Doses of efavirenz can be safely reduced in patients who have high blood concentrations of the drug, Dutch investigators report in the October 1st edition of the Journal of Acquired Immune Deficiency Syndromes. Reducing the dose of the drug meant that patients were less likely to discontinue treatment with efavirenz due to side-effects, and reducing the dose of the drug did not increase the risk of viral load becoming detectable.
Efavirenz (Sustiva, also in the combination pill Atripla) is one of the drugs recommended for first-line antiretroviral treatment. The drug has a potent anti-HIV effect, is easy to take and has a mild side-effect profile.
However, a proportion of individuals who start treatment with efavirenz report central nervous system side-effects. These can include problems sleeping, vivid dreams, and depression. Although such side-effects are often mild and transient, a small number of patients discontinue treatment with efavirenz because of them.
There is some evidence that such side-effects are more likely to occur if a patient has high blood concentrations of efavirenz.
Investigators from the Netherlands therefore undertook a 48-week study to see if patients with high concentrations of efavirenz in their blood could safely reduce their daily dose of the drug, and if such dose reductions meant that an individual was less likely to discontinue their treatment with efavirenz.
The study involved patients who started treatment with efavirenz between 1998 and 2007. Blood levels of the drug in these individuals was checked using therapeutic drug monitoring.
A total of 180 patients with high blood concentrations of efavirenz (above 4 mg/l) either reduced their dose of the drug or continued to take the standard 600mg daily dose.
The efavirenz dose was reduced to 400mg in 47 patients. This achieved a reduction in mean plasma concentrations of the drug from 6.8 mg/l to 4 mg/l, which was statistically significant (p < 0.001).
Two patients had their dose reduced from 600mg to 200mg. In one patient, this achieved a reduction in levels of the drug from 6.4 mg/l to 2.78 mg/l. In the other patient, levels of efavirenz fell from 27.7 mg/l to 11 mg/l. Therefore the dose of efavirenz was further reduced to 100 mg, resulting to a fall in concentrations of the drug to 2.7 mg/l.
Levels of efavirenz remained above the threshold of efficacy (1 mg/l) in all 42 patients who had a second post-reduction measurement. However, the investigators note that 22 patients still had a blood concentration of the drug of 4 mg/l or above despite a dose reduction to 400mg, and that many of these individuals continued to have high concentrations of the drug despite further dose reductions.
After a year of follow-up, 14 patients who continued to take the standard dose of efavirenz had discontinued treatment with the drug compared to only one patient who reduced their dose. This provided an estimated cumulative incidence of 12 vs 2%, a difference of borderline significance (p = 0.066).
Viral load remained below 50 copies/ml in 95% of patients who reduced their efavirenz dose compared to 86% who continued to take the 600mg dose. Treatment history and viral load at baseline were the factors most associated with virological outcome.
“This study demonstrated that therapeutic drug monitoring-guided efavirenz dose reduction may prevent toxicity-induced discontinuations in patients with high plasma concentrations”, comment the investigators.
They add, “we did not observe any detrimental effect of dose reduction on virological response.”
They conclude, “our study demonstrates that therapeutic drug monitoring-guided dose reduction can be considered in patients who have high efavirenz plasma concentrations. Dose reduction does not negatively affect virological efficacy and may prevent toxicity-induced discontinuations.”