resistencia trnasmitida e adquirida do hiv no brasil
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Resistencia Trnasmitida e Adquirida do HIV no Brasil. Amilcar Tanuri UFRJ, Brasil. Tipos de Resistencia. Resistencia Transmitida ou Primaria – Aquela que foi transmida de um individuo em uso de TARV para outro virgem de tratamento. - PowerPoint PPT PresentationTRANSCRIPT
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Resistencia Trnasmitida e Adquirida do HIV no Brasil.
Amilcar Tanuri
UFRJ, Brasil
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Tipos de Resistencia
• Resistencia Transmitida ou Primaria – Aquela que foi transmida de um individuo em uso de TARV para outro virgem de tratamento.
• Resistencia Secundaria – E aquela selecionada pelo uso de continuo ou nao de TARV
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Como Contar a Resistencia Transmitida ?
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Worldwide distribution of HIV-2, and HIV-1 subtypes and CRFs
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Maneiras standarizadas para contar as Mutacoes Resistencia
• Shafer et al, Aids (2007) proposed a list where:– IP: 31 mutations in 14 positions .– NRTI: 31 mutations in 15 positions+ T215
revertants– NNRTI: 18 mutations in 10 positions.
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List of protease mutations important for Surveillance
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List of NRTI RTmutations important for Surveillance
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List of NNRTI RTmutations important for Surveillance
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O Site de Standford desenvolveu uma nova lista
com as mutacoes balanceadas (CPR)
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Primary Resistance in Brazil
Site Population NNRTI NRTI PI Total MDR
(Rio de Janeiro, RJ), Varella et al., J Med Virol. 2007 , 79(8):1033-9.
20 Recent infection (RI)0 1.4% 0
52 cronic infection (CI)
(Salvador, BA), Pedroso et all., JAIDS, 45(2), 2007, pp 251-253
130 cronic infection with 20 kids included
11.4% 9.8% 5%
(Santos, SP) Sucupira et al., AIDS Patient Care STDS. 2007 ,21(2):116-28.
25 RI 0 22,7% 13,6% 36.8 %
65 CI 15% 21,7% 8,1% 25%
(Recife, PE) Medeiros et al., Mem Inst Oswaldo Cruz. 2006,101(8):845-9.
84 CI 0 3.6 0
(Rio de Janeiro, RJ ) Teixeira et al.; J. Med Virol. 2006
Jun;78(6):764-9.
27 (1994-7) UDI 22% 0
31 (1999-01) UDI 13% 7.9%
(Rio de Janeiro) Brindeiro et al. 2003
2,06% 2,36% 2,24%
(Sao Paulo, SP) Barreto et al., J Acquir Immune Defic Syndr. 2006,
41(3):338-41.
342 blood donors (1998-2002)
6.3%;
No change when (1998-2000) is compared with (2000-2002);
IR MDR>IC MDR
(Porto Alegre, RS) Rodrigues, R, Virus Res. 2006 ;116(1-2):201-7
108 (2004-5) 2% 1% 0 No MDR
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Tarnsmission of HIV DR strains among drug naive individuals with cronic infection (WATCH, 2006)
Bowles E et al., 4th EHDRW, Monte Carlo, March 2006.
América do Norte9.3%
América do Norte9.3%
América Latina5.0%
América Latina5.0%
Overall rate = 8.9% (n=6054)
Europa11.3%Europa11.3%
África5.7%África5.7%
Leste Asiático 9.4%
Leste Asiático 9.4%
S/SE Asia5.3%
S/SE Asia5.3%
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Primary HIV DR in different countries using recent infected population
Study (place) nDefinition of recent infection
Year Prevalence
REDADA 1 596 Clínico 1996-2002 10%
CDC 2 182 STARHS * 1997-2001 12%
San Francisco3 180 < 1 ano 2000-2002 26%
North Caroline 4 30 < 30 dias 1998-2003 13%
Canada†5 144 STARHS * 1997-2001 10%
Montreal 6 170 < 1 ano 1996-2003 12%
France 7 296 < 6 meses 2001-2002 11%
UK8 157 < 18 meses 1996-2003 17%
Madrid 9 74 < 1 ano 1997-2002 19%
Zurich /Geneve 10 453 < 1 ano 1996-2002 11%
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Primary HIV DR in different countries using cronic infected population
Estudo n year prevalence
REDADA 1 379 1996-2002 7%
CDC 2 900 1996-2002 7%
Canada 3 378 1997-2001 5%
France 4 363 2001 6%
REINO UNIDO 5 1 966 1996-2003 14%
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17
119
5
RC
*Mutations 41 + 67 + 70 + 215 +219
*
Wrin T, 40th ICAAC 2000
HIV DR Mutations impacting in RC (viral fitness)
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Tamanho amostral OMS THS Tabela 1. Inquérito do Limiar do HIV fármaco resistente: Plano de colheita e classificação (ref)
Número da Amostra Genotípica (NAG)
Limite inferior (LI)
Manuseamento total das amostras com HIVRES (MT)
Limite superior (LS)
Número da Amostra Genotípica (NAG)
Limite inferior (LI)
Manuseamento total das amostras com HIVRES (MT)
Limite superior (LS)
1 ND ______ ND 25 ND ______ 6 2 ND ______ ND 26 ND ______ 6 3 ND ______ ND 27 ND ______ 6 4 ND ______ ND 28 ND ______ 6 5 ND ______ ND 29 ND ______ 6 6 ND ______ ND 30 ND ______ 6 7 ND ______ ND 31 ND ______ 6 8 ND ______ ND 32 ND ______ 6 9 ND ______ ND 33 ND ______ 6 10 ND ______ ND 34 1 ______ 6 11 ND ______ ND 35 1 ______ 7 12 ND ______ ND 36 1 ______ 7 13 ND ______ ND 37 1 ______ 7 14 ND ______ 5 38 1 ______ 7 15 ND ______ 5 39 1 ______ 7 16 ND ______ 5 40 1 ______ 7 17 ND ______ 5 41 1 ______ 7 18 ND ______ 5 42 1 ______ 7 19 ND ______ 5 43 1 ______ 7 20 ND ______ 5 44 2 ______ 7 21 ND ______ 5 45 2 ______ 7 22 ND ______ 5 46 2 ______ 8 23 ND ______ 5 47 2 ______ 8 24 ND ______ 5 STOP STOP STOP STOP
Os testes genotípicos das amostras podem parar quando a classificação da prevalência do HIVRES for feita com base neste quadro. A classificação da prevalência do HIVRES é feita quando, entre os números de amostras genotípicas (ver a coluna NAG), a analise total das amostras com HIVRES (na coluna MT na mesma linha horizontal) é menor do que o limite inferior especifico na coluna LI para a esquerda da coluna MT, ou maior do que o limite especifico superior na coluna LS a direita da coluna MT. Quando uma dessas condições ocorre, a prevalência do HIVRES pode ser classificada como sendo <5% (se o MT é <do que número LI na mesma linha horizontal) ou> 15% (se o MT é> do que o número LS). Se nenhuma destas condições é satisfeita, e a colheita de amostras esta completa, a prevalência é classificada como sendo >5%, < 15% depois de 47 amostras terem submetidas ao teste genotípico. A analise deve ser feita para cada fármaco ou classe farmacêutica em questão.
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HIV prymary resistance and its impact in 1st line regimens.
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Time to reach VL<500 copies/ml(USA)Susan Little et al. N Eng J Med, 2002
• Time to reach VL<500 copies/ml in group with IC50<2,5 (low # of HIVDR) when compared with IC50>2,5
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Time to show therapeutical failureSusan Little et al. N Eng J Med, 2002
• Time to show failure when the isolate has a IC50>10 in the primary infection
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NGS aumentou a sensibilidade na identificacao das mutacoes
• Este aumento gerou muita controversia quanto o cut-off para considerar a mutacao relevante > ???%
• Tambem nao se sabe muito o impacto na resposta terapeutico.
• A analise fica mais confiavel junto com a analise do nivel da carga viral
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Como esta se Comportando as taxas de Resistencia Primarias
no Mundo
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Prescripción de ARV – pacientes que han iniciado TAR en 2012
ITRNN X IPITRNN 66,2%IP 33,8%
ITRNNNevirapina 6,7%Efavirenz 93,3%
IPLopinavir 64%Atazanavir 33%Fosamprenavir 3%
ITRNAZT 71,2%TDF 27,6%ABC 0,8%
Definición de líneas de tratamiento
1ª línea: AZT X TDF
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Periodo: 2012
Genotipificaciones sin R o I = 14%
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ITRN ITRNN
IP 3ª línea
Susceptible Resistente
Pacientes >13 años
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Resistencia ITRN
Pacientes >13 años
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Resistencia ITRNN
Pacientes >13 años
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Resistencia IP
Pacientes >13 años
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Resistencia 3ª línea
Pacientes >13 años
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Primero fracaso terapéutico: cambiar ITRN o ITRNN?
Primero Fracaso Terapéutico: Resistencia a ITRN (Pacientes que han iniciado TAR con ITRNN, 2011 y 2012)
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Primero Fracaso Terapéutico: cambiar ITRN o ITRNN?
Primero Fracaso Terapéutico: Resistencia a ITRNN (Pacientes que han iniciado TAR con ITRNN, 2011 y 2012)
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RENIC Study
• What is RENIC?
Rede Nacional de Identificação e Caracterização do HIV.
BRESNET
Brazilian Resistance Network
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• RENIC/BRESNET Started in 2001 to study the HIV primary resistance in Brazil.
• 1st survey was done in 2002 targeting recent diagnosed patientes attending VCT sites spread in spanned metropolitan regions located in eight different Brazilian states, Rio Grande do Sul (n ¼ 139), Parana (n= 147), Sao Paulo (n = 100), Rio de Janeiro (n = 83), Mato Grosso do Sul (n = 7), Para (n ¼=17) , Bahia (n = 12), and Ceara (n =30), that covered 65% of Brazilian AIDS Epidemic.
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RENIC2002 Characteristics
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RENIC2002 Characteristics
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RENIC2007/8 Characteristics
• A new RENIC survey was placed in 2007/8. This done using the HIV Threshold Survey methodology (HIV-THS, WHO), targeting the four major Brazilian regions, selecting the 6 more populated state capitals, Sao Paulo, Rio de Janeiro, Salvador, Porto Alegre, Brasilia, and Belem.
• We were able to sequence samples from 210 individuals with recent HIV diagnosis, 17 of them (8.1%) carrying HIV isolates with primary antiretroviral resistance mutations. Five, nine, and four isolates showed mutations related to resistance to NRTIs, NNRTIs, and PIs, respectively. Using HIV-THS we could find an intermediate level of resistance (5%-15%) in Belem/Brasilia, Sao Paulo and Rio de Janeiro, whereas lower level of resistance (<5%) was observed in the other areas.
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RENIC2007/8 Characteristics
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RENIC2007/8 Characteristics
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HIV-1 subtype prevalence in Brazil
RENIC2002 RENIC2007/8
New subtypes found in Brazil: CRF2-AG, and A.
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Primary resistance trend in Brazil Comparing RENIC 02 X 07/8
0,00
1,00
2,00
3,00
4,00
5,00
6,00
7,00
M41L
T69D
M184V
T¨215Y
/F
T215rev
K219R
K103N
Y188L
K238T
D30N
M46I
G48V
V82A
I84V
L90M
Mutations
Mu
tati
on
rat
e (%
)
RENIC 2007/8
RENIC 2002
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17
119
5
RC
*Mutations 41 + 67 + 70 + 215 +219
*
Wrin T, 40th ICAAC 2000
HIV DR Mutations impacting in RC (viral fitness)