Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study
Phase: PHASE2
Conditions: HIV, Pregnancy
Sponsor: University of Liverpool

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Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers 
and their Neonates: A Pilot Study 
DolPHIN I – Dolutegravir in Pregnant HIV mothers and Neonates 
SHORT TITLE: 
DolPHIN 1Study 
PROTOCOL NUMBER: 
PK-12 
EudraCT NUMBER 
 
NCT: 
NCT02245022 
VERSION NUMBER: 
21.3 
SPONSORS: 
University of Liverpool 
FUNDING: 
ViiV Limited 
AREA 
HIV 
Type 
Phase II 
GCP Compliance Statement 
This trial will be conducted in compliance with the protocol, with the principles of ICH Guideline E6 for 
Good Clinical Practice, the Declaration of Helsinki, and all applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
CHIEF INVESTIGATOR/PROTOCOL CHAIR 
EMAIL and TELEPHONE 
Professor Saye Khoo MD, FRCP                       
University of Liverpool 
70 Pembroke Place 
Liverpool L693GF, United Kingdom 
Phone:  +441517945560 
Email: khoo@liverpool.ac.uk 
 
 
 
INVESTIGATORS : 
 
Principal Investigator 
Mohammed Lamorde, MRCP, PhD 
Head, Clinical Trials Unit 
Infectious Diseases Institute,  
Makerere University College of Health Sciences 
(MakCHS), Kampala, Uganda 
Phone: +256414307291 
E-mail: mlamorde@idi.co.ug 
 
Principal Investigator 
Professor Catherine Orrell 
J52 Old Main Building, Groote Schuur Hospital 
Main Road, Observatory 
Cape Town, 7925 
 
Phone: +27216506958 
E-mail: catherine.orrell@hiv-
research.org.za 
 
Principal Investigator 
Professor Landon Myer 
Gugulethu Community Health Centre, Corner NY1 and 
NY3, Gugulethu, Cape Town 
 
Phone: +2721406 6661 
E-mail: landon.myer@uct.ac.za 
 

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ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACTG 
AIDS clinical trial group 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ARV 
Antiretroviral  
AUC 
Area under the curve 
bd 
Twice daily 
C12 
Concentration at 12 h 
CI 
Confidence interval  
CMAX 
Maximum concentration 
CMIN 
Minimum concentration 
CRF 
Case report form 
CV 
Coefficient of variation  
CYP 
Cytochrome P450 
IDSMB 
Independent Data & Safety Monitoring Board 
DTG 
Dolutegravir 
EFV 
Efavirenz (an NNRTI) 
FDA 
U.S. Food and Drug Administration 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
HIV 
Human immunodeficiency virus 
INSTI 
Integrase strand transfer inhibitor 
IP 
Investigational product 
LFTs 
Liver function tests 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NOAEL 
No observed adverse effect level 
NVP 
Nevirapine (an NNRTI) 
NRTI 
Nucleoside reverse transcriptase inhibitor 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PMTCT 
Prevention of mother-to-child transmission of HIV 
qd 
Once-daily 
RCT 
Randomized controlled trial 
SAE 
Serious adverse event 
SoC 
Standard of Care 
SSA 
Sub-Saharan Africa 
SUSAR 
Suspected unexpected adverse reaction 
TSC 
Trial Steering Committee 
UGT 
Uridinediphosphate glucuronosyl transferase 
ULN 
Upper limit of normal 
VL 
HIV viral load 
WHO 
World Health Organization 

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1 Contents 
2 
PROTOCOL SYNOPSIS ...................................................................................................................... 5 
3 
LAY SUMMARY ................................................................................................................................. 6 
4 
ETHICAL JUSTIFICATION, AND RISK-BENEFIT ANALYSIS .................................................... 6 
4.1 
Ethical Justification ....................................................................................................................... 7 
4.2 
Risk Assessment for Dolutegravir in Pregnancy ........................................................................ 10 
4.3 
Risk Management Plan ............................................................................................................... 13 
5 
DESIGN, OBJECTIVES AND ENDPOINTS .................................................................................... 16 
5.1 
Study Design ............................................................................................................................... 16 
5.2 
Primary Objectives ...................................................................................................................... 16 
5.3 
Secondary Objectives .................................................................................................................. 16 
5.4 
Primary Endpoint ........................................................................................................................ 16 
5.5 
Secondary Endpoints .................................................................................................................. 16 
6 
SUBJECT POPULATION .................................................................................................................. 17 
6.1 
Number of subjects ..................................................................................................................... 17 
6.2 
Inclusion criteria ......................................................................................................................... 17 
6.3 
Exclusion criteria ........................................................................................................................ 18  
6.4 
Selection of Participants.............................................................................................................. 18 
6.5 
Withdrawal of subjects................................................................................................................ 19 
7 
STUDY TREATMENTS .................................................................................................................... 19 
7.1 
Treatment Plans and Regimens ................................................................................................... 19 
7.2 
Dolutegravir ................................................................................................................................ 20 
7.3 
Prior and Concomitant Medication ............................................................................................. 20 
7.4 
Infant Nevirapine ........................................................................................................................ 21 
8 
STUDY SCHEDULES AND PROCEDURES ................................................................................... 21 
8.1 
Study Schedule ............................................................................................................................ 22 
8.2 
Screening..................................................................................................................................... 23 
8.3 
Randomisation ............................................................................................................................ 23 
8.3.1 
Drug dispensing visit, Day 1 ............................................................................................... 24 
8.3.2 
Visit 2, Day 7 (tolerance +/- 1 day) .................................................................................... 24 
8.3.3 
Visit 3, Day 14 (tolerance +/- 2 days) ................................................................................. 24 
8.3.4 
Visit 4, Day 28 (tolerance +/- 7 days) ................................................................................. 25 
8.3.5 
Visit 5, Delivery .................................................................................................................. 25 
8.3.6 
Visit 6, 2 weeks post-delivery (tolerance +/- 7 days) .......................................................... 25 
8.3.7 
Visit 7, 1, 2 or 3 days following switch to Standard of Care (SoC) .................................... 26 
8.3.8 
Visit 8, month 6 post-delivery (tolerance +/- 1 month) ...................................................... 26 
8.4 
Clinical Assessment/Early Termination Visit ............................................................................. 26 
9 
SAFETY MONITORING ................................................................................................................... 27 
9.1 
Intensive Virological Monitoring of First 8 Patients receiving DTG ......................................... 27 
9.2 
Maternal Assessments ................................................................................................................. 28 
9.3 
Infant Assessment ....................................................................................................................... 28 
10 
MANAGEMENT OF ADVERSE EVENTS .................................................................................. 29 
10.1 
Adverse Events ........................................................................................................................... 29 
10.2 
Serious Adverse Events .............................................................................................................. 30 
10.3 
Specific Toxicities/Adverse Event Management ........................................................................ 31 
10.3.1 
Liver chemistry stopping and follow up criteria ................................................................. 31 
10.3.2 
Allergic Reaction ................................................................................................................ 33 
10.3.3 
Rash ..................................................................................................................................... 33 
10.4 
Safety Reporting ......................................................................................................................... 34 

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10.4.1 
Pregnancy Reporting ........................................................................................................... 34 
10.5 
Adverse Event Reporting ............................................................................................................ 35 
10.6 
Management of Post-recruitment Illness .................................................................................... 35 
11 
DATA AND STATISTICAL ANALYSIS ..................................................................................... 35 
12 
STUDY MANAGEMENT ............................................................................................................. 36 
12.1 
Liverpool ..................................................................................................................................... 36 
12.2 
Sample Processing ...................................................................................................................... 36 
12.3 
Clinical Monitoring ..................................................................................................................... 36 
12.4 
Laboratory Monitoring ................................................................................................................ 36 
12.5 
Data Safety and Monitoring Group ............................................................................................. 37 
12.6 
Termination of the trial ............................................................................................................... 37 
13 
DATA HANDLING ....................................................................................................................... 37 
13.1 
Recording of Data ....................................................................................................................... 37 
13.2 
Source Documentation and Study Records ................................................................................. 37 
13.3 
Data management ........................................................................................................................ 37 
13.4 
Archiving and storage of data ..................................................................................................... 38 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................................. 38 
14.1 
Monitoring Arrangements ........................................................................................................... 38 
14.2 
Quality Assurance ....................................................................................................................... 38 
15 
ETHICS & ADMINISTRATION ................................................................................................... 39 
15.1 
Ethics Approval .......................................................................................................................... 39 
15.2 
Regulatory Approval ................................................................................................................... 39 
15.3 
Publication Policy ....................................................................................................................... 39 
15.4 
Drug Accountability .................................................................................................................... 39 
15.5 
Financial Aspects ........................................................................................................................ 39 
16 
REFERENCES ............................................................................................................................... 40 
17 
PROTOCOL SIGNATURE PAGE ................................................................................................ 42 
18 APPENDIX 1 SAFETY QUESTIONNAIRE ........................................................................................ 43 
19 APPENDIX 2  DAIDS GRADING SCALE .......................................................................................... 45 
20 APPENDIX 3 LIVERPOOL CAUSALITY ASSESSMENT TOOL FOR ADVERSE DRUG 
REACTIONS .............................................................................................................................................. 64 
21 APPENDIX 4 COMMUNITY CONSULTATION ............................................................................... 65 
22 APPENDIX 5 EDINBURGH POSTNATAL DEPRESSION SCALE  ................................................ 71 
 
 
 
 

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2 PROTOCOL SYNOPSIS 
Aim 
 
To evaluate dolutegravir (DTG) pharmacokinetics in pregnant 
HIV-infected women 
 
Rationale 
In developing countries many women present with a new HIV 
diagnosis in late pregnancy, and are at high risk of 
transmitting infection during delivery. Moreover, women may 
acquire NNRTI resistance from primary transmission, or use 
of nevirapine (NVP) in previous pregnancies. In these 
circumstances, DTG is likely to be more effective in reducing 
mother to child transmission of HIV than NNRTI-based 
regimens. 
 
Study design 
HIV positive pregnant women presenting with untreated HIV 
infection in late (≥28 -36 weeks gestation) pregnancy will be 
randomised 1:1 to receive DTG (50mg once daily) or standard 
of care (nevirapine or efavirenz) + 2 NRTIs. PK (0-24h) 
profile will be sampled in third trimester and post-partum. 
Although this is primarily a PK study (and has been powered 
as such) randomisation is included to allow comparison of 
plasma HIV VL responses against standard of care (NVP or 
EFV) and is essential for evaluation of secondary endpoints of 
safety and efficacy of DTG in pregnancy. 
 
Inclusions 
 Able to provide informed consent 
 Willing to participate, 
 Women age 18 years and above 
 Pregnant 
 Untreated HIV infection in late pregnancy at ≥28 – 36 
weeks gestation 
 
Exclusions 
 Received antiretroviral drugs in previous 6 months 
 Ever received integrase inhibitors 
 Serum haemoglobin < 8.0 g/dl 
 Elevations in serum levels of alanine aminotransferase 
(ALT) >5 times the upper limit of normal (ULN) or 
ALT >3xULN and bilirubin >2xULN (with >35% 
direct bilirubin) 
 eGFR < 50ml/min 
 Active Hepatitis B infection, history or clinical 
suspicion of unstable liver disease, or subjects with 
severe liver disease.  
 Severe pre-eclampsia (e.g. HELLP), or other 
pregnancy related events such as renal or liver 
abnormalities (e.g. grade 2 or above proteinuria, 
 
 

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elevation in serum creatinine (above 2.5 x ULN), total 
bilirubin ALT or AST) 
 Paternal non-consent (where disclosure to male partner 
has been made) 
 Clinical depression or clinical judgement suggests 
increased risk of suicidality 
 
Primary Endpoints 
 AUC0-24h  of DTG in third trimester and post-partum 
 
Secondary 
Endpoints 
 Safety and tolerability of DTG 
 Proportion with undetectable VL at delivery (+14 
days) 
Change in viral load over the first 4 weeks of therapy 
 Plasma protein bound/unbound PK  
 Cord:maternal plasma DTG ratio 
 Breast milk:maternal plasma DTG ratio 
 DTG levels in the breastfed infant with mother at 
steady-state , and time for DTG to become 
undetectable in infant blood 
 Proportion of mother to child transmission of HIV at 
six months postpartum 
 
Number recruited 
N=30 per group 
 
3 LAY SUMMARY 
Antiretroviral therapy (ART) in pregnancy is able to effectively reduce mother-to-child 
transmission (MTCT) of HIV. If untreated, the risk of transmission is around 25% (greater with 
high viral loads) but ART administered optimally during pregnancy may reduce this risk to 1-
2%. In order to successfully prevent infection, ART should be started in the first or second 
trimester, and should reduce maternal plasma viral load to undetectable levels. Unfortunately 
throughout low-middle income countries, MTCT rates are unacceptably high with an estimated 
240 000 newborn children infected annually. The main causes for this are undiagnosed or late 
diagnosis of maternal infection, suboptimal adherence to therapy and drug resistance, 
particularly in mothers who have previously received single dose nevirapine.  
 
In sub-Saharan Africa (SSA), women frequently engage with health services late in pregnancy, 
and new HIV diagnoses in the third trimester (≥28 weeks of pregnancy) are not uncommon. Risk 
of MTCT is high, especially as NNRTI-based therapy takes a median of 2 months to 
significantly reduce the HIV viral load, making it unlikely that commencement of these drugs in 
late pregnancy will offer protection of the infant from intrapartum transmission. 
 
4 ETHICAL JUSTIFICATION, AND RISK-BENEFIT ANALYSIS 

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Universal HIV testing of pregnant women in low/middle income countries continues to detect 
new HIV diagnoses, and many of these mothers present late in pregnancy (≥28 weeks gestation).  
First-line use of nevirapine (NVP) in this setting with limited virological monitoring, coupled 
with widespread administration of single-dose NVP to prevent mother-to-child transmission 
(PMTCT) has increased the prevalence of NVP drug resistance in these communities. The 
pattern of resistance mutations frequently confers resistance to efavirenz (EFV), the alternative 
NNRTI used in these populations. 
 
The combination of late presentation and significant risk of NNRTI resistance makes 
dolutegravir (DTG), an Integrase Strand Transfer Inhibitor (INSTI) an ideal choice in these 
women, providing safety and efficacy is established- this study seeks to evaluate the PK of DTG 
in pregnancy, and to evaluate VL responses, safety and tolerability. Should DTG prove safe and 
without major pharmacokinetic alterations resulting from pregnancy, these data may inform the 
design of a subsequent efficacy study. 
4.1 Ethical Justification 
Vertical transmission of HIV remains a significant challenge in developing countries and 
antiretroviral prophylaxis for PMTCT is an important tool towards elimination of paediatric 
infections. Between 2009 and 2010, coverage of antiretroviral prophylaxis for prevention of 
mother to child transmission was 42% and an estimated 1.48 million infants were born to women 
living with HIV (WHO 2010). Global efforts are geared towards improving access to 
antiretrovirals for PMTCT by simplifying antiretroviral treatment protocols while ensuring 
optimal outcomes for HIV-infected women and their children (WHO 2010; WHO 2012).  
 
Under consolidated antiretroviral guidelines issued by the WHO in 2013, efavirenz-based ART 
is now recommended the preferred NNRTI option for HIV-1 infected patients, including among 
women of childbearing age and pregnant women(WHO 2013). Uganda adopted the Option B+ 
strategy for PMTCT of HIV in April 2013, and South Africa in July 2014. Under this strategy, 
lifelong ART is offered to all pregnant ART naïve women irrespective of CD4 count with 
efavirenz-based ART as the preferred treatment option. However, the effectiveness of this 
regimen could be compromised in the event of large populations of women who may have been 
either exposed to single dose nevirapine in the past or among women with transmitted NNRTI 
resistance.  
 
The justification for studying DTG in pregnancy includes: 
a) Likely widespread availability of generic DTG in the coming years. The manufacturer has 
indicated its willingness to make DTG available in low income countries, and is currently 
engaging with generic manufacturers. Estimates from the Clinton Foundation suggest that 
generic manufacture of DTG will make this drug affordable either as an alternative first line, 
or else second line agent (Hill 2013). Clinical guidelines from the US and Europe currently 
rank INSTIs such as raltegravir and elvitegravir alongside NNRTIs as preferred first line 
agents.  INSTIs may replace NNRTIs in first line regimens due to their good safety and 
toxicity profile, lower propensity for drug interactions, and superior efficacy. Large phase III 
RCTs comparing raltegravir (Rockstroh, Dejesus et al. 2013), elvitegravir (Sax, DeJesus et 
al. 2012) and dolutegravir (van Lunzen, Maggiolo et al. 2012) against efavirenz-based 
therapy have shown superior virological outcome at 48 weeks, faster time to undetectable 

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viral load, lower incidence of adverse events, and fewer treatment discontinuations, and these 
findings have recently been confirmed in a meta-analysis (Messiaen, Wensing et al. 2013). 
 
b) Low risk for serious drug-drug interactions. The potential for drug-drug interactions is 
significantly less for INSTIs compared with other antiretrovirals (relative risk compared 
with raltegravir: boosted protease inhibitors [RR = 4.96], non-nucleoside reverse 
transcriptase inhibitors [RR = 2.48](Patel, Abdelsayed et al. 2011). These are particularly 
important considerations for low/middle income country settings where adults with newly 
diagnosed HIV infection often present with tuberculosis, or during antenatal screening in 
late pregnancy.  Here DTG may carry significant advantages over NNRTIs, and other 
INSTIs. In the absence of alternatives to rifampicin-based TB therapy, DTG and raltegravir 
exposures are only moderately reduced (Dooley, Sayre et al. 2013), compared to larger (50-
90%) reductions in concentrations of boosted PIs, nevirapine and elvitegravir. Dolutegravir 
is metabolized by glucuronidation (UGT1A1) with some contribution from CYP3A. 
 
c) Rapid viral load drop potentially beneficial in late diagnosis during pregnancy. In Sub-
Saharan Africa, pregnant mothers tend to engage with health services later in pregnancy 
compared with Europe, and new HIV diagnoses resulting from universal testing at ≥28w 
gestation are frequent. DTG results in a very rapid reduction in viral load; median time to 
undetectable viral load in the SINGLE study was 28 days vs. 84 days with Atripla 
(P<0.0001) (Walmsley, Antela et al. 2012). Use of DTG may lower risk of mother-to-child 
transmission of HIV in late presenters. Although meta-analysis shows no increase in birth 
defects with maternal efavirenz (Ford, Mofenson et al. 2010), there has been recent 
suspicion of neurological toxicity in a large French registry (Sibiude, Madelbrot et al. 2013) 
and neurodevelopmental delay in a South African cohort (Westreich, Rubel et al. 2010).  
 
d) Proven efficacy in patients with established drug resistance to other antiretrovirals.  In 
most resource-poor settings, options for anti-retroviral therapy are limited (2011), and the 
emergence of HIV drug resistance gives cause for concern (Hedt, Wadonda-Kabondo et al. 
2008; WHO 2012). In a cross-sectional study conducted among HIV-1 antiretroviral naïve 
patients in five African countries, the highest prevalence of transmitted resistance was 
observed in Kampala, Uganda 12.3% (22 of 179; 7.5-17.1)  (Hamers, Wallis et al. 2011). In 
Malawi, the prevalence of primary drug resistance in new infections was 6.1% which is 
comparable  with figures of ~3% for South Africa (Manasa, Katzenstein et al. 2012), and 
5.7% for Zambia (Hamers, Siwale et al. 2010), with over half of all mutations conferring 
resistance to  non-nucleoside reverse transcriptases (NNRTI) (Wadonda-Kabondo, Banda et 
al. 2012). Studies across Africa have shown that treatment response to NNRTIs in mothers 
and children exposed to nevirapine (particularly single dose) during pregnancy is blunted 
(Musiime, Ssali et al. 2009). In this context, a novel class of ARV which is safe, affordable 
and effective is an urgent need 
 
e) Safety profile in pregnancy. DTG is classified as FDA pregnancy Category B. There are no 
adequate and well-controlled studies in pregnant women. Because animal reproduction 
studies are not always predictive of human response, and dolutegravir was shown to cross 
the placenta in animal studies, the manufacturer recommends that this drug should be used 
during pregnancy only if clearly needed (ViiV 2013). 

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f) 
Necessity of investigating DTG PK in pregnant women. Alongside the clinical and 
humanitarian imperative to provide effective treatment for preventing HIV transmission in 
pregnant mothers with NNRTI-resistant HIV, there is an equally important ethical 
imperative to establish the safety, efficacy and pharmacokinetics of DTG in pregnant 
mothers and their breastfed infants in SSA, especially given the implementation of WHO 
Option B+, and the potential for widespread use of DTG in the foreseeable future. Previous 
experience suggests it is universally the case that pregnant women in SSA receive new 
antiretrovirals (ARV) ahead of any proper evaluation, and clinical studies (if undertaken at 
all) occur at a much later stage after many mothers and infants have been exposed. To 
ensure that this treatment does not risk therapeutic failure due to lower than anticipated 
exposure in pregnancy, intensive virological monitoring and other safeguards will be put in 
place for the first group of women enrolled in the study (see section 9.1), with scrutiny from 
the IDSMB.   
 
g) Importance of undertaking the study in SSA. Any pivotal study if undertaken in 
developed countries would have limited generalizability to an African setting because i) 
ARVs tend to be initiated later in gestation in newly presenting pregnant women, ii) the 
standard of care across SSA is likely to be an efavirenz or nevirapine-based regimen  iii) 
infant breastfeeding is recommended in the presence of ARVs  ii) host factors such as BMI, 
pharmacogenomics, ethnicity etc may impact on pharmacokinetics (PK) of ARVs. 
 
h) Continued administration of DTG for 2 weeks post-partum (whilst breastfeeding) to 
characterize PK in non-pregnant state. Under standard of care, the infant will receive 6 
weeks of ART prophylaxis (as nevirapine with or without zidovudine), and would be 
exposed to the NNRTI/NRTI/NRTI combination received by the mother under standard of 
care. In this study, infants will be exposed DTG via the breast milk for a 2 week period 
following birth. We believe this risk to be acceptable given the potential benefits. 
Furthermore, the risk is unlikely to exceed any potential risk of in utero exposure to DTG. 
Drug-drug interactions between directly administered NVP and DTG ingested via the breast 
milk are unlikely to have clinical significance, although we will study this. The potential 
risks of breastfeeding are fewer than those of giving formula feeding during the two week 
period that mothers continue to receive DTG postpartum, but the mother will be switched to 
standard of care regimen (EFV-based) at 2 weeks postpartum to minimise any potential risks 
to the infant of prolonged low-dose exposure through breast milk. (This time point chosen as 
a compromise between reversion of maternal PK to baseline non-pregnant state against 
minimising any potential risks to the infant)Replacement of breast feeding with formula 
feeding during the first two weeks post-partum would be unethical due to the loss of the 
immune benefits of colostrum to the neonate, risks intrinsic to formula feeding in low 
resource settings and increased risk of HIV transmission if mixed feeding occurs (Teasdale 
et al, 2011) The potential risks of low-level ARV causing drug-resistance in the infant 
should the PMTCT fail exist for the standard of care NNRTIs and NRTIs; it is not 
anticipated that DTG will carry a greater risk but nevertheless this is best monitored within a 
clinical trial setting before widespread uptake without monitoring. 
 
 

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4.2 Risk Assessment for Dolutegravir in Pregnancy 
FDA Category B. No studies have been conducted with DTG in pregnant women as pregnant 
women were excluded from the Phase IIb/III DTG clinical studies and subjects who became 
pregnant were required to discontinue from the studies.  
 
Fifty-two pregnancies were reported across the DTG clinical studies and compassionate use 
program through 16Jan2016 (ViiV, unpublished data); 37 for DTG- containing ART and 15 for 
comparator. Of the 37 pregnancies in subjects receiving DTG, 21 were reported in the ART-
naïve population (including one in a partner potentially exposed to DTG via the semen of a male 
subject), 12 in the ART-experienced (integrase inhibitor [INSTI]-naïve) population, 3 in the 
ART experienced (INSTI-resistant) population and one was reported in a completed Phase I, 
healthy volunteer study (DTG).  
 
Of the 52 pregnancies reported across the DTG clinical studies, 23 resulted in delivery of a 
normal healthy baby (including the partner pregnancy and a twin pregnancy), 13 in elective 
termination, one was ectopic (EFV/TDF/FTC) and 7 resulted in spontaneous abortions (3 for 
DTG, 2 for EFV/TDF/FTC and 1 each for RAL and DRV+RTV; all between 2 and 10 weeks 
gestation). In seven cases, the pregnancy was either ongoing or unknown (all DTG). During one 
pregnancy, involving an ART-experienced (INSTI-naïve) subject exposed to DTG plus abacavir, 
atazanavir and RTV, a routine ultra sound at 31 weeks gestation indicated a congenital anomaly 
of double outlet right ventricle with ventricular septal defect in the fetus. Surgery was performed 
following delivery but the Infant died on DOL 4 due to post-operative complications. The events 
were considered unrelated to IP by the reporting investigator. With the exception of this case, no 
other congenital anomalies have been reported. None of the cases resulting in adverse pregnancy 
outcome were considered reasonably attributable to IP by the reporting investigators. To date 
there has been no preclinical findings or evidence for an increased risk for teratogenic effects for 
DTG.  
 
The overall nonclinical reproductive and developmental toxicity profile for DTG in rats and 
rabbits suggests that DTG is not teratogenic and has a low potential for fetal risk. There were no 
effects on fertility or early embryonic development in rats orally administered DTG at ~1000 
mg/kg/day in males or females. The no adverse effect level (NOAEL) was 1000 mg/kg/day, 
which corresponds to ~33X the expected human exposure for a 50 mg once daily, based on 
gender averaged mean exposures achieved in the 4 week rat toxicity study. No adverse effects on 
fetal development were observed in pregnant rats orally administered DTG at ~1000 mg/kg/day. 
The NOAEL for maternal and fetal toxicity was1000 mg/kg/day, which corresponds to ~38X the 
expected human exposure for a 50 mg once daily dose. In an embryofetal development (EFD) 
study in rabbits, DTG was orally administered at 40, 200, or 1000 mg/kg/day to pregnant rabbits. 
Suppressed body weight gain (13.6% on gestation Day 19), decreased food consumption (up to 
53%) and scant or no faeces/urine associated with the decreased food consumption were noted in 
the 1000 mg/kg/day dams. Maternal toxicity at this dose precluded dosing DTG at higher doses 
in rabbits because maternal toxicity can confound teratogenicity assessment. Therefore, the dose 
of 1000 mg/kg/day was the maximal dose that could be administered in this embryo fetal 
development EFD study. 
 

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The NOAEL was 200 mg/kg/day for maternal general toxicity (~0.27X the expected human 
exposure for a 50 mg once daily dose) and 1000 mg/kg/day for maternal reproductive function 
and embryofetal development (0.56X the expected human exposure for a 50 mg once daily 
dose,). Of note, there were no teratogenic effects at 1000 mg/kg/day, a dose that exceeded the 
NOAEL for maternal toxicity. In a pre-and postnatal development study, DTG was administered 
to female rats at doses of 5, 50 or 1000 mg/kg/day from Day 6 of gestation to Day 20 of 
lactation. Suppressed body weight gain and decreased food consumption were noted in dams 
(F0) in the 1000 mg/kg/day group during the lactation period, which were associated with mild 
decreases in body weights in the offspring in the 1000 mg/kg/day group from pre-weaning until 
adolescence. There were no adverse effects on maternal pregnancy, parturition, lactation or 
offspring (F1) survival, behavioral or reproductive function. The NOAEL for maternal 
reproductive function was 1000 mg/kg/day (~32X above the expected human exposure for a 50 
mg once daily dose, based on exposures achieved in female rats in the 4 week toxicity study). 
Due to the decreased body weights of the offspring observed at higher doses, the NOAEL for 
pre- and postnatal development of the offspring (F1) was 50 mg/kg/day. This is~25X above the 
expected human exposure for a 50 mg once daily dose (extrapolated from gender mean 
exposures achieved in the rat 14 day toxicity study). Based on the fact that effects on offspring 
body weights were noted at doses where maternal toxicity was observed, and the presence of 
considerable safety margins expected at the proposed clinical doses, there is minimal risk for 
adverse effects on postnatal development in offspring of mothers receiving DTG. 
 
DTG is excreted in the milk of lactating rats. Following oral administration (50 mg/kg) to 
lactating rats on Day 10 postpartum, total radiocarbon concentrations in milk were up to 2-fold 
greater than those in maternal blood. The metabolite profile of milk indicated that parent DTG 
represented more than 95% of the total radiocarbon, consistent with the findings in plasma from 
female rats in an earlier study. These data suggest that F1 offspring in the pre- and postnatal 
toxicity study were exposed to the drug via the milk. Following oral administration of DTG (50 
mg/kg) to pregnant rats on Day 18 post conception, DTG-related material was found, by 
quantitative whole body autoradiography (QWBA) analysis, to be widely distributed to the 
fetuses over the 24- hour sampling period. These data indicate that DTG is able to cross the 
placental barrier. 
 
DTG is primarily metabolized through UGT1A1 with minimal renal excretion (<1% of total dose 
given orally). DTG is a drug with low clearance (~1 L/hr for CL/F after oral dosing), low volume 
of distribution (~12.5 L for Vd/F after oral dosing), and high plasma protein binding (>99%). 
The following physiologic changes during pregnancy may have impact on DTG PK  
 
Table 1  
Possible Physiological Changes During Pregnancy* 
Potential Impact on DTG PK 
Changes in total body weight and body fat 
composition. 
Increase clearance (CL) as well as the volume 
of distribution (Vd) 
Delayed gastric emptying and prolonged 
gastrointestinal transit time. 
Increase oral bioavailability, delayed time to 
observed maximal drug concentration (tmax) 

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Increase in extra cellular fluid and total body water. 
Increase Vd 
Increased cardiac output, increased stroke volume, and 
elevated maternal heart rate. 
Unlikely to have effect 
Decreased albumin concentration with reduced protein 
binding. 
Increase unbound fraction, CL, and Vd 
Increased blood flow to the various organs (e.g., 
kidneys, uterus). 
Unlikely to have effect 
Increased glomerular filtration rate.  
Unlikely to have effect 
Changed hepatic enzyme activity, including phase I 
CYP450 metabolic pathways (e.g., increased CYP2D6 
activity), xanthine oxidase, and phase II metabolic 
pathways (e.g., N-acetyltransferase 
May affect CL 
*FDA Guidance for Industry (2004): Pharmacokinetics in Pregnancy — Study Design, Data Analysis, 
and Impact on Dosing and Labeling. 
 
DTG has shown to be not prone to changes by demographic factors (age, gender, weight, etc) 
based on population PK analyses. Accumulated safety data showed that DTG is in general well 
tolerated and no PK/Pharmacodynamic (PD) relationship for safety measures has been identified. 
Therefore, despite the potential impacts of physiological changes on DTG PK, it is expected that 
DTG PK should not change significantly during pregnancy. The clinical dose of 50mg once daily 
will be used in this study and no therapeutic drug monitoring is needed. However, to ensure that 
this assumption is true within the study population, the first 8 patients commenced on DTG will 
have their antepartum PK samples batched and shipped to Liverpool for analysis ahead of the 
first IDSMB meeting so that any clinically relevant reductions in AUC that might compromise 
effectiveness 
of 
the 
regime 
can 
be 
identified 
early.

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4.3 Risk Management Plan 
Table 2 sets out ethical considerations and safeguards which will be used in a series of community, clinical and scientific consultations: 
Potential Risk of Clinical 
Significance Data/Rationale 
for Risk Mitigation Strategy 
Potential Risk of Clinical Significance 
Data/Rationale for Risk Mitigation Strategy 
Potential Risk of Clinical 
Significance Data/Rationale for Risk 
Mitigation Strategy 
Foetuses are most susceptible to 
potential teratogenic effects of 
drugs during 1st trimester 
 
With other ART agents, there are concerns with regard to 
teratogenicity (e.g., EFV) and maternal hepatic/rash toxicity 
(i.e. NVP). 
ZDV, ABC and 3TC have high level of transplacental 
transfer. Data available for teratogenic risk for DTG is 
described in 4.3. 
 
There is no specific mitigation of risk to 
the foetus. However, the risk is felt to be 
low based on all available data for DTG. 
Frequent visits to monitor clinical and 
laboratory parameters and routine care by 
the HIV care provider (via this protocol), 
and routine care by appropriate provider 
of healthcare to pregnant women 
Pregnancy can increase risks of 
HIV progression, complications 
and perinatal transmission 
 
The safe use of DTG in human pregnancy has not been 
established. DTG has been shown to cross the placenta in 
reproductive toxicity studies 
 
Treatment of the underlying HIV disease. 
Additionally women taking ART during 
pregnancy can reduce risk of transmission 
to infant (i.e. early control of viral 
replication) 
 
Hypersensitivity reactions (HSR) 
and rash 
 
Drug-related hypersensitivity risk is established with current 
first line ART regimens in local use. HSR has been observed 
uncommonly with DTG. Rash was commonly reported in 
DTG Phase IIb/III clinical trials; episodes were generally 
mild to moderate in intensity; no episodes of severe rash, 
such as Stevens-Johnson Syndrome, toxic epidermal 
necrolysis and erythema multiforme were reported.  
 
Specific/detailed 
toxicity 
management 
guidance is provided for suspected HSR 
with DTG (see Section 10.3.2) or rash 
with DTG (see Section 10.3.3) 
 
Drug induced liver injury (DILI) 
and other clinically significant 
liver chemistry elevations 
 
Non-clinical data suggested a possible, albeit low, risk for 
hepatobiliary toxicity with DTG. Drug-related hepatitis is 
considered an uncommon risk for ART containing DTG 
regardless of dose or treatment population. For subjects with 
hepatitis B (HBV) virus and/or hepatitis C (HCV) virus 
co-infection, improvements in immunosuppression as a result 
of HIV virologic and immunologic responses to DTG 
Subjects meeting the following criteria 
during the screening period are excluded 
from participating (Section 4.3). Alanine 
aminotransferase (ALT) >5 times the 
upper limit of normal (ULN) or ALT 
>3xULN and bilirubin >2xULN (with 
>35% direct bilirubin).Subjects positive 

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containing ART, along with inadequate therapy for HBV co-
infected subjects, likely contributed to significant elevations 
in liver chemistries. 
 
for HBV at screening (hepatitis B virus 
surface antigen positive [+HBsAg]) will 
have a full Hepatitis B panel performed 
and those with evidence of active disease 
(e antigen positive) will be excluded, as 
will those with an anticipated need for 
HCV therapy during the study.   
 
Specific/detailed liver stopping criteria 
and toxicity management guidance is 
provided for suspected DILI or other 
clinically 
significant 
liver 
chemistry 
elevations (Section 10.3.1) 
Gastrointestinal (GI) intolerance  
 
Non- clinical studies showed upper and lower GI toxicity, 
including vomiting, diarrhoea and gastric erosions observed 
in monkey toxicology studies (thought to be related to local 
and not systemic toxicity). Mild to moderate GI intolerance 
(mainly diarrhoea and nausea) is associated with DTG 
treatment in a small proportion of subjects; however there 
were no indications of an increased risk for peptic ulcers or 
serious erosions.  
 
Routine monitoring of GI symptoms will 
be performed. 
 
Renal function  
 
Mild elevations of creatinine have been observed with DTG 
which are related to a likely benign effect on creatinine 
secretion with blockade of OCT-2 receptor. DTG has been 
shown to have no significant effect on glomerular filtration 
rate (GFR) or effective renal plasma flow. Measurement of 
albumin/creatinine ratio confirmed there was no difference in 
the effect of DTG on albumin excretion compared with EFV 
or RAL. DTG is eliminated by renal excretion and exposure 
increases in patients with renal dysfunction.  
 
Subjects 
with 
a 
Calculated 
eGFR 
<50ml/min will have modification of 
NRTI dose as per National Guidelines 
Specific/detailed 
toxicity 
management 
guidance is provided for subjects who 
develop a decline in renal function.  
 
Creatine phosphokinase (CPK) 
elevations 
 
Asymptomatic CPK elevations mainly in association with 
exercise have been reported with DTG therapy.  
 
Specific detailed toxicity management 
guidance is provided for subjects who 
develop Grade 3 to 4 CPK elevations. 

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Increased occurrence of immune 
reconstitution 
inflammatory 
syndrome (IRIS) 
 
With rapid HIV-1 RNA decline and early recovery of CD4+ 
cell counts there could, theoretically, be an increase in cases 
of IRIS. 
The increased risk for HBV and HCV IRIS with DTG 
containing ART is addressed above; there was a low rate of 
other medical conditions frequently implicated in IRIS cases.  
 
Subjects positive for HBsAb at screening 
or with active HCV illness (anticipated to 
require therapy) are excluded from 
participating. Subjects will have routine 
laboratory monitoring 
 
Psychiatric disorders  
 
Psychiatric disorders including suicidal ideation and 
behaviours are common in HIV infected patients. The 
psychiatric profile for DTG (incl. suicidality, depression, 
bipolar and hypomania, anxiety and abnormal dreams) was 
similar or favourable compared with other ART. The 
reporting rate for insomnia was statistically higher for 
blinded DTG+ABC/3TC compared to EFV/TDF/FTC in 
ING114467; however, this was not duplicated in any other 
Phase IIb/III study conducted with DTG.  
 
 
Subjects 
who 
in 
the 
investigator’s 
judgment, poses a significant suicidality 
risk, will be excluded from participating 
in the study. Because of the elevated risk 
in the HIV- infected population, treatment 
emergent assessment of suicidality will be 
monitored during this study. Investigators 
are advised to consider mental health 
consultation or referral for subjects who 
experience signs of suicidal ideation or 
behaviour.  
 
 
 

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5 DESIGN, OBJECTIVES AND ENDPOINTS 
5.1 Study Design 
Open label randomized trial of DTG in late pregnancy. HIV+ pregnant women (untreated at ≥28-
36 weeks gestation will be randomized 1:1 to receive a DTG-based regimen compared with 
standard of care (regimen not containing INSTI).  
5.2 Primary Objectives 
1) To investigate the steady-state pharmacokinetics of DTG in HIV infected women during 
the third trimester of pregnancy and after two weeks post-partum 
 
5.3 Secondary Objectives 
1) To evaluate safety and tolerability of DTG in pregnant women 
2) To determine the proportions of bound and unbound drug 
3) To explore changes in PK between the third trimester of pregnancy and post-partum 
4) To evaluate placental transfer of drug, using cord blood samples 
5) To evaluate drug exposure in breast milk with mother at steady-state (2 weeks 
postpartum) 
6) Evaluation of neonatal drug exposure at maternal steady state 
7) Evaluation of time for infant levels to become undetectable 
 
Whilst the study has been powered to conclusively address the PK objectives listed 
above, the following data will also be collected to allow a complete description of the 
cohort. 
8) Proportion of mother to child transmission in each arm at six months postpartum 
9) Pharmacogenomic factors influencing transplacental and breast milk transfer of drug 
 
5.4 Primary Endpoint 
AUC0-24of DTG in pregnant women in third trimester and 2 weeks postpartum 
 
5.5 Secondary Endpoints 
 Safety and tolerability of DTG 
 Proportion of women in each arm with VL< 50 copies/mL, and <400 copies/mL at 
delivery (tolerance +14 days) 
 Change in viral load over the first 4 weeks of therapy 
 PK of the unbound fraction of drug 
 Cord:maternal plasma DTG ratio 
 Maternal plasma: breast milk DTG ratio at steady state, and at 1, 2 and 3 days after 
discontinuation of DTG (and transfer onto standard of care ARVs) 
 Infant DTG levels at maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days 
after maternal discontinuation of DTG 
 Incidence and severity of adverse events and laboratory abnormalities 
 Absolute values and changes over time in laboratory parameters 
 Proportion of subjects who discontinue treatment due to adverse events 

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 Prevention of mother to child transmission (evaluated as six months postpartum) 
 Potential pharmacogenomic factors affecting DTG PK in pregnancy and transfer to infant 
via placenta or breast milk 
6 SUBJECT POPULATION 
6.1 Number of subjects 
Previous data on 50mg qd DTG dosing in North American HIV-infected non-pregnant adults 
yielded an AUC 43.4μg.h/mL at steady state in healthy volunteers (CV 20%)(Min, Sloan et al. 
2011).  No data exist regarding within patient variability, but this is unlikely to exceed inter-
individual variability. Assuming the variance holds true for HIV-positive pregnant African 
women, recruitment of 30 subjects would yield >95% power (paired design) to show a difference 
of +25% difference in mean AUC (the FDA upper boundary for bioequivalence) at α=0.05. 
However data for other antiretrovirals, such as the protease inhibitors, suggest that variance is 
greater in pregnant women.  Sensitivity analyses of power-sample size relationships across a 
range of variances (CV 20-50%) are shown below. 
 
 
 
 
 
 
We have judged that recruitment of 60 pregnant women (30 on DTG) would a) allow us to detect 
with  80% power a dolutegravir AUC difference of 12% (CV20%), 16% (CV 30%), 22% (CV 
40%), 27% (CV50%), so that even with doubling in CV, there is >80% power to detect change in 
AUC outside the FDA bounds for bioequivalence [0.8-1.25] and b) allow meaningful 
comparison in virological dynamics between DTG and standard of care. 
 
6.2 Inclusion criteria 
Participants must meet all of the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Evidence of a personally signed and dated informed consent document indicating that the 
participant (or a legal representative) has been informed of all pertinent aspects of the 
study. 
2. Participants who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
3. Women age 18 years or older 
4. Pregnant  
5. Untreated HIV infection in late pregnancy( ≥28 weeks and <36 weeks gestation) (NB 
first 8 patients (the first 4 on each arm) will be between 28 and 32 weeks gestation) 
0
0.2
0.4
0.6
0.8
1
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Percentage Difference in Population Means
CV 20%
CV 30%
CV 40%
CV 50%

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6.3 Exclusion criteria 
Participants presenting with any of the following will not be included in the study: 
1. Received any antiretroviral drugs in previous 6 months 
2. Ever received integrase inhibitors 
3. Serum hemoglobin <8.0 g/dl 
4.  eGFR<50 ml/min* 
5. Elevations in serum levels of alanine aminotransferase (ALT) >5 times the upper limit of 
normal (ULN) or ALT >3xULN and bilirubin >2xULN (with >35% direct bilirubin).  
6. Active hepatitis B infection (patients with chronic stable HBV infection evidenced by 
positive HBsAg without evident clinical consequences remain eligible)* 
7. History or clinical suspicion of unstable liver disease (as defined by the presence of 
ascites, encephalopathy, coagulopathy, hyperbilirubinaemia, oesophageal or gastric 
varices or persistent jaundice). 
8. Subjects with severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such 
as renal or liver abnormalities (e.g. grade 2 or above proteinuria, elevation in serum 
creatinine (>2.5 x ULN),total bilirubin,ALTor AST)* 
9. Paternal non-consent for infant participation (where disclosure has taken place – see 
below) 
10. Clinical depression or clinical judgment suggests increased risk of suicidality 
 
*Hb, eGFR, ALT, bilirubin and Hepatitis B serology will be undertaken at Screening, with the 
results made available at the earliest opportunity.  
 
6.3.1 Considerations of Paternal Consent (Ugandan Site Only with reference to UNCST 
guidance) 
Whilst the father is a key stakeholder in a pregnancy, and in an ideal world, would be involved in 
all decisions relating to the wellbeing of both mother and child, this is not a clear-cut issue. A 
woman diagnosed with HIV in late pregnancy is a vulnerable individual, whom we have a duty 
of care to protect. It may not be in her best interests to immediately disclose her positive HIV 
status to her male partner, as this may risk violence and potential abandonment. It is therefore not 
possible to establish clear inclusion and exclusion criteria relating to paternal consent, although if 
a male partner who is cognisant and supportive of the mother’s HIV treatment expresses that he 
does not wish for participation in the study to proceed due to the potential risks of exposure of 
his unborn child to DTG, this shall be viewed as an exclusion criterion. 
 
The mother shall be asked whether she gives consent for her partner to receive an abbreviated 
version of the PIL; this shall contain the fundamental details of the study, the contact details of 
members of the study team and space for a signature to confirm that the father has read and 
understood this information. No witness signature is required as this is not a legal process. 
 
6.4 Selection of Participants 
Patients will be identified and screened at the antenatal clinics associated with the study. 
Pharmacokinetic sampling and subsequent study visits will be conducted at IDI or DTHF. 
 
 

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6.5 Withdrawal of subjects 
A subject is free to withdraw from the study at any time.  In addition, the Investigator may 
decide, for reasons of medical prudence, to withdraw a subject.  Safety bloods and HIV viral 
load results will be communicated to the clinicians responsible for routine care of the patients, 
and they can choose to withdraw a patient from the study at any time. If a subject discontinues 
study medication dosing, every attempt should be made to keep the subject in the study and 
continue to perform the required study-related procedures and follow-up procedures.  If this is 
not possible or acceptable to the subject or Investigator, the subject may be withdrawn from the 
study. 
Study medication may be discontinued in the following instances: 
 If the subject withdraws her consent. 
 If the Investigator considers in the interest of the subject (i.e. intercurrent illness, 
unacceptable toxicity) that it is best for her to withdraw her consent. 
 The subject’s clinician considers it in their best interests 
 The subject fails to comply with the protocol requirements or fails to cooperate with the 
Investigator. 
 The subject starts treatment with any disallowed medication without prior notification 
and consent of the Investigators. 
 The subject experiences a liver event (Section 10.3.1), hypersensitivity reaction (Section 
10.3.2) or severe skin rash (Section 10.3.3). 
 The HIV viral load has not declined sufficiently during the first four weeks of therapy 
(see detail in Sections 8.3 and 9.1) 
 
The date and reasons for the withdrawal will be clearly stated on the subject’s CRF. Non-
compliant subjects may be withdrawn and replaced at the discretion of the investigator. 
 
7 STUDY TREATMENTS 
7.1 Treatment Plans and Regimens 
1) Dolutegravir group (DTG+2 NRTIs) – to make best comparison with standard of care, 
these NRTIs should be those recommended by national policy. 
Patients randomized to the study drug will be commenced on an antiretroviral regimen 
comprising DTG 50mg once daily in combination with 2 NRTIs 
2) Standard of care (SoC) 
Patients randomized to receive standard of care will receive the currently used 
antiretroviral regimens in keeping with national policy. 
3) Backbone 2 NRTIs at treating physician’s discretion, according to National guidelines. 
Those with positive HBsAg will routinely be offered TDF and 3TC (this is in fact the 
standard of care NRTI backbone in both Uganda and South Africa) 
 
Additional Considerations for Hepatitis B (HBV) co-infected patients: Investigators should 
consult current treatment guidelines (e.g., IAS) when considering choice of NRTIs to combine 
with DTG for subjects with chronic HBV infection (HBsAg positive OR anti-HBc positive with 
HBV DNA present).  In addition, clinical trial and marketed use of 3TC, FTC and TDF have 
shown that some subjects with chronic HBV disease may experience clinical or laboratory 

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evidence of recurrent hepatitis upon discontinuation of 3TC, FTC or TDF, which may have more 
severe consequences in subjects with decompensated liver disease.  If 3TC, FTC or TDF is 
discontinued in subjects co-infected with HBV, periodic monitoring of both liver chemistry tests 
and markers of HBV replication should be considered. 
 
7.2 Dolutegravir 
In August 2013, the FDA approved DTG for HIV-1 treatment in adults and children over 12 
years of age and weighing > 40kg. Appendix A contains detailed safety data for Tivicay (ViiV 
2013).  Dolutegravir is available as 50mg tablets which do not require any special storage 
conditions. The absolute bioavailability has not been established. Peak concentrations of DTG 
are achieved 2.5 – 4.5 hours post dose, with no significant effect of diet (Song, Borland et al. 
2012), and the terminal half-life of 15 hours supports once daily dosing without the need for a 
boosting agent (Castellino, Moss et al. 2013) 
 
The safety assessment of DTG in HIV-1 infected treatment naïve subjects is based on the 
analyses of 48 week data from two ongoing, international, multicentre double blind trials, 
SPRING-2 (ING113086) (van Lunzen, Maggiolo et al. 2012; Raffi, Rachlis et al. 2013) and 
SINGLE (ING114467) (Walmsley, Antela et al. 2012) in which a total of 1655 patients received 
DTG, in combination with 2 NRTIs. The nature and frequency of adverse events are summarized 
in Table 2. 
 
In SPRING-2, involving 822 patients across 100 sites in North America, Europe and Australia, 
dolutegravir (coformulated with tenofovir/emtricitabine or abacavir/lamivudine) compared 
favourably with raltegravir both in terms of virological non-inferiority and with a comparable 
adverse event profile. The most commonly reported adverse effects were minor gastrointestinal 
disturbance (nausea or diarrhea), headache and nasopharyngitis. In both raltegravir and 
dolutegravir study arms, 2% of patients suffered adverse events necessitating a change in 
regimen. Three patients receiving DTG suffered a serious adverse event, namely aphasia, 
diarrhoea and hepatitis, each occurring in a single subject; no deaths related to the study drug 
(Raffi, Rachlis et al. 2013).Table 2: Treatment-emergent adverse drug reactions of at least 
moderate intensity (Grades 2 to 4) and ≥2% frequency in treatment-naïve subjects in SPRING-2 
and SINGLE trials (week 48 analysis). 
 
7.3 Prior and Concomitant Medication 
Patients should continue to take their prescribed medication, unless it is specifically 
contraindicated to take this medication with dolutegravir as indicated in the prescribing 
information for DTG. Both prior and concomitant medication prescribed during the course of the 
study will be recorded on the CRF. 
 
Patients who are concurrently prescribed medication containing divalent cations, such as ferrous 
sulphate or antacids, will be given specific advice to ingest dolutegravir either two hours before 
or six hours after these medications. 
 
 

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Table 3 
 
7.4 Infant Nevirapine 
Under routine PMTCT care, infants will be administered nevirapine syrup (with or without 
zidovudine/3TC) for the first four to twelve weeks of life (depending on risk stratification). 
These infants will potentially be exposed to a small dose of DTG via breastfeeding (data 
regarding the breast milk elimination of DTG are not available, hence this is an important 
secondary endpoint of DolPHIN). As DTG is a substrate of UGT1A1 with some contribution 
from CYP3A, NVP has the potential to decrease the levels of DTG, but this is unlikely to be of 
clinical significance as the infant DTG is not intended to be of therapeutic benefit.  
8 STUDY SCHEDULES AND PROCEDURES 
The schedule of assessments for each subject enrolled in the study is presented in the study 
flowchart and detailed in the text below. The shaded section illustrates how proposed study visits 
relate to the scheduled antenatal and postnatal care of the mother and infant; the study design has 
taken into consideration the logistical challenges of mothers attending clinic appointments in the 
early neonatal period and has sought to overlap with the scheduled visits occurring under 
standard of care. 

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8.1 Study Schedule 
Study Procedure 
Screening 
Randomisat
ion 
Study Period (Weeks post DTG start) 
Time 
0 (~28 
weeks 
gestation) 
1-7 days 
post 
screening 
1 
2 
4 
8 
 
+2 wks post 
partum  
1 day post 
change to 
SoC 
2 days 
post 
change 
to SoC 
3 days 
post 
change 
to SoC 
End of 
Study* 
Routine Obstetric Care 
 
ANC V2  
(24-28 
weeks) 
 
ANC V3 
(32-36 weeks) 
ANC V4  
(> 36 weeks) 
Postnatal 
visit 1 (~1 
week post) 
 
 
 
Postnatal 
visit 2 (~6 
months post) 
Recruitment 
X 
 
 
 
 
 
Estimated date of delivery 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Clinical assessment1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety questionnaire - mother 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety questionnaire - infant 
 
 
 
 
 
 
X 
X 
X 
X 
Safety bloods2 
X 
 
X 
X 
X 
X 
X 
 
 
 
HIV viral load 
X 
X5 
 
X 
X 
X 
X 
 
 
 
CD4 count 
X 
 
 
 
 
 
X 
 
 
 
Blood for maternal genomics 
 
 
 
X 
 
 
 
 
 
 
Randomisation 1:1 DTG vs SoC 
 
X 
 
 
 
 
 
 
 
 
Randomisation 1:1 to return on 
Day 1-3 after switch to SoC 
 
 
 
 
 
 
X 
 
 
 
Dispense SoC ART  
X 
 
 
 
 
 
 
 
 
 
Dispense Study Treatment3 
 
X 
X 
X 
X 
X 
X 
 
 
 
Blood PK (DTG arm)4 
 
 
 
X 
 
 
X 
X 
X 
X 
Cord& Maternal DTG level 
 
 
 
 
 
 
X 
 
 
 
 
BM DTG level 
 
 
 
 
 
 
X 
X 
X 
X 
Infant DTG level 
 
 
 
 
 
 
X 
X 
X 
X 
Edinburgh Postnatal Depression 
Scale 
 
 
 
 
 
 
 
X 
 
 
 
X 
ANC =Antenatal Clinic *If additional visit required for follow-up beyond 2 weeks postpartum 
1 
Clinical assessment – clinical questionnaire, blood pressure, heart rate, respiratory rate, urinalysis 
2 
Safety bloods: FBC, U&E, LFT, eGFR, ALT   
3 
SoC will be dispensed at screen to comply with local guidelines. If the participant is assigned at randomisation to the DTG arm, she will be switched to that regimen at day 1. 
4 
Patients in EFV arm will not undergo rich PK sampling, but have a single blood sample taken for ‘safety bloods’ and HIV viral load. 
5 
For women who are switching from efavirenz to DTG after randomisation.

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8.2 Screening 
Screening will take place in the antenatal clinics at the study sites. Any newly diagnosed patient 
will be counselled regarding their HIV diagnosis and the need to commence anti-retroviral 
therapy for life, both to reduce the risk of viral transmission to the infant, and for the health of 
the mother. Counselling will be undertaken by trained nurses and counsellors working in the 
ART clinic. Whilst it is emphasized that the woman should commence ART as soon as possible 
in order to increase the likelihood of an undetectable viral load by the time of delivery, it is also 
important to ensure the mother is engaged with treatment, understands the diagnosis, the need for 
treatment, the importance of robust adherence to therapy and the need to attend for follow-up 
visits at the appointed time. It is possible that this step cannot be completed in a single clinic visit 
on a single day, and therefore provision should be made for the patient to have a follow-up 
appointment within a few days. 
 
Each potentially eligible subject must sign an Informed Consent Form prior to the conduct of any 
screening procedures.  Subjects will be given the opportunity to ask any questions regarding the 
trial at this stage.  Screening evaluations will be used to determine the eligibility of each 
candidate for study enrolment.  Each subject being screened for study enrolment evaluation will 
be assigned a unique screening subject number.  Only one unique identifier will be allocated to a 
subject. 
The screening visit will evaluate: 
 Demographic details including age, gender, ethnicity 
 Full medical, drug (including contraceptives, herbal and recreational drugs) and social 
history 
 Weight, height and vital signs (temperature, blood pressure, heart rate, and respiratory 
rate) 
 Full blood count with a differential white cell count 
 Chemistry panel including eGFR (calculated from Cockroft-Gault formula) 
 Liver function tests 
 HIV-1 and 2 antibodies 
 CD4 count 
 HIV viral load 
 Hepatitis B surface antigen 
 Urinalysis 
 Results of these ‘screening bloods’ will become available within a week from screening, 
with appropriate clinical care provided, regardless of continued participation. 
 
Standard of care ART will be dispensed at screening, as policy requires women to start 
ART the same day they attend antenatal care and are diagnosed HIV-positive. 
 
8.3 Randomisation 
Once inclusion and exclusion criteria are complete, eligible subjects will be randomised into the 
2 arms on a 1:1 ratio using the randomisation schedule.  Because of the intensified safety 
monitoring of the first 16 patients enrolled in the study (as detailed under the specific visits 
below), a permuted block randomization will be undertaken to avoid asymmetrical allocation: 

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block 1 (N=8); block 2 (N=8); block 3 (N=44). Subjects will be assigned to study treatment in 
accordance with the computer generated randomization schedule.  The randomization schedule 
will be generated using permuted block randomisation by Randomizer for Clinical Trials 
(Institute for Medical Informatics, Statistics and Documentation, Medical University of 
Graz).Randomisation can occur on the Day 1 visit or prior to that. The participant does not need 
to be present. 
 
Following enrolment, subsequent study visits will take place at the research site, but there will be 
close liaison with the antenatal care clinics regarding the clinical care of the participants.  
 
8.3.1 Drug dispensing visit, Day 1 
Once the study team is satisfied that the patient understands her diagnosis, the need for 
treatment, and the importance of adherence, she will be provided with a 2 week supply of 
DTG+2NRTI or SoC and given both verbal and written instructions regarding their 
administration. Those randomised to the DTG arm will switch from SoC to DTG and 2 
NRTIs. Those randomised to SoC will remain on that regimen. A further blood sample for 
HIV viral load will be taken from those subjects switching to DTG. She will be given a contact 
number whereby she can raise any questions with a member of the study team at any time. In the 
event of no further problems, a follow-up appointment shall be made for the following week. 
 
8.3.2 Visit 2, Day 7 (tolerance +/- 1 day) 
For participants in  both study arms, clinical assessment will be undertaken, involving questions 
regarding the occurrence of any adverse events or difficulties in taking the medication, a physical 
examination, and performance of the panel of ‘safety’ bloods. If uneventful, a follow-up 
appointment shall be made for the following week. 
 
8.3.3 Visit 3, Day 14 (tolerance +/- 2 days) 
Patients randomized to the DTG arm will be asked to attend the research facility at 7.30 am, 
having not yet taken her morning dose of ART. Following a clinical assessment (including safety 
questionnaire), as detailed under Visit 2, Day 7, an intravenous cannula will be inserted into 
either antecubital fossa, and a trough blood sample taken at Time 0. Drug will then be 
administered with a standard breakfast and blood samples taken after 0.5, 1, 2, 3, 4, 6 and 8 
hours (5ml on each occasion, making a total of 40ml). Blood for measurement of HIV viral load 
will also be taken*. The cannula will then be removed. The patient will be asked to attend at 
08:00 the following day for a 24 hour blood sample (tolerance +/- 3 hours). Following this, the 
patient will be provided with a further 2 weeks medication, in addition to a reminder of how to 
contact the study team in the event of a query 
 
Patients randomized to the SoC arm will have a clinical assessment identical to the DTG arm and 
blood taken for HIV viral load (these samples will be batched rather than analysed in real-time). 
 
*HIV viral load will be processed with results within 7 days for the first eight patients in the 
DTG arm with the appropriate action on the result being detailed in Section 9.1 
 
 

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8.3.4 Visit 4, Day 28 (tolerance +/- 7 days) 
For participants in both study arms, clinical assessment will be undertaken, involving questions 
regarding the occurrence of any adverse events or difficulties in taking the medication, a physical 
examination, and performance of the panel of ‘safety’ bloods. Blood for HIV viral load will be 
taken. If uneventful, a follow-up appointment shall be made for the four weeks’ time. She shall 
be reminded of plans for labour and delivery, and provided with written information to take with 
her to the labour ward containing details of the study and how to contact the study team, in 
addition to the information she has already received. 
 
8.3.5 Optional Visit, Day 56 (tolerance +/- 10 days) 
For participants in both study arms who are recruited at less than 32 weeks gestation, an 
additional study visit will  be offered approximately 8 weeks after commencing ART. Clinical 
assessment will be undertaken, involving questions regarding the occurrence of any adverse 
events or difficulties in taking the medication, a physical examination, and performance of the 
panel of ‘safety’ bloods. Blood for HIV viral load will be taken. She shall be reminded of plans 
for labour and delivery.  
8.3.6 Visit 5, Delivery 
Following delivery, a sample of cord blood will be taken to measure DTG levels and a 
corresponding sample of blood will be obtained from a mother. If the birth has been 
uncomplicated, the patient will be given an appointment to attend the research facility in a 
further two weeks. In the South African centre, where possible, participation will be documented 
in the infant ‘road to health’ booklet. 
8.3.7 Visit 6, 2 weeks post-delivery (tolerance - 7 days) 
This study visit will coincide with the 1 week post-delivery assessment which will occur under 
SoC. This visit will focus on safety endpoints, including maternal bloods and a neonatal review 
of the infant by the Study Paediatrician. Both maternal and infant safety questionnaires 
(Appendix 3) will be administered in addition to the Edinburgh Postnatal Depression Scale 
(Appendix 5). Patients receiving SoC will be asked to provide a blood sample for HIV viral load. 
In the South African centre, if not already done postpartum, participation in the study will be 
documented in the infant ‘Road to Health’ booklet. 
 
Patients randomized to the DTG arm will be asked to attend the research facility at 7.30 am, 
having not yet taken her morning dose of ART. Following a clinical assessment, as undertaken 
on previous study visits, an intravenous cannula will be inserted into either antecubital fossa, and 
a trough blood sample taken at Time 0. Drug will then be administered with a standard breakfast 
and blood samples taken after 0.5, 1, 2, 3, 4, 6 and 8 hours (5ml on each occasion, making a total 
of 40ml). Blood for CD4 count and HIV viral load will also be taken. The cannula will then be 
removed. Blood (0.5mL) will also be sampled from the baby on two occasions to evaluate 
neonatal DTG exposure (one timed relative to a feed at anticipated maternal tmax, and one at a 
random time point relative to maternal dosing). The mother will be asked to provide two samples 
(3-5 ml) of manually expressed breast milk to measure the elimination of DTG in breast milk. 
The subject will be asked to attend at 08:00 the following day for a 24 hour blood sample 
(tolerance +/- 3 hours). 

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Following this visit, the mother will be counselled with regard to Standard of Care (SoC) 
antiretroviral therapy and follow-up schedules. DTG will be discontinued and she will be 
commenced onto the recommended NNRTI-based first-line regimen.  
 
Participants will then be randomized 1:1:1 to attend the following day, two days or three days 
later for a further single blood sample to measure DTG levels in maternal blood, breast milk and 
infant plasma. 
 
Patients randomized to the SoC arm will have a clinical assessment identical to the DTG arm and 
blood taken for HIV viral load (these samples will be batched rather than analysed in real-time). 
 
8.3.8 Visit 7, 1, 2 or 3 days following switch to Standard of Care (SoC) 
This visit refers only to participants who received DTG. Mothers will be assessed to ensure there 
have been no unexpected difficulties with regard to commencing SoC ART. A single blood 
sample from the mother and heel-prick blood (0.5 mL) from the infant will be taken for DTG 
levels. A sample of BM will also be collected for DTG measurement. 
 
8.3.9 Visit 8, month 6 post-delivery (tolerance +/- 1 month) 
We will incorporate an additional postnatal visit for both mother and infant, at 6 months 
following delivery. At this time point, a detailed neonatology evaluation will be conducted by the 
study paediatrician. 
 
If following full clinical assessment, there are no outstanding issues relating to the study, the End 
of Study forms will be completed and the patient transferred to Standard of Care HIV 
management, including first line national policy ART and follow-up within the ART clinic. 
 
8.4 Clinical Assessment/Early Termination Visit 
For early study termination, the mother (and infant) will be invited for review 10 weeks after 
finishing study medication or early termination.  The following evaluations will be performed: 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
 Haematology with a differential white blood cell count 
 Chemistry panel 
 Review of Adverse Events 
 Concomitant medications review 
 
The reason for the early termination of the subject should be clearly documented on the subject’s 
CRF.  The subject will not then be required to attend for a follow up visit unless deemed 
necessary in the opinion of the investigator (e.g. due to adverse event or to determine pregnancy 
outcome status if still pregnant at the time of early termination). 
 
Following completion of DTG, the patient should be transferred on to the routinely administered 
ART combination which comprises standard of care and followed-up by the antiretroviral clinic 
in accordance with National Guidelines. In many cases, this will be to an EFV-based regimen; 

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using cross-study comparisons to historical data, DTG does not appear to affect the 
pharmacokinetics of this agent and therefore a wash-out period is not necessary. EFV has the 
potential to reduce DTG levels, and therefore a clinically significant interaction is unlikely. 
 
9 SAFETY MONITORING 
Safety assessments will be conducted to characterize the safety and tolerability of DTG 
administered during pregnancy, including monitoring and recording all AEs and SAEs,  regular 
monitoring of haematology and blood chemistry, physical exams and monitoring and recording 
birth and maternal outcomes. 
 
9.1 Intensive Virological Monitoring of First 8 Patients receiving DTG 
To ensure that use of DTG-based ART in pregnancy does not risk therapeutic failure due to 
lower than anticipated exposure in pregnancy, three additional safeguards will be put in place for 
the first group of women enrolled in the study:  
1) The first eight patients to be randomized (the first four on DTG) will be at 28-32 weeks 
gestation, allowing sufficient time for a switch to standard of care before delivery if 
required. Viral loads will be undertaken in real time (turnaround time 7 days; baseline 
samples may be batched with week 2 sample). The IDSMB will review virological data 
from these 4 mothers on DTG. The following criteria for virological response will be 
utilized: 
 
At 2 weeks 
HIV viral load 
Action 
<1 log10 reduction or remains ≥10 000 copies/ 
ml 
Assess 
adherence 
or 
factors 
affecting 
absorption 
Further viral load in real-time at Day 28 visit 
>1 log10 reduction and <10 000 copies/ml 
No need for further real-time VL monitoring 
 
At 4 weeks 
HIV viral load 
Action 
<1 log10 or evidence of blunting of virological 
response between weeks 2 and 4 
Immediate switch to the Standard of Care 
EFV-based regimen 
>1 log10 reduction, but ≥ 10 000 copies/ml 
Continue DTG, but perform HIV VL two-
weekly until <1000 copies/ml 
>1 log10 reduction and <10 000 copies/ml 
No need for further real-time VL monitoring 
 
Patients and their clinicians may choose to withdraw participation at any point, and the clinical 
judgement around what constitutes an adequate virological response will also involve the 
treating medical team. 
 
2) The next eight mothers to be randomized will have the same virological scrutiny (for the 4 
women assigned to DTG) but may include women presenting up to 36 weeks gestation, as 
per the eligibility criteria of the study. These data will also be scrutinized by the IDSMB. 
 

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3) Recruitment will be suspended pending IDSMB review, and the IDSMB may choose at any 
point to request suspension of recruitment if it considers safety a major concern. 
 
4)  PK samples collected two weeks after start of therapy on these 8 women receiving DTG will 
be analysed for the interim IDSMB review to ensure that the AUC is not reduced to a level 
which might risk therapeutic failure.  
 
9.2 Maternal Assessments 
Laboratory baseline screening is outlined in Section 8 and includes: 
Full blood count (including automated WBC differential, platelets, haemoglobin, haematocrit), 
Urea, sodium, potassium, creatinine, creatinine phosphokinase, bilirubin, glucose. Glomerular 
Filtration Rate (GFR) will be estimated. Blood will be stored for maternal plasma HIV viral load 
and resistance assays. Urinalysis (dipstick). 
 
Clinical screening is also outlined in Section 8. 
 
The Edinburgh Postnatal Depression Scale (Appendix 5) will be administered at the early 
postnatal visit, with prompt liaison with psychiatric services should a risk of suicidality be 
identified. At IDI, Kampala, there is a regular mental health clinic within the HIV Prevention, 
Care and Treatment centre.   At DTHF the participant would be assessed by the DTHF unit 
psychologist and referred to the psychiatric services at the Gugulethu site. These services include 
a psychiatric sister and a mental health clinic managed by a psychiatric registrar.  See also 
Section 10.3.4. 
  
9.3 Infant Assessment 
Laboratory assessment(s) of the newborn is not mandated by this protocol, however, if a 
laboratory assessment is performed per local SoC and available please collect the following 
assessment information if available: Full blood count (including automated WBC differential, 
platelets, haemoglobin, haematocrit), urea, sodium, potassium, creatinine, creatinine 
phosphokinase, bilirubin, glucose within the first two weeks of birth. In addition, if possible, the 
infant outcomes will also be captured and the following parameters will be captured on the 
neonate at the time of delivery:  
Mode of delivery, length of rupture of membranes, use of foetal scalp monitors, and any 
complications, since can alter transmission risk.  
 Gestational age 
 Neonatal length and weight 
 Neonatal head circumference 
 Absence or presence of congenital malformations, with description of malformations 
where present 
 APGAR scores 
 IUGR 
 
Extended follow-up of infants. Between 3-6 months of age a paediatric assessment of infants 
will be offered to all participants. This is not mandated by the protocol. Assessments will be 

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performed as per local guidelines with including a history and physical examination. Infant 
laboratory assessments performed at baseline will be repeated. 
 
10 MANAGEMENT OF ADVERSE EVENTS 
10.1 Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with the study 
treatments.  An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
 
AEs observed by the Investigator, or reported by the subject, and any remedial action taken, will 
be recorded in the subject’s CRF and should be verifiable in the subject’s notes throughout the 
study.  The nature of each event, time of onset after drug administration, duration and severity 
will be documented together with the Investigator’s opinion of the causal relationship to the 
treatment. 
Procedures such as surgery should not be reported as AEs.  However, the medical condition for 
which the procedure was performed should be reported if it meets the definition of an AE.  For 
example, an acute appendicitis that begins during the AE reporting period should be reported as 
the adverse event and the resulting appendectomy noted on the CRF.  Planned procedures such 
as surgery planned prior to the subject’s enrolment into the study need not be reported as AEs if 
these are documented as planned at the screening visit. 
Clinically significant changes in physical examination and blood safety profiles should also be 
recorded as AEs. 
 
Severity should be recorded and graded according to the Division of Aids Table for Grading 
the Severity of Adult and Paediatric Adverse Events (2004)(Appendix 2). 
 
Note: There is a distinction between the gravity and the intensity of an AE.  Severe is a measure 
of intensity; thus, a severe reaction is not necessarily a serious AE.  For example, a headache 
may be severe in intensity but would not be classified as serious unless it met one of the criteria 
for serious events. 
 
The relationship to the study drugs of each AE will be assessed using the Liverpool Causality 
Tool (Appendix 3) with the following definitions: 
DEFINITE: 
distinct temporal relationship with drug treatment.  Known reaction to agent or 
chemical group, or predicted by known pharmacology.  Event cannot be explained by subject’s 
clinical state or other factors. 
PROBABLE: reasonable temporal relationship with drug treatment.  Likely to be known 
reaction to agent or chemical group, or predicted by known pharmacology.  Event cannot easily 
be explained by subject’s clinical state or other factors. 
POSSIBLE: 
reasonable temporal relationship with drug treatment.  Event could be explained 
by subject’s clinical state or other factors. 

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UNLIKELY: poor temporal relationship with drug treatment.  Event easily explained by 
subject’s clinical state or other factors. 
UNRELATED: 
the event occurs prior to dosing.  Event or intercurrent illness is due 
wholly to factors other than drug treatment. 
 
All AEs, however minor, will be documented in the CRF whether or not the Investigator 
concludes the event to be related to drug treatment. 
The AE reporting period will be from the screening visit until the subjects final study visit.  In 
addition, any untoward event that may occur within 30 days of discontinuation of investigational 
product that the Investigator assesses as possibly, probably or definitely related to the study drug 
medication should also be reported as an AE. 
 
AEs may be directly observed, reported spontaneously by the subject or by questioning the 
subject at each study visit. 
 
All AEs should be followed up until they are resolved or the subject’s participation in the study 
ends (i.e. until the final CRF is completed for that subject).  In addition, all serious and non-
serious AEs assessed by the Investigator as possibly related to the investigational medication 
should continue to be followed even after the subject’s participation in the study is over.  Such 
events should be followed until resolution, or until no further change can reasonably be expected.  
Deaths occurring more than 30 days after the final dose, which are considered to be unrelated to 
the study medication, should not be reported as a Serious Adverse Event. 
 
 
10.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
i) 
Results in death 
ii) 
Is life threatening 
iii) 
Requires in patient hospitalisation or prolongation of existing hospitalisation 
iv) 
Results in persistent or significant disability/ incapacity, or 
v) 
Is a congenital anomaly/ birth defect. 
vi) 
All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT 3xULN and bilirubin 2xULN (>35% direct) in patients treated with 
DTG. 
 
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and 
suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin 
2xULN, then the event is still reported as an SAE.  If PT is obtained, include values on the SAE 
form. PT elevations >1.5 x ULN suggest severe liver injury. 
 
Liver events: Liver event CRFs and liver imaging and/or liver biopsy CRFs (see Section 10.3.1) 
should be completed and reported to the Principal Investigator within one week of event onset. 
 
Suicidal Ideation or Behaviours: If any subject experiences a possible suicidality-related 
adverse event (PSRAE) while participating in this study that is considered by the Investigator to 

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meet International Conference on Harmonization (ICH)-E2A definitions for seriousness, the 
Investigator will collect information using a PSRAE CRF form in addition to reporting the event 
on a SAE CRF form. A PSRAE may include, but is not limited to, an event that involves suicidal 
ideation, a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in deciding 
whether an event is possibly suicide-related.  PSRAE forms should be completed and reported to 
the Principal Investigator within one week of the investigator diagnosing a possible suicidality-
related serious adverse event. 
 
10.3 Specific Toxicities/Adverse Event Management 
General guidelines for the management of specific toxicities that are considered to be related or 
possibly related to DTG are provided below. 
 
Subjects who permanently discontinue DTG for reasons of toxicity should be followed weekly 
until resolution of the AE and encouraged to complete the withdrawal and FU study evaluations 
as noted above. 
10.3.1 Liver chemistry stopping and follow up criteria 
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event aetiology during administration of IP and the follow-up period. IP will be 
stopped if any of the following liver chemistry criteria are met 
 
ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin; bilirubin fractionation 
required) 
 
NOTE: serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable 
and a subject meets the criterion of total bilirubin ≥ 2xULN, then the event meets liver 
stopping criteria; 
 
ALT ≥8xULN; 
 
ALT ≥3xULN (if baseline ALT is < ULN) with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia, OR; 
 
ALT ≥3x baseline ALT with symptoms or worsening of acute hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia; 
 
ALT ≥5xULN and <8xULN that persists > 2 weeks (with bilirubin <2xULN and no signs or 
symptoms of acute hepatitis or hypersensitivity); 
 
ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks; 
Subjects who develop ALT ≥5xULN should be followed weekly until resolution or stabilization 
(ALT <5xULN on 2 consecutive evaluations). 

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When liver chemistry stopping criterion is met, do the following: 
 
Immediately discontinue DTG and withdraw the subject from the study.  Subjects 
should not restart DTG due to the risk of a recurrent reaction. 
 
Evaluate for HELLP (Hypertension Elevated Liver enzymes Low Platelets) Syndrome and 
pregnancy-related steatosis in subjects with ongoing pregnancy. 
 
Notify the Principal Investigator of the event within 24 hours of learning its occurrence; 
 
Events of possible drug-induced liver injury with hyperbilirubinemia defined as ALT 
3xULN and bilirubin 2xULN (>35% direct) will be reported to the Principal Investigator 
as SAEs using the SAE CRF (see Section 10.2). 
 
Complete the liver event CRF for all events meeting liver stopping criteria, and report to the 
Principal Investigator within one week of first becoming aware of the event (see Section 
10.2); 
 
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed, and report 
to the Principal Investigator (see Section 10.2); 
 
Perform liver event follow up assessments (described below), and monitor the subject until 
liver chemistries resolve, stabilize, or return to baseline values as described below; 
 
Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat 
liver chemistries, liver event follow up assessments (see below), and close monitoring; 
 
A specialist or hepatology consultation is recommended; 
 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 
Consider the following additional tests to further evaluate the liver event: 
 
Viral hepatitis serology including: 
 
Hepatitis A IgM antibody; 
 
HBsAg and Hepatitis B Core Antibody (IgM); 
 
Hepatitis C RNA; 
 
Hepatitis E IgM antibody; 
 
Cytomegalovirus IgM antibody; 
 
Epstein-Barr 
viral 
capsid 
antigen 
IgM 
antibody 
(or 
if 
unavailable, 
obtain 
heterophileantibody or monospot testing); 
 
Syphilis screening 
 
Drugs of abuse screen including alcohol 
 
Serum acetaminophen test (APAP adduct test) 
 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 

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 
Fractionate bilirubin, if total bilirubin is greater than 1.5xULN; 
 
Obtain complete blood count with differential to assess eosinophilia; 
 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies; 
 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease; 
 
Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, 
fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as 
relevant on the AE report form; 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report form. 
Record alcohol use on the liver event alcohol intake case report form. 
10.3.2 Allergic Reaction 
Subjects may continue DTG for Grade 1 or 2 allergic reactions at the discretion of the 
Investigator. The subject should be advised to contact the Investigator immediately if there is any 
worsening of symptoms or if further systemic signs or symptoms develop. Antihistamines, 
topical corticosteroids, or antipruritic agents may be prescribed. 
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or probably related 
to DTG should permanently discontinue the investigational product regimen and the subject 
should be withdrawn from the study. Subjects should be treated as clinically appropriate and 
followed until resolution of the AE. 
10.3.3 Rash 
Mild to moderate rash is an expected adverse reaction for DTG- containing ART.  Episodes 
generally occur within the first ten weeks of treatment, rarely require interruptions or 
discontinuations of therapy and tend to resolve within two to three weeks.  No instances of 
serious skin reaction, including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis 
(TEN) and erythema multiforme, have been reported for DTG in clinical trials. 
Subjects with an isolated Grade 1 rash may continue DTG at the Investigator’s discretion.  The 
subject should be advised to contact the Investigator immediately if there is any worsening of the 
rash, if any systemic signs or symptoms worsen, or if mucosal involvement develops. Any 
patient who presents with a rash should have their liver function tests checked. 
Subjects may continue DTG for an isolated Grade 2 rash. However, DTG (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) should be 
permanently discontinued for any Grade 2 rash that is associated with an increase in ALT. The 
subject should be advised to contact the physician immediately if rash fails to resolve (after more 
than two weeks), if there is any worsening of the rash, if any systemic signs or allergic symptoms 
develop, or if mucosal involvement develops. 

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Subjects should permanently discontinue DTG (and all other concurrent medication(s) suspected 
in the Investigators causality assessment) for an isolated Grade 3 or 4 rash, and the subject 
should be withdrawn from the study.  Subjects should be treated as clinically appropriate and 
followed until resolution of the AE. 
The rash and any associated symptoms should be reported as adverse events (see Section 10.1) 
and appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
grading). 
If the aetiology of the rash can be definitely diagnosed as being unrelated to DTG and due to a 
specific medical event or a concomitant non-study medication, routine management should be 
performed and documentation of the diagnosis provided. 
10.3.4 Suicidal Risk Monitoring 
Subjects with HIV infection may occasionally present with symptoms of depression and/or 
suicidality (suicidal ideation or behaviour). In addition, there have been some reports of 
depression, suicidal ideation and behaviour (particularly in patients with a pre-existing history of 
depression or psychiatric illness) in some patients being treated with integrase inhibitors, 
including DTG.  Therefore, it is appropriate to monitor subjects for suicidality before and during 
treatment.  
Subjects should be monitored appropriately and observed closely for suicidal ideation and 
behaviour or any other unusual changes in behaviour at all study visits. It is recommended that 
the investigator consider mental health consultation or referral for subjects who experience signs 
of suicidal ideation or behaviour. The Edinburgh Postnatal Depression Scale (Appendix 5) will 
also be administered at the early postnatal visit (see Section 9.2). 
If any subject experiences a possible suicidality-related adverse event (PSRAE) while 
participating in this study that is considered by the Investigator to meet International Conference 
on Harmonization (ICH)-E2A definitions for seriousness, the Investigator will collect 
information using a PSRAE CRF form (see Section 10.1). 
10.3.5 Decline in Renal Function 
Treatment with any fixed dose combination NRTI products containing 3TC, FTC or TDF must 
be discontinued in any Subject developing moderate to severe renal impairment during the study, 
as indicated by creatinine clearance measuring <50 mL/min via Cockroft-Gault. 
 
 
10.4 Safety Reporting 
10.4.1 Pregnancy Reporting 
Pregnancy complications (e.g., preeclampsia or eclampsia, prolonged hospitalization after 
delivery, for wound infections etc., seizures) and elective terminations for medical reasons must 

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be reported as an AE (Section 10.1) or SAE (Section 10.2).  Spontaneous abortions must be 
reported as an SAE (Section 10.2). 
 
Additionally, Investigators are requested to register each Maternal subject with the Antiretroviral 
Pregnancy Registry (APR) prospectively as soon as possible after the subject starts treatment as 
part of the study on Day 1, and before the pregnancy outcome (otherwise there is less likelihood 
of the subject being included in the APR). More information including copies of applicable 
CRFs and fax numbers are available at www.apregistry.com. 
 
10.5 Adverse Event Reporting 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
will be reported. For all AEs, the investigator must pursue and obtain information adequate both 
to determine the outcome of the AE and to assess whether it meets the criteria for classification 
as an SAE requiring immediate notification.   
 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs that 
meets the IRB, local and international regulations for reporting, expedited reporting will be done. 
All SAEs will be reported to the sponsor within 24 hours of knowing about the event. Further 
relevant follow-up information will be given as soon as possible. Follow-up will continue until 
the event resolves. 
 
All SAEs must be reported immediately.  The SAEs should be reported immediately to the 
Principal Investigator (within 24 hours of a member of the study team becoming aware of the 
event).  A SAE form should be completed, and an assessment of whether the SAE is a Suspected 
Unexpected Serious Adverse Reaction (SUSAR) conducted.  The Principal Investigator is 
responsible for determining whether the SAE is a Suspected Unexpected Serious Adverse 
Reaction (SUSAR) and for reporting this in accordance with Good Clinical Practice (GCP) and 
applicable regulatory requirements.  All SAE must be reported in accordance with local 
protocols for reporting adverse study events.  
 
All AEs will be reported on the AE page(s) of the CRF. For example, the same AE term should 
be used on both forms. AEs should be reported using concise medical terminology on the CRFs 
as well as on the form for collection of SAE information. 
 
10.6 Management of Post-recruitment Illness 
All subjects with post-recruitment illness will be monitored until symptoms resolve, laboratory 
changes return to baseline or until there is a satisfactory explanation for the changes observed. 
Patients will receive medical care including admission at the hospital associated with the study 
and patients will be managed in accordance with national treatment guidelines.  
 
11 DATA AND STATISTICAL ANALYSIS 
Primary PK endpoints will be estimated using non-compartmental methods (WinNonlin, 
Pharsight). For study drug concentrations, concentrations will be summarized descriptively (n, 
mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV and 

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confidence intervals) by day and nominal time. The CIs will be determined using logarithms of 
the individual geometric mean values; the calculated values will be then expressed as linear 
values. The changes in PK parameters will be considered significant when the CI do not cross 
the value 1. Individual subject and median profiles of the concentration-time data will be plotted 
by dose, cycle and day (single dose and steady-state) using nominal times.  Median profiles will 
be presented on both linear-linear and log-linear scales. The use of mathematical techniques (e.g. 
non-linear mixed effects) for modelling and simulation will also be explored, and data pooling 
(subject to quality assessment) with other studies is allowed.  
 
 
12 STUDY MANAGEMENT 
The day-to-day management of the DolPHIN study will be undertaken by the Study Team. A 
Trial Steering Committee (TSC) will oversee the conduct of the study, and will receive reports 
from the Study Team, and the IDSMB. The TSC will be able to stop or modify the study, acting 
on its own judgement or upon any recommendation from the IDSMB. 
 
The study site will be responsible for conducting the trial. The study site will collaborate with the 
affiliated antenatal clinics for this project for patient recruitment and follow up. Safety laboratory 
tests will be performed at laboratories which have achieved appropriate accreditation by the 
relevant professional body.  
 
12.1 Liverpool 
The Liverpool Bioanalytical Facility (BAF) is GCLP-accredited, and provides mass 
spectrometry based drug concentration measurement in plasma, CSF, breast milk, genital 
secretions, tissue and cells. We currently undertake work for large clinical trials consortia 
(funded by the UK MRC, Wellcome Trust, Gates Foundation, NIHR and other funders) as well 
as for the pharmaceutical industry. Data analyses are supported by model based (population PK) 
approaches established through Wellcome Trust Programme Grant funding. 
 
12.2 Sample Processing 
Following collection, study bloods will be processed and stored locally at IDI or UCT prior to 
shipment and analysis at the BAF laboratory. A Material Transfer Agreement between the 
Infectious Diseases institute or University of Cape Town and the University of Liverpool will be 
developed prior to commencement of the study. 
 
12.3 Clinical Monitoring 
At each study day visit including screening, the patient will be assessed by the research physician 
or nurse.  In addition, patients will be given details of how to reach a member of the study team 
in an emergency. 
 
12.4 Laboratory Monitoring 
Safety bloods (haemoglobin, white cell count, platelets, urea, creatinine, electrolytes, ALT) will 
be performed at every study visit. Additionally, should an adverse event be reported, further 
samples will be taken as soon as practically possible. The anti-retroviral efficacy of the novel 
combination compared with standard of care will be monitored by measurement of CD4 count 

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and HIV viral load at baseline, and delivery (tolerance +14 days). Severity of abnormalities will 
be defined according to the DAIDS criteria in Appendix 4. 
 
12.5 Data Safety and Monitoring Group 
An independent data safety and monitoring group (IDSMB) will be formed and will monitor 
study data according to the IDSMB charter. The IDSMB is scheduled to meet prior to the 
enrolment of the first patient, during the scheduled interim analysis (after the first 16 patients 
have delivered) and upon completion of the study. At each point the IDSMB will review 
laboratory and clinical data relating to mother and child. At the interim analysis, the IDSMB will 
discuss (in closed session) whether the study should be stopped, continued or modified, and will 
convey this recommendation to the Trial Steering Group. Further IDSMB meetings may be 
convened (at the discretion of the IDSMB chair, or upon request from the Trial Steering 
Committee) if unexpected data emerge, or following any modification of the study. Any Serious 
Adverse Events (SAEs) or Suspected Unexpected Serious Adverse Reaction (SUSARs) (see 
Section 11 of the protocol) will be reported to the IDSMB in a timely manner. 
 
12.6 Termination of the trial 
The Sponsor or Investigator may terminate either part of, or the entire study for safety or 
administrative reasons.  A written statement fully documenting the reasons for such a termination 
will be provided to the Ethics Committee and the Regulatory Authority as appropriate. 
 
13 DATA HANDLING 
13.1 Recording of Data 
The data collected during the study will be recorded in an individual, subject specific Case 
Report Form (CRF).  In order to maintain confidentiality, the subject will be identified only by 
subject number and initials on the CRF.  All CRFs should be completed legibly by an 
appropriate member of the study team who should be identified.  A CRF must be completed for 
each subject who signs a consent form and undergoes any screening procedures. 
 
Corrections to the data on the CRF will only be made by drawing a single line through the 
incorrect data (so as not to obscure the original entry) and inserting the correct data next to the 
original entry.  The incorrect data must never be obliterated using correction fluid.  Each 
correction will be initialled and dated by the person making the correction. 
 
 
13.2 Source Documentation and Study Records 
The subject’s number and date of entry into the study, along with a study identifier, should be 
recorded in the subject’s study records.  The following should also be recorded in the study 
records; confirmation of written consent, the subject’s clinical status, date of every study visit, 
date study medication was given, concomitant medications, copies of all relevant reports and 
laboratory tests, comments on results and reference to any adverse events. 
 
13.3 Data management 
Data will be entered into a study specific database by designated staff on a regular basis from 
completed CRFs, to ensure that it is up to date.  The database will be kept on a secure PC.  

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Access to the database will be given to authorised personnel only and a log of authorised 
personnel will be stored in the trial master file. 
 
Any data anomalies or values found to be outside normal ranges will be checked with the 
Investigator.  When corrections are required these will be made on CRF and the study database 
will be amended. 
 
Data sharing with other studies is allowed, on discretion of the study team, who will evaluate 
potential collaborations on a case by case basis, depending on the scientific merit, research 
governance, costs and data quality. The guiding principle will always be to maximize the wider 
benefits of this study wherever possible. 
 
13.4 Archiving and storage of data 
Following completion of the study, subject records, CRF and other study documentation will be 
retained by the Investigator in accordance with Good Clinical Practice and applicable regulatory 
requirements. 
 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 Monitoring Arrangements 
The purpose of monitoring is to verify the rights and well-being of human subjects are protected; 
that trial data is accurate, complete and verifiable with source data; that the trial is conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
 
The Sponsor will act as monitor of the study.  The Investigator must agree to allow the study 
monitor to inspect all CRF and corresponding source documents, e.g. original medical records, 
subject records and laboratory raw data, access to the clinical supplies, dispensing and storage 
areas and agree to assist with their activities if requested.  The Investigator should provide 
adequate time and space for monitoring visits. 
 
The monitor will query any missing or spurious data with the Investigator, which should be 
resolved in a timely manner.  A monitoring log will be maintained recording each visit, the 
reason for the visit, the monitor’s signature and Investigator’s or designee’s confirmation 
signature. 
 
 
14.2 Quality Assurance 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary 
for sponsor authorised Quality Assurance personnel and/or authorised personnel from an external 
regulatory agency to conduct an audit/inspection of an Investigational site.  The purpose of an 
audit is to assess the quality of data with regard to accuracy, adequacy and consistency, and to 
assure that studies are in accordance with GCP and Regulatory Agency guidelines.  Having the 
highest quality data from studies is an essential aspect of drug development. 
 
The Investigator will be given sufficient notice to prepare for such visits, which are planned to 
take usually between one and two days and may be conducted at any stage during the study.  The 

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audit will involve the review of all study related documentation, which is required by GCP to be 
maintained by each site, review of drug storage, dispensing and return, review of all study related 
supplies and review of source documents against the CRF to assure the adequacy and 
accuracy of the information which has been recorded, including the verification of any AE which 
have occurred. 
 
15 ETHICS & ADMINISTRATION 
15.1 Ethics Approval 
 
The study protocol, subject information and consent form, available safety information, subject 
recruitment procedures (e.g. advertisements), information about payments and compensation 
available to the subjects and documentation evidencing the Investigator’s qualifications will be 
submitted to the Ethics Committee for ethical review and approval according to local regulations, 
prior to the study start.  Any changes, which may need to be made, will be submitted in the form 
of numbered and dated protocol amendments in accordance with local regulations. 
 
15.2 Regulatory Approval 
As required by local regulations, approval of the appropriate regulatory bodies will be obtained, 
prior to study initiation. 
 
15.3 Publication Policy 
A whole or part of this study results will be communicated, orally presented, and/or published in 
appropriate scientific journals.  Full anonymity of subject’s details will be maintained 
throughout.  All communications will be available on our website www.hiv-druginteractions.org. 
 
15.4 Drug Accountability  
The investigator will ensure that the IP will only be used in accordance with the protocol.  Drug 
supplies will be kept in a secure, limited access storage area under the recommended storage 
conditions.  A drug accountability log will be kept with the investigational supplies for 
reconciliation purposes.  This should be used to record the identification of the subject to whom 
the IP was dispensed, the date and quantity of IP dispensed.  This will be verified by the study 
monitor. 
 
15.5 Financial Aspects 
This trial is being funded by ViiV.  The University of Liverpool will administer the funds, act as 
Sponsor for this study, and provide appropriate insurance in accordance with current 
arrangements for clinical trials conducted in sub-Saharan Africa. 
 
 
 
 

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16 REFERENCES 
Malawi Integrated Guidelines for Providing HIV Services (2011). Lilongwe, Ministry of Health, Malawi. 
Cohen, K. and G. Meintjes (2010). "Management of individuals requiring antiretroviral therapy and TB 
treatment." Curr Opin HIV AIDS5(1): 61-69. 
Dooley, K. E., P. Sayre, et al. (2013). "Safety, tolerability, and pharmacokinetics of the HIV integrase 
inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 
1 study among healthy subjects." J Acquir Immune Defic Syndr62(1): 21-27. 
Flys, T., D. V. Nissley, et al. (2005). "Sensitive drug-resistance assays reveal long-term persistence of 
HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants 
after the administration of single-dose NVP: HIVNET 012." J Infect Dis192(1): 24-29. 
Hamers, R. L., M. Siwale, et al. (2010). "HIV-1 drug resistance mutations are present in six percent of 
persons initiating antiretroviral therapy in Lusaka, Zambia." J Acquir Immune Defic Syndr55(1): 95-
101. 
Hedt, B. L., N. Wadonda-Kabondo, et al. (2008). "Early warning indicators for HIV drug resistance in 
Malawi." Antivir Ther13 Suppl 2: 69-75. 
Jacob, M. S., A. Durairaj, et al. (2011). "Detection of HIV drug resistance mutations in pregnant women 
receiving single dose Nevirapine in south India." Indian J Pathol Microbiol54(2): 359-361. 
Koole, O. and R. Colebunders (2011). "Reducing mortality from HIV infection and tuberculosis." Lancet 
Infect Dis11(7): 494-495. 
Lawn, S. D., L. Myer, et al. (2006). "Burden of tuberculosis in an antiretroviral treatment programme in 
sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control." 
AIDS20(12): 1605-1612. 
Manasa, J., D. Katzenstein, et al. (2012). "Primary drug resistance in South Africa: data from 10 years of 
surveys." AIDS Res Hum Retroviruses28(6): 558-565. 
Messiaen, P., A. M. Wensing, et al. (2013). "Clinical Use of HIV Integrase Inhibitors: A Systematic 
Review and Meta-Analysis." PLoS One8(1): e52562. 
Min, S., L. Sloan, et al. (2011). "Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of 
dolutegravir as 10-day monotherapy in HIV-1-infected adults." AIDS25(14): 1737-1745. 
Musiime, V., F. Ssali, et al. (2009). "Response to nonnucleoside reverse transcriptase inhibitor-based 
therapy in HIV-infected children with perinatal exposure to single-dose nevirapine." AIDS Res Hum 
Retroviruses25(10): 989-996. 
Niemi, M., J. T. Backman, et al. (2003). "Pharmacokinetic interactions with rifampicin : clinical 
relevance." Clin Pharmacokinet42(9): 819-850. 
Rockstroh, J. K., E. Dejesus, et al. (2013). "Durable Efficacy and Safety of Raltegravir versus Efavirenz 
When Combined With Tenofovir/Emtricitabine In Treatment-Naive HIV-1 Infected Patients: Final 
Five-Year Results From STARTMRK." J Acquir Immune Defic Syndr. 
Sax, P. E., E. DeJesus, et al. (2012). "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir 
versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: 
a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks." Lancet379(9835): 
2439-2448. 
Teasdale CA, Marais BJ, Abrams EJ. HIV: prevention of mother-to-child transmission. Clin Evid 
(Online). 2011 Jan 17;2011 
van Lunzen, J., F. Maggiolo, et al. (2012). "Once daily dolutegravir (S/GSK1349572) in combination 
therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a 
dose-ranging, randomised, phase 2b trial." Lancet Infect Dis12(2): 111-118. 
Wadonda-Kabondo, N., R. Banda, et al. (2012). "Prevalence of transmitted HIV drug resistance among 
newly diagnosed antiretroviral therapy-naive pregnant women in Lilongwe and Blantyre, Malawi." 
Clin Infect Dis54 Suppl 4: S324-327. 

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Wagner, T. A., C. M. Kress, et al. (2010). "Detection of HIV-1 drug resistance in women following 
administration of a single dose of nevirapine: comparison of plasma RNA to cellular DNA by 
consensus sequencing and by oligonucleotide ligation assay." J Clin Microbiol48(5): 1555-1561. 
Walmsley, S., A. Antela, et al. (2012). Dolutegravir (DTG; S/GSK 1349572) + Abacavir/Lamivudine 
once daily statistically superior to Tenofovir/Emtricitabine/Efavirenz: 48-week results - SINGLE 
(ING114467). ICAAC. Glasgow. 
WHO (2010). Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for 
a Public Health Approach. 2010 Revision. WHO. Geneva, World Health Organisation. 
WHO (2012). Programmatic Update: Use of Antiretroviral Drugs for Treating Pregnant Women and 
Preventing HIV Infection in Infants, World Health Organisation. 
WHO (2012). WHO HIV drug resistance report 2012. Geneva, WHO. 
Zeh, C., P. J. Weidle, et al. (2011). "HIV-1 drug resistance emergence among breastfeeding infants born 
to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention 
of mother-to-child transmission: a secondary analysis." PLoS Med8(3): e1000430. 
 
 
 

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17 PROTOCOL SIGNATURE PAGE 
I agree to conduct the trial in accordance with ICH-GCP and the applicable regulatory 
requirements and with the approved protocol. 
I agree to comply with the procedures for data recording/reporting 
I agree to permit monitoring, auditing and inspection and to retain the trial related essential 
documentation for the period of time required according to ICH-GCP. 
Name of Chief Investigator: Professor Saye Khoo 
 
Signature:         
 
 
 
Date:    5th July 2017 
 
 

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18 APPENDIX 1 SAFETY QUESTIONNAIRE 
a) Maternal Safety Questionnaire 
 
1) Since your last clinic visit have you had any new symptoms?  
Y/N 
 
2) If Y, which of the following:   
 
Nausea, vomiting, diarrhoea 
Fever, chills, sweating 
Skin rash, itch 
Chest pain, breathlessness, fast heart beat 
Headache, drowsiness, visual disturbance,  
Dizziness, poor sleep, low mood 
Eyes going yellow, dark urine 
Change in bowel habit 
Other (state): __________________________ 
3) Have you taken your medication as prescribed?  
 
 
Y/N 
4) If not, why not? 
 
 
 
______________________________________ 
5) Have you taken any new medication since your last visit?  
 
Y/N 
6) If Y, which?  
 
 
 
______________________________________ 
7) Have you any other new concerns about your health? 
_________________________ 
 
 
 
 

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b) Infant Safety Questionnaire 
 
1) Have you any concerns about your infant’s health?  
Y/N 
 
2) If Y, which of the following?  
Poor feeding 
Irritability, lethargy 
Difficulty breathing 
Skin rash 
Fever, chills 
Eyes going yellow, or dark urine 
Loose motions Diarrhea?  
Other (state): ____________________________ 
 
 
 
 

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19 APPENDIX 2  DAIDS GRADING SCALE 
Division of Aids Table for Grading the Severity of Adult and Paediatric Adverse Events (2004) 
Note: as the inclusion criteria for this trial is people ≥18 years old, the paediatric (<18years) AE’s were 
removed from the appendices. 
The Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events (“DAIDS AE grading table”) is a 
descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE 
term. 
General Instructions 
Estimating Severity Grade 
If the need arises to grade a clinical AE that is not identified in the DAIDS AE grading table, use the category “Estimating Severity 
Grade”. For AEs that are not listed in the table but will be collected systematically for a study/trial, protocol teams are highly 
encouraged to define study specific severity scales within the protocol or an appendix to the protocol. (Please see “Template 
Wording for the Expedited Adverse Event Reporting Section of DAIDS-sponsored Protocols”.) This is particularly important for 
laboratory values because the “Estimating Severity Grade” category only applies to clinical symptoms. 
Grading Adult and Paediatric AEs 
The DAIDS AE grading table includes parameters for grading both Adult and Paediatric AEs. When a single set of parameters is 
not appropriate for grading specific types of AEs for both Adult and Paediatric populations, separate sets of parameters for 
Adult and/or Paediatric populations (with specified respective age ranges) are given in the table. If there is no distinction in the 
table between Adult and Paediatric values for a type of AE, then the single set of parameters listed is to be used for grading the 
severity of both Adult and Paediatric events of that type. 
Determining Severity Grade 
If the severity of an AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), 
select the higher of the two grades for the AE. 
Definitions 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer/movement, continence, and 
feeding. 
 
Young Children 
Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
LLN 
Lower limit of normal 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment of an AE. 
NA 
Not Applicable 
Operative Intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual Social & Functional 
Activities 
Adult 
Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
 
 
 
 
 
 
Young Children 
Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
 
 

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CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified 
elsewhere in this DAIDS 
AE grading table 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
basic self-care functions 
OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
SYSTEMIC 
Acute systemic allergic 
reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with medical 
intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
NA 
Fatigue 
Malaise 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Incapacitating fatigue/ 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C 

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Pain (indicate body site) 
DO NOT use for pain 
due to injection (See 
Injection Site Reactions: 
Injection site pain) 
See also Headache, 
Arthralgia, and Myalgia 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing inability to 
perform usual social & 
functional activities 
Disabling pain causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
(other than emergency 
room visit) indicated 
Unintentional weight 
loss 
NA 
5 – 9% loss in body 
weight from baseline 
10 – 19% loss in body 
weight from baseline 
weight from baseline 
OR Aggressive 
intervention indicated 
[e.g., tube feeding or 
total parenteral 
nutrition (TPN)] 
INFECTION 
Infection (any other 
than HIV infection) 
Localized, no systemic 
antimicrobial treatment 
indicated AND 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Systemic 
antimicrobial 
treatment indicated 
OR Symptoms 
causing greater than  
minimal interference 
with usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention (other than 
simple incision and 
drainage) indicated 
Life-threatening 
consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain (pain 
without touching) Or 
Tenderness (pain when 
area is touched) 
Pain/tenderness 
causing no or minimal 
limitation of use of limb 
Pain/tenderness 
limiting use of limb 
OR Pain/tenderness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Pain/tenderness causing 
inability to perform usual 
social & functional 
activities 
Pain/tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction (localized) 
 
Adult > 15 years 
Erythema OR 
Induration of 5x5 cm – 
9x9 cm (or 25 cm2 – 
81cm2) 
Erythema OR 
Induration OR Edema 
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Necrosis (involving 
dermis and deeper 
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Pruritis associated with 
injection 
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to 
injection site AND 
Relieved spontaneously 
or with < 48 hours 
treatment 
Itching beyond the 
injection site but not 
generalized OR 
Itching localized to 
injection site 
treatment 
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable by 
study participant (or by 
caregiver for young 
children and disabled 
adults) 
Thinning or patchy 
hair loss detectable 
by health care 
provider 
Complete hair loss 
NA 
Cutaneous reaction – 
rash 
Localized macular 
rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR Stevens-
Johnson syndrome OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR Toxic 
epidermal necrolysis 
(TEN) 
Hyperpigmentation 
Slight or localized 
Marked or 
generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or 
generalized 
NA 
NA 
Pruritis (itching – no 
skin lesions)  
(See also Injection Site 
Reactions: Pruritis 
associated with 
injection) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing inability to 
perform usual social & 
functional activities 
NA 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
exam) 
Asymptomatic AND No 
intervention indicated 
Asymptomatic AND 
Non-urgent medical 
intervention 
indicated 
Symptomatic, non-life 
threatening AND Non 
urgent medical 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 

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Cardiac ischemia/ 
infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Haemorrhage 
(significant acute blood 
loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND 
packed RBCs (for children 
 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children > 10 cc/kg) 
indicated 
Hypertension 
 
Adult > 17 years 
(with repeat testing 
at same visit) 
> 140 – 159 mmHg 
systolic OR > 90 – 99 
mmHg diastolic 
> 160 – 179 mmHg 
systolic OR > 100 – 
109 mmHg diastolic 
> 180 mmHg systolic OR > 
110 mmHg diastolic 
Life-threatening 
consequences (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated (other than 
emergency room visit) 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluid replacement 
Symptomatic, IV fluids 
indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Pericardial effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, 
moderate or larger 
effusion requiring no 
intervention 
Effusion with non-life 
threatening physiologic 
consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated 
Prolonged PR interval 
 
Adult > 16 years 
PR interval 0.21 – 0.25 
sec 
PR interval > 0.25 sec 
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 sec 
Complete AV block 
Prolonged QTc 
 
Adult > 16 years 
Asymptomatic, QTc 
interval 0.45 – 0.47 sec 
OR Increase interval < 
0.03 sec above baseline 
Asymptomatic, QTc 
interval 0.48 – 0.49 
sec OR Increase in 
interval 0.03 – 0.05 
sec above baseline 
Asymptomatic, QTc 
Increase in interval 
baseline 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated 
serious ventricular 
dysrhythmia 

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Thrombosis/embolism 
NA 
Deep vein thrombosis 
AND No intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure) 
Deep vein thrombosis 
AND Intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive procedure) 
Embolic event (e.g., 
pulmonary embolism, 
life-threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss of 
consciousness 
Present with 
transient loss of 
consciousness 
NA 
NA 
Ventricular dysfunction 
(congestive heart 
failure) 
NA 
Asymptomatic 
diagnostic finding 
AND intervention 
indicated 
New onset with 
symptoms OR Worsening 
symptomatic congestive 
heart failure 
Life-threatening 
congestive heart failure 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased oral 
intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with significant 
weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention 
indicated (e.g., 
diuretics or 
therapeutic 
paracentesis)  
Symptomatic despite 
intervention 
Life-threatening 
consequences 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
Radiologic, endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas 
Constipation with manual 
evacuation indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhoea 

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Adult and Paediatric 
1 year 
Transient or 
intermittent episodes 
of unformed stools OR 
Increase of ≤ 3 stools 
over baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 – 6 
stools over baseline 
per 24-hour period 
Bloody diarrhoea OR 
Increase of ≥ 7 stools per 
24-hour period OR IV fluid 
replacement indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia- 
Odynophagia 
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention 
indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral intake 
Mucositis/stomatitis 
(clinical exam) Indicate 
site (e.g., larynx, oral)  
See Genitourinary for 
Vulvovaginitis  
See also Dysphagia- 
Odynophagia and 
Proctitis 
Erythema of the 
mucosa 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
Nausea 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 – 48 hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room 
visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
haemorrhage, sepsis) 
Proctitis (functional-
symptomatic) 
Also see 
Mucositis/stomatitis for 
clinical exam 
Rectal discomfort AND 
No intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of  
vomiting with no or 
mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 

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NEUROLOGIC 
Alteration in 
personality-behaviour 
or in mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis) 
Alteration causing no or 
minimal interference 
with usual social & 
functional activities 
Alteration causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Alteration causing 
inability to perform usual 
social & functional 
activities 
Behaviour potentially 
harmful to self or 
others (e.g., suicidal 
and homicidal ideation 
or attempt, acute 
psychosis) OR Causing 
inability to perform 
basic self-care functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioural/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Changes causing no or 
minimal interference 
with usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities 
Delirium OR 
obtundation, OR coma 
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing 
no or minimal 
interference with usual 
social & functional 
activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities 
Disabling ataxia causing 
inability to perform 
basic self-care functions 
Cognitive and 
behavioural/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Disability causing no or 
minimal interference 
with usual social & 
functional activities OR 
Specialized resources 
not indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing inability 
to perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
CNS ischemia (acute) 
NA 
NA 
Transient ischemic attack 
Cerebral vascular 
accident (CVA, stroke) 
with neurological 
deficit 

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Developmental delay – 
Paediatric ≤16 years 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated (other than 
emergency room visit) 
OR Headache with 
significant impairment 
of alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping causing 
inability to perform usual 
social & functional 
activities 
Disabling insomnia 
causing inability to 
perform basic self-care 
functions 
Neuromuscular 
weakness (including 
myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on 
exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with usual 
social & functional 
activities 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
alteration (including 
paresthesia and painful 
neuropathy) 
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing no 
or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care functions 

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Seizure: (new onset) – 
Adult ≥ 18 years 
See also Seizure: 
(known pre-existing 
seizure disorder) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure: (known pre-
existing seizure 
disorder) – Adult ≥ 18 
years 
For worsening of 
existing epilepsy the 
grades should be based 
on an increase from 
previous level of 
control to any of these 
levels. 
NA 
Increased frequency 
of pre-existing 
seizures (non-
repetitive) without 
change in seizure 
character OR 
Infrequent 
breakthrough 
seizures while on 
stable medication in 
a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or 
focality) 
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure – Paediatric < 
18 years 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting < 
5 minutes with < 24 
hours post ictal state 
Seizure, generalized 
onset with or without 
secondary 
generalization, 
lasting 5 – 20 minutes 
with < 24 hours post 
ictal state 
Seizure, generalized onset 
with or without 
secondary generalization, 
lasting > 20 minutes 
Seizure, generalized 
onset with or without 
secondary 
generalization, 
requiring intubation 
and sedation 
Syncope (not 
associated with a 
procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing inability 
to perform usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to 70 – 80% 
FEV1 or peak flow 50 
– 69% 
FEV1 or peak flow 25 – 
49% 
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory distress 

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Adult ≥ 14 years 
Dyspnea on exertion 
with no or minimal 
interference with usual 
social & functional 
activities 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
Joint pain causing no or 
minimal interference 
with usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing inability 
to perform usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
See also Arthralgia 
 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint swelling 
causing inability to 
perform usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care functions 
Bone Mineral Loss 
 
Adult ≥ 21 years 
BMD t-score -2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
 
Paediatric < 21 
years 
BMD z-score -2.5 to -
1.0 
BMD z-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
Myalgia (non-injection 
site) 
Muscle pain causing no 
or minimal interference 
with usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention 
indicated 
Symptomatic bone pain 
with radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care functions 
GENITOURINARY 

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Cervicitis (symptoms) 
(For use in studies 
evaluating topical study 
agents) 
For other cervicitis see 
Infection: Infection (any 
other than HIV 
infection) 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
basic self-care functions 
Cervicitis (clinical exam) 
(For use in studies 
evaluating topical study 
agents) 
For other cervicitis see 
Infection: Infection (any 
other than HIV 
infection) 
Minimal cervical 
abnormalities on 
examination (erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial disruption 
< 25% of total surface 
Moderate cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or 
friability) OR 
Epithelial disruption 
of 25 – 49% total 
surface 
Severe cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR Epithelial 
disruption 50 – 75% total 
surface 
Epithelial disruption > 
75% total surface 
Inter-menstrual 
bleeding (IMB) 
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic 
examination 
Inter-menstrual 
bleeding not greater 
in duration or 
amount than usual 
menstrual cycle 
Inter-menstrual bleeding 
greater in duration or 
amount than usual 
menstrual cycle 
Haemorrhage with life 
threatening 
hypotension OR 
Operative intervention 
indicated 
Urinary tract 
obstruction (e.g., stone) 
NA 
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction 
Obstruction causing life 
threatening 
consequences 
Vulvovaginitis 
(symptoms)  
(Use in studies 
evaluating topical study 
agents) 
For other vulvovaginitis 
see Infection: Infection 
(any other than HIV 
infection) 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
basic self-care functions 

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Vulvovaginitis (clinical 
exam) 
(Use in studies 
evaluating topical study 
agents) 
For other vulvovaginitis 
see Infection: Infection 
(any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption < 
25% of total surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
of 25 - 49% total 
surface 
Severe vaginal 
abnormalities on 
examination OR Epithelial 
disruption 50 - 75% total 
surface 
Vaginal perforation OR 
Epithelial disruption > 
75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention 
indicated 
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Visual changes (from 
baseline) 
Visual changes causing 
no or minimal 
interference with usual 
social & functional 
activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes causing 
inability to perform usual 
social & functional 
activities  
Disabling visual loss in 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
accumulation (e.g., 
back of neck, breasts, 
abdomen) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR Obvious 
changes on casual visual 
inspection 
NA 
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of 
current medications 
to regain glucose 
control 
New onset with initiation 
of medication indicated 
OR Diabetes uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar 
nonketotic coma) 
Gynecomastia 
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR Obvious on 
casual visual inspection 
NA 

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Hyperthyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy (e.g., fat 
loss from the face, 
extremities, buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR Obvious on 
casual visual inspection 
NA 

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LABORATORY 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY Standard International Units are listed in italics 
Absolute CD4+ count – 
Adult and Paediatric > 
13 years (HIV 
NEGATIVE ONLY) 
300 – 400/mm3 
300 – 400/µL 
200 – 299/mm3 
200 – 299/µL 
100 – 199/mm3 
100 – 199/µL 
< 100/mm3 
< 100/µL 
Absolute lymphocyte 
count – Adult and 
Paediatric > 13 years 
(HIV NEGATIVE ONLY) 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
< 350/mm3 
< 0.350 x 109/L 
Absolute neutrophil count (ANC) 
 
Adult and 
Paediatric, > 7 days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
< 500/mm3 
<0.500 x 109/L 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 50 mg/dL 
< 0.50 g/L OR 
< 0.25 x LLN OR 
Associated with gross 
bleeding 
Haemoglobin (Hgb) 
 
Adult and Paediatric 
≥ 57 days (HIV 
POSITIVE ONLY) 
8.5 – 10.0 g/dL 
1.32 – 1.55 mmol/L 
7.5 – 8.4 g/dL 
1.16 – 1.31 mmol/L 
6.50 – 7.4 g/dL 
1.01 – 1.15 mmol/L 
< 6.5 g/dL 
< 1.01 mmol/L 

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LABORATORY 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
 
Adult and Paediatric 
≥ 57 days (HIV 
NEGATIVE ONLY) 
10.0 – 10.9 g/dL 
1.55 – 1.69 mmol/L OR 
Any decrease 
2.5 – 3.4 g/dL 
0.39 – 0.53 mmol/L 
9.0 – 9.9 g/dL 
1.40 – 1.54 mmol/L OR 
Any decrease 
3.5 – 4.4 g/dL 
0.54 – 0.68 mmol/L 
7.0 – 8.9 g/dL 
1.09 – 1.39 mmol/L OR 
Any decrease 
≥ 4.5 g/dL 
≥ 0.69 mmol/L 
< 7.0 g/dL 
< 1.09 mmol/L 
International 
Normalized Ratio of 
prothrombin time (INR) 
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 
124,999/mm3 
100.000 x 109 – 124.999 
x 109/L 
50,000 – 99,999/mm3 
50.000 x 109 – 99.999 x 
109/L 
25,000 – 49,999/mm3 
25.000 x 109 – 49.999 x 
109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 – 2.500 x 
109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 1.999 x 
109/L 
1,000 – 1,499/mm3 
1.000 x 109 – 1.499 x 
109/L 
< 1,000/mm3 
< 1.000 x 109/L 
CHEMISTRIES Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life 
threatening 
consequences 
pH < 7.3 with life 
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase  
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 

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LABORATORY 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Alkalosis 
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life 
threatening 
consequences 
pH > 7.5 with life 
threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT)  
1.25 – 2.5 x ULN  
2.6 – 5.0 x ULN  
5.1 – 10.0 x ULN  
> 10.0 x ULN 
Bicarbonate, serum, 
low  
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Bilirubin (Total) 
 
Adult and Paediatric 
>14 days 
1.1 – 1.5 x ULN  
1.6 – 2.5 x ULN  
2.6 – 5.0 x ULN  
> 5.0 x ULN 
Calcium, serum, high (corrected for albumin) 
 
Adult and Paediatric 
≥ 7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low (corrected for albumin) 
 
Adult and Paediatric 
≥ 7 days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the 
manufacturer 
Cardiac troponin T 
(cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL OR Levels 
consistent with 
myocardial infarction or 
unstable angina as 
defined by the 
manufacturer 
Cholesterol (fasting) 

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LABORATORY 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
>7.77 mmol/L 
NA 
Creatinine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
Glucose, serum, high 
 
Non fasting  
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
 
Fasting  
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
 
Adult and Paediatric 
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
< 2.0 x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life 
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life 
threatening 
consequences 
LDL cholesterol (fasting)  
 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 

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LABORATORY 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
 
Adult and Paediatric 
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
≤ 120 mEq/L 
≤ 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS Standard International Units are listed in italics 
Hematuria 
(microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
 
Adult and Paediatric 
≥ 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
> 3.500 g/d 
 
∗Values are for term infants. 
† Use age and sex appropriate values (e.g., bilirubin), including preterm infants. 
 
 

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20 Appendix 3 Liverpool Causality Assessment Tool for Adverse Drug 
Reactions 
 
 
 
 

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21 Appendix 4 Community Consultation 
 
Potential Concern 
Response 
Safeguard 
Why is the study 
targeting pregnant 
women? These are a 
very vulnerable 
group of individuals. 
 
We recognise that pregnant women with a new HIV diagnosis 
are indeed vulnerable, socially, emotionally, mentally and 
importantly also from the point of view of having a higher than 
usual risk of transmitting HIV to their infant.  Because mother 
to child transmission is potentially preventable, and in women 
presenting late in pregnancy the window of opportunity to 
provide effective treatment is very small indeed, we believe that 
this group is especially important to study, since dolutegravir 
may well become the drug of first choice in this scenario. 
 
Within the existing maternity service, trained nurses 
and counsellors are available to help with 
psychosocial issues.  We accept a new diagnosis will 
be traumatic, and we will not be recruiting mothers 
who have evidence of mental illness or excessive 
stress, or decline to give consent. 
 
We will be submitting this proposal to ethics 
committees in the UK and in the countries where the 
study is to be undertaken 
 
Is the drug really safe 
in pregnancy? What 
if toxicity or side 
effects develop? 
 
Most drugs that are licensed for use lack safety data in 
pregnancy, because these studies are rarely performed.  The 
almost universal scenario is for a new drug to become licensed 
(with only reproductive toxicity and pregnancy date derived 
from animal studies guiding FDA pregnancy risk category).  
That drug then becomes widely deployed including to pregnant 
women.  For a few drugs (including antiretrovirals) specific 
pregnancy registers are established in certain countries in order 
to track drug safety in mothers and their newborn infants.   
 
There is an ethical argument that states that if a drug is going to 
be widely deployed (eg. a first or second line antiretroviral 
agent), and inevitably administered to large numbers of 
pregnant women, it is better to know in advance of any registry, 
that the dosing is optimised, and ideally a small number of 
women and their babies are closely followed in order to 
ascertain safety and efficacy.  The problem with registries is 
that although they may contain large numbers of people, safety 
We will conduct close virological, haematological 
and biochemical monitoring for toxicity.  These will 
include existing toxicities which are already 
recognised, plus unanticipated toxicities in the 
mother and the infant.   
 
We will also establish a data safety monitoring group 
(IDSMB).  This will be an independent international 
committee made up of experts in drug safety and HIV 
pharmacology, as well as community representatives.  
The IDSMB is scheduled to meet prior to the 
enrollment of the first patient, during the interim 
analysis (after the first 10 patients have delivered) 
and upon completion of the study. At each point the 
IDSMB will review laboratory and clinical data 
relating to mother and child. The committee will have 
an independent Chair, and have the power to stop the 
study at any stage if it feels that the safety of patients 

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monitoring data (eg blood tests) tend to be sparse. 
is being compromised.  Equally, if during the course 
of the study (and before all patients are enrolled) 
there is clear evidence of statistical superiority, or 
likely futility of the study, the committee is able to 
recommend that the study is terminated prematurely. 
 
You expect this drug 
to be better than the 
current standard of 
care in Uganda. What 
if that doesn’t hold 
true in pregnancy?  
We will be tracking HIV viral load closely during the course of 
the study up to the point of delivery.  We will also be 
confirming (with molecular tests) infection in the newborn 
infant. 
 
 
IDSMB as above 
The researchers 
propose to use a 
combination of 
ARVs which differs 
from the currently 
used national policy 
(based on WHO B+ 
guidance). Whilst the 
data obtained may be 
useful, is this safe for 
the individual 
mother? 
Studies investigating the safety and efficacy of dolutegravir in 
non-pregnant patients have shown it to have few side effects, 
and to bring about a rapid reduction in HIV viral load, which 
will be a great advantage to women who are diagnosed with 
HIV towards the end of their pregnancy. We specifically aim to 
recruit women who, if given the current standard regimen, 
would remain at substantial risk of transmitting the HIV to their 
infant. We therefore anticipate a beneficial effect for the 
individual. 
 
From what is known about how the body handles drugs during 
pregnancy, there is no reason to anticipate that the effects of the 
drug will differ during pregnancy. 
Community advisory group (Friends Council), 
Uganda 
 
Ongoing review by IDSMB 
 
Balanced against any potential risk to a group of 
closely monitored volunteers, is an ethical imperative 
to make sure that treatment of pregnant women is 
evidence based, rather than occurring on a 
widespread basis with no clinical or virological 
monitoring 
What relevance is 
this drug to Africa? 
Will such a new drug 
be affordable? Or are 
people in developing 
countries being 
‘used’ in studies 
which only people in 
Europe and America 
will benefit from? 
 
The manufacturer of dolutegravir (ViiV Healthcare) is working 
with generic manufacturers to prioritise generic versions of 
dolutegravir (target -within eighteen months of FDA licensing 
on 12th August 2013).  ViiV are already in discussion with key 
generic manufacturers.  The World Health Organisation has 
been discussing the potential role of dolutegravir as either a 
second line or even a first line regimen for low and middle 
income countries.  The Clinton Foundation has estimated that 
with scale up of manufacturing costs, the potential pricing of a 
generic version of dolutegravir could match the cheapest 
component of the current first line regimen in Uganda.   
There is strong evidence that dolutegravir will be 
affordable, available, and widely utilised in Sub 
Saharan Africa.   

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What are the side 
effects? 
All ARVs have some side effects. For dolutegravir, these are 
most commonly nausea or gastro-intestinal disturbance, 
headaches or a feeling of weakness and fatigue. 
Patients enrolled in the study will be monitored 
closely for any adverse effects which are either 
noticeable clinically, or detectable on blood tests. As 
detailed above, the DSMB will closely monitor the 
individuals enrolled in the study to ensure safety 
 
How safe is this drug 
for my baby ? 
There are no safety data in newborn infants (and this study will 
contribute important knowledge). Dolutegravir is classified as 
an FDA Category B drug (Animal reproduction studies have 
failed to demonstrate a risk to the fetus and there are no 
adequate and well-controlled studies in pregnant women). 
 
If introduced into first/second line treatment, many 
infants will be exposed in Africa without any close 
monitoring or evaluation. Our safety assessments are 
clinical (neonatology examination, infant safety 
evaluation questionnaire) , pharmacological and 
virological. 
 
Why is dolutegravir 
being continued for 2 
weeks after delivery 
(when the mother is 
breastfeeding) ? 
 
It is essential to compare drug exposure in the same person 
during and after pregnancy- otherwise changes in drug exposure 
could be related to diet, ethnicity and other factors. Late 
presentation renders a mother unlikely to be undetectable at the 
time of delivery, and many infants could also be receiving an 
oral dose of HIV during breastfeeding, so effective ‘post 
exposure prophylaxis’ to the infant may carry potential benefits 
as well as risks. 
 
 
Close monitoring of infant safety (see above), and 
virological studies of breast milk, and PK studies in 
maternal and infant plasma as well as breast milk. 
Who is funding this 
study, and what are 
their roles? 
 
This study is being funded by ViiV Healthcare, who will also be 
providing drug. The study design, execution and analysis will 
be carried out by a team of independent researchers based at the 
University of Liverpool, Infectious Diseases Institute based at 
Makerere University and the antenatal clinic at SRH.  
 
The protocol will be discussed with ViiV, who will be asked for 
input, and also to provide any unpublished data on safety in 
pregnancy. The responsibility for the final version of the 
protocol rests with the Principal Investigator. 
 
Transparency of funding will be ensured. All study 
personnel and IDSMB members will be asked for a 
Declaration of Interests, to be individually signed and 
dated. 

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22 Appendix 5: 
 
EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS) 
NAME: _____________________________________________________ 
 
 
Baby’s Age: ______________________ 
 
 
As you have recently had a baby, we would like to know how you are feeling.  Please UNDERLINE which comes closest 
to how you have felt IN THE PAST 7 DAYS, not just how you feel today. 
 
Here is an example, already completed. 
I have felt happy: 
 
                Yes, all the time. 
                Yes, most of the time. 
                No, not very often. 
                No, not at all. 
 
This would mean, “I have felt happy most of the time” during the past week.  Please complete the other questions in the 
same way. 
 
In the Past 7 Days:    
 
1. I have been able to laugh and see the funny side of things as much as I always could. 
 
0 – As much as I always could 
1 – Not quite so much now. 
2 – Definitely not so much now 
3 – Not at all 
 

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2. I have looked forward with enjoyment to things. 
 
0 – As much as I ever did 
1 – Rather less than I used to 
2 – Definitely less than I used to  
3– Hardly at all 
 
 
3.  I have blamed myself unnecessarily when things went wrong. 
3 – Yes, most of the time. 
2 – Yes, some of the time 
1 – Not very often 
0 – No, never 
 
4. I have been anxious or worried for no good reasons. 
 
         0 – No, not at all. 
1 - Hardly, ever 
2 – Yes, sometimes 
3  - Yes, very often 
 
5. I have felt scared or panicky for no very good reason. 
 
3– Yes, quite a lot 
2 – Yes, sometimes 
1 – No, not much 
0 – No, not at all 
 
6. Things have been getting on top of me. 
 
3– Yes, most of the time I haven’t been able to cope at all 
2 -  Yes, sometimes I haven’t been coping as well as usual 

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1 – No, most of the time I have coped quite will 
0 – No, I have been coping as well as ever 
 
7. I have been so unhappy that I have had difficulty sleeping 
 
3– Yes, most of the time 
2 – Yes, sometimes  
1 – Not very often 
0 – No, not at all 
 
8. I have felt sad or miserable 
 
        3-Yes, most of the time 
        2- Yes, quite often 
1- Not very often 
0- No, not at all 
 
9. I have been so unhappy that I have been crying 
     3-Yes, most of the time 
 
2- Yes, quite often 
     1 -Only occasionally 
     0 – No, not at all 
 
10. The thought of harming myself has occurred to me. 
3-Yes, quite often 
2-Sometimes 
1-Hardly ever 
0-Never 
 
 
 
 

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Screening Tool for PPD 
 
Edinburgh Postnatal Depression Scale (EPDS) [Cox, Holden & Sagovsky 1987] 
 
The EPDS is a self-rated questionnaire that has been used in Europe and Australia for over 10 years to screen 
women for PPD.  It asks women to rate how they have been feeling in the last 7 days and consists of 10 short 
statements of common depressive symptoms with 4 choices per statement.  Each statement is rated on a scale of 0 
– 3 with possible total scores ranging from 0 – 30. 
 
To administer the test you give the woman a pen and the questionnaire and ask her to answer the questions in 
relation to the past 7 days.  The questionnaire should only take a few minutes to complete. 
 
Scoring the questionnaire only take a couple of minutes with practice. 
Questions 3,5,6,7,8,9 and 10 are scored: statement 1 = 3 points, statement 2 = 2 points, statement 3 = 1 point and 
statement 4 = 0 points. 
 
A cut-off score of 12.5 has been shown to detect major depression and a woman who meets this threshold can be 
further assessed.  Asking a woman to complete such a questionnaire not only makes her stop and think about how 
she has been feeling but also indicates a willingness on the part of the person giving the questionnaire to listen to 
how she is feeling.