Lower dose efavirenz effective in two studies

1 December 2014. Related: Conference reports, Antiretrovirals, HIV 12 Glasgow 2014.

Polly Clayden, HIV i-Base

Efavirenz (EFV) dosed at 400 mg daily remained non-inferior to 600 mg at 96 weeks, and 300 mg was effective as maintenance HIV therapy, according to data from EFV two dose reduction studies presented at the 2014 HIV Drug Therapy Glasgow Congress. [1,2]

ENCORE1 was a multinational, double blind, placebo-controlled study that compared the efficacy and safety of 400 mg and 600 mg EFV with tenofovir/emtricitabine as first-line HIV treatment in adults. At 48 weeks, the primary analysis established that 400 mg EFV was non-inferior to 600 mg. [3]

Dianne Carey from the Kirby Institute, New South Wales, Sydney, Australia, presented data showing the durability, safety and efficacy from the extended follow up of the study.

The primary end point was proportions of participants with viral load <200 copies/mL using a 10% non-inferiority margin. There were 630 participants in the intention-to-treat (ITT) analysis: 321 and 309 received 400 mg and 600 mg EFV; the mean age was 36 years; 32% were women; 37%, 33% and 30% were African, Asian and Caucasian, respectively.

A total of 585 participants completed 96 weeks of randomised treatment: 299 and 286 on 400 mg and 600 mg EFV.

At 96 weeks 90.0% of participants in the 400 mg EFV and 90.6% in the 600 mg EFV arms had viral load <200 copies/mL, difference -0.6 (95% CI -5.2 to 4.0), p=0.72.

Non-inferiority was also shown for viral loads <50 copies/mL, difference -0.4 (95% CI -5.8 to 4.9) and was retained regardless of baseline viral load: >100,000 copies/mL, difference -1.6 (95% CI -8.9 to 5.6).

There was no difference between arms in time to loss of virological response >200 copies/mL, or change from baseline viral load.

The mean change from baseline CD4 count at 96 weeks was significantly higher in the 400 mg EFV arm: difference 25 cells/mm3 (95% CI 2 to 48), p=0.03. This difference was observed from week 4 of the study – Dr Carey commented that this difference might be an artefact and probably has no clinical significance.

A substantial proportion of participants (89%) reported adverse events (AEs) in the study; 5% were grade 3 or 4. There was no difference in the frequency or severity of AEs between arms: difference 0.09 (95% CI -4.73 to 4.90) p=0.97.

Participants receiving 600 mg EFV were significantly more likely to report an AE definitely or probably attributable to EFV: 47.9% vs 37.7%, difference -10.2% (95% CI -17.9 to -2.51) p=0.01. More participants stopped EFV due to related AEs in the 600 mg arm: 23.0% vs 8.3%, difference -7.3 (95% CI -14.9 to 0.4), p=0.07, but this did not reach significance. The proportions of participants with EFV related serious AEs was small, approximately 1%, with no difference between arms.

In a related presentation, Chien-Ching Hung from the National Taiwan University Hospital showed data from an open-label, single arm, observational therapeutic drug monitoring (TDM) guided switch study to 300 mg EFV maintenance ART among participants who were stable on 600 mg.

Dr Hung explained that a previous study from the same group found a considerable proportion of HIV positive Taiwanese adults receiving EFV at the standard dose had higher than recommended plasma concentrations – strongly correlated with weight and CYP 2B6 G516T SNP (associated with slower metabolism of EFV).

Based on the 48-week results of ENCORE1, the investigators looked at a reduced dose of EFV as maintenance therapy for people with high concentrations at the standard dose.

Participants were enrolled who had received EFV 600 mg containing ART for at least six months, with viral load <200 copies/mL, C12 EFV >2 ng/mL and who were not taking any concomitant medicines known to affect EFV concentrations.

The investigators designed a pill cutter to divide the 600 mg tablets in two. EFV C12 were determined 4 to 12 weeks after switch using high-performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase-chain-reaction.

The primary endpoint was viral load <50 copies/mL in ITT analysis at 24 and 48 weeks.

A total of 157 participants were included: 94.3% men; mean age 39 years, weight 64 kg (32.4% <60 kg) and BMI 22; 25.8% HBsAg-positive and 6.0% anti-HCV-positive; and 42.3% had CYP2B6 G516T or TT genotypes.

The mean baseline EFV C12 plasma concentration before switch (n=150) was 3.43 mg/L (IQR 2.48 – 3.99), which decreased to 1.74 mg/L (1.34 – 2.09), giving a mean reduction of 47.0% (IQR, 38.3 – 55.1%) four weeks after switching. The extent of the reduction was similar across the whole population of polymorphisms.

The proportions of participants with viral load <50 copies/mL were 98.7% (n=157), 97.1% (n=138) and 98.6% (n=69) at baseline, two and three months respectively.

Almost 80% of participants reported EFV related adverse events at baseline and about 80% of these reported improvement after switching to the lower dose.

Comment

Results from ENCORE1 were first announced in July 2013. Subsequent discussions since have identified the need to confirm that the 400 mg dose will be robust in the presence of TB treatment and in the third trimester of pregnancy. Pharmacokinetic studies to look at these two questions are designed and ready to go. These need to be funded and completed.

References:

1. Carey D. Efavirenz 400 mg daily remains non-inferior to 600 mg: 96 week data from the double-blind, placebo-controlled ENCORE1 study. 
 HIV Drug Therapy Glasgow Congress, 2-6 November 2014. Oral abstract 0421. Journal of the International AIDS Society 2014, 17(Suppl 3):19523
   http://www.jiasociety.org/index.php/jias/article/view/19523
   http://aps.mediasite.com/mediasite/Play/8387d9c242e0475f9061f79ca65e65e41d?usehtml5=true
2. Yang S-P et al. Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring. HIV Drug Therapy Glasgow Congress, 2-6 November 2014. Oral abstract 0422. Journal of the International AIDS Society 2014, 17(Suppl 3):19524
   http://www.jiasociety.org/index.php/jias/article/view/19524/html
   http://aps.mediasite.com/mediasite/Play/7734fa38a31343a782af56e52278bc7f1d?usehtml5=true
3. ENCORE1 Study Group. 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. The Lancet, 26 April 2014;383 (9927):1474 – 1482.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62187-X/abstract?rss%3Dyes