13-country trial finds low-dose efavirenz as effective as standard

Caution is urged with rifampicin coadministration

Virologic response at 48 weeks was similar with 400 mg of efavirenz daily and the standard 600 mg daily in a double-blind randomized trial involving antiretroviral-naive people in 13 countries across the world. Safety was better with the lower dose.

Efavirenz is licensed for treatment of HIV infection in combination with other antiretrovirals at a dose of 600 mg once daily. Some earlier evidence suggested that a dose of 400 mg may be as effective and perhaps would cause fewer side effects. A lower dose could also save money.

ENCORE1 randomized antiretroviral-naive adults to 400 or 600 mg of efavirenz daily plus tenofovir/emtricitabine in Argentina, Australia, Chile, Germany, Hong Kong, Israel, Malaysia, Mexico, Nigeria, Singapore, South Africa, Thailand, and the UK. All participants had a viral load above 1000 copies/mL and a CD4 count between 50 and 500 cells/μL. While 37% of participants were African, 33% were Asian and 30% white. One third of study participants were women.

The primary endpoint was a viral load below 200 copies/mL after 48 weeks of treatment in a modified intention-to-treat analysis. Noninferiority of 400 mg to 600 mg would be demonstrated if the lower limit of the 95% confidence interval (CI) for the difference in viral load was less than –10%.

Pretreatment CD4 count averaged 273 cells/μL (standard deviation 99) and median pretreatment viral load was 4.75 log10 copies/mL (about 56,000 copies/mL).

At week 48 the intention-to-treat analysis involving 630 people determined that 94.1% in the 400-mg group and 92.2% in the 600-mg group had a viral load below 200 copies/mL, a result demonstrating the virologic noninferiority of the lower dose in antiretroviral-naive people (difference 1.85%, 95% CI –2.1 to 5.79). Virologic response rates did not differ according to pretreatment viral load. Results were similar in a noncompleter-equals-failure analysis and a per-protocol analysis.

CD4-cell gains were significantly greater in the 400-mg group (+25 cells/μL, 95% CI 6 to 44, P = 0.01), though that difference may not be clinically meaningful.

Similar proportions of people taking 400 or 600 mg of efavirenz had any adverse event (89.1% and 88.4%), but the percentage with a drug-related adverse event was significantly lower in the 400-mg group (difference –10.5%, 95% CI –18.2 to –2.8, P = 0.01). A significantly lower proportion of people in the 400-mg group stopped treatment because of adverse events (2% versus 6%, difference –3.96%, 95% CI –6.96 to –0.95, P = 0.01).

The researchers calculate that lowering the efavirenz dose from 600 to 400 mg daily could save $21 per patient per year and may save between $233 million and $336 million over 3 years.

The ENCORE1 investigators propose that “400 mg efavirenz should be recommended as part of routine care, although we urge caution with rifampicin coadministration.”

Source: ENCORE1 Study Group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014; Feb 7. pii: S0140-6736(13)62187-X.

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Source: IAS

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By Mark Mascolini

Published: Feb. 19, 2014, 12:57 p.m.

Last updated: Feb. 19, 2014, 1:59 p.m.

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