Reply to Darcis and Berkhout

To the Editor—With interest we read the comment by Darcis and Berkhout on our article about human immunodeficiency virus type 1 (HIV-1) resistance dynamics in patients failing maintenance monotherapy with the second-generation integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) [1]. Indeed, caution is warranted when stating that DTG does not elicit resistance in vivo. There is no complete picture yet of which mutations are relevant for DTG resistance in clinical practice. For example, Pham et al recently validated the S230R mutation that is associated with low-level resistance against DTG [2]. Still, no known resistance-associated mutations have been detected in the majority of virologic failures on DTG. The effect of mutations outside integrase on INSTI susceptibility has recently received increasing attention. An in vitro study by Malet et al showed that mutations in the highly conserved 3ʹ-polypurine tract (3ʹ-PPT) can lead to high-level resistance against DTG and other INSTIs [3]. Subsequently, we presented evidence that INSTI resistance via 3ʹ-PPT mutations can occur in patients treated with DTG [4]. The mechanism of 3ʹ-PPT–mediated INSTI resistance remains unknown. DTG excluding mutations in the HIV long terminal repeat end, which is the substrate of HIV integrase [5], or replication of unintegrated HIV [6] have been proposed as alternative mechanisms for DTG resistance. Current HIV genotypic resistance tests focus on mutations within the genes targeted by the antiretroviral drugs. In addition to DTG resistance mutations outside integrase, mutations outside HIV protease have been shown to contribute to HIV protease inhibitor resistance [7]. Thus, a more holistic view of antiretroviral drug resistance is needed. Given the availability of feasible HIV full-genome sequencing at relatively low costs, this should be implemented for resistance testing, in particular for cases of unexplained treatment failure (eg, adequate drug levels and no resistance-associated mutations detected in integrase). To fill in this gap, a global Registry On Second-gEneration inTegrase inhibiTor fAilures (ROSETTA) has been established [8]. ROSETTA aims to provide a global surveillance for virologic failure to second-generation INSTIs and other HIV inhibitors, and links HIV sequences to clinical and virological information. Furthermore, full-length HIV sequencing will be offered to its contributors, and candidate mutations possibly associated with resistance may be validated by phenotyping. This approach should develop a better and more complete understanding of resistance against INSTIs and other antiretroviral drug classes in clinical practice. Financial support. This work was supported by the Erasmus Trustfonds. Potential conflicts of interest. I. E. A. W. reports receiving personal financial support from Gilead Sciences outside the submitted work. B. J. A. R. reports receiving research grants from Erasmus Trustfonds during the conduct of the study; receiving research grants from Gilead and MSD outside the context of this work; receiving personal financial support from Gilead, Bristol-Myers Squibb (BMS), and GL Pharmaceuticals outside the submitted work; receiving travel grants from BMS, MSD, ViiV, Gilead, and AbbVie outside the submitted work; and participating in an advisory board organized by ViiV outside the submitted work. D. A. M. C. v. d. V. reports receiving grants from Gilead Sciences, MSD, ViiV, and Janssen and personal financial support from Janssen, all outside the submitted work. S. D. P. reports receiving consultancy and travel-related financial support from Luminex outside the submitted work. M. E. v. d. E. reports participating in an advisory board organized by ViiV (nonfinancial support) outside the submitted work. C. A. B. B. reports receiving speaker’s fees from ViiV outside the submitted work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Presented in part: 15th European Meeting on HIV and Hepatitis, Rome, Italy, 7–9 June 2017. Abstract 14; 16th European AIDS Conference, Milan, Italy, 25–27 October 2017. Abstract PE16/6; 11th Netherlands Conference on HIV Pathogenesis, Epidemiology, Prevention, and Treatment, Amsterdam, The Netherlands, 22 November 2017. Abstract O07.

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