Prospective Cohort Evaluating Pregnancy Rates, PK Interactions Among HIV+ Women on EFV Initiating LNG Implant or DMPA (FP-ART)

A Prospective Cohort Evaluating the Pregnancy Rates and Pharmacokinetic Interactions Among HIV-infected Malawian Women on Efavirenz Initiating the Levonorgestrel Implant or the Depot Medroxyprogesterone Acetate Injectable

The purpose of this study is to compare the pregnancy rates among women who are using the HIV drug Efavirenz and either the birth control injection or implant.

Study Overview

• Status: Completed
• Conditions: HIV Infections

Detailed Description

Objective 1: To compare the typical-use pregnancy rates of 710 HIV+ DMPA-users on EFV with 710 HIV+ LNG implant users on EFV through a prospective observational cohort.

The investigators will enroll 710 HIV-infected women on EFV who are initiating the LNG implant and 710 HIV-infected women on EFV who are initiating the DMPA injectable and follow them 1 month after contraceptive initiation and then every 6 months until the end of the 4-year study time period. The investigators will recruit and enroll over a period of 2 years; those who are enrolled at the beginning of the enrollment period may complete up to 4 years of follow-up, whereas those who are enrolled at the end of the 2-year enrollment period will complete 2 years of follow-up. Women will have urine, blood, and hair specimens obtained at each study visit. The primary outcome will be incident pregnancy, evaluated by urine pregnancy testing. The secondary outcome will be contraceptive continuation, evaluated by palpation (for LNG implant) and review of the woman's medical record and study forms (for DMPA). A marginal structural Poisson model will be used to estimate the effect of implant compared to DMPA upon pregnancy incidence. The investigators will adjust for key potential confounders, including frequency of intercourse, age, and body mass index (BMI).

Objective 2: To assess whether greater EFV exposure (measured by hair concentrations) is associated with contraceptive failure in LNG implant users in a 2:1 nested case-control study of 240 LNG implant users.

The investigators estimate that a maximum of 120 pregnancies will occur among LNG implant users in the cohort in Objective 1. From this cohort, the investigators will compare 80 pregnant women who were using the LNG implant at the time of conception and 160 controls who had intercourse during the previous 3 months and were not pregnant after a similar period of LNG implant use. A conditional logistic regression model will be used to assess the association between EFV hair concentrations and contraceptive failure; key potential confounders the investigators will adjust for in the analysis include frequency of intercourse, age, weight, and length of time on EFV. The data for this Objective's exposure, outcome, and confounders will be derived from the Data Collection Forms and study specimens obtained in Objective 1.

Objective 3: To evaluate the effect of EFV 400 mg daily on LNG concentrations among a subset of 25 women enrolled in the prospective cohort study who initiated the LNG implant.

The investigators plan to enroll 25 of the 710 EFV users from their prospective cohort in Objective 1 who are initiating the LNG implant into the pharmacokinetic sub-study. All 25 of these women will be enrolled from 1 health facility, Area 18 Health Centre, and all women will be taking EFV 400 mg daily, which is the standard dose that Malawi will be implementing this year due to its equivalent efficacy but decreased cost and side effects when compared to EFV 600 mg daily. Follow-up visits for women in the sub-study will be conducted at 4, 12, 24, 36, and 48 weeks post-implant initiation. Since these women would already be attending visits at 4, 24, and 48 weeks post-implant initiation, there will only be 2 extra study visits for these sub-study participants at 12 weeks post-implant initiation (Visit 1a) and 36 weeks post-implant initiation (Visit 2a). During the extra Visits 1a and 2a, urine, blood, and hair specimens will be obtained so that pregnancy testing can be performed and blood and hair can be stored for VL, EFV, and LNG testing.

• Study Type: Observational
• Enrollment (Actual): 1382

Contacts and Locations

Study Locations

• Malawi
  • Lilongwe, Malawi
    • UNC Project

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

710 HIV-infected women on EFV who are initiating the LNG implant and 710 HIV-infected women on EFV who are initiating the DMPA injectable

Description

Inclusion Criteria:

1. Age 18-40 years
2. Documented HIV-infected status
3. Current use of EFV
4. Fluency in English or Chichewa (the most commonly-spoken language in Malawi)
5. Not currently pregnant (to be confirmed by urine pregnancy test)
6. Initiation of DMPA or the LNG implant within the past 28 days (to be confirmed by verification in the woman's Health Passport and palpation of the implant if applicable)
7. No use of their current contraceptive during the 3 months before they recently initiated it (i.e., they must be newly starting and not just continuing their chosen contraceptive)
8. No desire for pregnancy in the next 4 years
9. Most recent HIV VL <1,000 copies/mL (as per Malawi guidelines, women who have VL ≥1,000 copies/mL will need to be referred for possible 2nd-line ART without EFV)

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pregnancy rates of 710 HIV+ DMPA-users on EFV	urine pregnancy testing	4 years
pregnancy rates of 710 HIV+ LNG implant users on EFV	urine pregnancy testing	4 years
EFV concentration from blood	A validated HPLC-UV assay for EFV will be used for plasma analysis. Concentrations of EFV in a range of 10 to 10,000 ng/mL will be analyzed.	4 years
EFV concentration from hair	Using an IR-MALDESI imaging source coupled to a Thermo Q-Exactive/H-ESI II Bundle mass spectrometer, ~1 cm samples of hair, which will give resultant band intensities over the hair will be analyzed. EFV concentrations at each band intensity will be quantified based on a standard curve.64 Both the total and average concentrations over the 6-month period will be analyzed.	4 years
The LNG concentrations from serum	The sensitivity of the LNG is 0.05 ng/ml, and the intraassay and interassay coefficients of variation (CVs) are 4.4% and 8.9%.	4 years
HIV viral load from plasma	HIV RNA in the range of 40-10,000,000 copies/mL	4 years
DNA quantitated from whole blood	Using a Qiagen DNA extraction kit for blood, 1uL of whole blood will be processed to obtain DNA. This DNA will be quantitated and 120ng will be used in the assay.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
contraceptive continuation	palpation (for LNG implant) and review of the woman's medical record and study forms (for DMPA).	4 years

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Jennifer Tang, MD, MSRC, UNC-CH

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2017
• Primary Completion (Actual): December 10, 2021
• Study Completion (Actual): December 10, 2021

Study Registration Dates

• First Submitted: May 11, 2017
• First Submitted That Met QC Criteria: May 11, 2017
• First Posted (Actual): May 15, 2017

Study Record Updates

• Last Update Posted (Actual): February 25, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Pregnancy rates; pharmacokinetic interactions; Women on efavirenz; initiating the Levonorgestrel Implant; initiating the Depot Medroxyprogesterone Acetate Injectable
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 17-0471; 1R01HD088279-01A1 (U.S. NIH Grant/Contract); UNCPM-21701 (Other Identifier: UNC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No