Response letter to SEJ Todd et al. – Early clinical experience of dolutegravir in an HIV cohort in a larger teaching hospital

Dear Editor,

We read with interest the experiences of SEJ Todd et al.’s use of dolutegravir (DTG). ¹ We would like to reflect on their experiences by sharing the findings from our own patient cohort, with particular focus on DTG-associated adverse events. We reviewed all patients who were commenced on DTG-containing antiretroviral regimens over a three-year period: a total of 178 patients.

Fifty-nine of the 178 patients (33%) experienced adverse events. Psychiatric side effects were the most frequent with 20% (35/178) of patients reporting at least one psychiatric side effect. These findings correlate with those by Todd et al., who report a 35% adverse event incidence, with 25% suffering psychiatric side effects. Of the 35 patients with psychiatric side effects in our cohort, 69% suffered sleep disturbance, 43% mood disturbance and 17% anxiety. One of the 35 patients had suicidal ideation and self-harm which stopped two weeks after discontinuation of DTG. Other common side effects were: gastrointestinal (10%) and neurological (7%). Ten patients (6%) in our cohort had to stop their DTG-containing regimen, similar to the 10% discontinuation rate in Todd et al. In our cohort, 70% (7/10) stopped due to adverse events, four due to psychiatric side effects, two due to musculoskeletal problems and one due to dermatological complications. DTG discontinuations occurred between weeks 2 and 20.

We found no significant difference in rates of adverse events between treatment-naïve and treatment-experienced patients. There was also no significant difference between rates of adverse events in patients with and without abacavir-containing regimens.

Our data confirm the increased risk of neurological adverse events published by other studies.^2–4 Sabranski et al. have presented the largest cohort to date where neuropsychiatric adverse drug reactions (ADRs) were more common in DTG-containing regimens compared to regimens with other integrase inhibitors (p<0.0001), with adverse effects generally resolving quickly after discontinuation. ³ Other studies have reported 4.3% and 4.4% rates of DTG discontinuation, respectively, (mainly driven by neuropsychiatric side effects)^2,4 and SINGLE, the only randomized placebo-controlled trial of DTG that actively looked for central nervous system side effects, found a 7% rate of anxiety, 8% rate of depression, 8% rate of insomnia and 10% rate of sleep problems. ⁵

The Medicines and Healthcare Products Regulatory Agency (MHRA) ‘Yellow Card’ data reveal 485 DTG-related ADRs since 2014. ⁶ Of these patients, 128 were serious, with 11 being fatal. Similar to our data, psychiatric and neurological ADRs were common, with 128 and 53 reported, respectively. Within the psychiatric ADRs there were two attempted and two completed suicides. There have also been 10 reports of depression developing.

In conclusion, our data confirm the relatively high rate of neuropsychiatric adverse events with DTG. Clinicians need to be alert to the development of neurological and psychiatric side effects in patients on DTG and more work needs to be done to identify those at increased risk of these side effects.