HIV e Tuberculose -...
Transcript of HIV e Tuberculose -...
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HIV e TuberculoseO impacto da tuberculose na escolha
do tratamento
Beatriz Grinsztejn, MD,PhD
Instituto Nacional de Infectologia Evandro
Chagas
Fiocruz
Rio de Janeiro, Brasil
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Caso Clinico
Jose tem 32 anos, é zelador e foi diagnosticado com infecção pelo HIV
em 2010 após um diagnóstico de sífilis.
Nasceu na Bahia, vive no Rio de Janeiro nos últimos 15 anos, nunca
viajou para o exterior.
É tabagista desde os 15 anos, 20 cigarros ao dia, mora sozinho, não
usa alcohol or qualquer droga recreacional, tem 2 cães
É solteiro, homossexual e não tem parceiro fixo.
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Resultados de exames laboratoriais iniciais
• Contagem de linfócitos CD4:205 cells/mm3
• RNA HIV = 73,500 cópias/mL
• HbsAg neg, anti-HCV neg
• Clearance creatinina >90
• IGg Toxo reagente
• PPD não reator RX tórax normal
• VDRL 1:1 FTAabs positivo
• Orientado a iniciar TARV, não aceitou de imediato.
• Iniciado profilac=xia PCP com SMZ+TMP
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Evolução Clinica
José não retorna ao seu médico por um ano, reaparece com uma
massa cervical a esquerda, que a palpação tem consistencia
aumentada, sinais inflamatórios (++/4+).
Refere febre diária há 20 dias, sudorese noturna, nega tosse;relata
perda ponderal de aproximadamente 10 kg em 3 meses. Sem
outras adenopatias periféricas;hepatosplenomegalia.
RX tórax normal. CD4 51células/mm3, RNA HIV->750 000, clearence
creatinina normal
Hepatograma mostra aumento discreto de transaminases, fosfatase
alcalina 5x normal,LDH normal.
Hto 34,PCR 20
BAAR no escarro induzido negativo, Xpert negativo
Realizada punção massa cervical
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Qual o diagnóstico mais provável?
Qual o diagnóstico mais provável?
1.Linfoma
2.Tuberculose
3.Histoplasmose
4.Bartonellose
5.MAC
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Relatório da OMS 2013Controle global de tuberculose
No mundo todo, 9,6 milhões de novos casos incidentes de TB em 2013; 1,5 milhão de óbitos por TB
~1,13 milhão (13%) Casos de HIV+TB;400.000 mortes por HIV+TB a cada anoA TB é a principal causa de morte entre PVHIV, respondendo por um em cada cinco óbitos relacionados ao HIV
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HIV-TB
• Um terço das 35 milhões de pessoas que vivem com
HIV em todo o mundo estão infectadas com TB latente.
• Pessoas coinfectadas com TB e HIV tem 30 vezes mais
probabilidade de desenvolverem doença ativa por TB
quando comparados aos individuos não infectados pelo
HIV.
• A TB é a principal causa de morte entre pessoas
vivendo com HIV, respondendo por um em cada cinco
óbitos por AIDS
• TARV altamente eficaz em prevenir TB
• TB extrapulmonar é responsável por 10%-42% dos casos de tuberculose (TB), com % maiores entre crianças e individuoscoinfectados com HIV
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Havlir, Getahun et al. 2008 JAMA 300(4):423-430
O declínio no nível de CD4 está associado ao aumento
do risco de morbidade e mortalidade: Incidência de TB
"Zona de morte da TB"
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Diagnóstico TB
• Retardo diagnósticoaumentamortalidade
• Globalmentesomente 65% dos casos de TB sãodiagnosticados e tratados
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Como suspeitar e diagnosticar TB mais precocemente em pessoas com
HIV/AIDS?Confirmação diagnóstica pode ser dificil, sendo um desafio a coleta de tecidos, principalmente quandoprofundos
Doença tipicamente paucibacilar• Cultura (meio liquido ou solido)é o padrão ouro para
diagnóstico.• Estrutura laboratorial limitada e tempo de
processamento e retorno prolongados limita a utilidade da cultura na pratica clinica
• Histologia pode ser util
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Xpert MTB/RIF deve ser usado em vez de microscopia convencional, cultura etestes de susceptibilidade a medicamento como o teste diagnóstico inicial emadultos e crianças com suspeita de TB associada ao HIV (pulmonar e alguns tiposde TB extrapulmonar)
Precisamos diagnosticar e tratar rapidamente a TB nas PVHIV
Teste molecular de 2 horas para diagnóstico de MTB e resistência à rifampicinaOutros testes de drogas estão por vir
Mais sensíveis do que baciloscopia BAARUso em crianças e TB extrapulmonar
XPERT MTB/RIF:
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Como suspeitar e diagnosticar TB mais precocemente em pessoas com
HIV/AIDS?• O Xpert MTB/RIF (Xpert) assay (Cepheid Inc., Sunnyvale, CA, USA) é uma
metodologia molecular semi-automatizada que permite o rápido diagnóstico da TB através da detecçãodo DNA do Mycobacterium tuberculosis e a identificação simultanea das mutações que conferemresistencia a rifampicina (altamente preditora de TB multirresistente
• Evidencia sólida para diagnóstico de TB pulmonar emlocais com alta e baixa carga de TB com estimativas de sensibilidade quando utilizado para testar amostras de escarro BAAR + e BAAR – de 98% (95% CI,97 – 99%) e 68% (95% CI, 59 – 75%), respectivamente, e especificidade de 98% (95% CI, 97 – 99%).
Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, PaiM, Dendukuri N: Xpert(R) MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance inadults (Review). Cochrane database of systematic reviews
2013,
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Como suspeitar e diagnosticar TB mais precocemente em pessoas com HIV/AIDS?
• O Xpert MTB/RIF trouxe um importante avanço no diagnosticos da TB extrapulmonar, principalmente liquor, linfonodos e tecidos e foi incluido para esse
• Utilidade em diferenciar micobacterium Tb e não tuberculosis em qualquer amstraBAAR+
• Dois estudos na Africa do Sul usando amostras de linfonodos obtidas por agulhafina reportaram alta sensibilidade (0.93 Ligthelm et al.)(0.97 van Rie et al) sendoque a maioria dos pacientes incluidos nesses estudos eram infectados pelo HIV
• Sensibilidade inversamente proporcional ao grau da imunodeficiencia (van Rie A et al 2013).
• Sensibilidade não se mostrou inferior em pacientes infectados pelo HIV cm TB ganglionar (Denkinger et al) [44].
• Xpert MTB/RIF may be used as a replacement test for usual practice (including conventional microscopy, culture or histopathology) for testing specific nonrespiratory specimens (lymph nodes and other tissues) from patients suspected of having extrapulmonary TB Xpert MTB/RIF implementation manual: technical and operational ‘how-to’; practical considerations 2014
Van Rie A, Page-Shipp L, Mellet K, Scott L, Mkhwnazi M, Jong E, Omar T,
Beylis N, Stevens W, Sanne I, Menezes CN: Diagnostic accuracy and
effectiveness of the Xpert MTB/RIF assay for the diagnosis ofHIV-associated lymph node tuberculosis. European Journal of
ClinicalMicrobiology and Infectious Diseases 2013, 32:1409-1415.
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Expansão do Xpert
Stevens TB2016
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LAM: Teste de urina de beira do leito (Point of Care) para pessoas gravemente doentes que vivem com HIV
LF-LAM pode ser usado para auxiliar no diagnóstico de TBativa em adultos HIV positivos e com TB presumida que:
1) tenham contagem de linfócitos CD4 ≤ 100 ou2) estejam gravemente doentes, independentemente
da contagem de CD43) Benefício relativo à mortalidade
Lawn 2013, Wood TB2016
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Urine Lipoarabinomannan (LAM)
sensitivity specificity
HIV- 18% 90%
HIV+ 56% 95%
CD4<50outptinpt
67%85%
100%NA
CD4 50-100outptinpt
35%71%
100%NA
CD4>100outptinpt
4%53%
100%NA
• ELISA, newer Lateral flow point of care assay (like a pregnancy test)
• LAMis a 17.5kd glycolipid protein found in cell wall of MTB released from active or degrading MTB cells in urine
• Sensitivity highest in HIV+ with advanced immunosuppression
• “Niche clinical utility” rapid TB screening tool for HIV+ with low CD4, starting ART in high TB/HIV burden settings
Dheda PLOS 2010; Shah JAIDS 2009; Lawn AIDS 2009;
Lawn Lancet ID 2011; Minion Eur Resp J 2011
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5
1. Molecular detection
State of
science
NAAT platforms with the potential to be deployed at TB microscopy
centers
Mixing
for 2 min TB LAMP
• Development of fast follower platforms slower than expected.
• Promising amplification & detection technologies, but no proof-of-principle for point-of-care.
Key approaches to fill TB diagnostics gaps
New generation NAAT
platforms
From macrofluidics to microfluidics
Lab-on-a-chip
Isothermal amplification & solving problem of sample volume
Strategic
approach
Beyond Xpert – next generation molecular tools
Q-POC, QuantuMDx TrueLab, Molbio GeneDrive, Epistem
Enigma, UK Gentura Dx, USGreat Basin Scientific, US
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45,8% dos casos de TB não são diagnosticados antes do óbito
Prevalência de TB post-mortem em pacientes HIV-positivos
Lancet HIV 2015 online august 12 2015
Encontrando casos de TB - muito poucos, tarde demais
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TARV e Tuberculose
TARV precisa ser iniciada para esse paciente.É indicado
fazer teste de resistência pré TARV? Qual o melhor de
iniciar TARV?
1. Após completar o tratamento para TB?
2. Após 4 semanas de tratamento para TB
3. Após 8 semanas de tratamento para TB
4. Em até 2 semanas apos inicio do tratamento para TB
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CAMELIA (Camboja) SAPIT (África do
Sul)
STRIDE (multicontinentes)
Estratégia de tratamento de terapia imediata de TB + TARV precoce (2 vs 8 semanas) que salva vidas e reduz complicações do HIV
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Características-chave dos estudos sobre quando
iniciar TARV durante o tratamento de TB
Estudo Situação
Início de
TARV
Critérios-
chave
para
inclusão
Mediana de
CD4
(IQR)
Desfecho
primário
CAMELI
A(Blanc, ANRS)
Camboja
2
seman
as vs.
8
seman
as
BAAR+,
CD4 < 200
25
(10 – 56)Óbito
STRIDE(Havlir, ACTG)
Multinacio
nal
2
seman
as vs.
8-12
seman
as
TB clínica,
CD4 < 250
77
(36 – 145)
AIDS ou
óbito
1as 4
AIDS 2010 abstract THLBB106, CROI 2011 abstract 38, CROI 2011 abstract 39LB
Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011
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Efeito do momento de início da TARV sobre
óbitos (CAMELIA) ou morte/AIDS (STRIDE,
SAPIT)
0
2
4
6
8
10
12
14
16
18
CAMELI A STRI DE SAPI T
I mmediate Early
34% ↓ p=0,004
19% ↓
p=0,45
11% ↓
p=0,73
0
5
10
15
20
25
30
CAMELI A STRI DE SAPI T
I mmediate Early
34% ↓ p
= 0,004
42% ↓
p=0,02
68% ↓
p =
0,06
CD4 < 50Geral
Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011
Supressão viral - nenhum efeito do momento de início da TARV sobre a supressão ao final do
tratamento de TB
Trocas de TARV – mais altas no braço de tratamento imediato no SAPIT
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Momento de início de TARV em pacientes
com TB
• AIDS avançada (CD4 <50): TARV imediata (em 2 semanas) melhora a sobrevida
– Risco aumentado de IRIS, incluindo IRIS fatal
– Benefício global de sobrevida apesar disso
• CD4 >50: TARV precoce (~ 2 meses) proporciona um bom equilíbrio de riscos concorrentes de morte/AIDS vs. IRIS
• Ressalvas
– Envolvimento do SNC - nenhum benefício para terapia imediata, e pode haver maior risco (Torok, CID, 2011)
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Rifabutina + IPs com booster - alguns problemas
• Interações medicamentosas bidirecionais– RBT é metabolizada pelo citocromo P450 (CYP) 3A4, então
é preciso diminuir a dose quando administrada com inibidores de CYP3A4, como ritonavir, para evitar toxicidades
• Caro, não amplamente disponível• Dados de eficácia são escassos
– Estudos clínicos que compararam RBT a RIF foram conduzidos em grande parte com pacientes que não tomavam ARV
Não sabemos qual dose de RBT dar quando RBT é administrada com um IP.
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TARV em pacientes com TB-HIV
Você decidiu começar TARV. Qual o a base do
esquema de tratamento preferencial?
1. Nevirapina
2. Lopinavir/r
3. Efavirenz
4. Raltegravir
5. Atazanavir
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O que começar - Opções de cotratamento para
HIV/TB
▪ TARV baseada em efavirenz- preferencial– Guideline brasileiro e da WHO: efavirenz (EFV)-based regimen :opção preferencial para TARV em
indivíduos coinfectados com HIV-TB
– Limitações potenciais ao uso do EFV
• Efeitos adversos : rash, toxicidade SNC
• Resistência Transmitida aos NNRTIs
▪ TARV baseada em Raltegravir
▪ TARV baseada em Inibidor da protease+rifabutina
• Você inicia tratamento com tenofovir+lamivudina+efavirenz mas após uma semana recebe o resultado do teste de resistência que mostra resistência primaria NNRTI (K103N).
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ANRS 12 180 Desenho do estudo
Phase II open label randomized multicenter trial
W0 W 24 W48
1:1:1
+ RAL 800 mg bid
TDF245 mg qd + 3TC 300mg qd + EFV 600 mg qd
TDF245mg qd + 3TC 300mg qd + RAL 400 mg bid
+ RAL 400 mg bid
ANRS 12 180
Primary endpoint
HIV RNA<50copies/mL
TB drugs RHZE 2mo followed by RH 4mo
• HIV RNA>1000 cp/mL
• ART naïve
• Confirmed or probable TB
• RIF containing regimen
Sample size : 50 patients/arm, 80% power to show ≥70% success at W24
TDF245 mg qd + 3TC 300 mg qd
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▪ Nesse estudo de fase II, uma alta taxa de sucessovirológico foi alcançada na Sem 48 com RAL 400 mg BID emcombinação with TDF + 3TC
▪ No contexto da coinfecção por HIV e TB, RAL (400 mg bidou 800 mg bid) tem um bom perfil de segurança
▪ Os dados do sub-estudo de PK também respaldam o uso deraltegravir em combinação com rifampicina
▪ RAL, na dose de 400 mg de bid, parece ser uma alternativaadequada a EFV para pacientes coinfectados com HIV-1-e TBe deve ser considerado para avaliação adicional em umensaio de fase III
ConclusãoANRS 12 180REFLATE TB
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• Grande variabilidade interparticipantes na PK de RAL
• Os resultados em pacientes infectados pelo HIV com TB diferem dos resultados em participantes saudáveis
• O GMR com RAL 400 bid permanece dentro da faixa aceita para “interação medicamentosa não significativa” com rifampicina
• Neste estudo, as interações entre RAL e rifampicina com esquema de base de INH, PZA, EMB e TDF/FTC podem explicar as diferenças
• RAL 800 compensa totalmente a indução de rifampicina
Resumo do sub-estudo de PK
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Rifabutina + IPs com booster - alguns problemas
• Interações medicamentosas bidirecionais
– RBT é metabolizada pelo citocromo P450 (CYP) 3A4, então é preciso diminuir a dose quando administrada com inibidores de CYP3A4, como ritonavir, para evitar toxicidades
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Dolutegravir para pacientes coinfectados com HIV/TB
• DTG é um substrato de UGT1A1 e CYP3A, ambas as enzimas são
induzidas por RIF.
• Dar DTG duas vezes ao dia com RIF resultou em concentrações de
DTG semelhantes ou superiores às obtidas com DTG administrado
sozinho uma vez por dia.
• A combinação de múltiplas doses de RIF e DTG também foi bem
tolerada.
• Resultados encorajadores que fornecem dados farmacocinéticos e
de segurança para respaldar a avaliação de TARV baseada em
DTG e tratamento para TB contendo RIF em pacientes coinfectados
com HIV e TB.
• Ensaio clínico em andamento
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Evolução Clinica
O paciente inicialmente apresenta melhora dos sintomas mas após 6 semanasde tratamento apresenta recorrencia da febre e da sudorese noturna
Apresenta também linfadenopatia cervical bilateral, com sinais inflamatóriosexuberantes, drenando secreção amarelada a direita.
Sem febre, sem hepatoesplenomegalia
Teve ganho ponderal de 8kgRX torax normalRNA HIV indetectávelCD4 215Clearence Cr normalHepatograma normalPCR 50
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Qual o diagnóstico provável?
1.Infecção Bacteriana
2.Linfoma
3.IRIS
4.Bartonelose
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Clinical Case
• Co-amoxiclavulanate x 5days
• Ibuprofen
• A week later he was still symptomatic and have a fever of 38,4˚
• Given prednisone x 3 weeks
• Symptoms resolved within 15 days
• No need to stop ARV regimen
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36
Combination ART
Viral suppression
CD4 rise
Restoration of pathogen-specific immunity
Regression or prevention of opportunistic infections
Inflammatory reactions daysto months after starting ART
+ -
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Paradoxical-TB IRIS
• Recurrent, new or worsening TB symptoms, signs and/or radiological findings
• Incidence 8-45%
• Typically 1-4 weeks after ART initiation
• Usually TB culture negative
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38
Schematic representation showing the different forms of tuberculosis-associated IRIS and ART-associated tuberculosis
(Lancet Infect Dis Aug 2008)
Tuberculosis treatment status Outcome Case definition
Tuberculosis diagnosedand treatment startedbefore ART initiation
Not on tuberculosistreatment when ART
is initiated
ART initiated
Paradoxical reactionwithin 3 months
Active tuberculosisdiagnosed on ART
Paradoxicaltuberculosis-associated
IRIS
ART-associated tuberculosis(a subset of these patients
could have unmaskingtuberculosis-associated IRIS)
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IRIS rates on Integrase treatment
Will there be and increased rate as the fall in HIV RNA is so rapid?
Is there a the problem in LMICs in dealing with IRIS consequences?
Will steroids prevent IRIS?
– -waiting for the Pred-ART trial results
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But ........
What is the background rate with EFV based regimens?
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ACTG A5221 STRIDE: An international randomizedtrial of immediate vs early antiretroviral therapy
(ART) in HIV+ patients treated for tuberculosis
IRIS
Median CD4 =70 (34-146)
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42
Two arms of ART initiation after tuberculosis treatment onset:
‘‘early’’ (at 2 weeks) vs. ‘‘late’’ (at 8 weeks)
High frequency (26%) of paradoxical TB-IRIS in HIV-infected patients withadvanced immunodeficiency
Double the risk of developing TB-IRIS (HR 2.23) when ART was initiated at 2 weeks
Median time of TB-IRIS occurrence: 2 weeks, irrespective of early or lateART initiation
Low mortality directly related to TB-IRIS: 6/155 (3.9%) in accordance withpublished data
Median CD4 cell count: 26 cells/µL (12–62)
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N PR/IRI
S
Follow-up
time*
Incidence** (95%
CI)
p
Early arm 332 110 2 728.5 4.03 (3.34 – 4.86)<0.0001
Late arm 329 48 3 333.5 1.44 (1.09 – 1.91)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
TB
-re
latd
PR
/IR
IS p
roba
bili
ty (
%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Time aftre TB treatment initiation (weeks)
Early arm Late arm
CameliaIRIS significantly more frequent in the early arm
ANRS 1295/12160 - CIPRA KH001/10425
study
* expressed in person-months
** per 100 person-months
Time after TB treatment initiation (weeks)
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Severity of immune reconstitution inflammatory syndrome
Study arm
Early-
integrated am
N=214
Late-integrated
arm
N=215
Sequential
arm
N=213
p-
value
Number of patients
with IRIS43 18 19
Patients hospitalized
for IRIS, %(n)41.9 (18) 22.2 (4) 5.3(1) 0.01
Patients who received
steroids for IRIS,% (n)9.3 (4) 5.6 (1) 15.8 (3) 0.69
IRIS associated
deaths, % (n)4.7(2) 0 0 1.00
IRIS-SAPiT Study
*Median CD4 was 150(77-254) in Integrated arm
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REFLATE: IRIS
EFV RAL 400 RAL 800
n = 51 n = 51 n = 51
Grade 3 or 4 clinical AE, n (%) 13 (25%) 11 (22%) 12 (22%)
Grade 3 or 4 IRIS week 24 n 1 1 3
Any Iris event at week 48 n (%) 7 (14%) 4 (8%) 7 (14%)
ANRS 12 180
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ATHENA cohort study
2.7 times higher risk of IRIS for Integrase Inhibitors vs other classes
Two reports of myocarditis – Israel, plus death from myocarditis in FLAMINGO study
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IRIS in UK
Anecdotal – increased in last 18 months
Ongoing audit of IRIS rates as Raltegravir 800 bdhas become standard treatment
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IRIS in Botswana
Anecdotal reports from recent admissions in patients on DTG
Paradoxical IRIS
Crypto IRIS
Unmasking TB IRIS
But no crypto screening or prophylaxis at initiation
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IRIS in randomised trials of Integrase versus other classes
Most trials of DTG excluded people with active OIs or CDC C stage disease (e.g. ARIA, SINGLE, FLAMINGO)
Most trials had high median CD4 counts, recruiting mainly White men with a low risk of TB
Detailed analyses of IRIS generally not available from published papers
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IRIS in randomised trials of first-line integrase versus other classes
__________________________________________________________Trial n IRIS INT IRIS Control__________________________________________________________STARTMRK (RAL) n=563 21 15ARDENT (RAL) n=1809 1 0NEAT (RAL) n=805 1 0
SINGLE (DTG) n=833 1 2FLAMINGO (DTG) n=484 no details publishedARIA (DTG) n=595 no details published
WAVES (ELV) n=595 no details publishedGS0102 (ELV) n=707 no details publishedGS0103 (ELV) n=708 no details published__________________________________________________________Potential to evaluate associated symptoms: lymphadenopathy, tachycardia
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New randomised trials
_________________________________________________Trial Country (n) 48 wk results_________________________________________________ViiV TB study International (n=130) 2018?
Reflate-TB International (n=400) 2018?
NAMSAL Cameroun (n=606) 4Q2018
ADVANCE South Africa (n=900) 1Q2019_________________________________________________
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Obrigada!