<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/NCT03227731</url>
  </required_header>
  <id_info>
    <org_study_id>UKwaZulu</org_study_id>
    <nct_id>NCT03227731</nct_id>
  </id_info>
  <brief_title>Immediate or Deferred Pre-exposure Prophylaxis for HIV Prevention: Safe Options for Pregnant and Lactating Women</brief_title>
  <acronym>PrEP</acronym>
  <official_title>Immediate or Deferred Pre-exposure Prophylaxis for HIV Prevention: Safe Options for Pregnant and Lactating Women An Open-Label Randomised Control Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of KwaZulu</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centre for the AIDS Programme of Research in South Africa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical Research Council, South Africa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of KwaZulu</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      An Open Label randomized control study. To explore the safety of Truvada when used as PrEP&#xD;
      during pregnancy and lactation. Pregnant women considered at risk for HIV infection and&#xD;
      willing to participate in this randomized control study will be randomized to commencing PrEP&#xD;
      in pregnancy and continued use throughout breastfeeding or deferred PrEP until breastfeeding&#xD;
      cessation. All women will receive the standard of care for prevention of HIV and other&#xD;
      sexually transmitted infections.&#xD;
&#xD;
      Arm A: (Intervention): Standard HIV Prevention strategy plus a once daily dose of Truvada&#xD;
      (FTC 200mg/TDF 300mg tablet) initiated in pregnancy, continuing until cessation of&#xD;
      breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to&#xD;
      continue PrEP post breastfeeding cessation.&#xD;
&#xD;
      Arm B: (Control): Standard HIV Prevention strategy throughout pregnancy until cessation of&#xD;
      breastfeeding plus the offer to initiate PrEP post breastfeeding cessation.&#xD;
&#xD;
      Standard HIV prevention strategy includes risk reduction counselling, sexually transmitted&#xD;
      infection (STI) screening and treatment, condom promotion and inviting the sexual partner to&#xD;
      receive HIV counselling and testing (HCT) and referral for antiretroviral therapy (ART) if he&#xD;
      tests positive.&#xD;
&#xD;
      Main Outcome Measure: Renal function, pregnancy outcomes, bone health and infant growth.&#xD;
&#xD;
      Other Outcome Measure: Incident HIV infections, adherence to PrEP, drug resistance and&#xD;
      mother-to-child transmission of HIV.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      It is becoming increasingly evident that women remain vulnerable to HIV infection during&#xD;
      pregnancy and even more so postdelivery. In a meta-analysis, using data from 19 international&#xD;
      cohorts, Drake et al concluded that the pooled HIV incidence rate during pregnancy/postpartum&#xD;
      was 3.8/100 per woman years (PWY) (95% Confidence Interval (CI) 3.0-4.6): 4.7/100 PWY during&#xD;
      pregnancy and 2.9/100 PWY postpartum. In earlier South African studies (2005-2009)&#xD;
      investigators reported HIV seroconversion rates ranging from 1.3% to 3.0% in pregnancy [4-6].&#xD;
      Dinh et al in 2010-2012 reaffirmed the high seroconversion rate among pregnant women&#xD;
      attending public health facilities in South Africa; 3.3% (95% CI: 2.8%-3.8%) women&#xD;
      seroconverted in pregnancy [7]. In an evaluation of PMTCT program indicators in KwaZulu-Natal&#xD;
      in 2015 the HIV seroconversion rate among 78 906 pregnant HIV uninfected women was estimated&#xD;
      as 1.8% (95%CI 1.0-2.9) in pregnancy and 5% (among 26 455 breastfeeding women) in the&#xD;
      postnatal period.&#xD;
&#xD;
      Rationale:&#xD;
&#xD;
      Truvada, an antiretroviral agent containing emtricitabine (200 mg) and tenofovir disoproxil&#xD;
      fumarate (300 mg) in a fixed-dose combination (FDC) tablet formulation is widely used in&#xD;
      pregnant women as part of a combination treatment regimen and as prophylaxis to prevent&#xD;
      mother-to-child transmission of HIV. Truvada is also the drug of choice in PrEP and currently&#xD;
      recommended by the World Health Organization (WHO) for people at substantial risk of HIV&#xD;
      infection (incidence &gt;3%). Pregnant women were excluded from participating in PrEP trials&#xD;
      because of the lack of safety data in pregnancy. Available human and animal data suggest that&#xD;
      TRUVADA does not increase the risk of major birth defects overall compared to the background&#xD;
      rate and there are limited safety data for TDF/FTC when used in HIV uninfected pregnant&#xD;
      women. In the past five years, PrEP trials have explored the use of Tenofovir alone or in&#xD;
      combination with Emtricitabine in a once daily regimen, resulting in varying efficacy&#xD;
      outcomes that have been largely associated with adherence. Much of the safety data have been&#xD;
      generated in studies involving ART in HIV infected pregnant women. The majority of these&#xD;
      studies indicate no added adverse effect of TDF on pregnancy outcomes. The few studies of TDF&#xD;
      use in HIV uninfected women are treatment studies to prevent mother-to-child transmission of&#xD;
      Hepatitis B and only 2 studies of TDF as PrEP use among women who subsequently fell pregnant&#xD;
      post enrolment. However, exposure to TDF during pregnancy in these PrEP studies is limited&#xD;
      since TDF was halted once pregnancy was diagnosed. Only a handful of studies have&#xD;
      demonstrated the excretion of TDF into breastmilk and have concluded that these are&#xD;
      relatively low doses of exposure to the infant. When women were given TDF 300mg/FTC 200mg as&#xD;
      part of the triple drug regimen in Option B+ program in Malawi the Tenofovir concentrations&#xD;
      in breastmilk were very low (breast milk/maternal plasma ratio = 0.08) [59]. Additional&#xD;
      studies are needed to explore the effect of long term TDF exposure during breastfeeding on&#xD;
      child growth and child health. Considering HIV uninfected women are encouraged to breastfeed&#xD;
      for at least a year, studies exploring the long term effect of breastmilk exposure to TDF&#xD;
      when used as PrEP in the mother, are needed.&#xD;
&#xD;
      Goal:&#xD;
&#xD;
      To explore the safety of Truvada when used as PrEP in combination with current&#xD;
      recommendations for prevention of sexually transmitted infections in young women at&#xD;
      substantial risk of HIV acquisition during pregnancy and lactation.&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Pregnant women, at their first antenatal visit, HIV uninfected, without evidence of maternal&#xD;
      or fetal complications and at risk for HIV infection.&#xD;
&#xD;
      Sample Size:&#xD;
&#xD;
      To compare the frequency and seriousness of adverse events in women receiving&#xD;
      tenofovir/emtricitabine in pregnancy as opposed to women not receiving&#xD;
      tenofovir/emtricitabine in pregnancy, we have based our sample size on the main clinically&#xD;
      relevant pregnancy outcome. Although all pregnancy outcomes will be compared between the&#xD;
      intervention (immediate PrEP) and control (deferred PrEP) groups, we based our sample size on&#xD;
      the expected preterm delivery proportion among HIV uninfected women (South Africa 18.5%,&#xD;
      Botswana 19%). A sample size of 421 in the Immediate PrEP group and 421 in the Deferred PrEP&#xD;
      group (i.e. 842 in total) achieves 80% power to detect a non-inferiority margin difference&#xD;
      between the group proportions of 0.075 or 7.5%. The reference group proportion (deferred&#xD;
      PrEP) of pre-term delivery pregnancy outcome as a main clinically-relevant adverse event is&#xD;
      0.185 or 18.5%.&#xD;
&#xD;
      Study Design: An Open Label randomized control study. Pregnant women considered at high risk&#xD;
      for HIV infection will be randomized to commencing PrEP in pregnancy with continued use&#xD;
      throughout breastfeeding or deferred PrEP until breastfeeding cessation. Women in either&#xD;
      group will receive the standard of care for prevention of HIV and other sexually transmitted&#xD;
      infections.&#xD;
&#xD;
      Study Duration:&#xD;
&#xD;
      Mother: From the first antenatal visit in pregnancy until 18 months post-delivery.&#xD;
&#xD;
      Infant: From birth until 18 months of age. Approximately 12 months for planned accrual and 24&#xD;
      months for complete follow-up. The study period is expected to span 3 years.&#xD;
&#xD;
      Study Products:&#xD;
&#xD;
      Truvada (emtricitabine 200mg/tenofovir disoproxil fumarate 300mg) is in a fixed-dose&#xD;
      combination (FDC) tablet formulation and is proven safe for the prevention and treatment of&#xD;
      HIV in non-pregnant and non-lactating women.&#xD;
&#xD;
      Study Arms:&#xD;
&#xD;
      Arm A: (Intervention) Standard HIV Prevention strategy plus a once daily dose of Truvada (FTC&#xD;
      200mg/TDF 300mg tablet) initiated in pregnancy and continuing until cessation of&#xD;
      breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to&#xD;
      continue PrEP post breastfeeding cessation.&#xD;
&#xD;
      Arm B: (Control) Standard HIV Prevention strategy throughout pregnancy until 18 months&#xD;
      postdelivery plus the offer to initiate PrEP post breastfeeding cessation.&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
      • To compare the frequency and seriousness of specific adverse events related to TDF/FTC in&#xD;
      women and their children in Arm A (exposure to TDF/FTC) and Arm B (no exposure to TDF/FTC)&#xD;
      during pregnancy until breastfeeding cessation.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  To estimate HIV incidence in women in Arm A with Arm B at delivery and at 18 months&#xD;
           post-delivery.&#xD;
&#xD;
        -  To determine the interdependency of adherence to a once daily oral TDF/FTC regimen and&#xD;
           standard HIV prevention methods during pregnancy and postdelivery.&#xD;
&#xD;
        -  To measure antiretroviral drug (TDF/FTC) level in women and their infants in association&#xD;
           with adherence, safety and level of protection (plasma and breastmilk)&#xD;
&#xD;
        -  To detect drug resistance among women who acquire HIV infection and correlate the&#xD;
           treatment outcomes (after initiating immediate antiretroviral (ARV) treatment) with drug&#xD;
           resistance&#xD;
&#xD;
        -  To determine mother-to-child transmission of HIV among women who acquire incident&#xD;
           infections during pregnancy and breastfeeding and the frequency of drug resistance in&#xD;
           their infected babies&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 28, 2017</start_date>
  <completion_date type="Actual">December 30, 2021</completion_date>
  <primary_completion_date type="Actual">December 30, 2021</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Pregnant women considered at high risk for HIV infection will be randomized to commencing PrEP in pregnancy with continued use throughout breastfeeding or deferred PrEP until breastfeeding cessation. Women in either group will receive the standard of care for prevention of HIV and other sexually transmitted infections.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pregnancy Outcome-Preterm Deliveries</measure>
    <time_frame>Within 72 hours postdelivery</time_frame>
    <description>Number of preterm deliveries &lt; 37 weeks gestation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Bone Mineral Density in mother and infant</measure>
    <time_frame>6 weeks postdelivery, and thereafter 6 monthly until week 74</time_frame>
    <description>Number of participants with decreased bone mineral density of hip and spine</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pregnancy Outcome-Low Birth Weight</measure>
    <time_frame>Within 72 hours</time_frame>
    <description>Number of Low birth weight babies &lt;2500g</description>
  </primary_outcome>
  <other_outcome>
    <measure>Incident HIV infection</measure>
    <time_frame>Monthly during pregnancy and until 74 weeks postdelivery</time_frame>
    <description>Number of Incident HIV infections in women</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence to PrEP</measure>
    <time_frame>Monthly during pregnancy and until 74 weeks postdelivery</time_frame>
    <description>Number of women with &gt;90% adherence to PrEP</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">540</enrollment>
  <condition>HIV-1-infection</condition>
  <arm_group>
    <arm_group_label>Arm A (Intervention - Truvada)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard HIV Prevention strategy plus a once daily dose of Truvada (FTC 200mg/TDF 300mg tablet) initiated in pregnancy and continuing until cessation of breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to continue PrEP post breastfeeding cessation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (Control - Standard of Care)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard HIV Prevention strategy throughout pregnancy until 18 months postdelivery plus the offer to initiate PrEP post breastfeeding cessation</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Truvada</intervention_name>
    <description>Truvada (Truvada (emtricitabine 200mg/tenofovir disoproxil fumarate 300mg) is in a fixed-dose combination (FDC) tablet formulation and is proven safe for the prevention and treatment of HIV in non-pregnant and non-lactating women.</description>
    <arm_group_label>Arm A (Intervention - Truvada)</arm_group_label>
    <other_name>emtricitabine 200mg/tenofovir disoproxil fumarate 300mg)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At least 18 years old.&#xD;
&#xD;
          -  Confirmed HIV-1 uninfected.&#xD;
&#xD;
          -  Willing to provide screening informed consent&#xD;
&#xD;
          -  Currently pregnant&#xD;
&#xD;
          -  Considered high risk for HIV infection&#xD;
&#xD;
               -  Unprotected sex during pregnancy&#xD;
&#xD;
               -  HIV status of current sexual partner is positive or unknown&#xD;
&#xD;
          -  Results of Hepatitis B Virus (HBV) screening (HBsAg testing) available from specimen&#xD;
             obtained within 30 days prior to entry&#xD;
&#xD;
          -  Plans to deliver in the study affiliated hospital&#xD;
&#xD;
          -  Has no plans to move residence outside of the catchment area during the 18 months&#xD;
             following delivery&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HIV infected&#xD;
&#xD;
          -  &lt;18 years of age&#xD;
&#xD;
          -  The following laboratory values from a specimen obtained within 30 days prior to study&#xD;
             entry:&#xD;
&#xD;
               -  Hemoglobin &lt;9.5 g/dL&#xD;
&#xD;
               -  White Blood Cell Count (WBC) &lt; 1500 cells/mm3&#xD;
&#xD;
               -  Absolute Neutrophil Count (ANC) &lt; 750 cells/mm3&#xD;
&#xD;
               -  Platelets &lt; 100,000 cells/mm3&#xD;
&#xD;
               -  Alanine Aminotransferase (ALT) &gt; 2.5 x upper limit of normal (ULN)&#xD;
&#xD;
               -  Estimated creatinine clearance of &lt; 70 ml/min using the cockcroft-gault equation&#xD;
                  for women: {([140 - age (years)] x [weight (kg)]) ÷ [72 x serum Cr (mg/dL)]} x&#xD;
                  0.85&#xD;
&#xD;
               -  Hepatitis B surface antigen (HBsAg) positive&#xD;
&#xD;
          -  Participation in any other study&#xD;
&#xD;
          -  In labour - at onset or beyond&#xD;
&#xD;
          -  Serious illness (including TB) and/or hospitalization&#xD;
&#xD;
          -  Receipt of TB treatment within 30 days prior to study entry&#xD;
&#xD;
          -  Fetus detected with serious congenital malformation (ultrasound not required to rule&#xD;
             out this condition)&#xD;
&#xD;
          -  History of documented structural or conduction heart defect&#xD;
&#xD;
          -  Social or other circumstances which would hinder long-term follow-up, in the opinion&#xD;
             of the site investigator&#xD;
&#xD;
          -  Currently incarcerated&#xD;
&#xD;
          -  Substance or alcohol abuse (a score of &gt;8 on the WHO Alcohol Use).&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dhayendre Moodley, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of KwaZulu</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of KwaZulu-Natal</name>
      <address>
        <city>Durban</city>
        <state>KwaZulu-Natal</state>
        <zip>4001</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 30, 2017</study_first_submitted>
  <study_first_submitted_qc>July 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of KwaZulu</investigator_affiliation>
    <investigator_full_name>Dhayendre Moodley, PhD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Preexposure prophylaxis</keyword>
  <keyword>safety</keyword>
  <keyword>HIV prevention</keyword>
  <keyword>pregnant women</keyword>
  <keyword>lactating women</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Emtricitabine</mesh_term>
    <mesh_term>Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 19, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT03227731/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03227731
org study id: UKwaZulu
nct id: NCT03227731
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
An Open Label randomized control study. To explore the safety of Truvada when used as PrEP
      during pregnancy and lactation. Pregnant women considered at risk for HIV infection and
      willing to participate in this randomized control study will be randomized to commencing PrEP
      in pregnancy and continued use throughout breastfeeding or deferred PrEP until breastfeeding
      cessation. All women will receive the standard of care for prevention of HIV and other
      sexually transmitted infections.

      Arm A: (Intervention): Standard HIV Prevention strategy plus a once daily dose of Truvada
      (FTC 200mg/TDF 300mg tablet) initiated in pregnancy, continuing until cessation of
      breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to
      continue PrEP post breastfeeding cessation.

      Arm B: (Control): Standard HIV Prevention strategy throughout pregnancy until cessation of
      breastfeeding plus the offer to initiate PrEP post breastfeeding cessation.

      Standard HIV prevention strategy includes risk reduction counselling, sexually transmitted
      infection (STI) screening and treatment, condom promotion and inviting the sexual partner to
      receive HIV counselling and testing (HCT) and referral for antiretroviral therapy (ART) if he
      tests positive.

      Main Outcome Measure: Renal function, pregnancy outcomes, bone health and infant growth.

      Other Outcome Measure: Incident HIV infections, adherence to PrEP, drug resistance and
      mother-to-child transmission of HIV.
Background:

      It is becoming increasingly evident that women remain vulnerable to HIV infection during
      pregnancy and even more so postdelivery. In a meta-analysis, using data from 19 international
      cohorts, Drake et al concluded that the pooled HIV incidence rate during pregnancy/postpartum
      was 3.8/100 per woman years (PWY) (95% Confidence Interval (CI) 3.0-4.6): 4.7/100 PWY during
      pregnancy and 2.9/100 PWY postpartum. In earlier South African studies (2005-2009)
      investigators reported HIV seroconversion rates ranging from 1.3% to 3.0% in pregnancy [4-6].
      Dinh et al in 2010-2012 reaffirmed the high seroconversion rate among pregnant women
      attending public health facilities in South Africa; 3.3% (95% CI: 2.8%-3.8%) women
      seroconverted in pregnancy [7]. In an evaluation of PMTCT program indicators in KwaZulu-Natal
      in 2015 the HIV seroconversion rate among 78 906 pregnant HIV uninfected women was estimated
      as 1.8% (95%CI 1.0-2.9) in pregnancy and 5% (among 26 455 breastfeeding women) in the
      postnatal period.

      Rationale:

      Truvada, an antiretroviral agent containing emtricitabine (200 mg) and tenofovir disoproxil
      fumarate (300 mg) in a fixed-dose combination (FDC) tablet formulation is widely used in
      pregnant women as part of a combination treatment regimen and as prophylaxis to prevent
      mother-to-child transmission of HIV. Truvada is also the drug of choice in PrEP and currently
      recommended by the World Health Organization (WHO) for people at substantial risk of HIV
      infection (incidence >3%). Pregnant women were excluded from participating in PrEP trials
      because of the lack of safety data in pregnancy. Available human and animal data suggest that
      TRUVADA does not increase the risk of major birth defects overall compared to the background
      rate and there are limited safety data for TDF/FTC when used in HIV uninfected pregnant
      women. In the past five years, PrEP trials have explored the use of Tenofovir alone or in
      combination with Emtricitabine in a once daily regimen, resulting in varying efficacy
      outcomes that have been largely associated with adherence. Much of the safety data have been
      generated in studies involving ART in HIV infected pregnant women. The majority of these
      studies indicate no added adverse effect of TDF on pregnancy outcomes. The few studies of TDF
      use in HIV uninfected women are treatment studies to prevent mother-to-child transmission of
      Hepatitis B and only 2 studies of TDF as PrEP use among women who subsequently fell pregnant
      post enrolment. However, exposure to TDF during pregnancy in these PrEP studies is limited
      since TDF was halted once pregnancy was diagnosed. Only a handful of studies have
      demonstrated the excretion of TDF into breastmilk and have concluded that these are
      relatively low doses of exposure to the infant. When women were given TDF 300mg/FTC 200mg as
      part of the triple drug regimen in Option B+ program in Malawi the Tenofovir concentrations
      in breastmilk were very low (breast milk/maternal plasma ratio = 0.08) [59]. Additional
      studies are needed to explore the effect of long term TDF exposure during breastfeeding on
      child growth and child health. Considering HIV uninfected women are encouraged to breastfeed
      for at least a year, studies exploring the long term effect of breastmilk exposure to TDF
      when used as PrEP in the mother, are needed.

      Goal:

      To explore the safety of Truvada when used as PrEP in combination with current
      recommendations for prevention of sexually transmitted infections in young women at
      substantial risk of HIV acquisition during pregnancy and lactation.

      Study Population:

      Pregnant women, at their first antenatal visit, HIV uninfected, without evidence of maternal
      or fetal complications and at risk for HIV infection.

      Sample Size:

      To compare the frequency and seriousness of adverse events in women receiving
      tenofovir/emtricitabine in pregnancy as opposed to women not receiving
      tenofovir/emtricitabine in pregnancy, we have based our sample size on the main clinically
      relevant pregnancy outcome. Although all pregnancy outcomes will be compared between the
      intervention (immediate PrEP) and control (deferred PrEP) groups, we based our sample size on
      the expected preterm delivery proportion among HIV uninfected women (South Africa 18.5%,
      Botswana 19%). A sample size of 421 in the Immediate PrEP group and 421 in the Deferred PrEP
      group (i.e. 842 in total) achieves 80% power to detect a non-inferiority margin difference
      between the group proportions of 0.075 or 7.5%. The reference group proportion (deferred
      PrEP) of pre-term delivery pregnancy outcome as a main clinically-relevant adverse event is
      0.185 or 18.5%.

      Study Design: An Open Label randomized control study. Pregnant women considered at high risk
      for HIV infection will be randomized to commencing PrEP in pregnancy with continued use
      throughout breastfeeding or deferred PrEP until breastfeeding cessation. Women in either
      group will receive the standard of care for prevention of HIV and other sexually transmitted
      infections.

      Study Duration:

      Mother: From the first antenatal visit in pregnancy until 18 months post-delivery.

      Infant: From birth until 18 months of age. Approximately 12 months for planned accrual and 24
      months for complete follow-up. The study period is expected to span 3 years.

      Study Products:

      Truvada (emtricitabine 200mg/tenofovir disoproxil fumarate 300mg) is in a fixed-dose
      combination (FDC) tablet formulation and is proven safe for the prevention and treatment of
      HIV in non-pregnant and non-lactating women.

      Study Arms:

      Arm A: (Intervention) Standard HIV Prevention strategy plus a once daily dose of Truvada (FTC
      200mg/TDF 300mg tablet) initiated in pregnancy and continuing until cessation of
      breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to
      continue PrEP post breastfeeding cessation.

      Arm B: (Control) Standard HIV Prevention strategy throughout pregnancy until 18 months
      postdelivery plus the offer to initiate PrEP post breastfeeding cessation.

      Primary Objective:

      • To compare the frequency and seriousness of specific adverse events related to TDF/FTC in
      women and their children in Arm A (exposure to TDF/FTC) and Arm B (no exposure to TDF/FTC)
      during pregnancy until breastfeeding cessation.

      Secondary Objectives:

        -  To estimate HIV incidence in women in Arm A with Arm B at delivery and at 18 months
           post-delivery.

        -  To determine the interdependency of adherence to a once daily oral TDF/FTC regimen and
           standard HIV prevention methods during pregnancy and postdelivery.

        -  To measure antiretroviral drug (TDF/FTC) level in women and their infants in association
           with adherence, safety and level of protection (plasma and breastmilk)

        -  To detect drug resistance among women who acquire HIV infection and correlate the
           treatment outcomes (after initiating immediate antiretroviral (ARV) treatment) with drug
           resistance

        -  To determine mother-to-child transmission of HIV among women who acquire incident
           infections during pregnancy and breastfeeding and the frequency of drug resistance in
           their infected babies
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Pregnant women considered at high risk for HIV infection will be randomized to commencing PrEP in pregnancy with continued use throughout breastfeeding or deferred PrEP until breastfeeding cessation. Women in either group will receive the standard of care for prevention of HIV and other sexually transmitted infections.
primary purpose: Other
masking: None (Open Label)
measure: Pregnancy Outcome-Preterm Deliveries
time frame: Within 72 hours postdelivery
description: Number of preterm deliveries < 37 weeks gestation
measure: Bone Mineral Density in mother and infant
time frame: 6 weeks postdelivery, and thereafter 6 monthly until week 74
description: Number of participants with decreased bone mineral density of hip and spine
measure: Pregnancy Outcome-Low Birth Weight
time frame: Within 72 hours
description: Number of Low birth weight babies <2500g
measure: Incident HIV infection
time frame: Monthly during pregnancy and until 74 weeks postdelivery
description: Number of Incident HIV infections in women
measure: Adherence to PrEP
time frame: Monthly during pregnancy and until 74 weeks postdelivery
description: Number of women with >90% adherence to PrEP
arm group label: Arm A (Intervention - Truvada)
arm group type: Active Comparator
description: Standard HIV Prevention strategy plus a once daily dose of Truvada (FTC 200mg/TDF 300mg tablet) initiated in pregnancy and continuing until cessation of breastfeeding or 18 months postdelivery whichever is earliest and thereafter the option to continue PrEP post breastfeeding cessation.
arm group label: Arm B (Control - Standard of Care)
arm group type: No Intervention
description: Standard HIV Prevention strategy throughout pregnancy until 18 months postdelivery plus the offer to initiate PrEP post breastfeeding cessation
intervention type: Drug
intervention name: Truvada
description: Truvada (Truvada (emtricitabine 200mg/tenofovir disoproxil fumarate 300mg) is in a fixed-dose combination (FDC) tablet formulation and is proven safe for the prevention and treatment of HIV in non-pregnant and non-lactating women.
arm group label: Arm A (Intervention - Truvada)
other name: emtricitabine 200mg/tenofovir disoproxil fumarate 300mg)
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dhayendre Moodley, PhD
role: Principal Investigator
affiliation: University of KwaZulu
facility: 
country: South Africa
responsible party type: Principal Investigator
investigator affiliation: University of KwaZulu
investigator full name: Dhayendre Moodley, PhD
investigator title: Professor
mesh term: Tenofovir
mesh term: Emtricitabine
mesh term: Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
sharing ipd: No
provided document: 