Adequate cerebrospinal fluid exposure of efavirenz when dosed at 400 mg
Polly Clayden, HIV i-Base
Although 400 mg efavirenz (EFV) is gives cerebrospinal fluid exposure (CSF) exposure of EFV above that required for HIV suppression, exposure of metabolites might still be within the concentration range associated with toxicities – according to findings from the ENCORE1 trial.
ENCORE1 demonstrated that 400 mg of EFV once daily is non-inferior to the standard 600 mg dose. 
ENCORE1 participants, at five participating sites in London, Berlin, Bangkok and Khon Kaen, were eligible to enter a CSF substudy. The aim was to look at CSF exposure, as a surrogate for CNS exposure, of EFV and its major metabolites after at least 12 weeks of receiving the EFV and compare the two doses.
The results were published in Clinical Infectious Diseases, 25 December 2014, authored by Alan Winston and colleagues from the ENCORE1 CSF Substudy Team.
Between 12 and 24 weeks of starting ART in ENCORE1, the participants underwent CSF examination at least 8 hours after dosing. Cerebral imaging and assessments of blood clotting were performed as part of clinical practice before a lumbar puncture examination. The investigators made the following analyses on CSF samples: total protein; assessment of EFV; 8OH-EFV, and 7OH-EFV; and CSF HIV RNA level. Immediately before the CSF examination, blood sampling was done in order to assess plasma EFV, 8OH-EFV and 7OH-EFV concentrations.
Baseline characteristics were similar in the 400mg and 600 mg groups. CSF examination was successful in 28 participants (14 in each dosing group).
The investigators reported that mean CSF protein was 0.40 g/dL (range 0.24 – 1.02 g/dL). Plasma HIV viral load was undetectable in all participants: <5 copies/mL in all but one participant who had <10 copies/mL. CSF viral load was also undetectable in all with corresponding values.
Geometric mean (GM) CSF EFV, 7OH-EFV and 8OH-EFV concentrations for the 400 mg and 600 mg dosing groups were respectively: 16.5 (90% CI 13 – 21) and 19.5 (90% CI 15 – 25) ng/mL; 0.6 (90% CI 0.4 – 0.9) and (90% CI 0.4 – 1.0) ng/mL; 5.1 (90% CI 4.0 – 6.4) and 3.1 (90% 2.1 – 4.4) ng/mL.
CSF EFV concentration in all participants was greater than the proposed 50% maximal inhibitory concentration for wild type virus of >0.51 ng/mL. 80H-EFV concentration in CSF was greater than a proposed toxicity threshold of >3.3 ng/mL in 11/14 and 7/14 participants in the 400 mg and 600 mg groups respectively.
CSF concentration was significantly associated with plasma concentration, p<0.001, and cytochrome P450 2B6 genotype. CSF EFV GG to GT/TT geometric mean ratio (GMR), 0.56 (90% CI 0.42 – 0.74). CSF 8OH EFV concentration was not, p=0.242. GG/GT GMR, 1.52 (90% CI 0.97 – 2.36).
The authors also provided a detailed discussion on EFV CNS toxicities in the article. The substudy included an exploratory analysis of associations between CSF 80H EFV exposure and Depression Anxiety Stress Scales, an EFV symptom questionnaire (ESQ) and functional health status at 48 weeks.
There were associations between CSF 8OH EFV exposure and patient reported toxicities frequently associated with EFV: ESQ at 48 weeks, Spearman Correlation Coefficient 0.13, p=0.5. But the authors noted that these findings are limited by the post hoc nature of the analysis, the small number of participants and the predominately male Asian and white people enrolled.
They suggested that the pharmacogenomic observations in the substudy might provide plausible explanations for some of their pharmacokinetic findings. Higher CSF EFV exposure was seen in participants with GT or TT genotypes in CYP2B6, so for those with slower EFV metabolism genotype, plasma exposure is higher compared to those with faster – as expected CSF is also higher. But, such a signal was not observed for CSF 8OH EFV exposure, where CSF concentrations were similar between genotypes.
They postulated that pharmacokinetic processes involved in CSF 8OH EFV exposure might be subject to a saturation effect by which exposure to the metabolite is not dependent on plasma EFV exposure or CYP2B6 genotype. Instead, they suggest, this could be is a spillover from plasma 8OH EFV or local CNS production of 8OH EFV where this metabolite becomes “trapped” within the CNS compartment.
The authors also discussed EFV autoinduction – but did not conclude that a differing effect on autoinduction is a plausible explanation for their findings. An upregulation in efflux transporters that was dependent on EFV dose and affected the removal of 8OH EFV from the CNS might be another theoretical explanation for their findings, they suggested.
In conclusion, they write that in the main ENCORE1 study, there were no differences in the number of participants reporting adverse events, but more EFV-related ones were observed in the 600 mg than the 400 mg group. The authors believe that their substudy provides one plausible explanation for these findings.
Although EFV 400 mg was non-inferior to 600 mg, the reduction in EFV-associated adverse events was modest and the authors above suggest this possible explanation.
Last year, three leading HIV doctors suggested that the dominant role of EFV in first line therapy should be reconsidered.  They noted that “this should not only happen in high-income countries but ideally also in low-income settings, if alternative drugs are available, and this recommendation should be reflected in the treatment guidelines of the WHO and both governmental and non-governmental organisations”.
It is good to see that we finally have guidance for dolutegravir use in the UK. As experience with this drug grows and the price decreases, there will be increasing interest in using dolutegravir in both high and low-income countries as a more tolerable alternative to EFV.
For low-income countries, EFV is likely to remain the preferred first-line treatment for a while. WHO adoption of the 400 mg dose has been subject to considerable discussion, particularly concerning the robustness of the lower dose for people taking TB treatment and for women in the third trimester of pregnancy.
PK studies to look at efavirenz drug levels in these situations are still not underway.
- 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; 383:1474-82.
- Winston A et al. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomised controlled trial. Clin Infect Dis. Advance access (2014), doi: 10.1093/cid/ciu976, First published online: 11 December 2014.
- Raffi F et al. Has the time come to abandon efavirenz for first-line antiretroviral therapy? Journal of Antimicrobial Chemotherapy. 2014; 69: 1742–1747.