Immediate or Deferred Pre-exposure Prophylaxis for HIV Prevention: Safe Options for Pregnant and Lactating Women An Open-Label Randomised Control Study
Phase: PHASE2
Conditions: HIV-1-infection
Sponsor: University of KwaZulu

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Immediate or Deferred Pre-exposure Prophylaxis for HIV 
Prevention: Safe Options for Pregnant and Lactating Women 
 
An Open-Label Randomised Control Study 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:                     Dhayendre  Moodley  
 
Co-Principal Investigators:             Hoosen Coovadia 
                                                           Marie-Louise Newell 
                                                           Motshedisi Sebitloane  
 
 
              
                                                            
 
        
 
 
 
 
 
 
 
 
 
 
 
Version 1.0 
FINAL 
19 August 2016 

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PROTOCOL TEAM ROSTER:   
 
 
 
Dhayendre Moodley, PhD 
Principal Investigator 
Womens Health and HIV Research Unit 
University of KwaZulu Natal 
Congella, 4013,  
Durban, South Africa 
moodleyd1@ukzn.ac.za 
T: 27-31-260-4641 
F: 27-31-260-4549 
 
Hoosen Coovadia, FCP, PhD 
Co-Principal Investigator – Paediatrician 
Maternal Adolescent and Child Health 
School of Public Health 
University of Witwatersrand 
Durban, South Africa 
hcoovadia@match.org.za 
T: 27-31-275 1557 
F: 27-31-207 3239 
 
Marie-Louise Newell, MB, PhD 
Co-Principal Investigator – Epidemiologist 
Global Health 
Faculty of Medicine 
University of Southampton 
London, United Kingdom 
M.Newell@soton.ac.uk 
T: 023 8120 8692 
 
 
Motshedisi Sebitloane, FCOG 
Co-Principal Investigator - Obstetrician 
Dept Obstetrics and Gynaecology 
University of KwaZulu Natal 
Congella, 4013,  
Durban, South Africa 
Sebitloanem@ukzn.ac.za 
T:27-31-2604432 
 
Kimesh Naidoo, FCP 
Co-Investigator - Paediatrician 
Congella, 4013,  
Durban, South Africa 
Naidook9@ukzn.ac.za 
T: 27-31-260-4454 
F: 27-31-260-4549 
 
Megeshni Naidoo, MBChB 
Co-Investigator – Medical Officer 
Congella, 4013,  
Durban, South Africa 
 
 
 
 
 
Ottancia Mhlongo 
Co-Investigator  
Provincial Department of Health Advisor 
330 Langalibalele Street 
Pietermaritzburg, 3201, South Africa. 
mhlongo@kznhealth.gov.za 
 
Sherika Hanley, MBChB, MFamMed, FCFP 
Sub-Investigator - Research Clinician 
Umlazi Clinical Research Site 
Nelson R. Mandela School of Medicine 
Durban, South Africa 
Phone: 27 31 2604685 
Hanley@ukzn.ac.za 
 
 
Benn Sartorius, PhD 
Principal Statistician 
Discipline of Public Health Medicine 
University of KwaZulu-Natal 
Congella, 4013 
Durban, South Africa 
Sartorius@ukzn.ac.za 
 
 
Alicia Desmond, MPharm  
Protocol Pharmacist 
Congella, 4013,  
Durban, South Africa 
 
 
 
Lorna Madurai, PhD 
Laboratory Specialist 
Global Clinical Virology Laboratory 
Durban, South Africa 
Lorna.Madurai@globallabs.co.za 
 
 
Vani Chetty, BScHons 
Project Coordinator 
Umlazi Clinic 
University of KwaZulu-Natal, Private Bag X7, 
Congella 4013, Durban, South Africa  
Chettyv1@ukzn.ac.za 
T: 27-31-260-1935 
F: 27-31-260-4549 
 
 
 
 

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TABLE OF CONTENTS 
 
GLOSSARY 
 
 
5 
 
 
SYNOPSIS 
7 
 
 
1.0 BACKGROUND 
1.1 HIV Prevalence in Pregnant Women in South Africa 
1.2 HIV Incidence in Pregnant and Lactating Women in KwaZulu Natal  
1.3 International Studies of HIV Incidence in Pregnancy and Postpartum 
1.4 Behavioural Risk for HIV Acquisition in Pregnancy and Post-delivery  
1.5 HIV Acquisition in Pregnancy and Post-delivery and Effect on Mother-to-Child 
Transmission of HIV 
1.6 HIV Prevention in Women 
1.7 Antiretroviral PreExposure Prophylaxis to Prevent Mother-to-Child Transmission of 
HIV  
1.8 Antiretroviral PreExposure Prophylaxis to Prevent HIV Acquisition in Women  
1.9 Intervention 
1.10  Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Adult  Subjects 
1.11  Clinical Experience with and Safety of Emtricitabine and Tenofovir Disoproxil 
Fumarate – Truvada in Pregnancy and Breastfeeding  
1.12 Reference 
11 
11 
11 
12 
13 
 
14 
14 
 
15 
16 
18 
19 
 
20 
29 
 
 
2.0 AIMS AND OBJECTIVES 
2.1 Aim 
2.2 Primary Objective 
2.3 Secondary Objectives 
35 
35 
35 
36 
 
 
3.0   SETTING 
3.1   Population at Risk  
37 
37 
 
 
4.0   SELECTION OF PARTICIPANTS 
4.1   Selection and Enrollment of Subjects 
39 
39 
 
 
5.0    RANDOMISATION 
5.1  Screening and Enrollment 
5.2  Randomisation 
40 
40 
40 
 
 
6.0    STUDY TREATMENT CONSIDERATIONS 
6.1  Study Product Formulation and Storage Conditions 
6.2  Treatment Procedures 
6.3  Treatment Schedule 
6.4  Study Product Procurement 
6.5  Study Product Accountability 
6.6  Study Product Dispensing 
6.7  Study Product Returns 
6.8  Adherence Counselling 
6.9  Adherence Assessment 
 6.10 Concomitant, Prohibited, and Precautionary Medications 
6.11  Treatment after HIV Seroconversion 
6.12  HIV Prevention post breastfeeding cessation 
42 
42 
42 
42 
42 
42 
43 
43 
43 
43 
43 
43 
44 
 
 
7.0    ASSESSMENTS AND FOLLOW-UP PROCEDURES 
7.1  Source of Study Population 
7.2  Cohort Accrual and Follow-up 
45 
45 
45 

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7.3  Pre-screening 
7.4  Screening 
7.5  Enrollment 
7.6  Randomisation Procedures 
7.7  Post-randomisation Procedures 
7.8  Follow-up Visit after 1 month on Truvada 
7.9  Follow-up Visit until Delivery and Post-delivery 
7.10 
Follow-up Visit < 72 hours Post-delivery 
7.11 
Follow-up Visits Post Delivery 
7.12 
At Follow-up Visits during Product Use 
7.13 
Followup Visits for Infants 
7.14 
Follow-up Visits for Women who Seroconvert during Study Participation 
7.15 
Follow-up Visits for Children Born to Women who Seroconvert During Pregnancy 
or Breastfeeding 
7.16 
Stored Specimens 
7.17 
Participant Retention 
7.18 
Participant Withdrawal 
7.19 
Sexual Partners 
7.20 
Procedures for Assessing HIV Seroconversion 
7.21 
Procedures for Assessing Safety 
45 
45 
46 
46 
46 
46 
47 
47 
47 
47 
48 
48 
49 
 
50 
50 
50 
50 
51 
51 
 
 
8.0    SAFETY REPORTING  
8.1  Safety Follow-up Procedures: Medical 
8.2  Safety Follow-up Procedures: Psychosocial 
8.3  Documentation 
8.4  Internal and External Reporting 
8.5  Definitions 
53 
53 
54 
55 
55 
 
 
9.0    QUALITY MANAGEMENT  
9.1  Quality Assurance 
9.2  Quality Control 
57 
57 
57 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Method of Randomisation 
10.2 
Outcome Measures 
10.3 
Sample Size Calculations 
10.4 
Analysis Plan 
58 
58 
58 
58 
60 
 
 
11.0 
REGULATORY AND ETHICAL ISSUES 
11.1 
Regulatory Compliance 
11.2 
Participant Confidentiality 
11.3 
Ethical Considerations 
62 
62 
62 
62 
 
 
Appendix I – Screening Informed Consent 
 
Appendix 2 – Risk Assessment 
 
Appendix 3 – Enrollment Informed Consent 
 
Appendix 4 – Storage Informed Consent 
 
Appendix 5 - Schedule of Events for Mother 
 
Appendix 6 – Schedule of Events for the HIV Unexposed Infant 
63 
 
69 
 
70 
 
83 
 
87 
 
88 
 
 

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GLOSSARY 
 
Acronyms 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP 
Antepartum 
ART 
Antiretroviral therapy 
ARV 
Antiretroviral 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BF 
Breastfeeding 
BHITS 
Breastfeeding and HIV International Transmission Study 
BMD/C 
Bone mineral density/content 
CBV 
Combivir 
CDC 
US Centers for Disease Control and Prevention 
CI 
Confidence Interval  
Cr/Cr CL 
Creatinine/Creatinine Clearance 
CRF 
Case Report Form 
DBS 
Dried blood spot 
DXA 
Dual Energy X-Ray Absorptiometry 
EAE 
Expedited Adverse Event 
EBF 
Exclusive Breast Feeding 
EC 
Ethics Committee 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
FDA 
US Food and Drug Administration 
FDC 
Fixed dose combination 
FF 
Formula feeding 
FTC 
Emtricitabine 
GCLP 
Good clinical lab practice 
HBV 
Hepatitis B Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IP 
Intrapartum 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
L/D 
Labor and delivery 
LFT 
Liver Function Test 
MOP 
Manual of Procedures 
MTCT 
Mother-to-Child Transmission 
NAT 
Nucleic Acid Test 
PK 
Pharmacokinetic 
PMTCT 
Prevention of Mother-to-Child Transmission 
PP 
Postpartum 
POC 
Point of Care 
 
 

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GLOSSARY 
PoR 
Pharmacist of Record 
PrEP 
Pre-exposure prophylaxis 
SAE 
Serious Adverse Event 
SID 
Study Identification Number 
SIP 
Site Implementation Plan 
SOC 
Standard of care 
TB 
Tuberculosis 
TDF 
Tenofovir disoproxil fumarate 
TRV 
Truvada (fixed dose combination Emtricitabine-Tenofovir disoproxil fumarate) 
ULN 
Upper limit of normal 
HCT 
HIV Counselling and Testing 
WBC 
White blood count 
WHO 
World Health Organization 
WITS 
Women and Infants Transmission Study 
WY 
Women years 
 
 

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SYNOPSIS 
 
Background:  
There is increasing evidence that women remain vulnerable to HIV 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 PWY (95% CI 3.0-4.6): 4.7/100 PWY during pregnancy and 2.9/100 PWY 
postpartum. In earlier South African studies (2005-2009) we reported HIV seroconversion 
rates ranging from 1.3% to 3.0% in pregnancy [4-6]. In a more recent population based 
evaluation (2011-2012), Dinh et al 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 a recent (Jan-Aug 2015) evaluation of antenatal HCT and 
PMTCT program indicators in KwaZulu-Natal among 78 906 pregnant HIV uninfected women 
who retested during pregnancy, 1.8% (95%CI 1.0-2.9) seroconverted before delivery [KZN 
DOH, 2016]. In a similar evaluation of postnatal HCT indicators for Apr-Dec 2015 during 
which 26 455 women who were HIV negative during pregnancy were retested postnatally we 
reported a 5% seroconversion rate in the postnatal period alone.  Certain districts had 
distinctly higher postnatal seroconversion rates: Ethekwini (6.2%), Umgungundlovu (7.1%), 
Umzinyathi (9.1%), and Uthukela (7.1%) [KZN DOH, 2016]. The higher HIV incidence in 
women postpartum is hypothetically due to a longer exposure/observational period (12 – 18 
months) compared to exposure during the antepartum period (maximum 6-8 months). Other 
plausible reasons for the higher HIV incidence postpartum include possible behavioural 
changes and changes in relationship dynamics over a 12-18 month period.  
 
 
Rationale:  
Gilead Sciences developed Truvada, a product containing FTC 200 mg and TDF 300 mg in 
a fixed-dose combination (FDC) tablet formulation that was approved by the US FDA on 
August 2, 2004 and widely used in combination treatment regimens and as prophylaxis to 
prevent mother-to-child transmission of HIV in Sub Saharan Africa. PrEP using either daily 
oral tenofovir disoproxil fumarate (TDF) of co-formulated TDF/emtricitabine (TDF/FTC) has 
been shown to be effective for HIV prevention in men who have sex with men and in 
discordant couples. TDF-containing PrEP is currently recommended by the World Health 
Organization (WHO) for people at substantial risk of HIV infection (incidence >3%) and in 
December 2015. Pregnant women were excluded from participating in PrEP trials because 
of the lack of safety data in pregnancy as cautioned in the Drug Package Insert (“Because 
studies in humans cannot rule the possibility of harm, Truvada should be used in pregnancy 
ONLY if clearly needed”). 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 

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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 substantially high 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. 
 
SOC – Standard of Care: Risk reduction counselling, STI screening and treatment, inviting 
the sexual partner to receive HCT and referral for treatment and support if he tests HIV 
positive and condom promotion. 
 
SOC HIV 
Prevention 
 
R
a
n
d
o
m
i 
s 
e 
SOC HIV 
Prevention 
 
 
At ≥ 14 wks 
gestation 
Antepartum 
Peripartum 
Breastfeeding 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention  
 
OR 
 SOC HIV  
Prevention 
 
ARM A 
ARM B 
Option to Continue 
PrEP 
+ 
SOC HIV 
Prevention   
Post BF cessation 
Option to initiate  PrEP 
+ 
SOC HIV 
Prevention  

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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 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 
 
Main Outcome Measure: 
 
Serum Creatinine Clearance, adverse pregnancy outcomes (e.g., stillbirth, preterm 
delivery at < 37 weeks gestation, low birth weight <2500 grams, and congenital 
anomalies) and Bone Mineral Density among women 
 
Bone Mineral Density and growth parameters in neonates and infants until 18 
months of age. 
 
Other Outcome Measures: 
 
Confirmed presence of HIV infection detected by HIV NAT at scheduled 3 monthly 
visits until 18 months.  
 
Adherence –self reported use of study product, pill count during pregnancy and 
postdelivery 

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 
Condom Usage, unprotected sex acts, adherence to PrEP and perceived partners 
HIV status  
 
Antiretroviral drug level in plasma as a marker of adherence. 
 
Drug resistance – drug resistance mutations as detected by genotype analysis 
 
Mother-to-child transmission-reactive NAT testing performed in children born to 
mothers who acquire HIV infection during pregnancy and breastfeeding.  
 
 
 
 
 

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1.   BACKGROUND  
 
1.1. HIV Prevalence in Pregnant Women in South Africa 
 
South Africa has the largest burden of HIV disease globally [1]. Although South Africa 
(SA) recorded the greatest decline in new HIV infections in 2013 globally, 98 000 fewer 
than in 2010, SA still contributes the highest proportion of new infections (23%) in sub-
Saharan Africa. The rapid scale-up of ART provision and Universal Test and Treat 
programmes are expected to eliminate the HIV epidemic in South Africa, but 
mathematical models have seemingly overestimated the timing of the effect [2], and 
the effect of this new strategy on HIV incidence in the country will be more likely 
realised only after 10 years of implementation [2]. South Africa with a largely 
heterosexual HIV epidemic has through its expansive PMTCT programme initiated 
more women than males on ART. The effect of this can be seen in the antenatal 
seroprevalence trend. The HIV prevalence among ante-natal women aged 15 – 49 
years in the 2012 South African antenatal survey is estimated at 29.5% (95% CI 28.8-
30.2%)  and remains unchanged from 29.5% in 2011 (95% CI 28.7-30.2%) [3]. The 
prevalence in the older age groups is reflective of established infections, with the 
increase in prevalence in the older age groups (>35) due to greater antiretroviral 
treatment access and increased survival and increased parity among women with 
established HIV infections [4]. 
 
The antenatal HIV prevalence in the 15-24 year age group is a suggested proxy 
measure of HIV incidence because these adolescent girls and young women (AGYW) 
are more likely to have experienced recent sexual onset. The prevalence in this age 
group was 19.3% in 2012, not markedly lower than in previous years (20.1% in 2011 
and 21.8% in 2010) (Figure 1). These young pregnant women are likely to present with 
recently acquired infections (either preconceptual or very early in pregnancy) when 
they first seek antenatal care [4].  
 
 
Figure 1. Antenatal HIV Prevalence by Age Group in South Africa 2010-2012. 
 
1.2. HIV Incidence in Pregnant and Lactating Women in South Africa 
 
Women remain vulnerable to HIV during pregnancy and even more so postdelivery. In 
earlier South African studies (2005-2009) we reported HIV seroconversion rates ranging 
from 1.3% to 3.0% in pregnancy and postnatally [5-7]. The national incidence of HIV in 
pregnancy alone in 2005 was estimated as 10.7/100 PWY [95% CI 8.2–13.1][5]. 

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In a population-based evaluation (2011-2012), Dinh et al 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 a recent (Jan-Aug 2015) evaluation of antenatal HCT and PMTCT program indicators 
in KwaZulu-Natal among 78 906 pregnant HIV uninfected women who retested during 
pregnancy, 1.8% (95%CI 1.0-2.9) seroconverted before delivery [KZN DOH, 2016]. In a 
similar evaluation of postnatal HCT indicators for Apr-Dec 2015 during which 26 455 
women who were HIV negative during pregnancy were retested postnatally we reported 
a 5% seroconversion rate in the postnatal period alone.  Certain districts had distinctly 
higher postnatal seroconversion rates: Ethekwini (6.2%), Umgungundlovu (7.1%), 
Umzinyathi (9.1%), and Uthukela (7.1%) [KZN DOH, 2016]. 
 
In the past year (2015),  most districts reported antenatal seroconversion rates of 2% or 
more but more significantly seven districts reported high postnatal seroconversion rates 
ranging from 3.9 to 9.1% (Figure 2 below). Postnatal seroconversion rates were 2-6 
times higher than antenatal seroconversion rates. 
 
Figure 2. Antenatal and Postnatal Seroconversion Rates by District in KwaZulu Natal 
January-December 2015. 
 
1.3. International Studies of HIV Incidence in Pregnancy and Postpartum 
 
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 PWY (95% CI 
3.0-4.6): 4.7/100 PWY during pregnancy and 2.9/100 PWY postpartum (p = 0.18) [9] (Fig 
3). When compared to earlier studies, current programmatic data reflects a shift in the 
new HIV infection epidemic (Figures 2 and 3). The higher HIV incidence in women 
postpartum is hypothetically due to a longer exposure/observational period (12 – 18 
months) compared to exposure during the antepartum period (maximum 6-8 months). 
Other plausible reasons for the higher HIV incidence postpartum include possible 
behavioural changes and changes in relationship dynamics over a 12-18 month period. 
These risk factors are yet to be confirmed in prospective studies.   
 
2.1
1.4
1
2.7
2.1
2
2
1.5
2.9
2.1
2.1
2.8
6.2
3.9
3.1
4.1
7.1
1.7
9.1
7.1
3.2
4.7
0
1
2
3
4
5
6
7
8
9
10
Antenatal
Postnatal
% 

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Figure 3. A forest-plot of HIV incidence in pregnancy and postpartum as per a meta-
analysis of international studies by Drake et al, 2014  [9].  
 
HIV incidence was significantly higher in African than non-African countries (3.6% versus 
0.3%, respectively; p<0.001) and more importantly the meta-analysis revealed that risk 
of HIV in non-pregnant/non-postpartum women was not significantly different from the 
pregnant (HR 1.3, 95% CI 0.5-2.1) or postpartum women (HR 1.1, 95% CI 0.6-1.6). 
These findings support our rationale for pregnant and postpartum women to be regarded 
at similarly high risk as their non-pregnant counterparts. However, the impact of newly 
acquired maternal HIV infections on the unborn/lactating infant has far more outreaching 
consequences and for this reason these young pregnant women or lactating women 
need to be prioritized for access to PrEP.  
 
1.4. Behavioural Risk for HIV Acquisition in Pregnancy and Post-delivery  
In the KwaZulu-Natal HIV Incidence study involving 2835 pregnant women, the vast 
majority (63%) who tested HIV negative at their first antenatal visit continued to engage 
in unprotected sex during pregnancy and post-delivery, with abstinence during 
pregnancy reported among 17% of the women.  A behavioural intervention study in a 
South African urban community reported similar high risk sexual behavior among 
postpartum women [10].  At 14 weeks, 42% of women reported resumption of sexual 
activity since delivery, and this increased to 87% at 9 months. An estimated 17% of the 
sexually-active women tested positive for Chlamydia or N.gonorrhoea or T.vaginalis 
infections within 14 weeks of giving birth. Furthermore, inconsistent condom use was 
reported for 45% of the sexually active women at the 14 week post-delivery visit, 

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increasing to 59% at the 9 months visit post-delivery. Inconsistent condom use was 
significantly more common among HIV uninfected women at 14 weeks and at 9 months. 
In Malawi, where HIV incidence in pregnancy is reportedly 1%, sexual activity was most 
frequent in early pregnancy and in the non-pregnant state [11]. Although women 
continued to be sexually active during the course of pregnancy and postpartum, the 
number of sex acts decreased in the late pregnancy and early postpartum period (62%). 
Women also noticed a change in their partner’s behaviour in their late pregnancy and 
postpartum periods. Their partners spent more nights away from home or returned late 
at night.  In south-west Nigeria and in other African countries, traditional norms impose 
abstinence during pregnancy and in the postpartum period [12]. The question is whether 
such a practice alters partner behaviour, i.e. do men abstain as well or do they engage 
in extramarital sex.  In a community-based study in Nigeria, although men are known to 
generally have extramarital relationships (42.1%), the proportion of men with 
extramarital relationships is increased (43.7%) during the pregnancy and postpartum 
period and the chances of extramarital relationships in the abstinence period postpartum 
was much higher than in pregnancy (42.1% vs 48% p <0.001) [13].   
 
 
1.5. HIV Acquisition in Pregnancy and Post-delivery and Effect on Mother-to-Child 
Transmission of HIV 
 
An estimated 40 000 children are newly infected per annum in South Africa and the 
current mother-to-child transmission (MTCT) rate is 4% at 4-8 weeks despite the 88% 
ARV prophylaxis coverage [14]. Despite the encouraging reports of lower incidence of 
paediatric HIV infections as a result of PMTCT programmes, a study by Johnson et al 
modelled a 34% projected increase in MTCT from recently infected mothers in the 
absence of any intervention [15]. The study further cautions that MTCT from women who 
seroconvert during lactation will become the dominant mode of MTCT. In the KZN 
seroconversion cohort study, the group of HIV-exposed children was 2.3 times at higher 
risk of infection (MTCT 20.5% [8/9] vs 9.0% (83/925]) [5].  
 
 
1.6. HIV Prevention in Women 
 
For all the reasons previously argued in the search for female controlled methods to 
prevent HIV acquisition, women either during pregnancy or after delivery are also faced 
with similar challenges. However, the need for a safe and effective method of HIV 
prevention is more compelling and complicated because one would want to consider the 
unborn or breastfeeding child who could be exposed to antiretrovirals. Although there 
are no clinical trials that enrolled pregnant women in successful biomedical HIV 
intervention studies, there are reports of women falling pregnant subsequently [16,17]. 
In such cases, the study protocol may have dictated that study drugs be stopped and 
participants monitored for adverse events until end of pregnancy and end of lactation 
before recommencing study drugs. 
  
There are currently several proven interventions to prevent HIV acquisition in women. 
Figure 4 below provides an overview of all known prevention methods for men and 
women. One approach is to reducing infectiousness of the HIV infected sexual male 
partner through early antiretroviral treatment [18]. In a large African population-based 
prospective cohort study, it was found that individuals in a rural community with high 
ART coverage were 38% less likely to acquire HIV than individuals in a rural community 
with a lower ART coverage [19]. Another successful strategy is to provide pre-exposure 
antiretroviral prophylaxis to the HIV uninfected female partner [20]. 
 

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Figure 4: Evidence Based HIV Prevention Approaches for Men and Women 
 
 
1.7. Antiretroviral PreExposure Prophylaxis to Prevent Mother-to-Child Transmission 
of HIV  
 
A short course antiretroviral regimen given to HIV exposed infants during breastfeeding 
and that which prevented perinatal HIV transmission served as evidence of biological 
plausibility for using a simple antiretroviral regimen to prevent HIV acquisition in adults 
[21].  Progressive modifications in antiretroviral regimens and choice of drugs and wider 
access to populations at risk have resulted in a significant reduction in mother-to-child 
transmission rates worldwide [22]. In KwaZulu-Natal alone, we have seen transmission 
rates by 2 months of age drop from 23% to 2.4% within a decade (Fig 5), a decline in 
transmission rate once believed to be only possible in high-income countries [14,23].  

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Figure 5. Perinatal HIV transmission Rates in KwaZulu Natal (2003-2012) 
 
However, we have yet to eliminate all risks of mother-to-child transmission both during 
pregnancy and breastfeeding [22, 24]. Current PMTCT guidelines supporting a fixed 
dose combination of Tenofovir/Emtricitabine/Efavirenz as treatment of choice for all HIV 
positive pregnant women aim to maintain undetectable viral levels throughout 
pregnancy, breastfeeding and beyond (Option B+) [25,26]. The positive impact of this 
new strategy on the incidence of perinatal infections is yet to be reported but the positive 
impact on pregnancy outcomes among HIV positive women is already being realized 
[27].    In this multivariable analysis of HIV positive women delivering at a large regional 
hospital in KwaZulu-Natal, having received any antiretroviral regimen as opposed to not 
receiving any ARV was significantly associated with reduced odds of a stillbirth (OR 
0.08, 0.21 and 0.18 respectively), preterm birth (OR 0.52, 0.68 and 0.56 respectively) 
and low birth weight (0.37, 0.61 and 0.52 respectively) [27]. 
 
 
1.8. Antiretroviral PreExposure Prophylaxis to Prevent HIV Acquisition in Women  
 
In the past five years, scientists have made groundbreaking progress in identifying a 
safe and efficacious antiretroviral regimen to prevent HIV acquisition in men and women. 
These 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 (Fig 6). Importantly, no major safety concerns 
have been identified. Three studies in particular, Partners Prep Trial in Uganda and 
Kenya, the TDF-2 Trial in Botswana and the Fem Prep Trial in South Africa, Kenya and 
Tanzania have contributed to an intended policy change both at a local and international 
level [20, 29, 30]. 
 

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Figure 6: Antiretroviral Prevention Strategies for Women 
 
1.8.1. Partners Prep Trial (Truvada or Tenofovir in Uganda, Kenya) [20] 
A phase 3 randomised double-blind placebo controlled trial of daily oral Truvada 
(TDF/FTC) or Tenofovir (TDF) to prevent HIV transmission between 4,758 HIV 
discordant heterosexual partners in Uganda and Kenya. Study drug was 
discontinued among women who became pregnant during follow-up. Prevention 
efficacy among women was 71% for TDF and 66% for TDF/FTC. Adherence to 
study medication among pregnant women, notably for a shorter period since 
women were taken off study drug, was more than 90% by pill count and more 
than 80% by plasma drug level. Rates of adverse events did not differ between 
study groups, however gastrointestinal disorders and fatigue were more 
commonly reported in the groups receiving antiretroviral as compared to the 
placebo group. Resistance testing revealed TDF or FTC resistant viruses in 3 
of 14 infected individuals (21.4%) who were infected at enrollment, but no 
resistant viruses were detected in persons who were subsequently infected.  
 
1.8.2. TDF-2 Trial (Truvada in Botswana) [28] 
A phase 2 randomised double blind placebo controlled study to determine the 
safety and efficacy of daily oral Truvada (TDF/FTC) in preventing HIV 
acquisition among 1219 men and women was conducted in Botswana. 
TDF/FTC afforded 62% protection and efficacy did not differ by gender. Follow-
up was particularly low in this cohort with 33% of participants not completing 
study visits. Adherence to study medication was more than 80%, and nausea, 
vomiting and dizziness was reportedly more common among participants 
receiving TDF/FTC in the first month. Laboratory abnormalities and serious 
adverse events were similar in both groups. One of the 3 (33%) participants 
known to be infected at enrolment had TDF/FTC resistant viruses, while none 
of the 33 participants infected subsequent to enrolment demonstrated resistant 
viruses. Women who fell pregnant subsequent to enrolment were taken off study 
drugs and fetal loss was comparable in TDF/FTC and placebo groups as 
expected since exposure to TDF/FTC in pregnancy was limited. 
 

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1.8.3. FEM-PREP Trial (Truvada in South Africa, Kenya, Tanzania) [29] 
A phase 3 randomized double blind placebo-controlled study conducted in 
South Africa, Kenya and Tanzania revealed no statistically significant difference 
in HIV acquisition between women receiving TDF/FTC (4.7 infections per 100py) 
and women receiving placebo (5.0 infections per 100py). Adherence measured 
by level of study drug in the plasma was less than 50% among women receiving 
TDF/FTC. Nausea and vomiting in the first month were more commonly 
reportedly among women receiving TDF/FTC. Laboratory investigations also 
revealed slight elevation in ALT/AST levels in this study drug group. TDF/FTC 
resistant viruses were detected in 5 of 68 (7%) women who acquired infections 
after enrolment; 1 woman in the placebo group and 4 in the TDF/FTC group. 
Study drug was discontinued in women who fell pregnant subsequent to 
enrolment.  
 
1.8.4. The Ring Study (Dapivirine vaginal ring in South Africa and Uganda) [30] 
 
A phase 3 placebo controlled study has shown that a long acting HIV 
prevention method (monthly vaginal ring containing Dapivirine, a non-
nucleoside reverse transcriptase inhibitor) for women can safely reduce HIV 
infection in women by 31%. Higher efficacy (37%) however was only observed 
among women older than 21. 
 
1.8.5  ASPIRE (Dapivirine vaginal ring in South Africa and Malawi) [31] 
 
The second long acting vaginal ring study reportedly reduced HIV infections 
by 31%, but showed higher efficacy (61%) among women older than 25. The 
older women supposedly were more adherent to ring use. 
 
1.9. Intervention 
TRUVADA (tenofovir disoproxil fumarate/emtricitabine) is the antiretroviral drug to be 
used in this trial to prevent HIV acquisition. TRUVADA tablets are fixed dose 
combination tablets containing emtricitabine and tenofovir disoproxil fumarate. 
EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of 
cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, 
an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-
monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against 
HIV-1 reverse transcriptase.  
 
Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-
(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a 
thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine 
in the 5-position. It has a molecular formula of C8H10FN3O3S and a molecular weight 
of 247.24. Emtricitabine is a white to off-white crystalline powder with a solubility of 
appro
emtricitabine is -0.43 and the pKa is 2.65.  
 
Tenofovir Disoproxil Fumarate (TDF): TDF is a fumaric acid salt of the bis-
isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of 
tenofovir 
disoproxil 
fumarate 
is 
9-[(R)-2 
[bis][(isopropoxycarbonyl)oxy]- 
methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular 
 weight of 635.52. TDF is a 
white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25oC. 

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The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All 
dosages are expressed in terms of TDF except where otherwise noted.  
 
Formulation: TRUVADA tablets are for oral administration. Each film-coated tablet 
contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which 
is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also 
include the following inactive ingredients: croscarmellose sodium, lactose 
monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized 
starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which 
contains FD&C Blue #2 aluminium lake, hydroxypropyl methylcellulose 2910, lactose 
monohydrate, titanium dioxide, and triacetin.  
 
Pharmacokinetics:  
Emtricitabine: Following oral administration of EMTRIVA, emtricitabine is rapidly 
absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less 
than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is 
independent of concentration over the range of 0.02–200 μg/mL. Following 
administration of radiolabelled emtricitabine, approximately 86% is recovered in the 
urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 
3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is 
eliminated by a combination of glomerular filtration and active tubular secretion. 
Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is 
approximately 10 hours.  
 
Tenofovir Disoproxil Fumarate: Following oral administration of VIREAD, maximum 
tenofovir binds to human plasma proteins in vitro and the binding is independent of 
concentration over the range of 0.01–
–80% of the 
intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir 
is eliminated by a combination of glomerular filtration and active tubular secretion. 
Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir 
is approximately 17 hours.  
 
Overall, Study GS-US-104-172 demonstrated bioequivalence between the FTC-TDF 
combination tablet and the FTC capsule and TDF tablet formulations when 
administered separately. Administration of the FTC-TDF combination tablet with 
either a high-fat meal or light meal increased tenofovir exposure by approximately 
30% compared with fasted-state administration. Clinical experience with TDF 
indicates that the effect of food on tenofovir exposure is not of clinical relevance. FTC 
and TDF, either administered as a combination tablet (containing FTC 200 mg/ TDF 
300 mg) or co-administered as FTC 200 mg capsule and TDF 300 mg tablet were 
well tolerated. 
 
 
1.10 Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Adult 
Subjects  
 
No new adverse reactions to TRUVADA (TDF/FTC) were identified from two randomized 
placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected 
adults received TRUVADA once daily for pre-exposure prophylaxis [20,32]. Subjects 
were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled 
HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only 
males or transgender females of Hispanic/Latino (72%), White (18%), Black (9%) and 
Asian (5%) race [31]. The Partners PrEP trial enrolled both males (61-64% across 
treatment groups) and females in Kenya and Uganda [20].  

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Laboratory Abnormalities: Six subjects in the TDF-containing arms of the Partners PrEP 
trial discontinued participation in the study due to an increase in blood creatinine 
compared with no discontinuations in the placebo group [20]. One subject in the 
TRUVADA arm of the iPrEx trial discontinued from the study due to an increase in blood 
creatinine and another due to low phosphorous [32].  
 
In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) 
occurred in 6% of subjects receiving TRUVADA in the iPrEx trial. Grades 2-3 proteinuria 
(2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with TRUVADA 
in the iPrEx trial and Partners PrEP trial. 
 
Changes in Bone Mineral Density (BMD):  
In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the 
iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD 
ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the 
TRUVADA group compared with the placebo group, which returned toward baseline 
after discontinuation of treatment [33]. Thirteen percent of subjects receiving TRUVADA 
vs. 6% of subjects receiving placebo lost at least 5% of BMD at the spine during 
treatment. Bone fractures were reported in 1.7% of the TRUVADA group compared with 
1.4% in the placebo group. No correlation between BMD and fractures was noted. The 
Partners PrEP trial found similar fracture rates between treatment and placebo groups 
(0.8% and 0.6%, respectively). No BMD evaluations were conducted during this trial [20]. 
 
 
1.11 Clinical Experience With and Safety of  Emtricitabine and Tenofovir Disoproxil 
Fumarate (FTC and TDF) - Truvada in Pregnancy and Breastfeeding 
Emtricitabine (FTC, Emtriva™) in animal studies 
Fetal variations and malformations were not increased with FTC dosing in mice in 
systemic drug exposures that were 60 times higher than doses recommended in humans 
[34].  FTC crosses the placenta in mice and rabbits with average fetal/maternal drug 
concentration ratios of 0.4 in mice and 0.5 in rabbits. 
 
Emtricitabine (FTC, Emtriva™) in human studies – pregnancy and breastmilk 
 FTC is classified as FDA pregnancy category B. because of limited data demonstrating 
safety in pregnancy. In a study of 35 pregnant women given a dose of 400 mg FTC at 
the onset of labor, median cord/maternal drug ratio was 0.73, indicating significant 
placental transfer.  Median AUC after a 400 mg dose in labor was 15.5 mg*h/L, similar 
to levels in non-pregnant adults after a 200 mg dose.  Among 18 women receiving 
standard FTC dosing (200 mg/day) during the third trimester, median AUC of 8.6 
µg*h/mL was above the target of > 7 µg*h/mL, but only 12 of 18 women were above the 
target [35].  Mean cord/maternal blood ratio at delivery was 1.17. Exacerbations of HBV 
have been reported in patients after discontinuation of FTC [36]. Patients, who are co-
infected with HBV, may have increased values on liver function tests and exacerbation 
of hepatitis symptoms when FTC is stopped. Usually these symptoms are self-limiting; 
however, serious complications have been reported. The causal relationship to FTC 
discontinuation is unknown. 
 
Tenofovir Disoproxil Fumarate (TDF, Viread) in animal studies 
Tenofovir and TDF administered in toxicology studies to rats and monkeys at exposures 
(based on AUCs) between 6- and 12-fold higher than observed in humans caused bone 
toxicity [37, 38]. In monkeys, the bone toxicity was diagnosed as osteomalacia, and 
appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats 
and dogs, the bone toxicity manifested as reduced bone mineral density. Chronic dosing 
of rats in pregnancy noted no growth or reproductive problems when TDF was 

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administered at doses not associated with maternal toxicity [38].  At high doses of 
exposure (25 times the AUC achieved with therapeutic dosing), no fetal structural 
changes were seen.   
 
Chronic exposure of fetal monkeys to TDF at a high dose of 30 mg/kg (25 times the AUC 
levels achieved with therapeutic doses in humans) from days 20-150 of gestation did not 
result in gross structural abnormalities [37].  However significantly lower fetal circulating 
insulin-like growth factor levels were reported and were associated with body weights 
13% lower than untreated controls.  A slight reduction in fetal bone porosity was also 
observed within 2 months of maternal treatment.  However, a macaque treated for over 
10 years with 10 mg/kg/day of TDF has given birth over several years to three infant 
macaques, all of whom were normal and had no bone abnormalities at birth. 
Studies of intravenous TDF administration in pregnant cynomolgus monkeys reported a 
fetal/maternal concentration of 17% indicating some placental transfer [39]. 
 
Tenofovir Disoproxil Fumarate (TDF, Viread) in human studies  
Pharmacokinetic profile of TDF has only been described in HIV infected pregnant women 
when given in combination with other antiretrovirals as treatment. No data exists for TDF 
pharmacokinetics when given alone to HIV uninfected pregnant women as prophylaxis. 
TDF pharmacokinetics during the third trimester of pregnancy among 37 women 
receiving TDF as part of a combination treatment was reported by the IMPAACT P1026s 
Study team [40]. The median AUC for TDF was lower in the 2nd (1.9ug/ml) and 3rd (2.4ug 
h/ml) trimesters as compared to postpartum (3.0ug h/ml). The AUC postpartum was 
comparable to non-pregnant women. The AUC values in the P1026s study were 
comparable to the PANNA study (2.5 and 3,2ug h/ml) 3rd trimester and postpartum 
respectively [40]. Although TDF AUC exceeded the target (>1.99 ug h/ml) for 50% of 
women in 2nd trimester, 73% in the 3rd trimester and 84% postpartum it is likely that 
women weighing more than 90kg in the 3rd trimester are subject to decreased TDF 
exposure.. In three studies of pregnant women the cord-to-maternal blood ratio ranged 
from 0.60 to 0.99 indicating high placental transfer [40, 42, 43].  A dose of 600 mg of 
TDF in labor resulted in levels in the women similar to levels in non-pregnant adults after 
a 300 mg dose, suggesting higher doses are required for adequate levels during labor 
in term pregnant women [43].  This was confirmed in PACTG 394 and HPTN 057, which 
showed adequate tenofovir concentrations with 600 mg intrapartum doses and a small 
increase in tenofovir concentrations when the intrapartum dose was increased to 900 
mg [44, 45].  
  
TDF is designated as FDA pregnancy Category B based on animal and clinical data. In 
the Antiretroviral Pregnancy Registry, sufficient numbers of first trimester TDF 
exposures have been monitored to detect at least a two-fold increase in risk of overall 
birth defects but no such increase in birth defects has been observed.  The prevalence 
of birth defects after first trimester TDF exposure was 11 (2.2%) of 491 (95% CI 1.1-
4.0%) which is within the range of congenital anomalies reported in the general US 
population [46]. Safety data for TDF use in pregnancy is only available for HIV infected 
pregnant women. Low serum creatinine levels correlated strongly with lower AUC during 
the 3rd trimester in pregnancy. Women with target AUC had a serum creatinine level 
0.1mg/dl higher than women who did not achieve target AUC. Although clearance is 
much more rapid during 3rd trimester when compared to postpartum, the median half-life 
was similarly long during pregnancy and postpartum. TDF was well tolerated by women 
in the P1026s study [40]. A case series found TDF to be well tolerated among 76 
pregnant women, with two stopping therapy, one for rash and one for nausea.  All 78 
infants were healthy with no signs of toxicity, and all were HIV-uninfected [47].  Tenofovir 
appears to cross the placenta efficiently to achieve cord-maternal blood ratios 0.88 for 
P1026s and 0.82 in the PANNA study [40, 41]. 
 

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In a multi-centre study of antiviral safety and efficacy in HIV uninfected pregnant women 
with high HBV viral load (>7 log IU/ml) in Australia; lamivudine was used from 2007 to 
2010 and tenofovir disoproxil fumarate (TDF) from late 2010 [48]. Congenital 
abnormality rate and neonatal growth centiles were similar across cohorts. 
Adverse events and pregnancy outcomes from January 1, 2011 to June 30, 2013 were 
evaluated in a small cohort of 17 pregnant women with HBV infection in China [49]. 
There were no significant changes in serum creatinine and phosphorus levels during 
TDF treatment. In addition, no adverse events related to TDF treatment were observed. 
The mean birth weight was 3226.5±331.7 g, and the mean length at birth was 50.4±1.1 
cm. The growth and development of the infants was normal at birth, and no infants had 
birth defects related to TDF treatment. Exacerbations of HBV have been reported in 
patients after discontinuation of TDF [36]. Patients who are co-infected with HBV may 
have increased values on liver function tests and exacerbation of hepatitis symptoms 
when TDF is stopped. Usually these symptoms are self-limiting; however, serious 
complications have been reported. The causal relationship to TDF discontinuation is 
unknown.  
 
FTC and TDF Fixed Dose Combination Tablet (Truvada) in Pregnancy 
Gilead Sciences developed Truvada, a product containing FTC 200 mg and TDF 300 
mg in a fixed-dose combination (FDC) tablet formulation that was approved by the US 
FDA on August 2, 2004. TRUVADA has been evaluated in a limited number of women 
during pregnancy and postpartum. Available human and animal data suggest that 
TRUVADA does not increase the risk of major birth defects overall compared to the 
background rate. There are no safety data for TDF/FTC when used in HIV uninfected 
pregnant women. 
 
As of July 2011, the Antiretroviral Pregnancy Registry for HIV infected women has 
received prospective reports of 764 and 1219 exposures to emtricitabine- and tenofovir- 
containing regimens, respectively in the first trimester, 321 and 455 exposures, 
respectively, in second trimester, and 140 and 257 exposures, respectively, in the third 
trimester [46]. Birth defects occurred in 18 of 764 (2.4%) live births for emtricitabine-
containing regimens and 27 of 1219 (2.2%) live births for tenofovir-containing regimens 
(first trimester exposure) and 10 of 461 (2.2%) live births for emtricitabine-containing 
regimens and 15 of 714 (2.1%) live births for tenofovir-containing regimens (second/third 
trimester exposure). Among pregnant women in the U.S. reference population, the 
background rate of birth defects is 2.7%. There was no association between 
emtricitabine or tenofovir and overall birth defects observed in the APR.  
 
A review of obstetric records of 9445 HIV infected women in Botswana between 2009-
2011 concluded that adverse birth outcomes were not any different among women who 
received ZDV  or other 3 drug ART or women initiating TDF/FTC/EFV ((3% SB, 22% 
PTD and 12% SGA) [50]. 
 
The Antiretroviral Pregnancy Registry report ending Jul 2015 listed 60 cases of birth 
defects among 2608 first trimester exposures (2.3%; 95%CI 1.8-3.0) [51]. A prevalence 
similar to other antiretrovirals and furthermore the APR concluded that none of the 
antiretrovirals listed, including Tenofovir, contributed to the birth defects.  
 
All serious adverse events and their relationship to TDF in pregnancy were summarised 
in a recent review by Wang and Kourtis from the Global AIDS Program (US CDC) [52]. 
The authors have concluded that from the few studies included in the review adverse 
events were mild to moderate and none were related to TDF. The review also includes 
a summary of studies exploring bone health and foetal exposure to TDF. These studies 
are few in number and virtually all have found no significant association between 
maternal use of TDF during pregnancy and infant growth or bone abnormalities [53-56].  

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Although one US study reported 12% lower bone mineral content (BMC) in newborns 
exposed to TDF in pregnancy, the key authors of this study concluded from a similar 
study in an African cohort of HIV infected pregnant women that maternal TDF use was 
not independently associated with lower newborn BMC but a triple-ARV LPVr-containing 
regimen may have led to reduced bone mineralization [57, 58]. There are no studies that 
have explored the effect of TDF on newborn BMC among HIV uninfected women. 
Further studies are also needed to explore the effect of TDF exposure during pregnancy 
on long term child growth. 
 
 
SUMMARY OF PREGNANCY OUTCOMES IN STUDIES USING TDF OR TDF/FTC 
 
Much of the 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 in 
pregnant women. However, exposure to TDF during pregnancy in the PrEP studies is limited 
since TDF was halted once pregnancy was diagnosed. And although adherence to PrEP 
was lower in one study, the pregnancy outcomes were similar.   
 
TDF in HIV Infected Pregnant Women: 
Stillbirths: No significant differences in stillbirths in TWO comparative studies of HIV-
infected women receiving TDF-ART, nonTDF-ART or ZDV/sdNVP.  
Preterm Deliveries: There were no significant differences in preterm delivery rates between 
regimens, although in the PROMISE randomized trial. Women randomized to both TDF-ART 
and non-TDF (AZT/3TC-based) ART arms had non-significantly higher PTD rates than 
women randomized to the AZT/sdNVP arm.  
Very Preterm Deliveries: Two studies reported on very preterm delivery <34 weeks 
gestation (VPTD). In the PROMISE trial, the rate of VPTD was significantly higher in the 
women randomized to TDF ART compared to the non-TDF (AZT/3TC-based) ART; however, 
the VPTD rate in the TDF ART group was not significantly different from women randomized 
to AZT/sdNVP. 
Low Birth Weight:  All studies except one showed no significant difference in LBW rates 
between women receiving TDF ART and those receiving non-TDF ART. One study, the 
PROMISE study, reported significantly higher LBW rates in the women randomized to TDF 
ART or non-TDF ART when compared to AZT/sdNVP and rates were similar between the 
two ART regimens (TDF vs non-TDF). In the non-randomized Moodley study the rates of 
LBW were similar between women receiving TDF ART and AZT/sdNVP, as well as between 
those receiving TDF ART and non-TDF ART. One study compared LBW rates stratified by 
timing of TDF ART initiation, and observed no significant difference between TDF ART 
started preconception vs during pregnancy. 
Birth Defects: Four studies in HIV-infected women on ART reported on birth defects found 
no significant differences in birth defects between regimens. The international Antiretroviral 
Pregnancy Registry (APR) reported a birth defect rate of 2.3% among 2,608 infants exposed 
to TDF ART, not significantly different than the US population rate of birth defects from CDC 
surveillance, 2.7% (29). The APR noted that this number of first-trimester TDF ART 
exposures were sufficient to rule-out a 1.5-fold increased risk of overall birth defects as well 
as a 2-fold increased risk of defects in the most common classes (genitourinary and 
cardiovascular). There was also no difference in the APR in birth defects between those with 
first TDF ART compared to second/third trimester TDF ART exposure (2.3% vs 2.1%, 
respectively). 
 
 
 
 

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TDF in HBV infected Pregnant Women:  
TDF has also been used for prevention of perinatal hepatitis B virus (HBV) transmission in 
HBV-mono-infected pregnant women with high levels of HBV DNA (HBV DNA >log5-6 
copies/mL), where the risk of perinatal HBV transmission is high even when the infant 
receives hepatitis B immunoglobulin and HBV vaccine. In these instances, TDF, given as a 
single drug, is initiated in the third trimester of pregnancy and usually (but not always) 
stopped 1-2 months postpartum.  
Preterm Deliveries: In the HBV studies, including 143 women receiving TDF and 267 
women receiving 3TC or no drug, preterm delivery rates were not significantly different 
between regimens. 
Low Birth Weight: Three studies in HBV mono-infected women, including 102 women 
receiving TDF compared to 215 control (3TC or no drug) women, found no significant 
differences in LBW rates between TDF and control regimens in any of these studies. 
Birth Defects: No difference in the birth defect rate between the TDF regimens and control 
arms. 
  
TDF in HIV Uninfected Pregnant Women:  
There were TWO PrEP trials in which women were found to be pregnant after enrolment and 
study drug was discontinued after diagnosis (1-2 months of exposure).   
Still births: Spontaneous abortion rate was high in the PartnersPrEP and Voice studies, but 
not significantly different between the HIV uninfected women receiving TDF or TDF/FTC or 
Placebo. 
Preterm Deliveries: Overall Preterm delivery rates in these HIV-uninfected women 
were lower than observed in the HIV-infected population, ranging between 2-9% 
compared to 9-25%. No significant differences were observed in both studies 
between TDF or TDF/FTC and the comparison control groups. 
Low birth weight: The LBW rates in HIV-uninfected women (ranging from 0-5%) 
were much lower than observed for HIV-infected women (ranging from 10-20%), as 
also observed for PTD rates. 
 
The pregnancy outcomes in each of the above studies are tabulated below for each 
population group in a particular risk category. 
 
FTC and TDF Fixed Dose Combination Tablet (Truvada) during BREASTFEEDING 
The majority of HIV infected women in SubSaharan Africa and other low-income countries 
attending the public health sector will choose to breastfeed despite the risk of mother-to-child 
transmission (MTCT) of HIV. Protection against MTCT is widely available in the form of ARV 
treatment  (including TDF) of the mother or prophylaxis in the baby.   
 
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.  
 

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P a g e  | 25 
 
 
TABLE: Summary of Birth Outcomes in Studies of TDF or TDF/FTC Use in Pregnancy 
 
Study/Outcomes 
HIV Positive 
TDF - ART 
HIV Positive 
Non TDF - ART 
HIV Positive 
AZT/NVP 
HIV Positive 
No ARVs 
HIV Uninfected 
-TDF/TDF-FTC 
HIV Uninfected 
No ARVs 
Stillbirths 
Gibbs-Africa 2012 
8.0% (N=248) 
4.0% (N=110) 
 
 
 
 
Moodley-Africa 
2016 
2.2% (N=1629) 
4.2% (N=869) 
1.8% (N=957) 
13.5% (N=148) 
 
2.2% (N=130) 
Zash-Botswana 
Preconcept 
4.9%  (N=165) 
6.4% (N=2006) 
 
 
 
 
Zash-Botswana 
During Preg 
1.7% (N=231) 
4.9% (N=243) 
 
 
 
 
Bunge-Voice 
PrEP 
 
 
 
 
2.0% (N=66) 
4.0% (N=104) 
5.0% (N=100) 
Spontaneous Abortions 
Mugo-Partners PreP 
Africa 
 
 
 
 
27.7% (N=62) 
42.5% (N=80) 
32.3% (N=96) 
Bunge-Voice 
PrEP 
 
 
 
 
15.0% (N=66) 
19.0% (N=104) 
20.0% (N=100) 
Preterm Deliveries <37 weeks 
Gibbs-Africa  2012 
9.0% (N=248) 
11.0% (N=110) 
 
 
 
 
Ransom-US 
2015 
18.0% (N=630) 
16.0% (N=1395) 
 
 
 
 
Fowler-Africa 
2014 
18.5% (N=341) 
19.7% (N=346) 
13.5% (N=349) 
 
 
 
Moodley-Africa 
2016 
21.1% (N=1315) 
24.5% (N=685) 
20.1% (N=778) 
32.4% (N=100) 
 
18.5% (N=4820) 
Zash-Preconcept 
28.0% (N=165) 
31.0% (N=2006) 
 
 
 
 
Zash-During Preg 
19.5% (N=231) 
19.8% (N=243) 
 
 
 
 
Malaba-Preconcept 
20.1% (N=572) 
 
 
 
 
 
Malaba-During Preg 
18.4% (N=922) 
 
 
 
 
 
Greenup-HBV 
Australia-2014 
 
 
 
 
1.7% (N=58) 
5.7% (N=52) 
0% 
Chen-HBV 
Taiwan-2015 
 
 
 
 
7.8% (N=62) 
3.6% (N=56) 
Kochaksare-HBV 
Canada-2016 
 
 
 
 
8.3% (N=23) 
2.1% (N=138) 
Mugo-Partners PrEP 
Africa-2014 
 
 
 
 
2.5% (N=81) 
8.7% (N=46) 
7.7% (N=65) 
Low birth weight <2500g 
Gibbs-Africa 
2012 
15.0% (N=251) 
19.0% (N=115) 
 
 
 
 
Siberry US 
2012 
19.5% (N=449) 
19.1% (N=1580) 
 
 
 
 
Pintye Africa 
2015 
10.0% (N=89) 
7.0% (N=188) 
 
 
 
 
Fowler Africa 
2015 
16.9% (N=341) 
20.4% (N=346) 
8.9% (N=349) 
 
 
 
Moodley – Africa 
2016 
13.5% (N=1442) 
15.3% (N=768) 
10.0% (N=877) 
 
 
11.0% (N=5265) 
Malaba - Preconcep 
12.2% (N=572) 
 
 
 
 
 
Malaba – During 
Pregnancy 
12.0% (N=922) 
 
 
 
 
 
Celen – HBV 
2013 Turkey 
 
 
 
 
4.7% (N=21) 
4.3% (N=24) 
 
Greenup – HBV 
2014 Australia 
 
 
 
 
3.4% (N=58) 
1.9% (N=53) 
 
Kochaksaraei – HBV 
2016 Canada 
 
 
 
 
0% (N=23) 
0% (N=128) 
 

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P a g e  | 26 
 
 
 
 
 
 
 
 
 
 
 
Study/Outcomes 
HIV Positive 
TDF - ART 
Conclusion 
Le Roux et al.  
2016 (CROI)  
South Africa  
Comparative duration 
TDF  <12 w to >22 w 
Length 
<12 wk TDF: 49 (47-51);  
12-22 wk TDF: 49 (48-52); 
 >22 wk TDF: 49.5 (48-51) 
 
LAZ at ages 0-8 wk, 9-20 wk, 21-32 wk, 33-44 
wk, and >44 wk: median LAZ did not vary by 
duration of TDF exposure at any time point  
  
NO effect duration of TDF ART 
exposure on length growth  
 
Jao al.  
2016  
South Africa  
Comparative 
duration of TDF  
TDF <10 wk: 188  
10-24 wk: 326  
>25 wk: 132  
 
Femur length z-score (FLZ) median (IQR):  
o Baseline 0.20 (-0.11, 0.63)  
o Throughout gestation, median 0.30 (IQR -
0.03, 0.63)  
-score (HLZ) median IQR)  
o Baseline -0.10 (-0.45, 0.3)  
o Throughout gestation, median 0.22 (IQR -
0.26, 59)  
 
 
No difference in baseline or throughout gestation 
scores by duration TDF <10 wk, 10-24 wk, >25 
wk  
 
No effect of duration of TDF ART 
exposure on fetal bone growth  
 
Siberry et al.  
2016  
Malawi, S Africa, 
Uganda, Zimbabwe  
Comparative  
TDF: 113  
Non-TDF: 118 Zash-
Botswana 
Preconcept 
 
Estimated difference LS BMC g, adjusted mean 
(CI)  
o TDF triple vs AZT triple: 
 -0.08 (-0.16 to 0.1) (p=0.09)  
o TDF triple vs AZT/sdNVP: 0.01 (-0.08 to 0.1) 
(p=0.82)  
o AZT triple vs AZT/sdNVP: 0.09 (0 to 0.17) 
(p=0.05)  
 
 
o TDF triple vs AZT triple:  
1.76 (-2.43 to 5.95) (p=0.41)  
o TDF triple vs AZT/sdNVP: 
 9.73 (5.49 to 13.96) (p<0.001)  
o AZT triple vs AZT/sdNVP: 7.97 (3.97 to 
11.96 (p<0.001)  
  
Triple ART results in significantly 
lower whole body BMC than 
AZT/sdNVP, but not difference 
between TDF ART vs non-TDF ART 
regimens  
 

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P a g e  | 27 
 
 
TABLE: Summary of Fetal Abnormalities and Infant Bone and Growth Studies related to  TDF 
or TDF/FTC Use in Pregnancy 
Vigano et al.  
2011  
Italy  
Comparative  
TDF: 33  
Non TDF: 35  
 
BW g, median (range): TDF 2,830 (1310-3800) 
vs other ART 2,735 (1220-3700): BW <10%ile: 
TDF 12.1% vs other ART 11.4%  
-
59) vs other ART 46.8 (40-52); BL <10%ile: 
TDF 27.3% vs other ART 28.6%  
h HC cm median (range): TDF 33 (28-35) 
vs other ART 33 (28-38)  
other ART 17.1%  
other ART 14.3%  
0.6 (-2.4, 2.6) vs other ART 0.8 (-2.2, 4.4) 
(p=0.40)  
 
-0.8) vs 
other ART 0.05 (0.007-0.51) (p=0.039)  
(4.6-15.3) vs other ART 12.3 (6.6-18.6) 
(p=0.023) but all values wnl  
-1: TDF 3.7% (1/27) vs other ART 
4.1% (1/24)  
-216) 
vs other ART 124.4 (94-222) ((p=0.37)  
-
3.52) vs other ART 1.11 (0.28-3.8) (p=0.95)  
 
No difference TDF vs non-TDF ART 
for birth weight, length, HC, 23 mo 
weight, height, bone US, lab Ca, P, 
IGF-1, BAP, CTX. Significantly higher 
urine Ca/Cr ratio and lower PTH levels 
TDF vs non-TDF ART (but wnl)  
 
Siberry et al.  
2012  
USA  
Comparative  
TDF:449 (426 
infants)  
Non TDF:1,580  
 
LBW: TDF 19.5% vs other ART 19.1% (aOR 
0.73, p=0.14); no association with duration TDF 
exposure, p=0.88  
0.96, p=0.88); no association with duration TDF 
exposure, p=0.31  
 WAZ, dynamic cohort, adjusted mean 
(SD): TDF-0.63 (0.05) vs other ART -0.66 (0.04) 
(p=0.58)  
-0.25 vs other ART -0.16 
(p=0.29)  
-0.66 vs other ART -0.65 
(p=0.83)  
-1.5 SD: TDF 8.7% vs other ART 
9.0% (aOR 1.18, p=0.58)  
-1.5 SD: TDF 13.9% vs other 
ART 16.8% (aOR 0.82, p=0.39)  
-0.09 
(0.08) vs other ART -0.04 (0.06); (p=0.62)  
-0.17 
(0.07) vs other ART -0.03 (0.06); (p=0.04)  
(0.08) vs other ART 0.42 (0.06); (p=0.02)  
-1.5 SD: TDF 11.5% vs other 
ART 9.5% (aOR 1.25, p=0.42)  
-1.5 SD: TDF 7.9% vs other ART 
8.2% (aOR 0.95, p=0.87)  
-1.5 SD: TDF 6.2% vs other 
ARV 5.8% (aOR 1.17, p=0.67)  
 
No difference TDF ART vs non-TDF 
ART for LBW, SGA, birth WAZ, 
LAZ, HCAZ or birth z score <-1.5 SD; 
at 1 year, WAZ no difference but LAZ 
and HCAZ significantly lower with 
TDF than other ART; however, z score 
<-1.5 SD (severe delay) does not differ 
by regimen  
 

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P a g e  | 28 
 
 
TABLE: Summary of Maternal Bone Studies of TDF or TDF/FTC Use  
 
 
Study/Outcomes 
HIV Positive 
TDF - ART 
Conclusion 
Le Roux et al.  
2016 (CROI)  
South Africa  
Comparative duration 
TDF  <12 w to >22 w 
Length 
<12 wk TDF: 49 (47-51);  
12-22 wk TDF: 49 (48-52); 
 >22 wk TDF: 49.5 (48-51) 
 
LAZ at ages 0-8 wk, 9-20 wk, 21-32 wk, 33-44 
wk, and >44 wk: median LAZ did not vary by 
duration of TDF exposure at any time point  
  
NO effect duration of TDF ART 
exposure on length growth  
 
Jao al.  
2016  
South Africa  
Comparative 
duration of TDF  
TDF <10 wk: 188  
10-24 wk: 326  
>25 wk: 132  
 
Femur length z-score (FLZ) median (IQR):  
o Baseline 0.20 (-0.11, 0.63)  
o Throughout gestation, median 0.30 (IQR -
0.03, 0.63)  
-score (HLZ) median IQR)  
o Baseline -0.10 (-0.45, 0.3)  
o Throughout gestation, median 0.22 (IQR -
0.26, 59)  
 
 
No difference in baseline or throughout gestation 
scores by duration TDF <10 wk, 10-24 wk, >25 
wk  
 
No effect of duration of TDF ART 
exposure on fetal bone growth  
 
Siberry et al.  
2016  
Malawi, S Africa, 
Uganda, Zimbabwe  
Comparative  
TDF: 113  
Non-TDF: 118 Zash-
Botswana 
Preconcept 
 
Estimated difference LS BMC g, adjusted mean 
(CI)  
o TDF triple vs AZT triple: 
 -0.08 (-0.16 to 0.1) (p=0.09)  
o TDF triple vs AZT/sdNVP: 0.01 (-0.08 to 0.1) 
(p=0.82)  
o AZT triple vs AZT/sdNVP: 0.09 (0 to 0.17) 
(p=0.05)  
 
 
o TDF triple vs AZT triple:  
1.76 (-2.43 to 5.95) (p=0.41)  
o TDF triple vs AZT/sdNVP: 
 9.73 (5.49 to 13.96) (p<0.001)  
o AZT triple vs AZT/sdNVP: 7.97 (3.97 to 
11.96 (p<0.001)  
  
Triple ART results in significantly 
lower whole body BMC than 
AZT/sdNVP, but not difference 
between TDF ART vs non-TDF ART 
regimens  
 

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HIV Prevention Pregnancy Post-delivery Version 1.0                                                                                 19 August 2016 
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10.1111/hiv.12252. Epub 2015 May 11. 
 
41. Colbers AP, Hawkins DA, Gingelmaier A, et al. for the PANNA network. The 
pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-
infected pregnant women. AIDS. 2013 Mar 13;27(5):739-48. doi: 
10.1097/QAD.0b013e32835c208b 
 
42. Rodman J, Flynn P, Shapiro D, et al.   Pharmacokinetics and safety of tenofovir 
disoproxil fumarate in HIV-1-infected pregnant women and their infants.  13th CROI, 
Denver, CO, February 2006; Abstract 708. 
 

HIV Prevention Pregnancy Post-delivery Version 1.0                                                                                 19 August 2016 
P a g e  | 33 
 
 
43. Hirt D, Urien S, Ekouévi DK, et al. for the ANRS 12109 Team. Population 
pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates 
(ANRS 12109). Clin Pharmacol Ther. 2009 Feb;85(2):182-9. doi: 
10.1038/clpt.2008.201. Epub 2008 Nov 5. 
 
44. Flynn PM, Mirochnick M, Shapiro DE, et al for the PACTG 394 Study Team. 
Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and 
emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob 
Agents Chemother. 2011 Dec;55(12):5914-22. doi: 10.1128/AAC.00544-11. Epub 
2011 Sep 6. 
 
45. Mirochnick M, Taha T, Kreitchmann R, et al. for the HPTN 057 Protocol Team. 
Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and 
their infants during the first week of life. J Acquir Immune Defic Syndr. 2014 Jan 
1;65(1):33-41. doi: 10.1097/QAI.0b013e3182a921eb  
 
 
46. Brown RS Jr, Verna EC, Pereira MR, et al..Hepatitis B virus and human 
immunodeficiency virus drugs in pregnancy: findings from the Antiretroviral 
Pregnancy Registry. J Hepatol. 2012 Nov;57(5):953-9. doi: 
10.1016/j.jhep.2012.06.031. Epub 2012 Jul 2. 
 
47. Habert A, Linde R, Reittner A, et al.  Safety and efficacy of Tenofovir in pregnant 
women. 15th CROI, Boston, MA, February 3-6, 2008; Abstract 627a 
 
 
48. Greenup AJ, Tan PK, Nguyen V, et al. Efficacy and safety of tenofovir disoproxil 
fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus. J 
Hepatol. 2014 Sep;61(3):502-7. doi: 10.1016/j.jhep.2014.04.038. Epub 2014 May 5. 
 
49. Hu YH, Liu M, Yi W, Cao YJ, Cai HD. Tenofovir rescue therapy in pregnant females 
with chronic hepatitis B. World J Gastroenterol. 2015 Feb 28;21(8):2504-9. doi: 
10.3748/wjg.v21.i8.2504. 
 
50. Zash R, Souda S, Chen JY, et al. Reassuring Birth Outcomes with 
Tenofovir/Emtricitabine/Efavirenz used for Prevention of Mother to Child 
Transmission of HIV in Botswana. J Acquir Immune Defic Syndr. 2015 Sep 12. 
[Epub ahead of print] 
 
51. The Antiretroviral Pregnancy Registry, 2015. Interim Report. 
http://www.apregistry.com/forms/interim_report.pdf 
 
52. Wang L, Kourtis AP, Ellington S, Legardy-Williams J, Bulterys M. Safety of tenofovir 
during pregnancy for the mother and fetus: a systematic review. Clin Infect Dis 
2013; 57:1773–81. 
 

HIV Prevention Pregnancy Post-delivery Version 1.0                                                                                 19 August 2016 
P a g e  | 34 
 
 
53. Vigano A, Mora S, Giacomet V, et al. In utero exposure to tenofovir disoproxil 
fumarate does not impair growth and bone health in HIVuninfected children born to 
HIV-infected m others. Antivir Ther 2011; 16:1259–66. 
 
54. Ransom CE, Huo Y, Patel K, et al. Infant growth outcomes after maternal tenofovir 
disoproxil fumarate use during pregnancy. J Acquir Immune Defic Syndr 2013; 
64:374–81. 
 
55. Siberry GK,Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: 
early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26:1151–9. 
 
56. Pintye J, Langat A, Singa B, Kinuthia J, Odeny B, Katana A, Nganga L, John-
Stewart G, McGrath CJ. Maternal Tenofovir Disoproxil Fumarate Use in Pregnancy 
and Growth Outcomes among HIV-Exposed Uninfected Infants in Kenya. Infect Dis 
Obstet Gynecol. 2015;2015:276851. doi: 10.1155/2015/276851 
57. Siberry GK, Jacobson DL, Kalkwarf HJ, et al. for the Pediatric HIV/AIDS Cohort 
Study. Lower Newborn Bone Mineral Content Associated With Maternal Use of 
Tenofovir Disoproxil Fumarate During Pregnancy. Clin Infect Dis. 2015 Sep 
15;61(6):996-1003. doi: 10.1093/cid/civ437. Epub 2015 Jun 9 
 
58. George K. Siberry; Camlin Tierney; Lynda Stranix-Chibanda; for the IMPAACT 
P1084s Study Team. Impact of Maternal Tenofovir Use on HIV-Exposed Newborn 
Bone Mineral. CROI 2016 February 22–25, 2016 | Boston, Massachusetts. Abs. 36. 
59. Palombi L, Pirillo MF, Marchei E, et al. Concentrations of tenofovir, lamivudine and 
efavirenz in mothers and children enrolled under the Option B-Plus approach in 
Malawi. J Antimicrob Chemother. 2015 Dec 17. pii: dkv435. 
 
 
 

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2. AIM AND OBJECTIVES   
 
Pre-exposure antiretroviral prophylaxis comprising a daily dose of Truvada 
(Tenofovir/Emtricitabine) is a proven prevention strategy for same sex couples and 
discordant couples and now internationally recommended for individuals at substantial 
risk. The benefit of PrEP in high risk population groups significantly outweigh the 
potential threat of adverse events. The high risk population groups are MSMs, men in 
incarceration, commercial sex workers and adolescent girls and young women. 
Additional options for PrEP in young women through long acting antiretroviral 
(Dapivirine) prophylaxis in vaginal rings are also possible, but preclude use in 
pregnancy. 
 
Truvada (the antiretroviral drug of choice for PrEP) is classified as a FDA pregnancy 
Category B antiretroviral. Pregnancy and lactation are distinct contraindications to 
initiate PrEP because of the limited evidence of its (Truvada) adverse effects on the 
child. Despite this classification, Truvada has been endorsed by the WHO to be used as 
part of a treatment combination in HIV infected pregnant women and to reduce mother-
to-child transmission of HIV. Arguably the benefits of Truvada, either as prophylaxis for 
prevention of mother to child transmission or as part of a treatment regimen for the 
mother, certainly outweigh the potential risk of adverse events (minimal) in this HIV 
infected population. But, do the benefits of Truvada as PrEP outweigh potential risk of 
adverse events in HIV uninfected pregnant women? 
 
Because younger pregnant and lactating women are disproportionately at risk for HIV 
infection, a targeted intervention approach for HIV uninfected pregnant women aged 
between 18 and 24 years would yield a higher benefit:risk ratio. Therefore it would be 
ethically acceptable to demonstrate the safety of Truvada as PrEP in combination with 
current standard of care interventions to preventing sexually transmitted infections and 
HIV in this most vulnerable group of pregnant women. The Intervention  Package would 
therefore include a daily dose of Truvada (TDF/FTC), risk reduction counselling, STI 
screening and treatment, inviting the sexual partner to receive HCT and referral for 
treatment and support if he tests HIV positive and condom promotion. The Control Group 
of young pregnant women will receive the above package minus the antiretroviral 
prophylaxis - Truvada (TDF/FTC).  
 
2.1 Aim: 
 
To explore the safety of Truvada when used as PrEP in combination with current 
recommendations for prevention of sexually transmitted infections and HIV in young women 
at substantial risk of HIV acquisition during pregnancy and lactation.  
 
2.2  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. 
 
 
 

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2.3  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 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 
 
 
 
 
 

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3.  SETTING 
 
The Umlazi Research Clinic is a well-established research facility, which hosts HIV 
prevention research with a particular focus on the prevention of mother-to-child 
transmission for the past 7 years. The facility is well equipped to conduct large cohort 
studies as well as smaller pharmacokinetic and safety studies.  Umlazi, an urban and 
the third largest township in South Africa is located in the EThekwini District of 
KwaZulu-Natal. Umlazi is geographically divided into 26 sections and each section is 
alphabetically named as Section A or Section D or Section H, etc.  Its estimated 
population of 1.6 million has access to a single regional hospital, Prince Mshiyeni. With 
a bed state of 1200, this institution provides a comprehensive, integrated health service 
with elements of preventive, promotive, curative and rehabilitative health care. 
Approximately 1100 births are recorded per month deliveries per month. Prince 
Mshiyeni is the referral hospital for 17 primary health care clinics in Umlazi. Busiest 
clinics in Umlazi are H, D, U and K clinics. The priorities of these clinics are maternal 
and 
child 
care, 
HIV/AIDS 
and 
chronic 
diseases.  
 
Umlazi Township spans 26 sections and Umlazi Clinical Research Site is located on the 
grounds of Prince Mshiyeni Hospital. 
         
 
 3.1  Population at Risk 
 
Pregnant women seek antenatal care at any of the 17 primary health care clinics and 
deliver at the Prince Mshiyeni Memorial District hospital.  Women range in age between 
16 and 40 years, and almost half (46%) of the women who deliver at the hospital are 
adolescents are young women (<25 years). Approximately 25% are primigravid and 
the average gestational age at first visit is 28 weeks, although 48% register prior to 20 
weeks of gestation. The PHC clinics have an active PMTCT program. As prescribed in 
the National HIV treatment guidelines, pregnant women are offered HIV counselling 
and testing at their first antenatal visit. A serial HIV testing algorithm using Point of 
Care serological tests is implemented at all public health facilities. Women who are 
positive on the first POC test are immediately confirmed infected if the second POC 
test is also reactive. If pregnant women test negative on the first POC, they receive risk 
reduction counselling and informed of an opportunity to repeat the test 3 monthly during 
pregnancy and post-delivery.  
In a maternity audit conducted at the District Hospital (PMMH) during a 3 month period 
in 2011 and 2014, 1732 (37.3%) and 2219 (38.7%) women were HIV positive among 
the 4644 and 5738 deliveries respectively.  A third (34%) of the HIV infected pregnant 
women were <25 years and 52% of women who remained HIV negative by the time of 
delivery were between 18 and 24 years old. 
 
In a cohort study conducted at a PHC clinic in Umlazi, 38% (548/1446) of antenatal 
attendees tested HIV positive and almost half (47%) of these women were <25 years 

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of age.  The prevalence of Trichomonas, Chlamydia and Neisseria in pregnant women 
was 15.6%, 17.7% and 6.4% respectively. All three STIs were significantly more 
common in younger women <25yrs (17.2%, 21% and 8.6% vs 12.4%, 13.2% and 3.4% 
respectively) than older women. Among 636 pregnant women tested for HSV-2 
shedding in cervical secretions, 52 (8.18%; 95%CI 6.22-10.65) women tested positive 
by DNA PCR. HSV-2 shedding was detected in 10.4% of HIV positive women and 6.7% 
of HIV negative women. 
 
 

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4. SELECTION OF PARTICIPANTS 
 
4.1    Selection and Enrollment of Subjects 
 
          4.1.1  Inclusion Criteria  
 
At least 18 years old.  
 
Confirmed HIV-1 uninfected. 
 
Willing to provide screening informed consent   
 
Currently pregnant  
 
Considered high risk for HIV infection 
o <25 years of age 
o Unprotected sex during pregnancy 
o HIV status of current sexual partner is positive or unknown 
 Results of HBV screening (HBsAg testing) available from specimen obtained 
within 30 days prior to entry  
 Plans to deliver in the study affiliated hospital 
 Has no plans to move residence outside of the catchment area during the 18 
months following delivery 
 
 
4.1.2  Exclusion Criteria 
 
HIV infected 
 
>24 years of age and <18 years of age 
 
The following laboratory values from a specimen obtained within 30 days 
prior to study entry: 
o Hemoglobin <11 g/dL 
o WBC < 1500 cells/mm3 
o ANC < 750 cells/mm3 
o Platelets < 100,000 cells/mm3 
o ALT > 2.5 x upper limit of normal (ULN) 
o Estimated creatinine clearance of < 70mL/min using the Cockroft-Gault 
equation for women: {([140 – age (years)] x [weight (kg)]) ÷ [72 x serum 
Cr (mg/dL)]} x 0.85 
o Hepatitis B surface antigen (HBsAg) positive 
 
Participation in any other study 
 
In labour – at onset or beyond  
 
Serious illness (including TB) and/or hospitalization  
 
Receipt of TB treatment within 30 days prior to study entry 
 
Fetus detected with serious congenital malformation (ultrasound not 
required to rule out this condition) 
 
History of documented structural or conduction heart defect 
 
Social or other circumstances which would hinder long-term follow-up, in the 
opinion of the site investigator 
 
Currently incarcerated 
 
Substance or alcohol abuse (a score of >8 on the WHO Alcohol Use). 
 
 

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5.  RANDOMISATION 
 
5.1   Screening and Enrollment 
Women who meet preliminary eligibility criteria: HIV uninfected and at substantial risk 
will be screened for further eligibility criteria following a signed screening informed 
consent. Blood will be drawn for haematology, liver function tests, blood chemistry 
tests, serology and HepB sAg assay.   
Women who are confirmed eligible following screening will be requested to provide 
their informed consent for participation in the trial and thereafter enrolled in the study. 
Consent for specimen storage will also be sought. Enrolled participants will undergo a 
physical and pelvic examination accompanied by a genital specimen collection for 
storage. Blood will also be drawn for plasma, dried blood spot and cell pellet storage.  
 
 
5.2  Randomisation  
 
Following baseline clinical assessments, laboratory investigations and behavioural 
questionnaires, participants will be randomized to one of two arms (ARM A –
Immediate PrEP or ARM B –Deferred PrEP) See Figure below. All participants will 
receive risk reduction counselling, STI screening and treatment, an invitation to the 
sexual partner to receive HCT and referral for treatment and support if he tests HIV 
positive and condom promotion. The randomisation method is described under the 
statistical section.  
 
Randomisation – Treatment Arms 
 
 
SOC – Standard of Care:  Current recommendations for prevention and control of 
STIs in all pregnant women include:   
 
correct diagnosis by syndrome or laboratory diagnosis 
 
provision of effective treatment; 
SOC HIV 
Prevention 
 
R
a
n
d
o
m
i 
s 
e 
SOC HIV 
Prevention 
 
 
At ≥ 14 wks 
gestation 
Antepartum 
Peripartum 
Breastfeeding 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention 
PrEP 
(TDF/FTC) 
+ 
SOC HIV 
Prevention  
 
OR 
 SOC HIV  
Prevention 
 
ARM A 
ARM B 
Option to Continue 
PrEP 
+ 
SOC HIV 
Prevention   
Post BF cessation 
Option to initiate  PrEP 
+ 
SOC HIV 
Prevention  

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 
reduction in or prevention of further risk-taking behaviour through 
age-appropriate education and counselling; 
 
promotion and provision of condoms, with clear messages for correct 
and consistent use; and  
 
notification and treatment of sexually transmitted infections in sexual 
partners, where applicable. 
 
In the proposed study, we will screen for STIs using serological tests (syphilis, HSV-
2) and genital tract screening using PCR molecular technology (chlamydia, 
gonorrhoea and trichomoniasis). Until laboratory results are received (approximately 
1 week), pregnant women presenting with vaginal discharge or genital ulcers 
(symptomatic sexually transmitted infections) will be treated syndromically.  
 
 
 

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6.0   STUDY TREATMENT CONSIDERATIONS 
 
The drug to be used in this study is Truvada (tenofovir disoproxil fumarate/ emtricitabine) 
which is the antiretroviral drug to be used to prevent HIV acquisition. TRUVADA tablets 
are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil 
fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog 
of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, 
an 
acyclic 
nucleoside 
phosphonate 
(nucleotide) 
analog 
of 
adenosine 
5′-
monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-
1 reverse transcriptase.  
 
 
6.1  Study product formulation and storage conditions 
 
 Study Drug : Emtricitabine-Tenofovir disoproxil fumarate FTC-TDF Truvada® 
Formulation: 200 mg/300 mg tablets 
Appearance: Blue, capsule shaped, film-coated tablet that are debossed with “GILEAD” 
on one side 
Storage: 25oC (77oF) - Excursions permitted between 15-30oC (59-86oF). Keep 
container tightly closed. Each bottle contains thirty tablets with a silica gel desiccant 
canister that should remain in the original container to protect the product from humidity. 
 
 
6.2  Treatment Procedures 
 
ARM A: 
Pregnant women allocated to ARM A will initiate Truvada on the day of 
randomization and will continue throughout peripartum until cessation of 
breastfeeding and thereafter given an option to continue PrEP until 18 months 
postdelivery. 
 
ARM B: Pregnant women allocated to ARM B will only initiate Truvada at cessation of 
breastfeeding and thereafter given an option to initiate PrEP until 18 months 
postdelivery. 
 
 
6.3  Treatment Schedule 
 
The treatment schedule is a once daily uninterrupted course. 
 
 
6.4  Study product procurement   
 
The study site pharmacist will order Truvada from the manufacturer (Gilead Sciences).  
 
  
6.5  Study product accountability 
 
The study pharmacist will maintain complete accountability and storage condition 
records of all study products received from Gilead Sciences and subsequently 
dispensed to study participants. All study products will be stored at the site study 
pharmacy. All unused study products will be returned to Gilead Sciences after the study 
is completed and terminated.  
 
 
 

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6.6  Study product dispensing 
 
The site pharmacist will dispense a 28 day supply of tablets. The aim will be to provide 
the participant sufficient to last beyond the next scheduled visit. Dispensing of study 
product will be done either directly to the study participant or to authorized study staff if 
the participant is unable to present in person to the study pharmacy.  
 
 
6.7  Study product returns 
 
Participants must present with all remaining study product at each study visit conducted 
during the duration of the trial.   
 
 
6.8  Adherence counselling  
 
Adherence counselling will be provided to study participants upon enrolment and 
additionally at specified intervals. Counselling will address topics such as participant-
centred strategies to remember to take the tablets every day, to ensure the availability 
of the tablets both in the home and away from home; and to identify and discuss various 
challenges and situations that may impede daily tablet adherence.  
  
 
6.9 Adherence assessment 
 
Data on adherence to the daily regimen of TDF/FTC will be collected at each study visit 
via pilot tested interview tools and pill count. Additionally, stored plasma specimens 
collected during the trial at each scheduled visit from suspected HIV seroconvertors will 
be archived for analysis of markers of product adherence to enhance interpretation of 
the results of the study. 
 
 
6.10 Concomitant, prohibited, and precautionary medications  
 
The following medications are not permitted: 
 
 
Drugs containing emtricitabine or tenofovir disoproxil fumarate  
 
Adefovir dipoxil 
 
Lamivudine and other cytidine analogues 
 
Didanosine 
 
Cidofovir and other medicinal products that compete for active tubular secretion 
 
Drugs that reduce renal function 
 
 
6.11 Treatment after HIV Seroconversion 
 
Participants who seroconvert during pregnancy or during breastfeeding will stop Truvada 
and will be managed according to national guidelines. Women will receive the fixed dose 
combination of TDF/FTC/EFV as per national guidelines. The participant will be 
monitored for treatment response and drug resistance. They will continue in follow-up 
until end of study. 
 

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If daily Truvada is required to treat active replication of hepatitis B acquired after 
enrolment, that will take precedence over the randomization allocation. Participants will 
continue in follow-up until end of study. 
 
 
6.12 HIV Prevention Post Breastfeeding Cessation 
 
Participants in both arms will be offered PrEP post breastfeeding cessation until end of 
study at 18 months after the last participant enrolled has delivered. Thereafter, 
participants who remain at high risk will be referred to the nearest Dreams PrEP 
Demonstration site or the National PrEP Program site whichever is available at the time 
of study completion. The study is expected to be complete by June 2019. We believe 
that there would be at a minimum ONE PHC or NGO that will be a PrEP service 
delivery site in Umlazi by the time of study completion. PrEP is slated to be included in 
the PEPFAR-supported DREAMS initiative focused on young women and adolescent 
girls. PrEP is also included in the National Strategic Plan (NSP) for HIV, STIs and TB 
(2012-2016). 
 
 
 

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7.0   ASSESSMENTS AND FOLLOWUP PROCEDURES   
 
7.1  Source of Study Population 
 
HIV uninfected pregnant women attending any of the three busiest clinics in Umlazi (D, 
H and U Clinics) will be informed of the study. Interested volunteers will be transported 
to the Umlazi Research Clinic for screening. Distance between PHC clinics and the 
Research Clinic is approximately 5 to 10 km. 
 
 
7.2  Cohort Accrual and Follow-up 
 
Cohort accrual is expected to be completed in 12 months. Accrual to this study will be 
monitored by the Protocol Team in accordance with standard operating procedures. An 
overview of the study procedures for women and their infants are provided in Appendices 
5 and 6. The women will follow the basic antenatal care schedule. For participants with 
early antenatal booking (<12 weeks), return visits will be scheduled for 20, 26-28, 32-
34, and 38 weeks until delivery. Following delivery and a <72 hour postdelivery 
assessment women and their infants will be seen at 6, 10, 14 weeks and thereafter 4 
weekly until 18 months postdelivery.   
 
 
7.3 Pre-screening 
 
Pregnant women attending antenatal clinics at off-site locations in Umlazi will be pre-
screened by study staff to ascertain preliminary eligibility. These criteria include: 
 
 
18<24 years 
 
No major obstetric complications 
 
Women plan to reside in the area for the next 2 years 
 
Tested HIV negative at the off-site location 
 
During these interactions, the study staff will explain the study to the potential candidates 
for study participation. Process information (e.g. number of potential participants 
contacted, number potentially eligible, number interested in further screening) will be 
recorded and stored at the Research Site. Participant information will not be linked to 
participant identifiers. 
 
 
7.4  Screening 
 
Screening and enrolment procedures will be completed within 14 days. Eligibility will be 
determined using a combination of biomedical and behavioural criteria. If a participant is 
not enrolled within 14 days of providing informed consent for screening, the participant 
will not be re-screened or enrolled. Screening will be completed in a step-wise manner. 
Firstly, potential participants will be invited to screen for the study and asked to provide 
informed consent for screening (Appendix 1). Potential study participants will be 
assigned a screening number, followed with a risk assessment (Appendix 2) and the first 
series of biomedical screening procedures including confirmation of HIV uninfected 
status. If both HIV test results are negative, the potential participant will be invited to 
continue with the screening process and will be asked to provide demographic 
information, locator information and blood for chemistry and haematological tests.  
 

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7.5  Enrolment  
 
At screening, eligible participants will have been given a date to return to the clinic for 
enrollment. This date will be within two weeks of screening. If a participant does not 
return within 14 days of the screening visit, she will not be enrolled nor re-screened. 
At the enrollment visit, if the participant meets all eligibility criteria that can be known 
from the screening visit, study staff will obtain informed consent for study participation 
(Appendix 3). Informed consent will also be obtained for blood to be stored for future HIV 
related research (Appendix 4). A participant may refuse this procedure and still be part 
of the study. All study procedures listed in the Schedule of Evaluations for the mother 
(Appendix 5) and for the HIV unexposed infant (Appendix 6) will follow.   
 
There will be a clinic interview, during which baseline demographic, clinical and 
behavioural data will be collected on a case record form. The behavioural and lifestyle 
information provided by the individual together with results from the screening for 
sexually transmitted infections will inform the development of a personalised plan for 
reducing their risk. A personalised invite to the sexual partner will be provided to all 
participants. The invitation is intended to encourage partners to test for HIV and be 
referred for ART if HIV positive. Partners will also be informed of their options for HIV 
prevention and what is available in the public sector. 
Participants will receive supplies of condoms in quantities anticipated to last until the 
next visit. A participant can return between scheduled visits to obtain more condoms.  
 
 
7.6  Randomisation Procedures 
 
Randomisation will be performed on the day of the enrolment visit after the eligibility 
checklist is confirmed. Randomisation will be performed using a computer-generated 
randomization list. The participant’s study number, allocation and the date of 
randomization will be entered into the Trial Register at the Research Site. 
 
 
 
7.7  Post-randomisation Procedures 
 
All participants will receive support to the agreed plan to manage their personal risk and 
counselling about the importance of adhering to the agreed schedule of visits. A diary 
will be provided to record coital acts and condom use, different partners and pill taking 
when applicable. 
 
For participants starting Truvada immediately, the clinician and participant will go 
through the instructions for use Truvada. They will be issued with 1 bottle, containing 30 
tablets, and the next clinic appointment will be made for a four-week visit. They will be 
asked to tick the days they take the drug on the diary.  
 
 
7.8  Follow-up Visit after 1 month on Truvada 
 
This assessment will be required for women on immediate ART (1 month) and for women 
on deferred ART (post cessation of breastfeeding). 
 
There will be an interview to see if the participant has experienced any side effects 
sufficient to interrupt Truvada, and how they are coping with the daily regimen. Urine will 

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be collected for analysis. A blood sample will also be collected for a HIV test, renal 
function test (creatinine), other routine antenatal investigations and specimen storage.  
 
 
7.9  Follow-up Visits until Delivery and Post-delivery 
 
Following enrolment, women will follow the schedule of evaluations in Appendix 5. 
Women will remain on their assigned treatment arm until cessation of breastfeeding and 
thereafter follow their choice of either continuing or discontinuing ARV PrEP through the 
18 month postpartum visit. Each participant will have follow-up visits approximately 
every four weeks (28 days) until delivery and following  72 hour postdelivery assessment 
the participant will be given an appointment for 2 weeks, 6, 10, 14 weeks and thereafter 
4 weekly visits until week 74 (approximately 18 months post-delivery) at the study clinic.  
 
 
7.10  Follow-up Visit <72hours Post Delivery  
 
Participants will be advised to inform the staff by sending a text message when they are 
admitted to the Labour Ward of the adjacent Hospital. Nursing staff from the research 
site will also conduct daily postnatal ward rounds to track study participants. A postnatal 
study visit will be conducted within 72 hours. A maternity chart audit and further clinical 
assessments of mother and child will be completed prior to discharge from the hospital. 
The maternity chart audit will specifically be done to record any complications since the 
last study visit through admission and during the labour process. Pregnancy outcomes 
will be recorded in the maternal case report form.  Infant assessment and mother’s 
intention to breastfeed will be documented in the infant’s case report form. Women will 
be encouraged to breastfeed their infants for as long as possible. Study drug (Truvada) 
will be dispensed to women in the Treatment Arm. All participants will have a repeat HIV 
test, and blood drawn for chemistry and haematological investigations and for storage. 
 
 
 
7.11  Follow-up Visits Post Delivery  
 
Subsequent post-delivery visits will be scheduled for weeks 2, 6, 10, 14, 18 weeks,  and 
thereafter monthly until 18 months postdelivery. Study product discontinuation could 
occur at cessation of breastfeeding for participants in the Treatment Arm who choose 
not to continue PrEP. And study product will be dispensed to participants in the Control 
Arm who choose to commence PrEP post cessation of breastfeeding. Study product will 
be distributed until 74 weeks and thereafter participants will be referred for ongoing PrEP 
at the nearest PrEP Demonstration Site at a public health clinic.  
 
 
7.12  At Follow-up Visits during Product Use 
At follow-up visits antenatal week 4 through week 74, study staff will: 
 
 
Update contact information (when necessary); 
 
Conduct pill count of product returned by participant, and document any product 
returned to participant; 
 
Collect information on adherence to the daily pill-taking regimen; 
 
Conduct risk reduction counseling, including pre- and post-test HIV counseling and 
distribute condoms; 
 
Conduct study product adherence counseling; 
 
Conduct contraceptive counseling as appropriate, re-supply contraceptive method 
as needed; 

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 
Collect blood by venepuncture (10ml) and:  
 Perform HIV rapid antibody testing according to the algorithm described at the 
enrollment visit.  
 Test for ALT, AST, creatinine and phosphorus. If results are abnormal, repeat 
regularly until resolution to ≤ Grade 1 or until stabilization. Any required follow-
up will be done per local standard of care. 
 Store plasma and ULPC aliquots for HIV PCR testing, QA and confirmatory 
laboratory testing as needed. Also store one plasma aliquot (if sufficient sample 
available) and one serum aliquot for potential future HIV related research; 
 Screen and treat other STIs using the syndromic management approach 
 Collect cervical/vaginal swabs for storage and subsequent screening for STIs 
using molecular techniques. 
 
Conduct adverse event assessment as per the US Division of AIDS Adverse Event 
Reporting and Toxicity Grading; 
 
Conduct physical and/or pelvic examination if clinically indicated; and 
 
Record medications taken since last visit. 
 
Complete the Final Status CRF if the participant does not require further follow-up 
due to risk of Hepatitis B flare and/or HIV seroconversion.  
 
Participants will be allowed to complete each follow-up visit up to five days prior to and 
two (for the week 4 follow-up visit) or four (for later follow-up visits) days after their next 
4-week (28 days) target visit date. If participants complete a visit outside the given 
window for that specific visit, the visit will be regarded an interim visit and an appointment 
for the next scheduled visit will be given. 
 
 
7.13 Followup Visits for Infants  
 
Infants will be assessed at birth, 26 weeks, 50 weeks and 74 weeks. In addition to a 
full physical examination, a blood sample will be drawn for assessing renal function 
(Creatinine Clearance) and Hormonal growth factors. For infants exposed to 
TDF/FTC an additional blood sample will be collected for a drug level assessment. 
At each visit the following growth parameters will be recorded: weight, height and 
head circumference. Infant feeding modality will be recorded at each visit. Cessation 
of breastfeeding is defined as 28 days after last exposure to breastmilk. 
 
7.14  Followup Visits for Women who Seroconvert during Study Participation 
 
This section applies to enrolled participants who test HIV antibody positive on or prior to 
week 74 and participants who are HIV antibody negative and HIV PCR (RNA or DNA) 
positive at enrollment or any follow-up visit. Prior to initiation of the clinical trial, site-
specific seroconverter plans will be made in consultation with the Department of Health 
to ensure specific provisions for care and treatment according to the standard treatment 
guidelines. Study clinicians may share relevant laboratory results with the referral centre 
care providers provided that the participant provides verbal consent; such consent will 
be documented in the participant’s file.  
 
Any participant who is diagnosed as HIV positive at a follow-up visit will have her study 
product withdrawn at that study visit. She will receive post-test counselling. If testing of 
a second sample does not confirm the initially positive result, she may continue using 
study product. If the participant tests positive on the first sample and refuses to provide 
a sample for confirmatory testing, her product will be interrupted until a confirmatory test 
is done. Partners may come to the clinic for voluntary counselling and testing (VCT) 
according to site-specific SOPs. Participant will be asked if she still agrees to stay in the 
study until the last scheduled study visit (74 weeks). She will be referred to treatment 

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centres for appropriate care and treatment according to the site-specific seroconverter 
care plan and to ongoing HIV treatment or acute HIV infection trials where available. 
Effective referral will be facilitated by the study counsellors, who will provide voluntary 
one-on-one counselling and assistance to women in accessing health care or social 
support services (including help with transportation and communication with health care 
providers concerning health needs). The counsellors and/or other study staff will also 
follow up to ensure that participants have secured needed care or services and to 
determine any problems encountered by women referred from the trial. 
 
When a participant tests HIV positive on the first sample according to the study 
algorithm, she will be counselled and asked to immediately provide a second sample 
(10ml in EDTA tube) for a repeat of the HIV algorithm tests as confirmation of the first 
positive result. According to site SOPs the following samples will also be taken either 
immediately after the first sample is positive or after the second sample has confirmed 
the first positive result: 
 
 
10ml in EDTA tube for HIV PCR, HIV-1 viral load and resistance testing; 
and, 
 
2ml in BD CD4 stabilization tube or 3ml in EDTA tube for CD4 count; 
 
A plasma aliquot will be stored (long term storage) if sufficient sample is available for 
potential future HIV related research (if participant consented). If the visit of the HIV 
diagnosis does not coincide with a visit in which secondary endpoints are assessed, 
another 5-10ml blood in serum tubes (dependent on the site, see site specific lab SOPs) 
will be collected and tested for AST, ALT, phosphorus and creatinine; a serum aliquot 
will be stored (long term storage) for potential future HIV related research (if participant 
consented). HepBsAg testing will be done if appropriate. Procedures for early product 
withdrawal will also be done. 
 
Samples from her previous visit(s) will be tested by HIV PCR to better determine the 
infection time and length of exposure to Truvada while HIV infected. Samples from visits 
in which she was HIV PCR positive but HIV antibody negative will also be tested for 
resistance and drug levels. At her first follow-up visit after the diagnosis (week 4 post 
diagnosis), HIV testing according to the study algorithm will be repeated. HIV testing will 
stop if the first algorithm testing gives a positive result. At each monthly visit post HIV 
diagnosis, study staff will: 
 
 
Update contact information (when necessary); 
 
Update her medical history, including her medication; 
 
Conduct further risk reduction counselling and distribute free condoms 
 
 
7.15 
Followup Visits for Children Born to Women who Seroconvert During  
Pregnancy or Breastfeeding 
 
All HIV exposed infants will continue with study followup until 18 months of age. 
 
Infants born to women who seroconvert during pregnancy will have a HIV DNA PCR test 
performed at birth and 3 monthly thereafter until cessation of breastfeeding. These infants 
will also receive antiretroviral prophylaxis (according to the National PMTCT Guidelines) 
commencing at birth until breastfeeding cessation.  
 
Infants being breastfed by a mother who seroconverts during breastfeeding will have a HIV 
DNA PCR test performed at the visit when the mother’s HIV status is confirmed and 3 

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monthly thereafter until cessation of breastfeeding. The infant will commence antiretroviral 
prophylaxis according to the National PMTCT Guidelines.  
Infants with confirmed HIV infection (Positive HIV DNA PCR on 2 separate specimens) will 
be managed according to the National Treatment Guidelines and in addition to routine 
haematological and chemistry tests al blood sample will be drawn for resistance testing.   
 
 
7.16  Stored Specimens 
 
 
Any blood specimens (i.e. sera or plasma) collected during screening, enrollment, and 
all follow-up visits will be cryopreserved during the clinical trial and stored at the Global 
Clinical Lab repository. These specimens may be used for repeat and confirmatory 
analyses of effectiveness, safety endpoint parameters, and drug levels. These study 
samples will be destroyed after the final study report has been submitted. At enrollment, 
participants will be asked to sign a specimen storage informed consent form for long 
term storage of samples (ten years after final study report) for any future testing related 
to HIV research that falls outside of this study. These additional specimens will be stored 
for a period of 10 years and thereafter destroyed. 
 
  
7.17  Participant Retention 
 
The target retention rate will be 90% per annum. During the informed consent process 
the participant will be informed of the planned retention procedures. This is to ensure 
participant awareness of all the efforts that will be undertaken to contact them in the 
event that they miss a scheduled study visit throughout the participant’s Involvement in 
the study (up to 2 years for those who enroll early in pregnancy). Study participants will 
be informed that staff will attempt to make telephonic contact with them for missed visits 
or for unscheduled visits if the need arises, failing which home visits will be made.   
The Protocol Team will track retention rates. Once a participant is enrolled in the study, 
study staff will make every reasonable effort to ensure adequate locator information is 
available for follow-up tracking. A missed visit in either arm will prompt a single 
telephonic reminder, where the participant is spoken to directly and reminded of her 
clinic visit. A home visit will be triggered if a second clinic visit is missed. A home visit 
will be considered complete when the participant is met in person. A maximum of 3 
attempts will be made to complete a home visit. Retention efforts will be conducted by 
the same team for both arms. 
 
 
7.18  Participant withdrawal 
 
Participants may voluntarily withdraw from the study for any reason at any time. 
Designated study staff may also withdraw participants from the study in order to protect 
their safety. Participants may also be withdrawn if the South African MCC or the 
University of KwaZulu-Natal’s (UKZN) Biomedical Research Ethics Committee (BREC) 
terminates the study prior to its planned end date. Every reasonable effort will be made 
to complete a final evaluation of participants who withdraw or are withdrawn from the 
study. Study staff will record the reason(s) for all withdrawals in participants’ study 
records.  
 
 
7.19  Sexual Partners 
 
 
Sexual partners of study participants will be invited to attend the HCT services but not 
participate in the study. They will have access to HIV counselling and testing,  

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appropriate clinical referrals for HIV treatment, STI management and other medical 
conditions. Study staff will not obtain informed consent from any men, nor will they enroll 
or collect data from them. Whenever a participant tests positive for any STI (excluding 
HIV), she will be counselled to inform her partner(s)  and refer him/them to a clinic for 
testing. Treatment for any curable STI will be offered to the male partner if he comes to 
the study clinic. Local guidelines on partner notification will be followed. Participants will 
decide on disclosing their HIV status to their partners and study staff will support her 
decision. 
 
 
7.20  Procedures for Assessing HIV Seroconversion 
 
Women will have a rapid HIV test performed at every visit using the serial testing 
algorithm as per national guidelines. In the event of a reactive rapid HIV test, a repeat 
sample will be obtained and reactivity confirmed by HIV RNA PCR assay. In the event 
of a confirmed seroconversion, a genotypic drug resistance test will be performed to 
identify mutations as a result of exposure to Truvada. 
 
 
 
7.21  Procedures for Assessing Safety 
 
Participants will be asked one month after starting Truvada and at each subsequent 
scheduled visit whether they have had any admissions to hospital, or suffered from any 
significant illness that required medical attention. The site clinician will determine 
whether an illness meets the criteria for Serious Adverse Event (SAE) Reporting. SAEs 
will be reported to the UKZN BREC, Medicines Control Council and Department of 
Health. Participants will also be asked whether they have experienced any side effects.  
Clinical assessments during pregnancy will be conducted as per the national guidelines 
for maternity care.  
Maternal safety assessments during pregnancy and until 74 weeks study exit: All 
women will have bloods drawn for chemistry and haematological investigations at 
screening, enrolment, 2 weeks, 4 weekly until delivery, <72 hours of delivery, 2 weeks 
post delivery, 6 weeks, 10 weeks, 14 weeks and 4 weekly until 74 weeks (inclusive). 
Chemistry tests include liver function markers (ALT/AST/Phosporous), renal function 
(serum creatinine/urea/sodium/potassium), and bone density markers (serum calcium 
and magnesium).  
Bone mineral content in the mother will be measured by DXA scan at 6 weeks 
postpartum, 6 months, 12 months and 18 months. Both Hip and Spine DXA scans will 
be done at above scheduled visits. 
Within 72 hours of delivery, the participant with her maternity care record (MCR) will be 
reviewed by the study clinician. Fetal outcome in addition to other obstetric data will be 
extracted from the MCR. The following definitions will be used to document fetal 
outcome: 

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Maternal gestational age will be determined by clinical and obstetric assessments that 
will include an Ultrasound, measurement of symphysis fundal height and last menstrual 
date if known. Preterm delivery is defined as < 37 weeks. Moderate preterm delivery 32-
35 weeks and severe preterm delivery <32 weeks. 
The New Ballard method will be used to assess gestational age of neonate. In addition, 
neonates will be determined small for gestational age (SGA), average for gestational 
age (AGA) and large for gestational age (LGA). 
 
Fetal Growth: 
Fetal monitoring will include fetal growth and an ultrasound for fetal abnormalities. For 
fetal growth monitoring, we would measure the symphsis fundus height at each study 
visit, plot on graph against gestational age and compare with 10th, 50th and 90th centiles 
and previous measurements. Any measurement <10th centile or failure to increase will 
be referred for an ultrasound for further fetal assessment. 
Infants exposed to TDF/FTC either in-utero or during breastfeeding will have chemistry 
(serum creatinine) and haematological (complete blood count) at birth, 26 weeks (6 
month), 50 weeks (12 months), and 72 weeks (18 months).  
Infant Bone Growth: 
DXA scans of the lumbar spine and whole body of infants will be performed at 6 weeks, 
6 months, 12 months and 18 months to determine BMC and bone growth. 
Clinical Examination of Infants: 
Clinical examination of infants at birth will be conducted as per standard of care 
prescribed in the SA paediatric guidelines. This will include examination for physical 
abnormalities. 
Physical examination of infants will include OFC, weight, and length to monitor growth 
and also include assessments for neurodevelopmental milestones at 6 weeks, 3 months, 
6 months, 12 months and 18 months. 
 
 
NON-VIABLE FETUS (MISCARRIAGE)  
Less than 28 weeks* gestation and where there is no evidence of life at delivery.  
STILL BIRTH  
Gestational age of 28 weeks or more and where there is no evidence of life at delivery.  
NEONATAL DEATH**  
Death after a live birth whatever the duration of the pregnancy.  
When the gestational age is not known, a legal weight cut-off of 1000 g is used.  

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8.0   SAFETY REPORTING 
All study staff will prioritize participant safety while carrying out their day-to-day roles and 
responsibilities.  Potential safety issues requiring follow-up, treatment, and/or referral 
may be identified through study-related activities, including: 
 
 
Clinical evaluations:  Clinical staff (nurses, medical officers) may identify medical 
issues requiring follow-up, treatment, and/or referral when performing protocol-
specified clinical assessments, as well as when reviewing study laboratory test 
results.   
 
 
Laboratory evaluations:  The Medical Officers will be responsible for identifying 
laboratory test results requiring follow-up, treatment, and/or referral when performing 
protocol-specified tests. 
 
 
Questionnaires:  Study staff, both clinical and non-clinical, may identify medical, drug 
adherence and/or psychosocial issues requiring follow-up, treatment, and/or referral 
when administering questionnaires to participants. 
 
 
Counselling:  Study staff, both clinical and non-clinical, may identify medical, drug 
adherence and/or psychosocial issues requiring follow-up, treatment, and/or referral 
when providing counseling. 
 
 
Retention Activities: Study staff, both clinical and non-clinical, may identify medical 
and/or psychosocial issues requiring follow-up, treatment, and/or referral when 
conducting participant retention activities (e.g., visit reminders, locator contacts, and 
other outreach). 
 
 
8.1  Safety Follow-up Procedures:  Medical 
In accordance with their training, qualifications, and designated study responsibilities, 
clinical staff will assess potential medical safety issues and identify medically appropriate 
follow-up, treatment, and/or referral requirements.   
 
All follow-up actions, including diagnosis, treatment, and referrals, will be documented 
in chart notes. 
 
 
Medical emergencies will be managed per the site Clinical Emergency Treatment 
and Evacuation SOP      
 
Other medical issues will be managed per usual standards of care for medical 
practice in the study site locale.   
 
When appropriate and applicable, clinical staff will perform additional procedures to 
diagnose and treat medical problems.  Additional (interim) study visits will be 
scheduled as needed to ensure timely follow-up.  All visits, procedures, findings, 
and actions taken will be documented in chart notes.   
 
When medical issues are beyond the scope of services that can be provided through 
the study, clinical staff will actively refer participants to appropriate non-study health 
care providers for further evaluation and treatment.  
All medical issues will be followed to resolution or stabilization, with the current status 
and further action plans (if applicable) documented at each study visit until resolution or 
stabilization occurs. 

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All referrals will also be documented.  At each study visit after a referral is made, the 
attending medical officer will actively follow-up on the referral to determine whether the 
participant sought the services to which the child was referred, determine the outcome 
of the referral, and determine whether additional referrals are needed.  All follow-up 
actions, outcomes, and plans for next steps will be documented in chart notes. 
 
 
In the event that medical issues are reported during a study visit to non-clinical study 
staff members, these staff members will communicate the information to clinical staff 
during the visit so that clinical staff may assess the participant’s report and proceed 
as described above.  
 
 
In the event that medical issues are reported to non-clinical study staff off-site (e.g., 
during outreach activities),  these staff members will communicate the information -  
either upon return to the clinic or by phone - to the clinical/study co-ordinator  who 
will determine the appropriate course of follow-up action. 
 
 
8.2  Safety Follow-up Procedures:  Psychosocial 
In accordance with their training, qualifications, and designated study responsibilities, 
study staff will assess potential psychosocial safety issues and identify appropriate 
follow-up, treatment, and/or referral requirements.  
   
All follow-up actions, including diagnosis, treatment, and referrals, will be documented 
in chart notes. Psychosocial emergencies will be referred to the Medical Out-Patients 
Department (MOPD) of the hospital on whose premises our CRS is located. Other non-
emergency psychosocial issues will be managed per usual standards of care for medical 
practice in the study site locale.   
 
 
When appropriate and applicable, study staff will provide information and 
counselling to assist participants with addressing the issues.  All such counselling 
will be documented in chart notes. Should the participant require more intense 
counselling or intervention strategies, they will be referred to the local hospital 
psychologist. 
 
 
When psychosocial issues are beyond the scope of services that can be provided 
through the study, study staff will actively refer participants to appropriate non-study 
service providers for further evaluation and assistance.  
 
All psychosocial issues will be followed to resolution or stabilization, with the current 
status and further action plans (if applicable) documented at each study visit until 
resolution or stabilization occurs. 
 
All referrals will also be documented.  At each study visit after a referral is made, the 
attending medical officer will actively follow up on the referral to determine whether the 
mother of the participant sought the services to which the participant was referred, 
determine the outcome of the referral, and determine whether additional referrals are 
needed.  All follow-up actions, outcomes, and plans for next steps will be documented 
in chart notes. 
 

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 In the event that psychosocial issues are reported during a study visit to study staff 
who are not trained/qualified to respond to the issues, these staff members will 
communicate the information to the clinical/study co-ordinator during the visit so that 
an appropriately trained staff member can assess the participant’s report and proceed 
as described above.  
 
  In the event that psychosocial issues are reported to study staff who are not 
trained/qualified to respond to the issues off-site (e.g., during outreach activities),  
these staff members will communicate the information — either upon return to the 
clinic or by phone — to the clinical/ study co-ordinator who will determine the 
appropriate course of follow-up action. 
 
 
8.3  Documentation 
  
Study-staff will document all safety-related participant reports (histories), observations, 
findings, and actions taken in response to these.  In the event that study participants are 
hospitalized or otherwise treated by a non-study health care provider, every effort will be 
made to obtain copies of relevant medical records. These records will be copied and 
certified by the study receptionist. The clinical/study co-ordinator will oversee these 
efforts and all efforts will be documented in chart notes.  
 
  
8.4  Internal and External Reporting 
 
 
Individual study staff members will routinely communicate participant safety 
information to their supervisors on a day-to-day basis. Specific case management 
will be discussed as needed in regular staff meetings as well as in individual staff 
supervision sessions and will be documented in meeting notes or minutes.   
 
 
Participant safety information, including any unanticipated problems related to study 
participation, will be reported to the South African Medicines Control Council and 
UKZN BREC. 
 
 
Related specifically to adverse event reporting: 
 
 
Event evaluation Case report forms (CRFs) will be completed per instructions on 
the case report form. Medical Officers will complete these CRFs.  
 
 
8.5 Definitions 
Adverse Event: 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
research participant administered an investigational product and which may or may not 
have a causal relationship with the investigational product. As such, an AE can be an 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom or disease temporally associated with the use of an investigational product, 
whether or not considered related to the product. Study participants will be instructed to 
contact the study clinician to report any AEs their infants may experience. 
 
Serious Adverse Event: 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose 
that results in death, is life threatening, requires inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a 

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congenital anomaly/birth defect (April 1996 International Conference on Harmonisation 
(ICH), Good Clinical Practice: Consolidated Guidance, (ICH E6). Important medical 
events that may not be immediately life – threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above may also be considered to be serious. (October 
1994 ICH guidance (E2A), Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting). 
 
SUSAR:  Suspected, Unexpected Serious Adverse Reaction: 
Serious (see SAE definition above) 
Related (i.e. there is a reasonable possibility that the AE may be related to the study 
agent) 
Unexpected (see definition below) 
 
Unexpected AE: 
An AE, the nature or severity (intensity) of which is not consistent with the applicable 
agent information (Investigator’s Brochure, package insert, or summary of agent 
characteristics).   
 
 

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9.  QUALITY MANAGEMENT 
 
The Quality Management plan includes both Quality assurance (QA) and Quality Control 
(QC) 
 
9.1  Quality Assurance 
 
QA involves periodic, systematic objective review of trial related activities to ensure that 
the trial is performed and the data are generated, documented and reported in 
compliance with good clinical practice (GCP). 
 
The Clinical/study co-ordinator, medical officers and the Investigator will routinely review 
random selections of participant charts to ensure that protocol specifications related to 
participant safety are being followed and that appropriate clinical and psychosocial 
management is being provided and properly documented.  The clinical/study co-
ordinator, medical officers including the investigator will also review the charts of all 
participants experiencing serious and other expedited adverse events on a monthly 
basis to ensure proper management and documentation.  If at any time these reviews 
identify areas for improvement, the clinical/study co-ordinator will follow-up with relevant 
study staff to ensure that any oversight or deficiency is appropriately addressed.  All 
actions taken will be documented (e.g. in meeting minutes or training records). 
 
 
9.2  Quality Control 
 
QC processes are the activities that occur on a day to day basis to ensure that the data 
entered into the database is accurate and complete. 
 
The QC team has developed a QC plan based on our own experiences during the 
conduct of previous clinical trials. 
 
The site has developed specific templates for all visits which are guided by the case 
report forms and we have also implemented 3 different levels of the QC process. 
 
Level 1 QC– Source documents and CRF completion 
Rapid QC of source documentation is done Real-time. At this point the source 
documentation is checked for completeness at the end of the day but before the patient 
leaves the clinic.  If any information obtained during patient interview is missing and 
needs to be addressed immediately, it is flagged by the QC assistant and the relevant 
staff obtains the information.  Other missing information that does not need immediate 
attention is flagged and reviewed at a later time-point. After receipt of laboratory results 
(2-3 days), the CRF’s are completed and QC is conducted for CRF completeness.  
At level 1, all queries are resolved within (2-3 days) of the patient visit. 
 
Level 2 QC – Detailed review of Source documentation and CRF’s 
At this level all information transcribed onto the CRF’s are checked for accuracy and 
verified in the source documents. All Transcription errors are corrected at this time-point. 
If any information cannot be verified, the relevant staff members are asked to add a note 
to file to clearly explain the error or incorrect information.   
 
Level 3 QC- Computer system generated  
This level of QC occurs during data capturing.  The data management system prompts 
for any missing information that is required. If this information is not completed on the 
CRF, the data team refers these queries back to the QC team who resolves them 
accordingly. 

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10.   STATISTICAL CONSIDERATIONS 
 
 
10.1  Method of Randomisation 
 
Enrolled participants will be assigned at random, to one of the two study treatment arms 
in equal proportions.  The randomisation list used to assign individual study participants 
to one of the two treatment arms will be generated by the protocol statistician, using 
randomly permuted blocks. The randomisation statistician will provide the study 
pharmacy with sealed, opaque randomisation envelopes, sequentially labelled by PID. 
These envelopes will be assigned in sequential order to eligible study participants. Upon 
opening the envelope the pharmacist will add her name and signature as well as the 
time and date the envelope was opened. This being an open label study, the treatment 
assignment of a participant will be known by the participant and the study staff.   
 
  
10.2 Outcome Measures 
 
Main Outcome Measure: 
 
Renal Function estimated by Serum Creatinine Clearance, adverse pregnancy 
outcomes (e.g., stillbirth, preterm delivery at < 37 weeks gestation, low birth weight 
<2,500 grams, and congenital anomalies) and Bone Mineral Density among women
 
 
Bone Mineral Density and growth parameters in neonates and infants until cessation 
of breastfeeding. 
 
Other Outcome Measures: 
 
Confirmed presence of HIV infection detected by HIV NAT positivity at scheduled 3 
monthly visits until 18 months.  
 
Adherence –self reported use of study product and pill count 
 
Partners HIV status at enrollment confirmed by Two POC tests and Adherence 
measured at delivery and 18 months postdelivery 
 
Antiretroviral drug level in plasma as a marker of adherence. 
 
Presence of viral resistance mutations that have been selected by Truvada 
(K65R, M184V) in participants who acquire HIV infection 
 
Mother to child transmission-reactive NAT testing performed in children born to 
mothers who acquire HIV infection during pregnancy and post-delivery. 
 
Behavioural Risk: 
 
Number of sexual partners with whom participant had unprotected intercourse 
during pregnancy and postnatally 
 
Number of protected and unprotected acts of intercourse during pregnancy and 
postnatally 
 
Sexually transmitted infections acquired during pregnancy 
 
Sexually transmitted infections acquired postnatally 
 
Facilitators and barriers to adherence.  
 
10.3  Sample Size Calculation 
In view of the limited evidence of safety data from studies of  PrEP (TDF/FTC) use in 
pregnancy, we based our sample size on data provided in studies of ART treatment in HIV 
infected pregnant women. In few studies, comparisons were made to HIV uninfected 
pregnant women.   
 

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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.  
 
Adverse Pregnancy Outcomes 
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%. 
 
Maternal Adverse Events (2% margin difference) 
Other maternal adverse events will include abnormal chemistry (Grade >2) results. As 
reported in the PROMISE study, Grade 2 or higher chemistry abnormalities were significantly 
higher in HIV infected pregnant women randomized to TDF containing ART (3%) compared 
to AZT/sdNVP (1%) (p<0.03).  
 
Maternal and Infant Bone Mineral Density (4-7% margin difference)  
We have also used  the PROMISE study findings to determine the required sample size for 
reporting other clinically relevant adverse events such as maternal and infant bone mineral 
content. In the P1084s study, a substudy of PROMISE mothers, the lumbar spine BMD 
declined significantly more through week 74 in the maternal TDF-ART arm compared to the 
infant NVP arm; mean (95% CI) percent change -2.06% (-2.90, -1.23) versus +1.09% (0.11, 
2.07), mean difference -3.16% (-4.44, -1.87) (p-value< 0.001). Similarly, hip BMD declined 
significantly more through week 74 in the maternal TDF-ART arm compared to the infant 
NVP arm; mean (95% CI) percent change -5.37% (-5.99, -4.76) versus -3.05% (-3.72, -2.38), 
mean difference of -2.33% (-3.23, -1.42) (p-value< 0.001). We would require 150 infants 
exposed to maternal PrEP (TDF/FTC) and 150 infants unexposed (control group) based on 
80% power to detect a pair-wise difference of 4-5% in mean WB-BMC and 6-7% in mean 
LS-BMC. 
 
PASS 12 sample size software (Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, Utah, 
USA. www.ncss.com) was used to calculate the samples sizes for testing equivalence 
between the treatment and control groups (Blackwelder WC. “Proving the null hypothesis” 
in clinical trials. Controlled clinical trials. 1982 Dec 31;3(4):345-53). We assumed equal 
adverse events rates (proportions) across the two groups i.e. zero difference and a maximum 
D (difference) of 7.5% for equivalence of the two groups. The table below displays the sample 
sizes required to achieve a 80% power with α = 0.05 to establish equivalency for various 
adverse birth outcome prevalences based on actual data from the same setting published 
recently (Moodley, Theron et al. “Improved Pregnancy Outcomes with Increasing 
Antiretroviral Coverage in South Africa.” BMC Pregnancy and Childbirth 16 (2016): 35. PMC. 
Web. 3 Mar. 2016). Based on the largest observed adverse birth outcome prevalence for 
pre-term delivery yields the largest required sample size i.e. 421 per group or 842 in total 
based on the assumptions mentioned above.  
 
Based on current data (maternal adverse events, maternal and infant bone mineral content 
depletion), all other adverse birth outcomes and  maternal and infant adverse events can be 
housed within this sample size and will have smaller D as the relative prevalence decreases 
toward 0 i.e. narrower equivalence zones. Assuming a loss to follow-up of 5%, we would 
need 442 women in each group (884 in both arms combined) for the two year time frame of 
the study. 

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Main endpoint 1: sample size for safety in pregnancy for birth outcomes 
Prevalence adverse birth outcomes among HIV-ve (in descending order) 
Outcome 
n/N 
Prevalence 
Required sample size in 
each group for 
proposed equivalence 
trial 
Total required 
sample size for 
proposed 
equivalence trial 
Pre-term 
1096/5916 
18.5% 
421 
842 
LBW 
651/5916 
11.0% 
274 
548 
Small for GA 
429/5916 
7.3% 
189 
378 
VLBW 
141/5916 
2.4% 
64 
128 
Stillbirth 
130/5916 
2.2% 
58 
116 
Based on a non-inferiority trial design: A sample size of 421 in the treatment group and 421 in the control 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 (pre-term delivery birth outcome) is 0.185 or 18.5%. The treatment group proportion is assumed to 
be 0.26 or 26% under the null hypothesis of inferiority. The power was computed for the case when the actual treatment group 
proportion is 0.185 or 18.5%. The test statistic used is the two-sided Z test (unpooled). The significance level of the test was 
targeted at two-sided 0.05 or 5%.  
 
 
Secondary Endpoint 
 
PASS 12 sample size software (Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, 
Utah, USA. www.ncss.com) was to calculate this sample size. In order to show a 50% 
reduction in HIV infections, with significance level of 0.05 or 5% and 80% power, we would 
need to observe 66 HIV infections in total (44 in control arm [cumulative incidence of 
12.72%] and 22 in the intervention arm [cumulative incidence of 6.36%]).  This 
assumes an HIV incidence of 3 per 100 person years during the 6 months of pregnancy 
and 6 per 100 person years during the 18 months of breastfeeding [9].  Based on these 
assumptions, we would require 334 subjects in group or 668 in total. Assuming a loss 
to follow-up of 10%, we would need to increase this to 346 women in each group (692 
in both arms combined) for the two year time frame of the study. 
 
 
10.4  Analysis Plan 
 
Full details of the proposed analyses will be described in a statistical analysis plan that 
will be developed once enrollment to the study begins and prior to the commencement 
of analyses. Hence, here we limit the description of the proposed analyses to those for 
the primary safety endpoint.  
 
Analyses will use the principle of intention-to-treat (i.e., using the randomised treatment 
assignment, whether or not study drugs were actually taken) and will include all 
randomised participants. This is generally the more conservative approach for analysis 
of trial data. However, it has been proposed that the smaller differences commonly 
observed in intention-to-treat analysis have the opposite effect when testing 
equivalence or non-inferiority. Hence for sensitivity analysis purposes (and as a 
required by the FDA) we will also perform a per protocol data analysis for comparative 
purposes (Walker, E., & Nowacki, A. S. (2011). Understanding Equivalence and 
Noninferiority Testing. Journal of General Internal Medicine, 26(2), 192–196. 
http://doi.org/10.1007/s11606-010-1513-8). 
 

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Data will be processed and analyzed using Stata 13.0 (tataCorp. 2013. Stata Statistical 
Software: Release 13. College Station, TX: StataCorp LP.) and R 3.2.4 (R Core Team 
(2016). R: A language and environment for statistical computing. R 
  Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL 
  http://www.R-project.org/.).  
 
The primary objective is to compare the frequency and seriousness of adverse events 
in women receiving tenofovir/emtricitabine in pregnancy and their newborn as opposed 
to women not receiving tenofovir/emtricitabine during pregnancy and their newborn. 
The number of adverse events experienced during pregnancy and post-delivery will be 
summarized for each of the study arms.  This will also be stratified by seriousness of 
the adverse event.  The number of adverse events will be compared between the study 
arms using Fisher’s Exact test. Furthermore we will use the most widely used approach 
to test equivalence, namely the two one-sided test (TOST) procedure (Schuirmann DJ. 
A comparison of the two one-sided tests procedure and the power approach for 
assessing equivalence of average bioavailability. J Pharmacokin Biopharm. 
1987;15:657–680. doi: 10.1007/BF01068419). Furthermore we will also employ a 
hierarchical or random effects modeling approach for a non-inferiority analysis for the 
primary endpoints. 
 
A secondary objective is to compare the number of incident HIV infections in women 
during pregnancy alone and thereafter during breastfeeding. The analysis will be 
stratified by levels of PrEP adherence, partner involvement, condom usage and 
relationship dynamics.. The cumulative incidence and associated 95% confidence 
intervals will be calculated for each study arm. The number of incident events will be 
compared for statistical difference between the study arms using Fisher’s Exact test. 
 
 

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11. 
REGULATORY AND ETHICAL ISSUES 
 
11.1  Regulatory Compliance 
 
The study complies with the principles of the Declaration of Helsinki (2008). It will be 
conducted in compliance with approval from the South African Medicines Control 
Council and the University of KwaZulu-Natal Biomedical Research Ethics Committee.
 
  
 
11.2  Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that are 
transferred or transmitted off-site for processing will be identified only by a coded number 
to maintain subject confidentiality.  All records will be kept in a secured area with access 
limited to authorized personnel only.  All computer entry and networking programs will 
be performed with coded numbers only.  Clinical information will not be released without 
written permission of the participant. 
 
 
11.3  Ethical Considerations 
 
Pre-exposure antiretroviral prophylaxis comprising a daily dose of Truvada 
(Tenofovir/Emtricitabine) is a proven prevention strategy for same sex couples and 
discordant couples and now internationally recommended for individuals at substantial 
risk. The benefit of PrEP in high risk population groups significantly outweigh the 
potential threat of adverse events. The high risk population groups are MSMs, men in 
incarceration, commercial sex workers and adolescent girls and young women. 
Additional options for PrEP in young women through long acting antiretroviral 
(Dapivirine) prophylaxis in vaginal rings are also possible, but preclude use in 
pregnancy. 
 
Truvada (the antiretroviral drug of choice for PrEP) is classified as a FDA pregnancy 
Category B antiretroviral. Pregnancy and lactation are distinct contraindications to 
initiate PrEP because of the limited evidence of its (Truvada) adverse effects on the 
child. Despite this classification, Truvada has been endorsed by the WHO to be used as 
part of a treatment combination in HIV infected pregnant women and to reduce mother-
to-child transmission of HIV. Arguably, the benefits outweigh the potential risk of adverse 
events (minimal) in this HIV infected population. On the other hand, in all HIV uninfected 
pregnant women in general, the benefit may be minimal.  
Because younger pregnant and lactating women are disproportionately at risk for HIV 
infection, a targeted intervention approach for women in this particular group would be 
ethically acceptable to demonstrate the safety of the current standard approach to 
preventing sexually transmitted infections strengthened by the use of antiretroviral 
prophylaxis -Truvada (TDF/FTC). The Intervention  Package would therefore include a 
daily dose of Truvada (TDF/FTC), risk reduction counselling, STI screening and 
treatment, inviting the sexual partner to receive HCT and referral for treatment and 
support if he tests HIV positive and condom promotion. The Control Group of young 
pregnant women will receive the above package minus the antiretroviral prophylaxis - 
Truvada (TDF/FTC).  
 
Women participating in the PrEP study will receive compensation for travel costs 
incurred at each scheduled study visit. 
 
 
 
 

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APPENDIX 1 
SAMPLE INFORMED CONSENT FORM 
 
Immediate or Deferred Preexposure Prophylaxis for HIV 
Prevention: Safe Options for Pregnant and Lactating Women 
 An Open-Label Randomised Control Study 
 
SHORT TITLE FOR THE STUDY: Preventing HIV Infection in Young Women during 
pregnancy and breastfeeding using Antiretroviral Pre exposure Prophylaxis (PrEP) 
 
SCREENING 
 
INTRODUCTION 
You and your baby are being asked to take part in this research study because: 
o you are not infected with human immunodeficiency virus (HIV), the virus that causes 
AIDS 
o you are pregnant 
o you are at high risk for contracting HIV 
 
This study is sponsored by………………………….  The doctor in charge of this study at this 
site is ______________.  Before you decide if you want to participate in the screening 
tests, we would like to explain the purpose, the risks and benefits of participating, and what 
will be expected of you and your baby if you decide to participate.  This informed consent 
form gives you information about the screening tests.  You are free to ask any questions. 
After the screening has been fully explained to you and if you agree to participate, you will 
be asked to sign this consent form or make your mark (in front of a witness, if needed).  
You will be offered a copy of this form to keep.  
  
What is PrEP? 
PrEP means Pre-Exposure Prophylaxis, and it’s the use of antiretroviral medications (ARV’s) 
to reduce the risk of HIV infection in people who are HIV- negative. “Prophylaxis” means to 
give a drug in order to prevent a disease like HIV from occurring. 
 
Can anyone use PrEP? 
PrEP should be considered for people who are HIV-negative and at risk for HIV infection. 
This includes anyone who: 
 
Is in an ongoing relationship with an infected person 
 
Is not in a mutually monogamous relationship with a partner who has recently tested 
HIV-negative. 
 
For heterosexual couples where one partner has HIV and the other does not. PrEP 
is one of the several options to protect the uninfected partner during conception and 
pregnancy. 
 
Who is in a relationship but does not know whether the partner has tested. 
 
Oral PrEP 
It’s meant to be used consistently, as a pill taken every day, and to be used with other 
prevention options such as condoms. PrEP has been approved in America by the US Food 
and Drug Administration (FDA) for HIV prevention and has shown to be effective and safe. 
This tablet is known as Truvada. The medication interferes with HIV’s ability to copy itself in 
your body after you have been exposed to the virus. This tablet prevents it from establishing 
an infection and making you sick. Based on the data that has been collected to date the FDA 
announced its approval of daily oral Truvada in 2012. Such a regimen may be soon available 

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in South Africa for HIV negative women who are at substantially high risk of getting HIV. 
Pregnant women and breastfeeding women who are not HIV infected are not allowed to take 
Truvada because we do not have adequate safety data if Truvada is to be taken alone and 
for the sole purpose of preventing HIV infection. While Truvada, together with other anti-HIV 
medicines in South Africa, is used to treat HIV infected women during pregnancy and during 
breastfeeding and is known to be safe and highly beneficial in these women and their 
children, we don’t know if Truvada will be safe and as beneficial in HIV uninfected women 
and their children.  
 
Potential Benefits of PrEP use  
In clinical trials with heterosexually active adults, daily oral PrEP with TDF/FTC was safe 
and reduced the risk of HIV acquisition by an average of 63%-75%. Higher levels of 
protection (≥90%) were found among persons whose drug levels in their blood indicated 
that they had consistently taken the medication.  
The risk of HIV acquisition increases during pregnancy, as does the risk of HIV 
transmission to an infant born to a mother who becomes infected during pregnancy or 
breastfeeding. Therefore, an HIV-negative woman who believes her sexual partner tested 
positive for HIV or doesn’t know her partner’s HIV status may benefit from continuing PrEP 
use throughout her pregnancy and breastfeeding to protect herself and her infant. 
 
Potential Risks of PrEP use  
In PrEP studies, follow-up with persons taking medication has been conducted for an 
average of 1-4 years. Although no serious health risks were associated with PrEP use by 
HIV-uninfected adults, the long-term safety of PrEP has not yet been determined. 
In PrEP trials women were taken off medication as soon as pregnancy was detected. 
During these trials, no health problems have been associated with PrEP use by women in 
early pregnancy or for their offspring. However, the long-term safety of PrEP taken by HIV-
uninfected women after fetal (during pregnancy) or infant (during breastfeeding) exposure 
is not yet determined. 
No adverse effects have been found among infants exposed to TDF/FTC when the 
medications were taken as part of a treatment regimen for HIV-infected women during 
pregnancy or during breastfeeding (for which data suggest limited drug exposure). 
  
WHAT SHOULD YOU KNOW ABOUT SCREENING FOR THE PREP STUDY? 
o Your participation in the screening is entirely voluntary.   
o You may decide not to participate in the screening tests or to withdraw from the 
screening at any time without losing the benefits of your standard medical care. 
o Even if you agree to participate in the screening, it does not mean you have agreed to 
participate in the research study.  
o If you decide not to participate in the screening, you cannot participate in this research 
study, but you can still join another research study later, if one is available and you 
qualify.  
 
WHAT WILL HAPPEN IF YOU AGREE TO THE PrEP STUDY SCREENING? 
If you are interested in joining the PrEP Study, we will first do some screening tests to see 
if you are eligible.   
 
The study staff will ask you some questions about your health and pregnancy, review your 
antenatal and other available health records, and do a physical examination.  The study 
staff will draw about 1 tablespoon (15ml) of blood from you.   
o 
We will test you for HIV to confirm your status 
o 
We will test your blood to see how healthy you are  
o 
We will test to see if you are infected with Hepatitis B virus 

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You will be asked to return to this clinic to get the results of these blood tests.  These blood 
tests are the first step in determining if you will be able to join the study.  If the screening 
shows that you may be eligible, you will be provided more detailed information about the 
PrEP Study and be asked to sign another consent form like this one to participate in the 
study.   
 
If you join the PrEP Study, you will be randomly assigned by chance to one of two study 
groups, one group will begin PrEP immediately in pregnancy and the other group will begin 
PrEP after breastfeeding has stopped.  You will be followed throughout your pregnancy 
and through labour and delivery and for 18 months after your baby is delivered.  Your baby 
will be followed until he or she is 18 months old.    
 
WHY MIGHT THE STUDY DOCTOR STOP MY SCREENING TESTS EARLY?  
You will be withdrawn from the screening if at any time the screening tests show that you 
will not be able to participate in the study.  You may also be withdrawn from the screening if 
the study is cancelled or stopped.    
 
WHAT ARE THE RISKS OF STUDY SCREENING? 
Taking blood from you may cause slight pain, swelling, and bruising at the place where the 
blood is taken. Drawing blood can also cause fainting or infection, but this is rare.  The 
study doctors and staff will protect information about you and your participation in these 
screening tests to the best of their ability.  On your screening records, a code will be used 
instead of your name.  Only the study staff will know this code.  Study staff will make every 
possible effort to be sure that others do not learn your HIV status.  However, sometimes if 
you receive special treatments or attend a special clinic, it may make others wonder if you 
have HIV.  
 
WHAT ARE THE POSSIBLE BENEFITS OF STUDY SCREENING? 
These screening tests may or may not be of direct benefit to you.  The results of the 
screening tests will be shared with you and with the medical staff providing your antenatal 
care, if you wish, as this may help them know more about what care you need.  They will 
refer you for additional care if they find that your body’s system for fighting infections is 
weak.  If you do not know whether or not you are infected with hepatitis B, you will find out 
through the screening tests.   
  
WHAT ARE THE CHOICES IF YOU DO NOT WANT TO BE SCREENED FOR THE 
STUDY?  
You do not have to agree to be screened for this research study.  If you do not agree to the 
screening, your care will not be affected.  If you agree to take part in the screening, you can 
change your mind at any time without losing the benefits of your standard medical care.  
 
WHAT ABOUT CONFIDENTIALITY? 
Every effort will be made to keep personal information confidential.  This personal 
information may be disclosed, if required by law. Any publication of this study will not use 
your or your baby’s name or identify you or your baby personally.  
 
The outreach workers may contact you so we need to know the best way to reach you 
(such as home visit or phone call). Your records may be reviewed by the ethics committee 

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overseeing the study at this site, local regulatory authorities, study staff, study monitors, 
and the drug companies supporting this study. 
 
 
WILL THERE BE ANY COSTS OR PAYMENTS? 
The screening procedures, physical examinations and blood tests will be done free - at no 
cost to you - but you will not receive any payment for having the screening tests done. You 
will receive R150 for your time and transport costs.  
 
WHAT IF I DO NOT ENROLL INTO THE STUDY? 
If you decide not to take part in the PrEP Study or if you do not meet the eligibility 
requirements for this study, we will still use some of your information from the screening 
visits, some demographic (e.g., age, gender), clinical (e.g., disease condition, diagnosis), 
and laboratory information, so that the researchers may determine whether there are 
patterns or common reasons why people do not join the study. Only a code number will be 
used for this – not your name or other information that will identify you. 
 
WHAT HAPPENS IF EITHER MY BABY OR I ARE INJURED? 
It is possible that you could experience a problem or injury that would not have occurred if 
you did not participate in the screening. If the study doctor determines that you have been 
injured as a direct result of being in the screening, you will be given immediate treatment 
for those injuries at no cost to you and then referred for further care if needed.   
 
However, the study doctor may determine that your illness or injury would have happened 
even if you did not participate in the screening.  In that case, appropriate care and/or 
referral will likewise be provided for any illness or injury that occurs during screening.  You 
will not be giving up any of your legal rights by signing this consent form. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
If you ever have questions about this study or in case you are injured as a result of 
participation in this research study, you should contact _______________ (Tel 
_______________)  
 
Address:____________________________________ 
 

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If you ever have questions about your rights as a research subject or wish to report 
complaints/problems contact ________________________________(insert Ethics 
Committee details) 
  
If you have questions about this trial, you should first discuss them with your doctor or the 
ethics committee (contact details as provided on this form). After you have consulted your 
doctor or the ethics committee and if they have not provided you with answers to your 
satisfaction, you should write to the South African Medicines Control Council (MCC) at: 
The Registrar 
SA Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001

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SIGNATURE PAGE   
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered and you agree to take part in the screening for this study, please sign your 
name below. 
 
 
 
 
______________________________ 
________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
 
 
_________________________________ 
________________________________ 
Name of Study Staff Member Conducting 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
 
 
_________________________________ 
________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(if needed) 
 
 
 
 
 
 
 

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Appendix 2 
HIV RISK ASSESSMENT TOOL 
PID_________________________  
 
 
 
Initials: _____ 
1. How old are you?  
 <25  
 
1  
>25 
 
0 
 
2. Are you married or living with your partner? 
No 
 
1  
Yes 
 
0 
 
3. How old is your current partner? 
 >25 
 
1 
<25 
 
0 
 
4. What is the HIV status of your partner? 
Positive 
1  
Unknown 
1 
Negative 
0 
 
5. Does your partner have other girlfriends? 
Yes 
 
1  
I do not know 
1 
No 
 
0 
 
 
6. Does your partner provide you with financial support? 
Yes 
 
1  
No 
 
0 
 
7. Have you had any alcohol in the last 3 months? 
Yes 
 
1  
No 
 
0 
 
Final Score __________ 
 
High Risk   
 
 
>3 
Moderate or Low Risk  
<3 
 
Risk Assessment Tool modified from : An Empiric HIV Risk Scoring Tool to Predict HIV-1 Acquisition in African Women. 
Balkus JE, Brown E, Palanee T, et al. J Acquir Immune Defic Syndr. 2016 Feb 25. [Epub ahead of print] . 
:   
 

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Appendix 3 
SAMPLE INFORMED CONSENT FORM 
 
Immediate or Deferred Preexposure Prophylaxis for HIV 
Prevention:  
Safe Options for Pregnant and Lactating Women 
 An Open-Label Randomised Control Study 
 
SHORT TITLE FOR THE STUDY: Preventing HIV Infection in Young Women during 
pregnancy and breastfeeding using Antiretroviral Pre exposure Prophylaxis (PrEP) 
 
ENROLLMENT 
 
This study is sponsored by………………………….  The doctor in charge of this study at this 
site is ______________.   This study involves research. Research is not the same as medical 
care.  Research answers scientific questions. These answers can help find new medicines, 
treatments, vaccines, and even knowledge on how the human body works. Only people who 
want to participate will be part of this study. This informed consent form tells you about this 
study. You can ask questions at any time. You can discuss the study with others before 
deciding to join. No matter what your decision is, any other care that you get at this clinic will 
not change. 
 
Researchers and study staff are asking you to join this study because you are not infected 
with HIV, but you are at risk of becoming infected either during this pregnancy or after. The 
study staff will give you a copy of this form. 
 
 
1. WHY ARE RESEARCHERS DOING THIS STUDY? 
As explained when you agreed to participate in the screening, the specific purpose of the 
PrEP Study is to look at the safety of an anti-HIV medicine used to prevent a woman from 
getting HIV from her sexual partner, while she is pregnant and after delivery. We want to 
determine if the anti-HIV drug is safe for the unborn baby and yourself during your 
pregnancy and during breastfeeding.  
 
What makes me to be at higher risk for getting HIV?  
 
Young women who have multiple partners, or  
 
Have older partners, or 
 
Practice unprotected sex, or 
 
Whose partner is HIV positive, or  
 
Do not know their partners HIV status, or 
 
Have one or more of other sexually transmitted infections.  
Recently, research conducted  among discordant couples (i.e. one partner is HIV-infected 
and the other uninfected) showed that an anti-HIV medicine called Truvada (TDF/FTC) 
helps decrease the chance of women getting infected while they take a daily dose of the 
anti-HIV medicine. Truvada, which is a combination of tenofovir plus emtricitabine, has to 
be taken every day for a certain period while the woman is at risk. Such a regimen may be 
soon available in South Africa for HIV negative women who are at substantially high risk of 
getting HIV. Pregnant women and breastfeeding women who are not HIV infected are not 
allowed to take Truvada because we do not have adequate safety data if Truvada is to be 

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taken alone and for the sole purpose of preventing HIV infection. While Truvada, together 
with other anti-HIV medicines in South Africa, is used to treat HIV infected women during 
pregnancy and during breastfeeding and is known to be safe and highly beneficial in these 
women and their children, we don’t know if Truvada will be safe and as beneficial in HIV 
uninfected women and their children.  
 
 
2. WHAT WILL I NEED TO DO DURING THIS STUDY? 
During this study, you will be in one of TWO study groups. Researchers will "randomize" 
you into one of the study groups described here. Randomization means that you are put 
into a study group by chance.  Chance means “like flipping a coin”. Neither you nor the 
study staff can choose your study group. 
 
If you are in 
Group 1  
IMMEDIATE  PrEP  
You will start taking Truvada on the day you enrol into the study while 
you are pregnant and continue until you stop breastfeeding. Thereafter, 
you may choose to continue to take Truvada if you consider yourself to 
be at risk of HIV infection.  
If you are in 
Group 2 
DEFFERED  PrEP  
You will not receive Truvada during pregnancy and throughout 
breastfeeding. You may choose to receive Truvada after you have 
stopped breastfeeding if you consider yourself to be at risk of HIV 
infection.   
Note: No matter to which group you are allocated, you will also receive basic 
counselling on how to reduce your chance of becoming HIV infected, you will be 
provided condoms, you will receive a letter to invite your partner to be tested for HIV 
and referred for further care if needed, you will be tested/examined for other sexually 
transmitted infections and receive appropriate treatment. 
 
Once you join this study, you will need to come to this clinic about SEVEN times to 
continue with you antenatal care, and after delivery you will have to visit the clinic every 
month until baby is 18 months old.  
 
At most visits you will have the routine examinations, tests and procedures performed 
PLUS study specific examinations and tests as listed below:  
 
Routine:  
 Ultrasound examination – pregnancy screening to estimate stage of pregnancy and 
identify any abnormalities 
 Obstetric assessment - monitoring of fetal growth and to identify any sign/s that could 
result in complications in pregnancy. 
 Urine Collection – routine pregnancy screening for signs of infection or hypertension 
 
Study Specific: 
 Behavioural Risk assessment - study specific 
 Discussion of Coital Log – study specific 
 Physical Examination – study specific to assess physical well being   
 Blood Collection - study specific investigations. Approximately 12 ml blood (a little more 
than a tablespoon) will be collected for a HIV test, Full Blood Count, Chemistry, Kidney 
function test, and Storage if you give us permission. 
 Cervico-vaginal secretion and a swab collection – study specific investigations to 
examine any change in the tissue in the genital area that would give some explanation 

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for the HIV acquisition in pregnancy and postdelivery. This will be performed at every 
alternate visit during the study.  
 DXA Scan – to be done four times postdelivery for yourself and for your baby. This is an 
XRAY of your bones to determine bone strength.  
 
You will be followed throughout your pregnancy and through labour and delivery.  Once 
your baby is born, you and your baby will continue to be followed until baby is 18 months 
old.    
 
You will be seen two weeks and four weeks after you join the study; thereafter, you will be 
seen every four weeks while you are still pregnant.  Each visit will last about 1 hour. You 
will have routine medical check-ups at the study clinic. It is important that you attend all of 
these study visits.  If you do not come for a scheduled visit or if a test result comes back 
abnormal, the outreach worker will contact you to find out how you are doing. If at any time, 
you become sick you should let the study nurse or doctor know right away.  
 
You will deliver at this hospital (Prince Mshiyeni Hospital) assisted by the hospital staff and 
you and your baby will be examined after birth by the research staff.  You and your baby 
will return for a visit at 2 weeks after delivery, then 4 weekly until baby is 18 months old.   
 
Tests and procedures at the study visits 
 
 
Medical history, questionnaire, interviews, and physical exam 
We will ask you about your medical history and about any medications you have taken 
since the last visit and about how well you are taking the study drug, if still on them. 
You and your baby will have a physical exam. We will update your contact information 
(for example, your address and telephone number).  We may ask questions about your 
home life and general wellbeing.  At some visits, we will also ask questions about infant 
feeding and nutrition.   
 
 
Blood  
Blood will be collected from you for various tests. Some tests measure whether you are 
tolerating the study drugs and to check on your health, and to measure the amount of 
study drug in your blood. But the important test is to determine if you get HIV infected.  
You will have approximately 10 to 32 ml (1 to 3 tablespoons) of blood taken at all visits.   
 
We will collect about 5 ml (1 teaspoon) from your baby at certain visits to make sure 
that the medications you are taking are not harming your baby.    
 
You will be given the results of blood tests that might affect your or your baby’s health 
care as soon as possible, usually at the next study visit.  Some of your blood and your 
baby’s blood will be tested immediately, and some of the blood may be kept and used 
later for study-specified tests.  
 
Later, we will ask you if you are willing to have some of your blood and your baby’s 
blood saved even after the study is over for future tests not yet specified. This stored 
blood might be used later to answer other research questions. You can still participate 
in the Study whether or not you agree to have your and your baby’s blood stored after 
the study is completed.  We will review the details with you and you will be asked to 
sign a separate consent form like this one if you agree to have your own and your 
baby’s blood stored.   
 
Breast milk 
We will ask you to express up to 20 ml of breast milk (about 2 tablespoons), which will 
be kept to look for the presence of study medications. 

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The Tables below give you some guidance to visits in the study and what procedures to 
expect for yourself and your baby at these visits. 
For You (Mother): 
 
ANTENATAL 
LABOUR AND 
DELIVERY 
POSTNATAL 
 
SCREENING 
1ST ANTENATAL 
VISIT 
2ND ANTENATAL 
ENROLMENT 
>14W 
3RD ANTENATAL   
2 WEEKS 
SUBSEQUENT 
4 WEEKLY 
ANTENATAL  
VISITS
<72 HOURS 
POST 
DELIVERY 
2 WEEKS 
6  WEEKS 
10 WEEKS 
14 WEEKS 
SUBSEQUENT 
4 WEEKLY 
POSTNATAL  
VISITS
74  
WEEKS/STUDY 
EXIT 
Study Informed Consent  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Storage Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Documented HIV test result 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV Risk Assessment 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
Hx, Signs/Sx  of STIs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
Obstetric Assessments 
X 
X 
X 
X 
 
 
 
 
 
 
 
DXA Scan Hip and Lumbar Spine 
 
 
 
 
 
 
X 
 
 
X* 
X 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Sexual Behaviour Questionaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Adherence Interview  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Condom Usage Interview 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Risk Reduction Counselling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Investigations 
RPR Test 
2ml 
 
 
 
 
 
 
 
2mL 
 
2mL 
HIV Rapid Test (finger prick) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hep B Surface Antigen 
2ml 
 
 
 
 
 
2mL 
 
 
 
2ml 
ALT/AST/Phosporous 
 
2ml 
 
2mla 
 
 
 
2ml 
 
2mla 
 
CBC 
2ml 
2ml 
2mla 
2mL 
 
 
 
2mL 
2mla 
 
Serum Creatinine 
2mL 
 
  
2mL 
 
2mL 
 
 
2mL 
  
2mL 
2mL 
2mL 
 
2mL 
Stored EDTA Plasma, DBS /cell 
pellets 
 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
Stored Breast Milk (during BF 
only)   
 
 
 
 
 
10mL 
10mL  10mL 
10mL 
10mL 
10mL 
Cervical Vaginal Swabs 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
TOTAL BLOOD VOLUME 
8ml 
12ml 
14ml 
16ml 
12ml 
12ml 
12ml 
14ml 
14ml 
16ml 
12ml 
 
 
 
DXA Scan at 6 and 12 months 
For the Baby: 
 
BIRTH 
6 
WEEKS 
26 
WEEKS 
50 
WEEKS 
72 WEEK/STUDY EXIT VISIT 
Physical Exam  
X 
X 
X 
X 
X 
Growth Parameters and neurodevelopmental milestones 
X 
X 
X 
X 
X 
DXA Scan Lumbar Spine and Whole Body 
 
X 
X 
X 
X 
Laboratory Investigations 
 
CBC 
2mL 
2ml 
2mL 
2mL 
2mL 
Serum Creatinine 
2mL 
2ml 
2mL 
2mL 
2mL 
Stored DBS 
X 
X 
X 
X 
X 
TOTAL BLOOD VOLUME 
4ml 
4ml 
4ml 
4ml 
4ml 

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3. HOW LONG WILL I BE IN THIS STUDY?  
 If you decide to join, you will be in this study for about 24 months including this visit. 
 
4. HOW MANY PARTICIPANTS WILL BE IN THIS STUDY? 
There will be 842 pregnant women participating in this study, 421 in the Immediate PrEP 
Group and 421 in the Deferred Prep Group.   
 
5. WHAT POSSIBLE RISKS CAN I EXPECT FROM PARTICIPATING IN THIS 
STUDY? 
In this study, study staff will take some blood from you.  This procedure rarely can cause an 
infection. Taking blood from you may cause a low blood cell count or “anemia” and make 
you feel tired. You may also experience some discomfort when study staff conduct a 
genital examination and collect genital secretions using a soft cup, swab, syringe and a 
cytobrush in that order. 
Taking part in this study may involve some risks and discomforts. These include possible 
side effects of the anti-HIV medicine (Truvada) that you may take, possible risks and 
discomforts from the study tests, and possible risks to your privacy.  More information is 
given on each of these types of risks below.   
 
Side Effects of Truvada (Anti-HIV Medicine) for Women 
Some side effects are minor, while others can be severe.  Some are common, while others 
are rare.  If you join the study, the study staff will tell you about the side effects of the 
antiHIV medicine you will take.  They will check for side effects during study visits and tell 
you what to do if you have any side effects.   
 
 In HIV-1 infected patients, the most common adverse effects (10 or more cases in every 
100 women) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, 
abnormal dreams, and rash.   
 
In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by 2 or 
more cases in every 100 women were headache, abdominal pain and weight decreased.  
 
First you should know about the possible severe side effects.  These effects are rare, but 
they can cause serious health problems. 
 
Blood and the lymphatic system disorders  
Common: Neutropenia (1-10%) 
Immune system disorders  
Common: Allergic reactions  (1-10%) 
Metabolism and nutrition disorders  
Common: Hypertriglyceridemia, hyperglycaemia (1-10%)  
The following side effects have been reported but frequencies are unknown: Hypophosphataemia, lactic 
acidosis, hypokalaemia  
  

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Other severe side effects are listed below: 
 
Inflammation of the pancreas.  The pancreas is an organ near the stomach.  When the 
pancreas becomes inflamed, it can cause pain in the belly, nausea, vomiting, and 
increased fats in the blood.  
 
 
Inflammation of the liver.  The liver is an organ near the stomach.  When the liver 
becomes inflamed, it can cause pain and swelling in the belly, nausea, and vomiting.  
 
 
Lactic acidosis, enlargement of the liver, and fatty liver, which can result in liver failure. 
Lactic acidosis is an imbalance in the blood that can cause weight loss, pain in the 
belly, nausea, vomiting, tiredness, weakness and difficulty breathing.  When the liver is 
enlarged, it can cause pain especially on the right side of the belly, swelling in the belly, 
nausea, vomiting, and loss of appetite.  It can also cause bleeding problems that can 
result in vomiting blood or dark coloured stools.  Fatty liver is when healthy liver cells 
are replaced with fat.  Sometimes it causes the liver to be enlarged, but doctors usually 
find out about it from tests of the blood.  They occur more often in women, pregnant 
women, people who are overweight, and people who already have liver problems. 
 
 
Kidney damage or failure. The kidneys are organs near the middle of your back (one on 
each side).  Doctors usually find out about kidney damage from tests of the blood.  
These effects can be caused by tenofovir. 
 
Thinning of the Bones: In clinical trials in HIV-1 infected adults and in a clinical trial of 
HIV-1 uninfected individuals, tenofovir DF was associated with slightly greater 
decreases in bone mineral density (BMD) and increases in biochemical markers of 
bone metabolism, suggesting increased bone turnover. These studies have been 
mainly conducted among HIV infected women. In a recent study conducted at this 
clinic, BMD decline between delivery and 74 weeks postpartum was significantly greater 
among HIV-infected breastfeeding women receiving TDF-ART compared to women not 
receiving ART. There were no bone fractures reported in this study, and long term 
consequences of this bone decline is not known. We will be conducting similar tests on you 
to determine if your bone content is also affected by Truvada. 
  
You should also know about the more common side effects, which are not severe.  There 
are many possible mild and moderate side effects.  Some people who take anti-HIV 
medicines have some of these effects, other people have different effects.  The more 
common mild and moderate side effects are:   
 
Overall Body Effects 
 Overall weakness, tiredness, or feeling 
unwell 
 Loss of appetite  
 Loss of weight  
 Changes in the placement of body fat, 
such as enlargement of the neck, 
stomach, and breasts and thinning of 
the arms, legs, and cheeks 
 Numbness or tingling in the hands, 
arms, feet, legs, or around the mouth  
 Pain in the hands or feet 
 Allergic reaction 
 Fever  
Effects on Your Muscles and Bones 
 Aches or pains  
 Loss of muscle  
 Muscle weakness  
 Bone thinning or softening (which 
could increase the chance of breaking 
a bone)  
Effects on Your Blood 
 Decreased blood cells  
 White blood cells help fight infection. 
 Red blood cells help store and 
transport energy through the body. 
Low red cells can cause weakness, 
tiredness, and dizziness. 
 Increased bleeding if you have 
haemophilia 
Effects on Your Skin 
 Rash, with or without itching  

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 Yellowing of the skin  
 Darkening of the palms and soles of 
feet  
 Increased blood sugar or development 
of diabetes 
 Increased fats in the blood that may 
increase the risk of heart problems 
 Other changes in blood test results 
that may indicate problems with the 
muscles, kidneys, liver, pancreas, or 
gall bladder. The blood tests that may 
be affected include tests of how well 
these organs are working, tests of 
substances made by these organs, 
and tests of fats in the blood. 
Effects on Your Head 
 Headache  
 Runny nose  
 Yellowing of the eyes  
 Blurred Vision 
 Changes in the sense of taste  
 Swelling of the face, lips, or tongue 
 
Effects on Your Chest 
 Cough  
 Shortness of breath  
 Heartburn  
Effects on Your Mind or Mental 
Function 
 Drowsiness  
 Trouble sleeping  
 Unusual dreams  
 Difficulty concentrating  
 Confusion  
 Depression  
 Agitation or anxiety  
 Exaggerated feeling of well being  
 Hallucinations  
 Feeling of strangeness or losing touch 
with reality 
 Dizziness  
Effects on Your Belly 
 Pain or discomfort in the belly 
 Nausea  
 Vomiting 
 Gas  
 Loose or watery stools  
 Inflammation of the gall bladder. The 
gall bladder is an organ near the 
stomach.  If it becomes inflamed, it can 
cause severe pain. 
 
Other Possible Risks of Truvada for Women 
 
Risk of Resistance:  All anti-HIV medicines can cause resistance.  Resistance has been 
seen in women taking one anti-HIV medicine during pregnancy and in women taking 
combinations of anti-HIV medicines during pregnancy.  When resistance occurs, a 
medicine no longer works against HIV, which can limit the choices of medicines a person 
can take against HIV in the future.  To avoid resistance, it is important to test for HIV at all 
scheduled study visits and to stop taking the study drug if HIV infection is confirmed. 
.   
Risks with Hepatitis B:  Some anti-HIV medicines are active against Hepatitis B.  For 
women who have Hepatitis B, and take anti-HIV medicines that are active against Hepatitis 
B, there are some risks.  Usually, women with Hepatitis B are treated with at least 2 
medicines that are active against Hepatitis B. For women who get 1 anti-HIV medicine that 
is active against Hepatitis B, the Hepatitis B could become resistant and harder to treat.   
In this study, women will stop study medications and receive the standard of care treatment 
for Hepatitis B.  
  
Side Effects of Anti-HIV Medicines for Babies 
The anti-HIV medicine that you take could affect your baby during pregnancy and after 
birth.   

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The anti-HIV medicine (Truvada) that some women in this study will take during pregnancy 
have been taken safely by thousands of other HIV infected women during pregnancy, and 
the only side effect seen in babies has been mild anaemia (low red blood cells), which got 
better on its own, with no treatment.  Some studies have suggested higher rates of 
premature (early) births with the use of this type of medicine, while other studies have not.  
There also is less information available for tenofovir and emtricitabine, but studies giving 
these medicines to women at labour and their newborn babies have not found serious 
problems.   
 
Babies may also receive some anti-HIV medicine taken by their mothers through breast 
milk but recent studies have detected negligible levels of Truvada in the breast milk.  It is 
not known how much of effect this low exposure may have on baby. We will monitor side 
effects in the baby related to exposure to the low level of Truvada in the breastmilk.  
 
Clinical trials evaluating tenofovir DF in children have noted that bone mineral density 
(BMD) decreases more rapidly in HIV-1 infected children who have received tenofovir 
DF. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric 
subjects as compared to the control groups. However, in all pediatric trials, skeletal 
growth (height) appeared to be unaffected. There were no bone fractures reported. The 
long term effect and the consequence of BMD decline is not yet known. In this study we 
will monitor your baby’s bone development. 
 
The study staff will check for side effects in babies during study visits and tell you what to 
do if your baby has any side effects.  
 
 
WHAT IF I BECOME PREGNANT AGAIN WHILE ON THE PrEP STUDY?  
If you wish to become pregnant again or think you may be pregnant again at any time 
during the study, please tell the study staff right away and we will test you using a blood or 
urine test. The study staff will talk to you about your choices.  
 
If you get pregnant again during the PrEP Study, you can continue on the study but you will 
be asked to stop study drugs. 
If you become pregnant again during the study, and are still pregnant at your last study 
visit, the study staff will contact you again to find out about the outcome of your pregnancy. 
 
Researchers want to know if the anti-HIV medicine you took during your pregnancy 
affected your baby.  This information may help find the best HIV drugs to use in pregnant 
women.  So, researchers will report this information to the "Antiretroviral Pregnancy 
Registry".  This computer database will not use your name or information that can identify 
you.  
 
You may face personal problems because of being in this study.  Family, friends, and 
others may worry, get upset, or treat you unfairly.  People may think that you have HIV or 
are likely to get it.    
You may feel embarrassed when answering personal questions about sex or having a 
physical exam.  You may feel anxious when waiting for your HIV test results. If you have 
these feelings, please tell the study staff so that they can find a way to help you. 
Researchers and study staff try hard to protect your privacy.  They also have a duty to 
maintain your privacy.  But there is a risk that others, including your partner, may find out 
that you are participating in this study.  Another social risk is that someone may use your 
personal information in a bad way.  For example, someone finds out your test results and 
shares them with others.  You could then have problems getting or keeping a job.  You may 

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no longer have your family’s or your community’s support.  These situations may cause you 
stress and embarrassment.  Researchers have ways to reduce these social risks. Some of 
these ways include limiting access to your study records, having your study visits in private, 
and using codes to identify you and your samples.  If you have any of these problems, 
please talk to the study staff, so that they can try to help you. 
  
There may be other risks that researchers do not know now.  If you feel something bad that 
you think is because of being in this study, you should tell the study staff.  Researchers will 
tell you about any new risks from this study or other studies that can affect your decision to 
stay in this study. 
 
 
6. WHAT POSSIBLE BENEFITS CAN I EXPECT FROM PARTICIPATING IN 
THIS STUDY? 
Researchers believe that the PrEP using Truvada may have a direct benefit to you.  
Also, researchers may learn some information from this study that may help others. 
 
 
 
7. WHAT OTHER CHOICES DO I HAVE? 
If you choose not to participate in this study: 
 
You could choose to get the available local standard of care  
 
You may choose to do nothing 
 
If you would like more information about the risks and benefits of each one of these 
choices, feel free to talk to the study staff.  You can also discuss these options with your 
doctor.  Regardless of your choice, any care that you get at this clinic outside of this study 
will not change. 
 
 
8. CAN I CHANGE MY MIND ABOUT PARTICIPATING IN THIS STUDY? 
Yes, you can change your mind at any time.  Your participation in this study is 
completely voluntary.  Tell the study staff if you are thinking about leaving or have decided 
to leave this study.  Again, any care that you get at this clinic outside of this study will not 
change. 
Study staff may want you to do some follow up visits and testing before you leave this 
study.  
 
 
9. CAN RESEARCHERS TAKE ME OFF THIS STUDY EARLY? 
Yes, researchers can take you off this study at any time: 
 
If they believe it is the best thing for you 
 
If you do not follow the study requirements 
 
If one of the groups watching over the study stops it  
Study staff may want you to do some follow up visits and testing before you are off this 
study.  
 
 

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10. WHAT HAPPENS IF I BECOME HIV INFECTED DURING THIS STUDY? 
If you do get infected, you and your baby will remain in the study.  You will be provided 
counselling about your care and treatment options.  You will be given anti-HIV 
medicines that are currently available to all HIV infected women in South Africa and 
your baby will also receive anti-HIV medicines to prevent him/her from getting HIV from 
you.  
 
11. WHAT HAPPENS AT THE END OF THIS STUDY? 
Once you finish this study, researchers cannot give you the anti HIV medicine for continued 
use.. If the medicine is made available by the Department of Health for women in your age 
group and risk category, and the drug was helping you, the study staff may be able to refer 
you to the nearest service point for access to Truvada as PrEP.  
 
 
12. WHAT WILL HAPPEN TO MY SAMPLES AT END OF THIS STUDY?  
 
Once this study ends, researchers may store some of your unused blood/body 
fluid/tissue.  Researchers may use these samples for future research. You need to let 
researchers store these samples to participate in this study. There is another informed 
consent form that explains what researchers may do with these samples. 
 
 
13. HOW WILL RESEARCHERS PROTECT THE PRIVACY OF MY 
INFORMATION?   
Researchers have protections in place to maintain your privacy.  They keep your study 
records in a secure place.  They do not use your name in publications, meetings, or stored 
samples.  They use a code to identify you and your samples.  They do not share any 
information that could identify you. 
 
 
14. WILL I HAVE TO PAY ANYTHING TO PARTICIPATE IN THIS STUDY? 
You will not have to pay for any study lab tests, procedures, or exams required for this 
study.  
 
 
15. WILL I RECEIVE ANY PAYMENT FOR MY PARTICIPATION IN THIS 
STUDY? 
No, you will not receive any payment. You will need to spend some time and maybe 
some money to participate in this study. Researchers will reimburse you for some of these 
expenses.  You will receive a total of R150 for transport costs, meals and for the time spent 
at the clinic.  You will receive this reimbursement at every scheduled study visit. 
 
 
16. WHO SHOULD I CONTACT IF I THINK THAT I AM HURT BECAUSE OF MY 
PARTICIPATION IN THIS STUDY?  
It is possible that either you or your baby could experience a problem or injury that would 
not have occurred if you did not participate in this study. If the study doctor determines that 
you or your baby has been injured as a direct result of being in this study, you and/or your 

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baby will be given immediate treatment for those injuries at no cost to you and then 
referred for further care if needed.   
 
However, the study doctor may determine that your or your baby’s illness or injury would 
have happened even if you did not participate in this study.  In that case, appropriate care 
and/or referral will likewise be provided for any illness or injury that occurs during the study. 
   
 
17. WHAT ARE MY RIGHTS AND WHO SHOULD I CONTACT IF I HAVE 
QUESTIONS? 
 
You have the right to leave this study at any time and for any reason.  The study 
staff will continue to treat you the same no matter what you decide.  You will not give up 
your legal rights by signing this informed consent form.  You also have the right to know 
about any new information from this study or other studies.  This information may affect 
your health, welfare, or decision to stay in this study. If you ever have questions about this 
study or in case you are injured as a result of participation in this research study, you 
should contact your doctor in this study – clinic tel.no. ___________  
Address: ___________________________________ 
 
 
 
17.1.1 If you ever have questions about your rights as a research subject or wish to report 
complaints/problems contact  
The Administrator or Chair 
Ethics committee details 
  
17.1.2 If you have questions about this trial, you should first discuss them with your doctor 
or the ethics committee (contact details as provided on this form). After you have 
consulted your doctor or the ethics committee and if they have not provided you with 
answers to your satisfaction, you should write to the South African Medicines Control 
Council (MCC) at: 
 
The Registrar of Medicines  
Medicines Control Council  
Department of Health  
Private Bag X828  
PRETORIA  
0001  
 
Fax: (012) 395 9201  
 
E-mail: mogobm@health.gov.za 
 
 
 
 

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DO I WANT RESEARCHERS TO TELL ME ABOUT IMPORTANT FINDINGS 
THAT ARE NOT PART OF THE STUDY GOALS AND THAT WERE FOUND 
BY CHANCE? 
 
Findings are important if they impact your health, welfare, or decisions about your 
health care.  
 
 
 
____ (Initials) Yes, I want researchers to 
tell me. 
 
____ (Initials) No, I don’t want researchers to 
tell me. 
 
 
 

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18. 
HOW DO I CONFIRM MY DECISION TO BE IN THIS STUDY? 
 
 
My signature below confirms: 
 
that I voluntarily decided to participate in this study 
 
that I had the opportunity to read this form or that it was read to me 
 
that this form was explained to me 
 
that I had the opportunity to ask questions  
 
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
Participant’s Signature/Mark/Thumb 
Print and Date 
 
 
 
Study Staff’s Name Obtaining Consent 
(Print)  
 
 
 
 
Study Staff’s Signature and Date 
Witness’ Name (Print)   
 
Witness’s Signature and Date 

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Appendix 4 
SAMPLE INFORMED CONSENT FORM 
 
Immediate or Deferred Preexposure Prophylaxis for HIV 
Prevention:  
Safe Options for Pregnant and Lactating Women 
 An Open-Label Randomised Control Study 
 
SHORT TITLE FOR THE STUDY: Preventing HIV Infection in Young Women during 
pregnancy and breastfeeding using Antiretroviral Pre exposure Prophylaxis (PrEP) 
 
FACT SHEET and CONSENT FORM for 
SPECIMEN STORAGE  
 
 
When you join this study, you will be asked to give permission for having some specimens 
that the doctor or nurse will take from you and your child saved in a repository. (A 
repository is a special laboratory with freezers where specimens like blood or tissue cells 
and body fluids that are taken from you during a study are kept. Your and your child’s name 
will not be on these specimens, only a special study number. The people who run the 
repository laboratory will not know your or your child’s name.) 
 
 
Why have a repository? 
 
Researchers can learn a lot from a study but as time goes by, the tests that they used get 
better or brand new tests are developed, and more can be learned with these better or new 
tests. When study volunteers consent to put specimens in the repository and consent to the 
researchers doing new tests on the specimens at some time in the future after their time in 
the study is ended, researchers can learn new information by being able to use the 
specimens. Your and your child’s rights and privacy will be protected in any of these new 
studies. 
 
 
How will my privacy and my child’s privacy be protected? 
 
The only record that you and your child participated in this study is at the clinic where it is 
kept separate from your and child’s health records and locked away. 
 
Your specimens and your child’s specimens in the repository will not have your name or 
your child’s name on them. The specimens will have a special study code. It will be the 
same code that is on your study record that is kept at the clinic. Again, none of this 
information will have your name or child’s name on it.  
 
 
How would a researcher get to use the specimens in the repository? 
 
If a researcher wants to do a test on specimens from the repository in the future, he or she 
will write up the idea and it will have to be approved by a committee to make sure the 
research is worthwhile. If the idea is approved, then coded specimens and coded 
information will be given to the researcher. The researcher will not know the names, 
addresses, or phone numbers of the people who gave the specimens to the repository. 
 

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Would I ever be contacted in the future about research using my / our specimens? 
 
All of the studies to be done in the future on your specimens in the repository will be for the 
particular reasons that you agreed to. If it is, then the research will go ahead since you 
would have agreed that these particular tests could be done without anyone contacting you 
to get your permission in the future.  
 
If the study to be done is not like the kind of tests you agreed could be done, then the 
committee will decide if you need to be contacted to give permission for the new study. 
 
 
I gave my permission to testing my specimen and my child’s specimens in the repository, 
but what if I change my mind? 
 
People always have the right to stop participating in research. So if you decide that you do 
not want researchers to be able to use the specimens in the repository, you can contact the 
clinic staff. They will tell the repository that the specimens with the study code number 
linked to your name and your child’s name in the clinic should not be studied. These 
specimens can be removed from the repository and destroyed if you tell us to do that.   
 
 
What type of research will be done with our specimens? 
 
Many different kinds of studies use specimens. Some researchers may develop new tests 
to find diseases. Others may develop new ways to treat or even cure diseases. In the 
future, some of the research may help to develop new products, such as tests and drugs. If 
this would happen and these tests or drugs make money, there are no plans to share that 
money with the people who gave the specimens.  
 
As part of this study (Preventing HIV Infection in Young Women during pregnancy and 
breastfeeding using Antiretroviral Pre exposure Prophylaxis (PrEP)), you are being asked to 
have some (blood, genital fluid and breastmilk) taken. These specimens will go into the 
repository for research to be done at some time in the future so that more information can 
come from your participation in this Study. 
 
You do not have to agree to store your specimens for future tests, for you to take part in 
this study. You will not lose any benefits to which you or your child is entitled if you decide 
against storing your specimens. 
 
You will also be asked to agree that these particular tests can be done without anyone 
contacting you to get your permission sometime in the future. No one doing these tests 
would know that these specimens came from you or your child and no one would contact 
you or your doctor or nurse with the results from these tests that might happen in the 
future.  
 
 

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CONSENT FORM 
 
What are the general HIV-related studies that can be done with the repository specimens? 
 
Researchers would like to store your specimens to understand why you have become 
infected with HIV or why/how have you avoided becoming infected.  HIV causes disease 
and complications, and how best to treat or prevent HIV infection and its complications. 
They need specimens from people who have HIV and from those who do not. Sometimes, 
the specimens can be used to learn something about new problems that people with HIV 
have like liver disease, diabetes, and heart disease. These general studies would not 
include any genetic testing (looking at your DNA). 
 
Benefits:  There are no direct benefits to you or your child. You will be helping researchers 
learn more about how to help people with HIV or at risk of HIV infection. 
 
Risks: The specimens would be collected as part of your study visits, in the same way we 
normally draw blood samples. Once in the repository, there are few risks. Your name or 
your child’s name will not be available to the repository or to the scientists who may be 
doing any future test. Since there are no plans to give participants the results of the tests 
performed on their stored specimens, you will not receive any information on your genetic 
makeup.     
 
 
I give permission for the use of my specimens and my child’s specimens for the purposes 
stated in the preceding section (general HIV-related tests). 
 
 
___________________________ 
 
___________________________   ________ 
Parent or Legal Guardian Signature  
Witness Signature 
 
 
Date 
 
 
 
 
 
 
(if needed) 
 
 
__________________________ 
 
__________________________     ________ 
Name of Study Staff Conducting  
 
Signature 
 
 
 
Date 
Consent Discussion 
 
 
 
 
 
 
 
 
 
 
 
 

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What are the special HIV-related studies that can be done with the repository specimens? 
 
Researchers in this study would also like to store your specimens and your child’s 
specimens to understand how HIV causes disease and complications, and how best to 
treat or prevent HIV infection and its complications through looking at how each person’s 
genetic makeup (your and your child’s DNA) either protects them or puts them at greater 
risk. It may be that researchers use some of your blood to make a “cell line”. That means 
the blood cells can keep dividing and give an endless supply of your DNA for tests to be 
done in the future. This kind of information will be particularly important as scientists work 
toward a vaccine that could protect people from AIDS. They need specimens from people 
who have HIV and from those who do not. 
 
Benefits:  There are no direct benefits to your child. Your child will be helping researchers 
learn more about how to help people with HIV or at risk of HIV infection. 
 
 
 
Risks: The specimens would be collected as part of your study visits. Once in the 
repository, there are few risks. Your name or your child’s name will not be available to the 
repository or to the scientists who may be doing any future test. Since there are no plans to 
give participants the results of the tests performed on their stored specimens, you will not 
receive any information on your or your child’s genetic makeup. 
 
 
I GIVE PERMISSION for the use of my and my child’s stored specimens for the purposes 
stated in the preceding section (special HIV-related tests). 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
Participant’s Signature/Mark/Thumb 
Print and Date 
 
 
 
 
 
 
 
Study Staff’s Name Obtaining Consent 
(Print)  
 
 
 
 
 
 
Study Staff’s Signature and Date 
Witness’ Name (Print)   
 
Witness’s Signature and Date 

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What if I have more questions? 
 
If you have any questions about the repository, about storage, or the use of your child’s 
samples, contact the study doctor _______________________. 
 
 
If you ever have questions about your rights as a research subject, giving consent 
as a research volunteer, or wish to report complaints/problems contact  
 
The Administrator or Chair 
Insert Ethics committee details 
  
If you have questions about this trial, you should first discuss them with your doctor 
or the ethics committee (contact details as provided on this form). After you have 
consulted your doctor or the ethics committee and if they have not provided you 
with answers to your satisfaction, you should write to the South African Medicines 
Control Council (MCC) at: 
The Registrar of Medicines  
Medicines Control Council  
Department of Health  
Private Bag X828  
PRETORIA  
0001  
 
Fax: (012) 395 9201                                          e-mail: mogobm@health.gov.za  

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________________________________________________________________________ 
 
I REFUSE to have any specimen collected from me or my child stored in the repository. 
 
 
 
 
 
 
Participant’s Name (print) 
 
Participant’s Signature/Mark/Thumb 
Print and Date 
 
 
 
 
 
 
 
Study Staff’s Name Obtaining Consent 
(Print)  
 
 
 
 
 
 
Study Staff’s Signature and Date 
Witness’ Name (Print)   
 
Witness’s Signature and Date 

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APPENDIX 5 
SCHEDULE OF EVENTS FOR MOTHER 
 
 
ANTENATAL 
LABOUR AND 
DELIVERY 
POSTNATAL 
 
SCREENING 
1ST ANTENATAL 
VISIT 
2ND ANTENATAL 
ENROLMENT 
>14W 
3RD ANTENATAL   
2 WEEKS 
SUBSEQUENT 
4 WEEKLY 
ANTENATAL  
VISITS
<72 HOURS 
POST 
DELIVERY 
2 WEEKS 
6  WEEKS 
10 WEEKS 
14 WEEKS 
SUBSEQUENT 
4 WEEKLY 
POSTNATAL  
VISITS
74  
WEEKS/STUDY 
EXIT 
Study Informed Consent  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Storage Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Documented HIV test result 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV Risk Assessment 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
Hx, Signs/Sx  of STIs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
Obstetric Assessments 
X 
X 
X 
X 
 
 
 
 
 
 
 
DXA Scan Hip and Lumbar Spine 
 
 
 
 
 
 
X 
 
 
X* 
X 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Sexual Behaviour Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Adherence Interview  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Condom Usage Interview 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Risk Reduction Counselling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Investigations 
RPR Test 
2ml 
 
 
 
 
 
 
 
2mL 
 
2mL 
HIV Rapid Test (finger prick) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hep B Surface Antigen 
2ml 
 
 
 
 
 
2mL 
 
 
 
2ml 
ALT/AST/Phosporous 
 
2ml 
 
2mla 
 
 
 
2ml 
 
2mla 
 
CBC 
2ml 
2ml 
2mla 
2mL 
 
 
 
2mL 
2mla 
 
Serum Creatinine 
2mL 
 
  
2mL 
 
2mL 
 
 
2mL 
  
2mL 
2mL 
2mL 
 
2mL 
Stored EDTA Plasma, DBS /cell 
pellets 
 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
10mL 
Stored Breast Milk (during BF 
only)   
 
 
 
 
 
10mL 
10mL  10mL 
10mL 
10mL 
10mL 
Cervical Vaginal Swabs 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
TOTAL BLOOD VOLUME 
8ml 
12ml 
14ml 
16ml 
12ml 
12ml 
12ml 
14ml 
14ml 
16ml 
12ml 
 
* DXA scan at 6 and 12 months 
 
 

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APPENDIX 6 
 
SCHEDULE OF EVENTS FOR HIV UNEXPOSED INFANTS 
 
 
BIRTH 
6 
WEEKS 
26 
WEEKS 
50 
WEEKS 
72 WEEK/STUDY EXIT VISIT 
Physical Exam  
X 
X 
X 
X 
X 
Growth Parameters and neurodevelopmental milestones 
X 
X 
X 
X 
X 
DXA Scan Lumbar Spine and Whole Body 
 
X 
X 
X 
X 
Laboratory Investigations 
 
CBC 
2mL 
2ml 
2mL 
2mL 
2mL 
Serum Creatinine 
2mL 
2ml 
2mL 
2mL 
2mL 
Stored DBS 
X 
X 
X 
X 
X 
TOTAL BLOOD VOLUME 
4ml 
4ml 
4ml 
4ml 
4ml