Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)
Overview
- Phase
- Phase 2
- Intervention
- Nuvaring
- Conditions
- HIV-1 Infection
- Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Enrollment
- 84
- Locations
- 21
- Primary Endpoint
- Etonogestrel Concentrations at Study Day 21
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief 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.
Detailed Description
This was a 28 day study from study entry through the final clinic visit. Post-entry visits were scheduled at Days 7, 14, 21 and 28. The Nuvaring was put in place at study entry and removed on day 21. A single pharmacokinetic (PK) blood sample was collected for assay of etonogestrel (ENG) and ethinyl estradiol (EE) at entry (day 0, prior to NuvaRing placement), and on days 7, 14, and 21 after placement of the NuvaRing. For participants on the ARV arms, intensive, 8-hour PK sampling, for assay of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV) respectively, was performed at study entry (day 0, prior to NuvaRing placement) and 21 days later. ARV sampling was performed at pre-dose (hour 0), and 1, 3, 4, 5, and 8 hours post-dose. Safety was assessed at each study visit.
Investigators
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
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.
Arms & Interventions
NuvaRing and no ART (Arm A)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days).
Intervention: Nuvaring
NuvaRing with EFV plus ≥2 NRTIs (Arm B)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). EFV is a non-nucleoside reverse transcriptase inhibitor taken at a dose of 600 mg once daily.
Intervention: Nuvaring
NuvaRing with EFV plus ≥2 NRTIs (Arm B)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). EFV is a non-nucleoside reverse transcriptase inhibitor taken at a dose of 600 mg once daily.
Intervention: EFV
NuvaRing with EFV plus ≥2 NRTIs (Arm B)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). EFV is a non-nucleoside reverse transcriptase inhibitor taken at a dose of 600 mg once daily.
Intervention: NRTIs
NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). ATV/r is a combination protease inhibitor taken at a dose of 300/100 mg once daily. Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor (NRTI) taken at a dose of 300 mg daily.
Intervention: Nuvaring
NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). ATV/r is a combination protease inhibitor taken at a dose of 300/100 mg once daily. Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor (NRTI) taken at a dose of 300 mg daily.
Intervention: ATV/r
NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). ATV/r is a combination protease inhibitor taken at a dose of 300/100 mg once daily. Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor (NRTI) taken at a dose of 300 mg daily.
Intervention: TDF
NuvaRing with ATV/r plus TDF + ≥1 NRTIs (Arm C)
Once NuvaRing is inserted into the vagina, the ring should remain in place (not be removed) continuously for 3 weeks (21 days). ATV/r is a combination protease inhibitor taken at a dose of 300/100 mg once daily. Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor (NRTI) taken at a dose of 300 mg daily.
Intervention: NRTIs
Outcomes
Primary Outcomes
Etonogestrel Concentrations at Study Day 21
Time Frame: Day 21
This evaluates the effect of EFV and ATV/r on etonogestrel by measuring etonogestrel concentrations on all three study arms 21 days after NuvaRing administration. The pharmacokinetic (PK) blood sample for measurement of etonogestrel on study day 21 was taken before the NuvaRing was removed. The assay lower limit of quantification for etonogestrel was 250 pg/mL; values \< 250 were assigned a value of half the lower limit (ie, 125 pg/mL).
Ethinyl Estradiol Concentrations at Study Day 21
Time Frame: Day 21
This evaluates the effect of EFV and ATV/r on ethinyl estradiol by measuring ethinyl estradiol concentrations on all three study arms 21 days after NuvaRing administration. The PK blood sample for measurement of ethinyl estradiol on study day 21 was taken before the NuvaRing was removed. The assay lower limit of quantification for ethinyl estradiol was 5 pg/mL ; values \< 5 were assigned a value of half the lower limit (ie, 2.5 pg/mL).
Secondary Outcomes
- Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.(Study days 7 and 14)
- ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C(Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C(Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B(Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B(Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C(Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL(Study day 0 and study day 21)
- Etonogestrel Concentrations Obtained on Study Days 7 and 14(Study days 7 and 14)
- EFV PK Parameter Area Under the Concentration-Time Curve (AUC0-24hours) Calculated Based on Intensive EFV PK Samples Obtained From Individual Participants Enrolled in Arm B(Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B(Intensive EFV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C(Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C(Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- RTV PK Parameter Cmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C(Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- RTV PK Parameter Tmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C(Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C(Intensive ATV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement).)
- RTV PK Parameter Cmin Determined Based on RTV Levels From Individual Participants Enrolled in Arm C(Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- RTV PK Parameter CLss/F Determined Based on RTV Levels From Individual Participants Enrolled in Arm C(Intensive RTV PK samples at pre-dose, 1, 3, 4, 5, and 8 hours post-dose on study day 0 (before vaginal ring placement) and on study day 21 (3 weeks after vaginal ring placement))
- Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.(Study days 0, 7, 14, 21 and 28)
- Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment(From day 0 to day 28)