Dolutegravir and side effects related to the central nervous system


Dolutegravir and side effects

Insomnia, dizziness, headache and other side effects-central nervous system occur more frequently in the daily lives of patients who use dolutegravir in a different way than the clinical trials suggested and occur commonly in women, people above 60 and people starting to use of abacavir concurrently affirmed a German research group at the International Congress on Medicinal Therapy in HIV Infection (HIV 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 Europe and United States treatment guidelines. Dolutegravir has a 'clean' side effect profile compared to some other commonly prescribed antiretroviral drugs. In particular, phase IIb and phase III studies showed a lower rate of central nervous system toxicity in patients receiving dolutegravir when the drug was compared with efavirenz.

Dolutegravir (Tivicay, also combined with abacavir / lamivudine Triumeq) is a second generation integrase inhibitor that is recommended in treatment guidelines as one of the preferred options for first-line treatment in the United States and Europe. Dolutegravir has a side effect profile "Clean" compared to some other commonly prescribed antiretroviral drugs.

Phase phase III studies showed a lower rate of central nervous system toxicity in patients taking dolutegravir when the drug was compared to efavirenz.

Since the marketing approval granted in 2014, emerging evidence from clinical practice suggests that dolutegravir is associated with a higher incidence of neuropsychiatric side effects than when it was in clinical trials.

Eg a cohort study in the Netherlands found that 14% of people who started ART with dolutegravir between 2014 and 2016 stopped using the drug because of side effects, predominantly insomnia, anxiety, depression and psychosis.

Gastrointestinal discomfort was cited as a reason for the change in dolutegravir in this cohort.

To examine the incidence of neuropsychiatric side effects associated with the drug, researchers in Germany concluded in a retrospective study among patients who began taking an integrase inhibitor between 2007 and 2016 in April when news of possible neuropsychiatric disorders such as side effects of dolutegravir which first emerged.

Clinical data banks participating in the studies routinely recorded the primary reason for changing treatment by providing investigators with consistent and unbiased information on the reasons for the changes compared to discontinuation rates within two years of starting therapy between dolutegravir, raltegravir (Isentress) and elvitegravir (Vitekta, also in Stribild), in order to determine if the side effect is specifically linked to dolutegravir or a side effect that occurs to some degree with all integrase inhibitors.

Researchers noted that the reasons that led to the disruption were due to insomnia, sleep disturbance, dizziness, agitation, anxiety, depression, lack of concentration, headache, "slowness of thought" pinprick feelings and stinging of plausible unexplained needles that are side effects of Dolutegravir.

A total of 1704 patients started receiving ART with an integrase inhibitor with the following indices:

  • dolutegravir 985;
  • elvitegravir 287;
  • raltegravir 678)

The mean follow-up ranged from 36 months to patients exposed to raltegravir and 11,5 months to patients exposed to dolutegravir.

Discontinuation due to any adverse event occurred more frequently to three persons exposed to elivitegravir than any exposure to raltegravir or dolutegravir, but when referring to rates of adverse events and neuropsychiatric leading to discontinuation of treatment were calculated, these were considered substantially superior to dolutegravir than for any other drugs of the same class.

Discontinuation due a Qualquer event adverse (12 months / rate) Discontinuation due a event neuropsychiatric (rate / 12 months)
Dolutegravir 7,6% 5,6%
Elvitegravir 7,6% 0,7%
Raltegravir 3,3% 1,9%

In the vast majority of cases, patients reported two or more neuropsychiatric events.

In all patients the neuropsychiatric problems disappeared rapidly after discontinuation of dolutegravir administration, but resurged in six patients who chose to resume dolutegravir treatment and in no case did collateral effects result in hospitalization.

In comparison, 14 patients stopped the TRAV with raltegravir due to neuropsychiatric effects, mainly headache or paresthesia, or insomnia.

Neuropsychiatric side effects that led to suspension of dolutegravir were most frequently observed in women in people with 60 years or older and subjects in which abacavir was given at the same time as dolutegravir.

The rates of neuropsychiatric side effects seen in the cohort reported in the studies were much higher than in clinical trials.

Romina Quercia of ViiV Healthcare reported a summary of clinical data trials.

Researchers have analyzed safety data from level III trials of dolutegravir 3.b phase without establishing a clear understanding of the frequency of neuropsychiatric side effects:

  • anxiety
    depression (depression, bipolar depression, suicidal thoughts and hypomania);
  • Insomnia and nightmare / abnormal dreams.

Four studies were included in the analysis, the following trials:

  1. Spring-2,
  3. Flamingo 48 weeks to 96 weeks
  4. all-female ARIA trial.

A total of 2634 participants were recruited for the four studies, 1,315 from which they were treated with dolutegravir.

The low rates of neuropsychiatric events were observed in all study arms treatments, with the majority being low -grade.

However, a higher incidence was observed in the single study compared to other trials, with 17% of patients using reported insomnia, 10% abnormal nightmares / dreams, 8% and 7% depression anxiety.

These rates were lower than those seen between patients with efavirenz.

Rates of neuropsychiatric side effects leading to treatment discontinuation were less than 5% in all trials.

Depression led to discontinuation of dolutegravir therapy by one patient with two other raltegravir-treated patients and seven treated with efavirenz stopping treatment because of this adverse event. Two patients will stop dolutegravir therapy because of insomnia with three patients receiving efavirenz discontinuing treatment for this reason.

Abnormal dreams / nightmares caused were related to the use of dolutegravir and seven patients taken to efavirenz as a reason to discontinue therapy.

There were no cases of withdrawal of dolutegravir because of anxiety, although four patients had efavirenz therapy withdrawn, for this reason during therapy.