Stepped doses reduce incidence and severity of efavirenz-related side-effects

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Gradually increasing efavirenz doses during the first two weeks of therapy with the drug reduces the incidence and severity of neuropsychiatric and sleep-related side-effects without compromising the effectiveness of the drug, Spanish investigators report in the August 4th edition of the Annals of Internal Medicine.

Efavirenz (Sustiva, also in the combination pill Atripla) is a widely used anti-HIV drug that is recommended for first-line antiretroviral therapy.



The fluid portion of the blood.


How well something works (in a research study). See also ‘effectiveness’.

clinical trial

A research study involving participants, usually to find out how well a new drug or treatment works in people and how safe it is.

dose-ranging trial

A clinical trial where two or more doses of a drug are compared to see which works best and is least harmful, usually done at an early stage of drug development.


A clinical trial where neither the researchers nor participants know which assigned treatment an individual participant in the trial is taking until after the end of the trial. This reduces the risk of biased results. 

Although the drug has a powerful anti-HIV effect and is easy to take, it can cause neuropsychiatric and sleep-related side-effects including dizziness, depression, nightmares and insomnia. Up to 50% of patients initiating therapy with efavirenz report these side-effects. Although they are often only mild and generally go away after a few weeks, they are more severe in a small number of patients and, in some cases, have been linked to suicidal thoughts.

It has been suggested that these side-effects are connected with levels of efavirenz in the blood. However, data supporting such a hypothesis are currently lacking. Nevertheless a dose-ranging study conducted early in the drug’s development showed that the incidence of neuropsychiatric side-effects was lower amongst patients taking the 200mg or 400mg dose than those taken the now licensed 600mg once-daily dose of the drug.

Investigators therefore wished to determine if gradually increasing the dose of efavirenz during the first two weeks of treatment with the drug reduced the incidence and severity of neuropsychiatric side-effects.

During the first few weeks of treatment with most antiretroviral drugs, drug levels will be abnormally high until the body becomes used to metabolising the drug, a state described as 'steady state'. The high drug levels that occur during the early weeks of treatment are responsible for many early, transient side-effects of treatment. The use of a lower lead-in dose to reduce side-effects is established practice with nevirapine (Viramune).

To evaluate the effect of lead-in dosing of efavirenz on side-effects, the Spanish research group designed a prospective, double-blind, randomised study involving patients starting HIV treatment for the first time, in Andalusia between 2006 and 2008.

A total of 114 individuals were recruited to the study. Of these 60 were randomised to take stepped doses of efavirenz. This involved taking a 200mg dose between days one and six inclusive, a 400mg dose between days seven and 14 inclusive, and the standard 600mg daily dose from day 14. The remaining 54 patients took the full 600mg dose from the outset. Both groups of patients also took two nucleoside reverse transcriptase inhibitors (NRTIs).

The safety and effectiveness of these two treatment strategies were assessed over a six-month period. Furthermore, on entry to the study and then on days seven, 14 and 30 the patients were asked to complete two questionnaires to determine the incidence and severity of neuropsychiatric and sleep-related side-effects.

The virological efficacy of both stepped and standard treatment was also assessed and plasma levels of efavirenz were monitored in a subset of patients.

Overall, 55% of patients developed neuropsychiatric or sleep disorders during the first week of therapy with efavirenz. However, a higher proportion of patients taking the 600mg dose of the drug from the outset experienced such side-effects than did individuals who took stepped treatment (66% vs 47%, p = 0.04).

Moreover, in the first week of treatment with the drug, individuals taking stepped treatment were less likely to report dizziness (33% vs 66%, p =0.001), feelings of drunkenness or hangover (21% vs 46%, p = 0.008), concentration problems (9% vs 23%, p = 0.038), and hallucinations (0% vs 6%, p = 0.056), than were patients taking the full dose of the drug.

During the second week, similar proportions of patients in the stepped and full-dose groups experienced neuropsychiatric and sleep problems (49% vs. 58%), but these tended to be less severe amongst patients taking stepped treatment.

Four weeks after starting treatment with efavirenz, 52% of patients still reported some neuropsychiatric or sleep disturbances, and overall 7% of patients discontinued treatment with the drug because of these side-effects.

Similar proportions of patients taking stepped and full-dose efavirenz had an undetectable viral load at all study points. This was also the case when the investigators restricted their analysis to patients with a baseline viral load above 100,000 copies/ml.

Two patients taking stepped treatment and four taking full-dose therapy experienced a sustained rebound in their viral load. A significant association was found between non-adherence and virological failure (p = 0.001).

CD4 cell increases were comparable in the two study arms.

The sub-study examining plasma levels of efavirenz found that, as expected, these were lower during the first two weeks amongst patients taking stepped therapy than those taking full-dose treatment (p = 0.047). No differences in plasma levels of efavirenz were observed 30 days after starting treatment. Patients with higher concentrations of the drug during the first week of treatment were slightly more likely to report dizziness, but this finding did not reach statistical significance.

“To our knowledge, this is the first randomized clinical trial directly comparing the incidence of efavirenz-related neuropsychiatric adverse events of efavirenz treatment given in stepwise doses with that of full-dose efavirenz treatment given from the first day,” write the investigators.

They conclude, “stepped-dose administration of efavirenz over two weeks significantly decreases the incidence and severity of neuropsychiatric adverse events, while apparently maintaining the same efficacy as the standard schedule.”


Gutierrez-Valencia A et al. Stepped-dose vs full-dose efavirenz for HIV infection and neuropsychiatric adverse events. Annals of Internal Medicine 151: 1-9, 2009.