Briana Santaniello
08/20/14
Journal Club
Lundgren J, Phillips A. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naïve adults
(ENCORE1): a randomized, double-blind, placebo-controlled, non-inferiority trial. The Lancet. 2014 Apr 26;383(9927):14741482.
Journal background information:
The Lancet: Peer-reviewed #2 (150): journals in general medicine category
Impact factor: 39●207
Authors:
Lundgren J: Chief physician and director of the Copenhagen HIV Programme
Phillips A: University College London School of Life and Medical Sciences Professor of
Epidemiology and Biostatistics
Funding:
Bill & Melinda Gates Foundation unrestricted grant
Study sponsor: Kirby Institute
Gilead Sciences: donated Truvada®
Mylan: provided the Efamat® and donated the matched placebo
Conflicts of interest:
Several contributors, members of the writing committee, and representatives from the ENCORE1 Study
Group receieved honoraria, research grant support, consultancy payments, etc. from Gilead, GlaxoSmithKline, Pfizer,
Janssen, Merck, and Bristol-Myers Squibb in current/previous years
Disease State Background:
1) HIV: virus which can be spread through sexual contact, injection drug use, pregnancy, childbirth, breastfeeding, occupational
exposure, and rarely through blood transfusions/organ transplants. 1
2) HIV eventually leads to a compromised immune system because the virus attacks T cells and uses the human’s own cells’
machinery to replicate itself. Over time, enough destruction of these cells leads to AIDS. 1
3) In U.S. alone: over 1.1 million people are infected. 1
4) Globally: over 33.4 million people are infected.1
Treatment Background:
1) Treatment is not curative; however it helps to reduce viral load, improve T-cell counts
2) Treatment is associated with numerous side effects
3) Most effective treatment: Highly Active Antiretroviral Therapy (HAART)
a. Drugs used in combination to achieve best viral load reduction
i. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, published by
the National Institutes of Health (NIH), state that “the optimal antiretroviral (ARV) regimen for a
treatment-naïve patient consists of two NRTIs in combination with a third active ARV drug from one of
three drug classes: an NNRTI, a PI boosted with ritonavir, or an INSTI.” 2
ii. The NIH-recommended NNRTI-based regimen consists of efavirenz, tenofovir, and emtricitabine. This
combination exists as a fixed-dose tablet marketed as Atripla® (efavirenz 600 mg/emtricitabine 200
mg/tenofovir 300 mg).
iii. WHO: Atripla® is first-line treatment for all antiretroviral-naïve HIV-infected individuals older than 3
years
iv. When Atripla® FDA approval trials were completed, only efavirenz 600 mg was tested
Study Purpose/Objectives/Rationale:
1) Lopez-Cortes L, Ruiz-Valderas R, Viciana P, et al. Pharmacokinetic Interactions Between Efavirenz and Rifampicin in HIVInfected Patients with Tuberculosis. Clinical Pharmacokinetics. 2002 Aug:41(9). 681-690.
a. Coinfected patients: HIV+ and TB+: Receiving HAART including efavirenz along with rifampicin (rifampin)
b. Presence of rifampin decreased the mean peak concentration, trough concentration, and area under the
concentration-time curve over the administration interval of efavirenz
c. Pharmacokinetics of efavirenz 800 mg plus rifampin ≈ efavirenz 600 mg without rifamcin
2) ENCORE1 Study Group Hypothesis: minimal effective efavirenz dose may be lower than 600 mg
3) No previous trials on this subject
4) Objective: To compare 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
5) Potential benefits of study findings:
a. Lower dose  lower incidence of adverse effects, lower cost, lower chance of resistance (?)
Primary Outcome: comparison between treatment groups of proportions of patients with HIV RNA < 200 copies/mL 48 weeks after
randomization
Secondary Outcomes: virologic endpoints (proportion of patients with plasma HIV RNA < 400 copies/mL and < 50 copies/mL, and
time to virologic failure), immunologic endpoints (mean change from baseline in CD4_ T cell count/µL), clinical endpoints (rate of
opportunistic disease or death, and rates of serious non-AIDS-defining illness and non-AIDS related mortality), metabolic endpoints
(mean/median change from baseline in fasted lipids, mean/median change from baseline in fasted glucose, and rates of initiation or
changes in existing lipid-lowering therapies), adherence (median scores of self-reported adherence to randomized study medications),
mean/median change from baseline in selected serum biochemical parameters, rates types and severity of adverse events, steady state
EFV concentrations measured by plasma and dried blood spot samples
Trial design:
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Continuation (Phase 3)
Allocation: Randomized
o computer-generated sequence with blocking factor of 4) to receive tenofovir plus emtricitabine with reduced daily
dose efavirenz (400 mg) or standard dose efavirenz (600 mg)
o Parallel assignment
Interventional:
o Safety/Efficacy study
o Non-inferiority trial
Masking: Double Blind (subject & investigator)
Participants:
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38 clinical sites: 13 countries
Modified intention-to-treat analysis:
o 630 patients (efavirenz 400 = 321; efavirenz 600=309)
 32% women
 37% African, 33% Asian, 30% white
Inclusion criteria:
o HIV-infected adults, >16 years of age, CD4 T-cell counts between 50 and 500 cells/µL, no previous AIDS-defining
illness, plasma HIV-1 RNA of ≥ 1000 copies/mL, no previous exposure to antiretroviral therapy, creatinine
clearance of ≥ 50 mL/min
Exclusion criteria:
o Pregnant, nursing mothers, uncontrolled active opportunistic or malignant disease, present or recent use of
prohibited or illicit medications adversely affecting participation or laboratory values outside predefined ranges
Methods:
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All patients received the same dose of tenofovir plus emtricitabine
o Efavirenz 400 mg group received two 200 mg efavirenz tablets plus one placebo tablet
o Efavirenz 600 mg group received three 200 mg efavirenz tablets
Study drug stored by independent site pharmacists
o Study efavirenz labeled only with kit list number
o Only study statistician knew what dose of efavirenz was; all others involved were masked
Clinic visits: weeks 0, 4, 12, 24, 36, 48
o Physical examination, adverse event reporting, biochemistry, hematology, immunology
o Local viral load quantification for clinical management (Abbot m200 Real Time HIV-1 Test)
o Adherence counseling and reporting (week 4 and 48)
o Self-reported responses: quality of life (SF 12) at weeks 0 and 48
o Questionnaire of efavirenz-related symptoms (weeks 0, 2, 4, and 48)
Statistical Analyses:
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Sample size: assumption = 85% participants randomized to standard efavirenz dosing would have viral load < 299 copies/mL
at 48 weeks
Non-inferiority (efavirenz 400) = lower 95% CI of difference between groups in proportion of viral load < 300 copies/mL at
48 weeks lying above ~ 10%
90% power to establish non-inferiority: 572 participants (286 per group) in modified intention-to-treat group
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Increased sample size to ensure >90% power: 630 total  93% power (modified intention-to-treat analysis)
o Differences in proportions between randomized groups: Pearson’s X2 or Fisher’s exact test derived p value
o t test: compare mean change from baseline for continuous endpoints by randomized groups
o Wilcoxon test: compare median change from baseline to week 48 by randomized group for SF 12 and efavirenz
symptom questionnaire
o Time-to-event endpoints: Cox regression analysis, estimated hazard ratio, Wald test (compared estimates)
Results for Primary Outcome: proportion of patients with a viral load < 200 copies/mL in modified intention-to-treat analysis was 302
(94.1%) of 321 in the efavirenz 400 mg group and 285 (92.2%) of 309 in the 600 mg group (difference 1.85, 95% CI -2.1 to 5.79) –
lower CI did not cross -10%  efavirenz 400 mg = non-inferior to efavirenz 600 mg
Results for Secondary Outcomes: 26 (8%) of participants in 400 mg group, 34 (11%) in 600 mg group had stopped randomized
efavirenz by week 48 (patients either died or were lost to follow-up); 10 (3%) in 400 mg group ceased treatment by week 4 vs. 16
(5%) in 600 mg group; Kaplan-Meier curves = no significant difference between groups in time to cessation of randomized efavirenz;
stopped efavirenz at a rate of 9.57 and 13.34 participants per 100 person years in 400 and 600 mg groups, respectively; no difference
in total number of adverse events between treatment groups (400 mg = 1173, 600 mg = 1182) or severity reported by participants.
Limitations: Potential for bias given that the pharmaceutical companies were involved in the pharmaceutical support portion of the
study.
Conclusion:
Not only are the results statistically significant, but they are also clinically significant. A reduction in the dose of efavirenz from 600
mg to 400 mg provides the same virologic response and has a lower incidence of side effects. This could potentially improve
tolerability and in turn, adherence. As the pharmaceutical manufacturers played a role in the study and were aware of the objectives of
the study, it is unlikely that a dose reduction would also lead to a reduction in price. Atripla already comes as a fixed dose tablet and
although 400 mg efavirenz can now be considered part of routine treatment, the fixed dose of efavirenz within Atripla cannot be
adjusted without the aid of the pharmaceutical company. The pharmaceutical company would be required to entirely reformulate the
product in order to comply with the new efavirenz dose which would likely result in price increases rather than decreases. In patients
receiving efavirenz without the fixed dose Atripla, I agree with the authors that 400 mg efavirenz should be considered for routine care
of HIV-infected antiretroviral-naïve paitents.