Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Nguyen, Hai Le; Ruxrungtham, Kiat; Delaugerre, Constance

doi:10.1159/000336658

Cited by 13 publications

(13 citation statements)

References 19 publications

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“…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.…”

Section: Discussionsupporting

confidence: 92%

“…Due to the limited number of patients enrolled in this study, the difference in the genetic barrier for each substitution between B and non-B subtypes could not be in- vestigated. 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].…”

Section: Discussionmentioning

confidence: 95%

“…Mutations associated with low-to intermediate-level resistance to NNRTs have been detected in treatment-naïve patients [10]. Previous studies have found differences in the resistance profiles of different subtypes to INSTIs [11,12]. Major INSTI-RAMs have been reported in treatment-naïve patients infected with HIV-1 subtype CRF02_AG [13].…”

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confidence: 99%

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

Chehadeh¹,

Albaksami²,

John³

et al. 2017

Intervirology

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Objectives: Resistance-associated mutations (RAMs) in the integrase of different HIV-1 subtypes were investigated in a cohort of patients never exposed to integrase strand transfer inhibitors (INSTIs). Methods: The viral RNA was extracted from plasma samples of 53 INSTI-naïve patients, and the integrase genetic region was sequenced and analyzed for subtype assignment and drug resistance. Results: The median viral load at sampling was 5.28 × 10⁴ RNA copies/mL. Bayesian phylogenetic analysis showed 85% of the HIV-1 isolates were non-B subtypes, with a predominance of subtypes C (22.6%) and CRF01_AE (26.4%). A total of 52 and 110 mutations were found in the integrase region of HIV-1 B and non-B subtypes, respectively. Nonpolymorphic INSTI-RAMs were not detected in this study. However, the accessory mutation E157Q was found in 1 patient with CRF02_AG, and the polymorphic mutations L74M/I that may contribute to a reduced susceptibility to INSTIs in the presence of major mutations were observed in 6 (13.3%) patients with non-B subtypes and 1 (12.5%) patient with the B subtype. Polymorphic mutations at positions known to harbor primary and accessory RAMs were also detected in this study. Conclusion: Our results highlight the importance of monitoring the emergence of INSTI-RAMS before and after the initiation of INSTI-based therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

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

Chehadeh¹,

Albaksami²,

John³

et al. 2017

Intervirology

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“…However, the contribution of HAdV B7 to the patient's death was not confirmed, and a role for rhinovirus, co‐detected in the nasopharyngeal aspirate, should not be excluded. Indeed, fatal respiratory infections associated with rhinovirus outbreaks have been described in previous reports …”

Section: Discussionmentioning

confidence: 85%

Adenovirus types associated with severe respiratory diseases: A retrospective 4‐year study in Kuwait

Chehadeh

Al-Adwani

John

et al. 2018

Journal of Medical Virology

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Human adenovirus (HAdV) infection can result in a severe respiratory disease. The aim of this study was to identify HAdV types detected in patients hospitalized for severe respiratory illness. The study population consisted of 743 patients with severe respiratory disease admitted to four major hospitals in Kuwait between January 2013 and December 2016. Respiratory specimens were retrospectively screened for 20 respiratory viruses by real-time PCR. The HAdV hexon gene was amplified and directly sequenced, and HAdV types were identified by performing Bayesian phylogenetic analysis. HAdV DNA was detected in 27 (3.6%) patients, with peaks in November and March. Most patients were infants and young children suffering from pneumonia or acute bronchiolitis. The detected HAdV types were C1, C2, C5, B3, and B7. Clusters of HAdV C1, C2, and C5 were observed with high posterior probability. All patients infected with HAdV C5 and 50% of patients infected with HAdV C2 or B7 were admitted to the intensive care unit (ICU). Co-infection with other viruses was detected in 44.4% of patients. The most common co-infecting virus was rhinovirus (HRV). HAdV/HRV co-infection was detected in two children who presumably developed disseminated HAdV infection and died. This is the first report describing the circulation of HAdV types associated with severe outcomes in Kuwait. These findings highlight the need for a national surveillance system to monitor changes in predominant HAdV types and increased numbers of severe respiratory infections.

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“…These studies have suggested that there may be important differences in the resistance profiles of subtype C, CRF01_AE and CRF02_AG, including a high prevalence of naturally occurring resistance in INI-naive subjects with CRF02_AG. 24 – 26 The CORONET project (Common Sequence Repository and Research Network for Integrase Inhibitors) is a European network for surveillance and collaborative research on INI resistance. A common repository is produced from genotypic resistance tests performed at multiple collaborating centres, which provide care for ethnically diverse cohorts.…”

Section: Introductionmentioning

confidence: 99%

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

Doyle

Dunn

Ceccherini‐Silberstein

et al. 2015

J. Antimicrob. Chemother.

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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.

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Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Cited by 13 publications

References 19 publications

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

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

Adenovirus types associated with severe respiratory diseases: A retrospective 4‐year study in Kuwait

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

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