Reply to Letter 'Morning dosing for dolutegravir-related insomnia and sleep disorders' by Capetti etal.

Abstract

We thank Capetti and colleagues for their interesting comments 1 which suggest that morning dosing may help resolve dolutegravir (DTG)-related insomnia and sleep disorders. In our retrospective study 2, we had no information on the timing of DTG administration in most of our patients. However, in our experience, patterns of adverse events leading to DTG discontinuation were heterogeneous and not limited to sleep disorders. They included dizziness, depression, headache, paraesthaesia, poor concentration and slow thinking. Although relatively rare, reversible and usually mild to moderate, these events were less frequently seen with elvitegravir or raltegravir. Since our initial publication, we have seen additional patients complaining of dizziness or cognitive problems 1–2 h after DTG intake, suggesting that peak plasma levels may be too high in these individuals. Other groups from the Netherlands 3, Italy 4, 5 and France 6 have also reported unexpected adverse events with DTG. These include anxiety, irritability and depression but also headache and musculoskeletal pain. In these patients, it seems unlikely that a switch to morning dosing would resolve neuropsychiatric symptoms. Of note, Capetti and colleagues have confirmed our observations that neuropsychiatric events were more frequent in older and in female patients, suggesting a pharmacokinetic problem. Indeed, recent pharmacokinetic studies have found higher drug exposure in older patients 7, 8 but also in patients treated with atazanavir or cobicistat 9, 10. We believe that there is an urgent need for more data on drug levels in these patient populations, especially in individuals who develop neuropsychiatric events. Capetti and colleagues' univariate analysis did not find a higher event rate with abacavir use. This is in contrast to our findings and those of other studies 3, 4 and it is debatable whether currently available data are sufficient to exclude a drug−drug interaction between abacavir and DTG 11, 12. More recently, a preliminary study from Japan reported an association between DTG plasma trough concentrations and neuropsychiatric events 13. However, it remains to be seen whether neuropsychiatric events are mainly driven by increased drug exposure and whether they represent a class effect, as such symptoms have also been reported, albeit at a lower incidence, with other integrase strand transfer inhibitors (INSTIs). Simple re-analysis of randomized clinical trials 14 in which patients and investigators may have been reluctant to report side effects (because they knew that patients could be removed from the study) does not sufficiently address these emerging concerns. Hinting at a high background rate of psychiatric conditions among people living with HIV (PLWH) 14 is stigmatizing and unhelpful as, in our experience, many patients without any prior psychiatric morbidity were affected. Given the widespread use and the anticipated long-term exposure to this drug class, we would urge the manufacturers to perform further studies evaluating neuropsychiatric events associated with INSTI use. This should include not only pharmacokinetics and pharmacogenetics, but also analysis of the sleep architecture in PLWH and neuropsychological testing in asymptomatic patients on INSTIs, in order to elucidate subclinical cognitive changes.