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  • Integrase inhibitors have been licensed for use

    2022-06-22

    Integrase inhibitors have been licensed for use in the UK since 2008. BHIVA now recommend starting all treatment naïve patients on a regimen containing two NRTIs, plus one of the following: a ritonavir boosted PI, an NNRTI, or an integrase inhibitor. They make further recommendations for patients with extensive drug resistance, suggesting two to three fully active agents including a ritonavir boosted PI and one agent with a novel mechanism (i.e. integrase inhibitor, Maraviroc or Enfuvirtide) depending on virus susceptibility [7]. These guidelines have resulted in increased usage of integrase inhibitors in both treatment naïve and treatment experienced patients. Integrase resistance has been detected in patients failing treatment with an integrase inhibitor and varies from 3% to 44% [8], [9], [10]. However, transmitted integrase resistance appears to be rare, with a small number of case reports [11], [12], [13]. There have been no reports of transmitted integrase resistance in the UK to date [5]. However, as very few UK laboratories perform baseline integrase resistance tests (101 performed UK-wide from 2010 to 2013); the true prevalence of transmitted integrase resistance is not known.
    Objectives
    Study design
    Results
    Discussion Baseline HIV resistance testing (PR and RT regions) is performed on all new HIV diagnosis, as per BHIVA guidelines. This is based on a reported TDR rate (NRTI, NNRTI and PI) of ∼6% [5]. In the present study, baseline resistance to PIs and NRTIs was lower than has been reported elsewhere, although patient samples contained a large number of accessory PI mutations that did not affect drug susceptibility. Baseline NNRTI resistance was high (38%), and in CHIR-090 to other reports on TDR, higher in IDUs than MSMs, however this was due to a large number of patient samples (n=30) from a recognised outbreak of HIV in IDUs which will be reported elsewhere [5], [20]. While there have been reports of integrase resistance developing in patients failing raltegravir treatment (3–40%), there have been no reports of transmitted integrase resistance in the UK to date (although this is based on a small number of samples tested) [5]. Consequently, BHIVA do not currently recommend performing integrase resistance testing at baseline. The integrase region was examined in 96 patient samples collected over a 12 month period. The majority of patients (n=85, 89%) had no integrase mutations and were susceptible to all three integrase inhibitors at baseline. This is in keeping with a number of studies investigating the incidence of baseline integrase resistance, where all found no cases of transmitted integrase resistance [5], [11], [28], [29], [30]. We found one patient had major integrase resistance at baseline. The patient sample contained the T66IT mutation, which is a non-polymorphic mutation commonly selected in patients on treatment that confers high-level resistance to elvitegravir [21], [22]. It is therefore thought to represent transmitted resistance and unlikely to have arisen as a natural polymorphism. There have been a small number of reported cases of transmitted integrase resistance to date world-wide [11], [12], [13]. As with our patient, they contained a major integrase inhibitor resistance mutation, (Q148H, Q148R or N155H), known to be associated with selective drug pressure rather than natural polymorphisms. These mutations have been reported in patients failing raltegravir-based treatment [31], [32]. Our patient also had the accessory integrase mutation, G163R, which is a naturally occurring polymorphism that confers low-level resistance to both raltegravir and elvitegravir [11], [23], [24], [25]. However, the patient remained susceptible to dolutegravir. Similar to the earlier reports of transmitted integrase resistance, our patient had resistance to another drug class, specifically, NNRTIs (E138A and V179E). While two of the patients reported previously contained multi-class resistance at baseline (resistance to NRTIs, NNRTIs, PIs and integrase inhibitors) [11], [12]. This patient was part of an outbreak of HIV in IDUs and it is interesting that other patients involved in the outbreak did not contain this integrase resistance mutation. While this patient has no history of treatment with HAART, it could be that someone in her transmission chain has been treated following diagnosis. This is something that will be investigated as part of a further/parallel study [19].