Unintended pregnancies among HIV-positive women have significant consequences for maternal morbidity and vertical transmission of HIV, and contraception prevents unintended pregnancies among the millions of HIV- positive women worldwide. Contraceptive implants are the most effective form of contraception available to HIV- positive in resource-limited settings. Implants, however, when combined with certain antiretroviral therapy (ART) regimens have reduced effectiveness leading to unintended pregnancies. Clinical and pharmacokinetic (PK) data now demonstrate drug-drug interactions between implants and efavirenz dosed at 600mg (EFV600) reducing implant effectiveness. The latest World Health Organization ART guidelines recommend the use of lower dose efavirenz at 400mg (EFV400) and dolutegravir in first line ART globally. Whether the same drug- drug interactions affect implant effectiveness with these newer ART regimens is unknown. Thus, critical gaps exist in current international and national HIV treatment and contraception guidelines regarding the concomitant use of ART and hormonal contraception. This project will close this important knowledge gap by prospectively assessing the PK and pharmacodynamics (PD) effects of EFV400 and dolutegravir on the plasma implant progestins (etonogestrel or levonorgestrel) and endogenous progesterone (a marker of ovulation suppression) concentrations. This proposal leverages an on- going PK study in Kenya evaluating implant progestin concentrations in women using EFV600. A total of 100 women on the different ART/implant combinations will undergo repeated plasma sampling up to 24 weeks after implant placement. Specifically, this project will determine if the PK/PD effects of EFV400 on implant progestin concentrations and proportion of women ovulating differ from those of EFV600 (Aim 1a) and of dolutegravir from EFV600 (Aim 1b). This project will also explore if pharmacogenetics (PG) polymorphisms in CYP450 enzymes known to affect progestin and ART metabolism will influence systemic concentrations of these hormones and ART regimens (Aim 2). This proposal directly addresses emerging concerns that different ART regimens could substantively and differentially impact contraceptive efficacy, and it explores this potential risk when these new regimens are just becoming available. It builds on the existing PK data in this field and expands it with PD and PG information. If our study demonstrates lack of improvement in progestin concentrations with EFV400 from EFV 600 and no effect on progestin concentrations with dolutegravir, these findings would support shifting ART guidelines to recommend dolutegravir-based ART as first-line ART?instead of alternative first-line?for women of reproductive age.

Public Health Relevance

Unwanted pregnancies among HIV-positive women should be avoided for the woman?s health and to prevent HIV transmission to her babies. Contraception, especially implants, can effectively prevent pregnancies but their effectiveness may be reduced when used together with medications that treat HIV. Therefore, testing the implant effectiveness when used in combination with the most commonly used HIV medications is important to help inform HIV-positive women what their best options are for HIV treatment and prevention of unwanted pregnancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI136645-02
Application #
9617223
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Turpin, Jim A
Project Start
2017-12-21
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195