Effect of Dolutegravir on Etonogestrel Levels in HIV-infected Women in Botswana

The Effect of Dolutegravir-based ART on Plasma Etonogestrel Levels in HIV-infected Women Using Contraceptive Implants in Botswana

The primary aim is to assess if etonogestrel (ENG) implant users taking dolutegravir (DTG) have a 20% or greater change in their ENG plasma levels, compared to women taking no antiretroviral therapy (ART). A secondary aim is to assess whether ENG implant users taking dolutegravir have significantly higher ENG plasma levels than ENG implant users taking efavirenz.

This is a cross-sectional, non-randomized evaluation to compare ENG levels between 3 and 12 months post-implant insertion in three groups of women: 1) women using DTG-based ART (n=90), 2) women using EFV-based ART (n=90), and 3) women using no ART (not HIV infected) (n=90). This study will be conducted in Botswana in Southern Africa among women using the ENG implant, and involves a one-time collection of blood and questionnaire.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Contraceptive Usage; Drug Interaction
• Intervention / Treatment: Drug: dolutegravir; Device: ENG implant; Drug: Efavirenz

Detailed Description

Efavirenz-based antiretroviral therapy is effective in treating HIV and had become standard in the World Health Organization (WHO) guidelines. However, despite its effectiveness in lowering viral load, there is also solid evidence that it decreases the effectiveness of etonogestrel-releasing implants. This presents a difficult clinical scenario in countries where the HIV burden is significant in reproductive age women.

Following the SINGLE trial, dolutegravir has replaced efavirenz in many settings as first-line ART. In 2016, Botswana became the first country in Africa to adopt this as a guideline, however, the effect that dolutegravir has on hormonal contraceptives has not been widely studied. This project seeks to understand the interaction between etonogestrel levels in HIV-infected women who are using dolutegravir-based ART by directly measuring etonogestrel blood levels using liquid chromatography-mass spectrometry in HIV-negative and HIV-infected women using contraceptive implants.

Because the implant is fairly new in Botswana, most participants will have had implants inserted 3-12 months prior to study. An HIV-infected, non-ART, comparison group is no longer permissible, practically or ethically, as countries across Africa, including Botswana, are moving to HIV "Test and Treat." This means that ART initiation is now occurring at time of HIV-diagnosis regardless of cluster of differentiation 4 (CD4) count or disease stage; therefore, in this study, the comparison group will be HIV-uninfected implant users. This comparison will answer the key question of whether the ENG implant when used simultaneously with DTG provides plasma ENG levels comparable to a group in which it has established contraceptive efficacy (i.e. HIV-uninfected, healthy women of reproductive age).

• Study Type: Observational
• Enrollment (Actual): 148

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Botswana-UPenn Partnership

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Reproductive-aged HIV-infected women using dolutegravir and using single-rod, etonogestrel-releasing subdermal implant.

Reproductive-aged HIV-infected women using efavirenz and using single-rod, etonogestrel-releasing subdermal implant.

Reproductive-aged HIV-unifected women using single-rod, etonogestrel-releasing subdermal implant.

Description

Inclusion Criteria:

• Etonogestrel implant as their sole method of hormonal contraception
• Etonogestrel implant in-situ for three to twelve months.
• Dolutegravir (DTG) use for at least 60 days (Using DTG-based ART-regimen if applicable)
• Efavirenz (EFV) use for at least 60 days (Using EFV-based ART-regimen if applicable)

Exclusion Criteria:

• Exclude women using concomitant enzyme-inducing drugs, including rifampicin for tuberculosis treatment and anti-convulsant medications (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine)

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DTG group; Reproductive-aged HIV-infected women taking dolutegravir-based ART and using single-rod, etonogestrel-releasing, subdermal implant (ENG implant)	Drug: dolutegravir; HIV integrase strand transfer inhibitor used in combination ART; Other Names: DTG; Tivicay; Device: ENG implant; Reversible contraception implant; Other Names: Nexplanon ®; Implanon NXT ®; single-rod, etonogestrel-releasing, subdermal implant
No ART group; Reproductive-aged HIV-uninfected women using single-rod, etonogestrel-releasing, subdermal implant (ENG implant)	Device: ENG implant; Reversible contraception implant; Other Names: Nexplanon ®; Implanon NXT ®; single-rod, etonogestrel-releasing, subdermal implant
EFV group; Reproductive-aged HIV-infected women taking efavirenz-based ART and using single-rod, etonogestrel-releasing, subdermal implant (ENG implant)	Device: ENG implant; Reversible contraception implant; Other Names: Nexplanon ®; Implanon NXT ®; single-rod, etonogestrel-releasing, subdermal implant; Drug: Efavirenz; non-nucleoside reverse transcriptase inhibitor used in combination ART; Other Names: Sustiva; EFV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference (percentage) in ENG plasma levels in the DTG group compared to no ART group	Difference between the DTG group and no ART group	Up to 12 months after implant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference (percentage) in ENG plasma levels in the DTG group compared to EFV group	Difference between the DTG group and EFV group	Up to 12 months after implant

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Carolyn L Westhoff, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2017
• Primary Completion (Actual): October 30, 2019
• Study Completion (Actual): December 11, 2019

Study Registration Dates

• First Submitted: November 6, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: February 4, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Efavirenz; Dolutegravir; Etonogestrel; DTG
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz; Dolutegravir; Etonogestrel
• Other Study ID Numbers: AAAQ8556

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No