Protease Inhibitors and Combined Oral Contraceptive Pharmacokinetics and Pharmacodynamics

Study Overview
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Brief Summary
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The project is a two-arm prospective cohort and pharmacokinetic study comparing levonorgestrel and ethinyl estradiol pharmacokinetics in HIV-positive women taking antiretroviral regimens that include ritonavir to those in women who take regimens known not to interact with combined oral contraceptives. In addition, the prevalence of ovulation will be measured in each group. Participants will take a combined oral contraceptive containing levonorgestrel and ethinyl estradiol for 21 days, during which they will undergo twice-weekly serum progesterones. On the final day, they will complete a pharmacokinetic study. The investigators hypothesize that levonorgestrel levels, as measured by area-under-the-curve from 0 to 72 hours, will be increased in women on ritonavir, while ethinyl estradiol levels will be decreased and ovulation, defined by a serum progesterone of at least 3 ng/mL, will be unchanged. This study will be the first to evaluate the effects of ritonavir on the pharmacokinetics of a combined oral contraceptive containing the progestin levonorgestrel. In addition, no previous studies have rigorously assessed ovulation in women taking protease inhibitors and combined oral contraceptives. As a result, this study will provide new information correlating pharmacokinetic changes with effects on ovulation.

Official Title
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Effects of Protease Inhibitor Use on Combined Oral Contraceptive Pharmacokinetics and Pharmacodynamics in HIV-positive Women

Conditions
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Contraception, HIV

Intervention / Treatment
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* Drug: Levonorgestrel and Ethinyl Estradiol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV positive Female Age 18-45 Using any of the following medication regimens: no ARV medication, entry inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), integrase inhibitors, and CCR5 agonists. Acceptable NRTI combinations include zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), didanosine (ddl), stavudine (d4T), abacavir (ABC), and tenofovir disoproxil fumarate (TDF) Ovulatory (mid-luteal progesterone >3ng/dL) Not planning to conceive during the study period Willing to abstain from grapefruit products If taking ritonavir, willing to use alternate non-hormonal contraception BMI < or = 40 Able to consent in English or Spanish No change in medication regimen for at least 21 days prior to study entry and no planned change during the study period CD4 > or =200, and/or not considered profoundly immuncompromised by primary HIV provider Exclusion Criteria: Using on the combination of ZDV at d4T Platelets <50,000 AST or ALT > twice upper limit of normal Bilirubin > twice upper limit of normal Use of other CYP3A4 inducing or inhibiting medications Pregnant or breastfeeding in last 30 days Use of DepoProvera in last 180 days Use of any other hormonal contraception in last 30 days Undiagnosed vaginal bleeding or invasive cancer of the reproductive tract ->50% change in tobacco use in the last month Initiation or titration of methadone therapy in the last month Uncontrolled thyroid disease Contraindication to estrogen use Inability to comply with study protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ritonavir<br>Participants taking antiretroviral regimens including ritonavir-boosted protease inhibitors will take a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol for 21 days. | Drug: Levonorgestrel and Ethinyl Estradiol<br>* All participants will take a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol for 21 days. Pharmacokinetics and pharmacodynamics will be compared between participants using antiretroviral regimens including ritonavir-boosted protease inhibitors and those using regimens that do not interact with oral contraceptives.<br>|
| Active Comparator: Control<br>Participants taking antiretroviral regimens known not to interact with oral contraceptives will take a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol for 21 days. | Drug: Levonorgestrel and Ethinyl Estradiol<br>* All participants will take a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol for 21 days. Pharmacokinetics and pharmacodynamics will be compared between participants using antiretroviral regimens including ritonavir-boosted protease inhibitors and those using regimens that do not interact with oral contraceptives.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levonorgestrel Area Under the Curve | Levonorgestrel AUC from 0 to 72 hours | 24 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ethinyl Estradiol Area Under the Curve | Ethinyl estradiol area under the curve from 0 to 72 hours | 24 days | 
| Serum Progesterone Level >3ng/dL Reflecting Ovulation | Progesterone >3ng/dL at any time during pill use | 21 days |