Lowering the dosage of efavirenz (Sustiva or Stocrin) from 600 to 400mg in an antiretroviral regimen did not
compromise efficacy, a finding that has the potential to substantially reduce
treatment cost in all regions of the world, according to data from the ENCORE1 study presented on Wednesday at the 7th International AIDS Society
Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur.
The non-nucleoside reverse transcriptase inhibitor
efavirenz is among the most widely used antiretroviral agents, and is a
preferred component of first-line therapy in HIV treatment guidelines from
Europe, the US, and the newly updated World Health Organization recommendations released at the conference.
Rebekah Puls of
the Kirby Institute in Sydney and colleagues conducted a study to assess
whether efavirenz would perform comparably at a lower dose – as suggested
by observational and phase 2 study data – which could
lower the cost of antiretroviral therapy and allow more people to be treated.
ENCORE1 was a
non-inferiority trial designed to compare the safety and efficacy of reduced-dose versus standard-dose efavirenz, used in combination with two
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for first-line
HIV treatment. The study was funded by the Bill and Melinda Gates Foundation.
The study randomised 636 treatment-naive people with HIV in 13 countries in
Europe, Africa, the Asia-Pacific region and Latin America. Africans, Asians and
Caucasians each accounted for approximately one-third of participants. About
two-thirds were men and the mean age was 36 years. The average CD4 count was
low, at just 99 cells/mm3, and three-quarters had fewer than 100
cells/mm3. One-third had high viral load (>100,000 copies/ml at
were randomly assigned to receive either the standard 600mg dose or a reduced
400mg dose of efavirenz once daily plus tenofovir and emtricitabine (the drugs
in the Truvada fixed-dose combination
pill). People in the standard-dose arm took three 200mg efavirenz pills, while
those in the 400mg arm took two efavirenz pills plus a matching placebo pill.
The 400mg and
600mg doses of efavirenz demonstrated similar efficacy in an intent-to-treat
analysis at 48 weeks, with 94 and 92%, respectively, suppressing HIV RNA below
200 copies/ml. Virological response rates were even higher – 98 and 97%,
respectively – in a per protocol or 'as-treated' analysis. This small and
non-significant difference between the treatment arms indicates that 400mg
efavirenz was non-inferior to the standard dose.
efavirenz dose remained non-inferior to the 600mg dose when participants were
stratified by viral load. Among those with HIV RNA below 100,000 copies/ml the
response rates were 95 and 93%, respectively, dropping only slightly to 93
and 91%, respectively, among those with higher levels.
Puls said the
study used the rather high 200 copies/ml cut-off because some countries do not
routinely use more sensitive viral load tests. However, she noted, lower-dose
efavirenz was also non-inferior when looking at viral load >50 copies/ml.
The mean CD4
cell count at 48 weeks was greater in the 400mg compared with the 600mg arm,
with the lower-dose arm gaining an additional 25 cells/mm3 on
doses were generally safe and well tolerated. The overall number and severity
of adverse events were similar in the two dose groups. Approximately half in
both arms experienced mild-to-moderate (grade 1 to 2) adverse events, falling to
7% with severe adverse events.
however, significantly fewer side-effects attributable to efavirenz – in particular, central
nervous system symptoms – in the 400mg arm compared with the 600mg arm (37 vs 47%, respectively),
and significantly fewer people taking the lower dose discontinued treatment due
to adverse events (2 vs 6%).
The researchers concluded that "400mg efavirenz was non-inferior to
600mg efavirenz when combined with Truvada in a treatment-naive, HIV-infected
adult population over 48 weeks".
Based on these findings, they suggested that the 400mg dose of efavirenz should
be considered for initial antiretroviral therapy in routine clinical practice.
Doing so would reduce cost by about one-third, or approximately $50USD at current
prices in resource-limited settings, according to Puls. This consideration takes on added
importance given the new WHO guidelines recommending treatment for everyone with a
CD4 count below 500 cells/mm3. She said that testing the lower dose
in pregnant women is next on the agenda.
Widespread adoption of the 400mg dose would
"lower the cost of treatment and permit better use of scarce resources in
global health budgets", Puls told reporters. "This could mean that
millions more people could receive life-saving treatment for the same amount of