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Antiretroviral Localization in Gut-Associated Lymphoid Tissue and Lower Female Genital Tract Tissue of HIV+ Subjects

2018年1月12日 更新者:Angela Kashuba, PharmD、University of North Carolina, Chapel Hill
The purpose of this research study is to find out how the drugs Truvada® (tenofovir/emtricitabine), Isentress® (raltegravir), Reyataz® (atazanavir), Sustiva® (efavirenz), and Selzentry® (maraviroc) get into the intestines and the female genital tract. All of these drugs are very effective at reducing the number of HIV viruses in the blood, however it is unknown how the drugs move around inside tissues where HIV might be hiding. This study will determine specifically where in the tissue the drug and the HIV are located through the use of a new technology that takes creates a picture of the tissue. This information will help scientists determine the best way to make new drugs to target the hidden HIV in tissue.

調査の概要

詳細な説明

Study Design

This is an observational study of TFV, FTC, RAL, ATZ, EFV, and MVC localization within GALT (terminal ileum & rectum), vaginal, and cervical tissues in the setting of undetectable plasma HIV. Participants will be selected on the basis of receiving either TFV/FTC/RAL, TFV/FTC/ATZ/r, TFV/FTC/EFV, or TFV/FTC/MVC as part of their ongoing HIV care. After participant education, informed consent, and screening for study eligibility, participants will be evaluated at baseline. All samples will be collected over the course of a 36 hour inpatient visit as described below.

Study Sampling

  1. Blood plasma will be collected after enrollment (approximately 2 hours after the start of the inpatient visit) and before the start of bowel preparation (approximately 2-12 hours after the start of the inpatient visit).
  2. Vaginal and cervical tissue will be collected after enrollment (approximately 2 hours after the start of the inpatient visit) and before the start of bowel preparation (approximately 2-12 hours after the start of the inpatient visit).
  3. Rectal and terminal ileal tissue will be collected at approximately 18 hours after the initiation of the bowel preparation.

Pharmacokinetic Analysis All blood, cervical, vaginal, ileal and rectal tissue samples will be analyzed by the Clinical Pharmacology and Analytical Chemistry Laboratory (CPAC) at the UNC School of Pharmacy, which is directed by the principal investigator, Angela Kashuba, PharmD. To visualize ARV localization within a tissue, one biopsy from each tissue site will be analyzed by IR-MALDESI using a previously established workflow for our laboratory.

HIV localization within tissues will be performed using in situ hybridization (ISH) in collaboration with the Haase lab at the University of Minnesota. This group has substantial experience in HIV RNA detection from human tissues, and preliminary studies have confirmed our ability to detect HIV RNA from serial slices of tissues.

Localization within tissue slices will be evaluated by IR-MALDESI. Measurement of the distribution of each ARV within pre-specified anatomical sub-regions across a tissue slice will allow for identification of areas where drug is either concentrating or lacking. ISH and IHC analysis of serial tissue slices will allow us to co-localize ARVs with HIV and HIV target cells. Once these anatomical areas have been visually identified, imaging software will be used to isolate and quantify the signal.

研究の種類

観察的

入学 (実際)

5

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

    • North Carolina
      • Chapel Hill、North Carolina、アメリカ、27514
        • University of North Carolina at Chapel Hill

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年~65年 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

女性

サンプリング方法

非確率サンプル

調査対象母集団

This study will consist of 22 HIV positive women between 18-65 years of age (inclusive) with an intact gastrointestinal tract, uterus and cervix who are available to complete all study procedures at UNC.

説明

Inclusion Criteria:

  1. Healthy HIV-positive female subjects between the ages of 18 and 65 years, inclusive on the date of screening, with an intact gastrointestinal tract, uterus, and cervix. Healthy is defined as no clinically relevant abnormalities that would interfere with the interpretation of results, or pose unnecessary risk onto volunteers due to study procedures.
  2. All subjects must have an undetectable viral load at the time of screening or a documented undetectable viral load within the preceding 3 months of screening.
  3. All subjects must be receiving one of the study regimens as part of their regular HIV care for at least 6 months preceding the date of enrollment.
  4. Subjects must not have a history of GI disease (e.g. Crohn's disease, irritable bowel syndrome, ulcerative colitis, diverticulitis, colon cancer) or have a history of GI surgery.
  5. All subjects (of childbearing potential) must have a negative serum pregnancy test at screening and negative urine pregnancy tests on days of sampling and should be using at least one of the following methods of contraception from the screening visit through 72 hours prior to inpatient admission (at which time the women will be asked to remain abstinent until after their follow-up visit):

    1. Systemic hormonal contraceptive (oral, depot, transdermal or implant)
    2. IUD placed at least 1 month prior to study enrollment
    3. Bilateral tubal ligation (Sterilization)
    4. Vasectomized male partners
    5. Condom + Spermicide
    6. Engaged in sexual activity with female only sex partners or abstinent for at least 3 months prior with no intention of becoming sexually active during the study period. Any history of recent or present concomitant male sex partners will be addressed and ruled out in the context of screening participants for eligibility for the protocol
  6. Body Mass Index (BMI) of approximately 18 to 37 kg/m2; and a total body weight > 45 kg (99 lbs).
  7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
  8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
  9. Subject must have documentation of a normal pap smear within 36 months of the screening visit, no procedures for abnormal cervical/vaginal pathology in the last six months, at least one prior gynecological visit as part of subject's routine medical history.
  10. Not receiving any known CYP3A4 inducers (rifampin, carbamazepine, St. John's wort) or inhibitors (ketoconazole, non-DHP calcium channel blockers, macrolide antibiotics) other than those contained in their HIV regimen for at least 6 months prior to enrollment.
  11. Subject must be willing to abstain from sexual intercourse, douching, and all intravaginal and intrarectal objects and products for at least 72 hours prior to enrollment until study completion.
  12. Subject must be Hepatitis B surface antigen negative as documented on screening labs (or documented in their clinical record).
  13. Subject must not be actively involved in the conception process.
  14. Subject must be able to swallow pills and have no allergies to any component of the study products (i.e. bowel preparation regimen)

Exclusion Criteria

  1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including documented drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
  2. Subjects with a history of hysterectomy or cervical resection that would preclude obtaining a cervical biopsy.
  3. Subjects who are pregnant, possibly pregnant or lactating.
  4. Subjects with a presence of abnormal vaginal discharge bleeding at screening.
  5. History of febrile illness within five days prior to enrollment.
  6. A positive urine drug screen for illicit substances (e.g. cocaine, methamphetamines) that would increase risk associated with sedation.
  7. Active Hepatitis B infection
  8. An untreated-positive test for syphilis, gonorrhea, Chlamydia, or trichomonas at screening. Tests for these STIs will be performed on samples from both the vaginal and rectal orifices.
  9. Any clinically significant laboratory chemistry or hematology result Grade 3 or greater according to the DAIDS Laboratory Grading Tables
  10. Treatment with an investigational drug within 4 months preceding the first dose of trial medication.
  11. History of regular alcohol consumption exceeding 14 drinks (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of spirits) per week.
  12. Participation in a clinical trial involving genital tract or rectal biopsies within 6 months preceding enrollment.
  13. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.
  14. History of sensitivity to heparin or heparin-induced thrombocytopenia.
  15. Allergy to lidocaine or Monsel's solution.
  16. Allergy to latex.
  17. Abnormal pap smear in the past 36 months
  18. Any degree of ectopy or abnormality evident during the pelvic exam at screening.
  19. Any condition which, in the opinion of the investigator, is likely to interfere with follow-up or ability to take the bowel preparation appropriately.
  20. Unwilling or unable to comply with the dietary and concomitant drug restrictions in regard to study drug administration as outlined in the study procedures and prohibited medications sections.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか?

デザインの詳細

コホートと介入

グループ/コホート
介入・治療
Efavirenz
Receiving efavirenz as part of their HIV regimen. Will undergo blood plasma collection, cervical and vaginal biopsy, and colonoscopy with ileal and rectal biopsy.
Approximately 3mL of blood will be taken from each subject just prior to the colonoscopy.
2 biopsies each will be collected from the vaginal wall and the cervix
10 biopsies each will be collected from the rectum and terminal ileum from each subject during the colonoscopy.
Atazanavir
Receiving atazanavir as part of their HIV regimen. Will undergo blood plasma collection, cervical and vaginal biopsy, and colonoscopy with ileal and rectal biopsy.
Approximately 3mL of blood will be taken from each subject just prior to the colonoscopy.
2 biopsies each will be collected from the vaginal wall and the cervix
10 biopsies each will be collected from the rectum and terminal ileum from each subject during the colonoscopy.
Raltegravir
Receiving raltegravir as part of their HIV regimen. Will undergo blood plasma collection, cervical and vaginal biopsy, and colonoscopy with ileal and rectal biopsy.
Approximately 3mL of blood will be taken from each subject just prior to the colonoscopy.
2 biopsies each will be collected from the vaginal wall and the cervix
10 biopsies each will be collected from the rectum and terminal ileum from each subject during the colonoscopy.
Maraviroc
Receiving maraviroc as part of their HIV regimen. Will undergo blood plasma collection, cervical and vaginal biopsy, and colonoscopy with ileal and rectal biopsy.
Approximately 3mL of blood will be taken from each subject just prior to the colonoscopy.
2 biopsies each will be collected from the vaginal wall and the cervix
10 biopsies each will be collected from the rectum and terminal ileum from each subject during the colonoscopy.

この研究は何を測定していますか?

主要な結果の測定

結果測定
メジャーの説明
時間枠
Antiretroviral tissue localization
時間枠:Samples collected within 24 hours post-dose
Tissues collected during inpatient stay will be frozen for later analysis (i.e. MSI-derived images of TFV, FTC, RAL, ATZ, EFV, and MVC localization within tissue slices.) to be completed within 6 months of tissue collection.
Samples collected within 24 hours post-dose

二次結果の測定

結果測定
メジャーの説明
時間枠
Quantitation of antiretroviral tissue concentrations by LC-MS/MS
時間枠:Samples collected within 24 hours post-dose
Tissues collected during inpatient stay will be frozen for later analysis (i.e. TFV, FTC, RAL, ATZ , EFV, and MVC concentrations in tissues as determined by LC-MS/MS) to be completed within 6 months of tissue collection.
Samples collected within 24 hours post-dose
Immunohistochemical images of CD3, CD4, and CD8 distribution within tissue slices
時間枠:Samples collected within 24 hours post-dose
Tissues collected during inpatient stay will be frozen for later analysis (i.e. IHC staining for localization of HIV target cells within serial slices of tissue) to be completed within 6 months of tissue collection.
Samples collected within 24 hours post-dose
in-situ hybridization images of HIV RNA distribution within tissue slices
時間枠:Samples collected within 24 hours post-dose
Tissues collected during inpatient stay will be frozen for later analysis (i.e. ISH staining for localization of HIV RNA within serial slices of tissue) to be completed within 6 months of tissue collection.
Samples collected within 24 hours post-dose
Quantification of antiretroviral tissue concentrations by MSI
時間枠:Samples collected within 24 hours post-dose
Tissues collected during inpatient stay will be frozen for later analysis (i.e. TFV, FTC, RAL, ATZ , EFV, and MVC concentrations in tissues as determined by MSI) to be completed within 6 months of tissue collection.
Samples collected within 24 hours post-dose

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

捜査官

  • 主任研究者:Angela DM Kashuba, PharmD、University of North Carolina, Chapel Hill

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2016年4月13日

一次修了 (実際)

2017年8月29日

研究の完了 (実際)

2017年8月29日

試験登録日

最初に提出

2015年12月17日

QC基準を満たした最初の提出物

2015年12月22日

最初の投稿 (見積もり)

2015年12月29日

学習記録の更新

投稿された最後の更新 (実際)

2018年1月17日

QC基準を満たした最後の更新が送信されました

2018年1月12日

最終確認日

2017年4月1日

詳しくは

本研究に関する用語

その他の研究ID番号

  • 15-2865

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

いいえ

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

HIVの臨床試験

Blood plasma collectionの臨床試験

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