Clinical trial NCT01903031: Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and ART
Official title: Evaluating Pharmacokinetic Interactions With Vaginal Ring Contraceptives and Antiretroviral Therapy (ART)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2013-07-19
Enrollment: 84
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Etonogestrel Concentrations at Study Day 21
timeFrame: Day 21
measure: Ethinyl Estradiol Concentrations at Study Day 21
timeFrame: Day 21
Secondary outcomes:
measure: Etonogestrel Concentrations Obtained on Study Days 7 and 14
timeFrame: Study days 7 and 14
measure: Ethinyl Estradiol Concentrations Obtained on Study Days 7 and 14.
timeFrame: Study days 7 and 14
measure: 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
timeFrame: 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).
measure: EFV PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
timeFrame: 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).
measure: EFV PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
timeFrame: 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).
measure: EFV PK Parameter Clearance (CLss/F) Determined Based on EFV Levels From Individual Participants Enrolled in Arm B
timeFrame: 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).
measure: ATV PK Parameter AUC(0-24h) Calculated Based on Intensive Atazanavir (ATV) PK Samples Obtained From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: ATV PK Parameter Cmin Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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).
measure: ATV PK Parameter Cmax Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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).
measure: ATV PK Parameter Time to Cmax (Tmax) Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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).
measure: ATV PK Parameter CLss/F Determined Based on ATV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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).
measure: Ritonavir (RTV) PK Parameter AUC(0-24h) Calculated Based on Intensive RTV PK Samples Obtained From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: RTV PK Parameter Cmin Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: RTV PK Parameter Cmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: RTV PK Parameter Tmax Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: RTV PK Parameter CLss/F Determined Based on RTV Levels From Individual Participants Enrolled in Arm C
timeFrame: 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)
measure: Proportion of Participants With Plasma HIV-1 RNA Levels <40 Copies/mL
timeFrame: Study day 0 and study day 21
measure: Percentage of Participants With Signs and Symptoms of Grade 2 or Higher Deemed Possibly, Probably or Definitely Related to Study Treatment
timeFrame: From day 0 to day 28
measure: Proportion of Participants With Progesterone Levels Greater Than 5 ng/mL.
timeFrame: Study days 0, 7, 14, 21 and 28
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California LA (5048)
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS (5112)
state: California
city: Aurora
country: United States
facility: University of Colorado Denver NICHD CRS (5052)
state: Colorado
city: Jacksonville
country: United States
facility: University of Florida Jacksonville (5051)
state: Florida
city: Chicago
country: United States
facility: Rush University Cook County Hospital Chicago NICHD CRS (5083)
state: Illinois
city: Newark
country: United States
facility: 31786 New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Bronx
country: United States
facility: Jacobi Medical Center Bronx
state: New York
city: New York
country: United States
facility: Columbia Physicians and Surgeons CRS (30329)
state: New York
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS (2951)
state: Rhode Island
city: Gaborone
country: Botswana
facility: Gaborone Prevention/Treatment Trials CRS (12701)
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (12101)
city: Kisumu
country: Kenya
facility: Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
city: San Isidro
country: Peru
facility: Investigaciones Medicas en Salud (INMENSA) (11302)
state: Lima
city: Lima
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (6601)
city: San Juan
country: Puerto Rico
facility: San Juan Hospital PR NICHD CRS (5031)
city: Johannesburg
country: South Africa
facility: Shandukani Research CRS (8051)
state: Gauteng
city: Bangkok
country: Thailand
facility: 31802 Thai Red Cross AIDS Research Center Treatment (TRC-ARC Treatment) CRS
state: Patumwan
city: Chiang Mai
country: Thailand
facility: 31784 Chiang Mai University HIV Treatment CRS
Study officials:
References:
citation: Scarsi KK, Cramer YS, Rosenkranz SL, Aweeka F, Berzins B, Coombs RW, Coughlin K, Moran LE, Zorrilla CD, Akelo V, Aziz M, Friedman RK, Gingrich D, Swaminathan S, Godfrey C, Cohn SE; AIDS Clinical Trials Group A5316 Study Team. Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study. Lancet HIV. 2019 Sep;6(9):e601-e612. doi: 10.1016/S2352-3018(19)30155-9.