The purpose of this pharmacokinetic (PK) study was to evaluate if a double dose (3 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.

This pharmacokinetic (PK) study evaluated if a double dose (3.0 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.

Participants were volunteers who did not require emergency contraception (EC) for contraception at the time of trial participation. This trial enrolled persons assigned female sex at birth who were 16 years of age or older. Group assignment was determined by disease status (HIV or TB; participants could not have been living with both HIV and TB), and, for those with HIV, by ART regimen at enrollment. Participants with HIV who were taking EFV-based ART were randomized to receive a standard dose LNG (Group A) or a double dose of LNG (Group B). Participants taking dolutegravir (DTG)-based ART were assigned to a standard dose of LNG (Group C). Participants in the continuation phase of active TB treatment taking RIF and isoniazid (INH) with or without ethambutol were assigned to a double dose of LNG (Group D).

At study entry, participants in Groups A and C received a standard single dose of LNG. Participants in Groups B and D received a double dose of LNG. Intensive PK monitoring was conducted pre-dose, and after the LNG dose. Participants were expected to remain at the clinical site while the initial 8 hour PK samples were collected, and to return to the clinical site for the 24 and 48 hour samples.

All participants completed self-report questionnaires to assess adherence to TB therapy and ART, menstrual history and patterns after LNG administration, and to collect adverse effects commonly reported with LNG (i.e., irregular bleeding patterns). Adherence to ART and RIF was also assessed by collecting hair samples and single plasma concentrations at entry. Participants were followed for 4 weeks.

Inclusion Criteria:

• Postmenarcheal female.

  • Note: Participant report and clinician's opinion were acceptable.

• The following laboratory values obtained within 30 days prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any ACTG network-approved non-US laboratory that operated in accordance with Good Clinical Laboratory Practices (GCLP) and participated in appropriate external quality assurance (EQA) programs.

  • Absolute neutrophil count (ANC) greater than or equal to 500 cells/mm^3
  • Platelet count greater than or equal to 50,000 platelets/mm^3
  • Hemoglobin greater than or equal to 8.0 g/dL
  • Aspartate transaminase (AST) less than 5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) less than 5 x ULN
  • Creatinine less than or equal to 1.5 x ULN
  • Total bilirubin less than or equal to 2.0 x ULN

• Negative serum or urine pregnancy test within 30 days prior to study entry and within 48 hours prior to entry (if screening occurred more than 48 hours prior to entry) by any US clinic or US laboratory that had a CLIA certification or its equivalent, or used a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or non-US clinic that operated in accordance with GCLP and participated in appropriate EQA programs. The serum or urine pregnancy test must have had a sensitivity of at least 25 mIU/mL.

• Had not had sex that could lead to pregnancy without contraception within 14 days prior to study entry as defined in the criteria below, according to participant self-report.

• Contraception requirements

  • All participants agreed not to participate in a conception process (e.g., active attempt to become pregnant or in vitro fertilization) for the duration of the study. Women of reproductive potential, who were participating in sexual activity that could lead to pregnancy, agreed to use at least one reliable method of contraception while in the study. Acceptable forms of contraceptives included:

    • Male condom with or without a spermicidal agent
    • Diaphragm or cervical cap with spermicide
    • Non-hormonal intrauterine device (IUD)
    • Bilateral tubal ligation
    • Male partner vasectomy

• Ability and willingness of participant or legal guardian/representative to have provided informed consent.

• Body mass index (BMI) (kg/m^2) available at entry. See the study protocol for BMI calculation instructions.

  • Note: A maximum of 5 participants with BMI greater than or equal to 30 kg/m^2 were allowed in each arm B-D and a maximum of 3 participants in Arm A.

• For participants with HIV: HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

  • Note: The term "licensed" referred to a US Food and Drug Administration (FDA)-approved kit, which was required for all investigational new drug (IND) studies, or for sites located in countries other than the United States, a kit that had been certified or licensed by an oversight body within that country and validated internally. Non-US sites were encouraged to use US FDA-approved methods for IND studies.
  • World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandated that confirmation of the initial test result must have used a test that was different from the one used for the initial assessment. A reactive initial rapid test was confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

• For participants with HIV: Received a stable qualifying concomitant ART regimen containing either once-daily DTG 50 mg or EFV 600 mg with no changes in the components of their ART for at least 30 days prior to study entry.

• For participants who were being treated for TB: HIV-negative at screening, documented within the prior 6 months by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load.

  • Note: The term "licensed" referred to a US FDA-approved kit, which was required for all IND studies, or for sites located in countries other than the United States, a kit that had been certified or licensed by an oversight body within that country and validated internally. Non-US sites were encouraged to use US FDA-approved methods for IND studies.
  • WHO and CDC guidelines mandated that confirmation of the initial test result must have used a test that was different from the one used for the initial assessment. A reactive initial rapid test was confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

• For participants who were living without HIV and being treated for TB: Received RIF and INH on a once daily dosing (7 days per week) schedule at study entry, after completion of the intensive phase of TB treatment.

  • Note: Inclusion of ethambutol as part of continuation phase of TB therapy was allowed.

• Ability and willingness of participant to have been contacted remotely for study visits.

Exclusion Criteria

• Known allergy/sensitivity or any hypersensitivity to LNG or components of the formulation.

• Bilateral oophorectomy, hysterectomy, or postmenopausal

  • Note: Postmenopausal was defined as amenorrhea for at least 12 consecutive months prior to study entry (in the absence of medications known to induce amenorrhea), and had a documented follicle stimulated hormone-release factor (FSH) measurement greater than 40 mIU/mL or a result in the testing laboratory's menopausal range. If an FSH level was not available, 24 consecutive months of amenorrhea prior to study entry (in the absence of medications known to induce amenorrhea).
  • Note: Clinical assessment and clinician's opinion were acceptable.

• Was currently pregnant, was within 6 weeks of delivery, or was currently breastfeeding an infant under 6 months of age.

  • Note: For recent pregnancy resolution during the first or second trimester, the participant was only eligible when the pregnancy test result was negative.

• Receipt of LNG within 30 days prior to study entry.

• Receipt of depo-medroxyprogesterone for 90 days prior to study entry, or norethisterone enanthate (NET-EN) within 60 days prior to study entry, or other hormonal contraceptives within 30 days prior to study entry.

• Used any drugs other than RIF and EFV known to: 1) induce CYP3A4 system within 30 days prior to study entry, and 2) inhibit the CYP3A4 system within 7 days prior to study entry. See the study protocol for prohibited and precautionary medications.

• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.

• Acute or serious illness that required systemic treatment and/or hospitalization within 14 days prior to study entry.

• Other medical, psychiatric, or psychological condition that, in the opinion of the site investigator, would have interfered with completion of study procedures and or adherence to study drug.

• For participants with HIV: Was currently receiving medications for TB infection.

• For participants with HIV: Had missed one or more of the prescribed doses of HIV medications within 3 days prior to study entry.

  • Note: The entry visit could have been rescheduled within the screening period once the participant had taken all prescribed doses within 3 days prior to study entry.

• For participants who were not living with HIV and were being treated for TB: Had missed one or more of the prescribed doses of TB medication within 3 days prior to study entry.

  • Note: The entry visit could have been rescheduled within the screening period once the participant had taken all prescribed doses within 3 days prior to study entry.

Individual participant data that underlie results in the publication, after deidentification.

Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH

• With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
• For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
• By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.