Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV

Abstract

Purpose

The updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women.

Methods

Ghanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared.

Findings

Of 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The C_max, C_min, AUC_0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV C_max, C_min, AUC_0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission.

Implications

We found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Introduction

Effective antiretroviral therapy (ART) during pregnancy is essential for maternal health and prevention of maternal-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Current World Health Organization (WHO) HIV treatment guidelines recommend a dolutegravir-containing regimen as the preferred first-line ART for adults and adolescents living with HIV,¹ with efavirenz (EFV) 400 mg as alternate first-line ART regimen and the standard 600 mg EFV dose to be used only in special circumstances.¹ Although the Safety and Efficacy of Reduced Versus Standard Dose Efavirenz Plus Two Nucleotides in Antiretroviral-Naïve Adults (ENCORE1) double-blind, placebo-controlled trial found that EFV 400 mg was virologically noninferior to the standard dose of EFV 600 mg during 96 weeks of follow-up,² pregnant women were not included in the trial. Altered physiologic changes during pregnancy, such as increases in total body water and fat stores, reduction in plasma albumin, and enhanced activities of drug metabolizing enzyme transporters, may lead to reduction in drug concentrations and suboptimal clinical effects.^3,4 In addition, EFV is metabolized primarily by hepatic CYP2B6 enzyme,⁵ and genetic polymorphisms of CYP2B6 (with varying frequency in different populations) are associated with wide interindividual variability in EFV exposure and clearance.⁶

It is currently not clear whether EFV 400 mg or 600 mg should be preferred in pregnant women. Although pharmacokinetic (PK) studies in the absence of clinical trial data may be helpful in clinical decision making, there are limited published PK studies in pregnant women from diverse populations. Among Thai women treated with EFV 600 mg once daily, an intensive PK study found that the median EFV AUC_0–24h did not differ during the third trimester of pregnancy and post partum, but median EFV concentration at 24 h after dosing (C_24h) was lower during pregnancy.⁷ Among women enrolled in a prevention of MTCT program in Nigeria treated with EFV 600 mg daily, EFV clearance was significantly increased and AUC_0–24h and C_min were reduced in pregnant women compared with postpartum controls with the CYPB26 extensive metabolizer genotype.⁸ In a study that enrolled 42 pregnant women from Europe, the United States, South America, and Africa on EFV 600 mg/day, EFV AUC_0–24h during the second and third trimesters of pregnancy was similar to that during early post partum.⁹ Although EFV C_24h was lower during the second and third trimesters of pregnancy compared with postpartum,⁹ the authors reported that EFV C_24h in pregnancy in their study was similar to the EFV C_24h in nonpregnant adults treated with EFV 400 mg/d that was found to be effective in the ENCORE1 trial.¹⁰ In the only published PK study of EFV 400 mg during pregnancy that enrolled women who were virologically suppressed with EFV 600 mg once daily, the median EFV C_24h was a median of 23% lower during the third trimester of pregnancy compared with the postpartum period, but the HIV viral load remained suppressed and no MTCT was observed.¹¹ However, there is no evidence that EFV 400 mg once daily used as initial therapy in ART-naive pregnant women would have achieved similar viral suppression.

Because EFV PK data in pregnant women are currently limited and dose reduction could pose a risk of ineffective ART for pregnant mothers and the developing child, additional evidence of adequacy of standard or reduced dose in different populations is essential. To date, no studies have evaluated EFV PK properties in Ghanaian pregnant or postpartum women. In addition, among 65 Ghanaian HIV-infected adults treated with EFV 600 mg/day, 30% had the CYP2B6 extensive metabolizer genotype, with a higher risk of low EFV mid-dose concentrations, and 19% were slow metabolizers.¹² Thus, the primary objective of our study was to determine and compare EFV PK properties during pregnancy and post partum in Ghanaian women living with HIV treated with EFV 600 mg once daily. At the time of our study between 2014 and 2016, the WHO guidelines recommended a simplified once-daily fixed-dose combination tablet of tenofovir disoproxil 300 mg/lamivudine 300 mg/EFV 600 mg for pregnant women for the prevention of MTCT.¹³ At the time, EFV 600 mg/day was the preferred dose, and EFV 400 mg/day was not yet introduced.¹³