Pharmacologic Strategies to Use the Levonorgestrel Implant in HIV-infected Women

A Pharmacokinetic Evaluation of Increased Dose Levonorgestrel Implant and Efavirenz-Based Antiretroviral Therapy In HIV-Infected Ugandan Women

The purpose of this study is to determine whether increasing the dose of the levonorgestrel subdermal contraceptive implant will overcome a detrimental drug-drug interaction with efavirenz based antiretroviral therapy.

Study Overview

• Status: Completed
• Conditions: HIV; Contraception
• Intervention / Treatment: Drug: Levonorgestrel; Drug: Efavirenz

Detailed Description

The investigators research team recently demonstrated that combined use of efavirenz (EFV) based antiretroviral therapy (ART), the only preferred first-line ART regimen in low and middle income countries, with a levonorgestrel (LNG)-releasing implant for one year reduced LNG plasma concentrations by approximately 50% compared to women not on ART. Importantly, the investigators also observed three unintended pregnancies (15%) in the investigators study group of women on EFV-based ART plus the LNG implant, in contrast to the <1% expected failure rate of the implant for women without drug interactions.

This study will determine if increasing the dose of the LNG-releasing subdermal implant effectively overcomes the known pharmacokinetic interaction with EFV- based ART. LNG pharmacokinetic results from the participants enrolled in this dose escalation study (n=28) will be compared to HIV-infected Ugandan women on standard dose LNG without concomitant EFV-based ART.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Women age 18 years to 45 years
4. Diagnosed with HIV infection
5. Desiring LNG subdermal implant as a contraceptive method
6. Receiving EFV-based ART for a minimum of 3 months prior to screening
7. Must agree to have concurrent highly effective non-hormonal contraception with a copper intrauterine device (IUD), if not previously medically sterilized.
8. Participants must have a negative urine pregnancy test at entry and report no unprotected sex since the last menstrual period or in the last two weeks.

Exclusion Criteria:

1. HIV RNA > 50 copies/mL at screening visit
2. Serum hemoglobin < 10.0 g/dl
3. Elevations in serum levels of alanine transaminase (ALT) above 5 times the upper limit of normal
4. Elevations in serum creatinine above 2.5 times the upper limit of normal
5. Use of drugs known to be contraindicated with LNG or EFV within 30 days of study entry. Due to the dynamic nature of drug interactions related to ART, the study team will review all concomitant medications at screening based on the US Department of Health and Human Services drug interaction table.
6. Currently pregnant or postpartum <30 days at study entry
7. Concurrent use of other hormonal contraception (Note: use of other forms of hormonal contraception is permissible until time of study enrollment/insertion of LNG implant. Transition from other forms of hormonal contraception to LNG subdermal implant will be accommodated according to LNG product labeling)
8. For the EFV group, participants determined to be ineligible for IUD placement by the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use
9. If participation in the study puts the participant at unacceptable risk based on the judgment of the study staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Efavirenz group; HIV-infected women receiving efavirenz-based antiretroviral therapy plus increased dose levonorgestrel subdermal implants.	Drug: Levonorgestrel; Increased dose levonorgestrel implant plus efavirenz-based antiretroviral therapy.; Other Names: Jadelle; SinoImplant; Drug: Efavirenz; Participants will receive efavirenz-based ART as part of standard of care; Other Names: Sustiva; Atripla; Stocrin; EFV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levonorgestrel plasma concentrations	We will compare levonorgestrel plasma concentrations between the participants who are receiving increased dose levonorgestrel implants plus efavirenz to historical control participants of HIV-infected Ugandan women not receiving efavirenz.	24-weeks after implant placement

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levonorgestrel plasma concentrations	We will compare levonorgestrel plasma concentrations between the participants who are receiving increased dose levonorgestrel implants plus efavirenz to historical control participants of HIV-infected Ugandan women not receiving efavirenz.	48 weeks after implant placement
Levonorgestrel plasma concentrations	This arm will only be continued if safety measures are met at weeks 24 and 48.	Years 2-3 after implant placement
Number of adverse events reported by the participant or provider during the study period	Adverse events reported by participants	48 weeks after implant placement

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in levonorgestrel concentrations between patients based on pharmacogenetic polymorphisms	Levonorgestrel PK described by pharmacogenetic polymorphisms	48 weeks after implant placement
Influence of patient weight (in kg) on levonorgestrel concentrations	Levonorgestrel PK described by weight	48 weeks after implant placement
Participant satisfaction with the contraceptive implant reported as a likert scale based on a patient questionnaire	Patient reported satisfaction with contraceptive method	48 weeks after implant placement

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Liverpool; Northwestern University Feinberg School of Medicine; Infectious Diseases Institute, Uganda
• Investigators: Principal Investigator: Kimberly K Scarsi, PharmD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2017
• Primary Completion (Actual): December 5, 2019
• Study Completion (Actual): March 30, 2020

Study Registration Dates

• First Submitted: March 2, 2016
• First Submitted That Met QC Criteria: March 23, 2016
• First Posted (Estimated): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: efavirenz; contraceptive implant; levonorgestrel
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Cytochrome P-450 CYP3A Inducers; Contraceptives, Oral, Synthetic; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Levonorgestrel; Efavirenz
• Other Study ID Numbers: 0234-16-FB; 1R01HD085887-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No