Clinical Trial on the Effects of Progestin-based Contraception in the Genital Tract of HIV-infected and Uninfected Women
Condition: HIV; Contraception
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine the acceptability of randomization to contraceptive
      options and estimate the effect of progestin contraception on HIV genital shedding and
      inflammatory/immune perturbations in women who may or may not be on antiretroviral therapy,
      as well as in HIV-uninfected women controls. It is hypothesized that progestin-containing
      contraception will lead to inflammatory changes that may affect the local immune activity,
      influencing HIV acquisition or transmissibility risk.
    

Detailed description: 
      Hormonal contraception is a central component in the prevention of unintended pregnancy;
      however there are concerns that certain methods may increase the risk of heterosexual HIV
      acquisition and transmission. Some studies, but not others, have suggested a link between
      hormonal contraceptive use and enhanced HIV-susceptibility, more rapid HIV disease
      progression, and increased transmissibility to partners. Hormonal contraception modifies the
      genital mucosa in several ways, and the interactions of the endocrine and immune system are
      complex but incompletely understood. In some cross-sectional studies, hormonal contraceptives
      appear to be associated with increased shedding of HIV DNA, but not RNA, in the genital
      tract, and the significance of these findings for HIV transmissibility are unclear. Very few
      studies have examined genital HIV shedding prospectively before and after initiation of
      contraception. The effects of hormonal contraception in the setting of antiretroviral therapy
      (ART) are also unknown.

      Hormonal contraception, particularly injectable DMPA, is widely used in many parts of the
      world, including settings with high HIV prevalence. It is important that the effects of
      hormonal contraception on HIV acquisition and HIV shedding and subsequent transmissibility be
      determined. The effect of progestin contraceptive implants, such as the levonorgestrel rod
      implant (LNG implant), on HIV shedding is unknown, and it will be of interest to evaluate it
      compared with the injectable progestin (DMPA), given their different kinetics of hormone
      release, differences in progestin type, and the high efficacy of both methods.

      We propose a pilot study among 100 HIV-infected women and 30 uninfected women in Lilongwe,
      Malawi randomized to either DMPA or LNG implant to: 1) assess the effect and compare the
      impact of type of progestin-containing contraception (injectable versus implant) on HIV viral
      shedding in the genital tract of HIV+ women, 2) assess the effect and compare the impact of
      type of progestin-containing contraception (injectable versus implant) on inflammatory/immune
      markers in the genital tract of both HIV+ and HIV- women, and 3) assess the interaction of
      progestin-based hormonal contraception and ART by examining: i. contraceptive efficacy
      (measured by systemic hormone levels and pregnancy rate during follow-up), and ii. ART
      efficacy (by drug concentrations in blood and genital tract and HIV viral load response in
      the plasma in women on ART).

      An overall study aim is to determine the feasibility and need for a larger study of
      determinants of HIV transmissibility and acquisition in this population.

      The study would take place at Bwaila Maternity Hospital, which was the site of the
      CDC-sponsored Breastfeeding, Antiretrovirals, and Nutrition (BAN) clinical trial, a partner
      project with this study. Women attending the clinics at Bwaila (a large proportion of whom
      participated in the BAN study) who desire to start hormonal contraception will be informed of
      the new study and counseled on the progestin-based contraceptives that are available within
      the study. BAN women will be specifically targeted for recruitment through radio messages.
      Eligible women who provide informed consent and agree to randomization to either DMPA or the
      LNG implant will be enrolled. HIV-infected women may be on ART or they may be pre-ART.

      To address the primary outcomes of HIV shedding and mucosal immune activation, we will
      quantify genital tract HIV RNA and inflammatory/immune markers at two time points before and
      four time points after randomization of the 100 HIV-infected and 30 HIV-uninfected women to
      DMPA or LNG-implant. The two time points prior to randomization will occur within the prior
      menstrual cycle, so that one visit occurs in the follicular phase and the other occurs in the
      luteal phase of the cycle. Assessments after initiation of contraception will occur on days
      3, 30, 90, and 6 months. Antiretroviral levels in the blood and genital tract will also be
      assessed at these time points.

      Based on recent evidence suggesting that the LNG implant may have decreased contraceptive
      efficacy when used in combination with the antiretroviral efavirenz, study follow-up will be
      extended to include visits at about 9, 12, 15, 18, 21, 24, 27, 30, and 33 months after
      initiation of contraception for a total of 6 additional visits per participant. Not all
      participants will start the study extension at the same time point, so the 6 additional
      visits can span from about 9 months to 24 months after contraceptive initiation to about 18
      months to 33 months after contraceptive initiation. Assessments at these visits will address
      the outcomes of contraceptive and ART efficacy and HIV shedding.

      To analyze the effects of progestin contraception on HIV shedding, as well as the effect of
      each contraceptive type, HIV-infected women on progestin-based contraception will be compared
      within each study arm (before and after initiation of contraception), as well as between the
      two contraceptive arms. Antiretroviral use will be evaluated for an independent effect on HIV
      shedding and also to determine if it modifies the effect of menstrual cycle or progestin
      contraception on HIV shedding. To analyze the effects of progestin contraception on genital
      inflammatory/immune markers, both HIV-infected and HIV-uninfected women on progestin-based
      contraception will be compared separately and combined, with HIV status treated as a
      potential effect modifier, within each study arm (before and after initiation of
      contraception), as well as between the two contraceptive arms. This study will provide
      information on acceptability of randomization to contraceptive options, overall study
      retention, and estimates of the effect of progestin contraception on HIV genital shedding and
      inflammatory/immune perturbations in women who may or may not be on antiretroviral therapy,
      as well as in HIV-uninfected women controls. This information will be instrumental in
      determining the need for and feasibility of a larger study to address these outcomes.
    

Intervention name(s): Depo-Medroxyprogesterone Acetate; Progestin Contraceptive (Jadelle)
Intervention type(s): Drug; Drug
Intervention description(s): 150 mg Depo-Medroxyprogesterone Acetate administered every 13 weeks; 2 implants containing 75 mg of levonorgestrel will be implanted and will last for up to 5 years
Other intervention name(s): Depo provera; DMPA; injectable contraception; Jadelle; Contraceptive Implant
Intervention MeSH terms: Medroxyprogesterone Acetate; Contraceptive Agents; Medroxyprogesterone; Progestins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: contraceptive implant; Depo-Medroxyprogesterone Acetate; Hormonal Contraception; progestin