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Correspondence

First reported case of integrase (R263K, G163R) and reverse transcriptase (M184V)-transmitted drug resistance from a drug-naive patient failing Triumeq

Cochrane, Saraha; Daniel, Jessicab; Forsyth, Sophieb; Smit, Erasmusc

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doi: 10.1097/QAD.0000000000001919
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We report a case of confirmed transmission of R263K integrase mutation, which has not previously been described. R263K is a rare nonpolymorphic mutation, selected by raltegravir/dolutegravir in vivo and elvitegravir/dolutegravir in vitro. It confers low-level phenotypic reductions in elvitegravir susceptibility (∼5-fold) and minimal reductions in raltegravir and dolutegravir susceptibility. The Stanford database classes raltegravir and dolutegravir susceptibility as low-level, which increases to intermediate-level and low-level resistance when G163K is also present [1].

Patient Y, a 40-year-old woman, presented to our clinic for testing as a heterosexual sexual contact of HIV. A fourth generation test was completed 6 weeks following exposure. She was found to be HIV-positive, subtype C. Baseline bloods showed CD4+ 925 cells/μl (42%) and viral load 1723 copies/ml. Her avidity index of 0.628 indicated recent infection. She was treatment-naive and last tested HIV-negative 3 months prior.

Her contact (male patient Z) was known to have developed R263K, M184V and G163K/R as a result of poor adherence to Triumeq with subsequent virological failure. This was identified on genotypic testing using Sanger. Patient Z had fully susceptible subtype C virus at baseline (viral load 26 366 copies/ml), although integrase resistance testing was not performed at this point in accordance with national British HIV Association (BHIVA) guidelines [2]. He denied previous antiretroviral (ARV) therapy prior to starting Triumeq in spite of the low baseline viral load. He achieved an undetectable viral load after just 2 months of therapy. However, 8 months later, his viral load rebounded (909 267 copies/ml) because of poor adherence, and he disengaged from regular follow-up. Interestingly, the rebound viral load was much higher than his baseline and it could be argued that the patient may not have disclosed previous ARV therapy at baseline.

Baseline resistance on female patient Y confirmed all three drug resistance mutations (G163K/R, R263K and M184V) had been transmitted. She was commenced on Truvada and Rezolsta and her viral load became undetectable after 2 months on treatment.

R263K has been described in the SAILING trial in two patients who failed dolutegravir therapy who were integrase-naive but treatment-experienced [3]. Studies have identified that R263K reduces strand-transfer activity by decreasing the affinity of integrase for target DNA. In tissue culture, both viral infectivity and replication were also reduced. These effects have been found to be more pronounced in subtype C HIV-1 compared with subtype B [4]. Furthermore, R263K in combination with M184V has been shown to substantially reduce infectivity compared with a single substitution [5,6].

We believe this is the first case to describe sexual transmission of R263K and M184V mutations. Our case is also unique as we describe a drug-naive patient failing Triumeq with three resistance mutations. Patient Z had a high viral load prior to transmission, most probably because of poor adherence, which is likely to have increased the risk of transmission. However, it is interesting that the resistant virus transmitted out of his mixed population (Table 1) raising the question whether these mutations do indeed reduce viral fitness. Patient Y who had resistant virus population as her wild-type virus subsequently had low baseline viral load, which may suggest the virus is less fit or could be because of variance in immune responses.

Table 1
Table 1:
Treatment responses of patient Z and patient Y.

We could not identify any cases in published literature where M184V and R263K mutations were detected in combined ART (cART)-naive patients who fail first-line Triumeq. Previous studies have indicated it is rare for R263K to develop in the presence of nucleoside reverse transcriptase inhibitor (NRTI) mutations including M184V [7]. Our cases illustrate that this is not only possible, but also can also pose a risk of transmission in spite of reduced viral fitness observed in vitro[4]. A previous ultradeep sequencing baseline resistance study suggested that R263K, present as a minority species in two patients, may have been transmitted [8]. Our patient was diagnosed during seroconversion; it is possible that these unfit mutations would have reverted back to wild-type consensus amino acids at a later date.

With increasing use of integrase inhibitors, it is likely we will see more primary resistance to this class. It is important to consider baseline integrase resistance testing in patients who may be at risk of these transmitted mutations, particularly in the context of transmitted resistance to other ARV classes, to ensure a robust regimen is chosen. This is supported by current BHIVA guidelines [2]. There is growing evidence supporting the use of dolutegravir in dual therapy [9,10]. However, if baseline integrase resistance is not reviewed prior to starting therapy, there is a risk of patients commencing a regime containing only one fully active agent, placing them at risk of further resistance and jeopardising treatment options for the future.

Acknowledgements

The case was identified and managed by J.D., S.F. and E.S. S.C. completed the literature review and writing of the initial article. All authors contributed to refinement of the article and approved the final manuscript.

Conflicts of interest

S.C. has no conflicts of interest. S.F. and J.D. have organized meetings sponsored by Gilead, ViiV, MSD and Janssen. E.S. has received honoraria from ViiV and Gilead.

References

1. Stanford University. HIV drug resistance database: INSTI resistance notes. Available at: https://hivdb.stanford.edu/dr-summary/resistance-notes/INSTI/. [Accessed 19 February 2018]
2. British HIV Association. Guidelines for the routine investigation and monitoring of adult HIV-1-positive individuals 2016. Available at: http://www.bhiva.org/documents/Guidelines/Monitoring/2016-BHIVA-Monitoring-Guidelines.pdf. [Accessed 19 February 2018]
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