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Reduced initial dosing of efavirenz linked to fewer side effects

Efavirenz, sold under the brand names Sustiva and Stocrin and found in the fixed-dose combination sold as Atripla, is a powerful anti-HIV drug that can be taken once daily and is thus widely prescribed in high-income countries. However, in more than 50% of users, efavirenz can cause side effects, including the following:

difficulty falling asleep;
nightmares;
vivid dreams.

Other side effects can include:

dizziness;
lightheadedness;
difficulty concentrating.

According to researchers, these side effects usually last for the first two to four weeks of treatment. Moreover, they are supposed to be mild in severity. In addition to the common side effects listed above, in rare cases efavirenz can cause disturbing problems such as the following:

depression;
aggressive behaviour;
paranoia;
psychosis;
hallucinations;
suicidal thoughts.

In HIV positive adults, efavirenz is commonly prescribed at a fixed dose of 600 mg once daily, usually taken at bedtime. Some researchers say that efavirenz’s side effects are linked to high levels of this drug that can occur in the blood or brain. To try to reduce the negative impact of this drug on people starting therapy, researchers in Spain conducted a clinical trial.

In this study, one group of people initially received a reduced dose of efavirenz, which was then increased to the full dose over several weeks. The other group of people received efavirenz at the standard dose. The Spanish research team found that reducing the dose of efavirenz, at least initially, resulted in fewer and less intense side effects. Until these findings are confirmed in a larger trial, the results need to be considered preliminary.

Study details

Researchers at several clinics in Spain conducted a double-blind placebo-controlled study comparing two regimens as follows:

escalating-dose group (58 volunteers) – efavirenz was taken at 200 mg/day for the first six days, then increased to 400 mg/day for the following six days, after which it was taken at the standard adult dose of 600 mg/day.
standard-dose group (50 volunteers) – efavirenz was taken at a dose of 600 mg/day from the start of the study.

In addition, for the first two weeks of the study, all participants received placebo efavirenz pills to help conceal which participants received escalating doses of efavirenz.

All volunteers received additional anti-HIV medications throughout the study, mostly commonly:

tenofovir + emtricitabine (FTC) as the fixed-dose combination sold as Truvada;
abacavir + 3TC, as the fixed-dose combination sold as Kivexa.

None of the study participants had major psychiatric illness or liver damage or were using methadone before entering the study.

The average profile of participants when they entered the study was as follows:

20% females, 80% males;
age – 40 years;
viral load – about 60,000 copies;
CD4+ count – 240 cells;
hepatitis C virus infection – 10%.

Results—differences in side effects

Participants who took the escalating doses of efavirenz had fewer side effects (47%) from this drug than participants who took the standard regimen (60%). Specific side effects that were statistically different between the two groups during the first week were as follows:

dizziness – 32% in the escalating-dose group had this problem compared to 66% in the standard dose group;
feeling hung over or drunk – 21% vs. 46%;
difficulty concentrating – 9% vs. 23%;
hallucinations – 0% vs. 6%.

The following conditions were not improved by dose escalation:

anxiety;
depression;
sleeping issues (difficulty falling asleep, feeling sleepy during the daytime, nightmares).

During the 2nd week of the study, when the dose of efavirenz was increased to 400 mg/day in the escalating-dose group, side effects were similar in both groups but generally more severe in the standard-dose group.

In the 4th week of the study, when all participants were taking the full dose of efavirenz and side effects are supposed to be diminishing, the research team reported that 52% of all participants were still experiencing “some efavirenz-related neuropsychiatric adverse events.” Over the course of the study, 7% of participants left because of these side effects—two in the escalating-dose group and four in the standard-dose group.

Results—immune system and HIV

Both regimens seemed equally effective at suppressing HIV levels in the blood. After six months, the proportion of participants in each group whose viral load was less than 50 copies was as follows:

escalating-dose group – 78%;
standard-dose group – 68%.

This difference was not statistically significant.

Also after six months, both groups had similar increases in CD4+ cell counts as follows:

escalating-dose group – 151 additional CD4+ cells
standard-dose group – 130 additional CD4+ cells

Again, this difference was not statistically significant.

Treatment failure

Virologic failure occurred in six participants—two in the escalating-dose group and four in the standard-dose group. In two cases this was because of poor adherence, in two others because of very high pre-therapy viral loads (more than 1 million copies), and the in final two cases researchers were not sure.

Bear in mind

In this study, the number and severity of efavirenz-related side effects were less in people who began therapy with a reduced dose of this drug.

Note that this was a relatively small study. A much larger and costly trial would have been needed to statistically prove that the regimens were roughly equivalent in their ability to suppress HIV.

Other research teams in the European Union are examining ways of reducing the long-term side effects of efavirenz, in some cases by reducing the dose after first checking levels of this drug in the blood.

—Sean R. Hosein

REFERENCES:

Aberg JA, Cespedes MS. Neuropsychiatric complications of antiretroviral therapy. Drug Safety. 2006;29(10):865-74.
van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. Journal of Acquired Immune Deficiency Syndrome. 2009; in press.
Gutiérrez-Valencia A, Viciana P, Palacios R, et al. Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: A randomized trial. Annals of Internal Medicine. 2009 Aug 4;151(3):149-156.

Created on: 08/18/2009

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