Integrase-resistant HIV in an antiretroviral-naive patient in Australia

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Integrase strand transfer inhibitors (INSTIs) have become an important part of antiretroviral therapy (ART) since the introduction of raltegravir in 2007 [1,2]. International guidelines recommend INSTIs, raltegravir, dolutegravir, or elvitegravir, as part of the regimens for treatment initiation in ART-naive individuals because of their potency and ease of use [3–5]. Standard genotypic drug resistance testing in ART-naive persons involves testing for mutations in the reverse transcriptase and protease genes, but INSTI-genotype testing is only recommended where INSTI resistance is suspected [3,4], and there are only four reports of transmitted drug resistance (TDR) to INSTIs (Table 1).Table 1: Reported cases of transmitted integrase HIV drug resistance.A 27-year-old woman was diagnosed with HIV infection in 2016 after a screen for sexually transmitted infections. She described a flu-like illness several weeks prior to her test consistent with seroconversion. A previous HIV antibody test was negative in 2014. She had no history of ART, injecting drug use, or travel outside of Australia. She was not aware of any sexual contacts with HIV infection or other history of ART. Investigations revealed subtype B virus with viral load of 25 409 copies/ml and CD4+ T-lymphocyte cell count of 1209 × 106/l (53%). Routine HIV genotypic resistance testing revealed no reverse transcriptase or protease mutations, but detected a Y143HY mutation in the integrase gene. According to the Stanford HIV database, this mutation confers high-level resistance to raltegravir, potential low-level resistance to elvitegravir but none to dolutegravir [10]. The impact of Y143H on INSTI resistance was further assessed with other algorithms: Agence Nationale de Recherches sur le SIDA (ANRS) and REGA (via the HIValg program, Stanford University, Stanford, USA) and Geno2pheno (Saarbrücken, Germany) [11–13]. There was variable agreement across the algorithms with Geno2pheno predicting reduced susceptibility to raltegravir, REGA conferring intermediate resistance to raltegravir, and ANRS predicting resistance to both elvitegravir and raltegravir. With limited clinical information existing on the effect of this mutation on INSTI resistance, this variability is not unexpected. There are three main mutation pathways which reduce susceptibility to raltegravir: Q148, N155, and Y143. The Y143 mutation occurs less commonly than Q148 or N155 but reduces susceptibility to raltegravir by up to 20-fold. Resistance is also markedly increased (>100-fold) if there is a coexistent T97A mutation. Y143H is reported less frequently than Y143R or Y143C mutations, which also confer high-level raltegravir resistance. Y143H has been reported as a transition step between wild-type Y143Y and the resistant Y143R and therefore often present in a mixture. A mixed population of Y143HY was detected in our patient consistent with these observations [14]. Site-directed mutagenesis experiments have shown that, on its own, Y143H reduces susceptibility to raltegravir by 2.6-fold [15]. Reports of resistance to INSTIs are now not uncommon. One or more major integrase resistance mutations were detected in 471/3012 (15.6%) of the US patients undergoing integrase genotypic resistance tests from 2009 to 2012 [16]. Integrase resistance mutations were detected in 113/255 (44.3%) raltegravir recipients across Europe with virological failure [17]. Our testing of treatment-naive and experienced patients in Victoria, Australia revealed that 9.4% harboured a drug resistance mutation that conferred high-level INSTI resistance (Victorian Infectious Diseases Laboratory, data not published). Mutations likely occurred in highly treatment-experienced individuals, with most having concomitant mutations to other drug classes. Many studies of treatment-naive individuals reported no integrase resistance mutations [16–18]. Our TDR surveillance data (2010–2015) of individuals either seroconverting or HIV infection of less than 12 months (n = 461) undergoing integrase genotypic resistance tests identified accessory mutations only and no mutation that conferred high-level resistance to INSTIs (unpublished data). Only four cases of TDR to INSTI have been reported (Table 1) [6–9]. Three had coexisting resistance protease and reverse transcriptase mutations. This case, the first report of INSTI resistance in an ART-naive patient in Australia, highlights the need to remain vigilant about detection of TDR to INSTIs. With the increasing use of INSTIs, it is likely that more individuals will acquire INSTI-resistant HIV. Current guidelines recommend testing for integrase resistance only in those patients with suspected resistance at baseline, yet our patient demonstrated single-class resistance and had no risk factors for INSTI resistance [3,4]. It is therefore unlikely that the resistance mutation would have been detected had it not been requested. This reiterates the need to consider testing for INSTI resistance at baseline for all patients as this class of antiretrovirals is increasingly used and guidelines need to consider specifically recommending integrase testing as part of routine care of people newly diagnosed with HIV. Acknowledgements J.H.M. is supported by an NHMRC early career fellowship. J.H.M.'s institution has received grant funding from Merck Sharp and Dohme, ViiV healthcare, Bristol-Myers Squibb, Pfizer, and Gilead and funding for attendance at advisory boards for Gilead and ViiV healthcare. I.W. has received research funds from Gilead Sciences and MSD, consulting funds from Bristol-Myers Squibb and Gilead Sciences, and chairing fees from Abbott and MSD. Conference support from MSD, ViiV Healthcare, and Abbott. Conflicts of interest None.

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