A large French study of people taking HIV treatment that contained an integrase inhibitor found that approximately one person in forty who started treatment with dolutegravir stopped taking the drug due to neuropsychiatric side-effects, a significantly higher rate than observed in people taking either elvitegravir or raltegravir, a poster presentation at last month’s 22nd International AIDS Conference (AIDS 2018) showed.
However, this discontinuation rate is much lower than rates observed in some other studies with smaller samples.
Another study presented at the conference, an analysis of five clinical trials of dolutegravir, sponsored by the drug’s manufacturer ViiV Healthcare, found that neuropsychiatric side-effects were more likely to occur in people with a prior history of psychiatric problems. Use of dolutegravir did not increase the risk of a person ever experiencing a neuropsychiatric side-effect, nor did use of dolutegravir with abacavir.
Dolutegravir is marketed as Tivicay, and in the three-drug combination pill Triumeq, and in combination with rilpivirine as Juluca. The drug is recommended as a preferred option for first-line antiretroviral treatment in European and United States treatment guidelines and in World Health Organization guidelines, both because of superior efficacy but also because of improved tolerability compared to efavirenz, a drug also associated with central nervous system side-effects.
In 2016, several studies showed that neuropsychiatric side-effects such as insomnia, anxiety or depression were occurring at much higher rates in people taking dolutegravir than clinical trials of the drug had indicated. One study found that as many as 14% of people had stopped dolutegravir because of side-effects, but others found lower rates. Clinical trials have reported that fewer than 5% of people who take dolutegravir stop the drug due to these side-effects.
To investigate the incidence of discontinuation due to side-effects in a large population of patients, and to compare with other integrase inhibitors to detect any effect of the entire drug class, French researchers looked at all patients who received treatment with an integrase inhibitor between 2006 and 2016 (choosing the end of 2016 as the cut-off date in order to avoid any bias in prescribing behaviour that might have arisen as a result of the news of dolutegravir side-effects).
The study sample comprised 21,315 people treated at 18 HIV centres in France. A total of 6274 received dolutegravir, 3421 received elvitegravir and 11,620 received raltegravir. The study population was predominantly male and started treatment with an integrase inhibitor at a median age between 44 and 49, depending on the integrase inhibitor. People taking elvitegravir were more likely to be taking the first antiretroviral regimen (23.1%), while people taking dolutegravir were more likely to be taking the drug combined with abacavir (66.4%).
The analysis looked at all discontinuations and the reason for discontinuation of an integrase inhibitor.
Of those who received dolutegravir, 786 discontinued the drug (21.9% due to neuropsychiatric events). In comparison, 6.5% of those who discontinued elvitegravir (691) did so because of a neuropsychiatric side-effect, as did 3.5% of those who discontinued raltegravir (5910) (discontinuation of raltegravir was more frequent than for other drugs because approximately a third of people who started the drug later simplified their regimen for reasons other than adverse events).
The rate of discontinuation for neuropsychiatric side-effects was 2.7% in those taking dolutegravir compared to 1.3% for elvitegravir and 1.7% in those taking raltegravir (p < 0.001). The nature of the neuropsychiatric side-effect leading to treatment discontinuation was not specified by all doctors, so it was not possible to detect whether specific problems, such as insomnia, occurred more frequently in those receiving dolutegravir compared to other drugs.
People taking dolutegravir were approximately two-and-a-half times more likely to discontinue the drug compared to people taking either elvitegravir (adjusted hazard ratio, 2.27, 95% CI 1.63-3.17, p < 0.0001) or raltegravir (aHR 2.46, 95% CI 2-3.04, p < 0.001). Discontinuation due to neuropsychiatric side-effects was slightly more common in treatment-experienced people (aHR 1.57, 95% CI 1.11-1.22, p = 0.012) and in people with a previous history of antiretroviral drug discontinuation due to neuropsychiatric events (aHR 1.36, 95% CI 0.99-1.87, p = 0.06). There was also a trend, short of statistical significance, towards a higher rate of treatment discontinuation due to neuropsychiatric events in women (aHR 1.19, 95% CI 0.97-1.46, p = 0.09). The study found no association between the use of abacavir and dolutegravir and discontinuation due to neuropsychiatric events.
Overall, said Lise Cuzin, presenting the findings, the rate of discontinuation due to neuropsychiatric events was broadly in line with findings from another large study, of the Swiss HIV Cohort, which found that 2% of people switched away from dolutegravir due to neuropsychiatric side-effects in the first year of treatment
A meta-analysis of five clinical trials of dolutegravir updated previous research on neuropsychiatric side-effects presented at the Congress on Drug Therapy in HIV Infection in 2016, which showed a very low rate of treatment discontinuation due to neuropsychiatric side-effects. This meta-analysis included additional data from the SAILING study in treatment-experienced people, and longer-term data from the SINGLE 1 study in previously untreated people. The analysis compared 1672 people randomised to receive dolutegravir and 1681 receiving non-dolutegravir regimens.
The analysis found no significant difference in the incidence of neuropsychiatric adverse events between those who received dolutegravir and those who did not (5.26 vs 5.21 per 1000 person-years of follow-up, adjusted relative rate 1.05, 95% CI 0.9-1.21, p = 0.55). The use of dolutegravir with abacavir was not associated with an increased risk of neuropsychiatric adverse events.
Overall, approximately one in four people reported at least one neuropsychiatric side-effect. Neuropsychiatric events were reported more frequently in people with a psychiatric history (aRR 1.75, 95% CI 1.43-2.13, p < 0.001), and in North America compared to Europe (aRR 1.33, 95% CI 1.07-1.65) or the rest of the world (aRR 1.36, 95% CI 1.36, p < 0.001). When the analysis considered the total number of events, rather than the number of people affected by events, the findings were similar, except that dolutegravir treatment was associated with a greater risk of neuropsychiatric events (aRR 1.35, 95% CI 1.12-1.62, p = 0.015).
The nature of the neuropsychiatric event was recorded in all clinical trials included in this analysis. Headache and insomnia were the most frequently reported events regardless of the regimen taken.
Cuzin L et al. Integrase inhibitors and neuropsychiatric adverse events in a large prospective cohort. 22nd International AIDS Conference, Amsterdam, abstract TUPDB0107, 2018.
Van Wyk et al. Variables associated with neuropsychiatric symptoms in PLWH receiving dolutegravir-based therapy in phase III clinical trials. 22nd International AIDS Conference, Amsterdam, abstract TUPDB0102, 2018.