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

Abstract

BackgroundProtease 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.MethodologyPartial 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.ResultsIn 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.ConclusionsAmong 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.

Detection of Gag C-terminal mutations among HIV-1 non-B subtypes in a subset of Cameroonian patients

“…As previously reported by Soldi et al in a subtype F highly-prevailing setting, the presence of NRTI mutations was associated to some PI/r resistance mutations (i.e. I50LV) in patients failing PI/r treatment 24 . Indeed, some studies revealed that some inserts at the P6 region within the Gag gene may favor virus escape from nucleoside reverse transcriptase inhibitors (NRTI) through greater accumulation of resistance mutations, leading to high level of resistance to this drugs class 25 .…”

Exploring Drug-Resistant Mutations in Protease Inhibitors and Subtype Distribution Among HIV-1 Positive Patients in Lorestan Province, Iran

“…Nine PR drugs have been approved for clinical AIDS treatment, including SQV, indinavir (IDV), ritonavir (RTV), NFV, amprenavir (APV), LPV, ATV, tipranavir (TPV), and darunavir (DRV). While some studies suggest that resistance to PIs is not as common as resistance to other antiretroviral drugs, others have found that resistance can emerge within weeks to months of starting treatment, with PI resistance becoming increasingly prevalent in HIV-positive patients (16,17). For instance, a recent study by Obsa et al identified that out of 56 patients analyzed, 14 (25%) had PI resistance mutations, significantly higher than figures recorded for nonnucleoside RT inhibitors (NNRTIs) (5/56, 9%) and IN inhibitors (2/56, 4%) (18).…”

Evaluation of C-terminal p7 (NC)-p6 Gag genetic variants among HIV-1 non-B subtypes in a subset of Cameroonian patients

“…This could mean that some Gag mutations with high frequencies in patients failing PI/r may have been induced during RTI treatment, showing its role in resistance to PI/r, as Romero Soldi et al in 2019 showed that NRTI mutations and subtype F were associated to the emergence of some PI/r drug resistance mutations like I50LV in patients failing PI/r treatment 21 . Indeed, some studies revealed that some inserts at the P6 region within the Gag gene may favor virus escape from nucleoside reverse transcriptase inhibitors (NRTI) through greater accumulation of resistance mutations, leading to high level of resistance to this drugs class 22 .…”