The Effect of Protease Inhibitors on the Pharmacokinetics of Oral Norethindrone Contraception
Condition: Pregnancy; HIV; AIDS
Study type: Interventional

Summary: 
      The purpose of this study is to learn if women taking the atazanavir and ritonavir have lower
      levels of a birth control medication called norethindrone. Norethindrone (also called the
      mini pill) is an FDA (Food and Drug Administration) approved progestin-only birth control
      pill used to prevent pregnancy. Norethindrone is the standard medication used in women who
      take the progestin only pill to prevent pregnancy. There are other birth control pills which
      contain different medications. The investigators want to learn if HIV medications (atazanavir
      and ritonavir) make the blood level of this birth control pill higher or lower. If the levels
      of norethindrone are too low it may not work to prevent pregnancy. The investigators also
      hope to learn about changes in the vaginal fluids and cervical fluids when women are taking
      this birth control pill.
    

Detailed description: 
      BACKGROUND/RATIONALE : It is recognized that there is a dearth of clinically applied,
      population based, empiric data to guide contraceptive recommendations in HIV + women on
      ARVs.(1) Protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI
      ) induce micro enzyme systems such as CYP 3a4, which in turn alters the bio-availability and
      pharmacokinetics of other concurrently administered medications.(2) Empiric trials from small
      samples, often of 10-20 HIV negative subjects, have demonstrated that concurrent
      administration of combined oral contraceptives (COC) and a PI or a NNRTI have been associated
      with decreased plasma ethinyl estradiol (EE) levels. These pharmacokinetic findings have
      raised concern that decreased bio-availability of EE may result in decreased contraceptive
      efficacy, with possible increased unintended pregnancy. Some of these COC studies have
      demonstrated that there is no change in the serum levels of norethindrone (NET) on
      ARVs.(3-16) However, there are no published trials focused on oral NET or oral progestin-only
      pills (POP) to guide management in HIV+ women.(17)

      OBJECTIVES:

      Primary objective of this study is:

      To detect a ±40% difference in AUC of serum NET in HIV+ women taking ATV/RTV as compared to
      AUC of NET in HIV+ women taking an ARV regimen that has demonstrated no interaction with NET
      in the past.

      Primary endpoint: Natural log-transformed NET PK parameter AUC from 0 to 72 hours following
      oral administration, with multiple discrete serum data points for each subject on ATV/RTV.
      This will be compared to natural log-transformed NET PK AUC from 0 to 72 hours following oral
      administration, with multiple discrete serum data points for controls HIV+ women taking an
      ARV regimen that has demonstrated no interaction with NET in the past.

      The secondary objectives of this study are:

      To evaluate the effect of ATV/RTV on other PK exposure endpoints and parameters of NET (with
      natural log transformation). The sample and control groups mentioned above will again be
      compared. Endpoints include:

      minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), time to Cmax
      (Tmax), and half-life (T1/2).

      SAMPLE SIZE: Recruitment of 16 participants in each arm, with the goal of attaining 32
      evaluable HIV-1-seropositive female subjects in total.

      POPULATION/STUDY ARMS: HIV-1-infected female subjects 18-44 years of age

      METHODOLOGY/INTERVENTIONS/FOLLOW-UP: A two-arm, open-label, prospective, steady state trial
      to characterize the pharmacokinetics (PK) of oral norethindrone (NET) as a progestin only
      contraceptive pill (POP) in HIV+ women receiving atazanavir and ritonavir therapy (ATV/RTV).
      The investigators will identify a control group of HIV+ women who are taking ARV regimens
      that have not significantly altered oral NET levels in prior trials. Subjects will be
      enrolled in the trial for approximately 4 weeks A 28 day continuous packet of NET 0.35 mg
      will be provided to all enrolled volunteers for 21 days of continuous administration. Women
      who participate in this study will demonstrate a means of continuing their ARV regimens for
      the duration of the study, ARV therapy will not be provided by this study. On day 22 subjects
      will be admitted for serial pharmacokinetic (PK) specimens collection following the final
      study dose of NET.

      Subjects will be enrolled into one of the 2 arms based on their current ARV regimen.

      Study group: Women on stable ARV/RTV (300/100mg daily) with additional ARV regimens that have
      not significantly altered oral NET levels in prior trials. (n=12).

      Control group: Stable on current ARV, no protease inhibitors (PI), ARV regimens that have not
      significantly altered oral NET levels in previous research.

      OUTCOMES: Intensive PK sampling for NET will be performed in those in intervention and
      control arms after 21 days of NET administration. To determine side effect profile of NET by
      self-administered daily questionnaire during the 3-4 week study enrollment period

      STATISTICS: Area under the concentration-time curve (AUC), peak plasma concentration, and the
      lowest plasma concentration for NET in HIV+ women receiving this PI therapy will be
      determined and compared to similar values in HIV positive control subjects who are not taking
      PI therapy. Statistical consultation will be obtained from the USC Keck School of Medicine
      Department of Bio statistics and Laboratory of Applied Pharmacokinetics
    

Intervention name(s): Norethindrone acetate
Intervention type(s): Drug
Other intervention name(s): Both control and experimental group with take norethindrone. However the experimental group will be taking a protease inhibitor: atazanavir and ritonavir
Intervention MeSH terms: Ritonavir; Atazanavir Sulfate; Norethindrone; Norethindrone Acetate; Protease Inhibitors
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: contraception; mini pill; norethindrone; atazanavir; ritonavir; norvir; reyataz; pregnancy prevent; birth control; HIV; AIDS; antiviral; antiretroviral