Integrase Strand Transfer Inhibitor Resistance in Integrase Strand Transfer Inhibitor-Naive Persons

Abstract

There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.

Keywords: HIV-1; antiretroviral therapy; drug resistance; integrase; surveillance.

FIG. 1.

Flow chart of the study selection process. Of 2,141 studies identified through the PubMed search performed in August 2020, 1,775 studies were excluded based on a review of the study title and/or abstract. Of the remaining 366 studies, 290 were excluded for one of the listed exclusion criteria. Of the 75 additional studies identified through the GenBank search that met study inclusion criteria, 27 had not been identified in the PubMed search.

FIG. 2.

Distribution of the 16,481 sequences in GenBank according to sample year.

FIG. 3.

The prevalence of nonpolymorphic INSTI surveillance DRMs, nonpolymorphic mutations rarely selected during INSTI therapy, and common polymorphic INSTI-selected mutations by sample year. The total number of sequences during each time period is shown above each set of histograms. DRM, drug-resistance mutation; INSTI, integrase strand transfer inhibitor.

FIG. 4.

Temporal trend in the yearly proportion of sequences with one or more polymorphic INSTI-selected mutations. The diameter of each circle is proportional to the number of samples sequenced that year. The polymorphic INSTI-selected mutations include A49P, L74M, T97A, E157Q, G163R/K, and D232N. The fitted line shows the fixed effect of sample year in generalized linear mixed model logistic regression. The yearly change in the odds (odds ratio [OR]), 95% CI and p-value of a sequence containing polymorphic INSTI selected mutations are indicated. CI, confidence interval.