Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades

Abstract

ObjectivesThe aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.MethodsThe cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).ResultsNo major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades.ConclusionsNo major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.

Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan

“…In this study conducted in Taiwan, where raltegravir was only available for clinical use since 2009, we demonstrate that the prevalence of major mutations to INSTI remains relatively low in INSTI-naive patients, 0.6% (6/948) among ART-naive and 1.7% (6/359) among ART-experienced/INSTI-naive patients, which is somewhat different from the absence of major mutations in ART-naive patients reported in the US and Europe101112. Other than these major mutations, the prevalence of mutations at resistance-associated positions with a Stanford HIVdb score ≧ 10 was 5.3% and 38.1%, respectively, in ARV-naive and raltegravir-experienced patients.…”

“…With one or two major mutations, such as Q148HKR ± G140SA, N155H ± E92Q or Y143CR ± T97A, a marked reduction of viral susceptibility to raltegravir and elvitegravir has been observed. According to recent publications from resource-rich countries such as the United States and Europe, transmitted INSTI resistance remains rare101112. Nevertheless, the prevalence of transmitted INSTI resistance may increase in the next several years when the use of INSTI-containing ART increases.…”

Resistance-Associated Mutations and Polymorphisms among Integrase Inhibitor-Naïve HIV-1 Patients in Kuwait

“…This agrees with previous reports indicating that major INSTIassociated mutations were very uncommon in INSTI-naïve patients [12,[22][23][24][25]. However, in 1 patient with HIV-1 subtype CRF02_AG, the accessory mutation E157Q was detected.…”

“…However, previous studies showed that the genetic barriers among different subtypes were similar in most of the major INSTI-RAMs [12]. Nevertheless, different genetic barriers were observed between different subtypes in some major nonpolymorphic mutations, e.g., G140C/S, and polymorphic mutations, e.g., V72I, L101I, T124A, T125K, and V201I [11,12,22,25,37].…”

Current views on interferon therapy for HIV

“…Furthermore, in the case of the drugs being developed, such as the new entry inhibitors and maturation inhibitors (entering phase II and III clinical trials, respectively) [34], it is assumed that those circumstances would arise only very rarely. Whatever the case, the utility of Peg-IFN in patients with high-level resistance and few treatment options has not been tested in clinical trials, which therefore warrants further study.…”