Avaliação da resistência transmitida e adquirida entre crianças e adolescentes infectados pelo HIV-1 / Evaluation of transmitted and acquired resistance among HIV-1 infected children and adolescents

Crianças e adolescentes infectados pelo HIV e em uso de terapia antirretroviral (TARV) requerem uma atenção especial por ser um grupo mais vulnerável. Algumas limitações como fatores psicológicos e socioeconômicos, podem afetar na adesão ao tratamento e levar à falha terapêutica. O teste de genotipagem é importante para a identificação de mutações de resistência a drogas (Drug Resistance Mutation ­ DRM) para subsidiar na troca de antirretrovirais (ARV). O presente estudo teve como objetivo avaliar a resistência transmitida e adquirida entre crianças e adolescentes do Estado de São Paulo, a partir de amostras analisadas no Instituto Adolfo Lutz. No total, 324 sequências parciais do gene da polimerase do HIV-1 (RNA ­ Sequenciamento de Sanger) foram avaliadas, com genotipagem de entre 2009 e 2019. Os dados clínicos e laboratoriais, subtipo viral, DRMs e resistência aos antirretrovirais (Genotypic Susceptibility Score ­ GSS) foram avaliados contribuindo para os resultados desta pesquisa. Para avaliar os preditores da supressão viral dos pacientes em tratamento, foram realizadas análises de regressão logística. Entre os pacientes sem tratamento (naives) n=76, a taxa de resistência transmitida foi de 13,2% (10/76) de acordo com a ferramenta CPR e de 17,1% (13/76) quando considerado as mutações pelo algoritmo GRI-HIVdb. A resistência adquirida nos pacientes tratados em falha virológica (n=248), foi observada nas três classes de ARV, principalmente para os inibidores da transcriptase reversa análogo de nucleosídeo (ITRN) que foi de 83,4% (206/248). Das sequências dos pacientes expostos pelo menos a um IP (162/248), o Darunavir (DRV) foi o que apresentou a menor taxa de resistência (3,1%; 5/162). Após um ano da genotipagem, as crianças e adolescentes tratadas do subtipo B (55/110; 50,0%), C (6/7, 86,7%) e outras formas recombinantes (4/5; 80,0%) alcançaram a supressão viral de acordo com a métrica abaixo de 40 cópias/mL (p=0,004). Na regressão logística ajustada, a supressão viral teve associação (p≤0,05) com o sexo, níveis de faixa de carga viral (CV) e sequências do subtipo F versus B. Foi observada uma queda na resistência adquirida nas classes dos ITRN (p=0,011) e dos IP (p=0,000) no período de outubro de 2012 até agosto de 2018. Tanto os pacientes naives como os tratados apresentaram maior taxa de resistência no subtipo F e menor no subtipo C. Os resultados obtidos demonstram uma taxa intermediária de resistência transmitida e uma alta de resistência adquirida. O aumento do subtipo C na população pediátrica e com uma boa resposta ARV. Além disso, associação significativa do subtipo B com a supressão viral. (AU)

Children and adolescents infected with HIV and using antiretroviral therapy (ART) require special attention because they are a more vulnerable group. Some limitations, such as psychological and socioeconomic factors, can affect adherence to treatment and lead to therapeutic failure. The genotyping test is important for the identification of drug resistance mutations (Drug Resistance Mutation - DRM) to support the exchange of antiretrovirals (ARV). The present study is aimed to assess the transmitted and acquired resistance among children and adolescents in the State of São Paulo, based on samples analyzed at the Adolfo Lutz Institute. In total, 324 partial HIV-1 polymerase gene sequences (RNA - Sanger Sequencing) were evaluated, with genotyping between 2009 and 2019. Clinical and laboratory data, viral subtype, DRMs and resistance to antiretrovirals (Genotypic Susceptibility Score Score) - GSS) were evaluated contributing to the results of this research. To assess the predictors of viral suppression in patients undergoing treatment, logistic regression analyzes were performed. Among patients without treatment (naïve) n=76, the rate of resistance transmitted was 13.2% (10/76) according to the CPR tool and 17.1% (13/76) when considering the mutations by the algorithm GRI-HIVdb. The acquired resistance in patients treated for virological failure (n = 248), was observed in three classes of ARV, mainly for inhibitors of nucleoside analog reverse transcriptase (NRTI), which was 83.4% (206/248). Of the sequences of patients exposed to at least one PI (162/248), Darunavir (DRV) had the lowest resistance rate (3.1%; 5/162). One year after genotyping, children and adolescents treated for subtype B (55/110; 50.0%), C (6/7, 86.7%) and other recombinant forms (4/5; 80.0%), achieved viral suppression according to the metric below 40 copies / mL (p = 0.004). In the adjusted logistic regression, viral suppression was associated (p≤0.05) with gender levels of viral load range (CV), and subtype F versus B sequences. A decrease in the resistance acquired in the NRTI (p = 0.011), and PI (p = 0.000) classes, was observed in the period from October 2012 to August 2018. Both näive and treated patients had a higher resistance rate in subtype F and lower in subtype C. The results obtained demonstrate an intermediate rate of transmitted resistance and a higher rate of acquired resistance, also an increase in subtype C in the pediatric population and with a good ARV response, and in addition, a significant association of subtype B with viral suppression. (AU)

Major drug resistance mutations to HIV-1 protease inhibitors (PI) among patients exposed to PI class failing antiretroviral therapy in São Paulo State, Brazil.

BACKGROUND: Protease inhibitors (PI) are especially important in salvage therapy. Previous treatment failure with a PI containing regimen may elicit resistance mutations, reducing PI susceptibility and limiting treatment options. The aim of this study was to describe major PI mutations among patients exposed to at least one PI to evaluate predictors of mutation emergence and the impact of subtypes on resistance. METHODOLOGY: Partial HIV-1 pol sequences (Sanger Sequencing) from patients exposed to PI with virological failure were genotyped from January 2014 to December 2017. Drug resistance mutations (DRM), antiretroviral susceptibility (GSS) and subtypes, along clinical and laboratory parameters, were evaluated using logistic regression to access the predictors of mutation emergence. RESULTS: In 27.5% (466/1696) of the cases at least one major PI mutations was identified, most commonly M46 (14.7%), V82 (13.8%) and I54 (13.3%). Mutations to NRTI and NNRTI were observed in 69.6% and 59.9%, respectively, of the 1696 sequences. Full activity to darunavir was predicted in 88% (1496/1696), but was only 57% among those with at least one PI-DRM. Subtype C sequences had less major PI-DRMs (10%, 9/87) compared to B (28%, 338/1216) or F (35%, 58/168) (p <0.001) but adjusted analysis suggested that this association is not independent from a shorter treatment time and fewer regimens (OR 0.59, Confidence Interval 95: 0.2-2.5, p = 0.48). Subtype F, together with NRTI mutations and longer time on treatment was associated to presence of PI-DRM, to a lower darunavir GSS and to mutations at codon I50. CONCLUSIONS: Among patients with PI-DRM, full activity to darunavir was compromised in almost half of the cases and efforts to detect failure at earlier time are warranted, particularly for HIV-1 subtype F that showed association to the emergence of resistance, with potential impact in protease inhibitors sequencing. Furthermore, NRTI mutations may serve as an indicative of sufficient adherence to allow PI-DRM emergence.