A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy
Information source: University of Nebraska
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV; Contraception
Intervention: Levonorgestrel (Drug); Nevirapine (Drug); Efavirenz (Drug)
Phase: Phase 2
Status: Active, not recruiting
Sponsored by: University of Nebraska Official(s) and/or principal investigator(s): Kimberly K Scarsi, PharmD, MSc, Principal Investigator, Affiliation: University of Nebraska
Summary
The use of hormone contraception poses a significant challenge for the estimated 16 million
HIV-infected women of childbearing age. This is due to known drug interactions with
antiretroviral therapy (medicines used to treat HIV) that may jeopardize contraception
effectiveness. By evaluating the impact of antiretroviral therapy on a levonorgestrel
subdermal implant, the most widely available hormone implant in low and middle-income
countries, this study will translate its findings into an evidence-based approach to
co-manage these important medications. The investigators hypothesize that women receiving
nevirapine or efavirenz-based antiretroviral therapy will have a significant decrease in the
mean levonorgestrel plasma concentration measured six months after the implant's insertion
as compared to those women who are not taking antiretroviral therapy. Although the
implant's efficacy may be retained initially, the investigators propose that a decrease in
levonorgestrel concentrations in women receiving antiretroviral therapy may jeopardize the
implant's effectiveness near the end of its intended duration of use (5 years).
Clinical Details
Official title: A Pharmacokinetic Evaluation of Levonorgestrel Implant and Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Antiretroviral Therapy in HIV-infected Ugandan Women
Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Levonorgestrel plasma concentrations
Secondary outcome: NNRTI plasma concentrationsLevonorgestrel plasma concentrations
Detailed description:
Family planning services, including hormone contraceptives, are critical for HIV-infected
women, in whom prevention of unintended pregnancy not only decreases maternal and child
mortality, but also reduces the risk of mother-to-child HIV transmission. Similarly,
antiretroviral therapy (ART) is a lifesaving intervention that improves the health and
economic status of HIV-infected women throughout the world. Therefore, it is of significant
public health importance to guide the appropriate use these essential medications. To this
end, millions of HIV-infected women in low and middle income countries (LMIC) currently use
or are gaining access to subdermal progestin-containing implants as a preferred method of
long-acting reversible contraception. These implants are often combined with ART despite the
lack of critically needed pharmacokinetic (PK) drug-interaction data to inform their safe
and effective concomitant use. Highlighting this concern are several case reports of
unintended pregnancy that occurred in patients with subdermal progestin-containing implants
concurrently receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, the
most commonly used ART in LMICs. While NNRTIs are known to significantly decrease oral pill
progestin concentrations, no data are available to inform healthcare providers of the impact
of NNRTIs on progestin concentrations following release from subdermal implants. To fill
this critical gap in knowledge, the overall aim of this proposal is to conduct a PK study to
evaluate the combination of a levonorgestrel (LNG) implant and NNRTI (nevirapine or
efavirenz)-based ART in HIV-infected Ugandan women. The investigators propose that lower LNG
concentrations will be observed in patients on NNRTI-based ART and although the implant's
efficacy may be retained initially, this negative interaction will jeopardize implant
effectiveness near the end of its intended duration of use (5 years). The specific aims of
this project are (1) to characterize the PK of LNG released from a subdermal implant over
one year in HIV-infected women with and without NNRTI-based ART and (2) to evaluate the
potential for a bidirectional drug-interaction resulting from the long-term impact of
chronic progestin exposure on antiretroviral concentrations. To achieve these aims, this
study will enroll 20 HIV-infected women into each of three study groups: a control group not
receiving ART and two treatment arms consisting of patients receiving nevirapine- or
efavirenz- based ART. Using sparse PK sampling strategies, LNG, nevirapine or efavirenz
concentrations will be measured over one-year and compared between and within groups, as
appropriate. The LNG data will also be used to develop a PK model that will predict LNG
disposition over the following three years of intended use, allowing for identification of
the safe duration of LNG implant use in women on NNRTI-based ART. At the conclusion of this
project, the first evidence-based medical knowledge will be available to guide the safe and
effective concomitant use of subdermal LNG implants and NNRTIs, thereby improving management
of reproductive health in millions of HIV-infected women worldwide.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Female.
Criteria:
Inclusion Criteria:
- Evidence of a personally signed and dated informed consent document indicating that
the subject (or a legal representative) has been informed of all pertinent aspects of
the study.
- Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
- Women age 18 years or older
- Diagnosed with HIV-1 infection
- Desiring LNG subdermal implant as a contraceptive method
- Subjects not yet eligible for ART (based on the Ugandan Treatment Guidelines); or
subjects receiving nevirapine or efavirenz-based ART for a minimum of 1 month prior
to screening
Exclusion Criteria:
- For patients currently on ART: HIV-1 RNA > 400 copies/mL at screening visit
- Serum hemoglobin < 9. 0 g/dl
- Elevations in serum levels of alanine transaminase (ALT) above 5 times the upper
limit of normal
- Elevations in serum creatinine above 2. 5 times the upper limit of normal
- Use of drugs known to be contraindicated with levonorgestrel, nevirapine (NVP group
only), or efavirenz (EFV group only) within 30 days of study entry. Due to the
dynamic nature of drug interactions related to antiretroviral therapy, the study team
will review all concomitant medications at screening based on the US Department of
Health and Human Services drug interaction tables or the AIDS Clinical Trials Group
Drug Interactions Database.
- Currently pregnant or postpartum <30 days at study entry
- No concurrent use of other hormonal contraception is allowed during the study period
Locations and Contacts
Infectious Diseases Institute, Kampala, Uganda
Additional Information
Related publications: 42. Scarsi KK*, Darin KM, Nakalema S, Back D, Byakika-Kibwika P, Else L, Dilly-Penchala S, Cohn S, Merry C, Lamorde M. Levonorgestrel implant + EFV-based ART: Unintended pregnancies and associated PK Data. Conference on Retroviruses and Opportunistic Infections. Seattle, WA. February 23-26, 2015. Abstract #85LB. Scarsi K, Lamorde M, Darin K, Penchala SD, Else L, Nakalema S, Byakika-Kibwika P, Khoo S, Cohn S, Merry C, Back D. Efavirenz- but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant. J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19484. doi: 10.7448/IAS.17.4.19484. eCollection 2014.
Starting date: June 2013
Last updated: May 27, 2015
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