A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two Different Potent Regimens in HIV Infected Women Initiating Triple Antiretroviral Regimens Between 20 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission: NICHD P1081
Phase: PHASE4
Conditions: HIV Infections
Sponsor: Westat

 
NICHD P1081 
 
 
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VERSION: 3.0 
April 2, 2015 
 
A PHASE IV RANDOMIZED TRIAL TO EVALUATE THE VIROLOGIC 
RESPONSE AND PHARMACOKINETICS OF TWO DIFFERENT POTENT 
REGIMENS IN HIV INFECTED WOMEN INITIATING TRIPLE 
ANTIRETROVIRAL REGIMENS BETWEEN 28 AND 36 WEEKS OF PREGNANCY 
FOR THE PREVENTION OF MOTHER-TO-CHILD TRANSMISSION:  
NICHD P1081 
 
Sponsored by: 
 
 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 
and 
The National Institute of Allergy and Infectious Diseases (NIAID) 
 
 
Pharmaceutical Support Provided by: 
 
Merck and Company/Bristol Myers Squibb 
GlaxoSmithKline 
 
IND#: 112,049 
 
 
 
Protocol Co-Chair: 
  
 
 
Esau Joao, M.D. 
 
Protocol Co-Chair: 
  
 
 
Mark Mirochnick, M.D. 
 
NICHD Medical Officers: 
  
 
 
George Siberry, M.D., M.P.H. 
 
  
 
 
Nahida Chakhtoura, M.D. 
 
Clinical Trials Specialist: 
  
 
 
Roslyn Hennessey 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
Section 
Page 
 
 
NICHD P1081 PROTOCOL TEAM ROSTER ................................  
5 
 
 
List of Commonly Used Abbreviations ..............................................  
9 
 
 
SCHEMA ..............................................................................................  
11 
 
1.0 
INTRODUCTION................................................................................  
14 
 
1.1 
Background ................................................................................  
14 
1.2 
Study Rationale ..........................................................................  
15 
1.3 
Study Drugs ...............................................................................  
15 
1.4 
Dynamics of Viral Decay With ART.........................................  
19 
1.5 
Virion Infectivity Could Vary By HAART Regimen ................  
20 
1.6 
Transmission and Selection of Drug-Resistant HIV-1 ..............  
21 
1.7 
Genital Tract HIV RNA/DNA ...................................................  
23 
1.8 
Microbiome ................................................................................  
25 
 
2.0 
STUDY OBJECTIVES ........................................................................  
26 
 
2.1 
Primary Objectives.....................................................................  
26 
2.2 
Secondary Objectives.................................................................  
26 
2.3 
Exploratory Objectives ..............................................................  
26 
 
3.0 
STUDY DESIGN ..................................................................................  
27 
 
3.1 
Overview ....................................................................................  
27 
3.2 
HIV Drug Resistance Testing ....................................................  
28 
3.3 
Sparse Sampling PK ..................................................................  
28 
3.4 
Genital tract viral load ...............................................................  
28 
3.5 
Viral Decay and Viral Infectivity Dynamics .............................  
29 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ...........  
29 
 
4.1 
Inclusion Criteria .......................................................................  
29 
4.2 
Exclusion Criteria ......................................................................  
30 
4.3 
Disallowed Medications.............................................................  
31 
4.4 
Protocol Registration and Participant Enrollment 
Procedures ..................................................................................  
32 
4.5 
Co-enrollment Procedures .........................................................  
34 
 
 
 

 
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TABLE OF CONTENTS (continued) 
Section 
Page 
 
5.0 
STUDY TREATMENT .......................................................................  
34 
 
5.1 
Drug Regimens, Administration and Duration ..........................  
34 
5.2 
Drug Formulation.......................................................................  
35 
5.3 
Drug Supply, Distribution and Pharmacy ..................................  
35 
 
6.0 
PARTICIPANT MANAGEMENT.....................................................  
36 
 
6.1 
Toxicity Management ................................................................  
36 
6.2 
Participant Management ............................................................  
37 
6.3 
Criteria for Treatment Discontinuation ......................................  
42 
6.4 
Criteria for Study Discontinuation .............................................  
42 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING ............................  
43 
 
7.1 
Adverse Event Reporting to DAIDS ..........................................  
43 
7.2 
Reporting Requirements for this Study......................................  
43 
7.3 
Grading Severity of Events ........................................................  
44 
7.4 
Expedited AE Reporting Period.................................................  
44 
7.5 
CRF Recording Requirements for Laboratory Test 
Results, Signs, Symptoms, and Diagnoses ................................  
44 
 
8.0 
STATISTICAL CONSIDERATIONS ...............................................  
45 
 
8.1 
General Design Issues ................................................................  
45 
8.2 
Outcome Measures.....................................................................  
47 
8.3 
Randomization and Stratification ..............................................  
50 
8.4 
Sample Size and Accrual ...........................................................  
50 
8.5 
Monitoring .................................................................................  
53 
8.6 
Analyses .....................................................................................  
56 
 
9.0 
CLINICAL PHARMACOLOGY PLAN ...........................................  
57 
 
9.1 
Pharmacology Objectives ..........................................................  
57 
9.2 
Primary and Secondary Data .....................................................  
57 
9.3 
Laboratory Analysis and Reporting ...........................................  
58 
9.4 
Study Design, Modeling, and Data Analysis .............................  
59 
9.5 
Anticipated Outcomes ................................................................  
60 
 
 
 

 
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TABLE OF CONTENTS (continued) 
Section 
Page 
 
10.0 
HUMAN SUBJECTS ...........................................................................  
60 
 
10.1 
Institutional Review Board and Informed Consent ...................  
60 
10.2 
Participant Confidentiality .........................................................  
60 
10.3 
Study Discontinuation ................................................................  
61 
 
11.0 
PUBLICATION OF RESEARCH FINDINGS .................................  
61 
 
12.0 
BIOHAZARD CONTAINMENT .......................................................  
61 
 
13.0 
REFERENCES .....................................................................................  
62 
 
 
Appendices 
 
I 
MATERNAL SCHEDULE OF EVALUATIONS 
 
II 
INFANT SCHEDULE OF EVALUATIONS 
 
III 
DIETARY RECOMMENDATIONS FOR ANTIRETROVIRAL 
THERAPIES 
 
IV 
RESISTANCE MUTATIONS FOR ANTIRETROVIRAL STUDY 
DRUGS 
 
V 
VAGINAL SPECIMEN COLLECTION, PROCESSING AND 
SHIPPING 
 
VI 
SAMPLE INFORMED CONSENT 
 
VII 
EXTENSION PHASE: DEVELOPMENTAL ASSESSMENT OF 
INFANTS: NICHD P1081S 
 
 
 

 
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NICHD P1081 PROTOCOL TEAM ROSTER 
 
• Protocol registration materials should be submitted via the Division of AIDS (DAIDS) 
Protocol Registration System (DPRS): https://daidses.niaid.nih.gov/protocolregistration 
or can be sent via email to epr@tech-res.com.  
 
• General questions concerning this protocol should be sent via email to the full P1081 
protocol team at NICHD.teamp1081@fstrf.org.  
 
• Questions concerning clinical management of study participants and all communication 
regarding adverse experiences should be addressed to the P1081 Clinical Management 
Committee (CMC) at NICHD.p1081cmc@fstrf.org. Remember to include the 
participant’s Patient Identification Number (PID) when applicable. Please do NOT 
disclose the study arm to which a participant is randomized unless specifically requested. 
The appropriate team member will respond to questions via email. A response should 
generally be received within 24 hours (Monday - Friday). 
 
• For randomization or enrollment (Subject Enrollment System (SES)) screen questions, 
contact the Data Management Center (DMC) at 1-716-834-0900 x7301 or by email to 
rando.support@fstrf.org. 
 
• For computer and data entry (eData) screen problems email user.support@fstrf.org or call 
the DMC at 1-716-834-0900 x7302. 
 
• To order study agent, call the Clinical Research Products Management Center at (301) 
294-0741. For questions or problems regarding study drug supplies, records, and returns, 
contact the DAIDS Protocol Pharmacist at lpurdue@niaid.nih.gov. 
 
• For Expedited Adverse Event (EAE) questions, contact the DAIDS Regulatory Support 
Center (RSC) Safety Office via email at RSCSafetyOffice@tech-res.com; by telephone 
(1-800-537-9979 or 1-301-537-1709); or by fax (1-800-275-7619 or 1-301-897-1710). 
 
• For questions about the DAIDS Adverse Experience Reporting System (DAERS), email 
DAIDS-ESSupport@niaid.nih.gov. Questions may also be sent within the DAERS 
application. 
 
• Email the Computer Support Group (user.support@fstrf.org) at the DMC to have relevant 
site personnel added to the protocol email group NICHD.protp1081@fstrf.org. Inclusion 
in the protocol email group will ensure that sites receive important information about the 
study during its implementation and conduct. 
 
 

 
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Protocol Co-Chair 
Mark Mirochnick, M.D. 
Boston Medical Center  
771 Albany Street 
Dowling 4N, Room 4111 
Boston, MA 02118 
Phone: 617-414-3754 
Email: markm@bu.edu 
Protocol Co-Chair 
Esau Joao, M.D.  
5072- Hospital Federal dos Servidores do 
Estado - RJ 
Infectious Diseases Department 
Rua Sacadura Cabral 178 - Anexo IV, Quarto 
Andar – Saúde 
Rio de Janeiro 20221-903 
Brazil 
Phone:  55 21 2233 0018 
Email: esaujoao@gmail.com 
NICHD Medical Officer 
George Siberry, M.D., M.P.H. 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
Maternal and Pediatric Infectious Disease Branch 
6100 Executive Boulevard, Room 4B11H 
Bethesda, MD 20892 
Phone: 301-496-7350 
Email: siberryg@mail.nih.gov 
NICHD Medical Officer 
Nahida Chakhtoura, M.D. 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
Maternal and Pediatric Infectious Disease 
Branch 
6100 Executive Boulevard, Room 4B11G 
Bethesda, MD 20892 
Phone: 301-435-6872 
Email: nahida.chakhtoura@nih.gov  
Protocol Pharmacist 
Lynette Purdue, Pharm.D. 
Pharmaceutical Affairs Branch  
Division of AIDS, NIAID, NIH 
 
5601 Fishers Lane, Room 9E28 
Rockville, MD 20852 
Phone: 240-627-3061 
Email: lpurdue@niaid.nih.gov  
Clinical Trials Specialist 
Roslyn Hennessey 
Westat 
1600 Research Boulevard 
Rockville, MD 20850 
Phone: 301-517-8056 
Email: RoslynHennessey@westat.com  
Clinical Research Associate 
Lolita Kelley 
Westat 
1600 Research Boulevard 
Rockville, MD 20850 
Phone: 301-610-8812 
Email: lolitakelley@westat.com 
Protocol Pharmacologist 
Edmund Capparelli, Pharm.D. 
Pediatric Pharmacology Research Unit 
University of California, San Diego 
7910 Frost Street 
San Diego, CA 92123 
Phone: 858-246-0001 
Email: ecapparelli@ucsd.edu  

 
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Protocol Pharmacologist 
Brookie M. Best, Pharm.D., M.A.S. 
University of California, San Diego  
900 Gilman Drive, MC 0719 
San Diego, CA 92093-0719 
Phone: 858-822-5550 
Email: brookie@ucsd.edu  
Protocol Data Manager 
Linda Marillo 
Chief Protocol Data Manager 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7257 
Email: marillo@fstrf.org 
Protocol Data Manager 
Aaron Atlas, B.S. 
Protocol Data Manager 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7422 
Email: atlas@fstrf.org  
Protocol Statistician 
David Shapiro, Ph.D. 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-2426 
Email: shapiro@sdac.harvard.edu 
Protocol Statistician 
Meredith Warshaw, M.A. 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
651 Huntington Avenue, FXB-547 
Boston, MA 02115 
Phone: 617-432-2481 
Email: mwarshaw@sdac.harvard.edu 
Protocol Statistician 
Leavitt Morrison 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-3263 
Email: lmorriso@sdac.harvard.edu 
Protocol Virologist 
Lisa M. Frenkel, M.D. 
Seattle Children’s Research Institute and 
University of Washington 
1900 – 9th Avenue; 8th Floor 
Seattle, WA 98101-1304 
Phone: 206-987-5140 
Email: lfrenkel@u.washington.edu  
Laboratory Technologist 
Patricia Anthony, B.S., C.L.S. 
University of Southern California 
Maternal Child Adolescent Virology  
Research Lab 
1801 Marengo Street 
Los Angeles, CA 90033 
Phone: 323-226-4161 
Email: paanthon@usc.edu 
Laboratory Data Coordinator 
Oswald Dadson 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7238 
Email: dadson@fstrf.org  
Pharmaceutical Company Representative 
Daniel W. Seekins, M.D. 
Bristol-Myers Squibb 
Virology External Collaborations 
Group Medical Directo777 Scudders Mill Road, 
P11-26 
Plainsboro, NJ 08536 
Phone: 609-897-5825 
Email: daniel.seekins@bms.com 

 
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Pharmaceutical Company Representative 
Randi Leavitt  
Merck and Company 
Infectious Diseases-Clinical Research 
UG3D-305  
351 North Sumneytown Pike 
PO Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-7518  
Email: randi_leavitt@merck.com 
Pharmaceutical Company Representative 
Wendy Snowden, Ph.D. 
Director, International HIV Collaborative 
Studies 
GlaxoSmithKline R&D 
1-3 Iron Bridge Road 
Stockley Park West 
Uxbridge, Middlesex, UB11 1BT, UK 
Phone: 440-208-9664139 
Email: wendy.x.snowden@gsk.com 
Investigator 
Leon Sidi, M.D. 
5071- Hospital dos Servidores do Estado 
Infectious Diseases Department 
Rua Sacadura Cabral 178 - Anexo IV, Quarto 
Andar- Saúde 
Rio de Janeiro 20221-903 
Phone: 55 21 2233 0018 
Email: leon@diphse.com.br 
Investigator 
Dr. Fredrick Kipyego Sawe, MB.ChB., M.Med. 
5121- Kenya Medical Research Institute/Walter 
Reed Project 
Hospital Road PO Box 1357 
Kericho, 20200, Kenya 
Phone: +254 5220 30388/30686, Mobile +254 
724 255 623/703 247 902 
Email: Fredrick.sawe@usamru-k.org 
Investigator 
Blandina Theophil Mmbaga, M.D., M.Med., 
Ph.D. 
5118-Kilimanjaro Christian Medical Center 
Box 3010, Sokoine Road 
Moshi, Tanzania 
Phone: +255768435116 or +255786239258 
Email: blaymt@yahoo.com or 
blaymt@gmail.com  
Investigator 
Jose Henrique Pilotto, M.D.  
5097- Hospital Geral de Nova Iguaçu 
Avenue Henrique Duque Estrada Mayer 953 
Nova Iguaçu –Alto da Posse. 
Rio de Janeiro 26030-380 
Brazil 
Phone: 55 21 26673022 
Email: pilotto@unisys.com.br 
Investigator 
Sylvia Kaaya, M.D., Ph.D. 
5120-MUHAS University of Health and Allied 
Sciences 
PO Box 65001 
Dar es Salaam, Tanzania  
Phone: +255 22 2151680 (Office)/+255713 262 
756 (Cell) 
Email: skaaya@gmail.com  
Investigator: 
Professor Kulkanya Chokephaibulkit 
5115-Siriraj Hospital 
Faculty of Medicine Siriraj Hospital Department 
of Pediatrics 
2 Wanglang Road 
Bangkok-noi, Bangkok 
Thailand, 10700 
Phone: +662-419-7000 ext. 5671, +662-418-0545 
Email: kulkanya.cho@mahidol.ac.th 
 
 

 
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LIST OF COMMONLY USED ABBREVIATIONS 
3TC 
Lamivudine 
ACTG 
Adult AIDS Clinical Trials Group 
AE  
Adverse Event 
ALT 
Alanine aminotransferase 
ART 
Antiretroviral Therapy 
ARV 
Antiretroviral 
ASQ 
Ages and Stages Questionnaire 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice daily 
BRIEF 
Behavior Rating Inventory of Executive Functioning 
BSID-III 
Bayley Scales of Infant and Toddler Development, Third Edition 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CD4 
Cluster of Differentiation 4 
CI  
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
Clinical Management Committee 
CRF 
Case Report Form 
CVL 
Cervical-vaginal Lavage 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS, NIAID 
DDST 
Denver Developmental Screening Test 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic Acid 
DPRS 
DAIDS Protocol Registration System 
DSMB 
Data and Safety Monitoring Board 
EAE 
Expedited Adverse Event 
EC  
Ethics Committee 
EFV 
Efavirenz (Sustiva, Stocrin) 
FDA 
Food and Drug Administration 
HAART 
Highly Active Antiretroviral Therapy 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
II  
Integrase Inhibitor 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials 
INSTI 
Integrase Strand Transfer Inhibitors 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
LDMS 
Laboratory Data Management System 
MIRIAD 
Mother-Infant Rapid Intervention at Delivery 
MTCT 
Mother-to-Child Transmission 
 
 

 
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NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
Eunice Kennedy Shriver National Institute of Child Health and Human 
Development 
NIH 
National Institutes of Health 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NONMEM 
NONlinear Mixed-Effect Modeling 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
NVP 
Nevirapine 
OCTANE 
Optimal Combination Therapy after Nevirapine Exposure 
OHRP 
Office for Human Research Protections 
OR  
Odds Ratio 
PD  
Pharmacodynamic 
PCR 
Polymerase Chain Reaction 
PI  
Protease inhibitor 
PID 
Patient Identification Number 
PK  
Pharmacokinetic(s) 
PMTCT 
Prevention of Mother-to-Child Transmission 
PRO 
Protocol Registration Office 
QHS 
Every night 
RAL 
Raltegravir, Isentress 
RE  
Regulatory Entity 
RNA 
Ribonucleic Acid 
RSC 
Regulatory Support Center 
SAE 
Serious Adverse Event  
SES 
Subject Enrollment System 
TB  
Tuberculosis 
TNA 
Total Nucleic Acid 
TQQ 
Ten Questions Questionnaire 
UGT 
UDP-glucuronosyltransferase 
US  
United States 
VQA 
Virology Quality Assurance 
WHO 
World Health Organization 
WITS 
Women and Infants Transmission Study 
WPPSI-III 
Wechsler Preschool and Primary Scale of Intelligence, Third Edition 
ZDV 
Zidovudine, Retrovir 
 
 

 
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SCHEMA 
A PHASE IV RANDOMIZED TRIAL TO EVALUATE THE VIROLOGIC RESPONSE AND 
PHARMACOKINETICS OF TWO DIFFERENT POTENT REGIMENS IN HIV INFECTED 
WOMEN INITIATING TRIPLE ANTIRETROVIRAL REGIMENS BETWEEN 28 AND 36 
WEEKS OF PREGNANCY FOR THE PREVENTION OF MOTHER-TO-CHILD 
TRANSMISSION: NICHD P1081 
 
DESIGN: 
Multicenter two arm randomized open-label trial comparing the ability to 
achieve virologic suppression at delivery, tolerability, and safety. 
 
SAMPLE SIZE: 
334 evaluable mother-infant pairs (approximately 167 per arm), which is 
projected to require enrolling approximately 394 mother-infant pairs. 
 
POPULATION: 
Human Immunodeficiency Virus (HIV)-1 infected pregnant women with a 
gestational age between 28 and 36 weeks who are antiretroviral (ARV) 
naïve or have received short-course zidovudine (maximum of 8 weeks) only 
for prevention of mother-to-child transmission (PMTCT) in previous 
pregnancies, and their infants. 
 
STRATIFY BY: 
Gestational age at enrollment (28-30 weeks or 31-33 weeks or 34-36 weeks) 
and whether the women will use lamivudine/zidovudine or an alternative, 
locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone. 
 
REGIMEN: 
Antepartum – Participants will be randomized 1:1 
 
 
Arm A: Lamivudine 150 mg/zidovudine 300 mg* twice daily (BID) + 
efavirenz 600 mg every night (QHS). 
 
 
Arm B: Lamivudine 150 mg/zidovudine 300 mg* BID + raltegravir 400 mg 
BID. 
 
____________________ 
 
*Alternative, locally supplied NRTI backbone may be used in place of lamivudine/zidovudine with 
permission of protocol team obtained prior to randomization. 
 
 
Active labor:  
 
All participants will continue to receive study drugs during labor. In addition, 
in place of the oral fixed dose combination of lamivudine 150 mg/zidovudine 
300 mg (or alternative NRTI backbone), participants may receive intravenous 
zidovudine, other dosing regimens of oral zidovudine, oral lamivudine and/or 
additional drugs during labor, according to local standard of care/guidelines. 
 
 
Infants:  
 
Infants will receive ARV according to specific local guidelines. 

 
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TREATMENT 
DURATION: 
All women will receive their randomized study regimen from study entry 
through delivery. Women who meet local guidelines for receiving 
antiretroviral therapy (ART) will continue triple ART after delivery 
according to local guidelines. These women can receive study supplied 
drugs for up to 8 weeks after delivery to facilitate the transition to local 
standard of care for treatment for maternal health and/or prevention of breast 
milk transmission. Women who do not meet local guidelines for receiving 
triple ART will stop study supplied drugs immediately after delivery. 
Women randomized to Arm A (efavirenz) may continue lamivudine/ 
zidovudine for a period of time after stopping efavirenz at the discretion of 
the local investigator. 
 
STUDY  
DURATION: 
Women will be followed for 6 months after delivery. Infants will be 
followed until 6 months of age and may participate in an extension phase: 
developmental assessment of infants, lasting up to 4 years of age. 
 
OBJECTIVES:       Primary Objectives: 
 
1. 
To compare the ability of two triple ARV regimens (one 
containing efavirenz and the other raltegravir) begun during the 
third trimester of pregnancy to achieve a viral load of < 200 
copies/mL at the time of delivery. 
2. 
To compare the safety and tolerability of two triple ARV regimens 
(one containing efavirenz and the other raltegravir) begun during 
the third trimester of pregnancy. 
 
Secondary Objectives: 
 
1. 
To compare the kinetics of viral decay between the treatment 
regimens: 
a. Compare decay of plasma and vaginal HIV-1 RNA and DNA 
between the treatment regimens. 
b. Compare decay of plasma HIV-1 infectivity between the 
treatment regimens. 
2. 
To compare infant outcomes including stillbirth, premature birth, 
low birth weight, perinatal HIV transmission, neurodevelopmental 
outcomes and to compare (in HIV-infected infants) drug resistance 
between the two treatment regimens. 
3. 
To assess the baseline prevalence and selection of HIV-1 drug-
resistance to the study drugs, using standard genotyping and 
ultrasensitive genotyping methods. 
 
 

 
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Exploratory Objectives:  
 
1. To describe the population pharmacokinetic (PK) parameters of 
efavirenz and raltegravir during the third trimester of pregnancy and 
postpartum using sparse sampling and to evaluate potential 
relationships between PK parameters, pharmacogenomics and viral 
load changes. 
 
2. To describe the maternal vaginal and infant nasopharyngeal and 
oropharyngeal microbiome environment and the potential association 
with adverse outcome in HIV exposed uninfected children. 
 

 
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1.0 
INTRODUCTION 
 
1.1 
Background  
 
The current PMTCT strategies based on the use of triple ARV regimens after the 
first trimester through labor, appropriate management of delivery, and avoidance 
of breastfeeding have been successful in lowering the rates of HIV perinatal 
transmission to less than 2%.(1,2,3,4)  Results of clinical trials for PMTCT suggest 
that women receiving triple ARV regimens that effectively reduce HIV-1 
Ribonucleic Acid (RNA) to <1,000 copies/mL or undetectable levels are 
associated with significantly lower risk of perinatal HIV-1 transmission.(5,6,7,8)  
Townsend (9) published data from a study in a cohort of HIV-infected pregnant 
women from the United Kingdom and Ireland in which the transmission rate was 
only 0.1% in 2,117 pregnant women on triple ARV regimens who achieved viral 
suppression. Also, there was evidence that being on a triple ARV regimen at 
conception and starting a triple ARV regimen earlier in pregnancy were associated 
with a lower risk of transmission after adjusting for viral load. This strategy is 
strongly dependent on early access to prenatal care and availability of ARVs for 
PMTCT with viral suppression and appropriate approach of mode of delivery. 
 
A considerable number of pregnant women enter into prenatal care after the 28th 
week of gestation even in developed countries. Approximately one quarter of HIV-
infected persons in the United States (US) are unaware that they are infected.(10)  
The Mother-Infant Rapid Intervention at Delivery (MIRIAD) study, which was a 
prospective, multicenter study funded by the Centers for Disease Control and 
Prevention, offered voluntary, rapid HIV testing to women with undocumented 
HIV status late in pregnancy. Among 7,753 women with available test results from 
17 US hospitals, 52 (0.7%) were HIV-infected.(11)  Brazilian data published in 
2007 from a cohort of HIV-infected pregnant women at a public hospital showed 
that the mean gestational age of initiation of prenatal care was 24 ± 8 weeks of 
gestation.(3) 
 
Also, some pregnant women seroconvert late during pregnancy.(12)  A Brazilian 
study addressing primary HIV-1 infection during pregnancy showed an incidence 
of HIV-1 seroconversion of 0.8/1,000 (CI 95% 0.4-1.5/1,000).(13)  These women 
are more likely to transmit infection to their newborn, as plasma viral loads 
directly correlate with the risk of mother-to-child transmission (MTCT) of HIV-1. 
Decay dynamics of HIV-1 depend on the inhibited stage of the viral life cycle and 
are used as a measure of the effectiveness of ARV drugs and drug regimens.(14,15,16)  
Rapid reduction in viral load may be critical in minimizing both transplacental and 
intrapartum transmission of HIV-1 to the infant if ARV treatment is initiated late 
in pregnancy. 
 
 
 

 
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1.2 
Study Rationale  
 
Much virologic, immunologic and tolerability data derived from prospective 
clinical trials have shown the efficacy of various combinations of ARVs to treat 
HIV-1 infection. Most of these studies were done in HIV-infected adults with the 
primary efficacy outcomes based on the decline of plasma viral load within the 
first 24-48 weeks of starting therapy and on the durability of the virologic 
response, as well as changes in Cluster of Differentiation 4 (CD4)+ T-cell counts 
after 48 weeks of therapy. (17,18,19,20,21)  Suppressive ARV regimens containing the 
Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) efavirenz have been 
extensively studied in non-pregnant adults, demonstrating rapid reduction in 
plasma HIV viral load.(22,23)  ARVs in the newest class to be approved, integrase 
inhibitors (IIs), have proven to be very potent in pre-clinical, and phase II and III 
clinical studies in adult participants, are generally well tolerated, and demonstrate 
strong efficacy with rapid reduction in plasma viral load in both treatment-naïve 
and treatment-experienced participants. (21,24,25,26,27)  HIV-infected pregnant women 
presenting for care late in pregnancy need a rapid response and effective ART in 
order to minimize the risk of HIV transmission to their newborn. No data are 
available comparing the effects of NNRTIs and IIs in pregnant women. The goal 
of this protocol is to compare the safety, tolerance, virologic and pharmacologic 
responses of representatives of these two ARV classes in HIV-infected pregnant 
women presenting late for care. 
 
1.3 
Study Drugs 
 
1.3.1 Efavirenz (Sustiva®, Stocrin®) 
 
Efavirenz (Sustiva®, Stocrin®) is an NNRTI currently recommended as a 
first line agent for use in HIV-infected adults. In vitro studies show that 
efavirenz is an NNRTI that “tight-binds” in a nearly irreversible manner to 
the reverse transcriptase enzyme to make cell-free virions non-infectious. 
This property of efavirenz may rapidly reduce the infectivity of virions in 
maternal plasma, and thus reduce the risk of transmission to the infant 
during the decay phase of plasma viremia. 
 
In a preclinical developmental toxicology study, severe fetal 
malformations (anencephaly, anophthalmia, microophthalmia, cleft palate) 
were observed in 3 of 20 cynomolgus monkeys exposed to efavirenz 
throughout pregnancy. This led to an initial recommendation that 
efavirenz use should be avoided during the first trimester of 
pregnancy.(28,29,30,31)  However a recent review of human data on safety of 
efavirenz use in pregnancy found no increased risk of overall or central 
nervous system congenital anomalies with first-trimester exposure to 
efavirenz, and current World Health Organization (WHO) 
recommendations include use of efavirenz as first line therapy during 
pregnancy.(32)  Furthermore, efavirenz is also recommended as an 

 
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important alternative for HIV/tuberculosis (TB) co-infected pregnant 
women.  
 
Efavirenz PK data are available from P1026s for 25 women who received 
standard efavirenz doses of 600 mg once a day during the third trimester 
of pregnancy and again postpartum.(33)  Median (range) efavirenz area 
under the curve (AUC) during the third trimester was not different from 
postpartum (55.4 (13.5-220.3) µg*hr/mL vs. 58.3 (22.7-214.4 µg*hr/mL)), 
while 24 hour trough concentration (C24h) was significantly lower (1.60 
(0.23-8.13 µg/mL vs. 2.05 (0.31-8.43) µg/mL, p<0.05)). Efavirenz C24h 
exceeded the target of 1.0 µg/mL in 22 of 25 participants (88%) during the 
third trimester and 23 of 25 (92%) postpartum. These data suggest that 
standard efavirenz dosing of 600 mg once a day is appropriate for use in 
this protocol.(33)  
 
1.3.2 Raltegravir (Isentress®) 
 
Raltegravir (Isentress®) is an HIV-1 II with potent in vitro activity against 
HIV-1 strains including those resistant to currently available ARV drugs 
and has synergistic in vitro activity with currently available ARV drugs. 
Recent studies have highlighted differences in the first two phases of 
decay in plasma viremia with II-based therapy in which the first phase is 
slightly faster than that seen with standard NNRTI-based ART. 
Furthermore, II-based highly active antiretroviral therapy (HAART) also 
affects the dynamics of plasma viremia during the second phase of ART 
by reducing the viremia derived from chronically-infected cells. These 
unique properties of II-based ART may be highly desirable for pregnant 
women receiving ART aimed at decreasing MTCT.(34)  
 
Raltegravir PK in non-pregnant adults is characterized by rapid oral 
absorption (Tmax of around 3 hours) and a terminal half-life of around 9 
hours. Geometric mean PK parameters with chronic dosing of 400 mg 
twice a day are AUC0-12hr of 14.2 uM*hr [90% confidence interval (CI) 8.3 
25.8] and C12hr of 142 nM [90% CI 88 229].(25)  Raltegravir is eliminated 
primarily by hepatic metabolism, predominantly by UDP-
glucuronosyltransferase (UGT) 1A1 with minor contributions from 
UGT1A9 and UGT1A3.(35)  Raltegravir is not a substrate, inhibitor or 
inducer of cytochrome P450 enzymes.(46)  Food has been shown to have an 
unpredictable effect on raltegravir PK, and raltegravir has been 
administered without regard to food in phase III studies.(36)  
 
The standard raltegravir dose of 400 mg twice daily was chosen in order to 
maintain a C12h several fold above the in vitro IC95 of 0.033 ± 0.025 uM 
(0.015 ± 0.011 ug/mL).(46) Although limited data suggested a possible 
association between the short-term ARV activity of raltegravir (change 
from baseline in HIV RNA at day 10 and slope of HIV RNA decrease 

 
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from day 2 to 8) and the corresponding C12hr value on day 10 of treatment 
(but not AUC0-12hr or Cmax), pharmacodynamic (PD) analyses utilizing 
intensive PK sampling obtained from the initial phase II and III raltegravir 
protocols did not identify clinically meaningful correlations between 
raltegravir exposure, as measured by AUC or Ctrough, and longer term 
antiviral effects.(35) In a study of treatment naïve HIV-infected individuals, 
no differences were seen in antiviral response after 48 weeks of therapy 
among participants receiving 2 NRTIs plus raltegravir at doses of 100 mg, 
200 mg, 400 mg or 600 mg twice daily.(24)  In non-pregnant human adults, 
raltegravir at all doses studied had a safety profile much the same as 
placebo; no dose-related toxicities were observed. 
 
Developmental toxicity studies of raltegravir were performed in rabbits (at 
oral doses up to 1,000 mg/kg/day) and rats (at oral doses up to 600 
mg/kg/day). The highest doses in these studies produced systemic 
exposures in these species approximately 3 to 4 fold the exposure at the 
recommended human dose. In reproductive toxicity studies raltegravir did 
not affect fertility in either male or female rats at 600 mg/kg/day. In a 
toxicokinetic study in pregnant and lactating rats, raltegravir crossed the 
placental barrier with fetal exposure values up to 1.5 to 2.5 fold greater 
than in maternal plasma drug concentrations. It also concentrated in milk 
about 3 fold compared to plasma. In rabbits, mean drug concentrations in 
fetal plasma were approximately 2% of the mean maternal concentration 
at both 1 and 24 hours post dose at a maternal dose of 1,000 mg/kg/day. In 
developmental toxicity studies in rats, a slight increase in the incidence of 
supernumerary ribs relative to the control group was found at the highest 
dose of 600 mg/kg/day. No external or visceral abnormalities and no other 
fetal or postnatal developmental effects were noted at this dose. 
Raltegravir has not been shown to be genotoxic in a battery of in vitro 
assays in bacteria and mammalian cells designed to detect mutagenicity, 
direct Deoxyribonucleic Acid (DNA) damage or clastogenicity.(37) 
 
Data published by Iwamoto and colleagues concerning safety, tolerability 
and PK of raltegravir in healthy participants showed that the drug was well 
tolerated and exhibits a PK profile supportive of twice-daily dosing with 
multiple doses of 100 mg and greater achieving trough levels >33 nM. 
After multiple-dose administration, steady state was achieved within 2 
days.(27)  
 
Markowitz and colleagues published a study where 35 ARV naïve 
participants were enrolled (6–8 participants per treatment group) and 
completed 10 days of therapy. The mean baseline log10 HIV RNA level 
ranged from 4.5 to 5.0 log10 copies/mL in each group. On day 10, the 
mean decrease from baseline in the log10 HIV RNA level was -0.2 
copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 
copies/mL for the raltegravir 100-, 200-, 400-, and 600-mg treatment 

 
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groups, respectively.(38)  In another study conducted by the same author, in 
which 198 participants were enrolled (160 on raltegravir and 38 on 
efavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10 
copies/mL at baseline. At weeks 2, 4, and 8, the proportion of participants 
achieving an HIV-1 RNA level below 50 copies/mL was greater in each of 
the raltegravir treatment groups than in the efavirenz group. By week 24, 
all treatment groups appeared similar, with plasma HIV-1 RNA levels 
below 400 copies/mL in 85% to 98% of participants and below 50 
copies/mL in 85% to 95% of participants. These reductions were 
maintained through week 48, at which time 85% to 98% of participants 
had plasma HIV-1 RNA <400 copies/mL and 83% to 88% were <50 
copies/mL. Five (3%) participants on raltegravir and 1 (3%) on efavirenz 
experienced virologic failure before week 48.(24) 
 
Grinsztejn and colleagues published the results of a phase II randomized 
controlled trial of the safety and efficacy of raltegravir in treatment-
experienced participants with multidrug-resistant virus.(21)  They showed 
that in all raltegravir groups there was a decrease of about 2 log10 copies 
per mL in HIV-1 RNA from baseline noted as early as 2 weeks after 
initiation of treatment which was sustained through 24 weeks. The 
difference in change in viral load from baseline between the raltegravir 
and placebo groups at week 24 was –1·45 (95% CI –1·84 to –1·06) log10 
copies/mL with raltegravir 200 mg (p<0·0001), –1·52 (–1·90 to –1·14) 
log10 copies/mL with raltegravir 400 mg (p<0·0001), and –1·49 (–1·85 to 
–1·13) log10 copies/mL with raltegravir 600 mg (p<0·0001). 
 
Lennox and colleagues published in 2009 data from a study in which they 
compared the safety and efficacy of raltegravir with efavirenz as part of 
combination ART for treatment-naïve participants.(39)  The conclusion was 
that raltegravir-based combination treatment had rapid and potent ARV 
activity which was non-inferior to that of efavirenz at week 48. 
Furthermore, efavirenz is also recommended for HIV/TB co-infected 
pregnant women receiving anti-TB therapy.  
 
Raltegravir PK data from P1026s are available for 42 pregnant women 
who received standard raltegravir doses of 400 mg BID during the third 
trimester and postpartum.(40)  Third trimester median (range) raltegravir 
AUC was decreased (5.4 (1.4-36.5) µg*hr/mL vs. 11.6 (1.6-39.9) 
µg*hr/mL, p<.001) compared to postpartum, while there was no 
significant difference in median C12h (0.064 (0.0114-0.607) µg/mL vs. 
0.0797 (0.0199-1.340), p=0.3). Raltegravir C12h exceeded the PK target 
of 0.035 µg/mL in 33 of 41 (80%) women during the third trimester 
compared to 30/38 (79%) postpartum. These women demonstrated a high 
rate of virologic response to raltegravir, with HIV RNA viral loads below 
400 copies/mL in 92% of participants at delivery. Given this high rate of 
virologic response, the large variability in raltegravir plasma 

 
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concentrations seen in non-pregnant adults and the lack of a clear 
relationship between raltegravir concentrations and virologic effect, use of 
the standard non-pregnant adult 400 mg BID dose is recommended in 
pregnant women.(40,41) 
 
1.4 
Dynamics of Viral Decay With ART 
 
Some studies in non-pregnant adults have compared viral decay with different 
ARV regimens. The Adult AIDS Clinical Trials Group (ACTG) A5095 study 
compared three treatment regimens: zidovudine/lamivudine/efavirenz, 
zidovudine/lamivudine/abacavir, and a four-drug regimen of zidovudine 
/lamivudine/abacavir/efavirenz. ACTG A5095 established the superiority of the 
efavirenz-containing regimen to the triple-nucleoside abacavir-containing 
regimen.(42,43)  ACTG A5166s, a substudy of A5095, has shown that viral load 
declined more quickly in people treated with zidovudine, lamivudine and efavirenz 
than in those treated with zidovudine, lamivudine and abacavir. The faster viral 
load decline corresponded with the better virologic response in the efavirenz 
group, leading to suggestions that measurements of viral load decline might be an 
early predictor of longer-term response in clinical trials. Overall, the first phase of 
viral load decline was faster for those on the three-drug efavirenz regimen than for 
the triple-nucleoside combination. Viral load measurements were taken prior to 
and at study entry, and at days 2, 7, 10 and weeks 2, 4 and 8. Viral load fell at a 
faster rate in the efavirenz group than in the abacavir group during both the first 
phase and the second. The four-drug group was intermediate between the two. 
Viral load decay was modeled by a curve with two smooth exponential phases 
(“biexponential”); decay rates were estimated by fitting the observed data to the 
curve. In the model, the viral load decreases by a fixed percentage each day during 
each phase. This also yields a figure for the “half-life,” or time it takes for half an 
existing population of cells to disappear.(44) 
 
The findings from ACTG A5095 have been reinforced by a recent analysis of 
ACTG 5142, whose objectives were to compare phase-1 decay half-life of three 
regimens to evaluate gender differences and to relate phase-1 decay half-life to 
longer-term virologic responses: lopinavir/ritonavir + efavirenz vs. 
lopinavir/ritonavir + 2 NRTIs vs. efavirenz + 2 NRTIs. Phase-1 decay half-life was 
significantly shorter for efavirenz than for lopinavir (1.1 vs. 1.3 days, p = 0.03). 
They concluded that early viral clearance, as evaluated by phase-1 viral load decay 
and day 7 viral load change was greater for efavirenz than for lopinavir/ritonavir 
with efavirenz or lopinavir/ritonavir. Phase-1 decay was not different for 
participants by gender and race/ethnicity. Day 7 viral load change predicted week 
48 virologic outcome.(45) 
 
A phase II study (P004), evaluating ARV naïve participants enrolled for 48 weeks 
of combination therapy, with randomization to one of the four dosages of 
raltegravir or to efavirenz, in addition to tenofovir and lamivudine, showed that 
individuals in the raltegravir arm achieved an HIV RNA < 50 copies/mL earlier 

 
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than participants receiving efavirenz (p < .05). Plasma viral loads were 70% lower 
at initiation of second-phase decay for individuals taking raltegravir than for those 
taking efavirenz (P < 0.0001). This challenges the current hypothesis that second-
phase virus originates from infected long-lived cells, as an II should not impact 
viral production from this cell population.(34)  
 
Since the rate of decline of HIV-1 RNA viral load in women who begin triple ART 
during the third trimester is critical to determine the most desirable ARV regimen 
and there are no previous clinical trials that have addressed this issue, we are 
proposing to compare virologic suppression, kinetics of viral decay, PK, efficacy 
and safety with NNRTI and II containing ARV regimens. Further research is also 
needed on whether the effects of intensive combination treatment on viral load 
differ in various body compartments, such as plasma and genital tract secretions, 
and how this may relate to risk of perinatal transmission, so vaginal compartment 
HIV viral load will be assessed at several time points. 
 
1.5 
Virion Infectivity Could Vary By HAART Regimen 
 
While plasma viral load correlates directly with the risk of PMTCT, it does not 
completely determine the risk for in utero or peripartum HIV-1 transmission.(46)  
Factors such as the gestational age that ART is initiated, the transfer of ARV to the 
fetus/infant for chemoprophylaxis, maternal HIV-1 DNA load, and maternal CD4 
count also influence the risk of MTCT.(47,48)  One factor that has not yet been 
evaluated in clinical trials, and is especially pertinent to women beginning ART very 
late in gestation, is the effect of triple ARV regimens on the infectivity of cell-free and 
cell-associated virus, and its relation to the risk of MTCT.  
 
Figure 1: Cellular sites of ARV activity. Nucleoside/tide and non-nucleoside 
reverse transcriptase inhibitors (NRTI and NNRTI) block reverse transcription of 
viral RNA and integration of the cDNA, and interfere with HIV-1 infecting new 
cells. NRTI are added by the polymerase of reverse transcriptase to elongating 
cDNA, but by chain termination inhibit the formation of cDNA; NNRTI bind to a 
side pocket of the reverse transcriptase enzyme and through conformational 
changes impair its function; and integrase strand transfer inhibitors (INSTIs) block 
insertion of viral DNA into the human DNA.  
 

 
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Effective triple ART does not directly prevent HIV-1 infected cells from producing 
viruses. ART prevents infectious cycles. Rather, NRTI, NNRTI and INSTI inhibit 
the infection of new cells (Figure 1). During the first few months of ART the 
number of infected cells decreases and results in release of progressively fewer 
viral particles, which decreases plasma viral load. The plasma viral load declines 
in a predictable rate, in three phases; it falls below the limit of detection of clinical 
viral load assays when the infected cells that remain produce little virus. If 
protease inhibitors (PIs) are included in an ARV regimen, the inhibition of post-
production processing of viral proteins by PI causes cells to produce defective, 
non-infectious virus.  
 
Following initiation of triple ART, the infectivity of plasma decreases rapidly. 
During the time when the plasma HIV-1 RNA load remains detectable, the 
infectivity of virions to the fetus/infant should depend on pharmaco-dynamics and 
kinetics of the drugs used to treat HIV infection. 
 
Specific NNRTI have virucidal activity against HIV-1, due to the tight-binding 
mode of inhibition of reverse transcriptase.(49)  Efavirenz is one of several NNRTI 
that binds tightly, and in vitro rapidly inactivates the virus abolishing infectivity of 
virions that bud from the cells following removal of extracellular drug.(50)  Thus, 
efavirenz-based ART has the theoretical advantage of immediately reducing the 
infectious risk of an individual to his/her sexual partner and an infected mother to 
her fetus/infant.  
 
INSTI binding to HIV-1 integrase have been modeled, and relatively slow off-rates 
have been observed by this class of compounds, which suggests that the inhibitor 
may be stably bound to the preintegration complex.(51)  However, compounds vary 
in their off-rates. Comparison of the effects of efavirenz to raltegravir on the 
infectivity of viral particles could not be found. 
 
NICHD P1081 will include an evaluation of the differences in infectivity achieved 
with the use of efavirenz and raltegravir in late presenting pregnant women. 
 
1.6 
Transmission and Selection of Drug-Resistant HIV-1 
 
Transmitted drug-resistant HIV-1 identified in plasma by consensus sequencing 
(concentration > 25-50%) can persist in the plasma for 2 to 5 years (1,2,3,4), and 
appears to compromise the efficacy of ART.(7,8,9)  Low-level (< 25-50%) 
concentrations of drug-resistant mutants have been identified at the time of acute 
sero-conversion using assays with a greater sensitivity compared to consensus 
methods.(11,12) The prevalence and persistence of low-level mutants and their effects 
on ART have not been thoroughly described, although, recently, low concentration 
mutants were reported to diminish the efficacy of ART.(52)  
 
 

 
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Transmitted resistance has been detected by consensus sequencing in a small but 
significant proportion of pregnant women in Rio de Janeiro, and additional 
resistance was detected when pregnant women stopped ART postpartum. Among 
197 HIV infected but ARV-naïve pregnant women receiving care in Rio de 
Janeiro, resistance mutations were detected in 10.7% (NRTI mutations in 5.6%, 
NNRTI mutations in 2.0%, and PI mutations in 3.0%). Among 80 HIV-infected 
postpartum women in Rio de Janeiro who had received HAART during pregnancy 
five (6.5%) had new resistant virus detected upon stopping ART (2.5% for NRTI, 
3.75% for NNRTI).(53,54)  In another study in Brazil, new nelfinavir resistance 
mutations were detected in 4 (23.5%) of 17 women postpartum, and 3 women 
developed new zidovudine resistance mutations. No NNRTI resistance mutations 
were observed.  
 
The number of mutations required for a virus to become resistant to the ARV 
combination is often described as “the genetic barrier to resistance.” PIs, except for 
nelfinavir, require multiple mutations in the virus for high-level resistance. The 
requirement for multiple mutations is a significant obstacle to the selection of 
drug-resistant virus, thus PIs have a high genetic barrier to resistance. In contrast, 
most NRTIs require one or two mutations and NNRTIs and INSTIs require any of 
several single-base mutations. However, efavirenz has a long half-life, which is 
thought to preclude low drug-levels despite missed doses which can reduce the risk 
of selecting drug-resistant variants when the accompanying NNRTI similarly have 
long half-lives, such as tenofovir and emtricitabine. Raltegravir has a relatively 
shorter half-live and a similarly low genetic barrier to resistance.  
 
Very few studies have focused on the 
consequences of low-level drug-
resistance in pregnant women starting 
ART. One large study, Optimal 
Combination Therapy after 
Nevirapine Exposure (OCTANE), 
compared the quantity of drug-
resistance in women prior to starting 
nevirapine (NVP)-based ART, who 
either did or did not have a history of 
previous single-dose NVP. Among 
these women, the level of mutation 
was associated with virologic failure 
and death, in women previously 
treated with NVP, but similar levels 
were not predictive in women not 
treated with single-dose NVP (see 
Figure 2(55)). 
 
 
 

 
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Given uncertainties, an investigation of drug-resistant viruses present in pre-ART 
viral population at low-concentrations is warranted to further understand the role 
of pre-existing drug resistance on 1) viral suppression by the two different drug 
classes; and 2) selection of additional mutants when therapy is discontinued post-
partum. In NICHD P1081, we will determine the prevalence of drug-resistance 
mutations at high and low concentrations in women presenting for care late in 
pregnancy and whether low-frequency mutations appear to compromise the rate 
that ART suppresses viral replication.  
 
1.7 
Genital Tract HIV RNA/DNA 
 
Genital tract levels of HIV are independently associated with the risk of MTCT of 
HIV. In a sub-study of a randomized trial of breast versus formula feeding in 
Kenya, both cervical and vaginal HIV DNA levels were associated with the risk of 
infant HIV infection, after adjustment for CD4+ cell count, prematurity, genital 
ulcers, exposure to breast milk, and mastitis.(56)  None of the women in this study 
received ART. In a study from Thailand, genital tract HIV RNA levels were 
significantly reduced among women receiving zidovudine compared to placebo.(57)  
In both treatment groups, the risk of transmission to the infant was significantly 
associated with detectable HIV RNA in the cervical-vaginal lavage (CVL), in both 
high (> 10,000 copies/mL) and low (< 10,000 copies/mL) plasma HIV RNA 
groups. These data clearly showed the ability of ARV drugs to reduce genital tract 
RNA levels and the association of genital tract HIV levels with transmission. In a 
case-control analysis of a subset of women enrolled to the Women and Infants 
Transmission Study (WITS), the level of HIV DNA detected in CVL, but not the 
level of HIV RNA, was associated with the risk of vertical transmission of HIV 
among women not delivering by cesarean section before the onset of labor, thus 
with potential exposure of the infant to HIV in the genital tract.(58)  The adjusted 
risk of transmission increased by a factor of 2.28 (1.09-4.78) for each one log 
increase in CVL HIV DNA level. In this study, the majority of women were 
receiving ARVs, predominantly zidovudine monotherapy. Thus, data are 
consistent in showing an association between genital tract HIV levels and risk of 
vertical transmission, independent of plasma HIV RNA levels, but it is still not 
clear whether cell-free (RNA) or cell-associated (DNA) HIV is more important for 
transmission. In addition, the data available to date on genital HIV and 
transmission are from untreated women or women receiving zidovudine 
monotherapy. Triple ARV regimens may suppress genital tract viral load to a 
greater extent. This suppression may help to account for lower transmission rates 
among women on triple ARV regimens.  
 
The majority of studies have shown a correlation between plasma HIV RNA levels 
and genital tract HIV RNA levels or DNA detection. However, many studies 
demonstrate some women with persistently detectable genital tract HIV despite 
undetectable plasma HIV RNA. In studies done before the triple ARV era, plasma 
HIV RNA levels and CD4+ cell count depletion were consistently associated with 
detection of HIV RNA or DNA in the female genital tract.(59)  In one study of 

 
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women on various ARV regimens, HIV RNA was detectable in the genital tract 
from CVL among 25% of women with undetectable plasma HIV RNA. This 
finding was more frequent among women on less intensive ARV regimens.(60)  
However, even among women on triple ARV regimens, 8 (28.6%) of 28 had 
detectable HIV RNA, most with detectable plasma HIV RNA. In another study 
that evaluated plasma and genital tract RNA levels before and for 28 weeks after 
triple ARV initiation, 98% of women had undetectable plasma RNA and 95% had 
undetectable genital tract RNA after 18 weeks of therapy. With repeated sampling, 
47% of women had at least one episode of genital tract HIV detection despite 
consistently undetectable plasma HIV RNA levels.(61)  In a study of plasma and 
genital tract RNA levels among 38 pregnant women, 2 (22%) of the 9 women with 
undetectable plasma HIV RNA levels had detectable vaginal HIV RNA.(62)  A 
study of 268 women from the WITS detected genital tract HIV shedding in 57% of 
women overall, including among 130 (80%) of 163 women with detectable plasma 
RNA and among 27 (33%) of 83 women with plasma HIV RNA under 500 
copies/mL.(63)  Seventy-four percent of these 27 women were on ART, including 
14 (52%) on a PI. Other studies have confirmed the strong association between 
plasma HIV RNA levels and detection of HIV in the genital tract, and a small 
proportion of women with persistently detectable genital tract HIV even with 
undetectable plasma HIV RNA.(64,65)  In a subsequent study from WITS of 290 
women with undetectable plasma HIV RNA, 44 (15%) had detectable HIV RNA 
in cervical swab specimens.(66)  In a multivariable analysis of factors associated 
with genital tract HIV detection, only NNRTI use (compared to PI use, odds ratio 
(OR) 2.24, 95% confidence interval 1.13-4.45) and illicit drug use (OR 2.41, 0.96-
5.69) were found to be associated with genital tract detection of HIV RNA. Thus, 
plasma HIV RNA level is not an adequate predictor of genital tract HIV detection, 
and the risk of genital tract HIV shedding may vary by the ARV regimen used. 
 
Several studies have evaluated the rate of decrease of genital tract HIV RNA after 
initiation of ART. A drop of 0.9 log in both cervical and vaginal RNA levels was 
seen after 1 week of zidovudine therapy.(67)  A study of vaginal swab RNA levels 
among treatment-naïve women initiating stavudine, lamivudine, and NVP found an 
initial decay rate of 1.2 log10 virions/day.(68)  In a study in Brazil, genital tract HIV 
RNA in CVL decreased by a mean of 1.44 log10 after 1 month on triple ARV 
therapy, primarily zidovudine and lamivudine with either efavirenz or 
nelfinavir.(69)  Three women starting ARV therapy with detectable CVL RNA 
levels and studied intensively had a 0.7-2.1 log10 drop in genital tract RNA levels 
within 1-14 days of starting therapy.(70)  A drop in genital tract RNA levels of 1-2 
logs within 2-4 weeks of initiating ARV therapy would be expected with two 
nucleosides and either an NNRTI or unboosted PI based on current data. Data are 
needed on the change in genital tract HIV RNA levels on newer agents such as 
boosted PIs and IIs. 
 
As discussed above, a variety of sampling methods has been used for assessing 
HIV in the female genital tract. Possible options include CVL with a sterile 
solution, cervical wicks, cervical and vaginal swabs, or cytobrush samples from 

 
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the cervix. For virology, the best site for sampling, cervical os or vagina, has not 
been determined. Given that we will be sampling pregnant women, with the intent 
being to assess HIV levels and possible associations with vertical transmission, 
sampling of the vaginal milieu, rather than the cervical os, is reasonable. Vaginal 
secretions sampling will allow assessment of HIV levels that would be 
encountered by the infant during labor and vaginal delivery. CVL, while allowing 
sampling of the entire vaginal area, has been found to be less sensitive and more 
variable than either cervical sampling with wicks or cytobrushes or swabs.(71,72)  
Vaginal swabs have been shown to have similar results to cervical wicks, vaginal 
wicks and CVL cell pellet.(73)  Given that sampling of the vaginal milieu, rather 
than just the cervix, is desired and given the ease of obtaining specimens with 
vaginal swabs since no speculum placement is required, vaginal swab sampling 
has been chosen for determination of HIV RNA and DNA levels in this study. Use 
of the vaginal aspirator for the large number of vaginal specimens planned for 
virologic testing is cost prohibitive and its use for virologic testing has not been 
validated compared to other methods. 
 
1.8 
Microbiome 
 
The microbiome and metagenomics are transforming research on health and 
disease. This is true when it comes to pregnancy and pregnancy outcomes. There is 
a linkage between microorganisms, detected by DNA-sequencing technology, and 
preterm delivery, premature rupture of membranes, intrauterine growth restriction, 
gestational diabetes, late abortions, and still birth.(74)  Increased risk of HIV 
transmission to the partner and the newborn child has been associated with 
bacterial vaginosis and other disturbances of the microbiota caused by sexually 
transmitted infections.(75)  In a retrospective analysis of cervicovaginal specimens, 
the presence of lactobacilli species and Gardnerella vaginalis was significantly 
higher in 10 women who transmitted HIV to their children compared to 54 
nontransmitters.(76)  The vaginal/uterine microbiota directly or through an immune 
modulation may affect HIV vertical transmission as well as the health of HIV 
exposed uninfected children. 
 
HIV exposed uninfected children are an increasing population around the world. 
Morbidity and mortality among these infants are higher than in HIV unexposed 
children. It has been noted that these children have an increased incidence of lower 
respiratory tract infections and serious infections with encapsulated bacteria 
compared to HIV unexposed children.(77)  The maternal vaginal or infant oral and 
respiratory microbiota may play a role in these adverse infant outcomes.  
 
Maternal vaginal swabs and infant nasopharynx and oropharynx swabs will be 
collected for future evaluations of the microbiota. See Appendix V for more 
information.  
 
 
 

 
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2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.1.1 To compare the ability of two triple ARV regimens (one containing 
efavirenz and the other raltegravir) begun during the third trimester of 
pregnancy to achieve a viral load of < 200 copies/mL at the time of 
delivery. 
2.1.2 To compare the safety and tolerability of two triple ARV regimens (one 
containing efavirenz and the other raltegravir) begun during the third 
trimester of pregnancy. 
2.2 
Secondary Objectives 
 
2.2.1 To compare the kinetics of viral decay between the treatment regimens: 
a. Compare decay of plasma and vaginal HIV-1 RNA and DNA between 
the treatment regimens. 
b. Compare decay of plasma HIV-1 infectivity between the treatment 
regimens. 
2.2.2 To compare infant outcomes including stillbirth, premature birth, low birth 
weight, perinatal HIV transmission, neurodevelopmental outcomes and to 
compare (in HIV-infected infants) drug resistance between the two 
treatment regimens. 
2.2.3 To assess the baseline prevalence and selection of HIV-1 drug-resistance 
to the study drugs, using standard genotyping and ultrasensitive 
genotyping methods. 
2.3 
Exploratory Objectives  
 
2.3.1 To describe the population PK parameters of efavirenz and raltegravir 
during the third trimester of pregnancy and postpartum using sparse 
sampling and to evaluate potential relationships between PK parameters, 
pharmacogenomics and viral load changes. 
2.3.2 To describe the maternal vaginal and infant nasopharyngeal and 
oropharyngeal microbiome environment and the potential association with 
adverse outcome in HIV exposed uninfected children. 
 
 

 
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3.0 
STUDY DESIGN 
 
Primary Hypothesis: 
 
1) Efavirenz and raltegravir are effective, safe and tolerable as part of HAART regimens 
to be used in late pregnancy when rapid viral load suppression is for PMTCT of HIV. 
 
Secondary Hypotheses:  
 
1) Efavirenz-based triple ARV regimens will decrease the level and infectivity of plasma 
and cell-associated virus more rapidly (by 1 week of ART) compared to II-based triple 
ARV regimens.  
 
2) Transmitted HIV drug-resistance among women will be prevalent at 10-15% of the 
population. Transmitted resistance will be associated with delayed decay of plasma 
HIV-1 RNA levels compared to women without primary resistance, and, when ART is 
stopped with further selection of resistance (especially selection of lamivudine and/or 
NNRTI resistance).  
 
3.1 
Overview 
 
NICHD P1081 is a Phase IV multicenter, randomized, open-label trial to evaluate 
two different potent drug regimens in HIV-infected pregnant women initiating 
triple ARV regimens in the third trimester. The study population is HIV-1 infected 
pregnant women with gestational age 28-36 weeks who are ARV naïve or have 
received ART with short-course zidovudine (maximum of 8 weeks) for PMTCT in 
previous pregnancies, and their infants. 
 
Women will be randomized 1:1 to Arm A (lamivudine/zidovudine + efavirenz), or 
Arm B (lamivudine/zidovudine + raltegravir) to compare the ability to achieve a 
viral load < 200 copies/mL at the time of delivery, tolerability, and safety of two 
different potent drug regimens. Alternative, locally supplied NRTI backbone may 
be used in place of lamivudine/zidovudine with permission of the protocol team 
obtained prior to randomization. The randomization will be stratified based on 
gestational age at enrollment (28-30 weeks versus 31-33 weeks versus 34-36 
weeks) and the chosen NRTI backbone (lamivudine/zidovudine vs. alternative 
NRTI backbone). 
 
Women in Arm A will receive standard non-pregnant adult doses of efavirenz once 
daily. Women in Arm B will receive the standard non-pregnant adult dose of 
raltegravir BID. The randomization will be stratified based on whether 
lamivudine/zidovudine or a locally supplied alternative NRTI backbone will be 
used to ensure balance of alternative NRTI backbone use between study arms. 
 
All women will receive their randomized study regimen from study entry through 
delivery. Women who meet local guidelines for receiving ART will continue triple 

 
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ART after delivery and through breastfeeding according to local guidelines. These 
women can receive study drugs for up to 8 weeks after delivery to facilitate the 
transition to local standard of care. Women who do not meet local guidelines for 
receiving triple ART will stop study drugs immediately after delivery. Women 
randomized to Arm A (efavirenz) may continue lamivudine/zidovudine for a 
period of time after stopping efavirenz at the discretion of the local investigator.(78) 
 
Infants will receive ARVs according to specific local guidelines. 
 
Women will be followed for 6 months after delivery. Infants will be followed for 6 
months after birth and may participate in an extension phase: developmental 
assessment of infants, lasting up to 4 years of age. 
 
3.2 
HIV Drug Resistance Testing 
 
All women will have HIV drug-resistance testing done at a local Clinical 
Laboratory Improvement Amendments (CLIA) certified (for US sites) or DAIDS- 
Virology Quality Assurance (VQA) certified (for non-US sites) laboratory on a 
specimen drawn at screening.  Since these are late presenting women and it is 
important to start ARVs as soon as possible to maximize prevention of perinatal 
HIV transmission, the results of this test will not be required before enrollment and 
initiation of study ART. A participant, in conjunction with her local provider, can 
use her resistance test results to determine whether they warrant a reconsideration 
of remaining on study medication. All women enrolled will remain in study follow 
up for safety monitoring and virologic evaluations regardless of regimen 
changes.  Randomized participants who begin study therapy before resistance test 
results are available and are later discovered to have had detectable genotypic 
resistance to any of the study drugs in any of the study arms at screening (whether 
or not they decide to change study drugs) will be excluded from the primary 
analyses but included in secondary analyses (see Section 8.0 for details).  
 
3.3 
Sparse Sampling PK 
 
All women will have blood collected that may be used for ARV drug assays at the 
week 1 and subsequent visits until delivery, and, for study participants who 
continue triple ARV regimens at the week 2-4 postpartum visit. ARV assay data 
will be used to perform a population analysis of ARV PK during the third trimester 
of pregnancy. 
 
3.4 
Genital Tract Viral Load  
 
Vaginal swabs for maternal genital tract HIV RNA and DNA and microbiome 
polymerase chain reaction (PCR) will be collected on all women at entry, week 1, 
week 2, week 4, and every 2 weeks until delivery (36-38 weeks of gestation), and 
at 24 weeks postpartum. 
 

 
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3.5 
Viral Decay and Viral Infectivity Dynamics 
 
To study viral decay, serial determinations of plasma HIV RNA will be performed 
at local labs in all women to compare the rate at which plasma HIV-1 RNA 
decreases by study arm. Virion infectivity will be evaluated on plasma collected 
during visits week 1 until delivery and batch tested using an infectivity assay at the 
end of the study. The ratio of virion infectivity to HIV-1 RNA level will be 
compared between study arms.  
 
 
Refer to Appendix I, Maternal Schedule of Evaluations and Appendix II, Infant 
Schedule of Evaluations, for a complete description of the clinical and laboratory 
evaluations to be performed. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria  
 
4.1.1 Naïve to ART or have received ART with short course zidovudine 
(maximum of 8 weeks) for PMTCT in previous pregnancies.  
4.1.2 Willingness and ability to sign informed consent. Participant must be of an 
age to provide legal informed consent as defined by the country in which 
the participant resides. If not, the informed consent must be signed by a 
legal guardian/parent, as per country guidelines. 
4.1.3 Documentation of HIV-1 infection defined as positive results from two 
samples collected at different time points. The same method may be used 
at both time points. All samples tested must be whole blood, serum or 
plasma. Documentation maybe abstracted from medical records to satisfy 
these criteria for infection. 
The first test may be any of the following: 
 
• 
HIV-1/2 Antigen and Antibodies test and confirmed HIV-1 from HIV-
1/2 antibody differentiation test 
• 
Two rapid antibody tests from different manufacturers or based on 
different principles and epitopes 
• 
One rapid antibody test AND one [enzyme immunoassay OR Western 
blot OR immunofluorescence OR chemiluminescence] 
• 
One enzyme immunoassay AND one [Western blot OR 
immunofluorescence OR chemiluminescence] 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above limit of detection) 
• 
One qualitative HIV RNA PCR 
• 
One HIV culture (prior to August 2009) 
• 
One total HIV nucleic acid 
 

 
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If the first test(s) is positive, a second sample must be collected and tested 
using any of the tests listed above (except for qualitative RNA assays) at a 
laboratory participating in an appropriate external quality assurance 
program and either College of American Pathologists/CLIA approved (for 
US laboratories) or DAIDS-approved (for non-US laboratories). 
 
It is strongly recommended that all kits/methods of analysis are Food and 
Drug Administration (FDA) approved. 
 
4.1.4 Viable pregnancy with gestational age of  ≥ 28 to ≤ 36 weeks based upon 
menstrual history and/or ultrasound. 
 
Note: If menstrual history is unknown or if there is a discrepancy between 
menstrual history and ultrasound, determination of gestational age should 
be based upon best available methodology at each site. 
4.1.5 Participant intends to continue pregnancy. 
4.1.6 Willingness and intent to deliver at the participating clinical site and to be 
followed for the duration of the study at the site or associated outpatient 
facility. 
4.1.7 Participant willing to comply with study regimen. 
4.1.8 Participant agrees to use two reliable methods of contraception after 
delivery if randomized to the efavirenz arm and is sexually active. A 
barrier method of contraception (condoms, diaphragm, or cervical cap) 
together with another reliable form of contraception must be used for 4 
weeks after stopping efavirenz. 
4.2 
Exclusion Criteria 
 
4.2.1 Active labor defined as onset of regular contractions or cervical dilatation 
greater than 2cm. 
4.2.2 Use of ART during current pregnancy.  
4.2.3 Chemotherapy for active malignancy. 
4.2.4 HIV genotypic resistance, as defined in Appendix IV, to efavirenz or 
raltegravir or to NRTIs that will be included in the ART regimen. Note: A 
lack of HIV drug-resistance test results at the time of enrollment is not 
exclusionary. 
4.2.5 Serious active opportunistic infection and/or serious bacterial infection 
including active TB or unstable or severe medical condition within 14 
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4.2.6 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
4.2.7 Any clinically significant diseases (other than HIV infection) or clinically 
significant findings during the screening medical history or physical 
examination that, in the investigator’s opinion, would compromise the 
outcome of this study. 
4.2.8 Vomiting or inability to swallow medications due to an active, pre-
existing condition that prevents adequate swallowing and absorption of 
study medication. 
4.2.9 Known allergy/sensitivity to any study drugs or their formulations or 
sulfonamide allergy. 
4.2.10 The following laboratory values (within 30 days of enrollment):  
• 
Hemoglobin ≥ Grade 3 
• 
Absolute neutrophil count ≥ Grade 2 
• 
Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) 
≥ Grade 2 
• 
Serum creatinine ≥ Grade 1 
• 
Platelet count ≥ Grade 3 
4.2.11 Evidence of pre-eclampsia (such as persistent diastolic blood pressure > 
90 mmHg). 
4.2.12 Receipt of disallowed medications described in Section 4.3. 
4.3 
Disallowed Medications 
 
Participants will be randomized at time of enrollment and must be eligible to enroll 
in either study arm. Therefore participants receiving any disallowed medications 
listed below under any of the study medications are not eligible for enrollment. 
 
4.3.1 Raltegravir 
 
Raltegravir is eliminated mainly via a UGT1A1-mediated glucuronidation 
pathway and, therefore, the compound may be subject to drug-drug 
interactions when co-administered with drugs that are known to be 
UGT1A1 inducers or inhibitors. However, raltegravir is not anticipated to 
affect the metabolic clearance of drugs metabolized by UGT1A1 given its 
low UGT1A1 inhibitory (IC50 for the inhibition of UGT1A1 >50 µM) and 
induction potential. Since raltegravir is neither an inducer nor inhibitor of 

 
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cytochrome P-450 enzymes, raltegravir is not expected to result in 
metabolic drug interactions with substrates of cytochrome P-450. 
 
The following medications/therapies are contraindicated in this study 
because they are potent broad inducers of drug metabolism, inducers of 
CYP3A (thus potential inducers of glucuronidation), and their co-
administration with raltegravir will likely result in altered (lowered) drug 
levels of raltegravir: 
 
• 
phenobarbital 
• 
phenytoin 
• 
rifampin 
 
4.3.2 NRTIs 
 
There are no disallowed medications due to drug interactions with NRTIs. 
Stavudine (d4T) and zidovudine should not be used together.  
 
4.3.3 Efavirenz 
 
The following medications are disallowed due to potential drug 
interactions with efavirenz: 
 
• 
Rifampin, rifabutin, ergot derivatives, voriconazole, St. John’s Wort 
• 
Antihistamines: cisapride, loratadine, astemizole 
• 
Sedative hypnotics: alprazolam, clorazapam, diazepam, estazolam, 
flurazepam, midazolam (except during labor), triazolam, zolpidem 
• 
Anticonvulsants, except lamotrigine, gabapentin, and levetiracetam  
• 
Calcium channel blocker: bepridil 
4.4 
Protocol Registration and Participant Enrollment Procedures 
 
This protocol is open to all NICHD US and non-US sites that have been approved 
to participate by the NICHD network. Prior to implementation of this protocol, and 
any subsequent full version amendments, each site must have the protocol and the 
protocol informed consent form(s) (ICFs) approved, as appropriate, by their local 
institutional review board (IRB)/ethics committee (EC) and any other applicable 
regulatory entity (RE). Upon receiving final approval, sites will submit all required 
protocol registration documents to the DAIDS Protocol Registration Office (PRO) 
at the RSC. The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 

 
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Site-specific ICFs WILL be reviewed and approved by the DAIDS PRO and sites 
will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the 
Initial Registration Notification should be retained in the site’s regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites should implement the amendment immediately. Sites are required 
to submit an amendment registration packet to the DAIDS PRO at the RSC. The 
DAIDS PRO will review the submitted protocol registration packet to ensure that 
all the required documents have been received. Site-specific ICF(s) WILL NOT be 
reviewed and approved by the DAIDS PRO and sites will receive an Amendment 
Registration Notification when the DAIDS PRO receives a complete registration 
packet. A copy of the Amendment Registration Notification should be retained in 
the site’s regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Note that the “Extension Phase: Developmental Assessments in Infants” 
(Appendix VII) will not be activated for enrollment when Version 3.0 of the 
protocol opens. It is anticipated that site notification to activate this extension 
phase with guidance to begin enrolling infants to the extension phase will occur by 
a formal protocol action (likely a letter of Amendment). 
 
A Site Implementation Plan is required from each site participating in the study. 
International sites are required to complete section I, site accrual and capacity, and 
section II, plans for providing antiretroviral medications during labor and delivery. 
Domestic sites are only required to complete section II, plans for providing 
antiretroviral medications during labor and delivery. The plan will be submitted to 
the protocol team for review and approval before protocol registration can occur.  
 
Written informed consent for study participation must be obtained before any 
study related procedures are performed.  
 
For participants from whom a signed ICF has been obtained, a Screening Checklist 
PS2001 must be entered through the DMC SES prior to study enrollment. Eligible 
participants are enrolled through the DMC SES using the P1081 enrollment screen. 
For all participants from whom informed consent is obtained, but who are deemed 
ineligible or who do not enroll into the initial protocol step for any reason, a 
Screening Failure Results form must be completed and keyed into the database.  
 
 
 

 
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4.5 
Co-enrollment Procedures 
 
Co-enrollment of study infants into P1097, P1110 and P1115 are allowed. Co-
enrollment of study mothers to P1026s is permitted. Co-enrollment into other 
studies requires the approval of the NICHD P1081 protocol co-chairs and the co-
enrollment protocol team.  
 
5.0 
STUDY TREATMENT 
 
5.1 
Drug Regimens, Administration and Duration 
 
5.1.1 Drug Regimens 
 
• 
Women will be randomized to: 
 
Arm A: Lamivudine 150 mg/zidovudine 300 mg* BID + efavirenz 600 
mg QHS; or,  
 
Arm B: Lamivudine 150 mg/zidovudine 300 mg* BID + raltegravir 
400 mg BID 
______________ 
*Alternative, locally supplied NRTI backbone may be used in place of lamivudine/zidovudine with 
permission of protocol team obtained prior to randomization. 
 
Dosing during labor: All participants will continue to receive study drugs 
during labor. In addition, in place of the oral fixed dose combination of 
lamivudine 150 mg/zidovudine 300 mg (or alternative NRTI backbone), 
participants may receive intravenous zidovudine, other dosing regimens of 
oral zidovudine, oral lamivudine and/or additional drugs during labor, 
according to local standard of care/guidelines. 
 
Infants:  
 
Infants will receive ARVs according to specific local guidelines. 
 
5.1.2 Drug Administration 
 
• 
Lamivudine 150 mg/zidovudine 300 mg* 
Administered as one Lamivudine 150 mg/zidovudine 300 mg 
(Combivir) fixed-dose combination tablet by mouth BID 
 
• 
Efavirenz 600 mg  
Administered as one 600 mg tablet by mouth QHS on an empty 
stomach 
 
 
 

 
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• 
Raltegravir 400 mg  
Administered as one 400 mg tablet by mouth BID 
 
See Appendix III for dietary recommendations for ARTs. 
____________ 
*Alternative, locally supplied NRTI backbone may be used in place of lamivudine/zidovudine 
with permission of protocol team obtained prior to randomization. 
 
5.1.3 Treatment Duration 
 
All women will receive their randomized study regimen from study entry 
through delivery. Women who meet local guidelines for receiving ART 
will continue triple ART after delivery according to local guidelines. 
These women can receive study drugs for up to 8 weeks after delivery to 
facilitate the transition to local standard of care. Women randomized to 
Arm A (efavirenz) may continue lamivudine/zidovudine for a period of 
time after stopping efavirenz at the discretion of the local investigator. 
 
5.2 
Drug Formulation 
 
Lamivudine 150 mg/zidovudine 300 mg (Combivir) fixed-dose combination tablet. 
Store between 2° and 30°C (36° and 86°F). 
 
Efavirenz (Sustiva, Stocrin, EFV) 600 mg tablets. Store at 25°C (77°F); excursions 
permitted to 15° to 30°C (59° to 86°F). 
 
Raltegravir (Isentress, RAL) 400 mg tablets. Store at 20° to 25°C (68° to 77°F); 
excursions 15° to 30°C (59°to 86°F) and protect from moisture. Dispense in 
original container with desiccant. 
 
5.3 
Drug Supply, Distribution and Pharmacy 
 
5.3.1 Study Product Supply/Distribution 
 
Lamivudine 150 mg/zidovudine 300 mg (Combivir) fixed-dose 
combination tablet will be supplied by GlaxoSmithKline.  
Note: locally provided supplies of the innovator lamivudine 150 mg/ 
zidovudine 300 mg (Combivir) may be used in the event that study-
supplied lamivudine 150 mg/zidovudine 300 mg (Combivir) is not 
available at the site. Study supplies of lamivudine 150 mg/zidovudine 300 
mg (Combivir) cannot be used to replace local supplies. 
 
Efavirenz will be supplied by Merck for international sites and by Bristol-
Myers Squibb for US sites. Note: locally-provided supplies of the 
innovator efavirenz (Sustiva, Storcin) may be used in the event that study-

 
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supplied efavirenz is not available at the site. Study supplies of efavirenz 
cannot be used to replace local supplies. 
 
Raltegravir will be supplied by Merck and Company. 
Note: locally provided supplies of the innovator raltegravir may be used in 
the event that study-supplied raltegravir is not available at the site. Study 
supplies of raltegravir cannot be used to replace local supplies. 
 
Alternative, NRTI backbone and ARV regimen during labor and delivery 
used according to the specific local guidelines in place of lamivudine/ 
zidovudine (Combivir) will not be supplied by the study. 
 
5.3.2 Study Agent Acquisition/Distribution 
 
Study products will be available through the NIAID Clinical Research 
Products Management Center. The site pharmacist can obtain the study 
products for this protocol by following the instructions in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks. 
 
5.3.3 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study 
products received from the NIAID Clinical Research Products 
Management Center and subsequently dispensed. All unused study 
products in US clinical research sites must be returned to the NIAID 
Clinical Research Products Management Center  (or as otherwise directed 
by the sponsor) after the study is completed or terminated. The procedures 
to be followed are provided in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks in the section Study 
Product Management Responsibilities. 
 
6.0 
PARTICIPANT MANAGEMENT 
 
Questions concerning clinical management of study participants and all communication 
regarding adverse experiences should be addressed to the P1081 CMC at NICHD.p1081
cmc@fstrf.org. Remember to include the participant’s PID when applicable. Please do NOT 
disclose the study arm to which a participant is randomized unless specifically requested. The 
appropriate team member will respond to questions via email. A response should generally be 
received within 24 hours (Monday - Friday). 
 
6.1 
Toxicity Management 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (AEs) (DAIDS AE Grading Table), Version 2.0, dated November 
2014, must be used for screening eligibility and for grading toxicities when 

 
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specifically noted below and is available at http://rsc.tech-res.com/safetyand
pharmacovigilance/. Alternate explanations for clinical or laboratory abnormalities 
that may at first appear to be related to the study agent must be explored. 
 
Management of adverse experiences will be according to the best clinical practice 
and the judgment of the site investigator with any treatment modifications as 
described in Section 6.2. Laboratory normals will be the institutional values of the 
lab performing the tests. Abnormal clinical and laboratory findings should be 
followed until resolution to < Grade 2 or baseline.  
 
When a regimen or drug is stopped for toxicity, an alternative triple ARV regimen 
that does not predispose to the same toxicity (and which may contain drug(s) from 
the original regimen if not suspected to cause toxicity) should be immediately 
started. If this is not possible and the participant is receiving efavirenz, the 
participant may continue their NRTI combination for a period of time after 
stopping efavirenz at the discretion of the local investigator. 
 
6.1.1 General Toxicity Reporting Guidelines 
 
• 
Grade 1 or 2 Toxicity: No requirement to report to CMC. 
• 
Grade 3 or Grade 4 Toxicity:  
o The investigator should attempt to confirm any unexpected 
laboratory test results as soon as possible but always within 72 
hours to determine if the result was spurious. 
o The P1081 CMC must be notified of confirmed ≥Grade 3 Serious 
Adverse Events (SAEs) considered possibly, probably, or 
definitely related to study drugs within 72 hours at 
NICHD.p1081cmc@fstrf.org. (See Section 7.0 for EAE reporting 
guidance.)  
6.2 
Participant Management  
 
6.2.1 General Guidelines 
 
• 
The following general guidelines apply to all toxicities, unless 
superseded by directions in the following sections that give specific 
information on management of hypersensitivity reactions, liver 
toxicities, anemia, neutropenia, and elevated amylase. 
• 
If the study regimen must be permanently discontinued, another triple 
ARV regimen (which may contain drug(s) from the original regimen if 
not suspected to cause toxicity) should be started according to local 
guidelines. Study follow-up should continue regardless of regimen 
changes. 
 

 
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6.2.2 Management of General Toxicities 
 
• 
Grade 1 - Continue study drugs; routine monitoring.  
• 
Grade 2 - Continue study drugs; monitor closely with more frequent 
visits when clinically indicated. 
• 
Grade 3 - Continue study drugs while awaiting confirmatory results 
unless the clinician believes that remaining on study drugs would be 
unsafe. In this case, proceed as below. 
• 
Confirmed Grade 3 events - Study drugs should be discontinued until 
resolution to ≤Grade 2 or the site investigator has compelling evidence 
that the toxicity is definitely NOT related to study drugs. This must be 
discussed with and approved by the P1081 CMC within 72 hours of 
site awareness. If the event resolves to ≤Grade 2, in less than 7 days, 
study drugs can be restarted. If the toxicity does not resolve within 7 
days, the study drugs must be permanently discontinued and changed 
to another triple ARV regimen as described in Section 6.2.1. If the 
toxicity recurs or evolves to >Grade 3, the study drugs must be 
permanently discontinued and changed to another triple ARV regimen 
as described in Section 6.2.1. 
• 
Grade 4 (even before confirming) - All study drugs must be held or 
changed to another triple ARV regimen as described in Section 6.2.1 
unless the site investigator has compelling evidence that the event is 
not due to study drug and it would be in the best interest of the woman 
to remain on study drug. The CMC must be notified of all Grade 4 
events. This must be discussed with and approved by the P1081 CMC 
within 72 hours of site awareness. Participants experiencing AEs 
requiring permanent discontinuation of study drugs should be followed 
at least weekly until resolution of the AE to Grade ≤2 or baseline or 
until stabilized and no longer in need of such frequent monitoring, as 
determined by the site investigator. 
6.2.3 Cutaneous Toxicity and Suspected Hypersensitivity Reaction 
 
The study drugs must be permanently discontinued and changed to another 
triple ARV regimen as described in Section 6.2.1 if confirmed Grade 3 or 
4 skin toxicity occurs or if any grade cutaneous reaction occurs with any 
of the following: (a) systemic symptoms (fever, clinical hepatitis, muscle 
or joint aches); (b) allergic symptoms (urticaria, wheezing); (c) 
exfoliation; (d) mucosal involvement; or (e) elevated ALT >Grade 3, 
eosinophilia, granulocytopenia or renal dysfunction >Grade 3.  
 
 
 

 
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6.2.4 Liver Toxicity (clinical hepatitis and asymptomatic elevated 
transaminases) 
 
Grade 1 or 2 ALT (and not present at baseline): The participant must be 
carefully assessed for any symptoms or signs of hepatotoxicity, including 
fatigue, malaise, anorexia and nausea, jaundice, alcoholic stools, right 
upper quadrant pain or hepatomegaly. If asymptomatic, treatment may be 
continued. If symptoms or signs of clinical hepatitis are present, study 
drugs must be permanently discontinued and changed to another triple 
ARV regimen as described in Section 6.2.1. 
 
Participants with symptomatic or asymptomatic >Grade 3 elevations in 
ALT should have this finding confirmed with a second test within 72 
hours. Participants with confirmed >Grade 3 ALT elevation will have 
study drugs permanently discontinued and changed to another triple ARV 
regimen as described in Section 6.2.1. 
 
6.2.5 Specific Toxicity Management for Other Laboratory Abnormalities:  
 
Anemia 
Evaluate for causes of anemia other than drug toxicity. Therapy with iron, 
folate and erythropoietin are allowed if indicated. If no other cause of 
anemia is identified and Grade 2 or 3 toxicity is present (and not present at 
baseline), consider switching zidovudine to investigator-selected locally 
available NRTIs. Continuation of the study drugs is allowed with 
substitution for zidovudine. For confirmed Grade 4 toxicity for which a 
relationship to study drugs cannot be ruled out, study treatment must be 
permanently discontinued and changed to another triple ARV regimen as 
described in Section 6.2.1. 
 
Neutropenia  
Therapy with Granulocyte Colony-Stimulating Factor is allowed. If Grade 
2, 3, or 4 toxicity is present (and not present at baseline), consider 
switching zidovudine to investigator-selected locally available NRTIs. 
Continuation of the study drugs is allowed with substitution with 
zidovudine. Discuss change with the CMC.  
 
6.2.6 Management of Specific Toxicities During Pregnancy 
 
Creatinine: 
If >Grade 1, always evaluate for possible pre-eclampsia.  
 
Proteinuria:  
If >Grade 2, evaluate for possible pre-eclampsia. Grade 2-4 proteinuria by 
dipstick must be confirmed with a 24-hour urine collection. If Grade 2-3 
proteinuria is confirmed and pre-eclampsia is present, the participant may 

 
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continue study drugs. However, if Grade 3 proteinuria occurs without pre-
eclampsia or Grade 4 proteinuria is present, study drugs must be 
permanently discontinued and changed to another triple ARV regimen as 
described in Section 6.2.1. 
 
Nausea/vomiting: 
If >Grade 3 nausea/vomiting persists >3 days and is thought to be drug-
related and not pregnancy-related, study drugs must be permanently 
discontinued and changed to another triple ARV regimen as described in 
Section 6.2.1. 
 
If fetal demise occurs after study entry: 
The woman will continue to be followed on study/on treatment. In 
addition, the following must be documented: 
 
• 
Ultrasound or fetal assessment(s) performed as clinically indicated to 
diagnose fetal demise. 
• 
Assessment of antepartum complications which may have caused fetal 
demise (including but not limited to: placenta previa, abruptio 
placenta, unexplained vaginal bleeding, uterine/abdominal trauma, 
intrauterine growth retardation, oligohydramnios, polyhydramnios, 
maternal/fetal blood incompatibility, maternal alpha-feto protein 
abnormality, maternal infection, maternal substance use, cholestasis of 
pregnancy, maternal diabetes). 
• 
Obstetrical exam (fundal height, gestational age assessment, cervical 
examination if indicated). 
• 
Complete narrative of pregnancy course and assessment of relationship 
of fetal demise to study regimen sent to the P1081 CMC via email at 
NICHD.p1081cmc@fstrf.org. If available, copies of the placental 
pathology report and autopsy report are also requested. 
6.2.7 General Approach to Infant Toxicity Management 
 
Infants will be exposed to study drug in utero. Events related to study 
drugs will therefore be expected at birth or soon after.  
 
All infant events will be reported and assessed as to study drug 
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6.2.8 Follow-up of Abnormal Events and Laboratory Values 
 
All new abnormal clinical events and laboratory values occurring in 
enrolled participants will be followed closely until resolution. The urgency 
and frequency of repeat evaluations will depend on the clinical 
significance of the specific abnormality. Study clinicians will provide 
appropriate clinical management of AEs according to their best medical 
judgment and local practice. For any persistent Grade 3 or 4 clinical or 
laboratory study drug Serious Adverse Drug Reactions, evaluations should 
be repeated approximately weekly (or more frequently if necessary) until 
toxicity falls below Grade 2 or returns to baseline, and as appropriate 
thereafter. Alternate explanations will be sought for all clinical and 
laboratory abnormalities. 
 
6.2.9 Management of HIV Drug Resistance and Inadequate Virologic Response 
 
Per Section 3.2, study drugs may be started before the HIV drug-resistance 
test results from the specimen drawn at screening are available. If the HIV 
drug-resistance test results from the screening specimen identify resistance 
mutations to one or more study drugs (see Section 3.2 and Appendix IV), 
but the participant began study treatment before the resistance test results 
were available, the results should be discussed with the clinical care 
provider and the CMC. If the participant decides to discontinue one or 
more study drugs, another triple ARV regimen (which may contain 
drug(s) from the original regimen) should be started. All women enrolled 
will remain in study follow up for safety monitoring and virologic 
evaluations regardless of regimen changes. 
 
Inadequate virologic response will be managed according to local 
guidelines, in consultation with the CMC. In this study, inadequate 
virologic response is defined as follows: 
 
• 
For women with entry HIV RNA ≥10,000 copies mL, a decrease in 
HIV RNA of < 1.0 log10 after 4 weeks on study drugs. 
• 
For women with entry HIV RNA <10,000 copies/mL, HIV RNA > 
1,000 copies/mL after 4 weeks on study drugs.  
If local guidelines or the CMC’s recommendation require changing one or 
more study drugs, another triple ARV regimen (which may contain 
drug(s) from the original regimen) should be started. All women enrolled 
will remain in study follow up for safety monitoring and virologic 
evaluations regardless of regimen changes.  
 
 
 

 
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6.3 
Criteria for Treatment Discontinuation 
 
Study drugs may be discontinued for any of the following reasons: 
 
• 
The participant requires treatment with disallowed medications. 
• 
Drug toxicity that requires permanent study drug discontinuation as defined 
in Section 6.2. 
• 
The participant experiences inadequate virologic response that requires 
changing one or more study drugs per local guidelines or CMC 
recommendation, as described in Section 6.2.9. 
• 
Participant is repeatedly noncompliant with study treatment as prescribed, as 
determined by the site investigator. 
• 
Clinical reasons believed life threatening by the site investigator, even if not 
addressed in the toxicity management of the protocol. 
• 
Request of the primary care provider if s/he thinks the study treatment is no 
longer in the best interest of the participant. 
• 
Request by the participant. 
In the event of treatment discontinuation, the participant will be asked to continue 
scheduled evaluations until the end of the protocol. 
 
6.4 
Criteria for Study Discontinuation 
 
The participant will be discontinued from the study for any of the following 
reasons:  
 
• 
The participant or legal guardian refuses further treatment and/or follow-up 
evaluations and decides to discontinue participation in the study. 
• 
The investigator determines that further participation would be detrimental to 
the participant’s health or well-being. 
• 
The participant fails to comply with the study requirements so as to cause 
harm to him/herself or seriously interfere with the validity of the study results. 
• 
The study is cancelled at the discretion of the National Institutes of Health 
(NIH), the IRB or EC, FDA, Office for Human Research Protections (OHRP), 
or the pharmaceutical sponsor(s) or other governmental agencies. 
 
 

 
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7.0 
EXPEDITED ADVERSE EVENT REPORTING  
 
7.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined 
in Version 2.0, January 2010, of the DAIDS EAE Manual, which is available on 
the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
The DAERS, an internet-based reporting system, must be used for expedited AE 
reporting to DAIDS. In the event of system outages or technical difficulties, 
expedited AEs may be submitted via the DAIDS EAE Form. For questions about 
DAERS, please contact DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site 
queries may also be sent from within the DAERS application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. 
For questions about EAE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com). 
 
7.2 
Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0, January 2010, of the 
DAIDS EAE Manual, will be used for this study. 
 
The study agents for which relationship assessments are required are maternal 
raltegravir, efavirenz, lamivudine, zidovudine and other maternal ARV agents used 
during the study.  
 
In addition to reporting all SAEs as defined above, other events that sites must 
report in an expedited fashion include fetal demises, malignancies, study drug 
overdoses, all immune reconstitution inflammatory syndrome events that qualify 
as SAEs, seizures and hepatotoxicities whether or not symptomatic or related to 
study drug, and all other Grade 3 or 4 related toxicities (except Grade 3 
neutropenia and anemia) for which a relationship to study drug cannot be ruled 
out. 
  
The death of any participant after enrollment or within 30 days of study 
completion, regardless of the cause, must be reported immediately and no later 
than 3 reporting days of first becoming aware of the death. After the 30-day 
period, deaths need to be reported only as part of long-term follow-up studies. If an 
autopsy is performed, the report must be provided. Reports of all deaths must be 
communicated as soon as possible to the appropriate IRB or EC and/or reported in 
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For all SAE’s submitted to the RSC, sites must file an updated SAE report to the 
RSC with the final or stable outcome (Status Code page 5 of the EAE form) unless 
the SAE reported in the initial EAE form already had a final or stable outcome. 
 
All reports submitted to the RSC must also be documented on the appropriate 
clinical case report forms (CRFs) and submitted to the study database through the 
eData system. Reconciliation of the two databases will be performed at regular 
intervals. 
 
7.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs 
(DAIDS AE Grading Table), Version 2.0, dated November 2014, must be used and 
is available on the RSC website at http://rsc.tech-res.com/safetyandpharma
covigilance/. 
 
7.4 
EAE Reporting Period 
 
The EAE reporting period for this study for the mothers is until 30 days after 
stopping maternal study drug and for the infants it is 30 days after birth. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
Serious Unexpected Suspected Adverse Events as defined in Version 2.0, January 
2010, of the EAE Manual will be reported to DAIDS for the duration of the 
participant’s enrollment in the study, and after study completion if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
7.5 
CRF Recording Requirements for Laboratory Test Results, Signs, Symptoms, and 
Diagnoses  
 
The results of all protocol-required laboratory tests performed at screening, entry, 
and post-entry must be recorded on CRFs, regardless of severity grade.  
 
All abnormal (severity Grade 1 and higher) signs, symptoms, and diagnoses 
occurring within 30 days prior to study entry must be recorded on CRFs. All 
abnormal (severity Grade 1 and higher) signs, symptoms, and diagnoses occurring 
post-entry must also be recorded on CRFs at all visits. 
 
 
 

 
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8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
General Design Issues 
 
This is a multicenter, international, two-arm, open-label randomized trial of two 
potent triple ARV regimens in HIV-infected pregnant women who are ARV naïve 
or have received short-course zidovudine (maximum of 8 weeks) only for PMTCT 
in previous pregnancies, and are initiating ARVs between 28 and 36 weeks 
gestation. The primary objectives are to compare the two regimens with respect to 
the ability to achieve a plasma viral load <200 copies/mL at delivery, tolerability 
and safety. The secondary objectives are to compare the kinetics of viral decay, 
compare infant outcomes, and assess baseline prevalence of HIV-1 drug resistance 
and selection of new drug-resistance mutations. The exploratory objectives focus 
on describing population PK parameters and their potential relationships with 
pharmacogenomics and viral load changes; and the maternal vaginal and infant 
nasopharyngeal and oropharyngeal microbiome environment and their potential 
association with adverse infant outcomes. 
 
The target sample size is 334 evaluable women (approximately 167 per arm), 
which is anticipated to require enrolling approximately 394 women over a period 
of approximately 3 years (see Section 8.4 for details). 
 
The choice of the primary efficacy endpoint is complex because women will enroll 
and deliver at various gestational ages, so that the duration of treatment prior to 
delivery will range from a few days to 12 weeks. Desirable characteristics for an 
ARV regimen being initiated in the third trimester of pregnancy for PMTCT 
include the ability to reduce viral load as quickly as possible, to achieve virologic 
suppression by the time of delivery, and to be well tolerated (to avoid treatment 
interruptions which could lead to loss of suppression).  
 
The primary efficacy analysis will compare the proportions of women who achieve 
viral load <200 copies/mL at delivery (or if there is no viral load measurement at 
delivery, at the closest measurement prior to delivery) and the primary tolerability 
analysis will compare the proportions of women who discontinue efavirenz or 
raltegravir (whichever was assigned) prior to delivery. However, an important 
secondary analysis will use a composite outcome measure that combines efficacy 
and tolerability, specifically a composite binary outcome measure of (1) rapid viral 
load decrease which is sustained until delivery, defined as both achieving a 
specified minimum drop in plasma HIV-1 RNA from entry to week 2 (see Section 
8.2.2 for details) and maintaining plasma HIV-1 RNA <1,000 copies/mL after 4 
weeks on study drugs until delivery, and (2) tolerability defined as remaining on 
efavirenz or raltegravir (whichever was assigned) until delivery. One limitation of 
this composite outcome measure is that the relative importance of its components 
may differ according to anticipated treatment duration; for example, for a woman 
who presents late in the third trimester, it may be most important to maximize the 
viral load reduction within the first 2 weeks even if tolerability issues arise after 

 
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several weeks of treatment, while for a woman who presents at the beginning of 
the third trimester, the ability to sustain viral load suppression and be tolerated for 
up to 12 weeks becomes more important. Since the regimen that achieves the best 
response rate on the composite outcome measure may not necessarily dominate all 
of its components, additional analyses will compare the treatment arms with 
respect to each component of the composite endpoint (rapid viral load decrease 
from entry to week 2, viral load <1,000 copies/mL after 4 weeks on study drugs 
until delivery, and tolerability) to provide additional insight into the results of the 
composite outcome measure analysis.  
 
HIV drug resistance testing for the study drugs will be done at screening. 
Depending on site capabilities for HIV drug resistance testing, results may only be 
available in 1-3 weeks. Since these are late presenting women and it is important to 
start ARVs as soon as possible to maximize prevention of perinatal HIV 
transmission, the women may be randomized and started on study ARV prior to 
receipt of the resistance test results. However, the women and their providers may 
decide to discontinue the study drugs once the HIV drug resistance test results are 
available, which greatly complicates the statistical analyses and interpretation of 
the study results. The frequency of resistance to specific study drugs may differ 
(e.g., efavirenz resistance may be more common than raltegravir resistance), which 
could lead to differential rates of study drug discontinuation in the randomized 
study arms. Also, the decision as to whether or not to change the study ARVs may 
be subjective and may depend on which study drug is involved (e.g., a regimen 
change may be more likely if an efavirenz resistance mutation is identified than if 
a lopinavir resistance mutation is identified, because high-level resistance can 
develop with just a single efavirenz resistance mutation but only with multiple 
lopinavir resistance mutations) and on factors that are also related to the likelihood 
of treatment success or failure (e.g., viral load), which could introduce 
confounding. Finally, the proportion of women who receive the results of the 
resistance test on the screening specimen before enrollment (and may therefore 
become ineligible for enrollment) may differ between sites. After extensive debate 
over various analysis approaches, the protocol team has decided that the best 
approach would be to exclude from the primary analysis all randomized 
participants who are later discovered to have had detectable genotypic resistance 
(as defined in Appendix IV) to any of the study ARVs in any of the study arms at 
screening (whether or not they decided to switch ARVs), and to increase the 
sample size accordingly to maintain the desired power. This post-randomization 
exclusion will be balanced across the randomized arms and avoid bias because it 
will be based on a pre-randomization characteristic (resistance to any of the study 
ARVs in any of the study arms), though the results of the primary analyses will 
generalize only to the population of women who do not have resistance to any of 
the study ARVs.  
 
The women who are excluded from the primary analyses due to resistance at 
screening will be included in secondary analyses, which will attempt to compare 
the two real-world strategies of starting therapy with either Arm A or Arm B and 

 
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possibly switching ARVs when the resistance test results become available. Note 
that these secondary analyses may be hard to interpret if women with resistance at 
screening are more often excluded from enrollment at some sites than at others 
(e.g., due to more rapid turnaround for the resistance testing). Data will be 
collected on the reasons for non-enrollment of women who have consented, to 
inform the interpretation of the results and permit sensitivity analyses restricted to 
sites with high rates of enrollment of the women who turn out to have drug 
resistance mutations in the specimen drawn at screening.  
 
An open-label trial is proposed because the number of pills per day and frequency 
of administration vary between treatment arms. Potential sources of bias with an 
open-label study include increased attribution and reporting of specific toxicities in 
a treatment arm. Also, physicians may be more likely to change ART if the 
treatment arm is perceived as suboptimal and this could introduce bias to the 
tolerability analyses. An attempt will be made to minimize these biases by setting 
up stringent criteria for toxicity management (Section 6.1), participant 
management including regimen modification (Section 6.2), treatment 
discontinuation (Section 6.3), and inadequate virologic response (Section 6.2.9).  
 
8.2 
Outcome Measures 
 
8.2.1 Primary Outcome Measures 
 
Efficacy:  
 
• 
Plasma HIV-1 viral load <200 copies/mL at the delivery visit (or if 
there is no viral load measurement at the delivery visit, viral load <200 
copies/mL within 3 weeks prior to delivery).  
 
Evaluable women will be those who have a viral load measurement at the 
delivery visit or within 3 weeks prior to delivery. Non-evaluable women 
(missing viral load measurement due to missed visits, specimen or 
laboratory error) will be excluded from the primary analysis. Sensitivity 
analyses will be conducted to assess the potential impact of missing 
evaluations on the conclusions of the study (see Section 8.6 for details). 
 
Tolerability until labor and delivery:  
 
• 
Discontinuation of efavirenz or raltegravir (whichever was assigned) 
prior to labor and delivery for any reason (including loss to follow-up) 
will be considered a treatment failure in this analysis (note: switching 
any of the NRTIs with continuation of efavirenz or raltegravir will not 
be considered a treatment failure).  
 
Women who received at least one dose of efavirenz or raltegravir will be 
evaluable for the tolerability analysis. 
 

 
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Safety through week 24 postpartum:  
 
• 
Maternal and infant AEs of Grade ≥3 as defined in the DAIDS toxicity 
table. 
 
Women who received at least one dose of a study drug, and their infants 
will be evaluable for the safety outcome measures. 
 
8.2.2 Secondary Outcome Measures 
 
Secondary Efficacy Outcome Measures 
 
• 
Virologic suppression to below the lower limit of quantification of the 
assay at delivery. 
• 
Composite outcome measure that combines efficacy and tolerance: 
binary outcome measure of (1) a successful viral load (plasma HIV-1 
RNA) decrease from entry to study week 2 (day 11-17) and viral load 
<1,000 copies/ml at all time points after 4 weeks on study drugs, until 
delivery; and (2) tolerability (remaining on the assigned study 
regimen). The viral load decrease and tolerability components of the 
composite outcome measure will be defined as follows:  
o Rapid viral load decrease for women who deliver after 4 weeks on 
study drugs: A successful viral load decrease is defined as having 
both (i) a plasma HIV-1 RNA level ≥2.0 log10 below baseline or 
<200 copies/mL at study week 2 (day 11-17) and (ii) a plasma HIV-
1 RNA level <1,000 copies/mL at all time points after 4 weeks on 
study drugs, until delivery. Evaluable women delivering after 4 
weeks on study drugs are those with a viral load measurement at 
study week 2 (day 11-17) and at least one subsequent viral load 
measurement after 4 weeks on study drugs and before or during 
labor/delivery. 
o Rapid viral load decrease for women who deliver before or at 4 
weeks on study drugs: A successful viral load decrease is defined as 
a plasma HIV-1 RNA level ≥2.0 log10 below baseline or <200 
copies/mL at study week 2 (day 11-17). Evaluable women 
delivering before or at 4 weeks on study drugs are those with a viral 
load measurement at study week 2 (day 11-17). 
o Tolerability: Discontinuation of efavirenz or raltegravir prior to 
delivery for any reason (including loss to follow-up) will be 
considered a treatment failure in this analysis (note: switching any 
of the NRTIs with continuation of efavirenz or raltegravir will not 
be considered a treatment failure). All women who received at least 
one dose of efavirenz or raltegravir will be evaluable for the 
tolerability component of the composite outcome measure. 

 
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The baseline value will be the value obtained at the study entry visit. If 
this value is not available, then the baseline value will be the screening 
value.  
 
Non-evaluable women (missing viral load measurement due to early 
delivery, missed visits, specimen or laboratory error) will be excluded 
from the analysis. Differential rates of non-evaluability or preterm 
delivery between study arms could lead to biased results; for example, an 
excess of preterm deliveries in one arm could lead to more women in that 
arm delivering before 4 weeks on study drugs and therefore not needing to 
maintain viral load <1,000 copies/ml after 4 weeks on study drugs, which 
could inflate the response rate in that arm. To address this concern, the 
rates of non-evaluability and preterm delivery will be compared between 
study arms, additional analyses will compare the study arms with respect 
to each individual component of the composite outcome measure, and 
sensitivity analyses will be conducted to assess the potential impact of 
missing evaluations on the conclusions of the study (see Section 8.6 for 
details). 
 
Kinetics of viral decay 
• 
Viral load in maternal blood and vaginal swabs at weeks 4 and 6 after 
starting treatment. 
• 
Log10 change in viral load from entry (or screening, if there is no entry 
viral load) to each time point prior to delivery.  
• 
Infectivity of plasma during the initial 2 weeks of ART. 
Infant outcomes 
• 
Stillbirth/fetal demise, premature birth (<34 or <37 weeks gestation), 
low birth weight (<1500 or <2500 grams), infant HIV infection status 
(per International Maternal Pediatric Adolescent AIDS Clinical Trials 
(IMPAACT) definitions), neurodevelopmental outcomes (described in 
Appendix VII); resistance in HIV-infected infants.  
HIV-1 drug resistance 
• 
HIV-1 drug resistance mutations at screening, at 2-4 weeks postpartum 
in women who have stopped ART, and at the time of inadequate 
virologic response (defined in Section 6.2.9) using standard and 
ultrasensitive genotyping methods.  
 
 

 
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8.2.3 Exploratory Outcome Measures 
 
• 
PK parameters as described in the Clinical Pharmacology Plan 
(Section 9.0). 
• 
Maternal vaginal or infant oral and respiratory microbiota.  
• 
Infant lower respiratory tract infections and serious infections with 
encapsulated bacteria.  
8.3 
Randomization and Stratification 
 
A dynamic permuted block system will be used to randomize women in 
approximately equal numbers to either the efavirenz-based or raltegravir-based 
triple ARV regimen, with balancing by institution. To ensure balance in the 
treatment groups, the randomization will be stratified by gestational age at 
enrollment (28-30 weeks or 31-33 weeks or 34-36 weeks) and the chosen NRTI 
backbone (lamivudine/zidovudine vs. alternative locally supplied NRTI backbone). 
There will be no limit on the number of women in each stratum. The rationale for 
stratifying the randomization by gestational age is that women who enter the study 
later in gestation will be less likely to achieve the desired viral load decrease 
compared with women who enroll earlier in gestation. The rationale for stratifying 
the randomization by the chosen NRTI backbone is ensure balance in the two 
treatment arms, in case of unforeseen differential effects on viral load, tolerance, 
safety, or pregnancy outcomes. 
 
8.4 
Sample Size and Accrual 
 
8.4.1 Sample Size 
 
The sample size was chosen to provide 80% power to detect an important 
difference between treatment arms in the primary efficacy outcome 
measure (defined in Section 8.2.1), with a two-sided Type I error rate (α) 
of 0.05, and allowing for interim efficacy analyses and non-evaluable 
women. A difference of 15% or more between treatment arm response 
proportions was deemed important to detect.  
 
In IMPAACT P1025, a cohort study of HIV-infected pregnant women at 
IMPAACT sites in the US, 67 (76%) of 88 women who initiated a triple 
ARV regimen (most commonly protease-inhibitor based) in the third 
trimester achieved a viral load <400 copies/mL at delivery, and the 
adjusted probability in a multivariable model was 79% (95% confidence 
interval 69% to 87%).(79)  In a multicenter randomized placebo-controlled 
trial of raltegravir-based versus efavirenz-based combination therapy in 
treatment-naïve adults (19% women) with no baseline resistance to 
efavirenz, tenofovir, or emtricitabine, the proportion of participants 
achieving viral load <50 copies/ml after 8 weeks of treatment (the 

 
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anticipated median duration of treatment in P1081) was approximately 
75% in the raltegravir arm and approximately 39% in the efavirenz arm 
(102); note that this analysis counted those who did not complete the study 
treatment as failures (3.2% in the raltegravir arm and 6% in the efavirenz 
arm), which differs from the P1081 primary endpoint. Based on these 
studies, the P1081 team anticipates the response proportion in the 
raltegravir arm to be approximately 75% and selected the sample size to 
provide 80% power to detect a difference in response proportions of 75% 
versus 60%.  
 
Table 1 shows the sample sizes required to provide 80% power to detect a 
15% difference in response probabilities between treatment arms with 
two-sided α=0.05, allowing for two interim efficacy analyses and non-
evaluable women (defined in Section 8.2.1). A sample size of 334 
evaluable women (approximately 167 per arm) would be required for 80% 
power to detect a difference in response proportions of 75% vs. 60% 
between treatment arms. If 5% of enrolled women are non-evaluable for 
the primary outcome measure and 10% of enrolled women (based on the 
studies summarized in Section 1.6) are excluded from the primary 
analyses due to genotypic resistance to any of the study drugs at screening 
(as defined in Appendix IV), a total of 394 women (approximately 197 per 
arm) would need to be enrolled. The proportions of women who are non-
evaluable or have genotypic resistance to any of the study drugs at 
screening will be monitored (see Section 8.5) and the target accrual will be 
modified accordingly if needed.  
 
Table 1: 
Sample size required to provide 80% power to detect a 15% 
difference in response proportions between treatment arms 
with two-sided alpha=0.05*. 
Response 
Proportions** 
Number of 
evaluable women 
per treatment arm 
Total accrual 
required per 
treatment arm# 
Total accrual 
required (both arms 
combined)# 
50% vs. 65% 
184 
217 
434 
60% vs. 75% 
167 
197 
394 
70% vs. 85% 
135 
159 
318 
80% vs. 95% 
90 
106 
212 
* Two-sided Chi-square test with continuity correction, allowing for two interim analyses 
and one final analysis with Haybittle-Peto spending function. Calculated using PASS 11 
software. 
**Each scenario also covers the symmetric scenario above 50% (obtained by subtracting 
each percentage from 100%); for example, the sample sizes for 60% vs. 75% would be 
the same as the sample sizes for 40% vs. 25%. 
# Allowing for 5% non-evaluable and 10% excluded due to ARV resistance at screening. 
 

 
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Table 2 shows the power to detect various 15% differences in response 
proportions between treatment arms with the selected sample size of 334 
evaluable women. The power would be at least 76% in all scenarios and would 
be greater than 80% if the response proportions were both above 60%.  
 
Table 2: 
Power to Detect Various 15% Differences in Response 
Proportions with N=334 Evaluable Women and alpha=0.05*. 
Response Proportions** 
Power with N=167 evaluable women per arm 
50% vs. 65% 
76% 
60% vs. 75% 
80% 
70% vs. 85% 
88% 
80% vs. 95% 
98% 
*Two-sided Chi-square test with continuity correction, allowing for two interim analyses 
and one final analysis with Haybittle-Peto spending function. Calculated using PASS 11 
software. 
**Each scenario also covers the symmetric scenario above 50% (obtained by subtracting 
each percentage from 100%); for example, the sample sizes for 60% vs. 75% would be 
the same as the sample sizes for 40% vs. 25%. 
 
In the event that the target number of evaluable participants is not reached, 
Table 3 gives the power to detect a 15% difference between arms (60% vs. 
75% or 65% vs. 80%) with different numbers of evaluable participants per 
treatment arm. The power would remain >75% if at least 155 women per 
arm were evaluable, and this sample size would provide at least 80% 
power to detect a 15% difference if both response proportions were above 
65%. 
 
Table 3: 
Power to Detect a 15% Difference in Response Proportions 
with Different Numbers of Evaluable Women*. 
Number of 
evaluable women 
per treatment arm 
Power to Detect Difference  
in Response Proportions of  
60% vs. 75% 
Power to Detect Difference  
in Response Proportions of  
65% vs. 80% 
145 
74% 
78% 
150 
75% 
79% 
155 
77% 
81% 
160 
78% 
82% 
165 
80% 
83% 
* Two-sided Chi-square test with continuity correction, allowing for two interim analyses 
and one final analysis with Haybittle-Peto spending function. Calculated using PASS 11 
software. 
 
 
 

 
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8.4.2 Accrual 
 
Enrollment to Version 2.0 of the P1081 protocol was paused on December 2, 
2014, and a total of 19 women were enrolled by then. The Version 2.0 
women who were enrolled to the efavirenz and raltegravir arms will be 
included in the Version 3.0 analyses and will count toward the target sample 
size. 
 
Enrollment to P1081 will resume when Version 3.0 of the protocol is 
approved. Taking into account the varying time required for regulatory 
and bioethics approval at the anticipated study sites, the protocol team 
expects that the Brazil, Thailand, and US sites will resume enrollment 
during the first 12 months after the Version 3.0 amendment is released and 
will enroll 30-35 women during that period; after all these sites are 
enrolling, the protocol team expects that the accrual rate will reach 10-11 
per month. The protocol team expects the African sites to be ready to 
begin enrollment about 12 months after the amendment is released and 
projects that the overall enrollment rate will reach about 18 enrollments 
per month (if all sites open as expected) in the second year after the 
amendment is released, so that enrollment can be completed during the 
third year after the amendment is released. The proportions of women who 
are non-evaluable (as defined in Section 8.2.1) or who are found to have 
had genotypic resistance to any of the study drugs at screening (as defined 
in Appendix IV) will be monitored and the target accrual will be modified 
accordingly if needed.  
 
The study team does not expect any clinically important race/ethnicity 
differences in the intervention effect and is not aware of any studies that 
strongly support or negate the existence of such differences. While the 
P1081 sample size is not sufficient to provide high statistical power to 
detect such differences, analyses describing the intervention effect 
according to race/ethnicity will be performed per NIH policy. Since P1081 
will not enroll men, it will not be possible to assess whether or not the 
intervention effect may vary according to gender.  
 
8.5 
Monitoring 
 
8.5.1 Routine Monitoring 
 
The core protocol team (which will have the same membership as the 
study CMC defined in Section 6.0) will have regular conference calls to 
ensure that its members are aware of ongoing issues concerning the 
conduct of the study and will review reports about the status of the study 
on a monthly basis (the frequency may be decreased if the study team 
deems this appropriate). These will include reports on accrual, baseline 
characteristics, AEs, specimen completeness, and the proportions of 

 
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women who are non-evaluable for the primary outcome measure or are 
found to have had genotypic resistance to any of the study drugs at 
screening (as defined in Appendix IV). These reports will present results 
that are pooled across the randomized treatment arms and not broken out 
according to arm.  
 
The core protocol team will monitor safety closely. A summary of 
maternal and infant AEs will initially be generated monthly to help 
identify possible safety issues early on. The frequency of these reports 
may be decreased to bimonthly or quarterly if no significant safety 
concerns are identified.  
 
Accrual to this study will be monitored by the NICHD and protocol co-
chairs in accordance with standard operating procedures. Also, the team 
will monitor site protocol activation of the African sites to ensure that the 
number of sites participating is sufficient to complete the accrual in a 
timely fashion. If accrual is not adequate to meet the enrollment goals 
specified in Section 8.4.2, the team will identify the reasons for lack of 
accrual and possibly amend the protocol accordingly. 
 
A full protocol monitoring plan with more specific details will be prepared 
before the study opens to accrual.  
 
8.5.2 Interim Analyses 
 
This study will also be monitored by a NIAID-sponsored Data and Safety 
Monitoring Board (DSMB). The DSMB will review information 
concerning accrual, characteristics of participants, quality and 
completeness of data and specimen collection, retention, AEs, and the 
proportions of women who are non-evaluable for the primary outcome 
measure or who are found to have had genotypic resistance to any of the 
study drugs at screening (as defined in Appendix IV) at least annually 
after the first woman is randomized.  
 
Two interim efficacy analyses will be conducted when data on the primary 
outcome measure are available for approximately one third and two thirds 
of the planned enrollment. Under the accrual assumptions in the protocol, 
we anticipate that these interim analyses would be reviewed 
approximately one year and two years after the first enrollment to Version 
3.0. The interim efficacy analysis schedule may be modified if accrual 
assumptions turn out to be inaccurate or if recommended by the DSMB.  
 
 
 

 
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The interim efficacy analyses will be based on comparison of the primary 
outcome measure between treatment arms, as described in Section 8.6. 
The Haybittle-Peto stopping boundary will be used as a guideline for 
considering a recommendation of early stopping. This guideline requires a 
p-value <0.001 at an interim analysis for early stopping to be considered. 
 
To assist with decisions about recommending early stopping for lack of 
benefit (futility), conditional power and predicted interval analyses will be 
presented to the DSMB. The conditional power analysis will assess the 
power to detect the hypothesized treatment differences specified in 
Section 8.4 upon continuation, conditional on the data observed so far. 
The predicted interval analysis will provide information on effect size 
estimates and potential improvement in precision upon continuation, under 
various assumptions regarding the data yet to be collected (e.g., that 
hypothesized treatment differences are true, that the observed trend 
continues, that the null hypothesis is true, and under best-case and worst-
case scenarios).(80)  As a non-binding guideline for lack of benefit 
(futility), if the conditional power is low, say less than 20%, and the 
projected improvements in precision of effect estimates upon continuation 
are small, a recommendation of early termination may be considered. 
However, due to the lack of and need for efficacy and safety data for 
potent ARV regimens in the P1081 study population, the protocol team 
requests that the DSMB consider both the results of the above analyses 
and other factors that may argue for or against continuation (including 
whether there are safety or ethical concerns, the accrual rate, information 
to be gained from secondary objectives and sub-studies, new internal or 
external scientific information, and the existence/progress of other trials 
addressing the study questions), in deciding whether to recommend early 
stopping.  
 
Although a recommendation for early termination would be based 
primarily on the primary efficacy analysis, consideration should be given 
to the consistency of effects seen on the primary and secondary efficacy 
outcome measures. Strong evidence of a difference in the primary 
outcome measure favoring one arm, but with evidence favoring the other 
arm with an important secondary efficacy outcome measure, might 
support the continuation of both arms. However, a significant difference 
between arms with respect to a secondary efficacy outcome measure, in 
the absence of strong evidence of a difference with respect to the primary 
outcome measure, would not be grounds for early stopping of an arm. 
 
 
 

 
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8.6 
Analyses 
 
A statistical analysis plan specifying full details of all proposed analyses will be 
developed prior to the commencement of analyses for the first review by the 
DSMB. Here we limit the description of the proposed analyses to those for the 
primary outcome measures. Unless otherwise indicated, all analyses will follow 
the intent-to-treat principle and will include all women randomized. As discussed 
in Section 8.1, women who are found to have had genotypic resistance at screening 
to any of the study drugs (as defined in Appendix IV) will be excluded from the 
primary analyses and included in secondary analyses. 
 
The primary efficacy analysis will be based on a comparison of the primary 
outcome measure, namely the proportions of evaluable women (as defined in 
Section 8.2.1) in each arm who achieve viral load <200 copies/mL at delivery using 
the Cochran-Mantel-Haenszel test, stratified according to gestational age at 
enrollment (28-30 weeks versus 31-33 weeks versus 34-36 weeks). [Note that the 
analysis will not be stratified according to the chosen NRTI backbone.] Secondary 
efficacy analyses will compare the treatment arms with respect to the composite 
efficacy/tolerability outcome measure and each component of this composite 
outcome measure (rapid viral load decrease from entry to week 2, viral load <1,000 
copies/mL after 4 weeks on study drugs until delivery, and tolerability). In light of 
the conservative spending function that will expend minimal Type I error in the 
interim efficacy analysis, unadjusted point estimates, p-values, and confidence 
intervals will be presented to summarize the results in the final analysis.  
 
Sensitivity analyses will be conducted to assess the potential impact of missing 
data on the conclusions of the study. Of primary concern are missing viral load 
measurements at delivery for women who have achieved a successful viral load 
decrease at time points at which measurements are available. The sensitivity 
analyses will be done in two ways: (a) as an extreme, by assuming that a missing 
viral load measurement at delivery would have shown successful or unsuccessful 
viral load decrease in a way that would minimize the difference between 
randomized groups, and (b) more plausibly, by assuming that a missing viral load 
measurement at delivery would have shown an unsuccessful viral load decrease 
with probability equal to the estimated probability of an unsuccessful viral load 
decrease at delivery among women in the same group who had that evaluation and 
had a successful viral load decrease at other evaluations prior to delivery. 
 
Secondary efficacy analyses will repeat the above analyses with all evaluable 
participants included, regardless of whether or not genotypic resistance to any of 
the study drugs was detected at screening. These analyses will compare the two 
real-world strategies of starting therapy with either Arm A or Arm B and possibly 
switching ARVs when the resistance test results become available, subject to the 
potential biases described in Section 8.1. These analyses will be conducted two 
ways: (1) with switching ARVs due to the screening resistance test results 

 
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considered to be a treatment failure; and (2) with switching ARVs due to the 
screening resistance test results not counted as a treatment failure. 
 
The final tolerability and safety analyses will each be based on a comparison of the 
proportions of women and infants in each arm who meet the primary tolerability 
and primary safety outcome measures specified in Section 8.2.1, using the 
Cochran-Mantel-Haenszel test, stratified according to gestational age at enrollment 
(28-30 weeks or 31-33 weeks or 34-36 weeks). 
 
The final analysis will be performed after all women and infants have completed 
the week 24 study visit.  
 
9.0 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Pharmacology Objectives 
 
The clinical pharmacology objectives of this study are: 
 
• 
To describe efavirenz and raltegravir PK parameters during the third trimester 
of pregnancy.  
• 
To assess the potential relationships between ARV concentrations and viral 
load changes/viral decay. 
Rationale – Few clinical trials describe the pharmacology of ARV drugs in 
pregnant women, limiting our ability to design appropriate dosing schedules for 
these agents in pregnant woman infected with HIV. The few ARV pregnancy 
pharmacology studies that exist have primarily involved non-randomized cohort 
studies with intensive PK sampling. The populations in these studies may represent 
only a subset of pregnant HIV-infected women and the studies include no PD 
assessments of the relationships between ARV concentrations and viral load 
response. As virologic response and MTCT may be related to drug exposure in 
plasma, data from this trial may greatly improve our understanding of both the PK 
and PD of ARVs during pregnancy. 
 
9.2 
Primary and Secondary Data 
 
9.2.1 PK Sampling Data  
 
9.2.1.1 
Dosing history (date, time and amount of last two doses of 
study drug prior to study dose and of study dose) 
9.2.1.2 
Last two meals (dates and times, description) (See Appendix 
III) 
9.2.1.3 
Height and weight on day of sampling and pre-pregnancy 
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9.2.1.4 
Date and time PK samples drawn 
9.2.1.5 
Efavirenz, 8-hydroxy-efavirenz and raltegravir concentrations 
in sparse PK samples 
9.2.1.6 
Ratio of unbound/total drug concentrations for efavirenz  
9.2.1.7 
Maternal plasma alpha-1 acid glycoprotein and albumin 
concentrations  
9.2.2 Demographic and Historical Data 
 
9.2.2.1 
Maternal age and race/ethnicity  
9.2.2.2 
Infant gestational age, birth length and weight 
9.2.2.3 
Date, name, frequency and route of administration for non-
ARV medications taken in last 7 days 
9.2.2.4 
Maternal laboratory studies: complete blood count (CBC) with 
differential and platelets, AST, ALT, total bilirubin, blood urea 
nitrogen (BUN), electrolytes, glucose, creatinine, total amylase 
and HIV RNA 
9.2.3 Infant HIV Infection Status 
 
9.2.4 PK Parameters 
 
9.2.4.1 
Population CL/F. V/F, and, t1/2; mean and population 
variances for all drugs 
9.2.4.2 
Individual predicted empiric Bayesian CL/F. V/F, t1/2, steady-
state pre-dose concentrations and AUC 
9.3 
Laboratory Analysis and Reporting 
 
Site: Plasma PK samples will be sent to the IMPAACT Specialized Clinical 
Pharmacology Laboratory at University of California, San Diego, where they will 
be assayed for plasma concentration of raltegravir, efavirenz and alpha-1 acid 
glycoprotein. Specimens may then be shipped to other IMPAACT or ACTG 
Specialized Clinical Pharmacology Laboratories depending on assay availability 
and work load. All samples will be destroyed after the primary assays have been 
completed for the PK/PD studies.  
Methods to be used: All methods will be standardized with a filed Methods Report, 
under Good Clinical Laboratory Practice conditions such as those currently used in 

 
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the University of California, San Diego and University of Alabama at Birmingham 
labs, or will be derived from published methods.  
Reporting of Assay Data: Assays will be batched in sufficient participant numbers 
to provide analysis by routine assays. All PK samples will be registered in the 
Laboratoy Data Management System (LDMS) database.  
9.4 
Study Design, Modeling, and Data Analysis 
 
Women will be randomized 1:1 to receive lamivudine/zidovudine* + efavirenz or 
lamivudine/zidovudine* + raltegravir to compare the virologic response, 
tolerability, and safety of two different potent drug regimens.  
*Or alternatively locally supplied NRTI backbone 
 
All women will have single random plasma samples collected for drug assay at 
study visits starting with week 1 after entry and at all subsequent antenatal visits. 
Samples will also be collected from participants still receiving study ARVs at the 
2-4 week postpartum visit.  
 
Demographic data, recent dosing history including food intake, delivery 
information and sample collection times will be collected. Alpha-1 acid 
glycoprotein and albumin concentrations will be determined from one of the PK 
samples. Raltegravir, or efavirenz and 8-hydroxy-efavirenz concentrations will be 
measured in these specimens.  
 
The sparse PK data from the single samples will be used in a population PK/PD 
analysis for each drug with the program NONlinear Mixed-Effect Modeling 
(NONMEM). An open one-compartment with first order absorption will be 
employed as the base model. Alternative and more complex models will be 
evaluated as indicated by the data. These data may be nested with intensive third 
trimester PK data from IMPAACT P1026s to assist in describing the drug 
absorption and distribution phases of the concentration time profile. The influence 
of covariates on ARV disposition will be assessed; specifically age, height, weight, 
sex, binding protein concentrations, ethnicity, 8-hydroxy-efavirenz concentrations 
and duration of therapy and laboratory measurements. 8-hydroxy-
efavirenz/efavirenz ratios will be used to assess CYP 2B6 activity and help 
identify the poor metabolizer phenotype sub-population. Empiric Bayesian post-
hoc estimates of individual participant’s apparent clearance, apparent volume of 
distribution and drug exposure will be determined and will be generated for further 
exploratory analyses. Relationships between drug exposure parameters and 
virologic response parameters will be explored. 
 
 
 

 
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9.5 
Anticipated Outcomes 
 
The data from this study will allow unique PK/PD analyses for raltegravir and 
efavirenz during pregnancy. PK parameters during pregnancy will be compared to 
historical PK data from non-pregnant adults and will provide additional 
information regarding the variability of ARV drug exposure during pregnancy. 
Post-hoc estimates of ARV AUC, plasma concentration at end of dosing interval 
and intra-participant variability will serve as the basis for exploratory analyses of 
the relationship between viral load changes and viral decay with raltegravir and 
efavirenz exposure.  
 
10.0 
HUMAN SUBJECTS 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
Guidelines and 45 Code of Federal Regulations Part 46. 
 
10.1 
Institutional Review Board and Informed Consent 
 
This protocol, the informed consent documents (Appendix VI) and any subsequent 
modifications must be reviewed and approved by the IRB or EC responsible for 
oversight of the study. Written informed consent must be obtained from the 
participant (or parents or legal guardians of participants who cannot consent for 
themselves, such as those below the legal age). The participant’s assent must also 
be obtained if he or she is able to understand the nature, significance, and risks of 
the study. The informed consent will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy of 
the consent form will be given to the participant (or parent or legal guardian). 
Each site which receives US Department of Health and Human Services funding 
and follows the US Code of Federal Regulations Title 45-Public Welfare, Part 46-
Protection of Human Subjects (also known as the Common Rule) should have on 
record at the site a plan that detects and addresses any change in guardianship 
occurring in pediatric participants and determines when a study participant must 
have a consent process which involves a legally authorized representative (LAR) 
other than a family member with guardianship. The plan will include how the site 
determines when a LAR is initially or no longer needed and how frequently the 
LAR re-signs the consent. The plan should follow all IRB/EC, local, state, national 
and/or host country guidelines. Confirmation of such a plan at a site should be 
submitted with protocol registration materials. 
 
10.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be 
identified only by a coded number to maintain participant confidentiality. All 
records will be kept in a secured area with limited access. All computer entry and 
networking programs will be done with coded numbers only. Clinical information 
will not be released without written permission of the participant, except as 

 
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necessary for monitoring by the FDA, Office for Human Research Protections 
(OHRP), the local IRB or EC, local or national regulatory agencies, NIH, study 
staff, and study monitors, and other sponsors, as applicable the Safety Monitoring 
Committee, and other sponsors, as applicable. 
 
 
The protocol chairs and all employees and coworkers involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, 
record, or other unpublished confidential information disclosed to those 
individuals for the purpose of the study. Prior written agreement from NIH must be 
obtained for the disclosure of any said confidential information to other parties. 
 
10.3 
Study Discontinuation 
 
The study may be discontinued at any time by NIH, FDA, and OHRP, the IRB or 
EC, the pharmaceutical sponsors, or other governmental agencies as part of their 
duties to ensure that research participants are protected.  
 
11.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by NICHD policies. Any 
presentation, abstract, or manuscript will be made available for review by the 
pharmaceutical sponsors prior to submission. 
 
12.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention. 
All infectious specimens will be sent using the ISS-1 SAF-T-PAK mandated by the 
International Air Transport Association Dangerous Goods Regulations-Packing 
Instruction 602. Refer to individual carrier guidelines (e.g., Federal Express or Airborne) 
for specific instructions. 

 
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49. 
Borkow G, J. Barnard T,.Nguyen M, Belmonte A, Wainberg MA, and Parniak MA. 1997. 
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retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoiside inhibitor of HIV-1 
reverse transcriptase. J. Virol. 71:3023-3030, 1997.  
50. 
Antimicrob Agents Chemother. 2002 Jun;46(6):1851-6. 
51. 
Langley HK, Samanta ZL, Walker MA, Krystal MR, and Dicker IB, The Terminal 
(Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissociation 
of HIV Integrase Strand Transfer Inhibitors. Biochemistry 2008, 47, 13481–13488. 
52. 
Coovadia A, Hunt G, Abrams EJ, Sherman G, Meyers T, Barry G et al.: Persistent 
Minority K103N Mutations among Women Exposed to Single-Dose Nevirapine and 
Virologic Response to Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy. 
Clin Infect Dis 2009. 
53. 
Ellis GM, Hitti J, Frenkel L. Increased Resistance to Lamivudine Detected in HIV-
Positive Pregnant Women Discontinuing Zidovudine (AZT), Lamivudine (3TC), and 
Nelfinavir (NFV): Results of PACTG 1022. CROI 2009. 
54. 
Pilotto JH, et.al.. Low emergence of drug resistance after HAART interruption at delivery 
in a cohort of HIV+ pregnant women in Rio de Janeiro, Brazil, 2008. XVII International 
AIDS Conference. 2008. 
55. 
Valerie F. Boltz, Yajing Bao, Shahin Lockman, Elias K. Halvas, Mary F. Kearney,1 
James A. McIntyre, Robert T. Schooley, Michael D. Hughes, John M. Coffin, and John 
W. Mellors; for the OCTANE/A5208 Team. Low-Frequency Nevirapine (NVP)–
Resistant HIV-1 Variants Are Not AssociatedWith Failure of Antiretroviral Therapy 
inWomenWithout Prior Exposure to Single-Dose NVP. J Infect Dis 2014. 
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John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A et 
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transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA 
shedding, and breast infections. J Infect Dis 2001, 183: 206-212. 
57. 
Chotpitayasunondh T, Vanprapar N, Simonds RJ, Chokephaibulkit K, Waranawat N, 
Mock P et al.: Safety of late in utero exposure to zidovudine in infants born to human 
immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal 
HIV Transmission Study Group. Pediatrics 2001, 107: E5. 
58. 
Tuomala RE, O’Driscoll PT, Bremer JW, Jennings C, Xu C, Read JS et al.: Cell-
associated genital tract virus and vertical transmission of human immunodeficiency virus 
type 1 in antiretroviral-experienced women. J Infect Dis 2003, 187: 375-384. 

 
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59. 
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and prevention. AIDS 1999, 13: 155-166. 
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Fiore JR, Suligoi B, Saracino A, Di SM, Bugarini R, Lepera A et al.: Correlates of HIV-1 
shedding in cervicovaginal secretions and effects of antiretroviral therapies. AIDS 2003, 
17: 2169-2176. 
61. 
Nagot N, Ouedraogo A, Weiss HA, Konate I, Sanon A, Defer MC et al.: Longitudinal 
effect following initiation of highly active antiretroviral therapy on plasma and cervico-
vaginal HIV-1 RNA among women in Burkina Faso. Sex Transm Infect 2008, 84: 167-
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62. 
Garcia-Bujalance S, Ruiz G, De Guevara CL, Pena JM, Bates I, Vazquez JJ et al.: 
Quantitation of human immunodeficiency virus type 1 RNA loads in cervicovaginal 
secretions in pregnant women and relationship between viral loads in the genital tract and 
blood. Eur J Clin Microbiol Infect Dis 2004, 23: 111-115. 
63. 
Kovacs A, Wasserman SS, Burns D, Wright DJ, Cohn J, Landay A et al.: Determinants 
of HIV-1 shedding in the genital tract of women. Lancet 2001, 358: 1593-1601. 
64. 
Debiaggi M, Zara F, Spinillo A, De SA, Maserati R, Bruno R et al.: Viral excretion in 
cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. Eur 
J Clin Microbiol Infect Dis 2001, 20: 91-96. 
65. 
Cu-Uvin S, Snyder B, Harwell JI, Hogan J, Chibwesha C, Hanley D et al.: Association 
between paired plasma and cervicovaginal lavage fluid HIV-1 RNA levels during 36 
months. J Acquir Immune Defic Syndr 2006, 42: 584-587. 
66. 
Neely MN, Benning L, Xu J, Strickler HD, Greenblatt RM, Minkoff H et al.: Cervical 
shedding of HIV-1 RNA among women with low levels of viremia while receiving 
highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2007, 44: 38-42. 
67. 
Mbori-Ngacha D, Richardson BA, Overbaugh J, Panteleeff DD, Nduati R, Steele M et 
al.: Short-term effect of zidovudine on plasma and genital human immunodeficiency 
virus type 1 and viral turnover in these compartments. J Virol 2003, 77: 7702-7705. 
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Graham SM, Holte SE, Peshu NM, Richardson BA, Panteleeff DD, Jaoko WG et al.: 
Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 
shedding. AIDS 2007, 21:501-507. 
69. 
Vettore MV, Schechter M, Melo MF, Boechat LJ, Barroso PF: Genital HIV-1 viral load 
is correlated with blood plasma HIV-1 viral load in Brazilian women and is reduced by 
antiretroviral therapy. J Infect 2006, 52: 290-293. 
70. 
Cu-Uvin S, Caliendo AM, Reinert S, Chang A, Juliano-Remollino C, Flanigan TP et al.: 
Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS 2000, 
14: 415-421. 

 
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71. 
Coombs RW, Wright DJ, Reichelderfer PS, Burns DN, Cohn J, Cu-Uvin S et al.: 
Variation of human immunodeficiency virus type 1 viral RNA levels in the female 
genital tract: implications for applying measurements to individual women. J Infect Dis 
2001, 184: 1187-1191. 
72. 
Baron P, Bremer J, Wasserman SS, Nowicki M, Driscoll B, Polsky B et al.: Detection 
and quantitation of human immunodeficiency virus type 1 in the female genital tract. The 
Division of AIDS Treatment Research Initiative 009 Study Group. J Clin Microbiol 2000, 
38: 3822-3824. 
73. 
John GC, Sheppard H, Mbori-Ngacha D, Nduati R, Maron D, Reiner M et al.: 
Comparison of techniques for HIV-1 RNA detection and quantitation in cervicovaginal 
secretions. J Acquir Immune Defic Syndr 2001, 26: 170-175. 
74. 
Solt I. 2014. The human microbiome and the great obstetrical syndromes: A new frontier 
in maternal–fetal medicine. Best Practice & Research Clinical Obstetrics & Gynaecology, 
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Farquhar C, Mbori-Ngacha D, Overbaugh J, Wamalwa D, Harris J, Bosire R, John-
Stewart G. Illness during pregnancy and bacterial vaginosis are associated with in-utero 
HIV-1 transmission. AIDS. 2010 Jan 2;24(1):153-5. PMCID: PMC2788745. 
76. 
Daniel N Frank, Olivier Manigart, Valériane Leroy, Nicolas Meda, Diane Valéa, 
Weiming Zhang, François Dabis, Norman R Pace, Philippe Van de Perre, Edward N 
Janoff. Altered vaginal microbiota are associated with perinatal mother-to-child 
transmission of HIV in African women from Burkina Faso. Journal of Acquired Immune 
Deficiency Syndromes: JAIDS 2012 July 1, 60 (3): 299-306. 
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HIV Hepatites - Enquete Perinatale Francaise - CO1/CO11 Study Group.Increased Risk 
of Serious Bacterial Infections Due to Maternal Immunosuppression in HIV-Exposed 
Uninfected Infants in a European Country. Clin Infect Dis. (2014) 59 (9): 1332-1345 
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Information 2007, 41: 733-742. 

 
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APPENDIX I  
MATERNAL SCHEDULE OF EVALUATIONS 
 
ANTEPARTUM 
 
POSTPARTUM 
Event Driven Evaluations 
Screening1 
Entry 
Week 12 
Day 7 
(± 2days) 
Week 22 
Day 14 
(± 3days) 
 
Week  
 4 (± 4 
days) 
Every 2 
weeks  
(+ 4 days) 
Labor/ 
Delivery collected during 
labor or < 48 hours 
postpartum  
Week  
2 (2-4 
weeks
)  
Week  
6 (± 7 
days) 
Week  
16 (± 14 
days) 
Week  
24 (± 14 
days) 
Inadequate 
virologic 
response 
Premature 
Study 
Discontinuation 
CLINICAL EVALUATIONS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
History/HIV assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Targeted physical exam4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology5 
1mL 
1mL 
 
1mL 
1mL 
 
1mL 
 
 
1mL 
1mL 
1mL 
1mL 
Chemistries6 
2mL 
2mL 
 
2mL 
2mL 
 
2mL 
 
 
 
2mL 
 
2mL 
Urine dipstick 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV confirmatory test7 
1mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV RNA PCR8 
6ml 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
 
 
 
6mL 
6mL 
6mL 
Vaginal swabs9 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
Genotyping for HIV-110 
5ml 
 
 
 
 
 
 
 
 
 
5ml 
 
 
CD411 
1mL 
1mL 
 
 
1mL 
 
1mL 
 
 
1mL 
1mL 
1mL 
1mL 
 
Other Studies12 
5mL 
5mL 
5mL 
5mL 
5mL 
5mL 
5ml 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
TOTAL BLOOD VOLUMES 
21mL 
15mL 
11mL 
14mL 
15mL 
11mL 
15mL 
5mL 
5mL 
7mL 
15mL 
18mL 
15mL 
APPENDIX I – FOOTNOTES FOR MATERNAL SCHEDULE OF EVALUATIONS 
1. 
Screening evaluations must be performed within 30 days prior to Entry. Laboratory results should be obtained. Entry and ART should be started as soon as possible.  
2. 
Visit must occur at least 48 hours after the previous visit. Preferred target days are Day 7 and Day 14 after Entry. 
3. 
A complete history is required at Screening and interim history (diagnoses and signs/symptoms) is required at subsequent visits. Screening only: Documentation of HIV infection for eligibility 
can be historical. 
4.  For physical exam, record height and weight at all visits. If fetal ultrasound is needed to confirm gestational age (must be completed before entry), results of ultrasound obtained through clinical 
care may be abstracted and used as confirmation of gestational age or fetal ultrasound can be performed during the screening process; fetal ultrasound is not required by the protocol if not needed 
to confirm gestational age. Presence of fetal heart tones should be documented at each visit until delivery. 
5. 
Hematology includes CBC with differential and platelet count.  
6. 
Chemistries include AST, ALT, total bilirubin, glucose and creatinine.  
7. 
Obtain only if source documentation is not available. Documentation of HIV infection for eligibility can be historical. 
8. 
6 mL EDTA blood sample will be collected for local real-time plasma HIV RNA testing using a CLIA-certified assay (for US laboratories) or DAIDS-VQA certified assay (for non-US 
laboratories).  
9. 
Two vaginal swabs to be collected and placed in sterile cryovial tubes for storage at <= -70 degrees Celsius freezer for batched testing of viral load and microbiome in the maternal reproductive 
tract. Refer to Appendix V for instructions on collection and processing. 
10. At Screening and whenever inadequate virologic response (defined in section 6.2.9) occurs, HIV genotyping will be performed at a local/regional laboratory. The laboratory performing the 
testing must have a record of successful performance for HIV genotyping in the VQA External Quality Assurance program. Enrollment may occur and study drugs may be started before the HIV 
genotype test results from the screening specimen are available.  
11. CD4 counts must be performed at a CLIA certified (for US sites) or DAIDS Immunology Quality Assurance -certified (for non-US sites) laboratory. Note: Only an absolute CD4 count is 
required for this protocol.  

 
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12. This plasma will be used for batched studies, including antiretroviral concentrations, low-level drug resistance, and viral infectivity. Plasma will be used to measure drug levels only through the 
2-4 week postpartum visit. 

 
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APPENDIX II  
INFANT SCHEDULE OF EVALUATIONS 
 
Birth 
(+48 
hrs) 
Week 2 
(2-4 
weeks) 
Week 6 
(± 7 
days) 
Week 16 
(± 14 
days) 
Week 
24 (± 
14 
days) 
Documentation 
of HIV infection 
Premature Study  
Discontinuation  
History1 
X 
X 
X 
X 
X 
 
X 
Physical exam2 
X 
X 
X 
X 
X 
 
X 
Offer participation in extension phase: INFANT DEVELOPMENTAL ASSSSMENT (Appendix VII) 
STUDY NEURODEVELOPMENTAL / NEUROPSYCOLOGICAL EVALUATIONS 3 
 
 
 
 
X 
 
 
Hematology4 
0.5mL 
0.5mL 
 
 
 
 
0.5mL8 
Chemistries5 
1mL 
 
 
 
 
 
 
HIV TNA or HIV DNA or HIV RNA6 
2mL 
2ml 
2mL 
2mL 
2ml 
 
2mL 
HIV-1 RNA PCR6  
 
 
 
 
 
2mL 
 
Genotyping7 
 
 
 
 
 
2mL 
 
Oral and nasopharyngeal swab collection 9 
 
X 
 
 
X 
 
 
TOTAL BLOOD VOLUME 
3.5mL 
2.5ml 
2mL 
2ml 
2ml 
4mL 
2.0ml - 2.5ml 
APPENDIX II – FOOTNOTES FOR INFANT SCHEDULE OF EVALUATIONS 
1. A complete history is required at birth and at subsequent visits. Birth history includes labor and delivery record, Apgar score, birth weight and length, gestational age, and sex. 
2. Physical exam includes length, weight, and head circumference. 
3. Sites will not start offering participation in this extension phase until the protocol team notifies them that enrollment into the extension phase has been activated.  
4. Hematology includes CBC with differential and platelet count. 
5. Chemistries include AST, ALT, and creatinine.  
6. HIV TNA (total nucleic acid), HIV DNA or HIV RNA: Obtain only if source documentation is not available. If the initial test is positive, confirm as soon as possible by HIV-1 RNA PCR. Tests 
must be performed at a CLIA certified (for US sites) or DAIDS VQA-certified (for non-US sites) laboratory. 
7. Genotyping will be completed if HIV infection is confirmed by the HIV-1 RNA. Genotyping must be drawn at the time of the confirmation of HIV-1 RNA PCR and must be performed at a 
CLIA certified (for US sites) or DAIDS VQA-certified (for non-US sites) laboratory. 
8. Obtain only if premature discontinuation occurs before week 6 visit. 
9. Two swabs (one from nasopharynx and one from oropharynx) to be placed in a sterile cryovial tubes for storage at <= -70 degrees Celsius freezer. 
 

 
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APPENDIX III 
DIETARY RECOMMENDATIONS FOR ANTIRETROVIRAL THERAPIES 
Efavirenz: Take on an empty stomach (fasting at least 1 hour before or 2 hours after a meal). 
 
Raltegravir: Take without regards to meals.  
 
Lamivudine/zidovudine: No food requirement. 
 
 
 

 
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APPENDIX IV 
RESISTANCE MUTATIONS FOR ANTIRETROVIRAL STUDY DRUGS 
Mutations in reverse transcriptase: 
Zidovudine (ZDV)  
M41L 
D67N 
K70R 
L210W 
T215Y/F 
K219K/Q 
insertion at 69-XX 
151-complex (A62V=V75I=F77L=116Y=Q151M 
 
Lamivudine (3TC) or Emtricitabine (FTC)  
K65R 
M184V 
 
Efavirenz (EFV)  
L100I 
K101P 
K103N 
V106M 
V108I 
Y181C/I 
Y188L 
G190S/A 
P225H 
 
Tenofovir disoproxil fumarate (TDF)1 
K65R 
insertion at 69-XX 
K70E 
M41L+L210W+ at least one of: D67N, K70R, T215F/Y or K219Q/E 
 
Footnote: 
1. Philip A Chan et al. Journal of the International AIDS Society 2012, 15:17701. 
http://www.jiasociety.org/index.php/jias/article/view/17701  
 
Mutations in integrase: 
Raltegravir (RAL) 
E92Q  
G140S/A 
Y143R/C 
Q148H/R/K 
N155H 

 
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APPENDIX V 
VAGINAL SPECIMEN COLLECTION, PROCESSING AND SHIPPING 
Vaginal Swabs for Virology Testing 
Vaginal swabs to evaluate genital tract HIV RNA and DNA levels and to evaluate the 
microbiome will be obtained on all women at entry, week 1, week 2, week 4, and every 2 weeks 
until delivery (36-38 weeks of gestation), and at 24 weeks postpartum.  
 
At each time point for vaginal collection, FLOQSwabs with nylon tips and plastic shafts will be 
inserted gently into the vagina to a depth of about 3 cm and rolled around the circumference of 
the vaginal wall. A single swab will be inserted at a time, but two swabs will be collected at each 
time point. After collection, each swab will be inserted into a cryovial, the end broken off and the 
tube capped. The tube will be labeled with the participant’s PI, date and time of collection, and 
specimen type. Specimens will be labeled with LDMS labels. Tubes will be frozen at -70oC or 
colder.  
 
The cryovials containing swabs should be transported to the processing lab within 1 hour if 
possible. If that is not feasible, they should be refrigerated and then transported on cold packs or 
wet ice or they could be frozen and transported on dry ice. If wet ice is used, then the cryovials 
should be placed inside a plastic bag to keep them dry during that transport. Swabs should be 
frozen at -70oC or colder within 4 hours of collection. 
 
Specimens will be batch shipped at the end of the study for virology testing to: 
Lisa M. Frenkel, M.D. – SPECIALTY LABORATORY (LDMS# 238) 
Professor/Department of Pediatrics and Laboratory Medicine 
Division of Infectious Diseases and Virology 
University of Washington 
Seattle Children’s Hospital and Research Institute 
1900 Ninth Avenue 
UW Mail Stop 359300 
Seattle, WA 98101-1304 
Phone: (206) 987-5140 
Email: lfrenkel@u.washington.edu 
 
Specimens will be batch shipped at the end of the study for microbiome testing to: 
Adriana Weinberg, M.D. 
University of Colorado Denver 
Mail Stop 8604 
12700 E. 19th Avenue, Room 11126 
Aurora, CO 80045 
Phone: 303-724-4480 
Email: adriana.weinberg@ucdenver.edu 
 
Vaginal swabs can be ordered from Quidel/Diagnostic Hybrids Inc., item #502CS01. 
Information is available at http://www.quidel.com/cultures-fluorescent-
tests/floqswabs/floqswabs 

 
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APPENDIX VI 
SAMPLE INFORMED CONSENT 
A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two 
Different Potent Regimens in HIV-infected Women Initiating Triple Antiretroviral Regimens 
Between 28 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission: 
NICHD P1081 
 
INTRODUCTION 
 
You and your baby are being asked to take part in this research study because you are infected 
with the Human Immunodeficiency Virus (HIV), the virus that causes AIDS and you have not 
taken any anti-HIV medication or have only taken a short course of zidovudine in past 
pregnancies. This study is sponsored by the National Institutes of Health (NIH). The doctor in 
charge of this study at this site is: (insert name of Principal Investigator). Before you decide if 
you want to be/want your baby to be a part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with 
you about this information. You are free to ask questions about this study at any time. If you 
agree to/allow your baby to take part in this study, you will be asked to sign this consent form. 
You will get a copy to keep.  
 
WHY IS THIS STUDY BEING DONE? 
 
In this study, one of two different anti-HIV medications will be given along with zidovudine and 
lamivudine to HIV-infected pregnant women to compare how safe the medications are, how 
tolerable they are and how well they can lower the amount of HIV in the blood. We will see if 
one of these two drugs, efavirenz, or raltegravir, lowers the amount of HIV in the blood 
faster than the other.  
 
WHAT DO I/DOES MY BABY HAVE TO DO IF I AM/MY BABY IS IN THIS STUDY? 
 
Screening visit to see if you can be in the study 
 
If you decide you want you and your baby to be in this study, we will do some tests to see if you 
are able to enter the study.  
 
• The screening visit will happen when you are about 24-36 weeks pregnant. 
• We will get a medical history and we will ask you questions about how you are feeling, 
what medications you are taking and information about alcohol and drug use. 
• You will have a physical exam that includes height, weight, and fetal heart rate.  
• A urine sample will be taken. 
• An exam will be done to see how long you have been pregnant. 
• We will take a blood sample to see if the HIV in your blood is resistant to any of the 
drugs that are being evaluated in this study. The results of this test are not required before 

 
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you enter the study. If, however, the results show that the HIV in your blood is resistant 
to any of the drugs being evaluated in this study, you and your doctor will decide if you 
should stay on the study drugs.  
• We will take blood samples to test you for HIV, to see how much HIV is in your blood, 
and to see how many CD4 cells (white blood cells that fight infection) are in your blood. 
• About 21 mL or 4 teaspoons (sites - add locally relevant description of blood volume) of 
blood in total will be taken from you for screening and other tests. 
• You will be told the results of these tests taken now and at other times during the study as 
soon as they are available.  
 
If you do not enroll into the study 
 
• If the tests show that you are not eligible to participate, you will continue to receive care 
from your usual provider who will help you decide if you should continue to take your 
HIV drugs or not after your baby is born. 
 
• If you decide not to take part in this study or if you do not meet the eligibility 
requirements, we will still use some of your information.  As part of the screening visits, 
some demographic (e.g., age, gender, race), clinical (e.g., disease condition, diagnosis), 
and laboratory (e.g., CD4+ cell count, viral load, HIV resistance testing) data are being 
collected from you so that the researchers may determine whether there are patterns or 
common reasons why people do not join the study. 
 
Study visits while you are pregnant if you enroll into the study 
 
• The first study visit will be done as soon as possible but within 30 days of the screening 
visit.  
• You will be randomized (like the flip of a coin) to have an equal chance of receiving one 
of two anti-HIV drug medications [sites insert locally relevant description] in one of the 
following study groups: 
o If you are in Arm A, you will take one lamivudine/zidovudine tablet two times a day 
plus one efavirenz tablet once each night on an empty stomach fasting at least 1 hour 
before or 2 hours after a meal. At any time during the study, if you stop taking 
efavirenz, your primary care physician may recommend that you continue to take 
lamivudine/zidovudine for a period of time.  
o If you are in Arm B, you will take one lamivudine/zidovudine tablet two times a day 
plus one raltegravir tablet twice a day. 
• If your doctor believes that you should not receive lamivudine/zidovudine, he may 
replace lamivudine/zidovudine with a different medication combination. Your doctor will 
make this decision before you are randomized to Arm A or Arm B. 
• If your doctor thinks you should continue to take anti-HIV medications for your own 
health you may continue to take study-supplied medications for up to 8 weeks after 
delivery while your doctor arranges your treatment.  
• You will come to the clinic up to 10 times while you are still pregnant and each visit will 
last about (sites – add local information about time for study visits). 

 
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• The total amount of blood to be drawn at each visit will be between 11-15 mL (less than 
3 to 4 teaspoons), [sites - add locally relevant description of blood volume] depending on 
the tests to be done.  
• You will have medical check-ups to include a history, physical exam and blood tests to 
see how much HIV is in your blood and to see how your body is fighting infection. Other 
information from your routine obstetrical care will be collected by the study. 
• We will ask you about when you took your most recent doses of medicines.  
• You will have vaginal swabs taken at each visit which can be obtained without the use of 
a vaginal speculum. Two swabs will be collected, one at a time. The swab will be gently 
inserted into the vagina for about 1 inch and rolled around the wall of the vagina. These 
swabs will be tested at the end of the study for amount of HIV and other microbes. You 
will not receive the results of these tests. 
 
Special blood studies 
 
During each study visit while you are pregnant, 5 mL or less than 1 teaspoon (sites – add locally 
relevant description of blood volume) of the blood will be used for special studies. These will 
include a measurement of the amount of medication in the blood, additional testing to see how 
fast HIV goes down in your blood, and additional testing for HIV resistance to medications. You 
will not receive the results of these special tests.  
 
Study visits while you are in labor 
 
While you are in labor, you may get intravenous (through a tube that is placed in a vein) 
zidovudine, which is given to HIV-infected pregnant women, along with the other drugs you 
have been taking. Your doctors may give you different or additional drugs during labor as part of 
your care, if they think you need them. 
 
• You will have a medical check-up to include a history, physical exam and blood tests to 
see how much HIV is in your blood and to see how your body is fighting infection. 
• We will ask you about when you took your most recent doses of medicines.  
• About 15 mL or 3 teaspoons (sites - add locally relevant description of blood volume) of 
blood in total will be drawn at this visit. 
• 5 mL or less than 1 teaspoon (sites – add locally relevant description of blood volume) of 
the blood will be used for special studies. 
 
 
 

 
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Study visits after you have your baby 
 
• You will be seen in the clinic four times after you have your baby.  
• Each visit will last about (sites – add local information about time for study visits) and 
the total amount of blood to be drawn will be between 5-15 mL or 1-3 teaspoons (sites - 
add locally relevant description of blood volume) of blood depending on the tests to be 
done.  
• You will have a medical check-up to include a history, physical exam and blood tests to 
see how much HIV is in your blood and to see how your body is fighting infection. 
• You will have a vaginal swab taken one time which can be obtained without the use of a 
vaginal speculum. Two swabs will be collected, one at a time. The swab will be gently 
inserted into the vagina for about 1 inch and rolled around the wall of the vagina.  
• 5 mL or less than 1 teaspoon (sites – add locally relevant description of blood volume) of 
blood will be used for special studies. These will include measurement of the amount of 
medication in the blood and additional testing for HIV resistance to medications. You 
will not receive the results of these special tests. 
• If you are taking efavirenz (Arm A), you should use two methods of contraception (a 
barrier method such as condom, diaphragm or cervical cap) together with another form of 
contraception for 4 weeks after you stopped taking efavirenz. 
 
Study visit if the amount of HIV in your blood is high 
 
• If your doctor finds that the study drugs are not working and the amount of HIV in your 
blood is higher than expected, you will have blood tests to measure the amount of HIV in 
your blood and to see how your body is fighting infection. You will receive the results of 
these tests as soon as they are available. 
• About 18 mL or 3-4 teaspoons (sites - add locally relevant description of blood volume) 
of blood in total will be taken at this visit. 
• 5 mL or less than 1 teaspoon (sites – add locally relevant description of blood volume) of 
the blood will be used for special studies. 
 
Study visit if you have to leave the study early 
 
• You will have a medical check-up to include a history, physical exam and blood tests to 
see how much HIV is in your blood and to see how your body is fighting infection. 
• About 15 mL or 3 teaspoons (sites - add locally relevant description of blood volume) of 
blood in total will be taken at this visit. 
• 5 mL or less than 1 teaspoon (sites – add locally relevant description of blood volume) of 
the blood will be used for special studies. 
 
Study treatment after your participation in this study ends 
 
• If your doctor thinks you should continue to take anti-HIV medications for your own 
health, you may receive study-supplied anti-HIV medications for up to 8 weeks after 
delivery while your primary care physician arranges your treatment. 

 
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Study visits for your baby 
 
• After you deliver your baby, your baby will start taking anti-HIV medication prescribed 
by your baby’s doctor. 
• Your baby will take anti-HIV medication for as long as your doctor prescribes it. 
• Your baby will be in this study until he/she is 6 months old. At the 6 month visit, you 
may be asked to have your baby continue in a study of child development that will last 
until 4 years of age.  
• At birth and four other times while your baby is in this study, your baby will have a 
medical check-up and a physical examination that includes length, weight, and head 
measurement.  
• Your baby’s blood will be taken at birth and four times during the study for routine tests 
and to test for HIV.  
• Each of your baby’s study visits will last about (sites – add local information about time 
for study visits) and the total amount of blood to be drawn will be between 2 and 4 mL or 
less than 1 teaspoon (sites - add locally relevant description of blood volume) of blood, 
depending on the tests to be done. 
• If your baby has a positive test for HIV infection, you will be asked to return for an 
additional blood draw of 4 mL, or less than 1 teaspoon, to confirm HIV infection. If your 
baby has HIV infection, your doctor will make sure you have a place to take your baby 
for HIV treatment and care.   
• Your baby will have a nose and mouth swab taken at two visits. A swab will be gently 
inserted into the nose and another into the mouth for about 1 inch and rolled around. Two 
swabs will be collected, one at a time. 
 
Storage of Blood Samples  
 
Your samples will be stored at a special laboratory facility [sites can amend according to local 
regulations]. The samples may be sent to the US.for storage and testing [sites can amend 
according to local regulations]. Only approved researchers will have access to them. People who 
work at the facility will also have access to your samples to keep track of them. These people 
won’t have information that directly identifies you. Your samples will not be sold or directly 
used to produce commercial products. All proposed research studies using your samples will be 
reviewed by the NIH. There is no time limit on how long your samples will be stored.  
 
The researchers do not plan to contact your regular doctor with the results of studies done using 
your stored samples. This is because research studies are often done with experimental 
procedures. The results of such studies should not be used to make decisions about your medical 
care. If the researchers decide that the result of a certain study provides important information for 
your medical care, your study doctor will be notified. If you would like to be contacted with this 
sort of information, you must notify the study staff of any changes in your address or phone 
number.  
You may decide that you do not want your samples stored for future research studies. You can 
still participate in this study even if you make this decision. You may withdraw your consent for 

 
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the storage and use of your samples at any time. If you withdraw your consent, these stored 
samples will be destroyed. Please read the following statement carefully and then mark your 
initials in the appropriate space provided. 
 
I agree to allow my blood samples to be stored for use in future NIH-approved, HIV-related 
research studies. 
 
__________ Yes 
 
__________ No 
 
__________ Date 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 394 HIV-infected women and their infants will take part in this study. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You and your baby will be in this study until 6 months after you have your baby. You may be 
asked for permission for your baby to continue in this study until he/she is 4 years of age. 
 
After the study 
 
If you/your baby can no longer come to the clinic for study visits before the end of the study, you 
and your baby will be asked to come to the clinic for a final study visit. This visit will include a 
medical history, physical exam, and blood tests to see how much HIV is in your blood and to see 
how well your body is fighting infection. If your baby is found to be infected with HIV [sites: 
add local referral information as appropriate]. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you/your baby off the study early without your permission if: 
 
• The study is cancelled by the National Institute of Child Health and Human Development 
(NICHD), US Food and Drug Administration (FDA), NIH, the drug companies 
supporting this study, the Office for Human Research Protections (OHRP), other national 
regulatory agencies, or the site’s Institutional Review Board (IRB) or Ethics Committee. 
An IRB is a committee that watches over the safety and rights of research participants. 
• You are/your baby is not able to attend the study visits as required by the study. 
• Continuing in the study may be harmful to you/your baby. 
 
If you/your baby have/has to stop taking the study medications before your participation in the 
study is over, the study staff will discuss other options that may be of benefit to you/your baby. 
The study doctor will ask you/your baby to continue to be part of the study and return for some 
study visits and procedures. 
 
 
 

 
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The study doctor may also need to take you/your baby off the study drug without your 
permission if: 
 
• Continuing the study drug may be harmful to you/your baby 
• You/your baby need(s) a treatment that you/your baby may not take while on the study 
• You are/your baby is not able to take the study drug as required by the study 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. The study treatments 
may involve risks to the fetus that are currently unforeseeable. If you have questions concerning 
additional study drug side effects please ask the medical staff at your site. 
 
Use of Combination Antiretroviral Drugs 
 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, signs and 
symptoms of inflammation from other infections may occur soon after anti-HIV treatment is 
started.  
 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
 
• Increase in fat around the waist and stomach area 
• Increase in fat on the back of the neck 
• Thinning of the face, legs, and arms 
• Breast enlargement 
 
Integrase Inhibitor 
 
Raltegravir, (RAL, IsentressTM) 
Merck & Co., Inc. 
 
The following side effects have been associated with the use of raltegravir: 
 
• Upset stomach 
• Headache 
• Tiredness 
• Weakness 
• Trouble sleeping 
• Rash, which can be severe 
• Feeling anxious 
• Depression, suicidal thoughts and actions 
• Paranoia (an abnormal sense of fear) 

 
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• Low blood platelet count 
• Muscle tenderness, weakness or injury which can be serious and lead to kidney damage 
 
Cancers have been seen in people who took raltegravir with other HIV drugs. The types of 
cancers seen are typical for people with very sick immune systems. It is unknown if the cancers 
were related to raltegravir use.  
 
If you develop a rash with any of the following symptoms stop using raltegravir and contact your 
Health Care Provider right away:  
• Fever  
• Generally ill feeling  
• Extreme tiredness  
• Muscle or joint aches  
• Blisters or sores in mouth  
• Blisters or peeling of the skin  
• Redness or swelling of the eyes  
• Swelling of the mouth or face  
• Problems breathing  
 
Sometimes allergic reactions can affect body organs, like the liver and cause liver problems 
which can lead to liver failure. Contact your Health Care Provider right away if you have any of 
the following signs or symptoms of liver problem: 
• Yellowing of the skin or whites of the eyes  
• Dark or tea colored urine  
• Pale colored stools/bowel movements  
• Nausea/vomiting  
• Loss of appetite  
• Pain, aching or tenderness on the right side below the ribs 
 
In some patients receiving raltegravir blood tests showed abnormally elevated levels of a muscle 
enzyme—creatine kinase which may cause muscle pain, tenderness or weakness this type of 
muscle break down can be serious and lead to kidney damage including kidney failure. Contact 
your HCP right away if you have any unexplained muscle pain, tenderness, or weakness…  
• Dizziness 
• Clumsiness and lack of coordination. 
 
Nucleoside Analogue 
 
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged liver) 
with steatosis (fatty liver) that may result in liver failure, other complications or death have been 
reported with the use of antiretroviral nucleoside analogues alone or in combination. The liver 
complications and death have been seen more often in women on these drug regimens. Some 
nonspecific symptoms that might indicate lactic acidosis include: unexplained weight loss, 
stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, weakness, dizziness and 
shortness of breath.  

 
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Lamivudine (3TC, EPIVIR®) 
GlaxoSmithKline 
 
The following side effects have also been associated with use of lamivudine: 
If you are infected with both Hepatitis B and HIV, you should be aware that your liver function 
tests may increase, and symptoms associated with hepatitis (an acute inflammation of the liver) 
may worsen if lamivudine is stopped. Although most of these cases have resolved without 
treatment, some deaths have been reported. 
 
• Headache 
• Feeling tired  
• Dizziness 
• Numbness, tingling, and pain in the hands or feet  
• Depression 
• Trouble sleeping 
• Rash 
• Upset stomach, vomiting, nausea, loose or watery stools  
• Pancreatitis (inflammation of the pancreas), which may cause death. If you develop 
pancreatitis, you may have one or more of the following: stomach pain, nausea, and 
vomiting  
• Abnormal pancreatic and liver function blood tests  
 
Zidovudine (RETROVIR®) 
GlaxoSmithKline 
 
The following side effects have been associated with use of zidovudine: 
 
• Decrease in the number of white blood cells that help fight infection  
• Decrease in the number of red blood cells that may cause weakness, dizziness, and 
fatigue  
• Muscle aches, weakness, and wasting 
• Headache 
• Upset stomach  
• Vomiting  
• Decrease in appetite  
• Vague overall feeling of discomfort  
• Lack of energy  
• Feeling tired  
• Sleeplessness 
• Heartburn 
 
 
 

 
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Non-Nucleoside Reverse Transcriptase Inhibitor  
 
Efavirenz (EFV, SUSTIVA®, STOCRIN®) 
Bristol-Myers Squibb or Merck & Co., Inc. 
 
The following side effects have been associated with the use of efavirenz: 
 
A small number of people may experience the following serious psychiatric problems: 
• Depression, which may be severe 
• Suicidal thoughts or attempts (rarely) 
• Aggressive behavior 
• Psychosis-like symptoms, such as abnormal thinking, paranoia, and delusions 
People with a history of psychiatric problems may be at greater risk for these serious psychiatric 
problems.  
Side effects associated with the central nervous system may include the following: 
• Dizziness 
• Trouble sleeping  
• Abnormal dreams  
• Drowsiness 
• Confusion 
• Difficulty concentrating 
• Hallucinations  
• A feeling of strangeness and losing touch with reality 
• An exaggerated feeling of well-being  
• Agitation or anxiety 
 
If alcohol or mind- or mood-altering drugs are used with efavirenz, it is possible that the central 
nervous system side effects could become worse. 
 
Serious liver problems and worsening liver disease can occur. These problems can be life-
threatening. People with these conditions may have abnormal liver function blood tests. If you 
are developing liver problems, you may have one or more of the following: yellowing of the skin 
or whites of your eyes, dark urine, pain on the right side of your stomach, loss of appetite, upset 
stomach or vomiting, pale-colored stools, itchy skin. 
 
Additional side effects include: 
• Rash, which in rare cases may be severe 
• Upset stomach  
• Loose or watery stools  
• Headache 
• Abnormal increases in the amount of triglycerides and cholesterol in the blood 
• Abnormal increases in pancreatic enzyme levels in the blood and/or inflammation of the 
pancreas (pancreatitis) which may result in stomach pain, nausea and/or vomiting.  
 

 
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Efavirenz and Pregnancy 
 
The use of this drug during pregnancy and especially early pregnancy should be avoided. 
Efavirenz may cause fetal harm when taken during the first 3 months of pregnancy. Serious 
birth defects, including open spine, water on the brain, and cleft palate, have been seen in 
the offspring of animals and women on efavirenz in early pregnancy. The risks of taking 
efavirenz later in pregnancy are not known. However, efavirenz taken after the first 3 
months of pregnancy are not expected to cause birth defects. The World Health 
Organization and some country guidelines recommend that it is safe for women to take 
efavirenz throughout pregnancy. 
 
A false-positive urine-screening test for marijuana has been seen with one particular test brand 
and has not been seen when using other screening tests or with tests used to confirm results for 
marijuana. 
 
There have been reports of increased bleeding in HIV-infected persons with hemophilia who 
were treated with protease inhibitors. It is not known if protease inhibitors were the cause of 
these bleeding episodes. 
 
Other Risks 
 
There is the risk of serious and/or life threatening side effects when non-study medications are 
taken with study drugs. For your/your baby’s safety, you must tell your/your baby’s HIV care 
provider and the study doctor or nurse about all medications you take/your baby takes before the 
start of this study and also before starting any new medications while you are/your baby is in the 
study. You must tell the study doctor or nurse before you or your baby join in any other research 
studies while on this study. 
 
The use of potent antiretroviral drug combinations may also be associated with altered fat 
metabolism including elevated triglycerides (fatty acid in the blood) and/or elevated cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may 
occur. If any unusual symptoms or changes happen, you should call your/your baby’s doctor 
immediately. It is also important that while participating in the study, you do not/your baby does 
not take any other prescription drugs or over-the-counter medications without first talking to 
your/your baby’s doctor or study nurse. 
 
If you are in Arm A (you take efavirenz) and you are sexually active, after delivery, you should 
use two methods of contraception (a barrier method such as condom, diaphragm or cervical cap) 
together with another form of contraception for 4 weeks after you stopped taking efavirenz. 
 
Social Risks 
 
If you join this study, some hospital staff and all study staff will know that you have HIV. These 
workers are very serious about your privacy. Study staff will make every possible effort to be 

 
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sure that others do not learn your HIV status. However, sometimes if you receive special 
treatment or attend a special clinic, it may make others wonder if you have HIV. 
 
Risks of Drawing Blood 
 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the 
body. A small blood clot may form at the site where the blood was drawn or there may be 
swelling in the area. There is a small risk of a minor infection at the blood draw site. 
Lightheadedness and fainting can also occur.  
 
Risks of Collecting Vaginal/Nasal/Oral Swabs 
 
Collection of swabs may cause minor discomfort during collection, but no other risks are 
expected. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
You/your baby may receive no benefit from being in this study. You and your baby may 
benefit from the more frequent monitoring of HIV levels and for side effects. Information 
learned from this study may help other pregnant women who have HIV if one of the drug 
combinations works better than the standard regimen of lamivudine/zidovudine usually 
given to pregnant women to decrease the chance of HIV passing to the baby. We do not 
know if taking raltegravir or efavirenz in addition to the other anti-HIV drugs will decrease the 
chance of your baby getting HIV. 
 
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• treatment with prescription drugs available to you/your baby 
• treatment with experimental drugs, if you/your baby qualify(ies)  
• no treatment (not recommended for pregnant women) 
 
If you choose not to be in this study, you will be offered the local standard treatment with 
anti-HIV drugs. Please talk to your doctor about these and other choices available to you/your 
baby. Your doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
United States sites 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the NIH. 
With this Certificate, the researchers cannot be forced to disclose information that may identify 
you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands 

 
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for information that would identify you, except as explained below. The Certificate cannot be 
used to resist a demand for information from personnel of the United States Government that is 
used for auditing or evaluation of federally funded projects or for information that must be 
disclosed in order to meet the requirements of the federal FDA.  
 
People who may review your records include the US FDA, the site IRB or Ethics Committee, 
other national regulatory agencies, the NIH, the OHRP, study staff, study monitors, and drug 
companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about you or your participation in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate of Confidentiality to withhold that 
information. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
Sites outside the United States 
Efforts will be made to keep your/your baby’s personal information confidential. We cannot 
guarantee absolute confidentiality. Your/your baby’s personal information may be disclosed if 
required by law. Any publication of this study will not use your/your baby’s name or identify 
you/your baby personally. 
 
Your/your baby’s records may be reviewed by the US FDA, the site IRB or Ethics Committee, 
other national regulatory agencies, the NIH, the OHRP, study staff, study monitors, and drug 
companies supporting the study, and their designees. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov,  as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for the study-related visits and procedures and the anti-HIV medications 
given to you or your baby in this study. Taking part in this study may lead to added costs to you 
and your insurance company. In some cases it is possible that your insurance company will not 
pay for these costs because you are/your baby is taking part in a research study.  
 
 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you are/your baby is injured as a result of being in this study, you/your baby will be given 
immediate treatment for your injuries. The cost for this treatment will be charged to you or your 

 
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insurance company. There is no program for compensation either through this institution or the 
NIH. You will not be giving up any of your legal rights by signing this consent form. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part/not to allow 
your baby to take part in this study or leave this study/take your baby out of the study at any 
time. Your decision will not have any impact on your participation or your baby’s participation 
in other studies conducted by NIH and will not result in any penalty or loss of benefits to which 
you or your baby are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your/your 
baby’s health, welfare or willingness to stay in this study. If you want the results of the study, let 
the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• name of the investigator or other study staff 
• telephone number of above  
 
For questions about your/your baby’s rights as a research participant, contact: 
 
• name or title of person on the IRB or other organization appropriate for the site 
• telephone number of above  
 
 
 

 
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SIGNATURE PAGE  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in and allow your baby to take part in this study, please sign 
your name below. 
___________________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
___________________________________ 
__________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
___________________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff Signature and Date 
___________________________________ 
__________________________________ 
Witness’ Name (print) 
Witness’s Signature and Date 
 
 

 
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APPENDIX VII 
EXTENSION PHASE: NEURODEVELOPMENTAL ASSESSMENT OF INFANTS: NICHD 
P1081S 
1. 
INTRODUCTION 
 
1.1 
Background  
 
Efavirenz has been associated with severe fetal neurological malformations 
(anencephaly, anophthalmia, microophthalmia) in cynomolgus monkeys exposed 
to efavirenz from the beginning of pregnancy. Cases of neural tube defects have 
been reported in human infants following first trimester efavirenz exposure, but a 
meta-analysis of 23 studies including 2026 live births after first trimester efavirenz 
exposure demonstrated a very low rate of neural tube defects (1 case; 0.05%) that 
was similar to the rate in the general population and no increase in overall rate of 
birth defects.(1)  Based on these and other data, the 2013 WHO guidelines 
recommended that efavirenz can be used safely as first-line therapy throughout 
pregnancy.(2) 
 
The present study includes administration of efavirenz to pregnant women in the 
third trimester, well after the formation of neural tube derivatives, and thus 
completely avoids contributing to the risk of congenital defects.  
 
Studies describing the effects of prenatal efavirenz exposure on infant 
neurodevelopmental outcomes are limited. Schneider, et al published an 
uncontrolled study documenting normal intellectual, psychomotor and growth 
outcomes in 13 infants born to HIV-1 infected pregnant women from Rwanda 
treated with triple ARV regimens including efavirenz at 8 weeks of pregnancy and 
continued for 6 months after delivery.(3)  Westreich conducted a Denver 
Developmental Screening Test (DDST) on 41 infants out of 136 (30%) whose 
mothers identified as having taken efavirenz from before conception; 11 of the 41 
infants (27%) scored as suspect for developmental delay.(4)  However, this 
uncontrolled study had no efavirenz-unexposed comparison group administered 
the DDST, the DDST norms are based on a US reference group and may not be 
applicable to other sociocultural settings, and the DDST is a screening rather than 
diagnostic test which has low to moderate specificity (0.43-0.80 in population for 
which test has been validated).(5)  In addition, only 30% of the efavirenz exposed 
infants underwent DDST, raising concern for bias in who was approached or 
willing to have DDST. These infants had efavirenz exposure from the very 
beginning of their in utero life, so there is no information about exposures that 
begin in the third trimester; in fact, the published manuscript (6) that includes the 
DDST data presented as a poster in 2010,(4) states that 75% of women who became 
pregnant while receiving efavirenz stopped their efavirenz during that pregnancy, 
so this study’s results may have very low applicability to late-pregnancy exposure. 
 
 
 

 
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Current WHO Guidelines (2) include triple ARV regimens with efavirenz as a 
recommended regimen for prophylaxis for PMTCT and for treatment of women 
throughout gestation. Furthermore, efavirenz is also recommended as an important 
alternative for HIV/TB co-infected pregnant women.  
 
Given the lack of data describing infant developmental outcomes following third 
trimester efavirenz use, this protocol includes an optional substudy that would 
perform screening and comprehensive neurodevelopmental assessments beginning 
at 1 year of age in both study arms to evaluate potential specific areas of deficit 
and broad developmental outcomes and to compare them between study arms.  
 
1.2 
Comprehensive Neurodevelopmental Assessments  
 
Comprehensive neurodevelopmental assessments will be done in the infants at 1 
and 4 years of age to monitor potential specific areas of deficit and broad 
developmental outcomes for each arm of the study.  
 
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-
III),(7) which covers cognitive, language and motor functioning will be 
administered at 1 year of age. All five scales will be administered: Cognitive, 
Language (Receptive and Expressive), Motor (Fine and Gross), Social-Emotional, 
and Adaptive Behavior (Conceptual, Social, and Practical). The Bayley scales are 
the most commonly used test instrument internationally to assess development in 
very young children, and has been used extensively in Africa and Brazil.(8)  The 
Bayley will require approximately 30-60 minutes to administer, depending on the 
time required to adapt the child to the test setting. 
 
The Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-
III),(9) which covers multiple domains including cognitive, language, visual 
processing, and processing speed, which has a motor component, will be 
administered at 4 years of age. The preschool version of the Behavior Rating 
Inventory of Executive Functioning (BRIEF),(10) a parent questionnaire, will be 
administered to assess executive functioning skills. The evaluation at age 4 will be 
able to cover neurodevelopmental domains in a more comprehensive fashion. 
These will take 1½ to 2 hours to administer. 
 
1.3 
Screening Neurodevelopmental Assessments 
 
Screening assessments will be completed at 1, 2, 3 and 4 years of age along with a 
physical examination in order to monitor for any developmental problems, to 
obtain additional information from parent report, and to support retention of 
participants.  
 
The Ages and Stages Questionnaire (ASQ) is a caregiver report screening 
questionnaire for children ages 4 months to 5 years, which will be completed with 
the caregiver by a trained assessor.(11)  The questions cover a broad range of 

 
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developmental milestones that can be observed by caregivers in the home setting. 
This measure has subscales including Communication, Gross Motor, Fine Motor, 
Personal-Social, and Problem-Solving, which covers the same domains as the 
Bayley subscales. The ASQ will provide some data on development for 1 year olds 
who cannot be tested for any reason, as well as providing a check on the validity of 
the adapted Bayley scores. The ASQ will provide monitoring data for years 2, 3 
and 4, and will again provide a validity check on the 4 year old neuropsychological 
assessment. The ASQ can be administered in 10-15 minutes. 
 
The Ten Questions Questionnaire (TQQ) is a brief screening for significant 
neurological impairment that has been frequently used internationally with no need 
for significant adaptation (other than translation). It will be administered at the 
same time as the ASQ. The TQQ can be completed in a few minutes. 
 
Feedback will be provided to parents/caregivers on whether the child’s 
performance in each developmental domain is broadly within age expectation. 
Specific scores will not be given as tests are not normed for each site. Referrals 
will be made for further intervention to available resources if problems are found. 
 
2. 
OBJECTIVE 
 
To compare infant neurodevelopmental outcomes in HIV-exposed infants between the 
two treatment regimens. 
 
3. 
STUDY DESIGN 
 
Infant Neurodevelopmental Assessments 
 
At 1 year of age, infants will have a comprehensive neurodevelopmental assessment 
using the BSID-III, which covers cognitive, language and motor functioning. At 4 years 
of age, infants will be tested using the WPPSI-III, which covers cognitive, language, 
visual processing, and processing speed. In addition, parent questionnaires measuring 
development and basic motor and sensory processing will be administered at 1, 2, 3 and 4 
years of age. 
 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
Infant who participated in NICHD P1081. 
 
4.2 
Enrollment Procedures 
 
Eligible participants may enroll into the “Extension Phase: Developmental 
Assessment of Infants” once notified by the protocol team that this extension phase 
has been activated for enrollment. 
 

 
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Participant enrollment is done through the Data Management Center (DMC) 
Subject Enrollment System (SES). When a signed informed consent form has been 
obtained, a Screening Checklist must be entered through the DMC SES. For all 
participants from whom informed consent is obtained, but who are deemed 
ineligible or who do not enroll into the initial protocol step for any reason, a 
Screening Failure Results form must be completed and keyed into the database. 
 
5. 
PARTICIPANT MANAGEMENT 
 
Questions concerning clinical management of study participants and all communication 
regarding adverse experiences should be addressed to the P1081 CMC at NICHD.p1081
cmc@fstrf.org. Remember to include the participant’s Patient Identification Number 
(PID) when applicable. Please do NOT disclose the study arm to which a participant is 
randomized unless specifically requested. The appropriate team member will respond to 
questions via email with a “cc” to NICHD.teamp1081@fstrf.org. A response should 
generally be received within 24 hours (Monday - Friday). 
 
5.1 
Criteria for Study Discontinuation 
 
The participant will be discontinued from the study for any of the following 
reasons:  
 
• The legal guardian refuses further follow-up evaluations and decides to 
discontinue participation in the study. 
• The investigator determines that further participation would be detrimental to 
the participant’s health or well-being. 
• The legal guardian fails to comply with the study requirements so as to cause 
harm to him/herself or seriously interfere with the validity of the study results. 
• The study is cancelled at the discretion of the NIH, the IRB or EC, FDA, 
OHRP, or the pharmaceutical sponsor(s) or other governmental agencies. 
6. 
EXPEDITED ADVERSE EVENT REPORTING  
 
6.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined 
in Version 2.0, January 2010, of the DAIDS EAE Manual, which is available on the 
RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
The DAERS, an internet-based reporting system, must be used for EAE reporting 
to DAIDS. In the event of system outages or technical difficulties, EAEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent 
from within the DAERS application itself. 
 

 
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Where DAERS has not been implemented, sites will submit EAEs by documenting 
the information on the current DAIDS EAE Form. This form is available on the 
RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. For questions 
about EAE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-
res.com). 
 
6.2 
Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0, January 2010, of the 
DAIDS EAE Manual, will be used for this study. 
 
The study agents for which relationship assessments are required are maternal 
raltegravir, efavirenz, lamivudine, zidovudine and other maternal ARV agents 
used during the study. 
 
In addition to reporting all SAE’s as defined above, other events that sites must 
report in an expedited fashion include malignancies, study drug overdoses, all 
immune reconstitution inflammatory syndrome events that qualify as SAEs, 
seizures and hepatotoxicities whether or not symptomatic or related to study drug, 
and all other Grade 3 or 4 related toxicities (except Grade 3 neutropenia and 
anemia) for which a relationship to study drug cannot be ruled out. 
 
The death of any participant after enrollment or within 30 days of study 
completion, regardless of the cause, must be reported immediately and no later 
than 3 reporting days of first becoming aware of the death. After the 30-day 
period, deaths need to be reported only as part of long-term follow-up studies. If 
an autopsy is performed, the report must be provided. Reports of all deaths must 
be communicated as soon as possible to the appropriate IRB or EC and/or 
reported in accordance with local law and regulations. 
 
For all SAEs submitted to the RSC, sites must file an updated SAE report to the 
RSC with the final or stable outcome (Status Code p. 5 of the EAE form) unless 
the SAE reported in the initial EAE form already had a final or stable outcome. 
 
All reports submitted to the RSC must also be documented on the appropriate 
clinical CRFs and submitted to the study database through the eData system. 
Reconciliation of the two databases will be performed at regular intervals. 
 
6.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs 
(DAIDS AE Grading Table), Version 2.0, dated November 2014, must be used 
and is available on the RSC website at  
http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
 
 

 
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6.4 
EAE Reporting Period 
 
Only Serious Unexpected Suspected Adverse Events as defined in Version 2.0, 
January 2010, of the EAE Manual will be reported to DAIDS for the duration of 
the participant’s enrollment in the study, and after study completion if the 
study staff become aware of the events on a passive basis (from publicly available 
information). 
 
6.5 
CRF Recording Requirements for Laboratory Test Results, Signs, Symptoms, and 
Diagnoses  
 
The results of all protocol-required laboratory tests performed at screening, entry, 
and post-entry must be recorded on CRFs, regardless of severity grade.  
 
All abnormal (severity grade 1 and higher) signs, symptoms, and diagnoses 
occurring within 30 days prior to study entry must be recorded on CRFs. All 
abnormal (severity grade 1 and higher) signs, symptoms, and diagnoses occurring 
post-entry must also be recorded on CRFs at all visits. 
 
7. 
STATISTICAL CONSIDERATIONS 
 
7.1 
Outcome Measures 
 
IQ scores (from the Bayley and Wechsler scales), executive functioning skills 
(from the BRIEF questionnaire), and neurodevelopmental deficits (from the TQQ 
and the ASQ). 
 
7.2 
Data Analyses 
 
Neurodevelopmental assessments will be given annually at ages 1 to 4 years. The 
infant neurodevelopmental data analyses will be performed after all infants have 
completed their year 1 evaluations and then again after all infants have completed 
the entire study.  
 
Neurodevelopmental data analyses will be based on comparisons of the two study 
arms. Two sample t-tests will be used to compare IQ scores between treatment 
arms at ages 1 and 4 years. For the TQQ and ASQ, which have binary (yes/no) 
outcomes, chi-square tests will be used to compare the frequencies of identified 
deficits between the two study arms. 
 
7.3 
Sample Size 
 
The sample sizes available for the neurodevelopmental analyses are expected to be 
smaller than for the primary outcomes both because of attrition and because not all 
participants will choose to participate. Loss to follow-up is expected to be 
relatively small at the 1 year assessment, but may increase significantly by the 4 

 
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year assessment. For this reason, sample sizes ranging from 50% to 90% of the 
original have been used for the following calculations. 
 
Table 1 shows the effect size detectable between the two study arms with 80% 
power and 0.05 two-sided α, and the precision (1/2 width of the 95% confidence 
interval) for estimating the within-arm mean, with sample sizes ranging from 50% 
to 90% of the initial sample. The effect sizes were calculated using PASS 11 under 
the model of two sample t-tests. The differences detectable with 80% power range 
from 0.32 to 0.43 standard deviations and the precision ranges from 0.16 to 0.22 
standard deviations. To obtain the minimum detectable effect size and precision 
for a specific test, the numbers in Table 1 need to be multiplied by the standard 
deviation of the test. For example, using an IQ test (i.e., Bayley or WPPSI) with a 
standard deviation of 15, this translates into 80% power to detect differences 
between arms of 4.8 to 6.5 IQ points, and precision (1/2 width of 95% confidence 
intervals) of 2.4 to 3.2 IQ points (see Table 1).  
 
Table 1: 
Detectable differences between two study arms with 80% power and alpha=0.05, and, 
precision for estimating the within-arm mean 
% of 
initial 
sample 
size 
Number of 
evaluable 
children per 
treatment arm 
Total 
number of 
children 
Minimum detectable effect size 
Precision of estimate  
of within-arm mean 
(1/2-width of 95% confidence 
interval) 
Number of 
standard 
deviations 
IQ points 
(s.d. of 15) 
Number of 
standard 
deviations 
IQ points  
(s.d. of 15) 
50% 
85 
170 
0.43 
6.5 
+/-0.22 
+/- 3.2 
60% 
101 
202 
0.40 
6.0 
+/-0.20 
+/- 2.9 
70% 
118 
236 
037 
5.6 
+/-0.18 
+/- 2.7 
80% 
135 
270 
0.34 
5.1 
+/-0.17 
+/- 2.5 
90% 
152 
304 
0.32 
4.8 
+/-0.16 
+/- 2.4 
 
The ASQ and TQQ both provide binary outcomes for various potential problem 
areas. Table 2 shows the detectible difference in proportion of participants 
experiencing neurodevelopmental deficits with 80% power and overall 2-sided α 
=0.05. The detectable difference in proportions between the study arms ranges 
from 0.12 to 0.22, corresponding to odds ratios from 0.22 to 0.51, depending on 
the available N and proportion in Arm 1. 
 
 
 

 
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Table 2: 
Detectable difference in proportion of participants experiencing neurodevelopmental 
deficits with 80% power and overall 2-sided α =0.05  
Proportion in 
Arm 1 
N/arm 
Detectible proportion in  
Arm 2 
Detectible difference in 
proportions 
Odds ratio 
0.20 
85 
0.05 
0.15 
0.22 
101 
0.06 
0.14 
0.26 
118 
0.07 
0.13 
0.30 
135 
0.08 
0.12 
0.33 
152 
0.08 
0.12 
0.36 
0.30 
85 
0.12 
0.18 
0.32 
101 
0.13 
0.17 
0.35 
118 
0.14 
0.16 
0.39 
135 
0.15 
0.15 
0.42 
152 
0.16 
0.14 
0.45 
0.40 
85 
0.20 
0.20 
0.37 
101 
0.21 
0.19 
0.40 
118 
0.23 
0.17 
0.44 
135 
0.24 
0.16 
0.46 
152 
0.25 
0.15 
0.49 
0.50 
85 
0.28 
0.22 
0.39 
101 
0.30 
0.20 
0.43 
118 
0.32 
0.18 
0.46 
135 
0.33 
0.17 
0.49 
152 
0.34 
0.16 
0.51 
 
 
8.0 
EXTENSION PHASE: INFANT SCHEDULE OF EVALUATIONS  
 
 
Week 521 
(Age 1 
year) 
Week 
1041 
(Age 2 
years) 
Week 
1561 
(Age 3 
years) 
Week 
2081 
(Age 4 
years) 
NEURODEVELOPMENTAL / NEUROPSYCOLOGICAL EVALUATIONS 
 
Bayley Scales of Infant and Toddler Development-Third Edition (BSID III)2 
X 
 
 
 
Ages and Stages Questionnaire (ASQ)2 
X 
X 
X 
X 
Ten Questions Questionnaire (TQQ)2 
X 
X 
X 
X 
Wechsler Preschool and Primary Scale of Intelligence (WPPSI III) and Behavior 
Rating Inventory of Executive Function-Preschool Version 2 
 
 
 
X3 
 
FOOTNOTES FOR EXTENSION PHASE: INFANT SCHEDULE OF EVALUATIONS 
 
1. Visit window is ± 30 days.  
2. Neurodevelopmental and neuropsychological evaluations may be performed outside the visit 
window with permission from the protocol psychologist. 
3. The WPPSI III cannot be administered until the child is at least 4 years old. 
 
 
 

 
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9.0  
REFERENCES 
 
1. 
Ford N, Mofenson L, Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Shaffer N, 
Renaud F. Safety of efavirenz in the first trimester of pregnancy: an updated systematic 
review and meta-analysis. AIDS. 2014 Mar;28 Suppl 2:S123-31. 
2. 
WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and 
preventing HIV infection. 
3. 
Schneider S, Peltier A, Gras A, Arendt V, Karasi-Omes C, Mujawamariwa A et al.: 
Efavirenz in human breast milk, mothers’, and newborns’ plasma. J Acquir Immune Defic 
Syndr 2008, 48: 450-454. 
4. 
Westreich D, Rubel D, Macdonald P, Maskew M, Nagar S, Jaffrey I et al. Pregnancy, 
efavirenz, and birth outcomes In Johannesburg, South Africa. 17th Conference on 
Retroviruses and Opportunistic Infections, San Francisco, CA 2010. 2010. Ref Type: 
Abstract. 
5. 
Council on Children With Disabilities; Section on Developmental Behavioral Pediatrics; 
Bright Futures Steering Committee; Medical Home Initiatives for Children With Special 
Needs Project Advisory Committee. Identifying infants and young children with 
developmental disorders in the medical home: an algorithm for developmental surveillance 
and screening. Pediatrics. 2006 Jul;118(1):405-20. Erratum in: Pediatrics. 2006 
Oct;118(4):1808-9. 
6. 
Westreich D, Maskew M, Rubel D, MacDonald P, Jaffray I, Majuba P. Incidence of 
pregnancy after initiation of antiretroviral therapy in South Africa: a retrospective clinical 
cohort analysis. Infect Dis Obstet Gynecol. 2012;2012:917059. doi: 10.1155/2012/917059. 
7. 
Bayley N: Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). San 
Antonio, TX: Pearson Assessments; 2006. 
8. 
Fernald LCH, Kariger P, Engle P, Raikes A: Examining early child development in low-
income countries: a toolkit for the assessment of children in the first five years of life. 
Washington, D.C.: World Bank; 2009. 
9. 
Wechsler D: Wechsler Preschool and Primary Scale of Intelligence, Third Edition., Third 
Edition edn. San Antonio, TX: Psychological Corporation; 2002. 
10. Gioia G, Espy K, Isquith P: Behavior Rating Inventory of Executive Function-Preschool 
version. Odessa, FL: Psycholoigcal Assessment Resources; 2002. 
11. Bricker D, Squires J: Ages and Stages Questionnaires: A Parent Completed, Child 
Monitoring System, 2nd Ed. edn. Baltimore, MD: Paul Brookes; 1999. 
 
 

 
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SAMPLE INFORMED CONSENT 
 
A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two 
Different Potent Regimens in HIV-infected Women Initiating Triple Antiretroviral Regimens 
Between 28 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission, 
Infant Development Substudy: NICHD P1081S 
 
INTRODUCTION 
 
You are being asked for your baby to take part in this research study because your baby 
participated in the first part of this P1081 study. This study is sponsored by the National 
Institutes of Health (NIH). The doctor in charge of this study at this site is: (insert name of 
Principal Investigator). Before you decide if you want your baby to be a part of this study, we 
want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with 
you about this information. You are free to ask questions about this study at any time. If you 
agree to/allow your baby to take part in this study, you will be asked to sign this consent form. 
You will get a copy to keep.  
 
WHY IS THIS STUDY BEING DONE? 
 
In this study, we want to measure how infants learn and develop over the first 4 years of life. We 
would like to understand if the development is different for infants whose mothers took efavirenz 
during pregnancy and infants whose mothers took raltegravir during pregnancy.  
 
WHAT DO I/DOES MY BABY HAVE TO DO IF MY BABY IS IN THIS STUDY? 
 
• At 1, 2, 3 and 4 years of age, your baby will have a physical examination that includes 
length, weight, and head measurement. You will be asked about your baby’s health at 
each of these visits. 
• When your baby is one year old, your baby will have a test to check his/her motor skills 
and behavior and learning abilities. This test is a series of developmental play tasks and 
takes between 30-60 minutes to administer. 
• At 1, 2, 3 and 4 years of age, you will be asked to complete two questionnaires about 
your baby’s development which will take about 10-20 minutes to answer. 
• When your baby is 4 years old, your baby will have a neuropsychological test to check 
his/her language and motor skills. This test will take about 1-1½ hours to complete. 
• You will be told whether your baby is developing according to his/her age expectation 
and a referral for further testing will be made if problems are found. 
• Each of your baby’s study visits will last about (sites – add local information about time 
for study visits). 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
Up to 334 infants may take part in this study. 

 
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HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You and your baby will be in this study until your baby is 4 years of age. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you/your baby off the study early without your permission if: 
 
• The study is cancelled by the NICHD network, US Food and Drug Administration (FDA), 
NIH, the drug companies supporting this study, the Office for Human Research Protections 
(OHRP), other national regulatory agencies, or the site’s Institutional Review Board (IRB) or 
Ethics Committee. An IRB is a committee that watches over the safety and rights of research 
participants. 
• You are/your baby is not able to attend the study visits as required by the study. 
• Continuing in the study may be harmful to you/your baby. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
There are no risks in taking the neurodevelopmental or neuropsychological tests other than 
your baby might find some parts of the tests difficult to do. 
 
Social Risks 
 
If you join this study, some hospital staff and all study staff will know that you have HIV. These 
workers are very serious about your privacy. Study staff will make every possible effort to be 
sure that others do not learn your HIV status. However, sometimes if you receive special 
treatment or attend a special clinic, it may make others wonder if you have HIV. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
You/your baby may receive no benefit from being in this study. You and your baby may 
benefit from the information you will receive about your baby’s development. Information 
learned from this study may help with advice to other pregnant women about which HIV 
drugs to take during pregnancy.  
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, your baby’s regular doctor can monitor your baby’s development 
at your baby’s regular check-ups.  
 
WHAT ABOUT CONFIDENTIALITY? 
 
United States Sites: 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the NIH. 
With this Certificate, the researchers cannot be forced to disclose information that may identify 

 
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you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands 
for information that would identify you, except as explained below. The Certificate cannot be 
used to resist a demand for information from personnel of the United States Government that is 
used for auditing or evaluation of federally funded projects or for information that must be 
disclosed in order to meet the requirements of the federal FDA.  
 
People who may review your records include the US Food and Drug Administration, the site IRB 
or Ethics Committee, other national regulatory agencies, the NIH, the OHRP, study staff, study 
monitors, and drug companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about you or your participation in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate of Confidentiality to withhold that 
information. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Sites outside the United States: 
Efforts will be made to keep your/your baby’s personal information confidential. We cannot 
guarantee absolute confidentiality. Your/your baby’s personal information may be disclosed if 
required by law. Any publication of this study will not use your/your baby’s name or identify 
you/your baby personally. 
 
Your/your baby’s records may be reviewed by the US FDA, the site IRB or Ethics Committee, 
other national regulatory agencies, the NIH, the OHRP, study staff, study monitors, and drug 
companies supporting the study, and their designees. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for the study-related visits and procedures given to you or your baby in 
this study. Taking part in this study may lead to added costs to you and your insurance company. 
In some cases it is possible that your insurance company will not pay for these costs because you 
are/your baby is taking part in a research study.  
 
 
 

 
NICHD P1081 
 
 
VERSION 3.0 
FINAL 
April 2, 2015 
 
Page 13 of 13 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you are/your baby is injured as a result of being in this study, you/your baby will be given 
immediate treatment for your injuries. The cost for this treatment will be charged to you or your 
insurance company. There is no program for compensation either through this institution or the 
NIH. You will not be giving up any of your legal rights by signing this consent form. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to allow your baby to take 
part in this study or leave this study/take your baby out of the study at any time. Your decision 
will not have any impact on your participation or your baby’s participation in other studies 
conducted by NIH and will not result in any penalty or loss of benefits to which you or your 
baby are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your/your 
baby’s health, welfare or willingness to stay in this study. If you want the results of the study, let 
the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• name of the investigator or other study staff 
• telephone number of above  
 
For questions about your/your baby’s rights as a research participant, contact: 
• name or title of person on the IRB or other organization appropriate for the site 
• telephone number of above  
 
SIGNATURE PAGE  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in or allow your baby to take part in this study, please sign 
your name below. 
 
___________________________________ 
__________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
___________________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff Signature and Date 
___________________________________ 
__________________________________ 
Witness’ Name (print) 
Witness’s Signature and Date