<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02247999</url>
  </required_header>
  <id_info>
    <org_study_id>999913037</org_study_id>
    <secondary_id>13-C-N037</secondary_id>
    <nct_id>NCT02247999</nct_id>
  </id_info>
  <brief_title>Improving Cervical Cancer Screening Among HIV-Infected Women in India</brief_title>
  <official_title>Improving Cervical Cancer Prevention Among HIV-Infected Women Using Novel HPV Based Biomarker Assays</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
        -  Cervical cancer is a major cause of cancer deaths among women. Most cases of cervical&#xD;
           cancer are caused by the human papillomavirus (HPV). HPV is more common in women who&#xD;
           have the human immunodeficiency virus (HIV). India has one of the highest rates of women&#xD;
           who have both cervical cancer and HIV infection.&#xD;
&#xD;
        -  Cervical cancer can be discovered in early stages by screening for HPV infection.&#xD;
           Researchers want to compare new cervical cancer screening tests for HIV-infected women.&#xD;
           They also want to know more about how HPV can lead to cervical cancer in HIV-infected&#xD;
           women. To do so, they will hold a study to screen HIV-infected women in India.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To improve cervical cancer screening methods in HIV-infected women in India.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Women at least 18 years of age who have HIV infection.&#xD;
&#xD;
        -  Participants will be recruited from HIV-focused health care clinics in Pune and Chennai,&#xD;
           India.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will have a physical exam and medical history. They will provide a urine&#xD;
           sample and proof of HIV infection.&#xD;
&#xD;
        -  Participants will have a gynecological exam. This will involve a pelvic exam and Pap&#xD;
           smear to collect cells for study. It will also involve a cervical exam to look for&#xD;
           precancerous cells. Cervical tissue may be collected.&#xD;
&#xD;
        -  Participants will also provide a blood sample for testing.&#xD;
&#xD;
        -  Participants will return in 2 weeks for the test results. If there are signs of&#xD;
           precancerous or cancer cells, participants will be referred to a doctor for treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      While HPV DNA testing is a highly sensitive screening method for cervical cancer, it cannot&#xD;
      differentiate between the majority of benign infections and few persistent infections linked&#xD;
      to cervical precancer. Given the high prevalence of carcinogenic HPV DNA and higher risk for&#xD;
      cervical precancer and cancer among HIV-infected women, there is a substantial need for&#xD;
      screening tests that are both adequately sensitive as well as specific, so as to maximize&#xD;
      detection while reducing false-positive referrals. Furthermore, the unique immunological&#xD;
      milieu in HIV-infected women presents significant opportunities to study natural history of&#xD;
      HPV-mediated cervical oncogenic process in the context of immunosuppression.&#xD;
&#xD;
      Objectives and Methods:&#xD;
&#xD;
      The primary objective is to evaluate the clinical performance of two novel biomarker assays&#xD;
      for detection of histologically-confirmed cervical intraepithelial neoplasia grade 2/3 or&#xD;
      more severe (greater than or equal to CIN2 and greater than or equal to CIN3) among&#xD;
      HIV-infected women. These tests include: (i) immunocytostaining by p16(INK4a)/Ki-67&#xD;
      (biomarkers correlated with the oncogenic transformation of cervical cells following&#xD;
      persistent carcinogenic HPV infection) and (ii) testing for HPV E6/E7 mRNA (expressed during&#xD;
      progression of a transient to a transforming HPV infection). Secondary objectives include&#xD;
      studying the association of risk factors and biomarkers with specific HPV genotypes and&#xD;
      studying the interaction of HIV and HPV in cervical disease categories and in the context of&#xD;
      immunosuppression.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      HIV-infected women, 18 years or older, with no history of previous treatment for cervical&#xD;
      precancer/cancer, not currently pregnant, and able to provide informed consent.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      This cross sectional study will be conducted in collaboration with Indian Council of Medical&#xD;
      Research (ICMR), in three institutions, with substantial experience in conduct of clinical&#xD;
      research on HIV/AIDS and HPV/cervical cancer: the National AIDS Research Institute (NARI) in&#xD;
      Pune, the National Institute of Epidemiology (NIE) in Chennai, and the Jawaharlal Nehru&#xD;
      Medical College (JNMC) in Belgaum. A total of 1000 HIV-infected women attending HIV care and&#xD;
      treatment clinics in Pune (n=400) and Chennai (n=400), and Belgaum (n=200) will be recruited.&#xD;
      According to routine practice, participants will undergo per-speculum examination and&#xD;
      cervical specimen collection, followed by a detailed diagnostic colposcopy exam with biopsies&#xD;
      as indicated for histological analysis. Cervical specimens will be used for liquid-based&#xD;
      cytology as well as simultaneous independent assessment with p16(INK4a)/Ki-67 and HPV E6/E7&#xD;
      mRNA testing. HPV DNA genotyping will be conducted by Linear Array HPV polymerase chain&#xD;
      reaction. We will estimate the clinical performance (sensitivity, specificity, positive and&#xD;
      negative predictive values, Youden s Index, and positive and negative likelihood ratios with&#xD;
      95% confidence intervals) of individual tests and combinations for prevalent detection of&#xD;
      histologically-confirmed greater than or equal to CIN2 and greater than or equal to CIN3&#xD;
      among HIV-infected women. Additionally we will estimate age-specific and disease-specific HPV&#xD;
      prevalence rates and HPV genotype composition, examine factors associated with greater than&#xD;
      or equal to CIN2/greater than or equal to CIN3 lesions, examine the relationships of&#xD;
      biomarker positivity at the HPV genotype-specific level, and evaluate the role of&#xD;
      immunosuppression on HPV-mediated carcinogenesis. This study will permit validation of&#xD;
      collection, transport, storage, and implementation protocols, allow evaluation of the field&#xD;
      adoption and efficacy of these newer assays, describe the sensitivity and specificity of any&#xD;
      of the tests or combinations with reasonable precision for a wide range of prevalence of&#xD;
      greater than or equal to CIN3, and provide a resource for studies of HIV-HPV coinfection.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 28, 2012</start_date>
  <completion_date type="Actual">October 8, 2020</completion_date>
  <primary_completion_date type="Actual">October 8, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cervical Intraepithelial Neoplasia Grade II or more severe</measure>
    <time_frame>At enrollment</time_frame>
    <description>Cervical Intraepithelial Neoplasia Grade II or more severe</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">1000</enrollment>
  <condition>Cervical Cancer</condition>
  <condition>HIV/AIDS</condition>
  <condition>HPV</condition>
  <condition>Cervical Intraepithelial Neoplasia</condition>
  <condition>Biomarkers</condition>
  <arm_group>
    <arm_group_label>Cohort</arm_group_label>
    <description>HIV-infected women attending HIV care and treatment clinics in Pune, Chennai, andBelgaum in India.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        The study population will be selected from HIV-infected women attending HIV care and&#xD;
        treatment clinics in Pune, Chennai, and Belgaum in India.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. Female greater than or equal to 18 years of age at study entry. This ensures that&#xD;
                  all participants are at or above legal age in India for giving informed consent.&#xD;
&#xD;
               2. Confirmed HIV-1 infection.&#xD;
&#xD;
               3. For women of reproductive potential, a negative urine pregnancy test with a&#xD;
                  sensitivity of &lt;25mlU/mL prior to study entry. This ensures that only&#xD;
                  non-pregnant women are included. While pregnancy is not an absolute&#xD;
                  contraindication for screening, certain invasive clinical procedures are often&#xD;
                  postponed until after pregnancy.&#xD;
&#xD;
               4. If recently given birth, must be at least 12 weeks postpartum.&#xD;
&#xD;
               5. Physical and mental ability and willingness of participant to provide written&#xD;
                  informed consent.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Current or prior history of cervical, vaginal, or vulvar cancer.&#xD;
&#xD;
          2. Prior treatment for cervical disease; including treatment by cervical cryotherapy,&#xD;
             LEEP, cervical conization, total or partial hysterectomy, chemotherapy, or radiation&#xD;
             therapy.&#xD;
&#xD;
          3. Prior cervical procedure in the past 6 months, including dilatation and curettage&#xD;
             (D&amp;C).&#xD;
&#xD;
          4. Serious illness requiring systemic treatment or hospitalization within 21 days prior&#xD;
             to study entry.&#xD;
&#xD;
          5. Active drug or alcohol use or dependence or any other condition that, in the opinion&#xD;
             of the site investigator, would interfere with the participant s ability to adhere to&#xD;
             study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicolas Wentzensen, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institute of Epidemiology (NIE)</name>
      <address>
        <city>Chennai</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <reference>
    <citation>Sahasrabuddhe VV, Luhn P, Wentzensen N. Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts. Future Microbiol. 2011 Sep;6(9):1083-98. doi: 10.2217/fmb.11.87.</citation>
    <PMID>21958146</PMID>
  </reference>
  <reference>
    <citation>Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, Tokugawa D, Bodelon C, Poitras N, Lorey T, Kinney W. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. Print 2015 Dec.</citation>
    <PMID>26376685</PMID>
  </reference>
  <reference>
    <citation>Mane A, Nirmalkar A, Risbud AR, Vermund SH, Mehendale SM, Sahasrabuddhe VV. HPV genotype distribution in cervical intraepithelial neoplasia among HIV-infected women in Pune, India. PLoS One. 2012;7(6):e38731. doi: 10.1371/journal.pone.0038731. Epub 2012 Jun 19.</citation>
    <PMID>22723879</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>September 20, 2014</study_first_submitted>
  <study_first_submitted_qc>September 20, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>October 8, 2020</last_update_submitted>
  <last_update_submitted_qc>October 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cervical Cancer</keyword>
  <keyword>HIV/AIDS</keyword>
  <keyword>HPV</keyword>
  <keyword>Biomarkers</keyword>
  <keyword>Screening</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Uterine Cervical Neoplasms</mesh_term>
    <mesh_term>Uterine Cervical Dysplasia</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02247999
org study id: 999913037
secondary id: 13-C-N037
nct id: NCT02247999
lead sponsor: 
Background:

        -  Cervical cancer is a major cause of cancer deaths among women. Most cases of cervical
           cancer are caused by the human papillomavirus (HPV). HPV is more common in women who
           have the human immunodeficiency virus (HIV). India has one of the highest rates of women
           who have both cervical cancer and HIV infection.

        -  Cervical cancer can be discovered in early stages by screening for HPV infection.
           Researchers want to compare new cervical cancer screening tests for HIV-infected women.
           They also want to know more about how HPV can lead to cervical cancer in HIV-infected
           women. To do so, they will hold a study to screen HIV-infected women in India.

      Objectives:

      - To improve cervical cancer screening methods in HIV-infected women in India.

      Eligibility:

        -  Women at least 18 years of age who have HIV infection.

        -  Participants will be recruited from HIV-focused health care clinics in Pune and Chennai,
           India.

      Design:

        -  Participants will have a physical exam and medical history. They will provide a urine
           sample and proof of HIV infection.

        -  Participants will have a gynecological exam. This will involve a pelvic exam and Pap
           smear to collect cells for study. It will also involve a cervical exam to look for
           precancerous cells. Cervical tissue may be collected.

        -  Participants will also provide a blood sample for testing.

        -  Participants will return in 2 weeks for the test results. If there are signs of
           precancerous or cancer cells, participants will be referred to a doctor for treatment.
Background:

      While HPV DNA testing is a highly sensitive screening method for cervical cancer, it cannot
      differentiate between the majority of benign infections and few persistent infections linked
      to cervical precancer. Given the high prevalence of carcinogenic HPV DNA and higher risk for
      cervical precancer and cancer among HIV-infected women, there is a substantial need for
      screening tests that are both adequately sensitive as well as specific, so as to maximize
      detection while reducing false-positive referrals. Furthermore, the unique immunological
      milieu in HIV-infected women presents significant opportunities to study natural history of
      HPV-mediated cervical oncogenic process in the context of immunosuppression.

      Objectives and Methods:

      The primary objective is to evaluate the clinical performance of two novel biomarker assays
      for detection of histologically-confirmed cervical intraepithelial neoplasia grade 2/3 or
      more severe (greater than or equal to CIN2 and greater than or equal to CIN3) among
      HIV-infected women. These tests include: (i) immunocytostaining by p16(INK4a)/Ki-67
      (biomarkers correlated with the oncogenic transformation of cervical cells following
      persistent carcinogenic HPV infection) and (ii) testing for HPV E6/E7 mRNA (expressed during
      progression of a transient to a transforming HPV infection). Secondary objectives include
      studying the association of risk factors and biomarkers with specific HPV genotypes and
      studying the interaction of HIV and HPV in cervical disease categories and in the context of
      immunosuppression.

      Eligibility:

      HIV-infected women, 18 years or older, with no history of previous treatment for cervical
      precancer/cancer, not currently pregnant, and able to provide informed consent.

      Design:

      This cross sectional study will be conducted in collaboration with Indian Council of Medical
      Research (ICMR), in three institutions, with substantial experience in conduct of clinical
      research on HIV/AIDS and HPV/cervical cancer: the National AIDS Research Institute (NARI) in
      Pune, the National Institute of Epidemiology (NIE) in Chennai, and the Jawaharlal Nehru
      Medical College (JNMC) in Belgaum. A total of 1000 HIV-infected women attending HIV care and
      treatment clinics in Pune (n=400) and Chennai (n=400), and Belgaum (n=200) will be recruited.
      According to routine practice, participants will undergo per-speculum examination and
      cervical specimen collection, followed by a detailed diagnostic colposcopy exam with biopsies
      as indicated for histological analysis. Cervical specimens will be used for liquid-based
      cytology as well as simultaneous independent assessment with p16(INK4a)/Ki-67 and HPV E6/E7
      mRNA testing. HPV DNA genotyping will be conducted by Linear Array HPV polymerase chain
      reaction. We will estimate the clinical performance (sensitivity, specificity, positive and
      negative predictive values, Youden s Index, and positive and negative likelihood ratios with
      95% confidence intervals) of individual tests and combinations for prevalent detection of
      histologically-confirmed greater than or equal to CIN2 and greater than or equal to CIN3
      among HIV-infected women. Additionally we will estimate age-specific and disease-specific HPV
      prevalence rates and HPV genotype composition, examine factors associated with greater than
      or equal to CIN2/greater than or equal to CIN3 lesions, examine the relationships of
      biomarker positivity at the HPV genotype-specific level, and evaluate the role of
      immunosuppression on HPV-mediated carcinogenesis. This study will permit validation of
      collection, transport, storage, and implementation protocols, allow evaluation of the field
      adoption and efficacy of these newer assays, describe the sensitivity and specificity of any
      of the tests or combinations with reasonable precision for a wide range of prevalence of
      greater than or equal to CIN3, and provide a resource for studies of HIV-HPV coinfection.
observational model: Cohort
time perspective: Cross-Sectional
measure: Cervical Intraepithelial Neoplasia Grade II or more severe
time frame: At enrollment
description: Cervical Intraepithelial Neoplasia Grade II or more severe
arm group label: Cohort
description: HIV-infected women attending HIV care and treatment clinics in Pune, Chennai, andBelgaum in India.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nicolas Wentzensen, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: India
citation: Sahasrabuddhe VV, Luhn P, Wentzensen N. Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts. Future Microbiol. 2011 Sep;6(9):1083-98. doi: 10.2217/fmb.11.87.
PMID: 21958146
citation: Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, Tokugawa D, Bodelon C, Poitras N, Lorey T, Kinney W. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. Print 2015 Dec.
PMID: 26376685
citation: Mane A, Nirmalkar A, Risbud AR, Vermund SH, Mehendale SM, Sahasrabuddhe VV. HPV genotype distribution in cervical intraepithelial neoplasia among HIV-infected women in Pune, India. PLoS One. 2012;7(6):e38731. doi: 10.1371/journal.pone.0038731. Epub 2012 Jun 19.
PMID: 22723879
responsible party type: Sponsor
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Uterine Cervical Neoplasms
mesh term: Uterine Cervical Dysplasia