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

Janaki Amin, Stephen Becker, Waldo Belloso, Marta Boffito, David Cooper, Brenda Crabtree-Ramirez, Chris Duncombe, Sean Emery, Sharne Foulkes, Andrew Hill, Heiko Jessen, Suresh Kumar, Man Po Lee, Marcelo Losso, Chidi Nwizu, Praphan Phanuphak, David Ripin, Tim Read, Jim Rooney, Kim SchafferEduardo Shahar, Alan Winston, Marcelo Wolff, Barnaby Young, Cecilia Abela, Mark Boyd, Dianne Carey, Amanda Clarke, Kymme Courtney-Vega, Carlo Dazo, Marina Delfino, Anna Donaldson, Natalie Espinosa, Tanya Johannesen, Peeraporn Kaew-On, Enmoore Lin, Alejandra Moricz, Jessica Taylor, Praphan Phanupak, Rebekah L. Puls*, Kanitta Pussadee, Parinya Sutheerasak, Louise Tomkins, Sasiwimol Ubolyam, Raja Iskandar Shah Bin Raja Azwa, Emiliano Bissio, Liliana Calanni, Arnaldo Casiro, Ploenchan Chetchotisakd, Jorge Contarelli, Nicholas Doong, Julian Elliott, Brian Gazzard, Mark Kelly, Norma Del Carmen Luna, Sergio Lupo, Oscar Garcia Messina, Lerato Mohapi, Richard Moore, David Nolan, Catherine Orrell, Carlos Perez, Sarah Pett, Jürgen Rockstroh, Khuanchai Supparatpinyo, Don Smith, Jaime Andrade Villanueva, Emanuel Vlahakis, Tony Kelleher, Philip Cunningham, Kate Merlin, Julie Yeung, Ansari Shaik, Bertha Fsadni, Alex Carrera, Melanie Lograsso, Roy Gulick, Brenda Crabtree-Ramiraz, Elan Winston, David Dunn, Matthew Dolan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

134 Scopus citations


Background: The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. Methods: ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staffwere masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than-10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. Findings: The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4.75 log 10 copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI-2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89.1%, efavirenz 600=88.4%; difference 0.75%, 95% CI-4.19 to 5.69; p=0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference-10.5%, 95% CI-18.2 to-2.8; p=0.01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference-3.96%, 95% CI-6.96 to -0.95; p=0.01). Interpretation: Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.

Original languageEnglish
Pages (from-to)1474-1482
Number of pages9
JournalThe Lancet
Issue number9927
StatePublished - 2014
Externally publishedYes


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