A daily dose of 400 mg efavirenz (EFV) is
non-inferior to the standard 600 mg dose:
week 48 data from the ENCORE1 study, a
randomised, double-blind, placebo
controlled, non-inferiority trial
Rebekah Puls for the ENCORE1 Study Group
Reduced dose antiretroviral drugs (ARV)
GFATM/WHO/PEPFAR plans to expand treatment to 15 million
people by 2015 will come at significant cost
Although reduced, the cost of ARV remains substantial
Dose reduction may be a means to reduce drug costs
Efavirenz (EFV) is a globally important ARV
WHO guidelines recommend EFV for first line
Phase II trial and observational cohort data suggest
comparable performance at lower daily doses
Encore1 study design
A randomized, double-blind, placebo-controlled, non-inferiority
clinical trial to compare the safety and efficacy of reduced dose
EFV with standard dose EFV plus 2N(t)RTI in ART-naïve HIVinfected individuals over 96 weeks
Patient population
ART-naïve HIV-infected adults with no prior AIDS, plasma HIV-1
RNA (pVL) >1,000 copies/mL, 50 <CD4+ T cells/µL <500, creatinine
clearance ≥50 mL/min, no pregnancy or nursing mothers
Randomisation
I. TDF/FTC + 400 mg EFV qd
(2 x 200 mg EFV + 1 x 200 mg matched placebo)
II. TDF/FTC + 600 mg EFV qd
(3 x 200 mg EFV)
1:1 (400mg:600mg), stratified by clinical site and screening pVL
Methods
Primary endpoint
Proportion of participants with pVL <200 copies/mL at 48 weeks
in the intention to treat (ITT, M=F) population, using a noninferiority margin of 10%
pVL determined retrospectively at a single, central laboratory
<50, <400 copies/mL
Sample size
630 patients to demonstrate non-inferiority of 400 mg EFV
assuming 85% participants taking 600 mg have <200 copies/mL,
at least 90% power for both ITT and PP analyses
Safety data
Adverse event (AE) summaries, cessation of study drugs
Changes from baseline in laboratory results
Participant disposition
Total screened
N=768
Withdrew consent
N=9
Randomized
N=636
Total ineligible
N=123
United
Kingdom
Germany
Israel
Hong Kong
Mexico
Nigeria
Chile
Argentina
EFV 400mg, N=324
EFV 600mg, N=312
Withdrew prior to commencing
randomized therapy N=3
Withdrew prior to commencing
randomized therapy N=3
ITT and NC=F, N=321
ITT and NC=F, N=309
PP, N=293
PP, N=271
South
Africa
Thailand
Malaysia
Singapore
Australia
Baseline characteristics
Characteristic
EFV 400mg
EFV 600mg
Total
N=321
N=309
N=630
Male, n (%)
221 (68.8)
206 (66.5)
427 (67.7)
Mean age in years (SD)
36.1 (10.0)
35.8 (10.0)
36.0 (10.0)
African
118 (36.8)
116 (37.4)
234 (37.1)
Asian
106 (33.0)
103 (33.2)
209 (33.1)
Caucasian
97 (30.2)
90 (29.0)
187 (29.6)
0 (0.0)
1 (0.3)
1 (0.2)
CDC category A, n (%)
264 (82.2)
265 (85.8)
529 (84.0)
Median pVL in log10 copies/mL (IQR)
4.76 (0.84)
4.73 (0.90)
4.75 (0.88)
<100,000
214 (66.7)
202 (64.4)
416 (66.0)
≥100,000
107 (33.3)
107 (34.6)
214 (34.0)
Mean CD4+ T cells/µL (SD)
273 (97)
272 (101)
273 (99)
100 < CD4+ T cells/µL ≤ 350, n (%)
244 (76)
224 (72)
468 (74)
Ethnicity, n (%)
Aboriginal Australian
pVL copies/mL, n (%)
Primary endpoint: non inferiority at week 48
EFV400 EFV600
%
%
Difference (95%CI)
p
ITT
94.1
92.2
1.8 (-2.1, 5.8) 0.36
NC=F
90.0
85.8
4.3 (-0.8, 9.4) 0.10
PP
98.3
97.4
0.9 (-1.5, 3.3) 0.47
favours
EFV600
-15
-10
-5
0
5
10
15
Difference in percentage of participants with pVL <200 copies/mL
favours
EFV400
Primary endpoint: non inferiority at week 48
EFV400 EFV600
%
%
Difference (95%CI)
p
ITT
94.1
92.2
1.8 (-2.1, 5.8) 0.36
<105 strata
94.9
92.9
2.0 (-2.7, 6.8) 0.40
≥105
92.7
91.1
1.7 (-5.3, 8.6) 0.64
NC=F
90.0
85.8
4.3 (-0.8, 9.4) 0.10
<105 strata
90.4
84.8
5.6 (-0.9, 12.1) 0.09
≥105
89.5
87.5
2.0 (-6.1, 10.2) 0.63
PP
98.3
97.4
0.9 (-1.5, 3.3) 0.47
<105 strata
≥105
98.9
97.4
97.6
97.0
1.2 (-1.5, 4.0) 0.70
0.3 (-4.1, 4.8) 1.00
favours
EFV600
-15
-10
-5
0
5
10
15
Difference in percentage of participants with pVL <200 copies/mL
favours
EFV400
Distribution of participants : NC=F <200 copies/mL
EFV 400 mg EFV 600 mg
Total
N=321
N=309
N=630
n (%)
n (%)
n (%)
32 (10.0)
44 (14.2)
79 (12.5)
pVL >200 copies/mL
5 (1.6)
7 (2.3)
12 (1.9)
Death
2 (0.6)
3 (1.0)
5 (0.8)
Withdrew consent
3 (0.9)
3 (1.0)
6 (1.0)
Lost to follow up
4 (1.2)
3 (1.0)
7 (1.1)
Missing data @ week 48
1 (0.3)
5 (1.6)
6 (1.0)
Stopped EFV due to VF
1 (0.3)
2 (0.6)
3 (0.5)
Stopped EFV for other reason
16 (5.0)
21 (6.8)
40 (6.4)
289 (90.0)
265 (85.8)
554 (87.9)
Failures
pVL <200 copies/mL
Mean change from baseline to week 48 pVL
1
mean difference (95%CI)
-0.06 log10 copies/mL (-0.19, 0.07), p=0.350
pVL log10 copies/mL
0
-1
-2
-3
-4
EFV 400 mg
EFV 600 mg
-5
0
4
8
12
16
20
24
28
32
36
40
44
48
Mean change from baseline to week 48 CD4+ T cells
300
250
mean difference
(SD)
25 cells (6, 44)
p=0.009*
CD4+ T cells/µL
200
150
100
50
0
EFV 400 mg
EFV 600 mg
-50
0
4
8
12
16
20
24
28
Time (weeks)
32
36
40
44
48
Adverse events - overall
Adverse events
EFV400
n (%)
EFV600
n (%)
Total
n (%)
Number of AEs
1,173 (49.8)
1,182 (50.2)
2,355 (100)
Grade 1/2
1,119 (47.5)
1,118 (47.4)
2,237 (95.0)
Grade 3/4
54 (2.3)
65 (2.7)
117 (5.0)
Serious adverse
events
EFV400
N=321
n (%)
EFV600
N=309
n (%)
Difference
(95%CI)
Total numbers of SAEs
31 (46.2)
36 (53.7)
Number with SAE
23 (7.17)
22 (7.12)
0.05% (-3.98, 4.07) 0.980
Number with SAE
related to study drug
3 (0.93)
4 (1.29)
0.36% (-1.98, 1.27) 0.670
p
Adverse events - related to study drug
EFV400
N=321
EFV600
N=309
Difference
(95%CI)
p
Number (%) patients
reporting AE
286 (89.1)
273 (88.4)
Number (%) patients
with study drug
related AE
118 (36.8)
146 (47.2)
-10.5% (-18.2, -2.8) 0.008*
Number (%) patients
stopping drug due to
related AE
6 (1.9)
18 (5.8)
-3.96 (-6.96, -0.95) 0.010*
Efavirenz adverse events*
60
EFV400
EFV600
Proportion of participants (%)
50
272
40
231
30
105
20
68
10
62 78
13 12
21 22
0
CNS
Psychiatric
Rash
Gastrointestinal
Respiratory
1
0
Hepatotoxicity
*categorised according to the EFV Product Information
Conclusions
400 mg EFV was non-inferior to 600 mg EFV when
combined with Truvada in a treatment-naive, HIVinfected adult population over 48 weeks
Evidence of reduced EFV-related side effects with
lower dose
400 mg EFV should be considered for initial ARV
treatment.
Acknowledgments
We extend our grateful thanks to all the volunteers who have been participating in this study. The
study was funded from the following sources: an unrestricted grant from the Bill & Melinda Gates
Foundation (Grant ID 51040); the Australian Government Department of Health and Ageing; the
University of New South Wales. We thank Gilead Sciences Inc for their very kind donation of
Truvada™ to undertake this project and Matrix Laboratories (Mylan Inc.) for their supply of efavirenz
and matched placebo. The Kirby Institute is affiliated with the Faculty of Medicine, University of New
South Wales, Australia.
Protocol Steering Committee – Waldo Belloso, Marta Boffito, David Cooper, Chris Duncombe,
Sean Emery, Sharne Foulkes, Andrew Hill, Heiko Jessen, Suresh Kumar, Man Po Lee, Brenda
Crabtree-Ramirez, Marcelo Losso, Praphan Phanupak, Rebekah Puls, Jim Rooney, Eduardo
Shahar, Alan Winston, Marcelo Wolff, Barnaby Young
DSMB – Matthew Dolan, David Dunn, Roy Gulick
Sydney coordinating team – Sean Emery, Rebekah Puls, Dianne Carey, Carlo Dazo, Anna
Donaldson, Mark Boyd, Kymme Courtney-Vega, Janaki Amin, Sarah Pett, Jessica Taylor, Enmoore
Lin, Tanya Johannesen, Tony Kelleher, Philip Cunningham, Kate Merlin, Julie Yeung, Ansari Shaik,
Bertha Fsadni, Alex Carrera, Melanie Lograsso Buenos Aires coordinating team – Marcelo
Losso, Waldo Belloso, Cecilia Abela, Marina Delfino, Lucas Roby, Alejandra Moricz, Silvia Pizzuto,
Silvana Marangón Bangkok coordinating team – Praphan Phanupak, Amanda Clarke, Kanitta
Pussadee, Louise Tomkins, Parinya Sutheerasak, Peeraporn Kaew-on, Sasiwimol Ubolyam
Acknowledgments
Australia: Alfred Hospital – Julian Elliot, Michelle Boglis, Janine Roney. Melbourne Sexual Health Centre – Tim
Read, Helen Kent, Julie Silvers. Northside Clinic – Richard Moore, Thai Lim, Jeff Wilcox. AIDS Medical Unit – Mark
Kelly, Abby Gibson, Lucy Bird. Royal Perth Hospital – David Nolan, Julie Robinson, Laura Barba. Albion St Centre:
Don Smith, Jega Sarangapany, Denise Smith. Burwood Road General Practice: Nicholas Doong, Nam Phan, Jeff
Hudson. Taylor Square Private Clinic: Emanuel Vlahakis, Amrita Patel, Isobel Prone. St Vincent’s Hospital: David
Cooper, Sarah Pett, Karen MacRae. Argentina: CAICI - Sergio Lupo, Liliana Trape, Luciana Peroni. Hospital
Italiano - Waldo Belloso, Marisa Sanchez, Mariana de Paz Sierra. Hospital Ramos Mejia - Marcelo Losso, Mariana
Kundro, Patricia Burgoa. Hospital Posadas - Hector Laplume Lucia Daciuk. Hospital Rawson - Norma Luna, Daniel
David, Laura Nieto. FUNCEI - Valeria Confalonieri, Emiliano Bissio, Pablo Luchetti. CEADI - Oscar Garcia Messina,
Olivia Gear, Adrian Rodriguez. CEIN - Liliana Calanni, Susana Calanni, Daniel Clafunao. Chile: – Hospital San
Borja-Arriaran - Marcelo Wolff, Claudia Cortes, Gladys Allendes. Hospital de la Universidad Catolica Pontificia Carlos Perez, Jimena Flores. Germany: Medical Group Practice Berlin – Heiko Jessen, Arne Jessen, Luca Stein,
Carmen Zedlack, Maria Koch. Bonn University – Jurgen Rockstroh, Brigitta Späth, Christoph Boesecke. Israel:
Rambam Medical Centre – Eduardo Shahar, Eynat Kedem, Garmal Hassoun. Hong Kong: Queen Elizabeth
Hospital - Man-Po Lee, Patrick CK Li, Pansy PC Yu. Malaysia: UMMC - Raja Iskandar Shah Raja Azwa, Sharifah
Faridah Syed Omar, Sasheela Sri La Sri Ponnampalavanar. Hospital Sungai Buloh - Suresh Kumar, Yasmin Gani,
Henry Chang. Mexico: Hospital General de Guadalajara - Jaime Andrade Villanueva, Angeles Gonzalez, Lucero
Gonzalez. INCMNSZ- Brenda Crabtree Ramirez, Juan Sierra Madero, Maru Zghaib. Singapore: Tan Tock Seng
Hospital - Barnaby Young, Evelyn Chia, Andy Loh. South Africa: Desmond Tutu HIV Centre - Catherine
Orrell, Richard Kaplan, Robin Wood. Josha Research - Sharne Foulkes, Neo Tsikoane, Nadia Grace. Chris Hani
Baragwanath Hospital - Lerato Mohapi, Maureen Mohata, Ashaan Naidoo. Nigeria: BUTH - Chidi Nwizu, George
Chima, Vera Labesa. PSSH - Chidi Nwizu, Henriatta Selle Tiri, Jonathan Bulu. Thailand: HIV-NAT - Praphan
Phanuphak, Amanda Clarke, Anchalee Avihingsanon. Khon Kaen University - Ploenchan Chetchotisakd, Siriluck
Anunnatsiri, Parichat Seawsirikul. RIHES - Khuanchai Supparatpinyo, Patcharaphan Sugandhavesa, Patchanee
Samutarlai. United Kingdom: St. Mary’s Hospital – Alan Winston, Borja Mora-Peris, Siobhan McKenna. Chelsea
and Westminster Hospital –Brian Gazzard, Marta Boffito, Chris Higgs.