Recent observations on intolerance of dolutegravir: differential causes and consequences

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In their letter, Cattaneo et al.[1] add important information to the discussion about whether the observed side-effects may be because of a pharmacokinetic drug interaction between abacavir and dolutegravir (DGV). A study performed by their group that included 60 patients showed a significant difference in DGV through levels only when DGV was combined with atazanavir, which is an inhibitor of the glucuronidation process [2]. However, considering subgroup sizes and the large variation observed between patients on the same regimen, this does not exclude a more relative effect of abacavir on DGV exposure. In general, by defining the type and pathophysiologic mechanism of an unintended effect of a medical treatment, the action of cofactors can be fully appreciated and studied. When it comes to the investigation of a suspected causal relationship between the level of drug exposure and unintended effects, data about drug levels in patients with the side-effect studied (e.g. neurotoxicity in the case of DGV) and in patients clearly without this effect are indispensable. To the best of our knowledge, our field still awaits these data for DGV; if, indeed, intolerance to DGV represents type A unintended effects [3,4], and thus these likley are dose related; for example, functional genetic polymorphisms in enzymes involved in the absorption and metabolic pathways of DGV may be clinically relevant but prone to remain undetected in smaller series of patients. The valid remarks made by Cattaneo et al.[1] as they point out the differences between the pharmacodynamic properties of different integrase inhibitors, attest to the hypothesis that the neuropsychiatric side-effects can be a secondary exaggerated pharmacodynamic effect of DGV (and thus type A). At present, however, particularly because of the lack of detailed pharmacological data in patients with side-effects, some or all of the observed adverse events associated with DGV may still be type B unintended effects (Table 1).
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