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HomeHIV/AIDSNeuro-psychiatric side effects with dolutegravir

Neuro-psychiatric side effects with dolutegravir

A large study by French researchers at CHU de Martinique, INSERM UMR 1027 – Toulouse, Nice University Hospital, Pitié Salpetrière University Hospital, Paris, Marseille University Hospitals, Reims Universtiy Hospital, Lyon University Hospital, Strasbourg University Hospital, Cochin University Hospital, Paris, Nantes University Hospital and Montpellier University Hospital, 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 neuro-psychiatric 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 neuro-psychiatric 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 neuro-psychiatric 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 US treatment guidelines and in World Health Organisation 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 neuro-psychiatric 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 neuro-psychiatric 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 neuro-psychiatric side-effects in the first year of treatment

A meta-analysis of five clinical trials of dolutegravir updated previous research on neurop-sychiatric 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 neuro-psychiatric 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 neuro-psychiatric side-effect. Neuro-psychiatric 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 neuro-psychiatric 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.

Abstract 5059
Background: In 2016 an unexpectedly high frequency of dolutegravir (DTG) discontinuation for neuropsychiatric reasons was reported, these effects might be more frequent when DTG was used with abacavir (ABC), in women, or in ageing people. Our objective was to search in our large prospectively collected cohort the patients who were treated with an integrase inhibitor (INSTI) and to analyze the frequency and causes of discontinuation.
Methods: The Dat"AIDS cohort is prospectively collected in 18 HIV reference centers in France. Data for all patients starting an INSTI containing regimen between 01/01/2006 and 31/12/2016 were extracted. All causes – chosen by the physician in a limited list of items – of an INSTI containing regimen discontinuation were analyzed, and patients" characteristics related with discontinuation due to neuropsychiatric side effects were searched for.
Results: INSTI were prescribed to 21 315 patients: 6 274 treated with DLT, 3 421 with elvitegravir boosted by cobicistat (EVG/c), and 11 620 with raltegravir (RAL), see Table 1. Discontinuation was observed in 12.5%, 20.2% and 50.9% of the DTG, EVG/c, and RAL treated patients, respectively (p< 0.001). The main reason for DTG and EVG/c discontinuation was intolerance (respectively 7.1% and 9.4% of the patients, p< 0.001). For RAL, treatment simplification (18.7%) was the leading reason. Discontinuation for neuropsychiatric reasons was described in respectively 2.7%, 1.3% and 1.7% of the DTG, EVG/c and RAL treated patients (p< 0.001). In multivariate analysis, discontinuation for a neuropsychiatric reason was related to DTG – versus EVG/C (HR=2.27; 95%CI 1.63-3.17; p< 0.0001) and versus RAL (HR=2.46; 95%CI 2.00-3.40; p< 0.0001), while neither gender (HR for women=1.19; 95%CI 0.97-1.46; p=0.09) nor age (p=0.12) were related. The association with abacavir was not retained in the final model, due to a confusion factor, most of the patients treated by DTG receiving ABC whereas none of the patients treated by EVG/c and few of those treated by RAL did.
Conclusions: Although discontinuation for side effects was less frequent with DTG than with EVG/c, neuropsychiatric side effects were more frequent with DTG, but still remained rare (2.7%). No patient"s characteristic could be related with these side effects in this very large population.

L Cuzin, P Puglies, C. Katlama, I Ravaux, F Bani-Sadr, T Ferry, D Rey, J Lourenco, S Bregigeon, C Allavena, J Reynes

Abstract 12021
Background: Analysis of phIII clinical trials for DTG concluded that selected neuropsychiatric symptoms (NPs) occurred at similar frequencies compared with controls. Some observational cohort data suggest that NPs result in higher rates of discontinuation among DTG users. Potential factors associated with discontinuations due to NPs reported in some cohorts include ABC co-administration, older age and female gender. We performed a meta-analysis to assess variables associated with NPs, and explored whether insomnia was associated with subsequent NPs.
Methods: Studies included: SPRING-2, SINGLE, FLAMINGO, ARIA, SAILING. NPs included: Insomnia, anxiety, depression, suicidality, nightmares/abnormal dreams, headache. Exposure adjusted incidence of NPs was calculated from frequencies of reported adverse events (AEs); 95%CIs are based on exact binomial 2-sided CIs. Poisson mixed effects meta-regression models were used to conduct two analyses of pre-specified variables in a backward selection on the incidence rate of AEs in patients treated with A) DTG (N=1,672) versus nonDTG (n =1,681) and B) DTG+ABC (n=943) vs DTG+nonABC (n=729). Significance level was 10%. Insomnia as a precursor to other NPs was analyzed descriptively.
Results: Identified variables associated with NPs are shown in the figure. Overall, adjusted estimates [SE] for NPs rates per 1,000 person years were 5.26 [0.068] with DTG versus 5.21 [0.07] with nonDTG (aRR 1.05 [95%CI 0.9, 1.21, p=0.55]), and 5.4 [0.079] with DTG+ABC versus 5.3 [0.085] with DTG+nonABC (aRR 1.1 [95%CI 0.89, 1.37, p=0.37]). Descriptive analyses of first insomnia events and subsequent non-insomnia events are in the table. First insomnia events with subsequent non-insomnia NPs occurred infrequently (2.2%), with higher rates of first occurrence of non-insomnia NPs (23%).
Conclusions: In this meta-analysis including 3,353 participants, the rate of NPs was similar between DTG and non-DTG treated patients. Variables associated with increased NPs in the DTG vs nonDTG analysis were past psychiatric history, non-EU residence and, in contrast with previous findings, younger age. Within the DTG vs DTG+ABC analysis, past psychiatric history and country of residence showed significant association. Concomitant ABC use was not a variable associated with NPs. There was no indication that insomnia was associated with subsequent CNS

J van Wyk, J Oyee, S Barthel, J Koteff, B Wynne, L Curtis, V Vannappagari, N Payvandi, V Carr, T Vincent, M Aboud

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[link url=""]AIDS 2018 abstract 5059[/link]

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