Virological outcomes of various first-line ART regimens in patients harbouring HIV-1 E157Q integrase polymorphism: a multicentre retrospective study

Abstract

Background Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%–5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. Methods A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens. Results E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. Conclusions The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

Population-based nanopore sequencing of the HIV-1 pangenome to identify drug resistance mutations

“…Here, we define “fixed” and “nonfixed” mutations as mutations found in > 90% and 15–90% of the population of nanopore sequencing reads, respectively. For Sanger sequencing-based DR test results based on pol PR-RT (2253–3269 nt) or pol IN (4230–5093 nt), mixed bases at heterogeneous peaks were manually picked from electropherogram data 4 , 17 – 19 . As shown in Fig.…”

“…Genotypic coreceptor tropism, that is, CCR5 (R5) or CXCR4 (X4) usage, was also examined based on V3 amino acid sequences using the geno2pheno-C_NGS-Sanger tool 20 ( https://coreceptor.geno2pheno.org/ ). For the nanopore sequencing data, sequence contexts present in ≥ 15% of the population in each sample were used, while for the canonical test using Sanger sequencing data, nucleotide sequences of the env c2c5 gene (6896–7652 nt) from three independent amplicons for each sample were analyzed to identify low-abundance variants within each sample at the most heterogeneous env 4 , 17 – 19 . We observed high concordance (98.1%) between two methods for both genotypic tropism tests (Fig.…”