Evaluation of Pharmacokinetic Drug-drug Interactions Between Hormonal Contraceptives and Doravirine-containing ART Among Women Living With HIV in South Africa

NCT04669678 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: STUDY00011487MISP 59559
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

The study investigators are conducting an observational, parallel group pharmacokinetic (PK) study among women living with HIV (WLHIV) already on 1st line antiretroviral therapy (ART) and virally suppressed, 18-45 years old (inclusive), to evaluate any bidirectional drug-drug interactions (DDIs) between doravirine (DOR)-containing ART and hormonal contraceptive methods. This PK study will enroll women in five distinct groups, each with 21 participants (total of 105 participants), and follow them for approximately 18-30 weeks.

Conditions

HIV Infections; Contraception; Drug-drug Interaction

Outcome Measures

Primary Outcomes (2)

• Hormonal Contraceptive Concentrations

  Mean hormone concentrations

  at 2,4,8,12 weeks for IM DMPA and SC MPA or 2,4,8,12,20,24 weeks for ETG implants and IUD groups after contraceptive method initiation

• DOR Concentrations

  Mean DOR concentration at 24 hours (C24 hours)

  at 2,4,8,12 weeks for IM and SC DMPA or 2,4,8,12,20,24 weeks for ETG implants and IUD groups after contraceptive method initiation

Secondary Outcomes (1)

• Number of Participants With HIV Viral Suppression (i.e. ART Efficacy)

  at 12-24 weeks after contraceptive initiation

Study Arms (5)

Group 1 DOR + ETG

EXPERIMENTAL

100mg DOR-containing ART \[oral tablet taken daily\] + 68mg ETG implant (follow up for 30 weeks)

Drug: Etonogestrel (ETG) implant

Group 2 DOR + IM DMPA

EXPERIMENTAL

100mg DOR-containing ART \[oral tablet taken daily\] + 150mg IM DMPA (follow up for 18 weeks)

Drug: Intramuscular depo-medroxyprogesterone acetate (IM DMPA)

Group 3 DOR + SC MPA

EXPERIMENTAL

100mg DOR-containing ART \[oral tablet taken daily\] + 104mg SC MPA (follow up for 18 weeks)

Drug: Sub-cutaneous medroxyprogesterone acetate (SC MPA)

Group 4 DOR + IUD

EXPERIMENTAL

100mg DOR-containing ART \[oral tablet taken daily\] + 1 non-hormonal IUD device (follow up for 30 weeks)

Device: Non-hormonal intrauterine device (IUD)

Group 5 DTG + DMPA

ACTIVE COMPARATOR

50mg DTG-containing ART \[oral tablet taken daily\] + 150mg IM DMPA DMPA administered at enrolment (follow up for 18 weeks)

Drug: Intramuscular depo-medroxyprogesterone acetate (IM DMPA)

Interventions

Etonogestrel (ETG) implant DRUG

Contraceptive progestin implants are thin rods inserted under the skin of a woman's arm. The most widely available implant in South Africa is currently Implanon®/Nexplanon®/Implanon NXT®, containing etonogestrel (ETG, 3-keto desogestrel). Implanon® consists of a single rod of ethylene vinyl acetate and contains 68 mg of ETG; it is manufactured by Merck and is approved for 3 years.

Group 1 DOR + ETG

Intramuscular depo-medroxyprogesterone acetate (IM DMPA) DRUG

DMPA (150 mg of depo-medroxyprogesterone acetate (MPA)/ml IMI) is the most commonly used injectable contraceptive worldwide, and the most commonly used method of reversible injectable contraception in sub-Saharan Africa.

Group 2 DOR + IM DMPA; Group 5 DTG + DMPA

Sub-cutaneous medroxyprogesterone acetate (SC MPA) DRUG

SC MPA or Sayana® Press is a single-dose container with 104 mg medroxyprogesterone acetate (MPA) in 0.65 mL suspension for injection. Sayana® Press is indicated for medium-long term female contraception.

Group 3 DOR + SC MPA

Non-hormonal intrauterine device (IUD) DEVICE

The NOVA T-380 non-hormonal IUD consists of a T-shaped polyethylene frame wound with copper wire, along with two monofilament threads to aid in removal of the IUD. IUDs may be left in place for up to 5 years.

Group 4 DOR + IUD

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• HIV-positive
• Currently on 1st line ART (namely EFV- or DTG-containing ART),
• Have documented or confirmed viral suppression for HIV (defined as \<40 copies/mL) within 3 months prior to study screening and after the start of the current ART regimen
• Contraception use:
• a) Not currently on reliable contraception and intending to or willing to initiate use of study hormonal/non-hormonal contraceptive methods 6 weeks after DOR lead in period (and willing to continue use for subsequent 12 to 24 weeks),
• Able and willing to comply with all study procedural requirements,
• Able and willing to provide informed consent for study participation in either English or Zulu,
• Able and willing to provide adequate locator information, as defined in site SOPs,
• Negative pregnancy test at Screening and Enrollment, and
• At Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal products, or vaccines for the duration of study participation.

You may not qualify if:

• Currently on 2nd line, 3rd line, or salvage ART regimens,
• Currently pregnant or intending to become pregnant within the next 6 months,
• Currently breastfeeding or intending to breastfeed within the next 6 months,
• Use or anticipated use of drugs for the duration of the study period known to interact with hormonal implants, DMPA/MPA, or the respective ART regimen
• Current or planned concomitant use of other hormonal contraceptives,
• Currently obese (BMI≥30),
• Has any of the following laboratory abnormalities at Screening Visit:
• Haemoglobin abnormality Grade 2 or higher
• Calculated creatinine clearance less than 50 mL/min by the Schwartz Equation
• Per participant report at Screening and Enrollment, intends to do any of the following during her study participation period:
• relocate away from the study site
• travel away from the study site for a time period that would interfere with product resupply and study participation
• Per participant report and/or clinical evidence of any of the following:
• Known adverse reaction to any of the study products (ever),
• Participation in any other research study involving drugs, medical devices or vaccines within 60 days of enrollment,

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Merck Sharp & Dohme LLC: collaborator
• Wits Reproductive Health and HIV Institute: collaborator
• University of Washington: collaborator

Study Sites (1)

Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site

Johannesburg, 2001, South Africa

Location

Related Publications (3)

• Patel RC, Stalter R, Onono M, et al. Dolutegravir-containing ART does not reduce etonogestrel implant concentrations. Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Virtual (Boston).

  BACKGROUND

• Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, Kaplan R, Lupinacci L, Rodgers A, Xu X, Lin G, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C, Martin EA; DRIVE-AHEAD Study Group. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clin Infect Dis. 2019 Feb 1;68(4):535-544. doi: 10.1093/cid/ciy540.

  PMID: 30184165 BACKGROUND

• Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Xu X, Rodgers A, Lupinacci L, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C; DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018 May;5(5):e211-e220. doi: 10.1016/S2352-3018(18)30021-3. Epub 2018 Mar 25.

  PMID: 29592840 BACKGROUND

MeSH Terms

Conditions

HIV Infections

Interventions

etonogestrel

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

First, that not all participants adhered to their ART optimally limits exposure-outcome relationship ascertainments. Second, our timings of blood collection for doravirine analyses were suboptimal, resembling "random" time sampling; assuming this sampling is non-differential between the groups, our estimates will be biased towards the null. Third, the doravirine + etonogestrel implant group for hormone concentrations' outcome is compared to a historical group from a similar study but in Kenya.

Results Point of Contact

• Title: Rena C Patel
• Organization: University of Alabama at Birmingham

renapatel@uabmc.edu

2059348145

Study Officials

• Anna Wald, MD, MPH

  University of Washington

  STUDY CHAIR

• Thesla Palanee-Phillips, MMed Sci PhD

  Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Different groups receive different interventions at same time during study.

Study Record Dates

• First Submitted: November 25, 2020
• First Posted: December 17, 2020
• Study Start: November 17, 2021
• Primary Completion: February 5, 2024
• Study Completion: February 5, 2024
• Last Updated: April 8, 2025
• Results First Posted: April 8, 2025

Record last verified: 2025-03

Locations

ZA (1)