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Dolutegravir and central nervous system side-effects: abacavir, older age increase the risk
Keith Alcorn, 2016-10-25 18:40:00
Insomnia, dizziness, headache and
other central nervous system side effects are occurring more frequently with
everyday use of dolutegravir than clinical trials had suggested, and are most
likely to occur in women, people over 60 and people starting abacavir at the
same time, a German research group told the International Congress on Drug
Therapy in HIV Infection in Glasgow on Tuesday.
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 United States treatment guidelines.
Dolutegravir has a `clean` side-effect profile in comparison with some other
commonly-prescribed antiretroviral drugs. In particular, phase IIb and phase
III studies showed a lower rate of central nervous system toxicities in
patients receiving dolutegravir when the drug was 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 treatment 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 among 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 centres routinely record the main reason for changing
treatment, providing investigators with consistent and unbiased information
about reasons for switching.
They compared discontinuation rates within two
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 a side effect that occurs to some degree with all
Investigators 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 were
initiated on 1950 integrase inhibitor-containing regimens (dolutegravir 985;
elvitegravir 287; raltegravir 678) with median follow up ranging from 36 months
for raltegravir-exposed patients to 11.5 months for dolutegravir-exposed
Discontinuation due to any adverse
event occurred more frequently among people exposed to elivitegravir than
either raltegravir or dolutegravir, but when twelve-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
Discontinuation due to neuropsychiatric event
Forty-nine patients discontinued
dolutegravir due to neuropsychiatric events, most commonly insomnia or sleep
disturbance (36), dizziness (13), headache or parasthaesia (16), poor
concentration or slowed thinking (8) or depression (7). In the vast majority of
cases patients reported two or more neuropsychiatric events. In all patients
the neuropsychiatric problems disappeared quickly after dolutegravir was
stopped, but re-emerged in six patients who chose to resume dolutegravir
treatment. In no cases did the side effects result in hospitalization.
In comparison, 14 patients stopped
raltegravir due to neuropsychiatric events, mainly headache or parasthaesia, or
Neuropsychiatric side effects
leading to discontinuation of dolutegravir were more frequently observed in
women (HR = 2.64; 95% CI, 1.23-5.65, p = 0.012), those aged 60 years and over
(HR = 2.86; 95% CI, 1.42-5.77, p = 0.003) and individuals who started abacavir
at the same time as dolutegravir (HR = 2.42; 95% CI, 1.38-4.24, p = 0.002).
The rates of neuropsychiatric side
effects seen in reported cohort studies have been much higher than in clinical
trials. Romina Quercia of ViiV Healthcare reported a summary of data from
Investigators analysed safety data
from phase III/IIIb dolutegravir trials involving treatment-naïve 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/abnormal dreams.
Four studies were 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 to the four studies, 1315 of who were treated with dolutegravir.
Low rates of neuropsychiatric events
were seen in all study treatment arms, with most being low-grade (1-2).
However, a higher incidence was observed in the SINGLE study compared to other
trials, with 17% of dolutegravir patients reporting insomnia, 10%
nightmares/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 one patient, with two raltegravir-treated and seven
efavirenz-treated individuals stopping treatment because of this adverse event.
Two patients stopped taking dolutegravir because of insomnia with three
efavirenz-treated patients stopping treatment for this reason.
Abnormal dreams/nightmares caused
two dolutegravir and seven efavirenz patients to cease therapy.
There were no cases of withdrawal of
dolutegravir because of anxiety, though four patients stopped efavirenz for