Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART
Condition: HIV-1 Infection
Intervention: Nuvaring; EFV; ATV/r; TDF; NRTIs
Intervention description: NuvaRing is made of ethylene vinylacetate copolymers (28% and 9% vinylacetate) and magnesium stearate, is latex free, and contains 11.7 mg etonogestrel and 2.7 mg ethinyl estradiol. NuvaRing has an outer diameter of 54 mm and a cross-sectional diameter of 4mm. Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). After being in place for the first 21 days of the study, the ring may be removed after the day 21 study visit evaluations have been completed.; Participants received EFV 600 mg daily with two or more NRTIs; Participants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs; Participants received 300 mg of tenofovir in Arm C; Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C
Intervention MeSH terms: Ritonavir; Atazanavir Sulfate; Tenofovir; Efavirenz; Reverse Transcriptase Inhibitors; Ethinyl Estradiol; Etonogestrel; NuvaRing; Estradiol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 84.0
Sex: Female
Minimum age: 16 Years
Healthy volunteers: No

Summary:

      This study was done to look at a method of hormonal birth control, called the NuvaRing, and
      specific anti-HIV medications, called antiretrovirals (ARVs). Some studies of women who use a
      hormonal birth control method (specifically oral pills, patches, and injections) and take
      ARVs have shown that ARVs interact with the hormones released by the birth control
      medication. These interactions may cause the birth control to be less effective at preventing
      pregnancy. There is also concern that hormonal birth control can increase HIV spreading to
      others, but more studies are needed to determine if this is true. The investigators did not
      know whether the NuvaRing and ARVs interact when they are used together, so this study looked
      to see if certain ARVs (efavirenz and atazanavir/ritonavir) interact with the two hormones
      released by NuvaRing. This will help us to determine if NuvaRing is safe and effective for
      women with HIV infection who are taking ARVs. The study also included HIV-infected women who
      were not on ARVs but used the NuvaRing to show us what the hormone levels are like in a
      similar group of women not on ARVs.

      Vaginal rings are also currently being studied to deliver anti-HIV medications that may
      prevent HIV acquisition, and to provide birth control over a longer period of time (more than
      1 month). Since vaginal rings will become more commonly used to administer medications, the
      investigators wanted to better understand the potential for drug interactions with drugs
      given vaginally. This study will also help us understand the potential for drug interactions
      between ARVs given orally, and other drugs given through vaginal rings, like the NuvaRing.
      Additionally, this study will help us understand how hormones released from a vaginal ring
      affect the amount of HIV virus in the genital tract, the bacterial make-up (microbiome) of
      the female genital tract, and the immune system within the genital tract, all of which may
      affect the chances of spreading HIV.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Documented HIV-1 infection.

          -  Participants must have been receiving either 1) EFV 600 mg daily with 2 or more NRTIs,
             2) ATV/r 300 mg/ 100 mg daily with TDF 300 mg and 1 or more additional NRTIs, or 3) no
             ART. ART regimens should have been stable for 30 days prior to study entry with no
             plans to change therapy during the first 28 days of this study. Participants receiving
             no ART should have had no plans to initiate ART during the first 28 days of the study.

        NOTE: Participants must have had access to their ART regimens through their primary care
        providers. ART medications were not supplied by this study.

          -  For participants on ART, documentation of plasma HIV-1 RNA ≤400 copies/mL was obtained
             within 60 days prior to study entry.

          -  For participants not on ART, CD4+ cell count must have been ≥350 cells/mm^3, obtained
             within 60 days prior to study entry.

          -  Laboratory values within 60 days prior to study entry:

               -  Platelet count ≥50,000 platelets/mm^3

               -  Hemoglobin ≥8.0 g/dL

               -  Aspartate transaminase (SGOT) and alanine aminotransferase (SGPT) <5 x upper
                  limit of normal (ULN)

               -  Creatinine ≤1.5 x ULN

               -  Total bilirubin ≤2.0 x ULN

          -  Last menstrual period ≤6 months prior to study entry. If last menstrual period >6
             months prior to study entry without another cause for amenorrhea, such as recent
             pregnancy, serum follicle-stimulating hormone (FSH) must have been checked and be ≤40
             mIU/mL to be eligible for enrollment.

          -  Premenopausal females with at least one functioning ovary.

          -  Documentation of Pap smear within 1 year prior to study entry.

          -  Negative serum or urine-HCG pregnancy test with a sensitivity of ≤25 mIU/mL within 60
             days prior to study entry and within 24 hours prior to study entry

          -  All participants must have agreed not to participate in a conception process (eg,
             active attempt to become pregnant or in vitro fertilization) for the duration of the
             study. Because it was unknown if ARVs adversely affect the efficacy of NuvaRing as a
             contraceptive method, participants of reproductive potential, who were participating
             in sexual activities that could lead to pregnancy, must have agreed to use an
             additional reliable form of contraception while in the study. Acceptable additional
             methods of contraception included:

               -  Condoms (male or female)

               -  Non-hormonal intrauterine device (IUD)

        Other hormonal forms of contraception were not allowed during the study period.

        Condoms should have been used to prevent transmission of HIV and sexually transmitted
        diseases between sexual partners.

        NOTE: Participants with bilateral tubal ligation or non-hormonal IUD were eligible to be
        enrolled.

        Exclusion Criteria:

          -  Received depot medroxyprogesterone acetate (DMPA) within 4 months prior to study
             entry.

          -  Received other hormonal therapies (eg, oral contraceptive agents, hormone- containing
             vaginal ring, contraceptive patch, hormone replacement therapy, anabolic therapies,
             including nandrolone decanoate or megestrol acetate) within 30 days prior to study
             entry.

          -  Breastfeeding.

          -  Less than 6 weeks postpartum at study entry.

          -  Use of any prohibited medications within 30 days prior to study entry.

          -  Initiated, discontinued, or changed doses of drugs that are CYP substrates or known to
             have drug interactions with ethinyl estradiol or etonogestrel within 30 days prior to
             study entry.

          -  Bilateral oophorectomy.

          -  For women older than 35 years of age, smoking 15 or more cigarettes per day.

          -  History of invasive cancer of the reproductive tract; known or suspected malignancy of
             the breast, or known increased risk for breast cancer; undiagnosed abnormal vaginal
             bleeding; liver tumors; or serious ocular disorders at any time prior to study entry.

          -  Chronic immunosuppressive conditions other than HIV.

          -  Use of systemic or inhaled corticosteroids such as for acute therapy for Pneumocystis
             pneumonia (PCP) or asthma exacerbation and prednisone ≥10 mg (or equivalent) for any
             reason other than a stable or tapering dose.

          -  History of deep venous thrombosis or pulmonary embolism.

          -  History of cerebral vascular or coronary artery disease.

          -  Severe uncontrolled hypertension within 60 days prior to study entry.

          -  Diabetes with vascular involvement.

          -  Clinically active cervical or vaginal infection at study entry. NOTE: Gonorrhea,
             chlamydia, and trichomonas testing was performed during screening using techniques
             available at the local sites and documented in source documentation and case report
             forms (CRFs). Testing for bacterial vaginosis, performed using techniques available at
             the local sites, was only necessary if the participant was symptomatic and the
             provider felt treatment might be necessary. Women with genital herpes lesions waited
             to be screened until the herpetic lesions had healed.

          -  Acute infections or other opportunistic diseases requiring medication within 14 days
             prior to study entry.