Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART

Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01903031

Enrollment

Registered

2013-07-19

Start date

2014-12-30

Completion date

2016-10-10

Last updated

2018-06-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1 Infection

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.

Interventions

DEVICENuvaring

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.

DRUGEFV

Participants received EFV 600 mg daily with two or more NRTIs

DRUGATV/r

Participants received ATV/r 300 mg/ 100 mg daily with tenofovir and one or more additional NRTIs

DRUGTDF

Participants received 300 mg of tenofovir in Arm C

DRUGNRTIs

Participants received two or more NRTIs in Arm B and one or more NRTIs in Arm C

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

16 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Etonogestrel Concentrations at Study Day 21	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	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

Measure	Time frame	Description
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).	This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of EFV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
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).	This evaluates the effect of NuvaRing on the EFV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
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).	This evaluates the effect of NuvaRing on the EFV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
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).	This evaluates the effect of NuvaRing on the EFV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/F defines apparent oral clearance
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)	This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of ATV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
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).	This evaluates the effect of NuvaRing on the ATV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
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).	This evaluates the effect of NuvaRing on the ATV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
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).	This evaluates the effect of NuvaRing on the ATV PK parameter Tmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Tmax defines time to maximum concentration since dose is initiated.
Etonogestrel Concentrations Obtained on Study Days 7 and 14	Study days 7 and 14	This evaluates the effect of EFV and ATV/r on etonogestrel by measuring etonogestrel concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).
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)	This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).
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)	This evaluates the effect of NuvaRing on the PK parameter Cmin of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.
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)	This evaluates the effect of NuvaRing on the PK parameter Cmax of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.
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)	This evaluates the effect of NuvaRing on the PK parameter Tmax of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Tmax defines time to maximum concentration since dose is initiated.
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)	This evaluates the effect of NuvaRing on the PK parameter CLss/F of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/F defines apparent oral clearance.
Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Study day 0 and study day 21	This evaluates the short-term impact of Nuvaring on virologic suppression in participants who have been administered Nuvaring alone or together with EFV or ATV/r by measuring proportion of participants with plasma HIV-1 RNA levels \<40 copies/mL at study day 0 (before vaginal ring placement) and study day 21 (three weeks after vaginal ring placement). An FDA-approved HIV-1 RNA assay was required.
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	This evaluates toxicity and safety of NuvaRing alone, NuvaRing with EFV, and NuvaRing with ATV/r. Signs/symptoms were graded using the DAIDS AE Grading Table was used. Participants with sign(s)/symptom(s) of grade 2 (moderate), 3 (severe), 4 (potentially life-threatening) or 5 (death) are included in the percentage. Relationship to study treatment was determined by the study co-chairs and DAIDS clinical representative.
Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Study days 0, 7, 14, 21 and 28	This evaluates alterations in progesterone levels due to the potential PK interaction between NuvaRing and the ARVs EFV and ATV/r by examining progesterone levels at study days 0 (before vaginal ring placement), 7, 14, and 21 (before vaginal ring removal), and study day 28, without regard to menstrual cycle status at study entry.
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).	This evaluates the effect of NuvaRing on the ATV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/f defines apparent oral clearance.
Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Study days 7 and 14	This evaluates the effect of EFV and ATV/r on ethinyl estradiol by measuring ethinyl estradiol concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).

Countries

Botswana, Brazil, Kenya, Peru, Puerto Rico, South Africa, Thailand, United States

Participant flow

Recruitment details

The first participant enrolled in December 2014 and final participant enrolled in September 2016. Enrollment took place at 21 US and non-US clinical research sites.

Participants by arm

Arm	Count
NuvaRing and no ART Participants who were not on ART were prescribed NuvaRing, to be inserted at entry and removed at Day 21.	27
NuvaRing With EFV Plus ≥2 NRTIs NuvaRing was inserted at entry and removed at Day 21. Participants also received EFV 600 mg daily with two or more NRTIs.	28
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs NuvaRing was inserted at entry and removed at Day 21. Participants also received ATV/r 300 mg/ 100 mg daily with tenofovir (TDF) 300 mg and 1 or more additional NRTIs.	29
Total	84

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	0	1	0
Overall Study	Lost to Follow-up	0	0	1
Overall Study	Missed Day 21 Primary Endpoint Visit	1	0	0
Overall Study	Not Able to Attend Clinic	1	1	0
Overall Study	NuvaRing removed prior to Day 21 visit	0	0	1
Overall Study	Protocol Violation	0	0	2
Overall Study	Withdrawal by Subject	0	1	1

Baseline characteristics

Characteristic	NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Total	NuvaRing and no ART	NuvaRing With EFV Plus ≥2 NRTIs
Age, Continuous	36 years	35 years	32 years	36 years
Race/Ethnicity, Customized Asian, Pacific Islander	5 Participants	8 Participants	3 Participants	0 Participants
Race/Ethnicity, Customized Black Non-Hispanic	14 Participants	44 Participants	12 Participants	18 Participants
Race/Ethnicity, Customized Hispanic (Regardless of Race)	9 Participants	29 Participants	11 Participants	9 Participants
Race/Ethnicity, Customized White Non-Hispanic	1 Participants	3 Participants	1 Participants	1 Participants
Region of Enrollment Botswana	0 Participants	5 Participants	4 Participants	1 Participants
Region of Enrollment Brazil	5 Participants	14 Participants	3 Participants	6 Participants
Region of Enrollment Kenya	2 Participants	8 Participants	3 Participants	3 Participants
Region of Enrollment Peru	0 Participants	10 Participants	6 Participants	4 Participants
Region of Enrollment Puerto Rico	2 Participants	3 Participants	1 Participants	0 Participants
Region of Enrollment South Africa	0 Participants	2 Participants	2 Participants	0 Participants
Region of Enrollment Thailand	5 Participants	8 Participants	3 Participants	0 Participants
Region of Enrollment United States	15 Participants	34 Participants	5 Participants	14 Participants
Sex: Female, Male Female	29 Participants	84 Participants	27 Participants	28 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 27	0 / 28	0 / 28
other Total, other adverse events	10 / 27	20 / 28	18 / 28
serious Total, serious adverse events	0 / 27	0 / 28	0 / 28

Outcome results

Primary

Ethinyl Estradiol Concentrations at Study 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).

Time frame: Day 21

Population: Participants who provided the Ethinyl Estradiol PK sample at day 21 were included in the analysis.

Arm	Measure	Value (MEDIAN)
NuvaRing and no ART	Ethinyl Estradiol Concentrations at Study Day 21	21.30 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Ethinyl Estradiol Concentrations at Study Day 21	11.40 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Ethinyl Estradiol Concentrations at Study Day 21	16.05 pg/mL

Comparison: Null hypothesis: There is no difference in concentrations of Ethinyl Estradiol on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with EFV plus ≥2 NRTIs.p-value: <0.001Wilcoxon (Mann-Whitney)

Comparison: Null hypothesis: There is no difference in concentrations of Ethinyl Estradiol on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with ATV/r plus TDF and ≥1 NRTIs.p-value: 0.004Wilcoxon (Mann-Whitney)

Primary

Etonogestrel Concentrations at Study 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).

Time frame: Day 21

Population: Participants who provided the Etonogestrel PK sample at day 21 were included in the analysis.

Arm	Measure	Value (MEDIAN)
NuvaRing and no ART	Etonogestrel Concentrations at Study Day 21	1860.00 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Etonogestrel Concentrations at Study Day 21	429.00 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Etonogestrel Concentrations at Study Day 21	3290.00 pg/mL

Comparison: Null hypothesis: There is no difference in concentrations of Etonogestrel on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with EFV plus ≥2 NRTIs.p-value: <0.001Wilcoxon (Mann-Whitney)

Comparison: Null hypothesis: There is no difference in concentrations of Etonogestrel on day 21 between the control arm (NuvaRing and no ART) and NuvaRing with ATV/r plus TDF and ≥1 NRTIs.p-value: <0.001Wilcoxon (Mann-Whitney)

Secondary

ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of ATV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).

Time frame: 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)

Population: The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C	AUC0-24h day 0	44313.7 h*ng/mL
NuvaRing and no ART	ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C	AUC0-24h day 21	36764.7 h*ng/mL

Secondary

ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the ATV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/f defines apparent oral clearance.

Time frame: 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).

Population: The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	CLss/F day 0	6.8 L/h
NuvaRing and no ART	ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	CLss/F day 21	8.2 L/h

Secondary

ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the ATV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.

Time frame: 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).

Population: The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Cmax day 0	4291.0 ng/mL
NuvaRing and no ART	ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Cmax day 21	3583.0 ng/mL

Secondary

ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the ATV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.

Time frame: 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).

Population: The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Cmin day 0	796.7 ng/mL
NuvaRing and no ART	ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Cmin day 21	599.4 ng/mL

Secondary

ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the ATV PK parameter Tmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Tmax defines time to maximum concentration since dose is initiated.

Time frame: 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).

Population: The analysis population is the 23 A5316 participants enrolled in Arm C (NuvaRing with ATV/r arm plus TDF and one or more NRTIs) eligible for the secondary outcome of ATV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Tmax day 0	2.9 hour
NuvaRing and no ART	ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C	Tmax day 21	3.0 hour

Secondary

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

This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of EFV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).

Time frame: 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).

Population: The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	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	AUC0-24h day 0	68949.1 h*ng/mL
NuvaRing and no ART	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	AUC0-24h day 21	57795.9 h*ng/mL

Secondary

EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B

This evaluates the effect of NuvaRing on the EFV PK parameter CLss/F obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. CLss/F defines apparent oral clearance

Time frame: 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).

Population: The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	CLss/F day 0	8.7 L/h
NuvaRing and no ART	EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	CLss/F day 21	10.4 L/h

Secondary

EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B

This evaluates the effect of NuvaRing on the EFV PK parameter Cmax obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmax defines maximum concentration observed within the first 8 hours of the 24 hour dosing interval.

Time frame: 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).

Population: The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	Cmax day 0	4541.0 ng/mL
NuvaRing and no ART	EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	Cmax day 21	3786.0 ng/mL

Secondary

EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B

This evaluates the effect of NuvaRing on the EFV PK parameter Cmin obtained from both sampling periods, before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. Cmin defines minimum concentration observed within the first 8 hours of the 24 hour dosing interval.

Time frame: 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).

Population: The analysis population is the 24 A5316 participants enrolled in Arm B (NuvaRing with EFV arm plus 2 or more NRTIs) eligible for the secondary outcome of EFV PK parameters.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	Cmin day 0	2121.5 ng/mL
NuvaRing and no ART	EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B	Cmin day 21	1766.0 ng/mL

Secondary

Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.

This evaluates the effect of EFV and ATV/r on ethinyl estradiol by measuring ethinyl estradiol concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).

Time frame: Study days 7 and 14

Population: Participants who provided the Ethinyl estradiol PK samples at day 7 and at day 14 were included in the analysis.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 7	18.05 pg/mL
NuvaRing and no ART	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 14	19.70 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 7	9.98 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 14	10.50 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 7	15.70 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.	Concentration at Day 14	16.55 pg/mL

Secondary

Etonogestrel Concentrations Obtained on Study Days 7 and 14

This evaluates the effect of EFV and ATV/r on etonogestrel by measuring etonogestrel concentrations on all three study arms 7 and 14 days after NuvaRing administration. 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).

Time frame: Study days 7 and 14

Population: Participants who provided the Etonogestrel PK samples at day 7 and at day 14 were included in the analysis.

Arm	Measure	Group	Value (MEDIAN)
NuvaRing and no ART	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 7	1970.00 pg/mL
NuvaRing and no ART	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 14	2070.00 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 7	427.00 pg/mL
NuvaRing With EFV Plus ≥2 NRTIs	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 14	437.00 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 7	3250.00 pg/mL
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Etonogestrel Concentrations Obtained on Study Days 7 and 14	Concentration at Day 14	3530.00 pg/mL

Secondary

Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment

This evaluates toxicity and safety of NuvaRing alone, NuvaRing with EFV, and NuvaRing with ATV/r. Signs/symptoms were graded using the DAIDS AE Grading Table was used. Participants with sign(s)/symptom(s) of grade 2 (moderate), 3 (severe), 4 (potentially life-threatening) or 5 (death) are included in the percentage. Relationship to study treatment was determined by the study co-chairs and DAIDS clinical representative.

Time frame: From day 0 to day 28

Population: All participants in whom NuvaRing was inserted

Arm	Measure	Value (NUMBER)
NuvaRing and no ART	Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment	7.4 Percent of Participants
NuvaRing With EFV Plus ≥2 NRTIs	Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment	3.6 Percent of Participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment	3.6 Percent of Participants

Secondary

Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL

This evaluates the short-term impact of Nuvaring on virologic suppression in participants who have been administered Nuvaring alone or together with EFV or ATV/r by measuring proportion of participants with plasma HIV-1 RNA levels \<40 copies/mL at study day 0 (before vaginal ring placement) and study day 21 (three weeks after vaginal ring placement). An FDA-approved HIV-1 RNA assay was required.

Time frame: Study day 0 and study day 21

Population: All participants in whom NuvaRing was inserted and with HIV-1 RNA data available.

Arm	Measure	Group	Value (NUMBER)
NuvaRing and no ART	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 0	0.22 proportion of participants
NuvaRing and no ART	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 21	0.17 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 0	0.93 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 21	0.85 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 0	0.89 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL	Proportion with HIV-1 RNA <40 copies/mL at day 21	0.85 proportion of participants

Secondary

Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.

This evaluates alterations in progesterone levels due to the potential PK interaction between NuvaRing and the ARVs EFV and ATV/r by examining progesterone levels at study days 0 (before vaginal ring placement), 7, 14, and 21 (before vaginal ring removal), and study day 28, without regard to menstrual cycle status at study entry.

Time frame: Study days 0, 7, 14, 21 and 28

Population: All participants included in the primary analyses who had progesterone data available. One participant on the EFV arm is excluded at day 14 visit because NuvaRing was out of the body for \>3 hours leading up to the visit.

Arm	Measure	Group	Value (NUMBER)
NuvaRing and no ART	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 21	0.00 proportion of participants
NuvaRing and no ART	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 14	0.00 proportion of participants
NuvaRing and no ART	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 0	0.08 proportion of participants
NuvaRing and no ART	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 7	0.08 proportion of participants
NuvaRing and no ART	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 28	0.00 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 14	0.04 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 0	0.04 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 7	0.24 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 21	0.00 proportion of participants
NuvaRing With EFV Plus ≥2 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 28	0.00 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 28	0.00 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 21	0.00 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 0	0.25 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 14	0.00 proportion of participants
NuvaRing With ATV/r Plus TDF and ≥1 NRTIs	Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.	Proportion with progesterone >5 at day 7	0.08 proportion of participants

Secondary

Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C

This evaluates the effect of NuvaRing on the PK parameter AUC(0-24h) of RTV before NuvaRing placement (at study day 0) and three weeks later (on study day 21), prior to NuvaRing removal. AUC(0-24h) defines area under the concentration-time curve over the period of 24 hours (pre-dose concentration was used to impute concentration at 24h).

Time frame: 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)