Immediate or Deferred Pre-exposure Prophylaxis for HIV Prevention: Safe Options for Pregnant and Lactating Women
Condition: HIV-1-infection
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Truvada
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): emtricitabine 200mg/tenofovir disoproxil fumarate 300mg)
Intervention MeSH terms: Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
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.
Masking: None (Open Label)
Primary purpose: Other
Keywords: Preexposure prophylaxis; safety; HIV prevention; pregnant women; lactating women