Approximately 10% of patients taking the
antiretroviral drug raltegravir (Isentress)
develop central nervous system (CNS) side-effects, research published in the
online edition of AIDS shows. The
development of CNS side-effects was associated with the co-administration of
tenofovir (Viread, also in Truvada, Atripla and Eviplera) and of proton pump inhibitors (drugs used to reduce gastric acid). The investigators believe
these drugs interact with raltegravir, increasing its plasma concentrations.
Raltegravir is the only integrase inhibitor
so far approved for the treatment of HIV. Clinical trials conducted during the
development of raltegravir showed that the drug had a good safety profile.
However, some people developed CNS symptoms and there have been case reports
of worsening depression and the development of insomnia in people initiating
Italian investigators therefore looked at
the prevalence of and risk factors for CNS side-effects in people taking
raltegravir in routine HIV care.
Their study sample included 453
raltegravir-treated participants. They were
monitored at six-monthly intervals, when they were asked if they had developed
CNS symptoms such as headache, dizziness, anxiety, depression and sleep
Two-thirds of the participants were men and
their median age was 46 years. The mean CD4 cell count was 378 cells/mm3
and mean viral load was 1250 copies/ml. The participants were followed for a median
of 23 months.
During this time, 47 individuals (10%)
developed at least one drug-related CNS side-effect.
Four people stopped taking their therapy
because of CNS symptoms.
There was evidence that the risk of CNS
symptoms was increased by certain drug interactions.
Symptoms developed in 14% of participants who
were taking the anti-HIV drug tenofovir, compared to 7% of those who were
taking an alternative antiretroviral (p = 0.03). CNS symptoms were observed in
26% of people taking a proton pump inhibitor, compared to 9% of
individuals who were not taking this type of therapy (p = 0.006).
After controlling for potential
confounders, the investigators found that concomitant treatment with tenofovir
almost doubled the risk of CNS symptoms (OR = 1.9; 95% CI, 1.0-3.5, p =0.04),
whereas treatment with a proton pump inhibitor was associated with a more than
three-fold increase in the risk of these symptoms (OR = 3.4; 95% CI, 1.3-8.8, p
The authors draw attention to the results
of pharmacokinetic studies that showed that tenofovir can increase plasma levels
of raltegravir by up to 64%, and that proton pump inhibitors can increase
raltegravir levels by up to 415%.
“Our data suggest a possible correlation
between high raltegravir plasma concentrations and CNS symptoms,” write the
They recommend “a careful evaluation of
patients with psychiatric disease prior to starting raltegravir and a
continuous monitoring of CNS symptoms in clinical practice in those starting
the drug”. The authors also stress the need to check for drug interactions than
could lead to an increase in raltegravir levels. Therapeutic drug level
monitoring could be useful, they suggest, for people experiencing CNS
“Further prospective studies are needed to
better clarify risk factors, the role of drug-interactions and the clinical
significance of CNS symptoms in patients receiving raltegravir,” conclude the