecological analyses [2], but there have not been detailed epidemiologic
investigations of “institutional amplifiers” or how targeting them might
impact population-wide TB dynamics.
Prisons are a plausible candidate “institutional amplifier” for TB, globally.
A recent meta- analysis estimated a median TB incidence rate ratio of 26 in
prisons compared with the refer- ence general population [3,4]. Genotypic
evidence has supported linkage between TB cases in prisons and the general
population [5,6], but these data have come from focal outbreaks and have
not clarified the extent to which spillover from prisons may drive
community epidemics [6–11]. Data on TB within correctional facilities are
frequently not made available to the pub- lic, and there is a paucity of data
on TB incidence following release from prison, hindering quantitative
investigations on the dynamics of TB epidemics in prisons and the general
popu- lation. This lack of data also impedes the development of
interventions to combat TB. Most prisons in LMICs rely upon passive case
detection, in which inmates are referred for diagnostic workup only after
they become symptomatic. WHO conditionally recommends active case
detection, including screening upon entry into prisons, but characterizes the
supporting evi- dence as very low quality [12]. Consequently, few countries
routinely perform enhanced TB control activities in prisons, such as entry
and exit screening, periodic mass screening, or pro- vision of isoniazid
preventive therapy (IPT). There is a clear need for more data to guide the
 45

design and selection of interventions to combat the spread of TB in prisons

and their sur- rounding communities.
To address these knowledge gaps, we utilized a unique opportunity to
link comprehensive incarceration and TB notification datasets in the
Brazilian state with the highest incarceration rate, Mato Grosso do Sul.
We estimated hazards of TB during incarceration and upon release from
prison, and we used these data to parameterize a mathematical model that
describes the transmission dynamics of TB in prisons and the general
population. We then projected the impact of interventions conducted
within the prisons on TB incidence in the general
 46

population, further generalizing this to settings with varying

incarceration rates and concen- trations of TB within prisons.

METHODS

Study setting
Brazil has the third-largest incarcerated population in the world [13], and a
rapidly growing proportion of TB cases occur in the correctional system
[5,14–16]. With a population of 2.6 million, the state of Mato Grosso do Sul
lies in central-west Brazil, adjoining Paraguay and Bolivia. The state has the
highest incarceration rate in Brazil (475 prisoners per 100,000 indi- viduals),
driven primarily by drug trafficking across country borders [17].

DATA COLLECTION

We determined the analysis plan prior to the capture of any data and
followed this plan with- out major adjustments. To calculate the annual
incidence of active TB among prisoners and ex-prisoners in Mato Grosso
do Sul, we used two electronic databases: Sistema de Informação de
Agravos de Notificação (SINAN, 2006–2015), the Brazilian Ministry of
Health’s mandatory reporting system for TB; and Sistema Integrado de
Gestão Operacional (SIGO, 2005–2014), the prison record system for Mato
Grosso do Sul. We limited our analysis to the period between January 1,
2007, and December 31, 2013, for which complete data were obtained from
both databases.
SINAN is populated with mandatory reporting forms that are filled out
by healthcare pro- viders on the day a TB diagnosis is determined.
Submitted data comprise a wide range of demographic and clinical
information including name, date of birth, date of death, date of TB
diagnosis, and mother’s name. We had access to SINAN data only for the
state of Mato Grosso do Sul.
SIGO contains the prison records of all individuals incarcerated in Mato
Grosso do Sul. We received permission from the state prison administration
agency to access SIGO within their prison computer network. In general,
information can only be accessed for one prisoner at a time in SIGO, and
only if the prisoner’s name or prison ID number are known; exportation of
the entire database was not feasible given the high sensitivity of the data and
the need to rigor- ously maintain confidentiality. We therefore obtained an
autogenerated report from the SIGO platform, available to certain
administrators, which described comprehensive prisoner move- ment within
the state’s prisons and contained prisoner name, a unique identifier, and all
dates of entry into, transfer between, and release from prison, along with
corresponding prison names.
 47

DATABASE LINKAGE

We identified prisoners and ex-prisoners who had been diagnosed with

active TB between 2007 and 2013 by matching individuals in SINAN
and the SIGO report (Fig 1). We limited SINAN to new adult active TB
diagnoses (as opposed to recurrent cases) in Mato Grosso do Sul
between the years 2007 and 2013 (n = 5,643). To link the two databases,
we constructed a name-matching algorithm in GREL using OpenRefine
version 2.6 [18], which combines pho- netic fingerprinting and a
distance function between strings, to identify “fuzzy” matches— names
that are similar but not necessarily identical—between SINAN and the
SIGO report [19,20]. We increased the allowable distance between
matched names until we achieved a sen- sitivity of 100% when
comparing the algorithm matches to an independent dataset of 42
confirmed active prisoner TB cases in the city of Dourados, Brazil
(within Mato Grosso do Sul), in 2013.

Fig 1. Flow diagram of database linkage and selection of individuals for survival analyses. MS, Mato Grosso do Sul; SIGO,
Sistema Integrado de Gestão Operacional; SINAN, Sistema de Informação de Agravos de Notificação; TB, tuberculosis.
https://doi.org/10.1371/journal.pmed.1002737.g001

The matching process produced 1,258 fuzzy matches between the two
databases. Two investigators independently queried each fuzzy match
 48

within the official SIGO database, which allowed for manual comparison
of date of birth, mother’s name, city of birth, and father’s name between
SINAN and SIGO. From the pool of fuzzy matches, we verified 615 cor-
rectly matched individuals who were diagnosed with active TB either
during or after a period of incarceration.

HAZARD ESTIMATION

We performed separate survival analyses for prisoners and ex-prisoners

with the primary end- point of TB diagnosis. We focused our analyses on
first incarcerations and the release period following first incarceration,
generating two cohorts: (1) prisoners who had their first incarcer- ation
between 2007 and 2013 and (2) ex-prisoners who had been released
from their first incarceration between 2007 and 2013.
For prisoners, we initiated follow-up at the start of first imprisonment
and censored indi- viduals at the time of release, death, or the end of the
study period. For ex-prisoners, we began follow-up at the date of release
from first incarceration and censored individuals at the time of
reincarceration (if they had multiple incarcerations), death, or the end of
the study period. All

Fig 2. Incidence of TB among (A) Mato Grosso do Sul prisoners and (B) ex-prisoners based on length of incarceration and length of time following
incarceration, respectively, with 95% bootstrap confidence intervals in blue shading. Histograms of individuals included in each survival analysis are overlaid. TB,
tuberculosis.

https://doi.org/10.1371/journal.pmed.1002737.g002

statistical analyses were performed in R version 3.5.0 [21]. We performed

right-censored sur- vival analyses for the prisoner and ex-prisoner cohorts
using the package “survival” [22] and generated smoothed estimates of the
 49

hazard functions using the package “muhaz” [23]. We constructed 95%

confidence intervals for hazard function estimates with 10,000 iterations of
bootstrap resampling with replacement (Fig 2). The incidence of TB was
calculated for both prisoners and ex-prisoners throughout the study period as
the number of new cases every 6 months divided by the number of
individuals at risk at the start of that time period and was then doubled to
annualize rates.
We performed multivariate Cox regression upon the ex-prisoner cohort
to identify any sig- nificant differences in active TB hazard between
individuals who were in male or female pri- sons, within the largest
maximum security prison or any other prison, or based on the duration
of first incarceration. We evaluated the proportional hazards
assumption through both graphical and statistical assessment of
Schoenfeld residuals.

MODEL

We created a mathematical model to simulate TB transmission dynamics

among prisoners, ex-prisoners, and the general population. The model
describes the prison population and cor- responding local general
population using a compartmental approach (Fig 3), characterizing the
transitions between disease states, and linking the distinct populations
of community members, prisoners, and ex-prisoners. Susceptible
individuals (S), upon infection, move to an early latent stage (E) from
which they can progress either directly (i.e., fast progression) to an
infectious stage (I) or to a late latent stage (L). Late latent individuals may
also progress to become infectious, and infectious individuals are
diagnosed, rendered noninfectious by treat- ment, and considered
recovered (R). Susceptible individuals are introduced into the popula-
tion via birth (μ) and die at an equivalent rate in this closed-population
model. Susceptible individuals are infected to the early latent stage with
a force of infection equal to the
 50

Fig 3. Compartmental model of TB transmission, describing the progression of disease from susceptible (S) to early latent infection (E), late latent infection (L),
infectious (I), and recovery (R) among prisoners (subscript p, pink boxes), ex-prisoners (subscript e, purple boxes), and other community members (subscript c,
blue boxes). Solid arrows represent the dynamics of TB transmission, whereas dotted arrows represent the dynamics of incarceration and release from prison.
The prison environment is shaded blue to distinguish it from the external environment, which comprises ex-prisoners and other community members. TB,
tuberculosis.

https://doi.org/10.1371/journal.pmed.1002737.g003

transmission parameter (β) multiplied by the proportion of infectious

individuals (I/N). Those with early latent infections progress to late
latency or infectiousness at rates w and τ, respec- tively. Late latent
individuals progress to the infectious stage at rate v, whereas infectious
indi- viduals are diagnosed and are immediately assumed to be started on
therapy and no longer infectious at rate d. Individuals can be reinfected
while in the late latent state (at rate α1 times the force of infection) or
recovered state (at rate α2 times the force of infection) back to the early
latent stage, which has a higher rate of progression to infectiousness.
Recovered individu- als are also susceptible to disease relapse at rate γ.
Parallel SELIR states exist for prisoners, ex- prisoners, and never-
incarcerated community members.
We parameterized the model with a combination of local data, well-
characterized values from literature, and fitted values; as the factors driving
TB transmission dynamics differ in the prison and community settings, the
parameter values differ between the three population groups modeled
 51

(Table 1). We did not model multidrug-resistant (MDR) TB or HIV, as rates

of both are low (<1% and <2%, respectively) in this context [24].
For the rates of TB progression among prisoners and case detection, which
are poorly char- acterized in the literature, we applied Latin Hypercube
Sampling [30] to sample from distributions of values supported by the
literature and a regularized sum-squared error process to select the sets
that generated model incidences that best fit our prisoner and ex-prisoner
incidence estimates. The model equations, calibration process, and
parameter fitting methods are further described in the Supporting
Information (S1 Text).

Table 1. Parameters used to describe TB natural history and epidemiology in a Brazilian state.

Variable Definition Prisoner Ex-prisoner Community Source

β effective contact rate 17.0 (10–30) 8.08 (4–12) 8.08 (4–12) Calculated
μ birth/death rate 0.017 0.017 0.017 [25]
τ rate of progression from early latent to infectious 0.09 (0.005–0.1) 0.03 (0.005–0.1) 0.01 (0.005–0.1) Calibration
v rate of progression from late latent to infectious .0008 .0008 .0008 [26]
w rate of progression from early latent to late latent 0.2 0.2 0.2 [27]
α1 susceptibility to reinfection upon reexposure 0.21 0.21 0.21 [28]
α2 rate of reinfection from recovered to early latent 0.21 0.21 0.21 [28]
γ rate of relapse from recovered to infectious 0.01 0.01 0.01 [29]
d rate of diagnosis and treatment initiation 0.55 (0.5–1.0) 0.85 0.85 Calibration
q rate of incarceration N/A 0.0182 0.00196 Calculated
r rate of release from imprisonment 0.5 N/A N/A Estimated from SIGO

Parenthetical values are the ranges used in sensitivity and uncertainty analyses. All rates are annual.
Abbreviations: SIGO, Sistema Integrado de Gestão Operacional; TB, tuberculosis.

https://doi.org/10.1371/journal.pmed.1002737.t001

INTERVENTION STRATEGIES

We investigated the effects of prison-based interventions on the incidence

of active TB after 10 years with our compartmental model of TB
transmission. We considered the effect of a 25% improvement in the
passive diagnosis rate, as may be achievable through replacement of spu-
tum smear microscopy with rapid molecular diagnostics and chest
radiography. We also inves- tigated an active case detection intervention,
whereby on a yearly basis, all individuals in the prisons are screened for
active TB, regardless of whether they are symptomatic, and are appro-
priately placed on therapy if found to have disease. We then tested an entry
screening program, in which all individuals entering prison are screened
for active TB. Similarly, we tested an exit screening program. Finally, we
modeled the provision of IPT, which aims to prevent disease by screening
individuals who enter the prison for latent TB and providing IPT if they
are found to be latently infected. Assumptions concerning the sensitivity,
 52

yield, and efficacy of these interventions are shown in the Supporting

Information (S1 Table). Uncertainty analyses were performed using Latin
Hypercube Sampling using the 100 best-fitting parameter sets from
model calibration.

SENSITIVITY ANALYSIS

We generalized our model of TB transmission in Mato Grosso do Sul to a

broader range of epi- demiologic scenarios in which the incarcerated
population size and the relative incidence of disease were varied across a
range of values observed in a recent meta-analysis [3]. We further varied
the rate of assortative mixing, modeled as the relative rate of mixing among
ex-prisoners and the general population, compared with their rate of
mixing between the groups. For these general models, we assumed that the
overall active TB incidence was the global average inci- dence (140 per
100,000 person-years) [12].

ETHICS STATEMENT

This study was approved by the following bodies: (1) the Stanford
University Institutional Review Board (IRB-34301), (2) the Federal
University of Grande Dourados (Opinion Number 877294), and (3)
Agencia Estadual de Administracao do Sistema Penitenciario (signed
docu- ment from the director of the state prison agency).

RESULTS

TB incidence among prisoners and ex-prisoners

Between 2007 and 2013, 25,939 individuals were incarcerated for the first
time in Mato Grosso do Sul, with a median duration of incarceration of 1.53
years (interquartile range [IQR]: 0.64– 2.68). Among these individuals, we
identified and verified 130 new active TB cases diagnosed during
incarcerations. Among 38,241 inmates released from prison for the first
time during this period, we verified 170 new cases (Fig 1). Median follow-
up after release was 2.56 years (IQR: 1.04–4.31). For prisoners, active TB
incidence increased from 111 per 100,000 person- years at the time of
incarceration to a peak of 1,303 per 100,000 person-years at 5.2 years, after
which it declined. Incidence at the median time of release (1.53 years) was
541 per 100,000 per- son-years. For ex-prisoners, active TB incidence was
229 cases per 100,000 person-years at release, declining to the baseline
community incidence [12], 42 cases per 100,000 person- years, at slightly
over 7 years (7.04 years) following release (Fig 2).
In Cox regression, the hazard of TB following release was 32% higher
for each additional year of incarceration (adjusted hazard ratio [AHR]: 1.32,
95% BCI 1.19–1.48, p < 0.0001). The largest maximum security prison in
 53

the state did not have a significantly higher AHR for active TB upon
release than all other prisons (AHR 1.65, 95% BCI 0.93–2.91, p = 0.09).
However, the hazard for active TB upon release from female prisons was
significantly lower than for male prisons (AHR 0.49, 95% BCI 0.29–0.84,
p = 0.009). The proportional hazards assumption was tested by evaluating
the relationship between Schoenfeld residuals and time for each individual
covariate, which was nonsignificant (p = 0.86 for global test).

IMPACT OF INTERVENTIONS ON TB INCIDENCE

We calibrated our model to contemporary estimates of baseline active TB

prevalence in pri- sons (2,400 per 100,000) and incidence in the
community (42 per 100,000). We then deter- mined the effects of various
interventions over a 10-year period, which are reported as relative
incidence reductions and associated 95% Bayesian credible intervals
(BCIs) (Fig 4).
If all individuals entering prisons were screened for active TB with 75%
sensitivity, disease incidence would decrease in prisons by 10.3% (95% BCI
5.2%–18.8%) and by 3.3% (95% BCI 1.9%–5.6%) outside. If all individuals
exiting prisons were screened, incidence would decrease in prisons by 14.8%
(95% BCI 8.2%–30.0%) and by 27.0% (95% BCI 25.0%–32.4%) outside.
Provision of isoniazid to those with latent TB at prison entry would reduce
incidence in pri- sons by 23.5% (95% BCI 14.8%–36.8%) and by 16.1%
(95% BCI 14.2%–18.2%) outside.
Improvement in the passive case detection rate by 25% would decrease
active TB incidence in prisons by 35.0% (95% BCI 30.1%–46.1%) and by
11.5% (95% BCI 10.0%–16.7%) outside. The single most effective
intervention implemented was an annual active case detection campaign;
this program would reduce active TB incidence in prisons by 47.4% (95%
BCI 44.4%–52.2%) and by 19.4% (95% BCI 17.9%–24.2%) outside.
Combining these five approaches would decrease active TB incidence in
prisons by 79.2% (95% BCI 70.2%–95.6%) and by 40.0% (95% BCI 36.1%–
44.3%) outside.
 54

Fig 4. Proportionate decrease in TB incidence over 10 years according to various prison-based interventions. Box and whisker plots describe uncertainty in
intervention effectiveness produced by Latin Hypercube Sampling analysis; boxes characterize 25th, 50th, and 75th percentile values; whiskers characterize a range
of values up to 1.5 times the IQR; and dots represent outliers beyond this range. IPT, isoniazid preventive therapy; IQR, interquartile range; TB, tuberculosis.

https://doi.org/10.1371/journal.pmed.1002737.g004

SENSITIVITY ANALYSES

The relative incidence of active TB among prisoners and the proportion of

prisoners in a pop- ulation were both strongly correlated with the
effectiveness of a prison-based active diagnosis intervention at the
community level (Fig 5). The intervention achieved maximum effectiveness
in a setting where there was a high proportion of incarcerated individuals
(1% of the popula- tion) and a high relative incidence of active TB in the
prisons compared to the community (a ratio of 75×). Conversely, the
percent decrease in general population TB incidence was at a minimum
when these two factors were the lower ends of the tested ranges (0.2% of
population incarcerated and 15× relative incidence). When we modify the
 55

assumption of proportionate mixing between ex-prisoners and other

community members to an assortative mixing pattern whereby each group
is three times more likely to contact individuals within their own group, the
magnitude of the intervention’s effectiveness remained considerable but was
lower (Fig 5).

Fig 5. Heatmap of percent decrease in community TB incidence brought about by active diagnosis intervention across ranges of relative TB incidence (prisoner/
community) and proportion of population incarcerated. Assumptions include (A) assortative mixing (3-fold relative rate of contact) for community members and
ex-prisoners and (B) proportionate mixing between community members and ex-prisoners. TB, tuberculosis.
https://doi.org/10.1371/journal.pmed.1002737.g005

DISCUSSION

There is a critical need to develop new TB control strategies to achieve

WHO’s global targets for 2035. One potential approach involves identifying
and targeting “institutional amplifiers” or “reservoirs” of TB. We found that
prisons in Brazil produce conditions favorable for ampli- fying TB epidemics
in the general population. Incarcerated individuals enter prison with a low
risk of TB, which increases rapidly over the course of 5 years, peaking at
over 1,300 cases per 100,000 person-years, or 30 times higher than that of
the general population. Upon release, former inmates have a nearly 5.5-
times-greater risk of active TB than the general population— a risk that
remains elevated for 7 years and is likely underestimated because of
outmigration. Focusing interventions on prisons may therefore have potent
effects on reducing rates of TB in the general population. We found that
focusing interventions on prisoners, who constitute less than 0.5% of the
population, would reduce the total active TB incidence in the population by
over 40%. The avertable TB burden is greater than the proportion of cases
 56

that occur among prisoners, because of the high turnover of this population
and dynamics of transmission in pri- sons and between prisons and
communities. These findings underscore the importance of identifying and
characterizing high-risk subpopulations for targeting TB control efforts.
A key question is whether the prison environment is the primary
driver of TB risk or whether high TB rates in prisons are primarily a
consequence of a population with preexisting high-risk attributes (e.g.,
HIV, substance abuse). The marked increase in TB risk that occurs upon
incarceration, along with the decline in incidence following release,
implicates the prison environment in driving disease in the population,
whether it is due to transmission or acquired host factors (e.g., malnutrition,
vitamin D deficiency) in the prison [31]. The observed peak of active TB
incidence at 5 years and subsequent decline is consistent with an extremely
high annual risk of infection occurring among a highly susceptible
population, such that the major- ity of inmates would be exposed within 3–
4 years. A recent study conducted in 12 prisons in Mato Grosso do Sul
demonstrated that only 9% of inmates had latent TB at the time of incar-
ceration, but an estimated 80% would be infected after 5 years [32]. The
decline in active TB hazard after 5–6 years of incarceration could be
explained by depletion of susceptible individu- als—the majority of
individuals have been infected and have either progressed to disease or
established latency. However, we note that we had limited data from
prisoners incarcerated over 5 years and caution against overinterpretation of
this finding.
We find an increased rate of TB notifications among ex-prisoners,
which declined steadily in the years following release but remained higher
than that of the general population for sev- eral years. Given low
transmission rates in the community, we believe this finding is driven
primarily by infections acquired within prisons, which manifest in the
years following release. Variability in disease progression and diagnosis
results in a long declining tail of notifications following exit from the high-
transmission prison environment [33]. Our model demonstrates that exit
screening would reduce the burden of disease among ex-prisoners and
therefore spill- over of TB from prisons into the community. Exit
screening could be even more effective in settings with low case-
detection rates in prison.
This is the first analysis to model the impact of prison-focused
interventions on preventing the spillover of TB into the general
population. WHO recently led a systematic review of the evidence on TB
case finding, but the panel was unable to reach consensus on active
screening among prisoners, citing very low-quality evidence [34]. The
conditional recommendation that it “should be considered” has not led to
widespread implementation among LMICs because of the resources and
high number of tests typically required to identify a case of active TB
[35,36]. Of the interventions modeled, we found active screening within
prisons to be the sin- gle most effective strategy in reducing TB incidence.
Whereas passive case detection, provision of IPT, entry screening, and
exit screening would have a more modest impact individually, a
combined intervention including all of these approaches, together with
mass screening, could avert nearly 80% of active TB cases in prisons and
40% of cases in the general population. Any public health interventions
directed toward prisons must consider the unique risks faced by prisoners,
 57

and care must be taken in the design and implementation of interventions

to ensure that human rights are protected. Interventions should be designed
to benefit prisoners’ health, with community benefit as a secondary
consideration.
Control programs often focus on entry screening in prisons, but our
findings suggest that exit screening could also play an important role in
reducing TB burden among prisoners at release and preventing
population spillover; we believe this should be considered as a possible
addition to guidelines. A three-phase program of screening at entry,
periodically during incar- ceration, and upon exit has been utilized
successfully in Malawi and may serve as a model [37].
To assess the generalizability of our model findings to other settings, we
examined the potential impact of interventions across a range of epidemiologic
scenarios for which the con- centration of a population’s TB within prisons
(the relative incidence rate and the size of the incarcerated population) varied
across a range seen in LMICs. As anticipated, the impact of targeted
interventions is greater in the settings with a larger incarcerated population
and greater disparities in incidence between prisons and the general
population. One critical unknown is the extent to which former prisoners mix
with the general population, for which data are not available. Higher levels of
assortative (e.g., “like with like”) mixing among ex-pris- oners would attenuate
the impact of prison-targeted interventions. However, given that the majority
of TB transmission does not occur between individuals known to one
another [38– 40], assortative mixing among ex-prisoners is not likely to
significantly curtail transmission to the general population. Moreover,
even with substantial assortative mixing, we find that inter- ventions
targeted to prisoners would have a substantial effect on the population TB
epidemic.
Our study has several limitations. We used state-level administrative
databases, which likely contain some degree of diagnostic or demographic
misclassification. To assess the hazard of primary TB, we limited our
analysis among prisoners and ex-prisoners to individuals free of TB at
baseline. This was done by filtering out individuals who were noted to have
an episode of active TB prior to ever entering the prison system. However,
we acknowledge that some individuals may have had prior TB that was not
captured in SINAN, and so some of these pri- mary TB cases may actually
be recurrent disease. We only assessed TB hazard for individuals who were
incarcerated for the first time, to mitigate analytical complexity; the
duration and frequency of recurrent incarcerations vary widely, and the
interpretation of TB risk across such variegated prisoner experiences would
be difficult. As such, our estimates of TB hazard only apply to individuals
who are newly incarcerated. However, our TB transmission model indeed
includes recidivism and multiple incarcerations in order to accurately
project the effect of interventions targeted to prisoners.
We were also unable to identify TB cases that occurred among ex-
prisoners who left the state, as we only had TB data for the state of Mato
Grosso do Sul. As a result, our findings con- cerning elevated TB incidence
among former prisoners are conservative, since they exclude TB cases that
may have occurred in other states. In a recent study of 13 prisons in Mato
Grosso do Sul, 36% of prison inmates reported being from another state in
Brazil [14]. These data sug- gest that a significant portion of the prison
population may leave the state following release, and so TB incidence
 58

among ex-prisoners may be considerably higher than we have calculated.

We assumed that the TB epidemic in the community and prisons is at steady
state, and popula- tion-level incidence has changed by <5% in the past 15
years; if TB incidence disparities are growing, as some evidence suggests
[17], our model would underestimate the benefits of inter- ventions targeted
in the prisons. Our model is a simplification of a complex process; we delib-
erately chose a parsimonious model structure that builds directly upon
widely used models in the TB literature. Although more complex models
would enable better fit to the local data [41], they would risk overfitting and
make it difficult to generalize results to other epidemiologic contexts.
Globally, more than 10 million individuals are incarcerated, an increase
of 20% since 2000 [13]. Virtually all studies of TB incidence in prisons
have found elevated risk compared to the general population, with
incidence rate ratios ranging from 2.5 to 151.1 [3]. Our data suggest that
prisons represent a major source of TB transmission that undermines
population-level TB control. The risk factors intrinsic to prison
environments, more so than inherently high-risk prison populations, drive
TB incidence, and targeted interventions within prisons could have a
substantial effect on the broader TB epidemic.

SUPPORTING INFORMATION

S1 Text. Description of equations, assumptions, calibration process, intervention scenar- ios, and sensitivity analyses
applied to model of TB transmission dynamics. TB, tuberculo- sis.

(DOCX)
S1 Table. Summary of prison-based interventions implemented in the model.

(DOCX)

S1 STROBE. STROBE Checklist.

(DOC)

ACKNOWLEDGMENTS

We would like to thank Paul Bourdillon, Tiffany Kung, Milinda Lakkam,

Otávio Miguel Lis- ton, and Nathan Lo for their assistance with this project.
We are grateful to Agência Estadual de Administração do Sistema
Penitenciário and the Brazilian Ministry of Health for providing access to
databases.
 59

AUTHOR CONTRIBUTIONS

Conceptualization: Tarub S. Mabud, Albert I. Ko, Ted Cohen, Julio Croda, Jason R.
Andrews.
Data curation: Tarub S. Mabud, Maria de Lourdes Delgado Alves,
Everton Lemos, Julio Croda.
Formal analysis: Tarub S. Mabud, Jason R. Andrews.
Funding acquisition: Jason R. Andrews.
Investigation: Tarub S. Mabud, Jason R. Andrews.
Methodology: Tarub S. Mabud, Albert I. Ko, Sanjay Basu, Katharine S.
Walter, Barun Math- ema, Caroline Colijn, Jason R. Andrews.
Project administration: Julio Croda, Jason R. Andrews.
Resources: Tarub S. Mabud, Julio Croda, Jason R. Andrews.
Software: Tarub S. Mabud.
Supervision: Julio Croda, Jason R. Andrews.
Validation: Tarub S. Mabud.
Visualization: Tarub S. Mabud.
Writing – original draft: Tarub S. Mabud.
Writing – review & editing: Tarub S. Mabud, Maria de Lourdes Delgado
Alves, Albert I. Ko, Sanjay Basu, Katharine S. Walter, Ted Cohen,
Barun Mathema, Caroline Colijn, Everton Lemos, Julio Croda, Jason R.
Andrews.

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6. DISCUSSÃO

Os resultados em 12 prisões estaduais de Mato Grosso do Sul, no ano de 2013,

demostraram baixa prevalência de ILTB (11,7% feminino; 22,5% masculino), alta taxa de TB
ativa (970 casos por 100 mil hab.) e ausência do rastreamento recomendados pela OMS e
MS. O cenário apresentado é de uma população que ao ingressar na prisão apresenta
prevalência muito baixa de ILTB (<10%), o que sinaliza baixa carga de TB na comunidade
(CARBONE et al., 2015).
Após um ano de acompanhamento desta população, com a realização do
rastreamento, observou-se 26% (IC 95%: 23 ± 29%) de risco de infecção na mesma, o que
leva a conclusão de que a taxa de infecção (risco anual de infecção dividido pela prevalência)
foi extremamente alta (> 36/ano), ocasionando maior risco de infecção após exposição. Esse
achado pode estar relacionado com a confluência de vários fatores, tais como superlotação
das celas, ambientes mal ventilados, e a baixa prevalência de infecção latente por TB (ILTB)
no encarceramento inicial, entre outros (URREGO et al., 2015; CARBONE et al., 2015;
AGUILERA et al., 2016; JOHNSTONE-ROBERTSON et al., 2011).
Estudos relacionados a superlotação nas prisões e a alta taxa de infecção na PPL tem
apresentado números mais elevados na população masculina em relação à feminina
(AGUILERA et al., 2016). Os achados corroboram esses estudos, pois a conversão do TT e a
incidência de TB ativa foram maiores nos homens do que nas mulheres (28% versus 10%, p
<0,01 e 1,94% versus 0,53%, respectivamente, p = 0,18).
Além da alta taxa de conversão observada, a incidência da doença com um ano de
rastreamento também se apresentou elevada, com 1.275 casos por 100.000. Esses dados
comparados com a população geral no Brasil e com a de Mato Grosso do Sul são
aproximadamente 40 vezes maiores (BRASIL, 2018). Percebe-se então a necessidade da
realização de intervenções o mais precocemente possível, uma vez que se tem configurada a
relevância deste cenário na saúde pública.
Entre os fatores de risco associados à TB ativa durante o rastreamento estão o uso de
drogas durante o ano (AHR 3,22; IC95% 1,05-9,89) e conhecer alguém com TB (AHR 2,86;
IC 95% 1,01-8,10). Embora dois estudos transversais anteriores tenham mostrado que o uso
de drogas estava associado à TB ativa entre PPL (ALAVI et al., 2014; ADESOKAN et al.,
2014), esta foi a primeira coorte de TB nas prisões que demonstrou a associação de dois
fatores individuais para TB ativa (p<0.05).
 63
O rastreamento anual realizado em nosso estudo demonstrou não ser suficiente para
efetivamente controlar a TB nas prisões; pois embora tenha sido realizada a detecção precoce
de casos (10% de baciloscopia positiva, comparado com 51% de casos identificados
passivamente); não ocorreu a redução do risco de doença subsequente nessas prisões; já
que a incidência da doença entre os PPL rastreados foi semelhante à identificada pelos
serviços de saúde (1,3% vs 1,7%, p=0,88), provavelmente devido a uma força extremamente
alta de infecção e a perda de seguimento > 50%.
Desta forma, múltiplas intervenções poderão ser necessárias para diminuir a
transmissão da TB nas prisões em países com poucos recursos, tais como medidas para
reduzir a superlotação e melhorar a ventilação (URREGO et al., 2015) com vistas a minimizar
o risco de progressão da infecção para o adoecimento.
Neste sentido, tem-se a compreensão de que novas abordagens são necessárias para
controlar a TB nesta configuração de alta transmissão, uma vez que os esforços atuais de
controle da TB não tem sido suficientes para alcançar a ambiciosa meta da OMS de reduzir
em 90% a incidência global de TB até 2035 (UPLEKAR et al., 2015; WHO, 2017).
Uma hipótese a ser considerada é a de que a presença de subpopulações de alta carga
da doença serve como “reservatório” ou até mesmo “amplificadores institucionais” da doença
para a comunidade, o que impacta negativamente nos esforços de controle da TB
(STUCKLER et al., 2008).
A transmissão da TB nas prisões tem um impacto significativo na comunidade em geral.
Estudo de caso controle realizado por Sachi et al. (2015) identificou que o encarceramento
prévio é o principal fator de risco associado a TB na população urbana, além disso, 54% das
cepas de Mycobacterium tuberculosis na comunidade foram relacionados com estirpes de
cepas encontradas nas prisões.
No Peru, Warren et al. (2018) ao analisar spillover de TB multidrogaresistente na prisão,
identificou aglomerados genéticos agregados espacialmente de TB-MDR na comunidade
semelhantes aos da prisão. Reforçando o efeito de transmissão da TB na população, o que
sugere que as intervenções na prisão podem ter benefícios que se estendem à comunidade
do entorno.
Desta forma, o estudo “Avaliação de estratégias de controle da tuberculose nas prisões
e prevenção de transbordamento para comunidades: um estudo observacional e de
modelagem no Brasil” foi delineado e possibilitou a quantificação das taxas de TB das prisões
e das comunidades locais estimando o risco de TB para uma amostra de 42.925 presos
brasileiros durante o encarceramento e após a sua saída. Os dados de encarceramento para
todos os presos e os casos (n = 5.643) de 2007 a 2013 do estado foram combinados das
 64
bases de dados de PPL e TB e, a seguir, foram estimadas a incidência a partir do momento
do encarceramento e o tempo de libertação da prisão.
No momento do encarceramento, no período de 2007 a 2013 observou-se as taxas de
TB aumentaram de 111 casos por 100.000 pessoas-ano para um máximo de 1.303 por
100.000 pessoas-ano (5,2 anos). Já, quando o fenômeno é observado após a saída do
encarceramento, tem-se uma incidência de TB de 229 por 100.000 pessoas-ano, que declina
progressivamente para 42 por 100.000 pessoas-ano, semelhante à incidência encontrada na
comunidade, mas alcançada a partir do sétimo ano do período.
O aumento acentuado do risco de TB que ocorre após o encarceramento, juntamente
com o declínio na incidência após a liberação, implicam o ambiente prisional na condução de
doenças na população, seja por fatores de transmissão ou hospedeiros adquiridos (por
exemplo, desnutrição, deficiência de vitamina D) na prisão (MACEDA et al., 2018). O pico
observado de incidência de TB em cinco anos e declínio subsequente é consistente com um
risco anual extremamente alto de infecção que ocorre entre uma população altamente
suscetível, de modo que a maioria dos presos seriam expostos dentro de 3 a 4 anos.
Com esses dados, elaborou-se um modelo comportamental de transmissão da TB e
encarceramento para avaliar os efeitos de intervenções na prisão quanto a incidência de TB
entre os PPL e a comunidade geral. Esta é a primeira análise que modela o impacto das
intervenções focadas dentro e fora das prisões.
Esse modelo, então propõe cinco estratégias que podem impactar na redução da TB
nos cenários das prisões e da comunidade, a saber:
Estratégia 1: Se todos os indivíduos que, ao entrarem nos presídios fossem rastreados
para TB com 75% de sensibilidade, a incidência da doença diminuiria em 10,3% (95% CI:
5,2%, 18,8%) e 3,3% (IC 95%: 1,9%, 5,6%) fora das prisões.
Estratégia 2: Se todos os indivíduos que, ao saírem das prisões fossem rastreados, a
incidência diminuiria nas unidades prisionais em 14,8% (IC 95%: 8,2%, 30,0%) e em 27,0%
(IC 95%: 25,0%, 32,4%) na comunidade.
Estratégia 3: Realização de tratamento com isoniazida para aqueles com TB latente
na entrada da prisão reduziria a incidência nas prisões em 23,5% (IC95%: 14,8%, 36,8%) e
em 16,1% (IC95%: 14,2%, 18,2%) na comunidade.
Estratégia 4: Melhorar em 25% da taxa de detecção de casos diminuiria a incidência
de TB nas prisões em 35,0% (IC 95%: 30,1%, 46,1%) e em 11,5% (IC 95%: 10,0%, 16,7%)
na comunidade.
 65
Estratégia 5: Se a intervenção mais eficaz implementada for a campanha anual de
detecção ativa de casos; esse programa reduziria a incidência de TB nas prisões em 47,4%
(IC95%: 44,4%, 52,2%) e em 19,4% (IC95%: 17,9%, 24,2%) na comunidade.
O resultado do estudo destaca que se houver a combinação dessas cinco estratégias,
a incidência de TB nas prisões diminuiria em 79,2% (IC95%: 70,2%, 95,6%) e em 40,0%
(IC95%: 36,1%, 44,3%) na comunidade.
Em relação as triagens nas prisões, questiona-se a recomendação da OMS da
realização da triagem da TB na entrada da prisão. Os achados deste estudo mostraram que
a incidência de TB é mais alta após a prisão do que na entrada e esse modelo considera a
triagem de saída mais eficaz do que a de entrada para a redução da incidência de TB na PPL,
sugerindo que a estratégia 2 apresentaria melhores taxas de redução.
Outro ponto a ser questionado é o de que, atualmente, a OMS recomenda triagem de
ILTB e tratamento preventivo com isoniazida nas prisões em países de renda média e alta
(GETAHUN; MATTEELLI; RAVIGLIONE, 2015) e o MS não recomenda tratar a PPL com um
teste tuberculínico positivo; embora estudo com grupos indígenas mostrou a eficácia do
tratamento para o controle da doença (YUHARA; SACCHI; CRODA, 2013).
Neste sentido, a estratégia 3, caso aplicada na entrada da prisão, poderia contribuir
com redução de casos em até 23,5% (IC95%: 14,8%, 36,8%) nas prisões e em 16,1% (IC95%:
14,2%, 18,2%) na comunidade geral.
Estudos com a utilização do fármaco isoniazida demonstraram redução de 60% a 90%
desse risco. Estudos de outros fármacos mostraram resultados semelhantes ao da isoniazida,
o que tem ampliado a disponibilidade de esquemas para o tratamento da ILTB (SMIEJA et al.,
2000; CHAN et al., 2012; BRASIL, 2017).
Experiências em prisões de Taiwan e do Japão corroboram em destacar o seu potencial
benefício para a população além de sugerir terapia mais curta para evitar o abandono. Neste
contexto, no ensaio clínico randomizado com presos de Taiwan, Chan et al., (2012) ao
comparar a segurança e a taxa de conclusão do regime de rifampicina diária de 4 meses (4R)
vs padrão de isoniazida diária de 6 meses (6H) para infecção por TB (ILTB) em PPL,
identificou que o fármaco rifampicina (4 meses) se mostrou mais seguro e tem uma conclusão
mais alta quando comparados com Isoniazida (6 meses) entre homens privados de liberdade.
No Japão, Kawatsu et al., (2018) ressaltam a possibilidade de introduzir regimes mais curtos
para o tratamento da ILTB e seu potencial benefício para a população com maior risco de
interromper o tratamento, como pessoas liberadas de instituições prisionais.
A estratégia 4 sugere melhoria em 25 % na taxa de detecção passiva de casos, que
pode ser alcançada substituindo a baciloscopia de escarro com exames mais sensíveis, tais
 66
como TRM e radiografia de tórax. Estudo nas prisões da região Sul do Brasil, conduzido por
Pelissari et al., (2018), evidenciou que uso combinado de métodos de diagnósticos durante
uma triagem foi muito mais eficaz na maximização do rendimento de TB do que usando
qualquer método sozinho. Ou seja, se os pacientes com radiografia de tórax anormal que
estava sem tosse e não investigados, 51% dos pacientes com TB teriam sido perdidos.
A OMS recentemente liderou uma revisão sistemática das evidências sobre o caso de
TB, mas o levantamento não conseguiu chegar a um consenso sobre a triagem ativa entre os
presos, citando evidências de baixa qualidade (WHO, 2013). Os países de baixa e média
renda alegaram que as recomendações não foram amplamentes atendidas devido a falta de
recursos necessários para implementação das medidas (KRANZER et al., 2010; SEKANDI et
al., 2015).
Das intervenções modeladas, a triagem ativa dentro das prisões mostrou-se estratégia
mais eficaz para reduzir a incidência de TB. Embora a detecção passiva de casos, a provisão
do tratamento da ILTB, a triagem de entrada e a triagem de saída tivessem um impacto mais
modesto individualmente, uma intervenção combinada incluindo todas essas abordagens,
juntamente com triagem em massa, poderia evitar quase 80% dos casos de TB nas prisões e
40% de casos de TB na comunidade.
Limitações importantes para ambos artigos devem ser consideradas. Para o artigo 1,
pode-se destacar que ao recrutar metade da população (3.380 / 7.221), a transmissão do
grupo não rastreado pode ter limitado todos os benefícios de transmissão em nível de
população do rastreamento.
Alcançar maior cobertura de rastreamento e rastreamento com maior frequência
provavelmente teria um impacto maior sobre a incidência subsequente de TB na população
rastreada e não rastreada.
Uma ressalva importante é que a média de tempo do encarceramento foi inferior a 2
anos nesta população, o que significa que a PPL sai rapidamente entre as exibições anuais,
potencialmente diminuindo o impacto desta intervenção, em que foi observado a perda de
rastreamento de 58%.
No artigo 2, por serem dados secundários, pode ocorrer algum grau de erro de
classificação diagnóstica ou demográfica. Também não foi possível identificar os casos de TB
ocorridos entre os ex-privados de liberdade que deixaram o estado, pois estavam disponíveis
somente dados de TB no estado do Mato Grosso do Sul. Há de se destacar que essas
descobertas sobre a elevada incidência de TB entre ex-PPL são conservadoras, pois excluem
os casos de TB que podem ter ocorrido em outros estados da federação.
 67
Para minimizar as limitações do modelo estratégico, que é uma simplificação de um
processo complexo, deliberou-se uma estrutura de modelo parcimoniosa que foi construída
diretamente sobre modelos amplamente mencionados na literatura relacionados a TB.
 68
7 CONCLUSÃO

A epidemia de TB na PPL representa não apenas um problema de justiça social, mas

também uma ameaça ao controle mais amplo da TB nesses ambientes.
Os achados apontam para alta taxa de ILTB e TB ativa em um ano de
acompanhamento, entre os privados de liberdade de Mato Grosso do Sul. A superlotação e a
movimentação dessa população, tornam as prisões reservatórios e amplificadores
importantes desta doença.
O rastreamento anual, por meio da nossa coorte prospectiva, não apresentou redução
do risco de doença subsequente nas 12 prisões estudadas, provavelmente devido a uma força
extremamente alta de infecção, e devido a perda de rastreamento (>50%). Os achados
sugerem a implantação permanentemente de rastreamento em massa, com oferta de exames
para o diagnóstico precoce da TB, independente de sinais e sintomas, tais como: Teste Rápido
Molecular para TB (Gene Xpert®), radiografia de tórax, baciloscopia e cultura de escarro.
Como estratégia de controle da TB nas prisões, sugere-se o rastreamento da TB na
entrada e saída da prisão, tratamento para ILTB com isoniazida entre aqueles infectados no
ingresso a prisão, melhoria de 25% na taxa de detecção de casos passivos e campanhas
anuais de detecção de casos ativos. Ao combinar as cinco estratégias prevê-se a diminuição
da incidência de TB nas prisões em 79,2% e em 40,0% na comunidade, em um prazo de dez
anos.
Nossas descobertas têm implicações claras para o planejamento e a seleção de
intervenções a serem realizadas em locais com grande contigente populacional em todo o
mundo. Estas evidências poderão subsidiar políticas públicas, com base na epidemiologia,
para fomentar o controle da TB nas prisões do Brasil e em outros países de baixa e média
renda, trilhando o caminho na busca das metas estabelecidas.
 69
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 74
ANEXO A – ARTIGO BASE DE LINHA
 75

Active and latent tuberculosis in Brazilian

correctional facilities: a cross-sectional study
Andrea da Silva Santos Carbone1, Dayse Sanchez Guimarães Paião1, Renata Viebrantz Enne Sgarbi1, Everton
Ferreira Lemos2, Renato Fernando Cazanti2, Marcos Massaki Ota2, Alexandre Laranjeira Junior2,
José Victor Bortolotto Bampi2, Vanessa Perreira Fayad Elias2, Simone Simionatto3, Ana Rita Coimbra Motta-Castro4,5,
Maurício Antonio Pompílio6, Sandra Maria do Valle de Oliveira7, Albert I Ko8,9, Jason R Andrews10 and
Julio Croda2,5*

Abstract
Background: Tuberculosis (TB) rates among prisoners are more than 20 times that of the general population in Brazil, yet
there are limited data available to facilitate the development of effective interventions in this high-transmission setting. We
aimed to assess risk factors for TB infection and evaluate the yield of mass screening for active disease among inmates.
Methods: We administered a questionnaire and tuberculin skin test (TST) to a population-based sample of inmates from
12 prisons in Central-West Brazil and collected sera for HIV testing and two sputum samples for smear microscopy and
culture from participants reporting a cough of any duration. Hierarchical Poisson regression models were used to evaluate
factors associated with latent tuberculosis infection (LTBI).
Results: We recruited 3,380 inmates, of which 2,861 (84.6%) were males from 8 prisons, and 519 (15.4%) were females from
4 prisons. Among the 1,020 (30%) subjects who reported a cough, we obtained sputum from 691 (68%) and identified 31
cases of active TB for a point prevalence of 917 (95% CI, 623–1302) per 100,000 prisoners. Evaluation of the two sputum
smear samples failed to identify 74% of the TB cases, and 29% of the cases reported less than 2 weeks of symptoms.
Obtaining a second culture identified an additional 7 (24%) cases. The prevalences of LTBI were 22.5% and 11.7% for male
and female prisoners, respectively and duration of incarceration (in years) was associated with LTBI in male and female in
the multivariable model (1.04, 95% CI, 1.01-1.07 and 1.34, 95% CI, 1.06-1.70, respectively). The prevalence of LTBI is
8.6% among newly incarcerated inmates, among whom LTBI prevalence significantly increased by 5% with each year of
incarceration.
Conclusions: Although the overall LTBI prevalence among inmates in Central-West Brazil is low, tuberculosis incidence is
high (>1,800/100,00), likely due to the high force of infection among a largely susceptible inmate population. Efforts to
reduce transmission in prisons may require mass screening for active TB, utilizing sputum culture in case-detection
protocols.
Keywords: Tuberculosis, Prisoners, TST, Infection, Active case detection, Screening cross-sectional study, Brazil,
Epidemiology

* Correspondence: juliocroda@ufgd.edu.br
2
Faculty of Health Sciences, Federal University of Grande Dourados,
Dourados, Brazil
5
Oswaldo Cruz Foundation, Campo Grande, Brazil
Full list of author information is available at the end of the article

© 2015 Carbone et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise
stated.
 76
subset of the system, in which prisoners do not leave the
Background
prison during their incarceration (in the contrast with the
Worldwide, the prevalence of tuberculosis (TB) among
“open” system for lower-risk offenders), there were a total of
prisoners is frequently an order of magnitude greater than that
9,913 inmates at 22 penal institutions. The popu- lation of the
in the general population [1]. In Brazil, which has the world’s
closed system in the 5 largest cities in the state (Campo
4th largest prisoner population, the incidence of TB in prisons
Grande, Corumbá, Dourados, Ponta Porã and Três Lagoas)
is approximately 20 times greater than that in the general
was included in a cross-sectional study performed between
population (>1,000 per 100,000 versus 46 per 100,000) [2,3].
January 2013 and December 2013 (Figure 1a). Twelve
Previous studies of Brazilian prisons have reported that the
prisons were included in the study, with a total of 7,221
prevalence of active TB and la- tent TB infection (LTBI)
prisoners representing 73% of the prisoners in the closed
range from 2 to 9% and from 40 to 73%, respectively [2-5].
system and 59% of the total prison population in the state. Of
The high incidence of TB in prisons contributes to a high
these 12 prisons, there were 8 male prisons (6,552 prisoners)
rate of TB transmis- sion among inmates, who serve as a
and 4 female prisons (669 prisoners).
persistent reser- voir for spillover TB transmission into the
general population [6,7].
Sample size calculation and study population
International and national guidelines concerning TB control
Prisoners who were 18 years of age and who consented to
in prisons recommend systematic screening using
participate were included in the study. Screening for
standardized symptom assessment and chest radiography to
tuberculosis (reported here) was performed alongside parallel
identify individuals requiring further investigation [8-12]. In
screening studies for HIV, Hepatitis B, Hepatitis C, and
particular, there remain critical questions about: the yield of
syphilis. The sample size was calculated based on the
symptom screening, smear microscopy and culture; the
expected prevalence of HIV, assuming 2% for HIV with a
number of sputum examinations that should be performed;
variation of 1%, power of 80% and alpha-type error of 5%.
and whether demographic attributes or re- ported risk factors
The study population is 7,221 prisoners, and the sample size
can effectively identify high-risk indi- viduals to target for
was 3,159 prisoners. We added 20% more individuals (total,
screening for LTBI and active TB.
3,771 prisoners) to account for an- ticipated loss due to
Few studies conducted in prisons in low- or middle- income
refusal to participate. Proportional stratified sampling was
countries have addressed the performances of smear and
performed using each prison as a unit of randomization. On
culture for screening active TB in the prisons [12-14]. In
the data collection day, the prisoners were ordered
Mato Grosso do Sul state, no control mea- sures other than
numerically in ascending order from the lists provided by the
passive case detection have been imple- mented, wherein
prison and a list of random numbers was generated using the
symptomatic inmates are referred for chest radiography,
Epi-Info 6.04 software (Atlanta, GA, USA).
smear and TB culture, all performed outside of the prisons.
Due to the high tuberculosis incidence, limited prison health
Data collection
budgets, and complex nature of conducting pub- lic health
Data collection for all twelve prisons was carried out over a
interventions in these settings, more evidence for mass
period of one year (01/07/2013 to 10/22/2013), with each
screening for tuberculosis is needed. We imple- mented a
prison being sequentially enrolled over a course of 1 to 3
large campaign in a network of 12 prisons in Central-West
weeks. Each participant underwent an interview util- izing a
Brazil to assess the yield of the mass screen- ing of inmates
standardized questionnaire. The variables obtained during the
for active TB. Furthermore, we evaluated the prevalence of
interview included gender, marital status, edu- cation,
tuberculin skin test (TST) positivity in this population to
smoking history, illicit drug use, diabetes, contact with a TB-
identify risk factors and risk groups for TB infection and to
positive individual (in the household or at other places), the
facilitate future intervention strategies. presence of a Bacillus Calmette-Guérin (BCG) vaccine scar
(as determined by inspecting the participant’s arm), previous
Methods
incarceration, number of prisoners per cell, TB symptoms in
Study setting and design
the cell and time in prison. The partici- pant’s race/skin color
Mato Grosso do Sul is a state in Central-West Brazil that
(i.e., white, black, indigenous, Asian or mixed) was self-
borders Paraguay and Bolivia. It is home to a popu- lation of
reported.
2.5 million people and has the highest rate of incarceration in
the country, predominately due to drug- trafficking crimes. In
Tuberculin skin testing
2013, there were 12,306 prisoners in the state, including
Two tuberculin units (0.1 ml) of RT23 PPD (Staten Serum
11,152 males and 1,154 females distributed between 37 penal
Institute, Copenhagen, Denmark) were injected
institutions. In the “closed”
intradermally into the volar aspect of the left forearm.

After 48 hours, the maximum diameter of the palpable
induration was measured by a trained TST reader. The TST
was considered to be positive if the induration was ≥10
mm, except in HIV-positive patients, for whom an
induration of ≥5 mm was considered to be positive.
Smear and culture for M. tuberculosis
All patients reporting a cough were asked to provide
sputum for an assessment of active TB. Two sputum
samples were collected, including one spot sample after
the interview and another the next morning. Smear mi-
croscopy and solid culture were utilized to test for Myco-
bacterium tuberculosis (M. tuberculosis). The smear was
conducted according to the Ziehl-Neelsen technique and
was read by a trained microscopist. After completing the
smear, the samples were processed using the Swab method
as described by Kudoh and Kudoh (1974) [15] and then
decontaminated using the Petroff method, with a 5-minute
exposure to 4% NaOH [16]. Culturing was performed
using modified Ogawa medium (pH 6.4) [17], inspected
daily for visible evidence of growth, and main- tained for
60 days until it was considered negative Time to culture
positivity was defined as the days from spu- tum collection
to identification and confirmation of
77
mycobacterial growth. Radiography was not available in the
prisons, and a TB case was therefore defined as the presence
of at least one positive smear or culture.
Tuberculosis outcomes
To assess outcomes of tuberculosis cases identified dur- ing
the screening study, we linked data on cases with cases
reported in the National Notifiable Diseases Information
System (SINAN). We classified outcomes according to
World Health Organization definitions, as utilized by the
Brazil national tuberculosis programme.
HIV serology
All participants were offered HIV testing by serum ELISA,
with positive tests confirmed by Western blot.
Data analysis
All questionnaires were entered twice into Research
Electronic Data Capture (REDCap), which is a secure on- line
database. The questionnaires were compared to search for data
entry errors. SAS version 9.2 (SAS Institute, Cary, NC, USA)
and the R statistical software, version 3.1.1 (R Foundation
for Statistical Computing, Vienna, Austria) were used to
analyze the univariate and multivariate models. The prevalence
of LTBI was expressed as the
 78

percentage among inmates screened, and the prevalence of Table 1 Sociodemographics, prison variables and
active TB was expressed as the cases per 100,000 individ- uals, tuberculin skin test results stratified by gender in Mato
consistent with conventional metrics. We estimated the disease Grosso do Sul, Brazil (N = 3,380)
duration by dividing the prevalence to inci- dence of active TB. Gender
Tuberculosis incidence was estimated from notification data (Number/percentage)
obtained from the National Notifi- able Diseases Information Variables Male Female P value
System (SINAN), from which we identified all new cases of N = 2,861 N = 519
active TB reported in the 12 prisons during the study period. TST-positive 620/2752 (22.5) 60/511 (11.7) <0.01
Dichotomized and cat- egorical data were analyzed with the
Active TB 29/2861 (1) 2/519 (0) 0.2
chi-squared test or Fisher’s exact test. For continuous variables,
Reason for admission <0.01
the t-test or analysis of variance (ANOVA) was utilized.
Univariate ana- lyses were performed to verify the associations Drug trafficking 1142/2360 (48) 383/437 (88)
between the dependent and independent variables. Poissson Theft 741/2360 (31) 30/437 (7)
regression analysis was used to estimate the crude prevalence Homicide 324/2360 (14) 14/437 (3)
ratios (PRs). Those achieving a pre-specified level of Sexual abuse 64/2360 (3) 1/437 (0)
significance (p < 0.05) were included in the multivariable Other 87/2360 (4) 9/437 (2)
analysis. Multi-level mixed Poisson regression models were
Sociodemographics
used to estimate the risks of latent and active TB associated
with sociodemographics and exposure variables for the Age, years, mean ± SD 32 ± 10 32 ± 10 0.52
individ- uals nested within the prisons. Marital status, single 1522/2840 (54) 332/506 (66) <0.01
Race <0.01
White 912/2747 (33) 137/470 (29)
Ethical issues 1366/2747 (50) 283/470 (60)
Mixed
All eligible participants provided written informed con- Black
sent prior to study participation. The study was ap- 370/2747 (14) 34/470 (7)
proved by the Research Ethics Committee at the Federal Indigenous 37/2747 (1) 4/470 (1)
University of Grande Dourados (Number 191,877). Every Asian 62/2747 (2) 12/470 (3)
active TB patient identified during the study was noti- Resides in MS 1889/2861(66) 277/519 (53) <0.01
fied, underwent TB treatment and was provided with re- Less than 4 years 1195/2794 (43) 282/514 (55) <0.01
ferrals. No preventive therapy was provided for LTBI of schooling
because the Brazilian Ministry of Health does not rec- Diabetes 78/2399 (3) 22/494 (5) 0.18
ommend the treatment of LTBI in prisons [8]. Current smoker 1551/2830 (55) 284/519 (55) 0.97
Drug use over 1543/2861(54) 199/519 (38) <0.01
Results
Among the 3,771 prisoners recruited for the study, 391 the last year 176/2817 (6) 14/518 (3) <0.01
Previous TB
HIV-positive 45/2847 (1.6) 10/518 (1.9) 0.56
matesrefused
(10%) refusing to participate
to participate, and had similar
3,380 characteristics
were enrolled. In-
such as age, sex and reason for admission compared to Prison
those who screened. All enrolled participants completed Previously incarcerated 1758/2836 (62) 207/517 (40) <0.01
the study protocol (Figure 1b). The mean age of the par- Knows someone with TB 1196/2784 (43) 124/511 (24) <0.01

ticipants was 33.2 years (range, 18–80 years). The major- ity Prisoners per cell, mean 16 ± 12 22 ± 15 <0.01
of these individuals was from the state of Mato Grosso do ± SD
Sul (64%) and were men (85%). The prisoners’ self-reported Duration of 20 ± 27 12 ± 13 <0.01
racial groups included white (33%), mixed (51%), black incarceration, months,
(13%), indigenous (1%) and Asian (2%) (Table 1). There was mean ± SD
considerable variation between prisons with respect to prior Other prisoners 845/2830 (30) 211/517 (41) <0.01
coughing in the cell
history of drug use during the previous year (17-70%) and
TB (1-11%), inmates reporting knowing someone with TB
(11-63%), previous

incarceration (28 -75%) and mean duration of incarcer- ation
(4.4-29.9 months) (Additional file 1: Tables S1a and b). The
most common reasons for the incarceration for men were
drug trafficking (48%), theft (30%) and homicide (14%).
Women were also most frequently
incarcerated for drug trafficking (87%), theft (7%) and
homicide (3%). Compared with women, men were more
likely to have used drugs during the past year (54% ver- sus
38%, p < 0.01), have a positive history of TB (6% ver- sus
3%, p < 0.01), know someone with TB (43% versus

24%, p < 0.01), or have been previously incarcerated (62%
versus 40%, p < 0.01), and their duration of incar- ceration
was longer (20 months versus 12 months, p < 0.01)
(Additional file 1: Tables S1a and b).
Of the 3,380 study participants, 1,020 reported a cough of
any duration, and 691 (68%) were able to produce spu- tum.
Thirty-one participants had bacteriologically con- firmed TB,
corresponding to a point prevalence of 917 (95% CI, 623–
1302) per 100,000 prisoners. Among the 31 cases, 29 (93%)
were culture-positive, and two were posi- tive by smear only.
Six cases were positive by both culture and smear, and
twenty-three of the 31 cases (74%) were culture-positive and
smear-negative (Figure 1b). The me- dian time to culture
positivity was 34 days (range, 18–66 days). Among the
smear-positive cases, 75% were positive according to the first
smear, and a second smear identified the remaining 25%. For
the culture-positive cases, 76% of the first specimens tested
positive, with an additional 24% positive by the second
culture only.
Among the TB patients, 29 (96.2%) were men (median age,
32 years; range, 22–55 years), and 16 (51.6%) were from a
single prison (EPJFC) (Additional file 1: Tables S1a and b).
Of the 27 patients notified and identified in the SINAN
electronic database, 21 (78%) completed the treatment and
were cured, 2 (7%) died, 2 (7%) defaulted,
and 2 (7%) was transferred. Among the 31 patients, 1 patient
had already been diagnosed with TB 6 months ago and four
reported having had prior TB (48 months, 36 months, 24
months and 12 months ago). In 2013, 142 TB cases from
12 prisons were reported to SINAN, which represented an
incidence of 1,839 per 100,000 in- habitants. Comparing TB
notifications for 2013 with the point prevalence estimated
here, the estimated duration of TB prior to diagnosis was 6
months.
The prevalence of TST positivity among the different prisons
ranged from 3.0% (EPFTL prison) to 32.0% (EPJFC prison)
and was higher among men (22.5%) than women (11.7%) (p
< 0.01). In a subset of 144 prisoners with ≤1 month of current
incarceration and no prior his- tory of imprisonment, the
prevalence of TST positivity was 7.6%. Its prevalence
increased significantly by 5% per year with time spent in
prison for the entire prisoner population, with a greater slope
of increase for women than for men (Figure 2).
Among the male prisoners, TST positivity was inde-
pendently associated with increasing age (adjusted preva-
lence ratio [APR], 1.02, 95% confidence interval [CI], 1.01-
1.02), race (with white race as the reference; mixed: APR,
1.34, 95% CI, 1.10-1.63; black: APR, 1.43, 95% CI, 1.10-
1.86; Asian: APR, 1.80, 95% CI, 1.16-2.90; indigenous:
APR, 1.25, 95% CI, 0.85-1.85), drug use within the past year
(APR, 1.29, 95% CI, 1.08-1.54), and years of incarcer- ation
(APR, 1.04, 95% CI, 1.01-1.07) (Table 2). Among the female
prisoners, TST positivity was independently
79
associated with increasing age (APR, 1.03, 95% CI, 1.00-1.06),
previous TB diagnosis (APR, 3.79, 95% CI,
1.52-9.48), previous incarceration (APR, 2.05, 95% CI, 1.16-
5.96), number of prisoners per cell (APR, 1.02, 95% CI, 1.01-
1.04), knowing someone with TB (APR, 2.05, 95% CI, 1.16-
3.52) and years of incarceration, among those without
incarceration history (APR, 1.34, 95% CI, 1.06-1.70) (Table
2).
Discussion
Previous studies in Brazilian prisons have found preva-
lences of LTBI ranging from 49% to 73% [2-4,18]. This
multicenter study, which was conducted in 12 prisons with
3,360 inmates of both genders in Mato Grosso do Sul,
revealed a comparatively low prevalence of LTBI that varied
from 15-33% in the male prisons and from 3- 16% in the
female prisons. In particular, during the first month of
incarceration, the prevalence was very low (7.9% in males
and 8.3% in females), which indicates that a large number of
individuals who enter prison are sus- ceptible to TB infection.
The low prevalence of LTBI combined with the high point
prevalence and incidence (951 and 1839 per 100,000,
respectively) highlight the urgent need for new interventions
in these settings to reduce TB transmission.
In this study, previous incarceration was a significant in-
dependent risk factor for LTBI among women, and trended
towards significance as a risk factor for men. A number of
studies in prisons have demonstrated that pre- vious
incarceration [19,20] is associated with TST positiv- ity. In
São Paulo, 55.1% of detainees have been identified as
infected individuals with previous arrests, and 75.6% have
LTBI [21]. Previous incarceration has been strongly
associated with TB among the urban population, and
genotypic data indicate that there is a considerable spill- over
into the Dourados general urban population [22]. Moreover,
duration of incarceration was associated with TST positivity,
controlling for other demographic risk fac- tors, which
further implicates prisons as the source of tu- berculosis
infection rather than high-risk characteristics of the inmate
population.
Taken together, the low prevalence of TB among indi- viduals
who were new to the prison system and the asso- ciation
between the duration of incarceration and LTBI positivity
imply that prisons are critical to TB transmis- sion. This
finding underscores the need to implement mea- sures to
control TB in this setting. This goal may require a combination
of biomedical interventions (improving diag- nostic capacity,
implementing active case detection strat- egies) and structural
interventions (reducing crowding, improving ventilation and
prison conditions) to achieve a substantial impact on the
extraordinary burden of TB in Brazilian prisons [23].
 80

We found a lower prevalence of TST-positive inmates in the
Centro de Triagem (CTAL = 16%) and Presidio de Trânsito
(PTCG = 15%) prisons, where prisoners are typic- ally held
temporarily; these facilities generally serve as en- trances into
the prison system. The highest prevalence rates were
observed in the prisons in which the inmates remained for
longer periods of time, such as the
Estabelecimento de Segurança Máxima prison (EPJFC =
32%); these prisons also had higher TB notification rates
(Additional file 1: Tables S1a and b). In these initial, more
temporary prisons, TB screening may be instituted using
smear and culture in symptomatic inmates, and an initial TST
should be conducted in asymptomatic individuals, who
should potentially be monitored during incarceration.

Table 2 Risk factors associated with LTBI among male and female prisoners
Male (N = 2752) Female (N = 511)
Variables Crude PR Adjusted PR Crude PR Adjusted PR
Sociodemographics
Age, per year 0.99 (0.98-0.99) 1.02 (0.67-1.53) 1.03 (1.00-1.05) 1.03 (1.01-1.06)
Marital status, single 0.89 (0.76-1.04) 0.84 (0.48-1.48)
Race
White
Mixed 1.31 (1.08-1.59) 1.34 (1.10-1.63) 1.36 (0.69-2.71)
Black 1.40 (1.08-1.81) 1.43 (1.10-1.86) 2.32 (0.89-6.04)
Indigenous 1.28 (0.63-2.60) 1.25 (0.59-2.68)
Asian 1.72 (1.07-2.76) 1.80(1.12-2.90)
Resides in MS 0.83 (0.71-0.98) 1.13 (0.67-1.89)
No education 0.82 (0.69-0.96) 0.68 (0.41-1.13)
Diabetes 1.14 (0.71-1.82) 0.34 (0.05-2.41)
Current smoker 1.21 (1.03-1.42) 1.74 (1.01-2.98)
Drug use over the last year 1.21 (1.02-1.42) 1.29 (1.08-1.54) 1.05 (0.62-1.75)
BCG scar
Previous TB 1.50 (1.14-1.98) 3.14 (1.42-6.91) 3.79 (1.52-9.47)
HIV-positive 1.34 (0.79-2.27) 0.90 (0.13-6.44)
Prison
Previously incarcerated 1.24 (1.05-1.48) 1.39 (0.83-2.33) 2.44 (1.17-5.10)*
Knows someone with TB 1.16 (0.98-1.37) 2.55 (1.54-4.24) 2.02 (1.16-3.52)
Prisoners per cell, per person 0.99 (0.98-1.00) 1.02 (1.01-1.04) 1.02 (1.01-1.04)
Duration of incarceration, years 1.04 (1.01-1.07) 1.04 (1.01-1.07) 1.06 (0.87-1.31) 1.34 (1.06-1.70)*
Other prisoners coughing in the cell 1.04 (0.88-1.24) 1.05 (0.61-1.78)
*Adjusted for significant interaction term between these variables (p = 0.01).

Currently, the Brazilian Ministry of Health does not
recommend treating LTBI in inmates with a positive TST
[8]. Our findings of the low LTBI prevalence upon prison
entry and high risk thereafter suggest that indi- viduals may
be screened upon incarceration and periodic- ally thereafter
to detect the development of infections. Recent infection,
rather than late reactivation, likely drives the majority of
tuberculosis in this setting. Thus, periodic screening, either
annually or among cellmates of a de- tected case, combined
with isoniazid preventive therapy may be an effective
intervention.
In the prisons examined in this study, as is common
throughout Brazil, TB diagnoses are made when inmates
present to the prison clinic with relevant symptoms (i.e.,
passive case finding). Actively searching for TB cases may
prove effective, as demonstrated by this study, which
detected 31 cases of active TB among 3,380 pris- oners
screened. We observed that the two smears failed to detect
74% of cases. This observation may indicate that individuals
were diagnosed earlier in their course of illness, but it also
suggests that a smear is insufficient for active case detection
in this setting. Additionally, be- cause a quarter of the cases
were only diagnosed follow- ing a second culture, we
advocate the collection of at least two specimens when
performing mass screening in prisons. Further studies are
needed to evaluate various diagnostic strategies, the yields
of various intervals of screening, and their cost-
effectiveness.
The prevalence of LTBI in our study was lower than that
identified in other studies [2,18]. This difference is likely due
to the low incidence of TB in the general population of the
state of Mato Grosso do Sul. Only two studies have estimated
the prevalence of TST in two prisons located in the first and
third most populous cit- ies in Brazil (São Paulo and
Salvador, respectively), in which the majority of prisoners
are former residents of slums, which are areas with high LTBI
rates.
The results of this study should be interpreted within the
context of the limitations of the data. We screened all
individuals who reported cough of any duration, which while
a more liberal screening definition than the WHO symptom
criteria (cough > 2 weeks), may never- theless fail to identify
a substantial proportion of tuber- culosis cases in this
population [12,14]. Additionally, one-third of the patients
reporting a cough were unable to produce sputum, and
resources for sputum induction in the prisons were not
available. Radiography is not available in prisons, and we
were unable to assess the utility of this important diagnostic
tool. We used solid (Ogawa) media for culture, due to low
costs and lower laboratory safety risks; this procedure may
be less sensi- tive than liquid media culture, but is more
widely avail- able in resource-limited settings and therefore
more generalizable. For all of these reasons, our estimate of
81
tuberculosis prevalence is likely low. The majority of cases
were detected in just one prison, and it is unclear whether this
was a higher-burden prison or whether these were point-
source outbreaks. Genotyping of iso- lates may further clarify
this issue.
Conclusions
The combination of the high TB prevalence identified in the
prisons evaluated, which is similar to reports from other
prisons in Brazil and in other countries [1-5], with the large
proportion of susceptible individuals initially entering into
the prison system contribute to a high force of infection in
this setting. Recent transmission, ra- ther than reactivation,
likely is driving the tuberculosis epidemic in these prisons,
and interventions will need to be focused towards
interrupting ongoing transmission. This situation represents
a social justice crisis, and mass screening for active and latent
TB infections must be implemented in Brazilian prisons.
Additional file
Competing interests
The authors declare that they have no competing interest.
Authors’ contributions
ASSC, DSGP, RVE, and EFL were involved in the study conception and
design, data collection, data analysis, and manuscript drafting. RFL, MMO,
ALJ, JVBB and VPFE were involved in the data collection and manuscript
drafting. SS, ASCMC, SMVLO, AIK, JRA and JC were involved in the study
design and manuscript review. All authors have read, edited and approved
the manuscript.
Acknowledgments
The authors are grateful to the State Agency of the Administration of Prisons for
their full support during the study period. We thank the prisoner participants,
without whom this study could not have been performed. Our appreciation also
extends to the staff of the UFGD TB study group for their support during the
study, including Junio Pereira Pardins, Vinícius Neonato de Oliveira, Guilherme
de Freitas Bezerra, and Sylka Rebelato Toppan. We would also like to extend
our gratitude to Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e
Tecnologia do Estado do Mato Grosso do Sul (FUNDECT, 0067/2012), the
Ministry of Education (PROEXT), the Brazilian National Research Council
(Ciências sem Fronteiras Program) and the Fogarty Global Health Equity
Scholars Program (NIH 1 R25 TW009338).
Author details
1
University Hospital, Federal University of Grande Dourados, Dourados, Brazil.
2
Faculty of Health Sciences, Federal University of Grande Dourados,
Dourados, Brazil. 3Faculty of Ambiental and Biological Sciences, Federal
University of Grande Dourados, Dourados, Brazil. 4Department of Biochemical
Pharmacy, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil.
5Oswaldo Cruz Foundation, Campo Grande, Brazil. 6Faculty of Medicine, Federal
University of Mato Grosso do Sul, Campo Grande, MS, Brazil. 7University
Hospital, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
8Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil. 9Department
of Epidemiology of Microbial Disease, Yale School of Public Health, New Haven,
CT, USA. 10Division of Infectious Diseases and Geographic Medicine, Stanford
University School of Medicine, Stanford, CA, USA.
 82

Received: 18 October 2014 Accepted: 15 January 2015

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prisons. Int J Tuberc Lung Dis. 2009;13(10):1247–52.
14. Fournet N, Sanchez A, Massari V, Penna L, Natal S, Biondi E, et al. Development and evaluation of tuberculosis screening scores in Brazilian prisons. Public Health.
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bacteriológico da tuberculose pulmonar no Amazonas.
J Pneumol. 1990;16:133–6.
17. David HL, Levy-Frebault V, Thorel MF: Mèthodes de Laboratoire pour Mycobactériologie Clinique. In. Edited by Pasteur I. Paris; 1989: 39–58.
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 83
ANEXO B - PRODUÇÕES CIENTÍFICAS E PREMIAÇÕES EM CONGRESSOS

Resumos Internacionais

The International Journal of Tuberculosis and Lung Disease

“Alarming of rates tuberculosis trasnmissions in brazilians prisions” (Cape Town, South Africa,
2015)
“High incidence of tuberculosis infection and disease in twelve Brazilian prisons” (Liverpool, United
Kingdom, 2016),

Resumos Nacionais

“High incidence of tuberculosis infection and disease in twelve Brazilian prisons” - Congresso
Brasileiro de Medicina Tropical (Maceió – AL, 2016), sendo premiado em 3º lugar, na categoria
Doutorado, recebendo o título de Jovem Pesquisador de 2016 da Sociedade Brasileira de Medicina
Tropical;
“Estratégias para controle da tuberculose nas prisões do Brasil” publicado na revista PECIBES
(UFMS) recebeu as premiações: 1º lugar no III Prêmio de Pós-Graduação stricto sensu Dr Durval
Batista Palhares (Consulpit – Humap) e o 3º lugar no I Prêmio painel Maria Elizabeth Moraes
Cavalheiros Dorval (Consulpit – Humap) (
“Identificação de estratégias para o controle da tuberculose em prisões brasileiras” no Boletim da
Sociedade Brasileira de Infectologia (SBI), premiado como um dos cinco melhores trabalhos
“Prêmio Manoel de Barros”
84
85
86
87
88
 89

Estratégias para controle da tuberculose nas prisões do Brasil

Everton Ferreira Lemos1, Dayse Sanches G. Paião2; Andrea da Silva Santos Carbone2;
Recebido –
10/10/2017, Renata viebrantz Enne Sgarbi2; Simone Simionatto2; Ana Rita Castro Mota- Coimbra1,3;
Aceito -
28/08/2018 Maurício Pompílio1; Albert Ko4; Jason Randolph Andrews5; Julio Croda1,2,3

1
Pós Graduação em Doenças Infecciosas e Parasitárias – UFMS
2
Universidade Federal da Grande Dourados – UFGD
3
Fundação Oswaldo Cruz – Mato Grosso do Sul - FIOCRUZ
4
Yale University – USA
5
Stanford University - USA

No Brasil, um dos 22 países com a maior taxa da tuberculose, a incidência de tuberculose (TB)
nas prisões, segundo a OMS, é 25-50 vezes maior do que a população em geral. Até o momento,
não há dados sistemáticos sobre estratégias de triagem eficazes para o diagnóstico precoce e
prevenção da tuberculose no contexto de alta taxa como as prisões de países de renda baixa e
média. Assim o presente estudo identificou intervenções efetivas de controle da tuberculose nas
prisões do Brasil. Trata-se de um estudo prospectivo de coorte entre os indivíduos encarcerados
de prisões no estado de Mato Grosso do Sul, Brasil. Etapa 1. Realizamos uma coorte no período
de 2013 - 2015 de 12 prisões nas 5 maiores cidades do Estado de Mato Grosso do Sul, com o
objetivo de avaliar as taxas de infecção e doença e avaliar o impacto da triagem anual nas prisões
brasileiras. Etapa 2. Iremos exibir uma coorte com a realização da radiografia de tórax,
baciloscopia/cultura e Gene Xpert. A TB pulmonar será identificada por meio da radiografia de
tórax, cultura anual e Gene Xpert. Na etapa 1. de 7.221 presos nas 12 prisões, recrutamos 3.771
para o estudo, e 3.380 (90%) consentiram participar e foram inseridos. Após 1 ano, 1.422
participantes permaneceram encarcerados na mesma prisão. Este subconjunto compreende a
coorte prospectiva em que as conversões de Teste Tuberculínico (TT) e a incidência de TB foram
avaliadas. Realizou-se um questionário e aplicação do TT. Os indivíduos foram acompanhados
durante um ano no estudo de coorte e realizou um novo TT. Utilizamos Cox Proportional Hazards
para estimar os índices de risco bruto e de risco ajustado para TB ativa. Encontramos um risco
anual de infecção tuberculosa de 26% (IC 95%: 23 ± 29%) e incidência de TB ativa de 1.771 (IC
95%: 1.115 ± 2.614) por 100.000 habitantes. Os casos identificados através do rastreio ativo eram
menos susceptíveis de serem baciloscopia positiva do que os detectados passivamente (10% vs
51%, p <0,01), sugerindo a detecção precoce dos casos. No entanto, não houve redução da
incidência da doença entre os indivíduos rastreados ativamente versus aqueles não rastreados
(1,77% vs. 1,69%, p = 0,95). A conversão de TT e a incidência de TB ativa foram maiores no
sexo masculino do que nas mulheres (28% versus 10%, p <0,01 e 1,94% versus 0,53%,
respectivamente, p = 0,18). A tosse produtiva relatada no início do estudo (AHR 2,63; IC 95%:
1,13-6,15) e o uso de drogas ao longo de um ano (AHR 3,93; IC 95%: 1,31-11,79) foram
associados com TB ativa durante um ano de seguimento. Etapa 2. Vamos utilizar uma Unidade
Móvel, adaptada com as instalações apropriadas para realização dos Raio X e Gene Xpert móvel.
Com os testes de radiografia de tórax, baciloscopia, cultura e Gene Xpert, permitirá a identificação
da melhor estratégia de diagnóstico e controle da TB nas prisões
 90

do Brasil, e poderá contribuir para o SUS, respondendo lacunas importantes no

rastreamento de casos de TB.
Palavras-chave: Tuberculose; Prisão; Epidemiologia.
Apoio Financeiro: Fundect – NHI/EUA
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 92

ANEXO C – PARECER COMITÊ DE ÉTICA EM PESQUISA

93
94
 95

ANEXO D – INFORMAÇÕES DE SUPORTE

(ARTIGO 2 - Evaluating strategies for control of tuberculosis in prisons and

prevention of spillover into communities: An observational and modeling study from
Brazil)
 96

SUPPORTING INFORMATION

Model equations and assumptions

We adapted widely used compartmental TB natural history and transmission models,
governed by a system of ordinary differential equations, to describe TB transmission
dynamics in a Brazilian state, among three groups: prisoners, ex-prisoners, and
community members (Figure 3). We assume no HIV, no MDR TB, and a single strain
model. In this setting, MDR TB is rare (<1%) and HIV prevalence is <2%, and are
therefore unlikely to alter model dynamics [1]. The subscripts p, e, and c in the following
equations and text denote prisoners, ex-prisoners, and community members,
respectively.

The transmission parameter, β was calculated for each population group in the model
using the following formula,

Equation 1:
β = λ/I

where λ is equivalent to the force of infection, and I can be estimated as the

prevalence of TB disease. For prisoners, both the force of infection for prisoners and
the TB prevalence were obtained from a recent prospective study of TB infection in
Mato Grosso do Sul prisons [2], yielding a βP of 17. For community members and ex-
prisoners, λ was estimated using the following formula,

Equation 2:
1
λ=− ln(1 − 𝑝𝑟𝑜𝑝𝑜𝑟𝑡𝑖𝑜𝑛 𝑖𝑛𝑓𝑒𝑐𝑡𝑒𝑑)
𝑡
 97

where t is time. In this equation, t is set to 25 years, the average age of first
incarceration, and cumulative risk of infection at age 25 is 10%, yielding a force of
infection of 0.0042. With the prevalence of TB disease in Brazil obtained from WHO
surveillance data [3], it is possible to then solve for β.

Because prisoners, ex-prisoners, and community members can all experience the same
disease states, the set of differential equations for these three groups is largely identical.
The equations differ in that ex-prisoners and community members can be incarcerated
at rate q, while prisoners can be released at rate r. Additionally, while prisoners are only
infected (and reinfected) at a rate proportional to the imprisoned infectious population,
ex-prisoners and community members are susceptible to infection (and reinfection)
through contact with any infectious individual outside of the prison.

Annual release rates were derived from the SIGO report. We solved the following
system of equations using known values from Mato Grosso do Sul to determine the
incarceration rates for community members and ex-prisoners (qc and qe) at model
equilibrium:

Equation 3:
dC/dt = μN - qcC - μC
dP/dt = qcC + qeE - rP -
μP dE/dt = rP - qeE - μE

Individuals are born into the model as either susceptible, early latent, or late latent
community members, at a rate proportional to the overall population of the model. Birth
and death are equilibrated to maintain a fixed population. Upon introduction into the
model, individuals are assumed to be adults and of incarcerable age (15 years old). The
proportion of susceptible, early latent, and late latent individuals born into the population
(at age 15) are governed by the following exponential equations:

Equation 4:
Proportion S = 1-(1-e-
rt
) Proportion E = ⅓(1-
e-rt) Proportion L =
⅔(1-e-rt)

Here, the rate (r) is equivalent to the per capita force of infection for a community
member, β(Ic/Nc), and the time (t) is 15 years. We assume that the ratio of late latent to
early latent individuals born into the population at age 15 is 2:1.
 98

We structured the model such that the total population is equal to 1, and each
compartment in the model is a proportion. For both the infectious and susceptible
individuals at the initiation of the model, we assumed that 0.5% were prisoners, 0.5%
were ex-prisoners and 99% were community members, and brought it to equilibrium as
governed by incarceration, release, birth and death rates.

We assumed proportionate mixing between community members and ex-

prisoners in our assessment of TB transmission, although we explored an
assortative mixing pattern in our sensitivity analysis.

Equation 5.
Np =
Sp+Ep+Lp+Ip+Rp Ne
= Se+Ee+Le+Ie+Re
Nc =
Sc+Ec+Lc+Ic+Rc

Prisoners
dSp/dt = -βp(Ip/Np)Sp - μpSp + qcSc + qeSe - rSp
dEp/dt = βp(Ip/Np)Sp - wpEp - τpEp - μpEp + qcEc + qeEe - rEp + α1βp(Ip/Np)Lp + α2Rp
dLp/dt = wpEp - vpLp - μpLp +qcLc + qeLe - rLp - α1βp(Ip/Np)Lp
dIp/dt = τpEp + vpLp - dpIp - μpIp +qcIc +qeIe + γRp - rIp
dRp/dt = dpIp - μpRp + qcRc + qeRe - rRp - α2Rp - γRp +qcIc +qeIe

Ex-prisoners
dSe/dt = -βe(Ie/(Ne+Nc))Se - βc(Ic/(Nc+Ne))Se - μeSe + rSp -qeSe
dEe/dt = βe(Ie/(Ne+Nc))Se + βc(Ic/(Nc+Ne))Se - weEe - τeEe - μeEe + rEp - qeEe +
α1(βe(Ie/(Ne+Nc))Le
+ βc(Ic/(Nc+Ne))Le) + α2Re
dLe/dt = weEe - veLe - μeLe + rLp - qeLe - α1(βe(Ie/(Ne+Nc))Le + βc(Ic/(Nc+Ne))Le)
 96

dIe/dt = τeEe + veLe - deIe - μeIe + rIp + γRe - qeIe

dRe/dt = deIe - μeRe + rRp - qeRe - α2Re - γRe

Community
dSc/dt = ((1-(1-e(-βc(Ic/Nc)15)))μN - βe(Ic/(Nc+Ne))Sc - βc(Ie/(Ne+Nc))Sc - μcSc -qcSc
dEc/dt = (1/3)(1-e(-βc(Ic/Nc)15))μN + βe(Ic/(Nc+Ne))Sc + βc(Ie/(Ne+Nc))Sc - wcEc - τcEc -
μcEc - qcEc + α1(βe(Ic/(Nc+Ne))Lc + βc(Ie/(Ne+Nc))Lc) + α2Rc
dLc/dt = (2/3)(1-e(-βc(Ic/Nc)15))μN + wcEc - vcLc - μcLc - qcLc - α1(βe(Ic/(Nc+Ne))Lc +
βc(Ie/(Ne+Nc))Lc)
dIc/dt = τcEc + vcLc - dcIc - μcIc + γRc - qcIc
dRc/dt = dcIc - μcRc - qcRc - α2Rc - γRc

Model calibration
We calibrated the model to our calculated TB incidence data from Mato Grosso
do Sul. We fitted only a small set of model parameters which was not well
characterized by past studies or our data (Table 1); attempting to fit all of the
parameters in our model would generate specious values which would nicely fit
data points, but lack real-world validity [9]. Parameter fitting allowed us to
characterize epidemiological parameters for which there is currently a poor
understanding, such as the rate of TB progression from high-risk early latency to
lower-risk late latency among prison inmates, as well as the rate of TB diagnosis
in the prisons.

To account for uncertainty in parameter selection, Latin Hypercube Sampling was

used to create 1000 parameter sets of τ, v, and d. The hypercube was populated
by drawing from uniform distributions containing plausible parameter values,
shown in parentheses in Table 1 for the relevant parameters. We then calculated
the sum squared error of each parameter set using the following equations:

Equation 6:
A = Sum squared error prisoners= Sum(Calculated incidence - model incidence)2
B = Sum squared error ex-prisoners and community = X*Sum(Calculated
incidence - mode incidence)2
Combined sum squared error = A+B

Here, X is a regularization parameter equal to the calculated incidence among

prisoners divided by the combined calculated incidence among community
members and ex-prisoners, introduced to prevent overfitting to the prisoner
incidence. We ordered the parameter sets from lowest to highest sum squared
error terms.

Intervention scenarios
Various administrative interventions were implemented in the model, as
described in S1 Table, to explore the effects of prison-based intervention on
 97

community TB burden. Each of the interventions was applied after the base
model reached equilibrium, and each intervention was run for a period of 10
years.

For the isoniazid preventive therapy intervention, two separate compartments

were introduced into the model. As individuals enter the prison, they are
screened for latent TB with a sensitivity of 0.79 [10]. If they are found to have
latent TB, they are voluntarily started on IPT with an assumed treatment
acceptance rate of 75%, which is represented by a compartment P, for a period
of 6 months. During this time, the individuals are essentially immune to TB
infection. After the course of IPT, the individuals move from compartment P to
compartment SL, representing the post-treatment group. These individuals are
susceptible to TB reinfection, and can progress to Ep at rate α2 times the force of
infection among prisoners, as they (like late latent individuals) are presumed to
have some immunity to re-infection. Normal rates of death and release from
prison apply to compartments P and SL. However, prisoners released from P are
released to Ee and Le (latent infections) proportional to their respective
populations in the prison. Prisoners released from SL become susceptible ex-
prisoners (Se).

Sensitivity analysis: relative incidence and proportion of prisoners

Our sensitivity analysis broadens the generalizability of our TB model, by varying
three different parameters: 1) the proportion of prisoners within the model
community, 2) the relative incidence of TB in the prisons compared to the
community, and 3) the mixing patterns of ex-prisoners and community members
outside the prison.

We modified our original model of TB transmission by fixing all parameters (best

fit values in Table 1) except the β terms, and fitting the combined
prisoner/community model incidence to 140/100k (global median) [3]. Where pp
is the proportion of prisoners, RI is the relative incidence, and Ic is the incidence
in the community, we use the following formula to calculate a matrix of Ic, for pp
range (.002, .01) and RI range (15, 75):

Equation 7.
pp*RI*Ic + (1-pp)*Ic = 140/100k

The incidence in prisons (Ip) is then calculated as the product of Ic and RI for
each point in the matrix. Thereafter, the prevalence in the community (Pc) and
in prisons (Pp) is calculated from each of the Ic,Ip values, as the product of
incidence and duration of infection (d).

We indirectly modify the population of prisoners in the model by modifying the

community incarceration rate (qc). To do so, we solve the system of differential
 98

equations (Equation 3) of individual movement between the three model

environments (community, prisoner, ex-prisoner) at steady state, for the values
of qc which produce the desired proportions of prisoners.

We then fit the model to each Pc,Pp value set (with β terms fitted as described in
Methods, and with qc coming from the values solved as described), to get the
model prevalence for the active diagnosis intervention, allowing us to calculate a
percent decrease for each point on the pp vs RI matrix of Pc,Pp values.

To assess intervention efficacy based on different mixing patterns for individuals

in the community, we performed the above sensitivity analysis with two different
assumptions: 1) ex- prisoners and community members mix proportionately
outside the prison; 2) ex-prisoners and community members assortatively mix,
such that they are three times more likely to interact with their own cohort than
the other (Figure 5). To modify the mixing patterns in the model, the β terms were
repurposed as follows. While βp was not changed, the βe and βc terms were
eliminated and replaced by β1 and β2 terms, where β1 was applied to terms in the
model indicating contact was occurring among members of the same cohort (ex-
prisoner or community), and β2 was applied to any term in the model indicating
contact between the two cohorts. The βp, β1, and β2 terms were then fit using the
same procedure described in methods, with the constraint that β1=β2 for the
proportionate mixing assumption, and β1=3*β2 for the assortative mixing
assumption.

REFERENCES

1. Sgarbi RVE, Da Silva Santos Carbone A, Paião DSG, Lemos EF,

Simionatto S, Puga MAM, et al. A cross-sectional survey of HIV testing
and prevalence in twelve brazilian correctional facilities. Yu X-F, editor.
PLoS One. 2015;10: e0139487. doi:10.1371/journal.pone.0139487
2. Carbone A da SS, Paião DSG, Sgarbi RVE, Lemos EF, Cazanti RF, Ota
MM, et al. Active and latent tuberculosis in Brazilian correctional facilities:
A cross-sectional study. BMC Infect Dis. 2015;15: 24.
doi:10.1186/s12879-015-0764-8
3. Organization WH. Global tuberculosis report 2013. World Health
Organization; 2013.
4. Salomon JA, Wang H, Freeman MK, Vos T, Flaxman AD, Lopez AD, et
al. Healthy life expectancy for 187 countries, 1990–2010: a systematic
analysis for the Global Burden Disease Study 2010. Lancet. Elsevier;
2012;380: 2144–2162.
5. Shea KM, Kammerer JS, Winston CA, Navin TR, Horsburgh CR.
Estimated rate of reactivation of latent tuberculosis infection in the United
States, overall and by population subgroup. Am J Epidemiol. 2014;179:
216–225. doi:10.1093/aje/kwt246
6. Sutherland I, Švandová E, Radhakrishna S. The development of clinical
 99

tuberculosis following infection with tubercle bacilli. Tubercle. 1982;63:

255–268. doi:10.1016/S0041- 3879(82)80013-5
7. Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, Horsburgh
CR. Risk of progression to active tuberculosis following reinfection with
Mycobacterium tuberculosis. Clin Infect Dis. Oxford University Press;
2012;54: 784–791. doi:10.1093/cid/cir951
8. Blower SM, McLean AR, Porco TC, Small PM, Hopewell PC, Sanchez
MA, et al. The intrinsic transmission dynamics of tuberculosis epidemics.
Nat Med. 1995;1: 815–821. doi:10.1038/nm0895-815
9. Jacquez JA. Identifiability and model distinguishability. Compart Anal Biol
Med. 1985; 309–354.
10. Kahwati LC, Feltner C, Halpern M, Woodell CL, Boland E, Amick HR,
et al. Primary care screening and treatment for latent tuberculosis
infection in adults: Evidence report and systematic review for the US
Preventive Services Task Force [Internet]. JAMA - Journal of the
American Medical Association. 2016. pp. 970–983.
doi:10.1001/jama.2016.10357
 100

APENDICE A - TERMO DE CONSENTIMENTO LIVRE E ESCLARECIDO

 101

TERMO DE CONSENTIMENTO LIVRE E ESCLARECIDO

“Estudo de Incidência e fatores de Risco de TB e Doenças Sexualmente

Transmissíveis na população privada de liberdade do estado de Mato
Grosso do Sul”

O Sr. (ª) está sendo convidado(a) a participar do projeto de pesquisa

“Fatores de Risco para TB Latente e HIV na população carcerária do Estado
do Mato Grosso do Sul”, durante o ano 2013 foi realizada uma pesquisa
denominada “Estudo Multicêntrico da prevalência de TB e HIV na população
carcerária do Estado do Mato Grosso do Sul”, onde se tinha o objetivo de
determinar a prevalência de TB ativa e latente bem como de doenças sexualmente
transmissíveis na população carcerária do Estado do Mato Grosso do Sul, estudo
este que você participou. Agora gostaríamos de dar continuidade a este estudo
objetivando estimar a incidência e os fatores de risco da TB latente bem como de
doenças sexualmente transmissíveis na população carcerária do estado do Mato
Grosso do Sul.
A população privada de liberdade vive em condições ambientais precárias,
por isso é uma população de extrema vulnerabilidade às doenças infecciosas como
a TB e as doenças sexualmente transmissíveis. Esse estudo irá ajudar a secretaria
municipal de saúde de cada município a programar medidas de controle da doença
específicas para esta população, além da possibilidade de programar medidas em
caráter estadual.
A sua participação nesta pesquisa se realizará em duas etapas. A primeira
etapa consistirá em responder um questionário, após iremos realizar a prova
tuberculínica, coletar a primeira amostra de escarro quando necessário, e coletar
20 ml sangue para realizar exames de HIV, hepatite B, hepatite C e sífilis. A
segunda etapa ocorrerá após 72-96 horas, e consistirá na avaliação da prova
tuberculínica e coleta da segunda amostra de escarro. A sua participação poderá
acarretar pequenos riscos a sua saúde, como danos psicológicos, pequenos
hematomas após a coleta de sangue ou aplicação da prova tuberculínica. A
participação no estudo não acarretará custos para você e não será disponível
nenhuma compensação financeira adicional. Se durante a aplicação do
questionário, realização da prova tuberculínica ou coleta do material o (a)
senhor (a) apresentar algum problema ou detectarmos que o (a) senhor (a)
precisa de acompanhamento especializado encaminharemos para
atendimento médico no hospital de referência do seu município.
O que irá acontecer com suas amostras de sangue? As amostras de
sangue serão coletadas como parte deste estudo. Elas serão armazenadas em
segurança no Laboratório de Virologia da UFGD, sobre responsabilidade do Dr.
Julio Henrique Rosa Croda por tempo indeterminado para possíveis pesquisas
futuras. Caso você não concorde com o armazenamento do seu sangue para
pesquisas futuras o seu sangue será desprezado. Atualmente, não se conhece a
finalidade de qualquer pesquisa futura e ela poderá estar ou não relacionada ao
presente estudo, mas é possível utilizá-las para desenvolver pesquisas para melhor
compreensão do diagnóstico, tratamento e futuras vacinas na TB, em DST e outras
doenças infecciosas. Nesses novos estudos, nova solicitação será enviada ao
Comitê de Ética em Pesquisa em Seres Humanos da UFGD. Você deverá decidir
 102

se gostaria de ser contactado para autorizar o estudo e se deseja saber o resultado

dessas novas pesquisas.
Para perguntas ou problemas referentes ao estudo ligue para Dr. Júlio
Henrique Rosa Croda, telefone (067) 34102320. Para perguntas sobre seus direitos
como participante no estudo chame o Comitê de Ética em Pesquisa com Seres
Humanos da UFGD, no telefone (067) 34102857.
Sua participação no estudo é voluntária. Você pode escolher não fazer parte
do estudo, ou pode desistir a qualquer momento. Você não perderá qualquer
benefício ao qual você tem direito. Se você desistir do estudo, isso não implicará
na continuidade do seu tratamento. Você não será proibido de participar de novos
estudos. Você poderá ser solicitado a sair do estudo se não cumprir os
procedimentos previstos ou atender as exigências estipuladas. Você receberá uma
via assinada deste termo de consentimento.
Após ser esclarecido (a) sobre as informações a seguir, no caso de aceitar
fazer parte do estudo, assine ao final deste documento, que está em duas vias.
Uma delas é sua e a outra é do pesquisador responsável. Em caso de recusa você
não será penalizado (a) de forma alguma. Em caso de dúvida você pode procurar
o Comitê de Ética em Pesquisa da Universidade Federal da Grande Dourados pelo
telefone (067) 34102857.

Declaração especifica de consentimento para ligação telefônica e visita

domiciliar:

( ) Permito receber uma ligação telefônica para coleta de informações e se

necessário agendamento de visita.
( ) Não autorizo receber telefonema.

_______________________________________________________
Julio Henrique Rosa Croda
Universidade Federal da Grande Dourados, Faculdade de Ciências da Saúde.
Rodovia Dourados Itaum Km 12, 79804-970 - Dourados, MS - Brasil - Caixa-
Postal: 322
Telefone: (067) 34102320

Declaro que entendi os objetivos, riscos e benefícios de minha participação na

pesquisa e concordo em participar.

Nome:_______________________________________.

RG: _________________________________________.
 103

APENDICE B – QUESTIONÁRIO
UNIVERSIDADE FEDERAL DA GRANDE DOURADOS
FACULDADE DE CIEÊNCIAS DA SAÚDE

Fatores de Risco para TB Latente e HIV na população carcerária do

Estado do Mato Grosso do Sul

INFORMAÇÕES GERAIS

1. Número do questionário __ __ __ __

2. Responsável pela coleta de dados: __________________________

3. Data da coleta de dados: ____/____/_____

4. Digitador: ____________________

5. Data da digitação: ____/____/____

6. Cidade: ________________

7. Presídio: ____________________________

8. Pavilhão: __________________________

9. Identificação da cela: __________________

10. Nome: ________________________________________________

11. Sexo: __

12. Data de Nascimento: ___/___/___

DROGAS
13. Qual seu peso? __ __ __

14. Qual sua altura? __ __ __

15. Você toma alguma medicação? __ (1) Sim (2) Não

16. Se sim, especifique qual medicação faz uso? _______________

Histórico de drogas e álcool

17. Você fumou no último ano? __ (1) Sim (2) Não. Se não, pular para a questão 41.

18. Sem sim, quantos cigarros você fuma por dia? __ __

Se o entrevistado fuma, pular para a questão 42

Você já usou alguma das seguintes drogas:

Você usou Quantas vezes você a usou? Durante: Em: Você usou na
no último (1) Menos de uma vez na (1) Dia (1) Dias de prisão?
ano? semana (2) Noite semana (1) Sim
(1) Sim (2) 1-2 vezes na semana (3) Os (2) Finais (2) Não
(2) Não (3) + de 3 vezes na semana dois de semana
(4) Todos os dias (3) Os dois
Álcool 19. 28. 37. 46. 55.
Maconha 20. 29. 38. 47. 56.
 104

Cocaína 21. 30. 39. 48. 57.

Crack 22. 31. 40. 49. 58.
(pedra)
Fumou 23. 32. 41. 50. 59.
heroína
Cheirou 24. 33. 42. 51. 60.
cola/
outros
solventes
Pasta 25. 34. 43. 52. 61.
base
Haxixe 26. 35. 44. 53. 62.
Injetou 27. 36. 45. 54. 63.
alguma
droga?
Quais:

TB

Histórico de sinais e sintomas relacionados a TB

64. Você teve TB no ultimo ano? __ (1) Sim (2) Não (3) Não sabe. Se não vá para a questão 70.

65. Onde? ____________ (pelo menos o último)

66. Quando foi realizado o último tratamento?__ __ meses.

67. Esquema utilizado (o último):________________________________________

68. Tempo que usou a medicação (o último): __ __

69. Tipo de alta (a última): __ (1) Cura (2) Abandono (3) Não sabe

70. Você conheceu alguém com TB no último ano? __ (1) Sim (2) Não (3) Não sabe. Se não, vá
para a questão 72

71. Você tem contato com essa pessoa? __ (1) Menos de uma vez na semana (2) 1-2 vezes na
semana
(3) + de 3 vezes na semana (4) Todos os dias

72. Há pessoas na sua cela com tosse, febre ou emagreceu? __ (1) Sim (2) Não

73. Você tem tosse? (1) Sim (2) Não. Se não vá para a questão 75.

74. Por quantas semanas? __ __

75. Você tem expectoração? __ (1) Sim (2) Não. Se não vá para a questão 78.

76. Sua expectoração tem sangue? __ (1) Sim (2) Não

77. Por quantas semanas? __ __

78. Você tem febre? __ (1) Sim (2) Não

79. Você sente falta de apetite? __ (1) Sim (2) Não

80. Você emagreceu neste último ano ou está emagrecendo? __ (1) Sim (2) Não.

81. Você tem sudorese noturna? __ (1) Sim (2) Não. Se não vá para a questão 83
 105

82. Por quantas semanas ou dias? ___

83. Você sente dor torácica? __ (1) Sim (2) Não

84 Você sente dificuldade para respirar? __ (1) Sim (2) Não

85 Você foi transferido de presidio no último ano? __ 1) Sim (2) Não

86 Em quantas alas diferentes você passou no ultimo ano? ___

87 Em quantas celas você passou no ultimo ano?

DOENÇAS SEXUALMENTE TRANSMISSÍVEIS

88. Você tem ou teve alguma doença sexualmente transmissível no último ano? __ (1) Sim (2) Não
(3) Não sabe
Se não vá para a questão 89.

89. Quantos tratamentos foram realizados? ___

90. Onde foi realizado o tratamento? ____________

91.. Há quanto tempo foi realizado o último tratamento?____ meses.

90. Você tem HIV? __ (1) Sim (2) Não

91. Você fez alguma transfusão sanguínea no último ano? __ (1) Sim (2) Não

92. Se sim, em que mês?_________

93. Você fez tatuagem no último ano? __ (1) Sim (2) Não

94. Se sim, em que mês?_________

95. Tipo da tatuagem: __ (1) caseira (2) profissional

96. Você fez piercing no último ano? __ (1) Sim (2) Não

97. Se sim, quantos? __

98. Você tem ou teve corrimento uretral no último ano? __ (1) Sim (2) Não

99. Você tem ou teve verruga no pênis ou vagina no último ano? __ (1) Sim (2) Não

100. Você tem ferida no pênis ou vagina? __ (1) Sim (2) Não

101. Você teve relação sexual com parceiro usuário de droga ilícita não-injetável no último ano? __ (1)
Sim (2) Não

102. Você teve relação sexual com usuário de droga injetável no último ano? (1) Sim (2) Não

103. Você teve relação sexual com parceiro com HIV no último ano? __ (1) Sim (2) Não

104. Tem parceiro sexual fixo? __ (1) Sim (2) Não

105. Se sim, há quantos tempo? __

106. Qual a quantidade de parceiros no último ano? __ __

107. Qual sua preferência sexual? __ (1) homossexual (2) heterossexual

108. Se for heterossexual, você já teve alguma relação homossexual? __ (1) Sim (2) Não

109. Você usou camisinha nas relações sexuais no último ano? __ (1) Sempre (2) Ás vezes (3) Nunca

110. Você fez compartilhamento de seringas/agulhas no último ano? __ (1) Sim (2) Não
 106

111. Você compartilhou no último ano objetos para realizar tatuagem, alicate, aparelho de barbear, para
uso de droga inalatória? __ (1) Sim (2) Não

112. Realizou alguma cirurgia no último ano? __ (1) Sim (2) Não

113. Se sim, em que mês?_______

EXAMES REALIZADOS
Prova tuberculínica

114. Realizada em: __ (1) MSE (2) MSD

115. Data: __/__/____ Horário: ___h ___min.

Avaliação:

116. Data da avaliação: ___/__/____ Horário: ___h ____min.

117. Resultado: _____ mm

Sorologias

118. Data da coleta de sangue: __/__/____

119. Anti-HIV 1/ 2: __ (1)Reagente (2) Não-reagente

120. Western Blot para HIV: __ (1)Reagente (2) Não-reagente