<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/NCT02249962</url>
  </required_header>
  <id_info>
    <org_study_id>14-1633</org_study_id>
    <secondary_id>R01HD080485</secondary_id>
    <nct_id>NCT02249962</nct_id>
  </id_info>
  <brief_title>Option B+: Study on Safety, Viral Suppression, and Survival on Second Line ART</brief_title>
  <acronym>S4</acronym>
  <official_title>Option B+: ART Safety and Durability During First and Subsequent Pregnancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health and Population, Malawi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of North Carolina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lighthouse Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To characterize safety, durability, antiretroviral treatment (ART) resistance, and clinical&#xD;
      outcomes for mothers and infants exposed to the efavirenz-based Option B+ regimen for&#xD;
      Prevention of Mother to Child Transmission (PMTCT) and HIV treatment in Malawi.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Option B+ is an innovative strategy pioneered within Malawi that provides universal lifelong&#xD;
      ART (tenofovir/lamivudine/efavirenz: TDF/3TC/EFV) for pregnant and breastfeeding women to&#xD;
      promote maternal health and prevent HIV transmission to infants. The safety of a TDF/3TC/EFV&#xD;
      based regimen used during pregnancy has not been systematically evaluated.&#xD;
&#xD;
      Objective 1: To characterize the long term safety, drug resistance patterns and clinical&#xD;
      outcomes among women and their infants enrolled in the Malawi Option B+ program using&#xD;
      TDF/3TC/EFV.&#xD;
&#xD;
        -  Hypothesis 1: Over 3+ years of anticipated treatment follow-up, TDF/3TC/EFV will be&#xD;
           associated with a toxicity rate requiring ART discontinuation of &lt;3% and &gt;90% virologic&#xD;
           suppression at 36 months.&#xD;
&#xD;
        -  Hypothesis 2: Women with baseline CD4 counts ≤ 350 cells/mm3 will experience greater&#xD;
           rates of clinical events, treatment failure and ART toxicity compared to those with CD4&#xD;
           &gt; 350 cells/mm3.&#xD;
&#xD;
      Objective 2: To critically evaluate women with subsequent pregnancies after initial&#xD;
      engagement in the Option B+ Program.&#xD;
&#xD;
      Objective 2a: To determine the prevalence of treatment failure among pregnant women&#xD;
      presenting to ANC on first-line therapy and evaluate the safety of ATZ/r based therapy among&#xD;
      those women requiring second-line therapy.&#xD;
&#xD;
        -  Hypothesis 1: HIVRNA testing at first ANC visit among women with subsequent pregnancies&#xD;
           will demonstrate that approximately 5% of women will be failing treatment and will&#xD;
           identify key risk factors associated with treatment failure.&#xD;
&#xD;
        -  Hypothesis 2: ATZ/r based therapy during pregnancy is associated with toxicity rates&#xD;
           requiring discontinuation in less than 5% of pregnant women.&#xD;
&#xD;
      Objective 2b: Among pregnant women defaulting from TDF/3TC/EFV, determine the treatment&#xD;
      response to re-initiation of first-line therapy, need for second-line therapy, and&#xD;
      characterize resistance.&#xD;
&#xD;
      - Hypothesis 1: Women re-engaging in care after program default will experience early ART&#xD;
      treatment failure due to HIV drug resistance that developed after ART cessation during&#xD;
      initial care.&#xD;
&#xD;
      Objective 3: To explore rates of adverse pregnancy and birth outcomes among women, presence&#xD;
      of birth defects, and infant developmental delay among infants exposed to EFV-based ART after&#xD;
      the first trimester (Objective 1), Efavirenz at conception (Objective 2a), and on second-line&#xD;
      therapy with ATZ/r based ART (Objective 2a).&#xD;
&#xD;
        -  Hypothesis 1: Efavirenz exposure during the first trimester is associated with a higher&#xD;
           rate of adverse pregnancy and birth outcomes than if exposed later in pregnancy.&#xD;
&#xD;
        -  Hypothesis 2: Infants exposed to EFV from first trimester will experience lower mean&#xD;
           scores on Bayley neurodevelopment domains than those exposed later in pregnancy.&#xD;
&#xD;
      The investigators will collect data for maternal treatment outcomes, including vital status,&#xD;
      per the national HIV program definitions: Alive, Dead, Default (&gt;3 months since last visit),&#xD;
      Stop, and Transfer Out. In addition to maternal treatment outcomes, the national HIV program&#xD;
      collects data regarding the following outcomes, which the investigators will also collect:&#xD;
      pregnancy and tuberculosis incidence after ART initiation, drug toxicity/ adverse event&#xD;
      (Rash, Hepatitis, Lactic Acidosis, Anemia, Peripheral Neuropathy), adherence measurement (by&#xD;
      pill count), WHO clinical stage at ART initiation, ART pharmacy refill information, and ART&#xD;
      regimen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2015</start_date>
  <completion_date type="Actual">September 2020</completion_date>
  <primary_completion_date type="Actual">September 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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of participants with failure on Option B+ first-line treatment</measure>
    <time_frame>Up to 36 months</time_frame>
    <description>Proportion of women who fail first-line treatment as indicated by one or more of the following criteria: WHO Stage 3 or 4 events (as defined by Appendix 60 of the Adult AIDS Clinical Trials Group (AACTG)), or DAIDS grade 3 or 4 toxicity (lab serum markers), or proportion with treatment discontinuation (or death), or proportion with virologic failure (as measured by HIV RNA levels)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic: progesterone level in women using contraceptive implant</measure>
    <time_frame>months 3, 6, 12, 24</time_frame>
    <description>Measure of serum progesterone and efavirenz levels among women with a contraceptive implant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Micronutrient assessment</measure>
    <time_frame>Baseline, months 6, 12, 24, 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal CD4 count</measure>
    <time_frame>baseline, months 12, 24, 36 post-ART initiation</time_frame>
    <description>Standard of care</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV RNA level measurement</measure>
    <time_frame>baseline, months 3, 6, 12, 24, 36</time_frame>
    <description>Standard of Care, measured to assess resistance to first-line ART</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PHQ-9 evaluation</measure>
    <time_frame>baseline, months 6, 12, 18, 24, 30, 36</time_frame>
    <description>Assess maternal psychological well-being</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Laboratory serum markers</measure>
    <time_frame>baseline, months 3, 6, 9, 12, 18, 24, 30, 36</time_frame>
    <description>Labs assessed include: renal function (creatinine and urinalysis), liver function, and hematology Measurements contribute to DAIDS grade 3 or 4 toxicity assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pregnancy outcome assessment</measure>
    <time_frame>At time of pregnancy completion (birth, termination)</time_frame>
    <description>Status of birth (live, stillborn, miscarriage), small for gestational age, congenital anomalies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV antibody testing- infant</measure>
    <time_frame>age 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant neuro-development assessment: Bayley score</measure>
    <time_frame>Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Family planning use and proportion of women with subsequent pregnancy by 36 months</measure>
    <time_frame>Up to 36 months</time_frame>
    <description>Assessing women's fertility preferences, usage of family planning methods, and pregnancy status post-ART initiation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ART Adherence: pill-count</measure>
    <time_frame>months 3, 6, 9, 12, 18, 24, 30, 36</time_frame>
    <description>Assessment of adherence to anti-retroviral medications via direct pill count at each clinic visit</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">12011</enrollment>
  <condition>HIV</condition>
  <condition>Infant Exposure to Efavirenz</condition>
  <arm_group>
    <arm_group_label>Overall cohort: HIV+ women on Option B+ and their infants</arm_group_label>
    <description>Women (n=8000) visiting an antenatal clinic for care who will be followed prospectively for Malawi standard treatment outcomes and pregnancy outcomes as patients on Option B+</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-cohort A: first HIV diagnosis</arm_group_label>
    <description>Women (n=300) who present to the antenatal care clinic and are diagnosed for the first time with HIV. These women will be started on Option B+ as anti-retroviral treatment, per Malawi Ministry of Health standard of care.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-cohort B: subsequent pregnancies failing 1st line ART</arm_group_label>
    <description>Women (n=150) who have failed first-line treatment (TDF/3TC/EFV) based on HIV RNA levels and CD4 count. These women will be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-cohort C: subsequent pregnancies who default from 1st line</arm_group_label>
    <description>Women (n=150) who are HIV+ and have a subsequent pregnancy who have not been adherent to first-line (Option B+: TDF/3TC/EFV). These women will be re-initiated on first-line treatment for 3 months, then evaluated to assess whether continuation on first-line treatment is sufficient, or if they need to be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood serum samples for:&#xD;
&#xD;
        -  HIV genotyping&#xD;
&#xD;
        -  micronutrient status&#xD;
&#xD;
        -  pharmacokinetics: efavirenz and progesterone levels for women using the contraceptive&#xD;
           implant only&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV+ pregnant women and their infants recruited from three clinic sites in Lilongwe,&#xD;
        Malawi.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female age ≥16 (includes adults and emancipated minors)&#xD;
&#xD;
          -  HIV positive by 2 rapid tests approved by the Malawi Ministry of Health&#xD;
&#xD;
          -  Willingness to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Female &lt;16 years&#xD;
&#xD;
          -  HIV negative&#xD;
&#xD;
          -  Incapable of providing informed consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mina C Hosseinipour, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Project- Malawi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC Project Malawi</name>
      <address>
        <city>Lilongwe</city>
        <country>Malawi</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malawi</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>September 11, 2014</study_first_submitted>
  <study_first_submitted_qc>September 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 2014</study_first_posted>
  <last_update_submitted>March 10, 2021</last_update_submitted>
  <last_update_submitted_qc>March 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>prospective</keyword>
  <keyword>cohort</keyword>
  <!-- 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/NCT02249962
org study id: 14-1633
secondary id: R01HD080485
nct id: NCT02249962
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
To characterize safety, durability, antiretroviral treatment (ART) resistance, and clinical
      outcomes for mothers and infants exposed to the efavirenz-based Option B+ regimen for
      Prevention of Mother to Child Transmission (PMTCT) and HIV treatment in Malawi.
Option B+ is an innovative strategy pioneered within Malawi that provides universal lifelong
      ART (tenofovir/lamivudine/efavirenz: TDF/3TC/EFV) for pregnant and breastfeeding women to
      promote maternal health and prevent HIV transmission to infants. The safety of a TDF/3TC/EFV
      based regimen used during pregnancy has not been systematically evaluated.

      Objective 1: To characterize the long term safety, drug resistance patterns and clinical
      outcomes among women and their infants enrolled in the Malawi Option B+ program using
      TDF/3TC/EFV.

        -  Hypothesis 1: Over 3+ years of anticipated treatment follow-up, TDF/3TC/EFV will be
           associated with a toxicity rate requiring ART discontinuation of <3% and >90% virologic
           suppression at 36 months.

        -  Hypothesis 2: Women with baseline CD4 counts ≤ 350 cells/mm3 will experience greater
           rates of clinical events, treatment failure and ART toxicity compared to those with CD4
           > 350 cells/mm3.

      Objective 2: To critically evaluate women with subsequent pregnancies after initial
      engagement in the Option B+ Program.

      Objective 2a: To determine the prevalence of treatment failure among pregnant women
      presenting to ANC on first-line therapy and evaluate the safety of ATZ/r based therapy among
      those women requiring second-line therapy.

        -  Hypothesis 1: HIVRNA testing at first ANC visit among women with subsequent pregnancies
           will demonstrate that approximately 5% of women will be failing treatment and will
           identify key risk factors associated with treatment failure.

        -  Hypothesis 2: ATZ/r based therapy during pregnancy is associated with toxicity rates
           requiring discontinuation in less than 5% of pregnant women.

      Objective 2b: Among pregnant women defaulting from TDF/3TC/EFV, determine the treatment
      response to re-initiation of first-line therapy, need for second-line therapy, and
      characterize resistance.

      - Hypothesis 1: Women re-engaging in care after program default will experience early ART
      treatment failure due to HIV drug resistance that developed after ART cessation during
      initial care.

      Objective 3: To explore rates of adverse pregnancy and birth outcomes among women, presence
      of birth defects, and infant developmental delay among infants exposed to EFV-based ART after
      the first trimester (Objective 1), Efavirenz at conception (Objective 2a), and on second-line
      therapy with ATZ/r based ART (Objective 2a).

        -  Hypothesis 1: Efavirenz exposure during the first trimester is associated with a higher
           rate of adverse pregnancy and birth outcomes than if exposed later in pregnancy.

        -  Hypothesis 2: Infants exposed to EFV from first trimester will experience lower mean
           scores on Bayley neurodevelopment domains than those exposed later in pregnancy.

      The investigators will collect data for maternal treatment outcomes, including vital status,
      per the national HIV program definitions: Alive, Dead, Default (>3 months since last visit),
      Stop, and Transfer Out. In addition to maternal treatment outcomes, the national HIV program
      collects data regarding the following outcomes, which the investigators will also collect:
      pregnancy and tuberculosis incidence after ART initiation, drug toxicity/ adverse event
      (Rash, Hepatitis, Lactic Acidosis, Anemia, Peripheral Neuropathy), adherence measurement (by
      pill count), WHO clinical stage at ART initiation, ART pharmacy refill information, and ART
      regimen.
observational model: Cohort
time perspective: Prospective
measure: Proportion of participants with failure on Option B+ first-line treatment
time frame: Up to 36 months
description: Proportion of women who fail first-line treatment as indicated by one or more of the following criteria: WHO Stage 3 or 4 events (as defined by Appendix 60 of the Adult AIDS Clinical Trials Group (AACTG)), or DAIDS grade 3 or 4 toxicity (lab serum markers), or proportion with treatment discontinuation (or death), or proportion with virologic failure (as measured by HIV RNA levels)
measure: Pharmacokinetic: progesterone level in women using contraceptive implant
time frame: months 3, 6, 12, 24
description: Measure of serum progesterone and efavirenz levels among women with a contraceptive implant
measure: Micronutrient assessment
time frame: Baseline, months 6, 12, 24, 36
measure: Maternal CD4 count
time frame: baseline, months 12, 24, 36 post-ART initiation
description: Standard of care
measure: HIV RNA level measurement
time frame: baseline, months 3, 6, 12, 24, 36
description: Standard of Care, measured to assess resistance to first-line ART
measure: PHQ-9 evaluation
time frame: baseline, months 6, 12, 18, 24, 30, 36
description: Assess maternal psychological well-being
measure: Laboratory serum markers
time frame: baseline, months 3, 6, 9, 12, 18, 24, 30, 36
description: Labs assessed include: renal function (creatinine and urinalysis), liver function, and hematology Measurements contribute to DAIDS grade 3 or 4 toxicity assessment.
measure: Pregnancy outcome assessment
time frame: At time of pregnancy completion (birth, termination)
description: Status of birth (live, stillborn, miscarriage), small for gestational age, congenital anomalies
measure: HIV antibody testing- infant
time frame: age 1 year
measure: Infant neuro-development assessment: Bayley score
time frame: Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
measure: Family planning use and proportion of women with subsequent pregnancy by 36 months
time frame: Up to 36 months
description: Assessing women's fertility preferences, usage of family planning methods, and pregnancy status post-ART initiation
measure: ART Adherence: pill-count
time frame: months 3, 6, 9, 12, 18, 24, 30, 36
description: Assessment of adherence to anti-retroviral medications via direct pill count at each clinic visit
arm group label: Overall cohort: HIV+ women on Option B+ and their infants
description: Women (n=8000) visiting an antenatal clinic for care who will be followed prospectively for Malawi standard treatment outcomes and pregnancy outcomes as patients on Option B+
arm group label: Sub-cohort A: first HIV diagnosis
description: Women (n=300) who present to the antenatal care clinic and are diagnosed for the first time with HIV. These women will be started on Option B+ as anti-retroviral treatment, per Malawi Ministry of Health standard of care.
arm group label: Sub-cohort B: subsequent pregnancies failing 1st line ART
description: Women (n=150) who have failed first-line treatment (TDF/3TC/EFV) based on HIV RNA levels and CD4 count. These women will be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.
arm group label: Sub-cohort C: subsequent pregnancies who default from 1st line
description: Women (n=150) who are HIV+ and have a subsequent pregnancy who have not been adherent to first-line (Option B+: TDF/3TC/EFV). These women will be re-initiated on first-line treatment for 3 months, then evaluated to assess whether continuation on first-line treatment is sufficient, or if they need to be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.
Blood serum samples for:

        -  HIV genotyping

        -  micronutrient status

        -  pharmacokinetics: efavirenz and progesterone levels for women using the contraceptive
           implant only
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 16 Years
maximum age: 50 Years
healthy volunteers: No
last name: Mina C Hosseinipour, MD, MPH
role: Principal Investigator
affiliation: UNC Project- Malawi
facility: 
country: Malawi
responsible party type: Sponsor