- Category: HIV Treatment
- Published on Wednesday, 03 July 2013 00:00
- Written by Liz Highleyman
Lowering the dosage of efavirenz (Sustiva) from 600 to 400 mg in an antiretroviral regimen did not compromise efficacy, and has the potential to substantially reduce treatment cost, according to data from the ENCORE1 study presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this week 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 from 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 randomized,double-blind, non-inferiority trial designed to compare the safety and efficacy of reduced dose versus standard dose efavirenz, used in combination with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for first-line HIV treatment. The study was funded by the Bill and Melinda Gates Foundation.
The study randomized 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 baseline.
Participants were randomly assigned to receive either the standard 600 mg dose or a reduced 400 mg 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 3 x 200 mg efavirenz pills, while those in the 400 mg arm took 2 efavirenz pills plus a matching placebo pill.
- The 400 mg and 600 mg doses of efavirenz demonstrated similar efficacy in an intent-to-treat analysis at 48 weeks, with 94% and 92% of patients, 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 non-significant difference between the treatment arms indicates that 400 mg efavirenz was non-inferior to the standard dose.
- The 400 mg efavirenz dose remained non-inferior to the 600 mg 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.
- 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 400 mg compared with the 600 mg arm, with the lower-dose arm gaining an additional 25 cells/mm3 on average.
- Both efavirenz doses were generally safe and well tolerated.
- The overall number and severity of adverse events where similar in the 2 dose groups.
- Approximately half of participants in both arms experienced mild-to-moderate (grade 1-2) adverse events, falling to 7% for severe adverse events.
- There were, however, significantly less side-effects attributable to efavirenz -- in particular central nervous system symptoms -- in the 400 mg arm compared with the 600 mg 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, "400 mg efavirenz was non-inferior to 600 mg efavirenz when combined with Truvada in a treatment-naive, HIV-infected adult population over 48 weeks."
Based on these findings, they suggested that the 400 mg 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 $50 at current prices, 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 efavirenz 400 mg 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 money."
R Puls et al (ENCORE1 Study Group). A daily dose of 400mg efavirenz (EFV) is non-inferior to the standard 600mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trial. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013). Kuala Lumpur, June 30-July 3, 2013. Abstract WELBB01.