Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03227731 |
| Other study ID # |
UKwaZulu |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
September 28, 2017 |
| Est. completion date |
December 30, 2021 |
Study information
| Verified date |
November 2022 |
| Source |
University of KwaZulu |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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
