HIV Glasgow: Dolutegravir and Central Nervous System Side-Effects -- Abacavir, Older Age Increase the Risk

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Insomnia, dizziness, headache, and other central nervous system (CNS) side effects are occurring more frequently with everyday use of dolutegravir than clinical trials had suggested, and are most likely to occur among women, people over age 60, and people starting abacavir at the same time, a German research group reported at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) this week.

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Dolutegravir (Tivicay, also combined with abacavir/lamivudine in Triumeq) is a second-generation integrase inhibitor that is recommended as one of the preferred options for first-line treatment in European and U.S. treatment guidelines. Dolutegravir has a "clean" side effect profile in comparison with some other commonly prescribed antiretroviral drugs. In particular, Phase 2b and Phase 3 studies showed a lower rate of central nervous system toxicities in patients receiving dolutegravir compared with efavirenz.

Since marketing approval was granted in 2014, emerging evidence from clinical practice suggests that dolutegravir is associated with a higher incidence of neuropsychiatric side effects than was observed in clinical trials. For example, a cohort study in the Netherlands found that 14% of people who started dolutegravir between 2014 and 2016 stopped the drug due to side effects, predominantly insomnia, anxiety, depression, and psychosis. Gastrointestinal distress was also cited as a reason for switching from dolutegravir in this cohort.

To examine the incidence of neuropsychiatric side effects associated with the drug, investigators in Germany therefore designed a retrospective study of patients who started an integrase inhibitor between 2007 and April 2016, when news of possible neuropsychiatric side effects of dolutegravir first emerged. Clinic databases at participating centers routinely record the main reason for changing treatment, providing investigators with consistent and unbiased information about reasons for switching.

The investigators compared discontinuation rates within 2 years of starting therapy between dolutegravir, raltegravir (Isentress), and elvitegravir (Vitekta, also in Stribild) in order to determine whether the side effect is specific to dolutegravir or one that occurs to some degree with all integrase inhibitors.

They looked for switches due to insomnia, sleep disturbance, dizzinesss, restlessness, anxiety, depression, poor concentration, headache, slowed thinking, or pins-and-needles sensations with no obvious explanation.

A total of 1704 patients initiated 1950 integrase inhibitor-containing ART regimens (985 dolutegravir, 287 elvitegravir, and 678 raltegravir), with median follow-up ranging from 36 months for raltegravir-exposed patients to 11.5 months for dolutegravir-exposed patients.

Discontinuation due to any adverse event occurred more frequently among people exposed to elvitegravir than either raltegravir or dolutegravir. But when 12-month rates of adverse events and neuropsychiatric events leading to the discontinuation of therapy were calculated, these were found to be substantially higher for dolutegravir than for other drugs in the same class.

 

Discontinuation due to any adverse event (12-month rate)

Discontinuation due to neuropsychiatric event (12-month rate)

Dolutegravir

7.6%

5.6%

Elvitegravir

7.6%

0.7%

Raltegravir

3.3%

1.9%

There were 49 patients who discontinued dolutegravir due to neuropsychiatric events, most commonly insomnia or sleep disturbances (36), dizziness (13), headache or parasthesia (16), poor concentration or slowed thinking (8), or depression (7). In the vast majority of cases patients reported 2 or more neuropsychiatric events. In all patients the neuropsychiatric problems disappeared quickly after dolutegravir was stopped, but re-emerged in 6 people who chose to resume dolutegravir-based treatment. In no cases did the side effects result in hospitalization.

In comparison, 14 patients stopped raltegravir due to neuropsychiatric events, mainly headache or parasthesia, or insomnia.

Neuropsychiatric side effects leading to discontinuation of dolutegravir were significantly more frequently observed among women (HR 2.64), those aged 60 years and over (HR 2.86), and individuals who started abacavir at the same time as dolutegravir (HR 2.42).

Clinical Trial Analysis

The rates of neuropsychiatric side effects seen in reported cohort studies have been much higher than in clinical trials. Romina Quercia from ViiV Healthcare reported a summary of data from clinical trials.

Investigators analyzed safety data from Phase 3/3bb dolutegravir trials involving treatment-naive patients to establish a clearer understanding of the frequency of neuropsychiatric side effects: anxiety, depression (depression, bipolar depression, suicidal thoughts and hypomania), insomnia, and nightmares or abnormal dreams.

There were 4 studies included in the analysis: the 96-week SPRING-2, SINGLE and, FLAMINGO trials, and the 48-week all-women ARIA trial.

A total of 2634 participants were recruited into the 4 studies, 1315 of whom were treated with dolutegravir.

Low rates of neuropsychiatric events were seen in all study treatment arms, with most being mild or moderate (grade 1-2). However, a higher incidence was observed in the SINGLE study compared to other trials, with 17% of dolutegravir recipients reporting insomnia, 10% nightmares or abnormal dreams, 8% depression, and 7% anxiety. These rates were lower than those seen among patients taking the comparator drug, efavirenz.

Rates of neuropsychiatric side effects leading to the withdrawal of treatment were below 5% in all trials.

Depression led to cessation of dolutegravir therapy by 1 patient, with 6 raltegravir-treated and 7 efavirenz-treated individuals stopping treatment because of this adverse event. Also 2 patients stopped taking dolutegravir because of insomnia with 3 efavirenz-treated patients stopping treatment for this reason. Abnormal dreams or nightmares caused 2 dolutegravir and 7 efavirenz patients to cease therapy. There were no cases of withdrawal of dolutegravir because of anxiety, though 4 patients stopped efavirenz for this reason.

10/28/16

Sources

R Quercia, J Roberts, C Hoffmann, et al. Psychiatric adverse events from the DTG ART-naive phase 3 clinical trials. HIV Drug Therapy 2016. Glasgow, October 23-26, 2016. Abstract P210.

M Sabranski, C Wyen,  M et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Drug Therapy 2016. Glasgow, October 23-26, 2016. Abstract 0214.