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.

Avaliação da resistência aos inibidores da protease em pacientes vivendo com HIV em falha terapêutica / Evaluation of resistance to protease inhibitors in patients living with HIV in therapeutic failure

Inibidores de protease (IP) são importantes nos esquemas de resgate para pacientes que não respondem à terapia antirretroviral (TARV). O uso prévio de IP pode limitar o tratamento e a detecção de mutações de resistência a estes medicamentos (IP-DRM) e pode subsidiar a seleção do regime. O objetivo deste estudo consistiu em descrever as mutações principais para os IP em pacientes do Estado de São Paulo, expostos a pelo menos um IP e que estavam falhando à terapia antirretroviral, para avaliar os preditores do surgimento de IPDRM e o possível impacto dos subtipos do HIV-1 na resistência. Foram avaliadas sequências parciais do gene da polimerase do HIV-1 (RNA - Sequenciamento de Sanger) de 1696 pacientes em falha virológica, com genotipagem entre 2014 e 2017. Mutações de resistência aos antirretrovirais (Drug Resistance Mutations - DRM), susceptibilidade aos antirretrovirais (Genotypic Susceptibility Score ­ GSS) e subtipo viral, juntamente com os parâmetros clínicos e laboratoriais, foram avaliados utilizando-se regressões logísticas para acessar os preditores do surgimento de DRM e sua relação com os subtipos do HIV-1 circulantes em São Paulo (B, C e F). No total, 466 sequências apresentaram pelo menos uma IP-DRM (27,5%), mais comumente nos códons M46 (14,7%; 250/1696), V82 (13,8%; 234/1696) e I54 (13,3%; 225/1696). Mutações para as classes dos ITRN e ITRNN estavam presentes em 69,9% (1181) e 59,9% (1016), respectivamente, das 1696 sequências analisadas. De todas as sequências, 1496 (88,2%) tiveram predição de atividade plena ao darunavir (DRV), mas apenas 57,1% das sequências com pelo menos uma IP-DRM tiveram atividade plena ao DRV (266/466). A presença de IP-DRM teve associação (p<0,05) com maior tempo em tratamento, presença de mutações para os ITRN, uso de algum IP e com o subtipo F. Sequências de subtipo C tiveram menor quantidade de IP-DRM (10%; 9/87) em comparação com as de subtipo B (28%; 338/1216) e de subtipo F (35%; 58/168) (p <0,001), mas a análise ajustada sugere que esta associação não foi independente do tempo de tratamento mais curto e de menos esquemas utilizados por pacientes com HIV-1 C (OR: 0,59; IC 95: 0,2 ­ 2,5; p=0,48). HIV-1 F, juntamente com presença de mutações para os ITRN e maior tempo em tratamento estão associados com a presença de IP-DRM, com GSS mais baixo para o DRV e com a presença de mutação no códon I50. Entre pacientes com IP-DRM, a atividade plena ao DRV foi comprometida e esforços para detectar precocemente a falha são necessários, particularmente para o subtipo F do HIV-1, que mostrou associação com o surgimento de resistência e potencial impacto na susceptibilidade aos IP. Além disso, os resultados sugerem que as mutações para os ITRN podem servir como indicativo de um nível minimamente suficiente de adesão terapêutica, que permita o surgimento de IP-DRM. (AU)

Protease inhibitors (PI) are important in the salvage regimens for patients failing antiretroviral therapy (ART). Previous PI use may limit treatment and the detection of PI drug resistance mutations (PI-DRM) may subsidize the regimen selection. The aim of this study was to describe the major PI mutations among patients from São Paulo State, exposed to at least one PI and failing antiretroviral therapy to evaluate the predictors of mutation emergence and the possible impact of HIV-1 subtypes on resistance. Were evaluated HIV-1 partial polymerase sequences (RNA - Sanger sequencing) from 1696 patients on virological failure, genotyped between 2014 and 2017. Drug resistance mutations (DRM), antiretroviral susceptibility (Genotypic Susceptibility Score ­ GSS) and virus subtype, along with clinical and laboratory parameters, were evaluated using logistic regressions to access the predictors of mutations emergence and its relation with the circulating HIV-1 subtypes (B, C and F) in São Paulo State. A total of 466 sequences showed at least one PI-DRM (27.5%), most commonly M46 (14.7%; 250/1696), V82 (13.8%; 234/1696) and I54 (13.3%; 225/1696). Mutations to NRTI and to NNRTI drug classes were present in 69.9% and 59.9%, respectively, of the 1696 analyzed sequences. Full activity to darunavir was predicted for 88% of the patients (1496/1696), but it was only 57% among those with at least one PI-DRM (266/466). Presence of a PI-DRM was associated (p<0.05) to longer total time on treatment, presence of a NRTI mutation, use of any PI and subtype F. Subtype C sequences had less major PI-DRMs (10%, 9/87) compared with B (28%, 338/1216) or F (35%, 58/168) (p <0.001) but adjusted analysis suggested that this association was 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 with the presence of PI-DRM, with a lower darunavir GSS and with mutations at codon I50. Among patients with PI-DRM, the full activity to darunavir was compromised in many cases and efforts to detect the failure at earlier time are warranted, particularly for HIV-1 subtype F that showed association with the emergence of resistance, with potential impact in protease inhibitors sequencing. Furthermore, the results suggest that NRTI mutations may serve as an indicative of a minimally sufficient level of therapy adherence to allow PI-DRM emergence. (AU)