A Study to Evaluate the Effects of Different Methods of Birth Control on the Drug Actions of Zidovudine (an Anti-HIV Drug) in HIV-Positive Women and to Compare Zidovudine Metabolism in Men and Women
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      The purpose of this study is to look at the effects of different methods of birth control
      (oral and injectable) on how the body absorbs, makes available, and removes zidovudine (ZDV).
      This study will also evaluate the differences in men and women in how the body absorbs, makes
      available, and removes ZDV.

      Past research has shown that the effectiveness of ZDV as an anti-HIV drug might be decreased
      in individuals who use certain methods of birth control. ZDV may also have different effects
      in men compared to women.
    

Detailed description: 
      Oral contraceptives have been shown to substantially enhance the glucuronidation of several
      compounds. One study reported enhanced glucuronidation of oxazepam, a compound that is
      conjugated via the same UDP-glucuronyl transferase isozyme responsible for ADV
      glucuronidation, suggesting that ZDV metabolism may be altered by concomitant oral
      contraceptive use. This potential enhancement of ZDV metabolism by oral contraceptives is
      expected to result in decreased plasma levels of the parent compound which may lead to
      diminished clinical efficacy in women using these drugs. It remains unclear whether the
      progesterone and/or estrogen component of oral contraceptives results in the observed
      glucuronidation changes.

      This open-label, pharmacokinetic trial is conducted in 2 steps. [AS PER AMENDMENT 6/12/01:
      The Depo-Provera IM group in Step 2 is filled. Female patients who choose to participate in
      Step 2 may enroll only in the Ortho-Novum 1/35 PO group.] [AS PER AMENDMENT 11/13/00: Female
      patients may choose to participate in Step 1 alone or both Steps 1 and 2.] Male patients may
      participate in Step 1 only as the control arm of the study. In Step 1, patients are
      stratified by sex; in Step 2, female patients are stratified by their choice of contraception
      (i.e., oral norethindrone/ethinyl estradiol [Ortho-Novum 1/35] or injectable
      medroxyprogesterone acetate [Depo-Provera]).

      Step 1 (males and females): At entry, all patients are randomized to receive ZDV either
      orally or orally and intravenously (IV) on Days 7 and 8. Female patients begin the study (Day
      0) between days 10-18 after the first day of their last menstrual period (LMP) (Cycle 1). At
      time of enrollment, female patients [AS PER AMENDMENT 11/13/00: who plan to participate in
      Step 2] choose the form of birth control instituted in Step 2: Depo-Provera or Ortho-Novum
      1/35. Male patients may enter Step 1 at any time. Patients continue taking their other
      pre-study antiretroviral drugs during Step 1. [AS PER AMENDMENT 6/3/99: Patients taking
      nelfinavir may participate only in the Depo-Provera arm.] Days 0-6: All patients receive oral
      ZDV. Day 7: Patients are randomized to receive:

      Arm 1 (females): oral ZDV for a total of 3 doses. Arm 2 (females): ZDV IV, then ZDV orally
      for a total of 2 oral doses. Arm 3 (males): control arm. Half of the male patients receive
      ZDV as in Arm 1 and the other male patients receive ZDV as in Arm 2.

      Day 8: Patients on all 3 arms receive the alternate form of ZDV to that received on Day 7.
      Day 9: Female patients resume their pre-study method of administration of ZDV. Male patients
      conclude their participation in the study on Day 8.

      Step 2 (females [AS PER AMENDMENT 11/13/00: opting to participate in Step 2]): At the onset
      of their second menstrual period (Cycle 2) since starting study, female patients start their
      choice of Ortho-Novum 1/35 or intramuscularly administered Depo-Provera [AS PER AMENDMENT
      6/12/01: Enrollment for Depo-Provera is closed]. Contraceptive therapy continues throughout
      Step 2. Step 2 Days 0-6: Between days 7-11 [AS PER AMENDMENT 6/3/99: Between days 7-18] of
      the third menstrual cycle (Cycle 3) since starting study, female patients continue their
      pre-study antiretroviral therapy (as done in Step 1) and begin another course of ZDV standard
      therapy 3 times daily. Days 7-8: Patients receive the original method of administration of
      ZDV (as randomized at study entry). Female patients return for a final safety visit within 1
      week of completing study Day 8 of Step 2.
    

Intervention name(s): Zidovudine
Intervention type(s): Drug
Intervention MeSH terms: Zidovudine
Primary purpose: Treatment
Keywords: Drug Interactions; Zidovudine; Sex Factors; Reverse Transcriptase Inhibitors; Contraceptives, Oral; Progestational Hormones, Synthetic; Anti-HIV Agents; Viral Load; Estrogens