Polly Clayden, HIV i-Base
Results from a pharmacokinetic (PK) study of 400 mg efavirenz (EFV400) during pregnancy, showed lower drug concentrations in the third trimester, compared with post-partum, but these were within adequate ranges described elsewhere. The findings were presented as a late breaker poster at IAS 2017. 
WHO guidelines recommend EFV400 as alternative first-line drug, with a disclaimer that no data exist on its use at this dose during the third trimester of pregnancy.
This study investigated the PK, efficacy and CYP2B6 pharmacogenetics of EFV400 in HIV positive women during third trimester (TT) and post-partum (PP). The aim was to provide data to support the removal of the WHO disclaimer to allow wider EFV400 first-line use.
It was an open-label, multicentre study conducted in UK and Uganda in women receiving tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and EFV 600 mg with an undetectable viral load (<50 cells/mm3), who switched to TDF/FTC/EFV400.
The investigators evaluated weekly therapeutic drug monitoring (TDM) 10–14 hours post dose, steady-state PK profiles during TT and PP, safety, virologic efficacy and polymorphisms in CYP2B6 (516C>T and 938T>C).
The primary endpoint was the comparison of EFV Ctrough TT vs PP using geometric mean ratios (GMR). A sample size of 25 provided at least 80% power to detect a 20% decrease in Ctrough during TT vs PP.
The study enrolled 25 women of African origin: baseline median age and CD4 were 29 years (range 18 to 41) and 561 cells/mm3 (range 152 to 882), respectively. All women had baseline viral load <50 copies/mL at enrolment and remained undetectable throughout the study (there were only two viral load blips, both confirmed <50 copies/mL, when repeated).
All of the infants were HIV uninfected. No women were excluded because of low EFV400 TDM results (<800 ng/mL in >3 consecutive visits).
GMR (TT/PP) of EFV400 Cmax, AUC, and C24trough were: 0.93 (90% CI 0.80 to 1.08), 0.84 (90% CI 0.72 to 0.99), 0.73 (90% CI 0.60 to 0.89).
Of 25 women, 23 were carriers of the CYP2B6 516G allele and only two were slow metabolisers.
EFV400 was well tolerated in pregnancy with no grade 3 or 4 laboratory abnormalities.
Cmax, AUC, and Ctrough in TT were 7%, 27% and 26% lower compared with PP but within ranges previously reported for EFV600 during TT and those measured in ARV-naive patients receiving EFV400 in ENCORE1. [2, 3]
All participants maintained a viral load <50 copies/mL, suggesting that EFV400 can be used in pregnant HIV positive women.
Like dolutegravir, EFV400 is an alternative option in 2016 WHO guidelines.
Evidence for efficacy in pregnancy at the lower dose (as described above) and with TB co-treatment (for which a PK study is ongoing) are needed for an unrestricted WHO recommendation.
- Boffito M et al. Pharmacokinetics, pharmacodynamics and pharmacogenomics of efavirenz 400mg once-daily during pregnancy and postpartum. IAS 2017. 23–26 July 2017. Paris. Poster abstract TUPDB0203LB.
- Schalkwijk S et al. Pharmacokinetics of efavirenz 600 mg QD during pregnancy and postpartum. CROI 2016. 22–25 February. Boston. Poster abstract 433.
- Puls R et al. 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. Lancet. 2014 Apr 26;383(9927):1474-82.