Resistência genotípica para inibidores da integrase do HIV-1 / Genotypic resistance to HIV-1 integrase inhibitors

A Integrase participa de uma das etapas fundamentais para a replicação do HIV, a inserção do DNA retrotranscrito no genoma humano. Atualmente já foram licenciados três inibidores da integrase (INIs) para o uso de pacientes naïve à terapia antirretroviral ou multi-experimentados, raltegravir (RAL), elvitgeravir (EVG) e dolutegravir (DTG). Embora esses medicamentos sejam eficientes e bem tolerados, a falha terapêutica pode estar associada a seleção de mutações em pelo menos quatro vias distintas(E92Q, Q148H/R/K, N155H e menos frequente a Y143R/H/C) associadas ou não à mutações secundárias. Este estudo teve por objetivo avaliar o gene da integrase em pacientes vivendo com HIV/AIDS. Foram incluídas 265 amostras de pacientes com perfis diferentes de exposições à terapia antirretroviral (TARV): naïve de TARV (n=34), naïve para INIs (n=59), em terapia com TARV+RAL com carga viral suprimida (n=35) e em terapia com TARV+RAL com falha virológica (n=137). As amostras dos pacientes com exposição a INIs foram coletadas no período entre julho de 2009 e maio de 2015. Sequências genéticas foram submetidas à websites e ferramentas de bioinformática para a análise de resistência aos antirretrovirais e determinação de subtipos virais. Nenhuma mutação principal foi observada em amostras de pacientes naïve para INIs, porém alguns polimorfismos observados parecem estar associados a certos subtipos do HIV-1. Entre os pacientes expostos as TARV+RAL, a maioria tinham poucos antirretrovirais ativos compondo a terapia. A adesão e a viremia nas semanas 12-24 após aTARV+RAL (p<0,01) apresentaram associação à supressão viral. Mutações principais para o INIs foram observadas em 62% dos pacientes em uso de TARV+RAL. Em um paciente houve a seleção da mutação F121Y, com evolução subsequente para Y143R. Entre os pacientes com falha virológica ao TARV+RAL, 35% apresentaram resistência intermediaria ou alta ao DTG,com associação das mutações G140S/A e E138A/K (p<0,001)...

Resistência genotípica para inibidores da integrase do HIV-1

A Integrase participa de uma das etapas fundamentais para a replicação do HIV, a inserção do DNA retrotranscrito no genoma humano.Atualmente já foram licenciados três inibidores da integrase (INIs) para o usode pacientes naïve à terapia antirretroviral ou multi-experimentados, raltegravir (RAL), elvitgeravir (EVG) e dolutegravir (DTG). Embora esses medicamentos sejam eficientes e bem tolerados, a falha terapêutica pode estar associada a seleção de mutações em pelo menos quatro vias distintas(E92Q, Q148H/R/K, N155H e menos frequente a Y143R/H/C) associadas ou não à mutações secundárias. Este estudo teve por objetivo avaliar o gene da integra-se em pacientes vivendo com HIV/AIDS. Foram incluídas 265amostras de pacientes com perfis diferentes de exposições à terapia antirretroviral (TARV): naïve de TARV (n=34), naïve para INIs (n=59), em terapia com TARV+RAL com carga viral suprimida (n=35) e em terapia com TARV+RAL com falha virológica (n=137). As amostras dos pacientes com exposição a INIs foram coletadas no período entre julho de 2009 e maio de2015...

The integrase part of one of the key steps for HIV replication, insertionof DNA retrotranscribed in the human genome. Currently they were alreadylicensed three integrase inhibitors (INIs) for the use of antiretroviral therapy naïve patients or multi-experienced, raltegravir, elvitegravir and dolutegravir. Although these drugs are effective and well tolerated, therapy failure may beassociated with selection of mutations in at least four distinct pathways(E92Q, Q148H/R/K N155H and less frequent Y143R/ F/C) or not associatedwith secondary mutations. This study aims to evaluate the integrase gene inpatients living with HIV/Aids. We included 265 samples from patients withdifferent profiles of exposure to antiretroviral therapy (ART): naïve to antiretroviral therapy (n=34), naïve to INIS (n=59), in therapy with TARV+RAL with suppressed viral load (n=35) and therapy with TARV+RAL withvirologic failure (n=137). Samples from patients exposed to INIs were collected between July 2009 and May 2015...

Transmitted drug resistance among recently diagnosed adults and children in São Paulo, Brazil

Transmitted drug resistance mutations (TDRM) have been a constant threat to treatment efficacy. We evaluated TDRM in plasma RNA of 217 antiretroviral therapy-naive patients from sites in the São Paulo metropolitan area, collected from 2012 to 2014. The partial HIV-1 polymerase region was sequenced using Big Dye terminators at an ABI 3130 Genetic Analyzer. TDRM was defined according to the Stanford database calibrated population resistance (CPR v.6.0), but other drug resistance mutations (DRM) considered at the IAS list (IAS, 2014) and at the Stanford HIV Database Genotyping Resistance Interpretation (GRI-HIVdb) were also described. Out of 78% (170/217) of patients with information on the time of diagnosis, most (83%, 141/170) had been recently diagnosed, with the first positive HIV serology at a median of 58 days (IQR 18-184). Subtype B predominated (70%), followed by subtype F (10%), BF (7.5%), C (7.5%), and BC (5%). TDRMs were observed in 9.2% (20/217, CI 95% 5.9% to 13.6%), mostly (5.2%) to nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral class. Among children and adolescents, only a single patient showed TDRMs. Additional non-CPR mutations were observed: 11.5% (25/217) according to IAS or 4.6% (10/217) according to GRI-HIVdb. Overall, 23.5% (51/217) of the cases had one or more DRM identified. TDRM prevalence differed significantly among some sites. These trends deserve continuous and systematic surveillance, especially with the new policies of treatment as prevention being implemented in the country.

Association of X4 tropism with disease progression in antiretroviral-treated children and adolescents living with HIV/AIDS in São Paulo, Brazil

Management of children with HIV/AIDS is specially challenging. Age-related issues do not allow for direct transposition of adult observations to this population. CXCR4 tropism has been associated with disease progression in adults. The geno2pheno web-base is a friendly tool to predict viral tropism on envelope V3 sequences, generating a false positive rate for a CXCR4 prediction. We evaluated the association of HIV-1 tropism prediction with clinical and laboratory outcome of 73 children with HIV/AIDS in São Paulo, Brazil. The CXCR4 tropism was strongly associated with a lower (nadir) CD4 documented during follow-up (p < 0.0001) and with disease severity (clinical event and/or CD4 below 200 cells/mm3) at the last observation, using commonly applied clinical cutoffs, such as10%FPRclonal (p = 0.001). When variables obtained during follow-up are included, both treatment adherence and viral tropism show a significant association with disease severity. As for viremia suppression, 30% (22/73) were undetectable at the last observation, with only adherence strongly associated with suppression after adjustment. The study brings further support to the notion that antiretroviral treatment adherence is pivotal to management of HIV disease, but suggests that tropism prediction may provide an additional prognostic marker to monitor HIV disease in children.