A systematic review of the genetic mechanisms of dolutegravir resistance

Abstract

Background: Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy.

Methods: We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons.

Results and conclusions: We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir's companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir's companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

Figure 1.

Flow chart of study selection process. Of 742 studies identified through a PubMed search performed in January 2019 using the search string ‘Dolutegravir or GSK1349572’, 229 were read in their entirety following an initial review of titles and abstracts. Following a full-text review of these 229 studies and of 35 additional studies from meeting presentations, 95 studies met our inclusion criteria, containing data on mutations emerging under dolutegravir selection pressure in vitro and in vivo; in vitro dolutegravir susceptibility; and the risk of virological failure and drug resistance in clinical trials and cohorts.

Figure 2.

Box plots of in vitro dolutegravir susceptibility results for 176 site-directed mutants and 105 clinical isolates containing R263K, G118R, N155H and/or Q148H/R/K. Purple plots indicate the fold reduction in susceptibility for viruses containing R263K with or without G118R, N155H and Q148H/R. Orange plots indicate the fold reduction in susceptibility for viruses containing G118R. Yellow plots indicate the fold reduction in susceptibility for viruses containing N155H with or without Q148H/R. Blue plots indicate the fold reduction in susceptibility for viruses containing Q148H/R/K. In addition to the four signature mutations, mutation patterns were characterized by the number of additional INSTI resistance mutations. The number of isolates with each pattern is shown in parentheses.