This study will 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. We do not know whether the NuvaRing and ARVs interact when they are used together, so this study will look 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 will also include HIV-infected women who are not on ARVs but will use 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, we want 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 HIV virus, the bacterial make-up (microbiome) of the female genital track, and the immune system within the genital tract, all of which may affect the chances of spreading HIV.

The product under investigation in this study is the NuvaRing. The NuvaRing is a vaginal ring that has been approved by the US Food and Drug Administration as a safe and effective method of hormonal birth control. NuvaRing is a flexible ring that is inserted into the vagina once a month and releases a small dose of hormones that prevents pregnancy.

Project description and scope

Brief Description:     

A5316 is a phase II, open-label, non-randomized, steady-state, parallel design trial to evaluate pharmacokinetic (PK) interactions between hormonal contraception (etonogestrel and ethinyl estradiol) delivered via a vaginal ring (NuvaRing) and efavirenz (EFV)- or atazanavir/ritonavir (ATV/r)-based regimens.  HIV-infected, non-pregnant women who are taking EFV- or ATV/r-based regimens or no antiretroviral therapy (ART) are eligible. Those subjects on ART will have intensive antiretroviral (ART) PK collected before and 3 weeks after placement of the NuvaRing.  All subjects will have weekly visits to collect blood for hormone analysis and cervicovaginal samples for immunological, microbiological and virological studies.

Objectives:

The primary objective of the study is to estimate the effect of ATV/r or EFV-based ART on the PK exposure of etonogestrel and ethinyl estradiol in HIV-infected participants using the NuvaRing.  The study will also estimate the effect of etonogestrel and ethinyl estradiol on the PK exposure of ATV, ritonavir (RTV), or EFV.  The safety of concomitant ART administered with the NuvaRing and the impact of the NuvaRing on virologic suppression, cervicovaginal immunology and microbiome will also be explored.

Requirements to Enter Study: 

     Inclusion Criteria

• Premenopausal HIV-infected women age ³16 years
• 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; stable for 30 days prior to entry with no plans to change therapy during study
• For participants on ART: HIV-1 RNA £400 copies/mL within 60 days prior to study entry
• For participants not on ART: CD4+ cell count ≥350 cells/mm³ within 60 days prior to study entry
• Laboratory values obtained within 60 days prior to study entry:

• Hemoglobin ³8.0 g/dL
• Platelet count ³50,000/mm³
• AST and ALT £ 5 ´ ULN
• Total bilirubin £2.0 x ULN
• Creatinine ≤1.5 x ULN
• Last menstrual period £6 months or verification of FSH £40 mIU/mL, unless there is a clinical reason for amenorrhea (such as pregnancy)
• Negative pregnancy test at screening and within 24 hours of entry 
• Documentation of Pap smear within 1 year prior to study entry

Exclusion criteria:

• Received depot medroxyprogesterone acetate (DMPA) within 4 months, or other hormonal therapies within 30 days prior to study entry
• Contraindications to receiving hormonal contraception; Receiving medications known to interfere with either ART or hormone metabolism
• Use of systemic or inhaled corticosteroids
• Less than 6 weeks postpartum at study entry
• Clinically active cervical or vaginal infection at study entry. (Gonorrhea, chlamydia, trichomonas, bacterial vaginosis testing will be performed during screening using techniques available at the local sites.)
• History of invasive cancer of the reproductive tract, malignancy or increased risk of breast cancer; abnormal vaginal bleeding, liver tumors; or serious ocular disorders 

Treatment: 

Eligible study participants will be enrolled into one of the study treatment arms:

Arm A: NuvaRing for 3 weeks with NO ART

Arm B: NuvaRing for 3 weeks with EFV 600 mg once daily plus ≥2 NRTIs

Arm C: NuvaRing for 3 weeks with ATV/r 300/100 mg once daily plus

 Tenofovir (TDF) 300 mg and ≥1 NRTI

NuvaRing will be provided by the study. Participants will be offered an extra NuvaRing at the day 28 visit. ART medications are not provided.           

Duration: 28 days (weekly study visits).  Vaginal aspirates will be collected at each visit. Intensive ART PK sampling will be performed over 8 hours before and after vaginal ring placement (Days 0 and 21) for the EFV and ATV/r groups.  If participants choose to use an optional vaginal ring after day 28, they will receive a follow-up phone call day 56.