Contraception, HIV
Conditions
Brief summary
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.
Interventions
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.
Sponsors
University of Southern California
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levonorgestrel Area Under the Curve | 24 days | Levonorgestrel AUC from 0 to 72 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ethinyl Estradiol Area Under the Curve | 24 days | Ethinyl estradiol area under the curve from 0 to 72 hours |
| Serum Progesterone Level >3ng/dL Reflecting Ovulation | 21 days | Progesterone \>3ng/dL at any time during pill use |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ritonavir 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.
Levonorgestrel and Ethinyl Estradiol: 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. | 5 |
| Control 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.
Levonorgestrel and Ethinyl Estradiol: 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. | 10 |
| Total | 15 |
Baseline characteristics
| Characteristic | Ritonavir | Control | Total |
|---|---|---|---|
| Age, Continuous | 38 years | 34.5 years | 35 years |
| Region of Enrollment United States | 5 participants | 10 participants | 15 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 7 | 0 / 10 |
| serious Total, serious adverse events | 0 / 7 | 0 / 10 |
Outcome results
Primary
Levonorgestrel Area Under the Curve
Levonorgestrel AUC from 0 to 72 hours
Time frame: 24 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ritonavir | Levonorgestrel Area Under the Curve | 321 ng/mL*h | Standard Deviation 61 |
| Control | Levonorgestrel Area Under the Curve | 243 ng/mL*h | Standard Deviation 83 |
p-value: <0.05t-test, 2 sided
Secondary
Ethinyl Estradiol Area Under the Curve
Ethinyl estradiol area under the curve from 0 to 72 hours
Time frame: 24 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ritonavir | Ethinyl Estradiol Area Under the Curve | 3867 ng/mL*h | Standard Deviation 976 |
| Control | Ethinyl Estradiol Area Under the Curve | 3270 ng/mL*h | Standard Deviation 744 |
Secondary
Serum Progesterone Level >3ng/dL Reflecting Ovulation
Progesterone \>3ng/dL at any time during pill use
Time frame: 21 days