Drug Interactions Between Lopinavir/Ritonavir and Oral or Patch Contraceptives in HIV Infected Women

Official Title: “A Phase II Pharmacokinetic Study of the Transdermal Contraceptive System and Oral Contraceptive in HIV-1 Infected Women on Lopinavir/Ritonavir”

The purpose of this study is to examine the drug interactions between a protease inhibitor (PI)-based regimen including lopinavir/ritonavir (LPV/r) and two forms of contraceptive medications in HIV infected women.

Both PIs and oral contraceptives are metabolized by the same pathway, which significantly decreases the effectiveness of oral contraceptives and limits the contraceptive choices available to HIV infected women. More effective hormonal contraceptive methods are necessary for preventing unintended pregnancy in women taking highly active antiretroviral therapy (HAART). Ortho Evra is a contraceptive patch that was approved by the FDA in 2001; it uses a transdermal contraceptive system, and higher rates of compliance have been associated with its use, compared to oral contraceptives. Because Ortho Evra is administered as a contraceptive patch worn on the skin, it may bypass the metabolic pathway common to both PIs and oral contraceptives, making it a viable contraceptive option for HIV infected women on PI-based regimens. The purpose of the study is to examine the interaction between a PI-based regimen containing LPV/r and two forms of contraceptive medications, Ortho Evra and an oral contraceptive, Ortho Novum (ON 1/35), in HIV infected women.

Participants will be enrolled in this study for 6 weeks and will be assigned to one of two study arms, depending on their HAART regimen at study entry. Participants in both arms will also be stratified by age. Arm A participants will receive 400 mg/100 mg LPV/r twice daily along with two or more nucleoside reverse transcriptase inhibitors (NRTIs). Arm B participants will receive a regimen containing only NRTIs or no HAART. HAART will not be provided by this study. All patients will receive a single dose of ON 1/35 on Day 1 and will start the Ortho Evra contraceptive patch on Day 3. A physical exam, pap smear, pregnancy test, viral load test, CD4 and CD8 counts, and blood collection will occur at or before study entry and on Day 24. Pharmacokinetic analyses will occur on Days 1 through 3, 17 through 19, and 24.

Intervention(s) in this Clinical Trial

• Drug: Lopinavir/ritonavir
• Drug: Ortho Novum 1/35
• Drug: Ortho Evra

Primary Measures

• Days 17, 18, 19, and 24 Ortho Evra transdermal contraceptive ethinyl estradiol (EE) area under the concentration-time curve (AUC)

Secondary Measures

• Intensive EE AUC pharmacokinetics (PK) after single dose Ortho Novum (ON) 1/35 and after Ortho Evra administration on Days 17, 18, 19, and 24
• Day 1 intensive EE AUC PK after single dose ON 1/35
• Days 17, 18, 19, and 24 norelgestromin (NGMN) AUC
• changes in HIV RNA viral load, CD4 and CD8 counts and their respective percentages, sex hormone binding globulin levels, and liver enzymes from baseline to Days 17, 18, 19, and 24
• occurrence of nausea and vomiting, breast tenderness, headache, skin irritation, vaginal bleeding, change in weight, change in blood pressure, change in appetite, mood changes, vaginal infection, and gallbladder disease
• PK parameters of LPV in Arm A at baseline and on Days 17, 18, 19, and 24

Inclusion Criteria for All Participants:

• HIV infected
• CD4 count of 200 cells/mm3 or more within 45 days of study entry
• HIV-1 RNA viral load less than 55,000 copies/ml within 45 days of study entry
• Parent or guardian willing to provide informed consent
• Negative pregnancy test within 45 days of study entry
• Willing to use acceptable forms of contraception
• Agrees not to change current smoking or non-smoking habits
• Agrees not to consume caffeine on Day 1, Days 17 through 19, and Day 24 until after the last blood sample of that day is drawn
• Agrees not to consume alcohol within 48 hours of PK sampling periods
• Patients on methadone maintenance therapy should be on a stable methadone dose for at least 60 days prior to study entry and continue maintenance therapy throughout the study

Inclusion Criteria for Arm A Participants:

• Have taken LPV/r for at least 60 consecutive days prior to study entry and taken the same dose twice daily for at least 14 days prior to study entry. Women switching from capsule formulation LPV/r to new tablet formulation of 200mg/50 mg LPV/r must be taking twice-daily doses of this formulation, for a total daily dose of 800 mg/200 mg
• LPV/r, for at least 7 days prior to study entry.

Inclusion Criteria for Arm B Participants:

• Have not taken or currently not taking a PI- or non-nucleoside reverse transcriptase inhibitors (NNRTI-) based regimen for at least 30 days prior to study entry, and not planning on starting PIs or NNRTIs during the 6-week study period. Women who have not been on HAART for at least 30 days prior to study entry are also eligible.
• For patients not receiving HAART, documentation that they have been counseled about the benefits of HIV treatment within 90 days of study entry and have elected not to initiate therapy

Exclusion Criteria for All Participants:

• Use of systemic hormonal therapies containing estrogens, progestins, or anabolic steroids (e.g., estrogen, progesterone, oral contraceptives, Mirena [levonorgestrol] intrauterine device [IUD], Progestasert [progesterone] IUD) within 60 days of study entry
• Anabolic therapies (nandrolone decanoate or megestrol) within 60 days of study entry
• Systemic glucocorticoids within 14 days of study entry
• Certain medical conditions. More information on this criterion can be found in the protocol.
• Need for prolonged bedrest after major surgery
• Smokers of ages 35 or older
• NNRTIs within 30 days of study entry
• Nausea, vomiting, or abdominal pain of Grade 3 or higher within 30 days of study entry
• Known allergy or sensitivity to ethinyl estradiol (EE), norelgestromin (NGMN), or components of the Ortho Evra contraceptive patch
• Known allergy or sensitivity to norethindrone or components of the ON 1/35 oral contraceptive pill
• Serious illness requiring systemic treatment or hospitalization within 14 days of study entry
• Undiagnosed abnormal vaginal bleeding
• Depo-Provera (medroxyprogesterone acetate) within 180 days of study entry
• Lunelle (estradiol cypionate and medroxyprogesterone acetate) within 90 days of study entry
• Use of certain medications within 30 days of study entry
• Current drug or alcohol use or dependence that, in the opinion of the investigator, may interfere with the study
• Unable to adhere to HAART, the Ortho Evra contraceptive patch, or single dose ON 1/35 regimens

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 13 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: National Institute of Allergy and Infectious Diseases (NIAID) NIH

Overall Clinical Trial Officials and Contacts

Lori Kamemoto, MD, MPH Study Chair Hawaii AIDS Clinical Research Program, University of Hawaii School of Medicine  

Information obtained from ClinicalTrials.gov on February 02, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00125983

Study ID Number: ACTG A5188

ClinicalTrials.gov Identifier: NCT00125983

Health Authority: United States: Food and Drug Administration

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