Depo-Medroxyprogesterone Acetate (DMPA, Depo-Provera) Use With Certain Anti-HIV Drugs in HIV-Infected Women

Condition(s) targeted: HIV Infections

Intervention: Indinavir sulfate (Drug); Ritonavir (Drug); Nelfinavir mesylate (Drug); Efavirenz (Drug); Nevirapine (Drug); Medroxyprogesterone acetate (Drug)

Phase: N/A

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Susan Cohn, Study Chair

The purpose of this study is to look at the level of depo-medroxyprogesterone acetate (DMPA or Depo-Provera) in the blood to see if is affected by certain anti-HIV drugs (nelfinavir [NFV], efavirenz [EFV], indinavir [IDV] in combination with ritonavir [RTV], and nevirapine [NVP]). This study will also look at the levels of these anti-HIV drugs to see if they are affected by DMPA.

DMPA is a hormonal birth control method that is given as an injection. It is not known if taking DMPA together with anti-HIV drugs changes the amount of DMPA and/or the amount of anti-HIV drugs in the blood. If higher levels of DMPA occur, side effects may increase. If lower levels of anti-HIV drugs occur, the drugs may become less effective against HIV. This study will look at the levels of anti-HIV drugs and DMPA in the blood when these medications are used together.

Official title: An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Between Depo-Medroxyprogesterone Acetate (DMPA, Depo-Provera) and Selected Protease Inhibitor (PI) and Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Therapies Among HIV-Infected Women

Study design: Treatment, Pharmacokinetics Study

Detailed description: DMPA, an injectable depot formulation of medroxyprogesterone (MPA), is a commonly used form of "progestin-only" contraception. Information is limited on the specific P450 isozymes that metabolize MPA; however, it appears that CYP3A4 is 1 pathway of hepatic clearance. Drugs known to be inhibitors of the CYP3A4 pathway (such as protease inhibitors [PIs]) may lead to elevated concentrations of MPA. Secondly, MPA given as DMPA injections has been shown to induce the activity of CYP3A4 by 25 percent. It is possible that this action may result in enhanced clearance of the substrates of CYP3A4, including PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs), which in turn may result in reduced drug exposure and possible ARV failure. This study is designed to address the lack of information on potential interactions between PIs or NNRTIs and DMPA.

Patients are enrolled into 1 of 5 arms based on their current ARV regimen:

Arm A (control group): No current ARVs or receiving nucleoside reverse transcriptase inhibitors (NRTIs) only.

Arm B: NFV (1250 mg bid or 750 mg tid) in combination with NRTIs. Arm C: EFV (600 mg qd) in combination with NRTIs. Arm D: IDV (800 mg bid) and RTV (100 mg bid or 200 mg bid) in combination with NRTIs.

Arm E: NVP (200 mg bid) in combination with NRTIs. Acceptable NRTIs and any fixed combination of these medications include: zidovudine (ZDV), lamivudine, didanosine, stavudine (d4T), zalcitabine, and abacavir; concurrent therapy using ZDV and d4T is not allowed. ARV therapy is not provided by this study. One dose of DMPA is provided to all patients at entry (Day 0) and an optional dose of DMPA will be available at the final visit (Week 12) for those who are interested in continuing with DMPA outside of the protocol and who do not experience adverse events from the first DMPA injection. Patients in Arms B, C, D, and E have intensive pharmacokinetic sampling done at entry and at Week 4 to measure ARV levels. All patients have blood tests at Weeks 2, 4, 6, 8, 10, and 12 to measure levels of DMPA and progesterone. In addition, tests to monitor HIV-1 RNA levels, CD4 and CD8 counts, hematology, blood chemistries, and liver function are performed periodically.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria

Patients may be eligible for this study if they:

- Are HIV-positive.

- Have plasma HIV-1 RNA (level of HIV in the blood) below 10,000 copies/ml within 30

days before study entry.

- Had their last menstrual period (LMP) less than 35 days before study entry.

- Have serum follicle-stimulating hormone below 40 MIU/ml if their LMP occurred more

than 35 days before study entry.

- Have been on the same anti-HIV drugs for at least 30 days before study entry, if

taking anti-HIV drugs. If not taking anti-HIV drugs, patients must have been told about anti-HIV drugs within the 3 months before study entry and have chosen not to take them now or in the future.

- Intend to continue on their anti-HIV drugs, if taking them, for at least 3 months

after study entry.

- Have a CD4 cell count above 200 cells/mm3 if taking anti-HIV drugs, or a CD4 cell

count above 350 cells/mm3 if not taking anti-HIV drugs, within 30 days before study entry.

- Have not had menopause (change of life) and have a normal reproductive system.

- Have not had any infections or AIDS-related diseases requiring drugs within 14 days

before study entry.

- Are 13 years of age or older.

- Are female.

- Have a negative pregnancy test within 30 days before study entry.

- Agree to avoid becoming pregnant for the entire study. If sexually active, agree to

use at least 1 barrier method of birth control (male or female condom with or without spermicide [a cream or gel that kills sperm] or diaphragm or cervical cap with spermicide) while receiving DMPA in this study.

- Have consent of a parent or guardian if under 18 years of age.

- Weigh at least 40 kg (88 lbs) and are within a certain range of their ideal body

weight.

Exclusion Criteria

Patients will not be eligible for this study if they:

- Have taken anti-HIV drugs within 30 days before study entry but have chosen not to

take them.

- Are taking only 1 NRTI.

- Are taking anti-HIV drugs other than those listed in the treatment groups, including

tenofovir, amprenavir, and lopinavir/ritonavir, or have taken tenofovir, amprenavir, or lopinavir/ritonavir within 30 days before study entry.

- Have taken ZDV and d4T together within 30 days before study entry.

- Are not able to take the anti-HIV drugs properly while on the study, in the opinion of

the investigator.

- Are allergic to DMPA, MPA, or any of the other ingredients in DMPA.

- Have received DMPA within 180 days before study entry.

- Have received other hormones (Provera, oral contraceptives, hormonal replacement

therapy, or anabolic drugs [e. g., nandrolone decanoate, megestrol acetate]) within 30 days before study entry.

- Are taking any of the following: amiodarone, astemizole, bepridil, buspirone,

carbamazepine, cimetidine, cisapride, clarithromycin, cyclosporine, dihydroergotamine, diltiazem, ergotamine, erythromycin, flecainide, glucocorticoids, grapefruit juice, St. John's wort, itraconazole, ketoconazole, lovastatin, midazolam, nefazodone, phenobarbital, phenytoin, pimozide, pioglitazone, propafenone, propofol, quinidine, rifabutin, rifampin, rosiglitazone, simvastatin, tacrolimus, terfenadine, ticlopidine, triazolam, or verapamil.

- Have taken any of the following drugs within 30 days before study entry: amiodarone,

astemizole, bepridil, buspirone, carbamazepine, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergotamine, erythromycin, flecainide, glucocorticoids, St. John's wort, itraconazole, ketoconazole, lovastatin, midazolam, nefazodone, phenobarbital, phenytoin, pimozide, pioglitazone, propafenone, propofol, quinidine, rifabutin, rifampin, rosiglitazone, simvastatin, tacrolimus, terfenadine, ticlopidine, or triazolam.

- Have started, stopped, or changed doses, within 30 days before study entry, of certain

drugs including: benzodiazepines, except midazolam and triazolam; bupropion; calcium channel blockers, except diltiazem and verapamil; fluconazole; lipid-lowering drugs except pravastatin (i. e., atorvastatin, cerivastatin, and fluvastatin, but not lovastatin and simvastatin); isoniazid; mexiletine; zaleplon; and zolpidem. The patient can, however, remain on stable doses of these drugs during the study.

- Are receiving methadone maintenance treatment for less than 60 days before study

entry.

- Are breast-feeding.

- Have had a baby within 30 days before study entry.

- Have had their uterus or both ovaries removed.

- Abuse drugs or alcohol.

- Cannot stop drinking alcohol 1 day before and during the testing at entry and at Week

4.

- Have had a change in smoking habits within 6 weeks before study entry. Patients may

have either stopped or started smoking more than 6 weeks before study entry.

- Have cancer of the reproductive system, vaginal bleeding of unknown cause, thyroid

problems, liver tumors, or serious eye problems at any time before study entry.

- Are taking investigational drugs without approval of the protocol chair.

San Juan City Hosp, San Juan 009367344, Puerto Rico

Univ of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States

Los Angeles County - USC Med Ctr, Los Angeles, California 90033, United States

Children's Hosp of Denver, Denver, Colorado 802181088, United States

Univ of Miami (Pediatric), Miami, Florida 33161, United States

Univ of Florida Health Science Ctr / Pediatrics, Jacksonville, Florida 32209, United States

Univ of Illinois College of Medicine / Pediatrics, Chicago, Illinois 60612, United States

Mt Sinai Hosp Med Ctr / Dept of Pediatrics, Chicago, Illinois 60608, United States

Chicago Childrens Memorial Hosp (Pediatric), Chicago, Illinois 60614-3394, United States

The Univ of Chicago Childrens Hosp, Chicago, Illinois 60637, United States

Indiana Univ Hosp, Indianapolis, Indiana 46202-5250, United States

Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States

Wishard Hosp, Indianapolis, Indiana 46202, United States

Tulane Univ / Charity Hosp of New Orleans, New Orleans, Louisiana 701122699, United States

Univ of Maryland, Institute of Human Virology, Baltimore, Maryland 21201, United States

Boston Med Ctr (Pediatric), Boston, Massachusetts 02118, United States

Children's Hosp of Michigan, Detroit, Michigan 48201, United States

Univ of Rochester Medical Center, Rochester, New York 14642, United States

SUNY Health Sciences Ctr at Syracuse / Pediatrics, Syracuse, New York 13210, United States

Beth Israel Med Ctr, New York, New York 10003, United States

Columbia Presbyterian Med Ctr, New York, New York 10032, United States

St Mary's Hosp (Univ of Rochester/Infectious Diseases), Rochester, New York 14642, United States

Community Health Network, Inc, Rochester, New York 14642-0001, United States

Univ of North Carolina, Chapel Hill, North Carolina 27514, United States

Univ of Cincinnati, Cincinnati, Ohio 452670405, United States

MetroHealth Med Ctr, Cleveland, Ohio 44109-1998, United States

Case Western Reserve Univ, Cleveland, Ohio 44106-5083, United States

Univ of Pennsylvania, Philadelphia, Pennsylvania 19104, United States

Univ of Texas Galveston, Galveston, Texas 775550435, United States

Children's Hospital & Medical Center / Seattle ACTU, Seattle, Washington 981050371, United States

Univ of Washington, Seattle, Washington 98104, United States

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Last updated: January 31, 2008