A Single-arm, Open-label, Study to Assess the Pharmacokinetics of Darunavir and Ritonavir, Darunavir and Cobicistat, Etravirine, and Rilpivirine in HIV-1 Infected Pregnant Women

There are many biological changes that occur during pregnancy, some of which may affect the
way HIV medications are absorbed, distributed and removed within the body. Some medications
have been used for HIV treatment during pregnancy, but little is known about how pregnancy
affects the class of drugs being used in this study. To participate in this study, patients
must be receiving 600mg of TMC114 (darunavir) taken with 100mg ritonavir twice daily or 800mg
of TMC114 (darunavir) with 100mg of ritonavir once daily or 800 mg of darunavir taken with
150mg of cobicistat taken once daily or 200mg of TMC125 (etravirine) (with or without
darunavir/ ritonavir) taken twice daily or 25mg of TMC278 (rilpivirine) taken once daily plus
additional antiretroviral drugs needed to construct an active antiretroviral regimen.
Darunavir and ritonavir, darunavir and cobicistat, etravirine, or rilpivirine will be
supplied to study participants. Darunavir and ritonavir are human immunodeficiency virus
(HIV) protease inhibitors (PIs); cobicistat is a pharmacoenhancer which boosts the levels of
darunavir but has no anti-HIV activity; etravirine and rilpivirine are non-nucleoside reverse
transcriptase inhibitor (NNRTI) of HIV. Twelve-hour or twenty four-hour blood sampling will
be done for each patient at each of three study visits: Visit 4 (2nd trimester), Visit 5 (3rd
trimester), and Visit 8 (6-12 weeks postpartum). Eight blood draws will be taken during each
visit: One prior to intake of study medication, and one for each of seven post-dose sampling
time-points (hours 1, 2, 3, 4, 6, 9 and 12). The study is designed primarily to examine the
pharmacokinetics of darunavir/ritonavir (darunavir/r), darunavir/ cobicistat, etravirine or
rilpivirine during the second and third trimesters of gestation, as well as postpartum.
Pharmacokinetics measures how the body absorbs, distributes and excretes medication. The
study will also examine any changes in anti-viral activity during pregnancy, and the
postpartum period. It will note any safety and tolerability of the medications used by the
mother, and will measure the level of darunavir/ritonavir, darunavir/ cobicistat, etravirine
or rilpivirine in the newborn's cord blood at the time of delivery; outcomes for both mother
and child will be assessed as well. During the treatment period, patients will be seen at
regular visits in the clinic, where the investigator will assess the patient's medical
condition, any Adverse Events and study drug compliance. Laboratory evaluations for efficacy
and safety will be done at regular visits as well as blood pressure monitoring. Up to
forty-eight (48) HIV positive pregnant women will participate in this study. Study enrollment
will be closed once 12 evaluable patients taking darunavir/ritonavir once daily, 12 evaluable
patients taking darunavir/cobicistat once daily, 12 evaluable patients taking
darunavir/ritonavir twice daily, 12 evaluable patients taking etravirine taking twice daily
and 12 evaluable patients taking rilpivirine once daily have been enrolled. The study will be
conducted at approximately 14 research centers in the United States and 1 in Puerto Rico. In
order to participate, patients must be pregnant for 13-24 weeks. The primary purpose (or
outcome) of the study is to assess the influence of pregnancy on the pharmacokinetics of
darunavir/ritonavir, darunavir/ cobicistat, etravirine or rilpivirine during the second and
third trimesters of gestation, as well as postpartum. Darunavir: One 600 mg or two 300 mg
tablets taken twice daily by mouth (two or four tablets a day total). Ritonavir: 100mg tablet
taken twice daily by mouth (two tablets a day total), together with darunavir. Darunavir: Two
400 mg tablets taken once daily by mouth (two tablets a day total). Ritonavir: 100mg tablet
taken once daily by mouth (one tablet a day total), together with darunavir. Darunavir/
cobicistat: a fixed dose combination containing 800mg of darunavir and 150mg of cobicistat.
Etravirine: Two 100 mg tablets taken twice daily by mouth (four tablets a day total).
Rilpivirine: One 25mg tablet taken once daily by mouth (one tablet a day total). Study
medication will be given from the baseline visit (second pregnancy trimester) until Visit 8
(up to 12 weeks after delivery).

Inclusion Criteria:

- Pregnant females (18-26 weeks of gestation)

- documented HIV-1 infection

- Receiving darunavir/ritonavir, darunavir/cobicistat, etravirine, or rilpivirine at the
time of study entry

- Willing to remain on darunavir/ritonavir, darunavir/cobicistat, etravirine, or
rilpivirine as well as a background regimen, for the duration of the study, including
12 weeks postpartum

- Able to comply with the protocol requirements and to provide written informed consent.

Exclusion Criteria:

- Patients with any currently active acquired immune deficiency syndrome (AIDS) defining
illness and AIDS-related opportunistic infection

- Patients using cytokine inhibitors (e.g., thalidomide), anabolic hormones, cytokines
(e.g., IL-2, INF), efavirenz, hydroxyurea, oral hypoglycemics, systemic chemotherapy
or known teratogenic agent

- Use of an investigational agent within 90 days

- Any known fetal anomaly

- Any current obstetric complication, including multiple gestations and pre-term labor

- Hepatitis B and/or C virus infection

- Grade 2 or higher anemia

- Thyroid disease

- Uncontrolled Diabetes Mellitus Types I and II, or gestational diabetes, as determined
by the investigator