Efavirenz dose reduction could help scale up antiretroviral therapy access

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.

ENCORE1 Study Group. Lancet. 2014 Feb 7. pii: S0140-6736(13)62187-X. doi: 10.1016/S0140-6736(13)62187-X. [Epub ahead of print]

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 staff were 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.

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 log10 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.

Abstract access [1]

Editor’s notes: Nearly 10 million people in low- and middle-income countries were receiving antiretroviral therapy (ART) by the end of 2012, with plans to expand coverage to 15 million by 2015. Several challenges must be overcome if this target is to be achieved. One of the most pertinent of these is how to fund this expansion in the current economic climate. Significant progress has already been made in reducing the cost of first-line drugs. The authors of this paper propose an alternative approach to lowering drug costs, namely dose reduction.

Evidence supporting the 600mg dose of efavirenz used in clinical practice is weak, with no difference found in the proportion of patients achieving viral suppression in the original dose finding trials of 200mg, 400mg and 600mg (unpublished). This trial in ART-naive individuals found that 400mg was non-inferior to 600mg of efavirenz in terms of viral suppression over 48 weeks of follow-up. Findings were similar when stratified by ethnic group (African, Asian, other) and body mass index, both factors which influence drug concentrations. Furthermore, fewer patients on 400mg reported adverse events which were related to efavirenz, and fewer patients with drug-related side effects on this dose stopped efavirenz. These promising results support a dose reduction strategy. However, longer term outcomes need to be evaluated and efficacy studies in patients with tuberculosis are needed before the 400mg dose is recommended for use in routine clinical practice. Certainly, if drug companies agree to manufacture this dose at scale, preferably in fixed-dose combination tablets, cost-savings could be considerable.  

Africa [6], Asia [7], Europe [8], Latin America [9]
  • [23]