Pharmacokinetic Properties of Antiretroviral and Related Drugs During Pregnancy and Postpartum
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
IMPAACT P1026s 
 
PHARMACOKINETIC PROPERTIES OF ANTIRETROVIRAL AND RELATED 
DRUGS DURING PREGNANCY AND POSTPARTUM 
 
(DAIDS Document ID 10040) 
 
 
A Multi-center Trial of the  
International Maternal Pediatric Adolescent AIDS  
Clinical Trials (IMPAACT) Network 
 
 
Sponsored By: 
 
The National Institute of Allergy and Infectious Diseases 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development 
The National Institute of Mental Health (NIMH) 
 
 
IND # 64,535 held by NIAID 
 
 
 
The IMPAACT Treatment Scientific  
 
Committee Chair:   
 
 
Elaine Abrams, MD 
 
Protocol Chair: 
 
 
 
Mark Mirochnick, MD 
 
Protocol Vice-Chair: 
 
 
Brookie Best, PharmD, MAS 
 
Protocol Vice-Chair: 
 
 
Alice Stek, MD 
 
NIAID Medical Officer: 
 
 
Elizabeth Smith, MD 
 
NICHD Medical Officer: 
 
 
Nahida Chakhtoura, MD 
 
Clinical Trials Specialist: 
 
 
Kathleen George, MPH  
 
 
 
 
Version 10.0 
2 February 2016 

 
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All questions concerning this protocol should be sent via e-mail to impaact.teamp1026s@fstrf.org. 
Remember to include the participant’s PID when applicable. A response should generally be received 
within 24 hours (Monday - Friday). For protocol registration questions, e-mail protocol@tech-res.com or 
call 301-897-1707. Protocol registration material can be sent electronically to epr@tech-res.com or via 
fax at 1-800-418-3544 or 301-897-1701. For EAE questions, e-mail DAIDSRSCSafetyOffice@tech-
res.com or call 1-800-537-9979 or 301- 897-1709, or fax 1-800-275-7619 or 301-897-1710. For 
enrollment questions, contact the Data Management Center at (716) 834-0900 or by e-mail 
sdac.random.desk@fstrf.org.   
 
Protocol Chair 
Mark Mirochnick, MD 
Boston Medical Center 
771 Albany Street 
Dowling 4N, Room 4111 
Boston, MA 02118 
Phone: 617-414-3754 
E-mail: markm@bu.edu 
 
Protocol Vice Chairs 
Alice Stek, MD 
Univ. of Southern California School of Medicine  
Los Angeles County Medical Center Maternal, 
Child and Adolescent HIV Program 
Obstetrics and Gynecology  
2020 Zonal Ave, IRD Building, room 218 
Los Angeles, CA  90033 
Phone: 323-226-3306 or 323-226-2200 
E-mail: stek@usc.edu  
 
Brookie Best, PharmD, MAS 
Division of Pharmacology 
and Drug Discovery 
Univ. of California San Diego 
9500 Gilman Drive, MC 0719 
La Jolla, CA 92093-0719 
Phone: 858-822-5550 
E-mail: brookie@ucsd.edu 
 
DAIDS Medical Officer 
Mary Elizabeth Smith, MD 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: 1-240-292-4788 
E-mail: betsysmith@niaid.nih.gov  
 
 
 
 
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MsGH 
Maternal and Pediatric Infectious Disease 
Branch 
Eunice Kennedy Shriver National Institute 
of Child Health and Human Development 
(NICHD) 
National Institutes of Health 
6100 Executive Blvd., Room 4B11 
Bethesda, MD 20892-7510 
Phone: 301-435-6872 
Email: nahida.chakhtoura@nih.gov 
 
Clinical Trials Specialist 
Kathleen George, MPH 
FHI 360 
359 Blackwell St, Suite 200 
IMPAACT Operations Office 
Durham, NC 22701  
Phone: 919-544-7040 x11150 
E-mail: kgeorge@fhi360.org  
 
Protocol Pharmacologists 
Edmund Capparelli, PharmD  
UCSD, Pediatric Pharmacology 
Research Unit 
7910 Frost Street #360 
San Diego, CA 92123 
Phone: 858-246-0001  
E-mail: ecapparelli@ucsd.edu 
 
 
 
 
 
 
 
 
 

 
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Francesca Aweeka, PharmD 
San Francisco General Hospital 
Department of Clinical Pharmacy 
UCSF Box 0622, 
Third & Parnassus 
San Francisco, CA  94143-0622 
Phone: 415- 476-0339 
E-mail: aweeka@itsa.ucsf.edu 
 
Tim Roy Cressey, PhD 
Program for HIV Prevention and Treatment 
(PHPT) 
Faculty of Associated Medical Sciences 
Department of Clinical Microbiology 
1110 Inthawaroros Road 
Muang, Chiang Mai 50200  
Thailand 
Phone: +66 53 894 431 
Email: tim@phpt.org 
 
Protocol Virologist 
Lisa M. Frenkel, MD 
Seattle Children's Research Institute and 
University of Washington 
1900 – 9th Ave; 8th Floor 
Seattle, WA 98101- 1304 
Phone: 206-987-5140 
E-mail: lfrenkel@u.washington.edu 
 
Pediatrician 
Sandra K. Burchett, MD, MS 
Clinical Director, Infect Disease Division 
Children's Hospital Boston  
300 Longwood Avenue  
Boston, MA  02115-5724 
Phone: 617-355-6832 
E-mail: sandra.burchett@childrens.harvard.edu  
 
Investigators 
Nantasak  Chotivanich, MD 
Department of Obstetrics & Gynecology 
Chonburi Hospital 
69 M. 2 Sukumvith Rd.,  
T.Ban Suan, Muang, Chonburi 20000 
Thailand 
Phone: +66-38-931-390 
E-mail: nantasak.cho@chaiyo.com 
 
 
 
Gonzague Jourdain, MD 
Insitut de Recherche pour le Devel  
(IRD) & Program for HIV Prevention and 
Treatment (PHPT) 
187/10 Changklan Rd 
Changklan, Muang,    
Chiang Mai 50100 
Thailand 
Phone: +66 53 819 125,310 
E-mail: gonzague@phpt.org  
 
Regis Kreitchmann, MD, PhD 
Irmandade da Santa Casa de Misericórdia de 
Porto Alegre 
Rua Prof. Annes Dias 285, 4th floor 
Porto Alegre, RS 90020090 
Phone: +55 51 9155565 
E-mail: regis.kr@terra.com.br   
 
Marije Van Schalkwyk, MD 
Stellenbosch University 
Faculty of Medicine and Health Sciences, 
R3020, Tygerberg Campus 
Francie Van Zijl Ave, Parow 7505, Cape Town, 
South Africa 
Phone : +27 21 9389483 
Fax : +27 21 9389709 
Email : marije@sun.ac.za  
 
Pooja Mehta, MD, MSHP 
Boston Medical Center 
85 East Concord Street  
Boston MA 02118  
Phone : 914-320-8712  
Email : pooja.mehta@bmc.org 
 
Field Representatives 
Emily  Barr , CPNP, CNM, MSN  
Pediatric Nurse Practitioner 
Colorado Children’s Hospital CHIP Program 
13123 E. 16th Avenue B-055 
Aurora, CO 80045 
Phone: 720-777-6752 
E-mail: emily.barr@childrenscolorado.org 
 
 
 

 
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Pra-ornsuda Sukrakanchana, BSN 
Institut de Recherche pour le Devel 
(IRD) & Program for HIV Prevention and 
Treatment (PHPT) 
187/10 Changklan Rd  
Changklan, Muang 
Chiang Mai 50100, Thailand 
Phone: +66 53 819125, 302 
Fax: +66 53-819130 
E-mail: praornsuda@phpt.org  
 
Protocol Statisticians 
Jiajia Wang, MS 
Harvard School of Public Health 
Center for Biostatistics in AIDS Research 
(CBAR) FXB Building, Room 601 
651 Huntington Avenue 
Boston, MA  02115 
Phone: 617-432-1464 
Email: jwang@sdac.harvard.edu    
 
David Shapiro, PhD 
Harvard School of Public Health 
Center for Biostatistics in AIDS Research 
(CBAR) FXB Building, Room 643B 
651 Huntington Avenue 
Boston, MA  02115 
Phone: 617-432-2426 
Email: shapiro@sdac.harvard.edu 
 
Laboratory Technologist 
Kittipong Rungruengthanakit, MSc 
Research Institute for Health Sciences 
Chiang Mai University PO Box 80 CMU Chiang 
Mai 50202 Thailand 
Phone:  66-5394-6148 
E-mail:  kittipong@rihes.org   
 
Protocol Data Manager 
Adriane Hernandez  
Frontier Science & Technology Research 
4033 Maple Road  
Amherst, NY  14226 
Phone: 716-834-0900 x7495 
E-mail: hernande@fstrf.org 
 
 
 
 
 
Laboratory Data Manager 
Amy Gonzalez, BS 
Frontier Science & Technology Research 
4033 Maple Rd 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7438 
Email: jennings@fstrf.org  
 
Westat Representative 
Rita Patel 
1441 W. Montgomery Avenue 
Rockville, MD 20850 
Phone: 301-294-3949 
E-mail:  ritapatel@westat.com    
 

 
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Tuberculosis Investigators  
Amita Gupta, MD, MHS 
Johns Hopkins University  
Phipps Building 540B 
600 North Wolfe Street  
Baltimore, MD  21287 
Phone: 410- 502-7696 
E-mail: agupta25@jhmi.edu   
 
Adrie Bekker, FCPaed (SA) 
Department of Neonatology 
Stellenbosch University of South Africa 
Tygerberg Hospital  
Francie van Zijl Drive, Tygerberg, 7505  
Phone: 27 21 938 9673  
Email: adrie@sun.ac.za 
 
Anneke Hesseling, MD, PhD 
Director, Paediatric Research 
Desmond Tutu TB Centre 
Department of Pediatrics and Child Health 
Stellenbosch, University South Africa 
Phone: +27 219389173 
Email: annekeh@sun.ac.za 
 
Anthony Garcia-Prats, MD 
Desmond Tutu TB Centre 
Department of Paediatrics and Child Health  
Stellenbosch University 
PO Box 19063 
Tygerberg, 7505 
Cape Town, South Africa 
Phone: +27 21 938 9173  
Email: garciaprats@exchange.sun.ac.za 
 
 
 
 

 
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TABLE OF CONTENTS 
GLOSSARY ....................................................................................................................................8 
SCHEMA  ....................................................................................................................................10 
1.0 
 INTRODUCTION ..............................................................................................................13 
1.1 
Background and Rationale ..........................................................................................13 
1.2  Clinical Pharmacology in Pregnancy ..........................................................................13 
1.3 
Pharmacokinetics of Approved Antiretroviral Drugs in Pregnancy ...........................14 
1.4  Use of Tuberculosis (TB) and Antiretroviral (ARV) Medicines during Pregnancy ..16 
1.5 
Contraceptives and Antiretrovirals .............................................................................18 
1.6 
Genital Tract HIV and Antiretroviral Concentrations ................................................19 
1.7 
Pharmacogenetics .......................................................................................................20 
1.8 
History of Versions 1.0 - 9.0 ......................................................................................21 
2.0 
 OBJECTIVES .....................................................................................................................22 
2.1 
Primary Objectives .....................................................................................................22 
2.2 
Secondary Objectives .................................................................................................22 
3.0 
 STUDY DESIGN................................................................................................................22 
3.1  Enrollment Procedures ................................................................................................23 
3.2  Maternal Antepartum and Postpartum Pharmacokinetic Sampling ............................24 
3.3 
Reporting of Pharmacokinetic Results .......................................................................25 
3.4 
Intrapartum Pharmacokinetic Sampling .....................................................................25 
3.5 
Infant Pharmacokinetic Sampling ...............................................................................26 
4.0 
 SELECTION AND ENROLLMENT OF PARTICIPANTS ..............................................26 
4.1  Maternal Inclusion Criteria .........................................................................................26 
4.2 
Maternal Exclusion Criteria ........................................................................................29 
4.3  Infant Enrollment Criteria ...........................................................................................29 
4.4 
Infant Requirements for Washout Pharmacokinetic Sampling ..................................29 
4.5  Enrollment Procedures ................................................................................................29 
4.6  Co-Enrollment Procedures ..........................................................................................30 
4.7 
Study Drug Formulations ...........................................................................................30 
5.0 
TOXICITY MANAGEMENT .............................................................................................31 
5.1  Toxicity Monitoring ....................................................................................................31 
5.2 
Bilirubin Toxicity Monitoring for Postpartum Women Receiving Atazanavir ..........33 
5.3  Criteria for Discontinuation ........................................................................................33 
6.0 
 EXPEDITED ADVERSE EVENT REPORTING..............................................................33 
6.1 
Adverse Event Reporting to DAIDS ..........................................................................33 
6.2  Reporting Requirements for this Study ......................................................................33 
6.3  Grading Severity of Events .........................................................................................34 
6.4  Expedited AE Reporting Period .................................................................................34 
7.0 
 DISALLOWED MEDICINES............................................................................................34 
7.1 
NRTIs .........................................................................................................................34 
7.2 
NNRTIs .......................................................................................................................34 
7.3 
PIs ...............................................................................................................................35 
7.4 
Integrase Inhibitors .....................................................................................................36 
7.5  Tuberculosis (TB) drugs .............................................................................................36 

 
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7.6  Combined Oral Contraceptives (COCs) and Etonogestrel Implant ............................37 
8.0 
STATISTICAL CONSIDERATIONS.................................................................................38 
8.1 
General Design Issues .................................................................................................38 
8.2 
Outcome Measures .....................................................................................................38 
8.3 
Randomization and Stratification ...............................................................................39 
8.4 
Sample Size and Accrual ............................................................................................39 
8.5 
Monitoring ..................................................................................................................43 
8.6 
Analysis ......................................................................................................................44 
9.0 
 CLINICAL PHARMACOLOGY PLAN ............................................................................46 
9.1 
Objectives ...................................................................................................................46 
9.2 
Primary and Secondary Data to be Accessioned ........................................................47 
9.3 
Study Design, Modeling and Data Analysis ...............................................................48 
10.0  DATA COLLECTION REQUIREMENTS .......................................................................51 
11.0  HUMAN SUBJECTS .........................................................................................................53 
11.1 Institutional Review Board (IRB) Review and Informed Consent .............................53 
11.2 Subject Confidentiality ...............................................................................................54 
11.3 Study Discontinuation ................................................................................................54 
12.0  PUBLICATION OF RESEARCH FINDINGS ..................................................................54 
13.0  BIOHAZARD CONTAINMENT .......................................................................................54 
14.0  REFERENCES ...................................................................................................................55 
TABLE A: Guidelines for Using Schedule of Evaluations and Sample Informed Consents ........60 
APPENDIX I-A: Schedule of Evaluations for Women on ARV Medicines without Tuberculosis 
Treatment  ....................................................................................................................................61 
APPENDIX I-B: Schedule of Evaluations for Women on ARV Medicines with Tuberculosis 
Treatment  ....................................................................................................................................63 
APPENDIX I-AMR: Additional Monitoring Requirements for Women on DRV and LPV ........65 
APPENDIX I-C: Schedule of Evaluations for HIV-Uninfected Women with Tuberculosis 
Treatment  ....................................................................................................................................66 
APPENDIX I-D: Schedule of Evaluations for Postpartum Women on ARV Medicines and 
Hormonal Contraceptives ..............................................................................................................68 
APPENDIX II: Schedule of Evaluations for Infants .....................................................................70 
APPENDIX III: Maternal Intensive Pk Sampling Schedule for ARV Medicines, Tuberculosis 
Treatment and Hormonal Contraceptives ......................................................................................72 
APPENDIX IV: Dietary Recommendations for Antiretroviral Medicines, Tuberculosis 
Medicines and Hormonal Contraceptives ......................................................................................74 
APPENDIX V: Maternal Pharmacokinetic Parameter Targets .....................................................75 
APPENDIX VI-A: Sample Consent Form for Women on ARV Medicines without Tuberculosis 
Treatment  ....................................................................................................................................81 

 
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APPENDIX VI-B: Sample Consent Form for Women on ARV Medicines with Tuberculosis 
Treatment (First Line and Second Line) ........................................................................................86 
APPENDIX VI-C: Sample Consent Form for HIV-Uninfected Pregnant Women on No ARV 
Medicines with Tuberculosis Treatment ........................................................................................93 
APPENDIX VI-D: Sample Consent Form for Postpartum Women on Antiretroviral Medicines 
and Hormonal Contraceptives........................................................................................................99 
APPENDIX VII: History of Version 1.0 to Version 9.0 .............................................................104 
 
 
 
 
 
 

 
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GLOSSARY 
 
3TC 
 
Lamivudine 
AAG 
 
Alpha-1 Acid Glycoprotein 
ABC 
 
Abacavir 
AE 
 
Adverse Event  
ALT 
 
Alanine Aminotransferase 
ART 
 
Antiretroviral Therapy 
ARV 
 
Antiretroviral 
ATV 
 
Atazanavir 
ATV/Cobi 
Atazanavir/ cobicistat 
ATV/r  
Atazanavir/ritonavir 
AUC 
 
Area Under the Curve 
b.i.d  
 
Twice A Day 
CBC 
 
Complete Blood Count 
CID 
 
Case Identification Number  
CVL 
 
Cervical-vaginal Lavage  
COCs  
Combined Oral Contraceptives 
CRF 
 
Case Report Form 
Cmin 
 
Plasma Concentration at the End of the 24 Hour Dosing Interval 
CYP 
 
Cytochrome 
d4T 
 
Stavudine 
DAIDS  
(United States) Division of AIDS  
ddI 
 
Didanosine delayed release (Videx® EC) 
DMC  
Data Management Center  
DTG 
 
Dolutegravir 
DRV 
 
Darunavir 
DRV/Cobi 
Darunavir/cobicistat 
DRV/r  
Darunavir/ritonavir 
EAE 
 
Expedited Adverse Event 
EC 
 
Ethics Committee, Enteric Coated 
EFV 
 
Efavirenz 
ELV/Cobi 
Elvitegravir/cobicistat  
EMB 
 
Ethambutol 
ENG 
 
Etonogestrel 
EVA 
 
Ethylene vinylacetate 
FDA 
 
(United States) Food and Drug Administration  
FTC 
 
Emtricitabine 
HIV 
 
Human Immunodeficiency Virus 
IMPAACT 
International Maternal, Pediatric, Adolescent AIDS Clinical Trials Network 
IND 
 
Investigational New Drug 
INH 
 
Isoniazid 
IRB 
 
Institutional Review Board 
LDMS  
Laboratory Data Management System 
LPC 
 
Laboratory Processing Chart 
LPV 
 
Lopinavir 
LPV/r  
Lopinavir/ritonavir (Kaletra® or Alluvia®) 
NFV 
 
Nelfinavir 
NIAID  
(United States) National Institute of Allergy and Infectious Diseases  
NICHD  
(United States) National Institute of Child Health and Human Development  
NIH 
 
(United States) National Institutes of Health  

 
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NNRTI  
Non-Nucleoside Reverse Transcriptase Inhibitor 
NVP 
 
Nevirapine 
OHRP  
(United States) Office for Human Research Protections 
P1022 
Randomized Trial of Protease Inhibitor Including Vs. Protease Inhibitor Sparing 
Regimens for Women who Initiate Therapy for HIV Infection During Pregnancy 
P1070 
Dose-Finding and Pharmacogenetic Study of Efavirenz in HIV-Infected and HIV/TB Co-
Infected Infants and Children ≥3 Months to <36 Months of Age 
P1078 
A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety 
of Immediate (Antepartum-initiated) Versus Deferred (Postpartum-initiated) Isoniazid 
Preventive Therapy among HIV-Infected Women in High TB Incidence Settings  
PI 
 
Protease Inhibitor 
PID 
 
Patient Identification Number 
PK 
 
Pharmacokinetic  
PZA 
 
Pyrazinamide 
q.d. 
 
Every day 
RIF 
 
Rifampicin 
RSC 
 
(United States) Regulatory Support Center  
RTV 
 
Ritonavir 
SAE 
 
Serious Adverse Event 
SIP 
 
Site Implementation Plan 
TAF 
 
Tenofovir Alafenamide Fumarate 
TB 
 
Tuberculosis 
TDF 
 
Tenofovir 
t.i.w.   
Three Times a Week 
ULN 
 
Upper Limit of Normal 
U.S. 
 
United States of America 
VQA 
 
Virology Quality Assurance 
WHO  
World Health Organization 
WITS  
Women and Infants Transmission Study 
ZDV 
 
Zidovudine 

 
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SCHEMA 
 
IMPAACT P1026s 
PHARMACOKINETIC PROPERTIES OF ANTIRETROVIRAL AND RELATED DRUGS 
DURING PREGNANCY AND POSTPARTUM 
DESIGN:  
 Phase IV, prospective pharmacokinetic (PK) study 
 
SAMPLE SIZE:  
Each study arm will enroll a minimum of 12 women and have a target enrollment 
of 25 women with evaluable 3rd trimester PK data for antiretroviral (ARV) and 
tuberculosis (TB) arms, or evaluable postpartum PK data for hormonal 
contraceptive arms. Women who do not have evaluable PK data will be replaced. 
Enrollment may be restricted to the second trimester and/or increased above 25 
so that evaluable 2nd trimester PK data are obtained from at least 12 women. 
Enrollment may also be increased above 25 to obtain additional second line TB 
drug data or infant washout PK data.  
POPULATIONS:  
Pregnant and postpartum women receiving the following medicines as part of 
clinical care and infants born to those women enrolled during pregnancy. 
 
STUDY ARMS:   
 
Antiretrovirals (ARVs) without tuberculosis (TB) Treatment (10 Arms): HIV-infected pregnant 
women ≥ 20 weeks gestation NOT on tuberculosis treatment receiving one or more of the following ARV 
drugs/drug combinations: 
 
- darunavir/ritonavir twice daily 600/100 mg b.i.d. or 800/100 mg b.i.d. until 30 weeks gestation; then 
800/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after postpartum 
hospital discharge until 2 week postpartum PK samples are drawn 
- darunavir/ritonavir twice daily 600/100 mg b.i.d. or 900/100 mg b.i.d. until 30 weeks gestation; then 
900/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after postpartum 
hospital discharge until 2 week postpartum PK samples are drawn 
- dolutegravir 50 mg q.d. 
- tenofovir alafenamide fumarate (TAF) 25 mg q.d. without cobicistat or ritonavir boosting 
- tenofovir alafenamide fumarate (TAF) 10 mg q.d. with cobicistat 
- tenofovir alafenamide fumarate (TAF) 10 mg q.d. with ritonavir 
- elvitegravir/cobicistat 150/150 mg q.d. 
- darunavir/cobicistat 800/150 mg q.d. 
- atazanavir/cobicistat 300/150 mg q.d. 
- Participants outside of Thailand only:  efavirenz 600 mg q.d.   
 
Antiretrovirals with First Line Tuberculosis Treatment (2 Arms - one for each ARV drug): HIV-
infected pregnant women ≥ 20 weeks gestation receiving one of the following ARV drugs/drug 
combinations and TB treatment with at least one of the following TB drugs at study entry: 
ARVs: 
- efavirenz 600 mg q.d. 
- lopinavir/ritonavir 800/200 mg b.i.d. 
 
 
 

 
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TB drugs: 
• 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.  
• 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
• 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
No Antiretrovirals with First Line Tuberculosis Treatment (1 Arm): HIV-uninfected pregnant 
women ≥ 20 weeks gestation receiving at least two of the following first line TB drugs at study entry: 
• 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
• 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
Second Line Tuberculosis Treatment for Drug-Resistant Tuberculosis with or without 
Antiretrovirals (1 Arm):  HIV-infected and HIV-uninfected pregnant women ≥ 20 weeks gestation 
receiving at least two of the following second line TB drugs at study entry: 
 
Injectable agents: 
• 
kanamycin 
• 
amikacin 
• 
capreomycin 
Fluoroquinolones: 
• 
moxifloxacin  
• 
levofloxacin 
• 
ofloxacin 
Oral bacteriostatic second-line agents: 
• 
ethionamide/prothionamide 
• 
terizidone/cycloserine 
• 
para-aminosalicylic acid  (PAS) 
Other agents: 
• 
high dose INH 
• 
bedaquiline 
• 
clofazamine 
• 
delamanid 
• 
linezolid 
• 
pretomanid 
 
Antiretrovirals with Postpartum Contraceptives (4 Arms): HIV-infected women 2-12 weeks (14-84 
days) post-delivery receiving one of the following ARV drug combinations AND starting postpartum 
contraceptives as listed below: 
- darunavir/cobicistat 800/150 mg q.d. or atazanavir/cobicistat 300/150 mg q.d. postpartum and starting 
combined oral contraceptives formulated with 30-35 µg ethinyl estradiol 
- darunavir/cobicistat 800/150 mg q.d. or atazanavir/cobicistat 300/150 mg q.d. postpartum and starting 
etonogestrel implant 
- efavirenz 600mg q.d. postpartum and starting combined oral contraceptives formulated with 30-35 µg 
ethinyl estradiol 
- atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting combined oral 
contraceptives formulated with 30-35 µg ethinyl estradiol 
 

 
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REGIMEN:  
Pregnant women will continue on ARV and TB medications as prescribed by 
their clinician. Women enrolled into the postpartum contraception arms will have 
their ARV and contraception medications prescribed by their clinician. The 
timing of antepartum and postpartum pharmacokinetic evaluations will vary by 
drug. If ARV drug concentrations are not adequate, dose adjustments may be 
made at the discretion of the care provider. The new dose may be different than 
the current United States Food and Drug Administration (FDA) approved dose. 
 
STUDY DURATION:  HIV-infected pregnant women without tuberculosis (TB) will be followed for 6 – 
12 weeks after delivery with the exception of women on DRV/r who will be 
followed for 2 – 3 weeks after delivery.  
HIV-infected and non-infected women receiving TB treatment (first or second 
line) will be followed for 2 – 8 weeks after delivery.  
Postpartum women will be followed until 6 – 7 weeks after the initiation of 
hormonal contraceptives.  
Infants will be followed for 16 – 24 weeks of life. 
 
PRIMARY OBJECTIVES: 
1. To describe the pharmacokinetic parameters during pregnancy of selected ARV drugs currently used 
in the clinical care of HIV-infected pregnant women, and to compare these parameters to a) historical 
pharmacokinetic data from non-pregnant women and b) postpartum pharmacokinetic data from the 
same women in the study cohorts. 
2. To describe the pharmacokinetic parameters during pregnancy and postpartum of selected ARV drugs 
(efavirenz, lopinavir/ritonavir) and first line TB drugs when co-administered as part of clinical care of 
HIV-infected pregnant women and of first line TB drugs when used in HIV-uninfected pregnant 
women. 
3. To describe the pharmacokinetic parameters during pregnancy and postpartum of second line TB 
drugs administered as part of clinical care to HIV-infected and HIV-uninfected pregnant women. 
4. To describe the pharmacokinetic parameters of ARV drugs in postpartum women before and after 
starting hormonal contraceptives. 
5. To describe the concentrations of ethinyl estradiol, etonogestrel and other progestins in women using 
hormonal contraceptives and selected ARV drugs as compared to historical controls not using those 
ARV drugs. 
 
SECONDARY OBJECTIVES: 
1. To compare ARV and TB drug concentrations in plasma from cord blood with those in maternal 
plasma at the time of delivery. 
2. To assess plasma protein binding of highly bound ARV drugs during pregnancy and postpartum. 
3. To assess ARV concentrations and HIV RNA/DNA concentrations in vaginal secretions among 
pregnant and postpartum and compare to simultaneous plasma concentrations. 
4. To explore genetic sources for variability in ARV and TB drug exposure in pregnant women and their 
infants. 
5. To describe maternal and infant safety and clinical outcomes. 
6. To describe the neonatal elimination of selected ARV and TB drugs acquired across the placenta after 
maternal dosing during pregnancy. 
7. To describe pharmacokinetics of ARV drug combinations in HIV-infected women on second line TB 
treatment.  
 
 

 
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1.0 
 
INTRODUCTION  
 
1.1 
Background and Rationale  
 
Clinical trials to study the pharmacokinetics of antiretroviral (ARV), tuberculosis (TB) and contraceptive 
drugs in pregnant and postpartum women are limited. The development of appropriate dosing regimens 
for ARV and TB drugs in the pregnant woman is critical to the health of both mother and fetus. 
Overdosing may lead to maternal adverse events and increased risk of fetal toxicity. Under dosing may 
lead to inadequate virologic or mycobacterial control, increased risk of development of drug resistance 
mutations and a higher rate of perinatal HIV and TB transmission. Both increased metabolism and 
suppressed immunologic response during pregnancy can leave the mother at risk for viral/mycobacterial 
breakthrough and progression of disease. Independent of pharmacologic factors, pregnant women may be 
at particular risk for progression of HIV and TB disease. Pregnancy produces a temporary physiologic 
and immunologic homeostasis between tissues that are antigenically different. In order to accommodate 
the fetus, the maternal immune system is at least partially suppressed with an elevation of glucocorticoids 
(implicated in inducing hepatic metabolism) as one component of this response (1).  
 
Clinical trials studying the drug interactions between ARVs and TB drugs or postpartum contraceptives 
are also lacking. An understanding of these drug interactions is necessary to ensure safe and effective use 
of ARVs, TB drugs and contraceptives in pregnant and postpartum women. While pharmaceutical 
companies rarely undertake clinical trials in pregnant women, it remains a priority for the IMPAACT 
network to obtain data on how pregnancy affects drug exposure so that safe and effective doses of ARVs 
and anti-tuberculin medications for pregnant women can be prescribed. Data on use of these drugs within 
the context of contraceptive use are also much needed and are a priority for the network and its sites. The 
network and its stakeholders would also support the use of P1026s data for any possible label 
modification for use of a drug during pregnancy or in the context of contraceptive usage, should that 
become a feasible possibility. Labels can and should include data about dosing in pregnancy, even if the 
dose is not changed. ARV drug pharmacology in neonates is different from that in older infants and 
children due to immaturity and the physiologic changes experienced by the neonate during the adaptation 
to the extrauterine environment in the first days of life. ARV drugs may be used in the neonate to prevent 
or treat HIV infection. Clinical trials studying the neonatal elimination of ARV drugs acquired across the 
placenta after maternal dosing during pregnancy are critical first steps in understanding the pharmacology 
of ARV drugs in neonates and establishing safe and effective neonatal dosing regimens.  
 
1.2  
Clinical Pharmacology in Pregnancy 
 
Historically, women have been underrepresented in clinical drug trials (2). Recent investigations 
demonstrate that pharmacokinetic (PK) parameters may differ in men and women, and that women may 
display distinct therapeutic and toxic responses to specific compounds. One area of active investigation is 
the impact of gender on hepatic drug metabolism. Women demonstrate increased clearance of various 
drugs (e.g. verapamil, diazepam, and midazolam) when compared to men owing to enhanced cytochrome 
(CYP) P450 isozyme activity (3, 4). Many antiretroviral agents, including protease inhibitors (PIs) and 
non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized by cytochrome P450 pathways. 
An understanding of the impact of gender differences on the metabolism of these drugs is needed in order 
to maximize efficacy and minimize toxicity of these agents when used in women (5-7).  
 
Pregnancy may have an additional profound effect on drug disposition. Pregnant women experience 
unique physiological changes that may result in clinically significant alterations in drug pharmacokinetics 
and pharmacodynamics. These changes begin early in gestation and include:  (a) increased 
gastrointestinal transit time that can alter the rate and extent of drug absorption; (b) large changes in total 
body water and fat, increasing drug distribution volume; (c) decreased albumin and increased alpha acid 

 
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glycoprotein (AAG) concentrations that may cause clinically relevant changes in drug protein binding; (d) 
increased cardiac output, ventilation, and hepatic and renal blood flow which may impact drug 
metabolism and elimination; (e) increased concentrations of endogenous glucocorticoids that may affect 
the activity of hepatic enzyme systems that regulate drug metabolism (1, 8-12). 
 
Placental drug transport is another critical aspect of perinatal pharmacology for which few data exist for 
many antiretrovirals. Transport of antiretroviral agents from mother to fetus may provide protection of the 
fetus against HIV infection across the placenta and at the time of birth, but may also expose the fetus to 
the risk of toxicity. Placental drug transfer may be studied by several techniques, all of which have 
advantages and disadvantages. In vitro methods, such as isolated perfused placenta preparations, are 
convenient but may not accurately reflect in vivo conditions. Chronically catheterized non-human animal 
models allow complete characterization of the relationship between maternal and fetal concentrations, but 
interspecies differences limit the extrapolation of these findings to humans. Human studies are limited to 
comparisons of the ratio of maternal drug concentrations, at the time of delivery, to those in cord blood. 
While this ratio provides information about only a single point in time, it is the only technique currently 
available for human subjects and, for now, is the most useful. 
 
Another tool, post-partum wash-out pharmacokinetic sampling in babies of mothers who are on the ARVs 
under study in P1026s and who are already exposed to the ARVs in utero can help set the stage for future 
studies of the ARVs in newborns and infants. By pairing the short term safety data, with limited sampling 
to characterize drug elimination in infants who have already received the ARV in utero, design of further 
studies including dose finding and pharmacokinetic/pharmacodynamic studies in newborns can be better 
informed.  
 
1.3 
Pharmacokinetics of Approved Antiretroviral Drugs in Pregnancy 
 
Pharmacokinetic evaluations during pregnancy of many approved antiretroviral drugs have traditionally 
been lacking or inadequate. For the past decade, P1026s has helped to address some of these gaps in 
scientific data for ARV exposure during pregnancy. Data are briefly summarized below for currently 
approved antiretroviral drug classes.  
 
1.31 
Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) 
 
The pharmacokinetics of nucleoside reverse transcriptase inhibitors, including zidovudine (ZDV), 
lamivudine (3TC), and stavudine (d4T) during pregnancy are similar overall to pharmacokinetics in non-
pregnant women (13, 14). While pregnancy does seem to alter pharmacokinetics for some drugs, such as 
abacavir (ABC), emtricitabine (FTC) and tenofovir (TDF), those changes are small in magnitude and 
likely not clinically significant (15, 16). Placental passage for nucleoside agents with chronic dosing is 
high, with approximately equal concentrations in cord blood and maternal blood paired samples. No dose 
adjustments are recommended for these nucleoside agents during pregnancy.  
 
Tenofovir PK in pregnancy when administered as the prodrug tenofovir disoproxil fumarate (TDF) was 
studied in earlier versions of P1026s. (17) A new tenofovir prodrug, tenofovir alafenamide fumarate 
(TAF), with improved cellular uptake and lower toxicity will soon be approved for use in the US. (18) 
The PK of TAF in pregnant women will be studied in Version 10.0 of P1026s. 
 
1.32 
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 
 
For nevirapine (NVP), the physiologic changes associated with labor and delivery have a significant 
impact on pharmacokinetic parameters seen with initial doses given during labor, including increases in 
volume, clearance, and half-life and decreases in maximum concentrations and area under the curve 

 
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(AUC). Since NVP autoinduces its own clearance during the first weeks of chronic therapy, initial dose 
data cannot be extrapolated to chronic dosing. Nevirapine pharmacokinetics with chronic dosing during 
pregnancy were studied in P1022, Randomized Trial of Protease Including vs. Protease Sparing Regimens 
for Women to Initiate Therapy for HIV Infection During Pregnancy and Version 2.0 of P1026s. A 
combined analysis of the NVP PK data from these 2 studies show no significant differences in 
pharmacokinetic parameters during pregnancy compared to postpartum (19). 
 
Although severe teratogenic effects were observed with EFV use in pregnant primates, similar effects 
have not been seen in observational studies in humans and its use throughout pregnancy is becoming 
more popular (20). Clinicians are encouraged to refer to the Perinatal Guidelines for updated information 
about the use of EFV during pregnancy (available at http://aidsinfo.nih.gov/guidelines/) (21). Our prior 
study of EFV PK in primarily Thai women showed increased clearance and lower trough concentrations 
during pregnancy, but the magnitude of changes were small and not likely clinically significant. Efavirenz 
PK in HIV-infected women outside of Thailand have not been adequately described, and will continue to 
be studied in version 10 of P1026s.  
 
Etravirine and rilpivirine are newer NNRTI’s whose pharmacokinetics have been studied in previous 
versions of P1026s.  
 
1.33 
Protease Inhibitors (PIs)  
 
Prior versions of P1026s have shown that plasma concentrations of protease inhibitors, including 
lopinavir (LPV), atazanavir (ATV), nelfinavir (NFV), saquinavir (SQV), indinavir (IDV), fosamprenavir 
(fAPV) and darunavir/ritonavir (DRV/r), are significantly decreased when standard adult doses are used 
in pregnancy compared to postpartum women (22-28). The largest decreases have been seen in the third 
trimester, while second trimester concentrations are generally decreased to a lesser extent. Cord blood to 
maternal concentration ratios of PIs are generally less than 20%. Higher than standard doses of 
lopinavir/ritonavir (LPV/r) and atazanavir/ritonavir (ATV/r) have been studied in previous P1026s arms. 
These increased doses during the third trimester raise the PI concentrations back to typical concentrations 
seen in non-pregnant women on standard doses for LPV/r (29, 30). P1026s Version 9.0 included arms 
studying increased doses of darunavir with ritonavir during pregnancy. These arms have not fully accrued 
and will continue in Version 10,0. 
 
Many of the completed protease inhibitor arms of P1026s involved protease inhibitors boosted with 
ritonavir. Recently cobicistat, a new antiretroviral pharmacoenhancer, has been licensed for use in 
boosting the PI’s atazanavir and darunavir, but no PK data are available for these drug combinations 
during pregnancy. P1026s Version 10 will include arms studying these protease inhibitor/cobicistat 
combinations.    
 
1.34 
Integrase Inhibitors 
 
Raltegravir was the first human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 
INSTI), commonly referred to as an integrase inhibitor, licensed for use in the US. Raltegravir was 
studied in earlier versions of P1026s. (31)  Two newer integrase inhibitors, elvitegravir, administered with 
the booster cobicistat, and dolutegravir, will be studied in this version of P1026s.  

 
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1.35  
Entry Inhibitors 
 
An arm to study maraviroc pharmacokinetics was included in previous versions of P1026s.  
 
1.4  
Use of Tuberculosis (TB) and Antiretroviral (ARV) Medicines during Pregnancy 
 
1.41 
First Line TB Drugs 
 
Tuberculosis and HIV co-infection is becoming increasingly common and requires treatment for both 
diseases, including during pregnancy. There are currently no data describing the PK during pregnancy of 
medicines used to treat TB. P1078, A Phase IV Randomized Double-Blind Placebo-Controlled Trial to 
Evaluate the Safety of Immediate (Antepartum-initiated) Versus Deferred (Postpartum-initiated) Isoniazid 
Preventive Therapy among HIV-Infected Women in High TB Incidence Settings will address isoniazid 
(INH) therapy in pregnancy but not as part of standard multi-drug TB therapy. Rifampicin (RIF), used in 
first line TB regimens, is a potent inducer of CYP P450 enzymes and has significant drug interactions 
with ARVs (32). Nevirapine and EFV drug exposure are reduced when dosed concurrently with RIF, and 
an increase of the EFV dose to 800 mg may be recommended (33). These factors are further complicated 
in the setting of pregnancy. Genetic polymorphisms will also play a role – individuals with the 2B6 
516TT phenotype have slow EFV metabolism and paradoxically increased EFV concentrations with RIF 
(34). Lopinavir metabolism is also significantly increased by RIF, and the recommendation is to either 
double the LPV/r dose or give additional RTV when LPV/r and RIF are administered together (32). The 
standard approach at IMPAACT network African sites is to use double doses of LPV/r in pregnant 
women on RIF-based TB therapy. This version of P1026s will continue to study the combination of TB 
drugs with the ARVs EFV and LPV/r. 
 
1.42 
Second Line TB Drugs  
 
Globally, the burden of multi-drug resistant TB (MDR-TB, i.e. Mycobacterium tuberculosis resistant to 
rifampicin and isoniazid) is increasing, against a background of increasing HIV prevalence. In 2013, 3.5% 
of all incident TB cases reported were resistant to M. tuberculosis, with only 48% of adult MDR-TB 
patients having favorable TB treatment outcomes (35). Many of these drug-resistant TB (DR-TB) cases 
occur in women of childbearing age of whom a proportion are or will become pregnant, and who are 
frequently also HIV co-infected. Current recommendations for MDR-TB treatment call for an intensive 
phase with at least 4 second-line TB drugs (Table 1) likely to be effective, including a second line 
injectable drug for at least 8 months duration. Treatment should also routinely include a fluoroquinolone 
and pyrazinamide, and the total duration of treatment should be at least 20 months.  
 
There are currently limited data available on the PK and safety during pregnancy of these second line TB 
drugs used to treat MDR-TB. The only PK data on fluoroquinolone use during pregnancy is provided by 
3 small studies, which include only short-term data and have conflicting results. Two separate studies 
showed low peak serum concentrations for moxifloxacin (36) and ofloxacin (37); however, another study 
reported peak serum concentrations comparable to non-pregnant adult target levels for moxifloxacin and 
levofloxacin in caesarean-sectioned women (38). PK data on the other second line TB drugs during 
pregnancy are limited to one  pharmacokinetic study on the use of amikacin reported in 1977, where 11 
pregnant women achieved a peak concentration of 24.23 ug/ml , following a single dose of intramuscular 
amikacin (39). 
 
A paucity of data also exists for potential drug/drug interactions between second line TB medicines and 
ARVs. Moxifloxacin concentrations may potentially be reduced by ritonavir, and clofazimine, a weak 
inhibitor of CYP3A4, may potentially increase protease inhibitor concentrations (40); however the 
presence and magnitude of these interactions have not been well described. Efavirenz increases para-

 
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aminosalicylic acid (PAS) clearance, resulting in lower PAS exposure (41). The novel TB drug 
bedaquiline, metabolized by cytochrome P450 (CYP) 3A, has a number of important drug/drug 
interactions with ARVs (42). (43).  
 
There are limited safety data available for the currently used second line TB drugs during pregnancy. 
Most of these drugs are classified by the FDA as safety class C, with the exception of amikacin and 
kanamycin, categorized as safety class D (Table 1).  In nonpregnant adults, use of injectable TB drugs has 
been associated with hearing deficits and of ethionamide and para-amniosalicylic acid with thyroid 
function abnormalities, but there are no data on these specific toxicities in pregnant women.   
Capreomycin, a cyclic polypeptide, is the injectable agent of choice for use in pregnancy (44),  although  
the evidence base regarding potential reduced ototoxicity compared to kanamycin and streptomycin, is  
limited (45, 46). No human pregnancy data are available for the newly licensed drugs bedaquiline (safety 
class B) and delamanid, used to treat adult MDR and more extensively drug-resistant TB, however these 
important drugs are becoming increasingly available.  
 
In summary, PK and safety data on the use of second line TB medicines are needed to address a large 
existing knowledge gap preventing optimal clinical care of MDR TB infected pregnant women and their 
infants. This version of P1026s will therefore study the PK and safety of second line TB medicines, with 
or without ARVs, during pregnancy. Table 1 lists the drug groups currently considered for the treatment 
of DR-TB during pregnancy, with key drugs to be prioritized for pharmacokinetic (PK) study highlighted, 
based on frequency of use. Samples for other TB drugs (e.g. those used for pre-XDR and XDR-TB, and 
ARVs) will be stored and analysed based on feasibility. 
 
Table 1. Drug groups considered for the routine treatment of MDR-TB during pregnancy, along with 
current FDA Safety Class. 
 
Group 
Group Name 
Drugs 
Pregnancy Safety 
Class# 
1 
First-line oral agents 
Ethambutol 
Pyrazinamide 
C 
C 
2 
Injectable agents 
Kanamycin* 
Amikacin 
Capreomycin 
D 
D 
C 
3 
Fluoroquinolones 
Moxifloxacin* 
Levofloxacin* 
Ofloxacin 
C 
C 
C 
4 
Oral bacteriostatic 
second-line agents 
Ethionamide* / Prothionamide 
Terizidone */ Cycloserine 
Para-aminosalicylic acid* 
C 
C 
C 
5 
Agents with unclear 
efficacy or concerns 
regarding usage 
High-dose isoniazid 
Clofazimine 
Linezolid 
Bedaquiline 
Delamanid 
Pretomanid (previously PA-824) 
C 
C 
C 
B 
(not yet classified) 
(not yet classified) 
*Second-line anti-tuberculosis drugs to be prioritized for PK study; samples will be stored for all other 
TB drugs and ARVs as used and will be analyzed as feasible (i.e. when reasonable numbers accrue) 
# FDA category definitions: A: No risk to human fetus in first trimester, B: No risk to fetus in animal 
studies, C: Adverse effects to fetus shown in animal studies, D: Risk for human adverse events in fetus 
 

 
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1.5 
Contraceptives and Antiretrovirals   
 
Limited data from small, mostly unpublished studies suggest that some ARV therapies might alter the 
pharmacokinetics of combined oral contraceptives (COCs). Few studies have measured clinical outcomes. 
However, contraceptive steroid levels in the blood decrease substantially with ritonavir-boosted protease 
inhibitors (47).  Such decreases have the potential to compromise contraceptive effectiveness. 
Conversely, contraceptives may lead to increased ARV exposure and potential toxicity or decreased ARV 
levels and inadequate viral suppression and resistance (48). Etonogestrel implant (Implanon/Nexplanon) 
is a long-acting (up to 3 years), reversible, contraceptive method. The contraceptive effect of etonogestrel 
implant is achieved by several mechanisms that include suppression of ovulation, increased viscosity of 
the cervical mucus, and alterations in the endometrium.  
 
Implanon, one of the commercially available etonogestrel implants is an off-white, non-biodegradable, 
etonogestrel containing a single sterile rod for subdermal use. Each rod consists of an ethylene 
vinylacetate (EVA) copolymer core, containing 68 mg of the synthetic progestin etonogestrel (ENG), 
surrounded by an EVA copolymer skin. The release rate is 60-70 μg/day in week 5-6 and decreases to 
approximately 35-45 μg/day at the end of the first year, to approximately 30-40 μg/day at the end of the 
second year, and then to approximately 25-30 μg/day at the end of the third year. After subdermal 
insertion of Implanon, ENG is released into the circulation and is approximately 100% bioavailable. The 
mean peak serum concentrations in 3PK studies ranged between 781 and 894 pg/mL and were reached 
within the first few weeks after insertion (49, 50). The mean serum ENG concentration decreases 
gradually over time declining to 192 - 261 pg/mL at 12 months (n=41), and 154 – 194 pg/mL at 24 
months. In vitro data shows that ENG is metabolized in liver microsomes by the cytochrome P450 3A4 
isoenzyme. The elimination half-life of ENG is approximately 25 hours. Excretion of ENG and its 
metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. 
 
In clinical use among women aged 18 to 35 years who received Implanon, 6 pregnancies during 20,648 
cycles of use were reported. Two pregnancies occurred in each of Years 1, 2, and 3. Each conception was 
likely to have occurred shortly before or within 2 weeks after Implanon removal. With these 6 
pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use (51, 52). 
Postmarketing experience in Australia evaluated 127 cases of pregnancy when using Implanon classified 
as product/method failures once other reasons had been excluded. Using the 204,486 Implanon devices 
subsidized in this period to estimate the population exposed and the 218 pregnancies reported, the 
approximate failure rate in postmarketing use was 1 in 1000 insertions (53).  
 
The acceptability, safety and efficacy of Implanon in HIV infected women was confirmed in 79 women 
followed in the public health setting in Brazil. Fifty-six of the women were taking antiretrovirals; 31 were 
taking a PI-based regimen and 25 were taking an NNRTI-based regimen. Women were followed for 3 
years after Implanon insertion. No pregnancies occurred in the 79 women. Two women required implant 
removal before three years after insertion due to excessive menstrual bleeding (54). There are no data 
describing drug/drug PK interactions between etonogestrel implants and ARV drugs. 
 
Few studies have evaluated interactions between COCs and the currently most commonly used ARVs 
such as LPV/r, ATV/r and EFV. Ethinyl estradiol concentration was reduced 42%, but no effect on 
norethindrone was observed with the use of LPV/r (55). In one study TDF was administered to 20 women 
and no interaction was observed with the concomitant use of COCs (56). Atazanavir/ritonavir was 
administered to 20 healthy women and significant increases in ethinyl estradiol (37%) and norgestimate 
(102%) concentrations were observed (57). There are no data evaluating the effect of COCs on LPV/r, 
ATV/r or tenofovir concentrations. 
 

 
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Recent cases of contraceptive failure have been reported in HIV infected women on efavirenz with both 
implanted etonogestrel (Implanon) and levornogestrel (Jadelle) contraception. (58-61)  While two PK 
studies have shown a marked reduction in levonorgestrel concentrations in women receiving Jadelle 
implants, no data are available for the interaction between efavirenz and etonorgestrel implants, which are 
the preferred contraceptive implants used at many IMPAACT P1026s sites. (62, 63)  Given the current 
WHO guidelines encouraging use of EFV/FTC/TDF as the first line cART regimen across populations, it 
is critical to examine possible drug/drug interactions between EFV and contraceptives in postpartum 
women as soon as possible. Version 10 of P1026s will continue to study the drug/drug PK interactions 
between EFV and both oral and implanted (etonogestrel) contraception in postpartum women, and will 
add arms studying the interactions between the new darunavir/cobicistat and atazanavir/cobicistat 
formulations with both oral and implanted (etonogestrel) contraception. 
 
1.6 
Genital Tract HIV and Antiretroviral Concentrations  
 
Genital tract levels of HIV are independently associated with the risk of maternal-to-child transmission 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 (64). None of the women in 
this study received ARV therapy. In a study from Thailand, genital tract HIV RNA levels were 
significantly reduced among women receiving ZDV compared to placebo (65). 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. This study clearly showed the ability of antiretroviral 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 in 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, suggesting exposure of 
the infant to cell associated HIV in the genital tract plays a role in HIV transmission (66). 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 ZDV 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 ZDV 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 (67). In one study of women on various antiretroviral 
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 (68). 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 (69). In a study of plasma and genital tract RNA levels among 38 
pregnant women, two (22%) of the nine women with undetectable plasma HIV RNA levels had detectable 

 
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vaginal HIV RNA (70). 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 (71). Seventy-four percent of 
these 27 women were on ARV therapy, including 14 (52%) on a protease inhibitor. 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 (72, 73). In a subsequent study from WITS of 290 women with 
undetectable plasma HIV RNA, 44 (15%) had detectable HIV RNA in cervical swab specimens (74). In a 
multivariable analysis of factors associated with genital tract HIV detection, only NNRTI use (compared 
to PI use, odds ratio 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. 
 
The levels of ARVs in the genital tract and potential effects on genital tract HIV levels vary by drug and 
class. An early study found that the detection of HIV RNA in CVL specimens was inversely related to the 
number of ARV drugs the woman was taking, while detection of HIV DNA in the genital tract occurred 
in similar proportions of women in various therapy groups (75). A study of LPV and IDV plasma and 
genital tract levels in non-pregnant women found markedly different penetration of the drugs into CVL. 
Lopinavir was detected in 7 (37%) of 19 samples at peak plasma time and in 4 (21%) at trough times. The 
median CVL/plasma ratio for LPV was 0.076 at peak and 0.070 at trough times. Indinavir was detected 
among 14 (93%) of CVL samples at peak and 12 (92%) of 13 at trough times, with the peak CVL/plasma 
ratio of 1.32 at peak and 3.8 at trough times (76). In two studies using aspiration of vaginal pool fluid for 
drug level determinations, genital tract/plasma concentration ratios were 4.11 for 3TC, 3.95 for 
emtricitabine (FTC), 2.35 for ZDV, 0.75 for TDF, < 0.08-0.26 for RTV, 0.21 for ddI, 0.18 for ATV, 0.08-
0.21 for LPV, 0.08 for ABC, 0.05 for d4T, 0.83-1.17 for NVP, 0.40-4.64 for IDV, and 0.004-0.25 for 
EFV (77, 78).  Similarly, in another study, pre-dose genital tract/plasma ratios were above one for 3TC, 
TDF, ZDV, ddI and FTC, while levels of ABC, RTV, and ATV were between 0.33-0.81, and levels of 
EFV, NVP, LPV, NFV and FPV were below 0.10 (79). Ratios three to four hours after oral dosing were 
lower but followed a similar pattern. In a study of pregnant women using the same aspiration technique 
and laboratory methods as the studies by Dumond and Min, genital tract/plasma ratios for ZDV and LPV 
were significantly lower than those in nonpregnant women, suggesting that genital tract drug levels from 
nonpregnant women cannot be extrapolated to pregnant women (80).  
 
Version 10 of P1026s will continue to include collection of vaginal secretions samples to allow 
assessment of antiretroviral concentrations in genital tract secretions and vaginal swab sampling to 
measure HIV levels that would be encountered by the infant during labor and vaginal delivery.    
 
1.7 
Pharmacogenetics 
 
Considerable variability exists in the pharmacokinetics of ARVs in both adults and children. In addition 
to the changes in drug disposition due to pregnancy, variations in genes that affect drug transport and 
metabolism creates variability in ARV exposure.  The commonly used non-nucleosides all exhibit genetic 
polymorphisms that impact drug metabolism. CYP 2B6 is responsible for a significant portion of NVP 
and EFV and the CYP 2B6 TT genotype at position 516 is associated with impaired metabolism of 
CYP2B6 substrates (81, 82). This genotype has been reported to be more common in African-Americans 
(20%) than in European-Americans (3%). The CYP 2B6 516 T/T is associated with more than double the 
EFV AUC in adults (83) and similar increases were observed by Saitoh et al in children (82). More 
recently other CYP2B6 genetic variations have been identified with functional increases and decreases in 
EFV metabolism (84). NVP is metabolized by both CYP 3A4 and CYP 2B6. Polymorphisms in CYP 2B6 
affect NVP exposure but these influences are not as large as for EFV. The most recently approved 

 
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NNRTI, etravirine, is not a substrate for CYP 2B6 but is metabolized by CYP 3A4, CYP 2C9 and CYP 
2C19 (85). Both CYP 2C9 and CYP 2C19 have well described genetic variations associated with 
impaired drug metabolism (86) and thus etravirine exposure will likely be increased in patients with CYP 
2C9 and/or CYP 2C19 poor metabolizer genotypes.  
 
There are also potential pharmacogenomic influences on protease inhibitor (PI) absorption and 
metabolism. Although currently available PIs are pharmacologically boosted by the CYP 3A inhibitor, 
RTV, making patients on RTV-boosted PIs phenotypically poor metabolizers, pharmacogenomic 
influences on PI exposure still exist. Genetic variants in ORM1 (ORM1*F1, ORM1*F2 and ORM1*S 
resulting from A to G transition at codons for aa position 20 in exon 1 and 156 in exon 5), SLCO1B1 
(rs4149056 and rs4149032), CYP3A5 and PXR (rs2472677)  have been identified to alter LPV or ATV 
pharmacokinetics (87-90). 
 
The identification of genetic influences on the pharmacokinetics of ARVs is rapidly increasing; however, 
the interplay between pharmacogenomics and other key factors are poorly understood. Preliminary 
pharmacokinetic results from infants receiving EFV in P1070, Dose Finding and Pharmacokinetic Study 
of Efavirenz in HIV-infected and HIV/TB co-infected Infants and Children ≥3 Months to <36 Months of 
Age, suggest that that genotype may have a more profound impact than in older populations with infant 
poor metabolizers having much higher EFV AUCs. Similar interactions between pregnancy and 
pharmacogenomics on ARV PK may exist and are in need of investigation. In addition to 
pharmacokinetic-pregnancy interactions, genetic differences in drug metabolism may also alter toxicity. 
Hepatotoxicity from TB therapy has been linked to drug metabolizing activity of N-acetyl-transerfates-2 
(NAT-2) and CYP 2E1 (91). More recently elevation of liver enzymes has been linked to the drug 
transporter MDR1 (also known as p-glycoprotein) (92).     
 
Among mothers and infants participating in washout PK sampling in this version of P1026s, informed 
consent will be sought for collection and testing of specimens to determine common single nucleotide 
polymorphisms (SNPs) associated with ARV transporters and drug metabolizing enzymes. These assays 
will allow exploratory analyses of pregnancy and pharmacogenomic influences on ARV disposition.  In 
addition, having pharmacogenomic information collected in P1026s participants will help expand the 
mechanistic understanding of extreme drug exposures or response during pregnancy. Whether a mother 
agrees to genetic testing for herself and/or her infant will otherwise not affect their participation in this 
study. It is entirely optional.  
 
1.8 
History of Versions 1.0 - 9.0 
 
 
See Appendix VII for a history of study arms included in protocol Versions 1.0 – 9.0.  
 
 
 

 
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2.0 
 
OBJECTIVES  
 
2.1 
Primary Objectives 
 
2.11 
To describe the pharmacokinetic parameters during pregnancy of selected ARV drugs 
currently used in the clinical care of HIV-infected pregnant women, and to compare these 
parameters to a) historical pharmacokinetic data from non-pregnant women and b) 
postpartum pharmacokinetic data from the same women in the study cohorts. 
2.12 
To describe the pharmacokinetic parameters during pregnancy and postpartum of selected 
ARV drugs (efavirenz, lopinavir/ritonavir) and first line TB drugs when co-administered 
as part of clinical care of HIV-infected pregnant women and of first line TB drugs when 
used in HIV-uninfected pregnant women. 
2.13 
To describe the pharmacokinetic parameters during pregnancy and postpartum of second 
line TB drugs administered as part of clinical care to HIV-infected and HIV-uninfected 
pregnant women. 
2.14 
To describe the pharmacokinetic parameters of ARV drugs in postpartum women before 
and after starting hormonal contraceptives. 
2.15 
To describe the concentrations of ethinyl estradiol, etonogestrel and other progestins in 
women using hormonal contraceptives and selected ARV drugs as compared to historical 
controls not using those ARV drugs. 
 
2.2 
Secondary Objectives 
 
2.21 
To compare ARV and TB drug concentrations in plasma from cord blood with those in 
maternal plasma at the time of delivery. 
2.22 
To assess plasma protein binding of highly bound ARV drugs during pregnancy and 
postpartum. 
2.23 
To assess ARV concentrations and HIV RNA/DNA concentrations in vaginal secretions 
among pregnant and postpartum and compare to simultaneous plasma concentrations. 
2.24 
To explore genetic sources for variability in ARV and TB drug exposure in pregnant 
women and their infants. 
2.25 
To describe maternal and infant safety and clinical outcomes 
2.26 
To describe the neonatal elimination of selected ARV and TB drugs acquired across the 
placenta after maternal dosing during pregnancy. 
2.27 
To describe pharmacokinetics of ARV drug combinations in HIV-infected women on 
second line TB treatment.  
 
 
3.0 
 
STUDY DESIGN  
 
This is a Phase IV prospective study to evaluate the pharmacokinetics of selected currently prescribed 
antiretroviral (ARV) medicines when used alone or with tuberculosis (TB) medicines during pregnancy or 
with postpartum hormonal contraceptives in HIV-infected pregnant and postpartum women. The washout 
PK of transplacentally acquired ARV and TB drugs will be studied in the infants born to study mothers 
who enter the study during pregnancy. HIV-uninfected pregnant women receiving TB treatment (first line 
or second line) will also be enrolled to serve as a control group to evaluate the interaction between TB 
and ARV drugs in pregnant women. Eligible women can enroll between 20 0/7 – 37 6/7 weeks gestation 
or 2-12 weeks postpartum, depending on study arm. All infants of mothers enrolled during pregnancy will 
be enrolled in-utero, after maternal enrollment. Enrolled infants who meet the requirements for washout 
PK sampling, as specified in Section 4.4, will undergo PK sampling.   
 

 
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Women must be currently receiving one of the ARV, TB drug, or hormonal contraceptives at the 
specified doses listed in the Schema. The drug/drug combinations selected for study are among those 
lacking PK data during pregnancy and postpartum and are most commonly used or are likely to be 
commonly used in the near future. If a woman is receiving two or more of the ARVs being studied she 
may be sampled for each drug/drug combination and be included in the enrollment for each arm. Maternal 
clinical and laboratory toxicities will be assessed through medical histories and physical examinations, 
and laboratory testing on each PK sampling day and at delivery. Women will continue to take their 
prescribed medicines throughout the course of their pregnancy. Medicines may be changed for toxicity or 
lack of efficacy by the clinical providers, but the protocol team should be notified of any medicine 
changes.  
 
Each study arm will enroll a minimum of 12 women and have a target enrollment of 25 women with 
evaluable 3rd trimester PK data in the ARV and TB arms, or evaluable postpartum PK data in the 
contraception arms. Enrollment may be restricted or adjusted so that 2nd trimester PK data are collected 
from at least 12 women. When combined enrollment in the increased dose darunavir arms reach 25 
participants, the PK data will be evaluated to determine if the data for these arms can be combined and 
whether enrollment of additional participants in these arms should continue. Sample size for an ARV or 
TB drug arm may be increased if additional infants need to be enrolled to collect infant washout PK data. 
The sample size of the second line TB drug arm may be increased above 25 to obtain additional data for 
less commonly used second line TB drugs.  
 
 
3.1  
Enrollment Procedures  
 
3.11 
Maternal Antepartum Enrollment (during pregnancy) 
 
Pregnant women who meet the eligibility criteria, as specified, in Section 4.1 will enroll in P1026s prior 
to or at the time of pharmacokinetic sampling. The initial PK sampling visit must occur within 5 days of 
participant enrollment. See Appendix I-A through I-C for a complete description of the procedures to be 
performed for each study arm, and Section 10 Data Collection Requirements, for a description of data to 
be collected. 
 
3.12 
Maternal Postpartum Enrollment (after delivery)  
 
 
 
Women receiving antiretroviral drugs and contraceptives, and who meet the eligibility criteria as specified 
in Section 4.1, will enroll in P1026s at 2-12 weeks after delivery. See Appendix I-D, Schedule of 
Evaluations for Postpartum Women on Antiretroviral Medicines and Hormonal Contraceptives, for a 
complete description of the procedures to be performed, and Section 10.0 Data Collection Requirements, 
for a description of data to be collected. 
 
3.13 
Infant Enrollment  
 
All infants of mothers enrolled during pregnancy (antepartum) should be enrolled in utero, immediately 
after the maternal enrollment, and followed in P1026s. Enrolled infants who meet the requirements 
specified in Section 4.4 will undergo washout PK sampling. See Appendix II, Schedule of Evaluations for 
Infants, for a complete description of the procedures to be performed.  
 
Note:   Infants, born to women enrolling postpartum (ARVs with postpartum contraceptives arms), will 
not be enrolled in P1026s.  
 

 
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3.2  
Maternal Antepartum and Postpartum Pharmacokinetic Sampling  
 
Intensive PK sampling will be performed to determine plasma concentrations of ARVs, TB medicines 
and hormonal contraceptives. Plasma alpha-1 acid glycoprotein (AAG) concentration and protein binding 
of highly bound ARV drugs will also be determined, as will ARV concentrations and HIV viral load in 
vaginal secretion samples. Women must be stable on the ARV and/or TB drug(s) being studied for at least 
two weeks prior to PK sampling. The timing of dosing for the three days prior to and the day of the PK 
evaluation must be the same, and must be the same for the PK evaluation(s) done during pregnancy and 
postpartum. Women are expected to revert back to standard dosing after discharge; if not, the study 
pharmacologist should be consulted prior to PK sampling. 
 
A woman receiving two of the ARV drugs/drug combinations being studied may be sampled for each 
ARV drug/drug combination, but the enrollment site will receive credit for enrollment of a single 
participant.  
 
The schedule of antepartum and postpartum pharmacokinetic sampling time points varies by drug and is 
described in Appendix III, Maternal Intensive Pharmacokinetic Sampling Schedule for Antiretroviral 
Medicines, Tuberculosis Treatment and Hormonal Contraceptives.  
 
On each PK sampling day, the study visit should be scheduled to start at the point in time that coincides 
with the end of the previous dosing interval. The dose(s) of the study drug(s) will be administered on site 
after the pre-dose sample is drawn. An intravenous catheter will be placed in an arm vein for serial blood 
collection. Participants having 12 hour sampling should remain in the clinic until the completion of PK 
sampling. Participants having 24 hour sampling may leave the clinic following the 12 hour time point, 
and return for the 24 hour time point.  
 
All women will be asked to report the time and a description of their two most recent meals and to 
carefully note the day and time of their previous two doses prior to the start of PK sampling.  In addition, 
the Perinatal Adherence Questionnaire will be administered on each PK sampling day to HIV–infected 
women. See Appendix IV, Dietary Recommendations for Antiretroviral Medicines, Tuberculosis 
Medicines and Hormonal Contraceptives, for dietary recommendations. 
 
3.21 
Genital Tract Viral Load and Drug Concentrations 
 
HIV-infected pregnant women not on TB drugs will have vaginal samples for ARV concentrations 
obtained at the second and third trimester and the 6-12 postpartum PK sampling visits. Samples will be 
obtained pre-dose and at 1, 2, and 4 hours after dosing. Samples for drug concentrations will be obtained 
with the soft plastic aspirator without speculum placement or by another appropriate technique and can be 
collected by the participant or by a clinician. Samples will be stored and batch shipped for testing. Since 
target drug concentrations for vaginal samples have not been determined, real time testing and reporting 
of vaginal specimen results to the sites will not be done. A single vaginal swab will also be obtained 
without speculum placement for viral load testing once during each PK visit. No vaginal specimens will 
be collected if contraindicated by a pregnancy complication such as placenta previa or premature rupture 
of membranes.  
 
 
 
 
 
 

 
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3.22  
Hormonal Contraceptive PK Sampling 
 
Women taking either darunavir/cobicistat or atazanavir/cobicistat or EFV after delivery and starting on 
combined oral contraceptives with ethinyl estradiol and any progestin or etonogestrel implant prior to 12 
weeks postpartum will have intensive PK sampling performed at 2-12 weeks postpartum (prior to 
contraceptive initiation) and again 6-7 weeks after contraceptive initiation. Oral contraceptives and the 
ARV being studied should be taken at the same time of day three days prior to PK sampling and on the 
day of PK sampling. 
 
3.3 
Reporting of Pharmacokinetic Results 
 
ARV plasma drug assays and pharmacokinetic calculations during pregnancy will be performed in real 
time during pregnancy and the results will be reported to the participant and her clinical caregiver. The 
participant and the clinical caregiver will also be informed if the estimated pharmacokinetic exposure 
parameter for an individual participant is less than the pharmacokinetic exposure target as described in 
Appendix V, Maternal Pharmacokinetic Parameter Targets, generally the 10th percentile for non-pregnant 
women. Based on the results of the ARV plasma drug assays, the participant’s clinical status and 
laboratory values, and the study pharmacologist recommendations (if any), the participant and clinical 
caregiver may decide to modify dosing. The new dose may not have been approved by the FDA. If dosing 
is modified, the clinical caregiver may elect to have repeat pharmacokinetic sampling performed during 
pregnancy after at least one week on the new dose. If the new dose meets the drug exposure target, the 
participant will remain on that dose until delivery. Dosing will revert to standard adult dosing at discharge 
from the hospital after delivery and pharmacokinetic sampling will be performed again at either 2-3 
weeks or 6-12 weeks postpartum, depending on study arm. If the new dose does not meet the drug 
exposure target, an alternative therapy should be considered, as no further dose adjustments will be 
allowed. Sampling will only be repeated once for participants who have dose adjustments, because 
pregnancy is a time limited condition and it is unlikely that there would be sufficient time for a third dose 
adjustment and pharmacokinetic assessment to be completed prior to delivery. If a woman remains on a 
dose postpartum for which evaluable antepartum PK parameters exist, postpartum PK sampling will be 
performed. If at least 12 women are enrolled in an arm and the estimated 3rd trimester pharmacokinetic 
exposure parameter (AUC or Cmin) for 6 or more of them falls below the pharmacokinetic exposure target, 
the protocol team will evaluate the pharmacokinetic data and with agreement of the Medical Officers, will 
determine whether enrollment in that cohort should be continued.  
 
TB plasma samples will be stored at the site and shipped when requested by the protocol team for batch 
testing. Results of TB drug concentration assays and pharmacokinetic calculations may be reported back 
to the participant and her clinical caregiver after the assays have been completed. A study pharmacologist 
will be available to assist with the interpretation of these results at the request of the clinical caregiver.  
 
Hormonal contraceptive samples will be stored at the site and shipped when requested by the protocol 
team for batch testing. Since target concentrations have not been clearly defined, hormonal contraceptive 
assay results will not be reported to the participant or her clinical caregiver. 
 
3.4 
Intrapartum Pharmacokinetic Sampling   
 
Transplacental passage of the ARV and TB drugs of interest will be assessed by measurement of drug 
concentrations in maternal plasma at the time of delivery and cord blood. A single maternal specimen will 
be drawn at the time the cord is clamped. A single specimen will also be obtained from the umbilical 
cord. 
 

 
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3.5 
Infant Pharmacokinetic Sampling  
 
Infants who meet the requirements criteria specified in Section 4.4 will have 4 blood samples collected in 
the first days of life. The timing of collection of these samples is described in Appendix II. Infant 
pharmacokinetic samples will be stored at the site until the maternal postpartum pharmacokinetic samples 
have been collected and then both sets of samples will be shipped to the appropriate pharmacology 
laboratory. 
 
 
4.0 
 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1  
Maternal Inclusion Criteria  
 
 
4.11 
Eligible participants must belong to one of the 5 groups described below: 
 
4.111 HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment 
receiving one or more of the following ARV drugs/drug combinations: 
 
- 
darunavir/ritonavir twice daily 600/100 mg b.i.d. or 800/100 mg b.i.d. until 30 weeks 
gestation; then 800/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg 
b.i.d. after postpartum hospital discharge until 2 week postpartum PK samples are drawn. 
- 
darunavir/ritonavir twice daily 600/100 mg b.i.d. or 900/100 mg b.i.d. until 30 weeks 
gestation; then 900/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg 
b.i.d. after postpartum hospital discharge until 2 week postpartum PK samples are drawn. 
- 
dolutegravir 50 mg q.d. 
- 
tenofovir alafenamide fumarate (TAF) 25 mg q.d. without cobicistat or ritonavir boosting 
- 
tenofovir alafenamide fumarate (TAF) 10 mg q.d. with cobicistat 
- 
tenofovir alafenamide fumarate (TAF) 10 mg q.d. with ritonavir 
- 
elvitegravir/cobicistat 150/150 mg q.d. 
- 
darunavir/cobicistat 800/150 mg q.d. 
- 
atazanavir/cobicistat 300/150 mg q.d. 
- 
Participants outside of Thailand only:  efavirenz 600 mg q.d.  
 
 
4.112 HIV-infected pregnant women ≥ 20 weeks gestation receiving one of the following 
ARV drugs/drug combinations and TB treatment with at least one of the following 
TB drugs at study entry: 
 
ARV’s: 
- 
efavirenz 600 mg q.d. 
- 
lopinavir/ritonavir 800/200 mg b.i.d. 
 
 
TB drugs: 
• 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.  
• 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
• 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
 
 

 
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4.113 HIV-uninfected pregnant women ≥ 20 weeks gestation receiving at least two of the 
following first line TB drugs at study entry: 
 
• 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
• 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
• 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
4.114 HIV-infected and HIV-uninfected pregnant women ≥ 20 weeks gestation receiving at 
least two of the following second line TB drugs at study entry: 
  
Injectable agents: 
• 
kanamycin 
• 
amikacin 
• 
capreomycin 
Fluoroquinolones: 
• 
moxifloxacin  
• 
levofloxacin 
• 
ofloxacin 
Oral bacteriostatic second-line agents: 
• 
ethionamide/prothionamide 
• 
terizidone/cycloserine 
• 
para-aminosalicylic acid  (PAS) 
Other agents: 
• 
high dose INH 
• 
bedaquiline 
• 
clofazamine 
• 
delamanid 
• 
linezolid 
• 
pretomanid 
 
Note: Infants of mothers enrolled during pregnancy (meeting criteria 4.111, 4.112, 4.113 and 
4.114 specified above) should be enrolled, in utero, immediately after maternal enrollment.   
 
4.115 HIV-infected women 2-12 weeks (14-84 days) post-delivery receiving one of the 
following ARV drug combinations AND starting postpartum contraceptives as listed 
below: 
 
- darunavir/cobicistat 800/150 mg q.d. or atazanavir/cobicistat 300/150 mg q.d. . postpartum 
and starting combined oral contraceptives formulated with 30-35 µg ethinyl estradiol 
- darunavir/cobicistat 800/150 mg q.d. or atazanavir/cobicistat 300/150 mg q.d. . postpartum 
and starting etonogestrel implant 
- efavirenz 600mg q.d. postpartum and starting combined oral contraceptives formulated 
with 30-35 µg ethinyl estradiol 
- atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting combined oral 
contraceptives formulated with 30-35 µg ethinyl estradiol 
 
4.12    The woman must be stable on the ARV drug/drug combination and/or TB drug 
combination for at least two weeks prior to PK sampling.  
 

 
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4.13 
If a woman is receiving a specific generic ARV formulation, the team has approved this 
formulation.  
 
4.14   HIV-infected pregnant women must be planning to continue on current ARV regimen 
until postpartum PK sampling is completed. HIV-infected postpartum women on 
hormonal contraceptives must be planning to continue on ARV and contraceptive 
regimens until final PK sampling is completed. 
 
4.15    For HIV-infected women:  
 
Confirmed HIV infection, documented by positive results from two samples collected at 
different time points prior to study entry. All samples tested must be whole blood, serum 
or plasma. All test methods should be FDA-approved if available. If FDA-approved 
methods are not available, test methods should be verified according to GCLP and 
approved by the IMPAACT central laboratory 
 
Sample #1 may be tested in a non-study laboratory (e.g., laboratories used by 
participant’s non-study medical providers and/or by PEPFAR and other public health 
programs). However, adequate source documentation, including the date of specimen 
collection, date of testing, test performed, and test result, must be available for filing in 
the participant’s study chart. If such documentation is not available, Sample #1 should be 
tested in a CAP/CLIA approved laboratory (for US sites) or a laboratory that operates 
according to good clinical laboratory practice (GCLP) guidelines, participates in 
appropriate external quality assurance programs, and is approved by the IMPAACT 
Central Laboratory (for non-US sites). 
 
Sample #1 may be tested using any of the following:  
• 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes 
• 
One EIA OR WB OR immunofluorescence OR chemiluminescence 
• 
One HIV DNA PCR 
• 
One HIV RNA PCR (above the limit of detection)  
• 
One HIV culture (prior to August 2009) 
• 
One total HIV nucleic acid 
 
Sample #2 must be tested in a CAP/CLIA approved laboratory (for US sites) or a 
laboratory that operates according to GCLP guidelines, participates in appropriate 
external quality assurance programs, and is approved by the IMPAACT Central 
Laboratory. 
 
Sample#2 may be tested using any of the following:  
• 
Rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope. 
• 
One EIA OR WB OR immunofluorescence OR chemiluminescence 
• 
One HIV DNA PCR 
• 
One HIV RNA PCR (above the limit of detection)  
• 
One HIV culture (prior to August 2009) 
• 
One total HIV nucleic acid 
 

 
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4.16   HIV-uninfected pregnant women must have documented negative HIV antibody test 
during current pregnancy.  
 
Note: adequate source documentation, including the date of specimen collection, date 
of testing, test performed, and test result, must be available. 
 
4.17   Participants enrolling in the 3rd trimester must enroll by 37 6/7 weeks gestation. 
 
4.18 
Participant can provide legal informed consent per local regulations. 
 
4.19 
If a woman has completed P1026s and becomes pregnant again, she may re-enroll in 
P1026s only if she is enrolled in a different arm than that studied during her initial 
enrollment.  
 
4.2 
Maternal Exclusion Criteria 
 
4.21 
Women on medicines known to interfere with absorption, metabolism, or clearance of the 
drug being evaluated (See Section 7.0). (rifampicin is permitted for women being 
evaluated for TB and ARV drug interactions).  
 
4.22 
Women if pregnant, carrying multiple fetuses. 
 
4.23 
Clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely 
to require a change in the medicine regimen during the period of study. 
 
4.3  
Infant Enrollment Criteria 
 
All infants of mothers enrolled during pregnancy (meeting criteria 4.111, 4.112, 4.113, and 4.114 
specified above) are enrolled, in utero, immediately after maternal enrollment.  
 
 
4.4 
Infant Requirements for Washout Pharmacokinetic Sampling  
 
Enrolled infants who meet the criteria specified below are eligible for Washout Pharmacokinetic 
Sampling 
 
4.41 
Born to HIV infected mother enrolled during pregnancy in an ARV arm (does not include 
infants born to HIV uninfected mothers receiving TB drugs).  
4.42 
Birth weight > 1000 grams 
4.43 
NOT receiving disallowed medications described in Section 7 
4.44 
Does not have any severe congenital malformation or other medical condition not 
compatible with life or that would interfere with study participation or interpretation, as 
judged by the site investigator.  
4.45 
Born after singleton delivery (not after multiple birth) 
 
4.5  
Enrollment Procedures 
 
This protocol is open to IMPAACT US and non-US sites that have been approved to participate by the 
IMPAACT 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) approved, as 

 
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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 (DAIDS PRO) at the Regulatory 
Support Center (RSC). The DAIDS PRO will review the submitted protocol registration packet to ensure 
that all of the required documents have been received.  
 
Site-specific informed consent forms (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) for an amended version of 
the protocol 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. 
 
A Site Implementation Plan (SIP) is required from each international site participating in the study. The 
plan must 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.  
 
If a woman has completed P1026s and becomes pregnant again, she may re-enroll in P1026s only if she is 
enrolling on a different arm than that studied during her initial enrollment. In this case, she may be re-
registered to the protocol using a case identification (CID) number. The site must contact the DMC 
Randomization Desk to register women who become eligible for re-enrollment. The Randomization Desk 
will re-register the mother using the site’s next available PID as the mother’s CID. The site will then use 
the CID to identify the mother when filling out the forms for the second pregnancy. 
 
4.6  
Co-Enrollment Procedures 
 
Co-enrollment into other protocols requires the approval of the protocol chairs of P1026s and the co-
enrollment protocol. 
 
4.7 
Study Drug Formulations 
 
No ARV drugs/drug combinations, TB drugs or contraceptive agents are supplied as part of this study. 
All drugs, including those being studied at non-standard doses, must be provided by participants’ clinical 
care providers by prescription.  
 
Participants may receive innovator (i.e., brand name or non-generic) or generic formulations of ARVs, 
TB drugs and contraceptives being studied in this version of the protocol. Unless stipulated in the 
protocol, generic ARV formulations must be a similar formulation, with similar expected bioavailability 
and drug release characteristics to the standard name-brand innovator formulation. Sites must contact the 

 
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protocol team prior to enrollment of participants receiving a specific generic ARV formulation to obtain 
approval for enrollment of participants receiving that specific formulation. All efforts should be made to 
ensure that participants receive the same product from the same manufacturer prior to all PK sampling 
periods. Protocol CRFs will record the name and manufacturer of each generic product used. 
 
For pregnant women on DRV/r or LPV/r: Some women on these drugs/drug combinations may be 
receiving non-standard (increased) doses during pregnancy and therefore additional monitoring is 
warranted for the duration of the study. Women who change dosing of other drugs to non-standard doses 
due to PK results will also have additional monitoring. Additional monitoring guidelines are outlined in 
Appendix I-AMR.  
 
Participants are expected to revert back to standard dosing after discharge; if not, the study 
pharmacologist should be consulted prior to PK sampling. 
 
 
5.0 
 
TOXICITY MANAGEMENT  
 
5.1  
Toxicity Monitoring  
 
 
For women receiving DRV/r, LPV/r or other non-standard doses of ARVs or TB drugs, toxicity 
monitoring is as follows. In the event of treatment-limiting toxicity, other ARVs may be substituted for 
the drug thought to be responsible for the toxicity. It is critical to maintain good virologic control during 
pregnancy to decrease the risk of vertical transmission. Alternate explanations for Grade 3 toxicities must 
be sought prior to study drug discontinuation. For Grade 4 toxicities, study drug should be discontinued, 
the laboratory value should be repeated, and alternate explanations for the toxicity should be considered. 
Toxicities caused by underlying infections or processes or by drugs other than the study regimen will not 
necessarily result in dose interruptions. Abnormal clinical findings and laboratory values should be 
followed at least every 2 weeks until the toxicity resolves to a Grade 2 and below.   
 
 
 
 
The general toxicity management schema is presented below, followed by specific guidelines for 
management of amylase, creatinine, proteinuria, gestational diabetes, and nausea/vomiting. 
 
• 
Grade 1 and  2 Toxicity:  
 
Continue the study regimen 
  
• 
Grade 3 Toxicity: 
 
Repeat laboratory evaluations within 72 hours to confirm. If the toxicity resolves to ≤ Grade 2, continue 
the study regimen.  
 
Participants with confirmed drug-related > Grade 3 toxicity should stop the study regimen and will be 
observed for resolution of the toxicity.  
 
- If the toxicity does not resolve to < Grade 2 within 14 days, the participant may switch to another 
antiretroviral regimen (or resume using standard adult doses if in the LPV/r or DRV/r study arm).  
- If the toxicity resolves to < Grade 2 within 14 days, restart the study regimen. If the toxicity recurs 
at > Grade 3 after restarting the study regimen, the participant may switch to another antiretroviral 
regimen or resume standard adult doses if in the  LPV/r or DRV/r study arm. Participants with 
persistent drug-related Grade > 3 toxicity will stop the study regimen and will be observed for 

 
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resolution of the toxicity. Participants will continue to be followed on study but off study drug for 
routine safety/toxicity monitoring. 
 
• 
Grade 4 Toxicity: 
 
Stop the study regimen. Repeat laboratory evaluations within 72 hours to confirm. If the toxicity is life-
threatening, the study regimen will not be restarted and the participant will be observed for resolution of 
the toxicity.  
 
If the toxicity is non-life-threatening, the study regimen will be stopped, and the participant will be 
observed for resolution of the toxicity.  
- If the toxicity does not resolve to ≤ Grade 2+ within 14 days, the participant will be off the study 
regimen and observed for resolution of the toxicity.  
- If the toxicity resolves to < Grade 2 within 14 days, restart the study regimen. If the toxicity recurs 
at > Grade 3 after restarting the study regimen, the participant will discontinue the study regimen and 
be observed for resolution of the toxicity. 
 
Specific Guidelines: 
 
• 
Elevated Amylase 
- For Grade 3 elevations of total amylase, the participant should be evaluated for symptoms of 
pancreatitis, and lipase should be checked. If asymptomatic and lipase < 2 x ULN, the study 
regimen may be continued at the discretion of the site investigator, with notification to the team.  
- For Grade 4 elevations of total amylase, obtain fractionated values. If found to be mostly 
pancreatic, or if the participant is symptomatic or has a lipase > 2 x ULN, the study regimen will 
be held until the toxicity resolves to Grade ≤ 2. If resolution occurs within 14 days and the initial 
episode was not life-threatening, restart the study regimen at the full dose. If symptomatic, 
lipase > 2 x ULN or Grade 4 elevations in fractionated pancreatic amylase recur, the study 
regimen should be stopped and the participant will be observed for resolution of the toxicity.  
- For ≥ Grade 3 elevations of pancreatic amylase, lipase should be checked.  
 
• 
Creatinine 
- 
If > Grade 1, evaluate for possible pre-eclampsia. The participant will be allowed to continue on 
the study regimen whether or not pre-eclampsia is present. 
 
• 
Proteinuria 
- Proteinuria with pre-eclampsia:  If Grade 2-4 proteinuria is confirmed and pre-eclampsia is 
present, the participant may continue the study regimen.  
- Proteinuria without pre-eclampsia:  Follow routine toxicity management as specified in Section 
5.1. 
• 
Gestational Diabetes 
- The participant will be allowed to continue on the study and study regimen whether or not 
gestational diabetes is present. 
 
• 
Nausea/Vomiting 
- If > Grade 3 nausea/vomiting persists for more than 3 days, antiemetics should be used as needed. 
If the nausea/vomiting is thought to be drug-related and not pregnancy-related, and symptoms do 
not return to < Grade 2 or to baseline within 14 days, stop the study regimen. If symptoms 
improve within 14 days, restart study regimen. 
 

 
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5.2 
Bilirubin Toxicity Monitoring for Postpartum Women Receiving Atazanavir 
 
If maternal total bilirubin ≤ 7.5 mg/dl and maternal direct bilirubin ≤ 2.5 mg/dl, no additional monitoring 
is required. If maternal total bilirubin > 7.5 mg/dl and/or maternal direct bilirubin > 2.5 mg/dl, follow 
toxicity monitoring guidelines according to grade as described above. 
 
5.3  
Criteria for Discontinuation 
 
Participants must be discontinued from the study if: 
 
• 
The participant or the participant’s mother or legal guardian refuses further participation.  
• 
The participant requires treatment with disallowed medications.  
• 
The participant discontinues all medications being studied for the arm on which they enrolled and is 
not being monitored for safety/toxicity outcomes.  
• 
The investigator determines further participation would be detrimental to the participant’s health or 
well-being. 
• 
The participant fails to comply with P1026s requirements, so as to cause harm to self or seriously 
interfere with the validity of the study results. 
• 
The study is cancelled at the discretion of IMPAACT, the Food and Drug Administration (FDA), 
NIAID, the Office for Human Research Protections (OHRP), or the local and/or national IRB or EC. 
 
 
6.0 
 
EXPEDITED ADVERSE EVENT REPORTING  
 
6.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (referred to as the 
DAIDS EAE Reporting Manual), dated January 2010, which is available on the RSC website at 
http://rsc.tech-res.com.  
 
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 NIAID Clinical Research Management System at 
CRMSsupport@niaid.nih.gov.  Questions 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/expeditedreportingdaers.aspx. 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 of the DAIDS EAE Reporting Manual, will be 
used for this study. Reporting requirements apply to both study mothers and their infants. 
 
The study agents for which relationship assessments are required are the drugs (and their boost 
counterparts) for which pharmacokinetic data is being obtained.  
 

 
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In addition to reporting all SAEs as defined above, other events that sites must report in an expedited 
fashion include fetal demises and Grade 4 hepatotoxicities whether or not symptomatic or related to 
study drug.   
  
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 SAE’s submitted to RSC, sites must file an updated SAE report to 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. 
 
6.3  
Grading Severity of Events 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, dated 
November 2014, (which can be at the following website:  http://rsc.tech-
res.com/safetyandpharmacovigilance/) must be followed.  
 
6.4  
Expedited AE Reporting Period 
 
The expedited AE reporting period for this study is the entire study duration for an individual participant 
(from study enrollment until study completion or discontinuation of the participant from study 
participation for any reason). 
 
After the protocol-defined AE reporting period, unless otherwise noted, only Suspected Adverse Events 
as defined in Version 2.0 of the EAE Reporting Manual will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available information). 
 
 
7.0 
 
DISALLOWED MEDICINES 
 
Since some medicines interfere with the pharmacokinetic profile of an antiretroviral drug, the following 
medicines are disallowed for two weeks prior to PK sampling of that drug. 
 
7.1 
NRTIs 
 
For tenofovir alafenamide fumarate, no medicines are disallowed. 
 
7.2 
NNRTIs 
 
For efavirenz, the following medicines are disallowed: 
 
• 
Anticonvulsants: carbamazepine, phenobarbital, phenytoin 
• 
Antifungal: voriconazole 
• 
Antihistamines:  astemizole, cisapride 
• 
Calcium channel blocker: bepridil 
• 
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine 
• 
Herbal products: St. John’s wort (Hypericum perforatum) 

 
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• 
Neuroleptic: pimozide 
• 
Protease Inhibitors: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, telapravir, 
tipranavir 
• 
Sedative hypnotics:  midazolam, triazolam 
 
7.3 
PIs 
 
 
For ALL protease inhibitors, which includes atazanavir (Reyataz®), darunavir (Prezista®), lopinavir + 
ritonavir (Alluvia®), ritonavir (Norvir®) and the pharmacoenhancer cobicistat (Tybost®) the following 
medicines are disallowed: 
• 
Alpha-1 adrenoreceptor antagonist: alfuzosin 
• 
Antiarrhythmics:  amiodarone, flecanide, propafenone, quinidine 
• 
Anticonvulsants: carbamazepine, phenobarbital, phenytoin 
• 
Antihistamines: astemizole, cisapride, terfenadine 
• 
Antimycobacterial: rifampin [disallowed for ARV-only study arms, but allowed for women enrolled 
on the ARV/TB study arms] 
• 
Calcium channel blocker: bepridil 
• 
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine 
• 
Herbal products: St. John’s wort (Hypericum perforatum) 
• 
HMG-CoA reductase inhibitors: lovastatin, simvastatin 
• 
Neuroleptic: pimozide 
• 
Non-nucleosides:  delavirdine, efavirenz, nevirapine 
• 
Phosphodiesterase-5 inhibitor: sildenafil for the treatment of pulmonary arterial hypertension 
• 
Sedative hypnotics:  triazolam, orally administered midazolam 
 
7.31 
Atazanavir 
 
 
For atazanavir, the following medicines are disallowed in addition to those listed above: 
• 
Antineoplastic: irinotecan 
• 
Protease inhibitor: indinavir 
• 
Proton pump inhibitors:  esomeprazole, lansoprazole, omeprazole, rabeprazole 
 
7.32 
Darunavir 
 
For darunavir, the following medicines are disallowed in addition to those listed above: 
• 
Antiarrhythmic: dronaderone 
• 
Anti-gout: colchicine 
• 
Anti-anginal: ranolazine 
 
7.33 
Ritonavir 
 
For all ritonavir containing regimens, the following medicines are disallowed in addition to those listed in 
section 7.5: 
• 
Antialcoholics: disulfiram, metronidazole 
• 
Synthetic corticosteroid:  fluticasone 
 
 
 
 
 

 
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7.34 
Cobicistat 
 
For cobicistat with either atazanavir or darunavir, the following medicines are disallowed in addition to 
those listed above: 
• 
Antiarrhythmic: dronaderone 
• 
Antineoplastics: irinotecan 
 
7.4 
Integrase Inhibitors 
 
For dolutegravir, the following medicines are disallowed: 
 
• 
Antiarrhythmic: dofetilide 
• 
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
• 
Herbal products: St. John’s wort (Hypericum perforatum) 
• 
Non-nucleosides:  delavirdine, efavirenz, etravirine, nevirapine 
• 
Protease Inhibitors: atazanavir, darunavir, ritonavir, telapravir, tipranavir 
 
For elvitagravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, the following medicines are 
disallowed: 
• 
Alpha-1 adrenoreceptor antagonist: alfuzosin 
• 
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin  
• 
Antifungals: ketoconazole, itraconazole, voriconazole 
• 
Antimycobacterial: rifampin 
• 
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine 
• 
GI motility agents: cisapride 
• 
Glucocorticoids: systemic dexamethasone 
• 
Herbal products: St. John’s wort (Hypericum perforatum) 
• 
HMG-CoA reductase inhibitors: lovastatin, simvastatin 
• 
Neuroleptic: pimozide 
• 
Phosphodiesterase-5 inhibitor: sildenafil when dosed as REVATIO for the treatment of pulmonary 
arterial hypertension 
• 
Protease Inhibitors: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, tipranavir 
• 
Sedative hypnotics:  triazolam, orally administered midazolam 
 
7.5  
Tuberculosis (TB) drugs 
 
For amikacin, the following medicine is disallowed: 
• 
cidofovir 
 
For bedaquiline, the following medicine is disallowed: 
• 
moxifloxacin 
 
For capreomycin, no medicines are disallowed. 
 
For clofazamine, no medicines are disallowed. 
 
For delamanid, the following medicines are disallowed: 
• 
Strong CYP 3A4 inducers: carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
 
For ethambutol, no medicines are disallowed. 

 
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For ethionamide/prothionamide, no medicines are disallowed. 
 
For isoniazid, the following medicines are disallowed: 
• 
Anti-anginals: ranolazine 
• 
Antiarrhythmics: dronedarone 
• 
Antibiotics: furazolidone, linezolid 
• 
Antineoplastic: procarbazine 
• 
Anti-Parkinsonian: levodopa, selegiline 
• 
Monoamine oxidase inhibitors: isocarboxazid, phenelzine, tranylcypromine   
• 
Selective norepinephrine reuptake inhibitors: atomoxetine 
 
For kanamycin, the following medicine is disallowed: 
• 
cidofovir 
 
For linezolid, the following medicines are disallowed: 
• 
Monoamine oxidase inhibitors: isocarboxazid, phenelzine, tranylcypromine   
 
For moxifloxacin, the following medicine is disallowed: 
• 
Bedaquiline 
 
For levofloxacin, no medicines are disallowed. 
 
For ofloxacin, no medicines are disallowed. 
 
For para-aminosalicylic acid (PAS), no medicines are disallowed. 
 
For pretomanid, no medicines are disallowed. 
 
For pyrazinamide, no medicines are disallowed. 
 
For rifampicin, the following medicines are disallowed: 
• 
Antifungals: voriconazole 
• 
Calcium channel blocker: nifedipine 
• 
Non-nucleosides: delavirdine, etravirine 
 
For terizidone/cycloserine, no medicines are disallowed. 
 
7.6  
Combined Oral Contraceptives (COCs) and Etonogestrel Implant 
 
For combined oral contraceptives or for etonogestrel implant, the following medicines are disallowed: 
 
• 
Anticonvulsants: barbiturates, phenytoin, carbamazepine felbamate, oxcarbazepine, topiramate  
• 
Antibiotics: rifampin, ampicillin, tetracyclines  
• 
Anti-inflammatories: phenylbutazone 
• 
Antifungal:  griseofulvin, itraconazole, ketoconazole 
• 
Herbal products: St. John’s wort (Hypericum perforatum) 
• 
Psychostimulants; modafinil 
 

 
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8.0 
 
STATISTICAL CONSIDERATIONS   
 
8.1 
General Design Issues 
 
This is a Phase IV prospective study to evaluate the pharmacokinetics of currently prescribed ARVs and 
TB drugs in pregnant women and ARVs and postpartum contraceptive agents prescribed in postpartum 
women. The washout PK of transplacentally acquired antiretroviral drugs will also be studied in infants 
born to mothers who enter the study during pregnancy.  
 
The primary objectives are to describe the maternal pharmacokinetic parameters of the study drugs and 
compare these parameters to those from a suitable control group. The control group data to be used for 
these comparisons will vary according to the type of study drug (ARV, TB drug, or contraceptive) and 
may include (i) historical pharmacokinetic data reported in the literature or from previously-evaluated 
arms of P1026s, (ii) postpartum pharmacokinetic data from the same women who were sampled during 
pregnancy, (iii) pharmacokinetic data from pregnant HIV-uninfected women receiving the TB drugs of 
interest (but not the ARV drugs), and/or (iv) ARV pharmacokinetic data after initiation of contraceptives 
from the same women who were sampled before starting contraceptives (Please see Section 8.6 for details 
on the control groups to be used and comparisons to be made for each type of drug). The secondary 
objectives are to compare ARV and TB drug concentrations in plasma from cord blood with those in 
maternal plasma at the time of delivery, to assess plasma protein binding of selected ARVs, to assess 
ARV and HIV RNA concentrations in vaginal secretions and compare to simultaneous plasma 
concentrations, to explore genetic sources of variability in ARV exposure, to describe maternal and infant 
safety and clinical outcomes, to describe the neonatal elimination of selected ARV drugs acquired across 
the placenta after maternal dosing during pregnancy, and to describe the pharmacokinetics of ARV drug 
combinations in HIV-infected women on second line TB treatment.     
  
The P1026s study design is opportunistic in that it enrolls women who are already receiving the study 
drugs as part of clinical care, but this design has one major limitation, namely that the results may be 
overly optimistic. Since participants must have been stable on the ARV drug/drug combination and/or TB 
drug combination for at least two weeks prior to PK sampling in order to enroll in the study, the study 
population will not include women who started the study drug and discontinued it within two weeks due 
to toxicity, intolerance, virologic failure, or any other reason. Thus, this study will not be able to identify 
pharmacokinetic, safety, or tolerance issues that occur very soon after drug initiation and estimates of the 
frequency of outcomes such as virologic response and mother-to-child HIV transmission may be overly 
optimistic. The fact that the results of this study will generalize only to the population of women who are 
able to stay on the study drugs for at least two weeks will be discussed as a limitation of the study in 
presentations and publications of results. The protocol team acknowledges this limitation, but feels that 
the PK data obtained using the current design will still be quite valuable nonetheless. 
 
8.2 
Outcome Measures 
 
8.21 
Primary Outcome Measures 
 
8.211 For ARVs and first-line TB drugs: The target pharmacokinetic parameter specified in 
Appendix V and other pharmacokinetic parameters listed in Section 9.24 
 
8.212 For second-line TB drugs: Pharmacokinetic parameters listed in Section 9.24 
 
8.213 For contraceptives: Concentration in plasma 
 

 
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8.22 
Secondary Outcome Measures 
 
8.221 Ratio of cord blood concentration to maternal blood concentration 
 
8.222 Ratio of unbound/total drug concentrations for the highly bound ARVs specified in 
section 9.0 
 
8.223  Rate of detection of study drugs in vaginal secretions; ratio of vaginal drug 
concentrations to simultaneous blood concentrations; rate of detection of HIV RNA/DNA 
in vaginal secretions and comparison to level in blood 
 
8.224  ARV and TB drug exposure (as measured by area under the curve or other PK 
parameters) during pregnancy and postpartum according to genotype  
 
8.225 Maternal and infant safety and clinical outcomes, including adverse events of grade 3 or 
higher and infant neurological events of grade 1 or higher, according the DAIDS toxicity 
grading table; adverse pregnancy outcomes including preterm birth, low birth weight, and 
fetal demise; congenital anomalies; and infant HIV infection status as defined according 
to the most current IMPAACT definition. 
 
8.226 Infant washout pharmacokinetics parameters listed in Section 9.24 
 
8.227 ARV exposure (as measured by area under the curve or other PK parameters) during 
pregnancy and postpartum.  
 
8.3 
Randomization and Stratification 
 
None. 
 
8.4 
Sample Size and Accrual  
 
8.41 
Sample Size 
 
The sample size calculations will be based on assessing whether therapeutic dosing regimens for the study 
drugs produce adequate drug exposure during pregnancy as compared to historical data from non-
pregnant adults. Such observations will be assessed to determine, if possible, whether the level of 
exposure to these drugs during pregnancy is adequate, or inadequate, based upon current knowledge.  
 
The PK exposure parameter of primary interest for sample size calculations will be the area under the 
curve (AUC), as determined from 12 hour sampling or 24 hour sampling (Refer to Appendix III for the 
sampling schedule for each drug). The AUC is commonly treated as following a log-normal distribution. 
 
Each study arm will enroll a minimum of 12 women and have a target enrollment of 25 women with 
evaluable 3rd trimester PK data for ARV and TB arms, or evaluable postpartum PK data for oral 
contraceptive arms. Women who do not have evaluable data will be replaced. Enrollment may be 
restricted or adjusted so that evaluable 2nd trimester PK data are obtained from at least 12 women. The 
sample size for an arm may also be increased if additional mothers and infants need to be enrolled to 
obtain evaluable infant washout PK data. Thus, the total number of participants enrolled per arm may be 
larger than 25 if women need to be replaced due to non-evaluable data, if additional women need to be 
enrolled to obtain 2nd trimester PK data, if additional mothers and infants need to be enrolled to obtain 
infant washout PK data and/or if additional women need to be enrolled to obtain enough second line TB 

 
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drug data.  When combined enrollment in the increased dose darunavir arms reaches 25 participants, the 
PK data will be evaluated to determine if the data for these arms can be combined and whether enrollment 
of additional participants in these arms should continue. Geometric means and 90% confidence intervals 
for oral clearance and key dose-adjusted parameters such as AUC, Cmax and Ctrough from both groups will 
be compared and enrollment will be stopped if these data are dose-proportional over this small dose 
range. 
 
The actual sample size will be based on the determination of PK exposure parameters, and whether or not 
the current dose provides adequate drug exposure to pregnant women. Based on data regarding drugs 
presently under study, the major concern is that the drug exposure in pregnant women might be lower 
than that seen in the non-pregnant population. Interim pharmacokinetic exposure monitoring will be 
implemented which compares each pregnant woman’s values to the distribution from a non-pregnant 
population, so that the question of whether the dose is too low will be tested by comparison to historic 
controls. Adequate exposure will be defined as fewer than 6 out of 25 pregnant women having PK 
exposure parameters below the 10th percentile for the non-pregnant population, because the team 
considers that having more than 20% of the women below the 10th percentile would be unacceptable. 
Consequently, if 6 or more of the pregnant women have PK exposure parameters below the 10th 
percentile, it will be concluded that the PK exposure in the pregnant population is lower than that of non-
pregnant population. Given the discrete nature of the data, if 6 or more participants have low PK exposure 
parameters, the lowest sample probability that can be achieved is 24%, 6 out of 25, and the exact 80% 
confidence limits are (13%, 38%). These confidence limits exclude the tenth percentile and indicate that 
the team is at least 90% confident that the true percentage of pregnant women having PK parameters 
below the 10th percentile for the non-pregnant population is > 10%. Note that the 10th percentile from the 
non-pregnant historic controls is being treated as a constant.  
 
Table 2 provides the probability of finding the exposure of the pregnant population to be lower than that 
of the non-pregnant population given the current dose with a sample size of 25 evaluable women. 
Consider four possible true cumulative probabilities in the pregnant population for the value of the 10th 
percentile from the non-pregnant population. If the true cumulative probability corresponds to .10 in the 
pregnant population the probability of finding the populations different is small (< 4%). If the true 
cumulative probability reaches .30 then the probability of finding a difference goes to .81. Finally, if it 
reaches .40 then the probability of finding a difference is .97, indicating that 3% of the time a difference 
will not be found. 
 
Table 2:  Probabilities of finding the exposure of the pregnant population to be lower than that of the 
non-pregnant population with a sample size of 25 evaluable women  
 
True cumulative probability 
associated with the value for the 10th 
percentile from the non-pregnant 
population in the pregnant 
population 
Probability of finding the exposure 
of the pregnant population to be 
lower than the non-pregnant 
population 
.10 
.033 
.20 
.38 
.30 
.81 
.40 
.97 
 
Antiretroviral and TB drugs will also be studied in a repeated measures design, in which each woman will 
be measured during pregnancy and postpartum, or in the second and third trimester, or before and after 
starting contraceptives, depending on the specific drug being studied. The comparisons will be made at 
the within participant level, using the Wilcoxon signed-rank test and 90% confidence limits for the 

 
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geometric mean ratio of the PK exposure parameter in the two conditions (pregnant versus non-pregnant, 
or second versus third trimester, or before versus after starting contraceptives). At this stage of the 
analysis, the test and confidence interval are assessing whether the drug exposure differs in the two 
conditions.    
 
Table 3 illustrates the width of the confidence limits and whether they would exclude the value of 1.0 
according to the standard deviation and observed point estimate, assuming that 12 participants have both 
antepartum and postpartum (or both second and third trimester or both pre- and post-contraceptive 
initiation) PK parameter measurements. If the confidence limits exclude 1.0, this would indicate that the 
PK exposure parameter is significantly lower (or higher) in one condition than in the other, with one-
sided p-value <0.05 (two-sided p-value <0.10). The dark shaded areas represent cases where the 
confidence limits exclude the value 1.0. For example, if the geometric mean of the observed ratios is 1.0 
and the standard deviation (SD) of the natural log observed ratio is 0.3, then the 90% confidence interval 
would be 0.86 to 1.17 so the true ratio of the geometric mean PK exposure parameter is likely to be close 
to one with high confidence. These results would indicate that no statistically significant difference 
between the pregnant and non-pregnant conditions was observed. For a SD of 0.3, the ratio would need to 
be as large as 1.25 (or as small as 0.80 to indicate a detectable difference between the two conditions (that 
is for the confidence limits to exclude the value 1.0). If the SD is 0.5 or 0.7, a ratio of 1.5 or greater (or 
0.67 or smaller) would be required to indicate a detectable difference. If the SD is 0.9 or higher, a ratio of 
2 or greater (or 0.5 or smaller) would be required to indicate a detectable difference. When there are more 
than 12 participants in a study arm who have both antepartum and postpartum (or both second and third 
trimester or both pre- and post-contraceptive initiation) PK parameter measurements, the confidence 
intervals will be narrower than those given in Table 3, and we will have a higher power to detect any 
difference in the ratio. 
 
Note:  The above examples are provided to give the reader a sense for the magnitude of the differences 
that will be detectable, based on the information in the following table. During the study, confidence 
limits will be calculated for the actual observed ratios and standard deviations. 
 
Table 3: 90% Confidence Limits for the Geometric Mean Ratio of the PK Exposure Parameter (n=12) 
SD 
OBS_RATIO 
Lower Confidence Limit (LCL) 
Upper Confidence Limit (UCL) 
0.3 
0.25 
0.21 
0.29 
 
0.5 
0.43 
0.58 
 
0.67 
0.57 
0.78 
 
0.80 
0.68 
0.94 
 
1 
0.86 
1.17 
 
1.25 
1.07 
1.46 
 
1.5 
1.28 
1.75 
 
2 
1.71 
2.34 
 
4 
3.42 
4.68 
0.5 
0.25 
0.19 
0.32 
 
0.5 
0.39 
0.65 
 
0.67 
0.52 
0.87 
 
0.80 
0.62 
1.04 
 
1 
0.77 
1.30 
 
1.25 
0.96 
1.62 
 
1.5 
1.16 
1.94 
 
2 
1.54 
2.59 
 
4 
3.09 
5.18 
0.7 
0.25 
0.17 
0.36 
 
0.5 
0.35 
0.72 
 
0.67 
0.47 
0.96 
 
0.80 
0.56 
1.15 
 
1 
0.70 
1.44 

 
IMPAACT P1026s Version 10.0  
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SD 
OBS_RATIO 
Lower Confidence Limit (LCL) 
Upper Confidence Limit (UCL) 
 
1.25 
0.87 
1.80 
 
1.5 
1.04 
2.16 
 
2 
1.39 
2.88 
 
4 
2.78 
5.75 
0.9 
0.25 
0.16 
0.40 
 
0.5 
0.31 
0.80 
 
0.67 
0.42 
1.07 
 
0.80 
0.50 
1.28 
 
1 
0.63 
1.60 
 
1.25 
0.78 
1.99 
 
1.5 
0.94 
2.39 
 
2 
1.25 
3.19 
 
4 
2.51 
6.38 
1.1 
0.25 
0.14 
0.44 
 
0.5 
0.28 
0.88 
 
0.67 
0.38 
1.18 
 
0.80 
0.45 
1.41 
 
1 
0.57 
1.77 
 
1.25 
0.71 
2.21 
 
1.5 
0.85 
2.65 
 
2 
1.13 
3.54 
 
4 
2.26 
7.07 
OBS_RATIO is the anti-log of the mean of the log ratios of the PK exposure parameters for the pregnant versus 
non-pregnant conditions (or 2nd vs. 3rd trimester, or pre- vs. post-contraceptive initiation). 
SD represents SD of the natural log of the observed ratio (OBS_RATIO). 
LCL and UCL are the lower and upper confidence limits, respectively, assuming a Student’s t distribution with 
n=12. 
The dark-shaded rows represent cases where the CI excludes the value 1.0, indicating that the PK exposure differs 
significantly in the pregnant vs. non-pregnant conditions (or 2nd vs. 3rd trimester, or pre- vs. post-contraceptive 
initiation). 
Based on past experience, standard deviations on the log scale of the order of 0.5 to 1.1 are likely for PI-containing 
regimens, whereas regimens containing only NRTIs tend to have smaller values. For the completed LPV/r arm, the 
standard deviation of 12 participants having both antepartum and postpartum AUC measurements was 0.68. For 
the completed ABC arm, the standard deviation of 17 participants was 0.31. 
 
8.42 
Accrual 
 
As of October 8, 2015, a cumulative total of 766 women and 316 children had been enrolled under 
P1026s protocol Versions 2.0-5.0 and 7.0-9.0 (Versions 1.0 and 6.0 did not open to enrollment). Over the 
preceding 12 months, the monthly accrual ranged from 14-17 women and 1-12 infants. In Version 10.0, 8 
new treatment arms have been opened and 10 treatment arms from Version 9.0 have been retained. The 
total number of new enrollments to be expected under Version 10.0 is very difficult to determine, because 
the actual enrollment to each arm and total enrollment to P1026s will depend on several factors: 
 
• 
Each study arm will have a target enrollment of 25 women with evaluable 3rd trimester PK data for 
ARV and TB arms, or evaluable postpartum PK data for oral contraceptive arms; 
• 
When combined enrollment in the increased dose darunavir arms reaches 25 participants, the PK data 
will be evaluated to determine if the data for these arms can be combined and whether enrollment of 
additional participants in these arms should continue; 
• 
Women who do not have evaluable data will be replaced, but will still be counted in the enrollment 
for that arm (which may therefore exceed 25); 
• 
Enrollment to an arm may be restricted or adjusted upward (above 25) so that evaluable 2nd trimester 
PK data are obtained from at least 12 women; 

 
IMPAACT P1026s Version 10.0  
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• 
All infants of women enrolled in the antepartum arms of P1026s will be enrolled in utero 
(immediately after maternal enrollment) and counted in the total enrollment to P1026s;  
• 
Enrollment to an arm may be adjusted upward (above 25) to obtain additional evaluable infant 
washout PK data; 
• 
Enrollment to an arm may be adjusted upward (above 25) to obtain additional second line TB drug 
data; 
• 
An arm may be closed early due to slow accrual; 
• 
An arm may be closed early if PK targets are not met in 6 women, at any time after at least 12 women 
have been enrolled. 
 
Thus, although the total number of participants actually enrolled in a given arm may be more or less than 
25, if the 10 retained arms in Version 9.0 were to complete enrollment of 25 evaluable women per arm 
(which would require enrollment of at least 136 additional women and 113 additional infants), the 8 new 
arms were to enroll 25 evaluable women per arm (which would require enrollment of at least 200 women 
and 150 infants), 15% of women (and their infants) need to be replaced due to lack of evaluable PK data, 
one would expect approximately 395 new maternal enrollments and 309 new infant enrollments to 
P1026s Version 10.0.  
 
8.5 
Monitoring 
 
8.51 
Interim PK Exposure Monitoring During Pregnancy (for ARVs only) 
 
Based on data regarding the ARV drugs presently under study, the major concern is that the ARV drug 
exposure in pregnant women will be lower than that of the non-pregnant population, and the interim PK 
exposure monitoring rules are designed to detect this scenario quickly. In each study arm, at any time 
after a minimum of 12 participants have been enrolled, if six or more pregnant women have the third-
trimester PK exposure parameter below the 10th percentile for the non-pregnant population, the study 
team will evaluate the adequacy of drug exposure in that arm, and with the agreement of the medical 
officers, determine whether enrollment to that arm should continue. The exact 80% confidence limits for 
6 participants with low drug exposure out of a total of 25 are (0.13, 0.38), which exclude 10% and 
indicate strong evidence that the distribution of the PK parameter of interest for the pregnant women is 
different from that for the non-pregnant women. If a statistical difference appears to be clinically 
important, then enrollment into that study arm will stop and a new study arm at a higher dose will be 
developed, if feasible. 
 
8.52 
Replacement 
 
Participants will be replaced if their antepartum ARV or TB pharmacokinetic data are deemed 
unevaluable.  A participant's antepartum pharmacokinetic data will be deemed unevaluable for the Stage 1 
analysis (described in Section 8.6), if they do not have adequate pharmacokinetic evaluations to determine 
the PK exposure parameter.  
 
Additional participants will be enrolled to any arm in which fewer than 12 participants have evaluable 
postpartum pharmacokinetic data. A participant’s data will be deemed unevaluable for the Stage 2 
analysis (described in Section 8.6), if (a) they do not have adequate pharmacokinetic evaluations to 
determine the PK parameters of interest  under both the pregnant and non-pregnant conditions (or both 2nd 
and 3rd trimester, or both pre- and post-contraceptive initiation), or (b) the patients' dosing regimen 
changed between the pregnant and non-pregnant conditions (or between the 2nd and 3rd trimester 
evaluation, or between the pre- and post-contraceptive initiation evaluation) in a way that was not 
specified in the protocol, or (c) there is a change in the underlying treatment during that time period (e.g., 

 
IMPAACT P1026s Version 10.0  
             Page 44 of 107                                        2 February 2016  
 
 
 
no longer receiving study drug, or receiving a disallowed medication). Changes in underlying treatment as 
well as data completeness will be monitored in order to replace unevaluable patients in a timely fashion 
 
An integral part of this protocol is reporting ARV drug assay results to the clinical caregivers of the 
participants. Knowledge of these results may impact which patients complete the sampling protocol 
without an ARV dosing change and which patients receive an ARV dosing change and need to be 
replaced. In this way the replacement of unevaluable patients may introduce a selection bias into the 
population available for the within patient comparison of the pregnant and non-pregnant condition. This 
potential bias is an inescapable consequence of the study design, but is outweighed by the ethical 
imperative to provide all potentially valuable clinical information to study participants. 
 
8.6 
Analysis  
 
The data analyses to address the primary objectives for each study arm will include descriptive statistics 
and the comparisons below. The mean as a measure of location and the standard deviation as a measure of 
dispersion as well as other descriptive statistics of interest will be calculated, along with confidence 
intervals. Within-participant comparisons (e.g., between pregnant versus non-pregnant conditions, second 
versus third trimester, or before versus after starting contraception) will be performed for continuous 
outcome measures using the Wilcoxon signed-rank test and for dichotomous outcome measures using 
McNemar’s test. Between-participant comparisons will be performed for continuous outcome measures 
using the Wilcoxon rank-sum test and for dichotomous outcome measures using the chi-square or Fisher 
exact test. 90% confidence limits for the geometric mean ratio of the PK exposure parameter in the 
pregnant versus non-pregnant conditions (or before versus after starting contraception) will also be 
calculated to describe the range of values that are consistent with the observed data and help the protocol 
team assess whether there is a clinically important difference in exposure in the two conditions. The 
confidence coefficient will be 90% rather than 95% to match the usual practice in the pharmacokinetic 
literature. For infant washout PK data, ARV taken with second-line TB drugs, and other secondary 
objectives, descriptive statistics will be summarized. 
 
As noted in Section 8.1, the comparisons to be performed to address the primary objectives will vary 
according to type of drug and timing of sampling. Table 4 summarizes these comparisons. The analysis of 
ARV drug PK parameters during pregnancy will follow a two or three stage approach. In Stage I, an 
individual woman’s PK exposure parameter during pregnancy will be compared in real time to the 10th 
percentile for that PK exposure parameter for that drug from a non-pregnant population, and the woman 
and her clinical provider will be notified if the woman’s value is below the 10th percentile. If there is 
strong evidence that the true percentage of pregnant women having the PK exposure parameter below the 
10th percentile for the non-pregnant population is greater than 10%, the study team will evaluate whether 
to stop enrollment early and whether to recommend that additional study of the drug/drug combination is 
necessary. (See Interim Exposure Monitoring in Section 8.51.)  
 
Table 4: Pharmacokinetic Parameter Comparisons to be Performed for Each Type of Drug for the 
Primary Objectives 
Type of Drug 
Analysis 
Stage 
Description of Pharmacokinetic 
Parameter Comparison 
Type of 
Comparison 
ARV without 
TB Drugs 
Stage 1 
Antepartum PK parameter vs. 10th percentile 
from external, non-pregnant population 
Between-participant 
Stage 2 
Antepartum vs. postpartum PK parameters 
Within-participant 
ARV with First 
Line TB Drugs 
Stage 1 
Antepartum ARV PK parameter vs. 10th 
percentile from non-pregnant population 
Between-participant 
Stage 2 
Antepartum vs. postpartum  ARV PK parameters 
Within-participant 

 
IMPAACT P1026s Version 10.0  
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Stage 2 for the ARV drugs taken during pregnancy will implement a repeated measures design, in which 
antepartum and postpartum measurements from each woman will be compared. This stage requires a 
minimum of 12 participants in each arm to have postpartum PK measurements. If less than 12 participants 
out of the 25 in any arm have postpartum measurements, more participants will be enrolled in that arm 
until the minimum postpartum measurement number of 12 is reached. The comparisons will be made at 
the within participant level, using the Wilcoxon signed-rank test to assess whether there is a statistically 
significant difference in the PK exposure parameter in the pregnant versus non-pregnant conditions. 90% 
confidence limits for the geometric mean ratio of the PK exposure parameter in the pregnant versus non-
pregnant conditions will also be calculated to describe the range of values that are consistent with the 
observed data and help the protocol team assess whether there is a clinically important difference in 
exposure in the pregnant versus non-pregnant conditions.  
 
For the ARV drugs being taken with first-line TB drugs, in addition to Stages 1 and 2, a third stage of 
analysis (Stage 3) will be performed which will compare the ARV PK exposure with first-line TB drugs 
to the PK exposure for these ARVs without first-line TB drugs in previously evaluated arms of the 
P1026s study. This analysis will involve a between-participants comparison of PK exposure parameters 
using the two-sample Wilcoxon rank sum test. 90% confidence limits for the geometric mean ratio of the 
PK exposure parameters in the two groups of women will also be calculated. 
 
For the first-line TB drugs, a Stage 1 analysis similar to that described above will be performed but only 
after completion of the concentration assays following batch shipment (refer to Section 3.3). Since the TB 
drug samples will not be shipped and assayed in real time and the duration of TB drug treatment is time 
limited, the participant may no longer be receiving the TB drug being studied when the TB drug assay 
results become available. The PK analysis for the first-line TB drugs will also include the Stage 2 
approach described above, in which a within-participants comparison of TB drug PK exposure during 
pregnancy and postpartum will be performed, separately for HIV-infected and HIV-uninfected women in 
Stage 3 
ARV PK parameter with TB drugs vs. ARV PK 
parameter without TB drugs in previous P1026s 
arm 
Between-participant 
First Line TB 
drugs with 
ARVs (HIV+) 
and 
First Line TB 
drugs without 
ARVs (HIV-) 
Stage 1* 
Antepartum TB drug PK parameter vs. 10th 
percentile from non-pregnant population 
Between-participant 
Stage 2 
Antepartum vs. postpartum TB drug PK 
parameter, separately for HIV+ and HIV- 
Within-participant** 
Stage 3 
TB drug PK parameter with ARV (HIV+) vs. TB 
drug PK parameter  without ARV (HIV-)  
Between-participant 
Second Line TB 
drugs with or 
without ARVs  
Stage 2 
Antepartum vs. postpartum TB drug PK 
parameters 
Within-participant** 
ARV  with 
Contraceptives# 
Stage 2 
Postpartum ARV PK parameter before  vs. after 
starting contraceptives  
 
Within-participant 
Contraceptives 
with ARVs 
Stage 3 
Postpartum contraceptive concentration with 
ARV vs. external historical controls not receiving 
ARV 
Between-participant 
*Stage 1 analysis for the TB drugs will not be done in real time and will only be done when batched PK data 
are available (unlike the Stage I analysis for ARVs). 
**This comparison may have a smaller sample size than 25 because some women may complete their TB 
treatment before the postpartum PK visit. 
#Interim AUC monitoring (Stage 1 analysis) is not done for these arms (only done during pregnancy). 

 
IMPAACT P1026s Version 10.0  
             Page 46 of 107                                        2 February 2016  
 
 
 
each study arm. Note that the sample size for this comparison may be less than the desired 25 evaluable 
women if some women complete their TB medication course before the postpartum visit where the PK 
sampling will be done. In addition, a Stage 3 between-participants comparison of first-line TB drug PK 
exposure in HIV-infected versus HIV-uninfected women will be performed (using the two-sample 
Wilcoxon rank sum test) to assess whether exposure to first-line TB drugs differs with vs. without 
concomitant ARV drug use and presence of HIV-infection. Note that if a significant difference is 
observed in the between-participants analysis, it will not be possible to determine whether this difference 
is due to ARV use or HIV infection.  
 
For the second-line TB drugs, the PK analysis will use the Stage 2 approach described above, in which a 
within-participants comparison of TB drug PK exposure during pregnancy and postpartum will be 
performed. Note that the sample size for these comparisons may be less than the desired 25 evaluable 
women per drug because the inclusion criteria for this study arm only require that women are receiving at 
least two of the specified second-line TB drugs, and because some women may complete their TB 
medication course before the postpartum visit where the PK sampling will be done. It may or may not be 
possible to perform a Stage 3 between-participants comparison of second-line TB drug PK exposure in 
HIV-infected versus HIV-uninfected women; depending on the number of women receiving each TB 
drug, it may be necessary to combine data from HIV-infected and HIV-uninfected women.  
 
For the ARV drugs being taken with postpartum contraceptives, the Stage 1 analysis above will not be 
performed (the Stage 1 analysis will only be done for ARV during pregnancy). A within-participants 
analysis similar to the Stage 2 analysis described above will be performed, except that the ARV PK 
exposure parameters before versus after starting contraceptives will be compared (instead of during 
pregnancy versus postpartum).  
 
For the contraceptives, a stage 3 analysis will be performed that will compare the contraceptive 
concentrations observed in P1026s women receiving a protease inhibitor to data from historical controls 
not receiving ARVs, as reported in the available literature.  
 
 
9.0 
 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Objectives 
 
This study’s primary objectives are to 1) determine the PK of antiretroviral drugs used as part of the 
management of pregnant HIV-infected women and to compare drug exposure among pregnant women 
with that of a) historical data in non-pregnant women and b) the same women postpartum; 2) describe and 
compare the concentrations of selected ARV and first line TB drugs in HIV-infected and first line TB 
drugs in HIV-uninfected pregnant women; 3) describe and compare the concentrations of selected second  
line TB drugs in HIV-infected and HIV-uninfected pregnant women;4) determine ARV concentrations in 
postpartum women before and after starting the use of hormonal contraceptives (combined oral 
contraceptives (COCs) and etonogestrel implants); and5) determine hormone concentrations in women 
using hormonal contraceptives and selected ARV drugs. Such observations will be assessed to determine, 
if possible, that the level of exposure to these drugs during pregnancy or postpartum is adequate, or 
inadequate, based upon current knowledge. This study has 7 secondary objectives: a) to compare ARV 
and TB drug concentrations in plasma from cord blood with those in maternal plasma at the time of 
delivery, b) to determine plasma protein binding of highly bound ARVs (>85% bound) during pregnancy 
and postpartum, c) to describe and compare ARV concentrations and HIV RNA/DNA concentrations in 
maternal blood and genital secretions, d) to explore genetic sources of ARV and TB drug exposure 
variability in pregnancy and postpartum,  e) to describe maternal and infant safety and clinical outcomes 
f) to describe the neonatal elimination of selected ARV and TB drugs acquired across the placenta after 

 
IMPAACT P1026s Version 10.0  
             Page 47 of 107                                        2 February 2016  
 
 
 
maternal dosing during pregnancy and g) to describe the pharmacokinetics of ARV drug combinations in 
HIV-infected women on second line TB treatment.   
 
There are few clinical trials describing the pharmacokinetics of ARV, antituberculosis and/or hormonal 
contraceptives in pregnant and postpartum women, limiting our ability to design appropriate dosing 
schedules for these agents in HIV-infected pregnant and postpartum woman. Overdosing may lead to 
maternal and/or fetal toxicity. Under dosing may lead to inadequate efficacy. An understanding of the 
pharmacokinetics of ARV and antituberculosis drugs during pregnancy and hormonal contraceptives 
postpartum is necessary for the safety and well-being of both HIV-infected mothers and their infants. 
 
9.2 
Primary and Secondary Data to be Accessioned 
 
9.21 
Pharmacokinetic sampling data  
 
9.211 Dosing history (date, time and amount of last two doses of study drug prior to study dose 
and of study dose) 
 
9.212 Last two maternal meals to include dates, times, description 
 
9.213 Pre-pregnancy weight and height at initial PK sampling, and weight at subsequent PK 
sampling visits and at or within 2 weeks before delivery 
 
9.214 Date and time PK samples drawn 
 
9.215 Ratio of unbound/total drug concentrations, if unbound drug measured 
  
9.216 Date and time of vaginal PK sampling 
 
9.217 Date and time when COC were started and the last dose was taken  
 
9.218 Date of etonogestrel implant insertion  
 
9.219 Genotype of drug metabolizing enzymes (CYP P450) 
 
 
9.22 
Delivery data 
 
9.221 Date, time and amount of last doses before delivery of all ARV agents 
 
9.222 Date and time of delivery 
 
9.223 Date and time of maternal blood drawing 
 
9.224 Date and time cord blood obtained  
 
9.23 
Demographic and historical data 
 
9.231 Maternal age and ethnicity 
 
9.232 Infant gestational age, birth length and weight  
 
9.233 Date, time and amount of last doses of all other medicines taken in last 7 days 

 
IMPAACT P1026s Version 10.0  
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9.234 Maternal laboratory studies:  liver function tests (ALT, AST, bilirubin), renal function 
tests (creatinine, BUN), albumin, Hgb, total amylase, lipase, genotype, phenotype 
 
9.24 
Pharmacokinetic Parameters 
 
9.241 Maternal limited sampling schedule:  Pre-dose concentration, Tmax, Cmax, AUC for all 
drugs. Cl/F, V/F, t1/2 if data sufficient or population analysis undertaken. 
 
9.242 Maternal full sampling schedule:  Pre-dose concentration, Cmin (end of sampling 
interval), Tmax, Cmax, AUC, Cl/F, V/F, t1/2. 
 
 
9.243    Infant washout sampling:  t ½, drug concentrations  
 
9.244    Genital secretions:  ARV concentrations in vaginal secretions and plasma 
 
9.25 
Infant HIV infection status 
 
9.3 
Study Design, Modeling and Data Analysis  
 
This study will determine the pharmacokinetics of ARV drugs, antituberculosis drugs and hormonal 
contraceptives in pregnant and postpartum women receiving standard and non-standard adult doses of 
these drugs as part of routine clinical care and the washout pharmacokinetics of transplacentally acquired 
antiretroviral and TB drugs in infants born to mothers receiving antiretroviral drugs during pregnancy. In 
some arms, pregnant women will be enrolled who are receiving increased doses of the antiretroviral drug 
of interest. If so, dose reduction to the standard adult dose will occur upon postpartum discharge from the 
hospital. Pregnant participants may enroll in the second or third trimester.  Pharmacokinetic sampling will 
be performed during the third trimester and postpartum for all pregnant participants and in the second 
trimester as well for those pregnant participants enrolling in the second trimester. Eligible women will be 
those HIV- infected or uninfected pregnant or postpartum women receiving treatment as part of clinical 
care with any of the specified ARV drugs, antituberculosis drugs or contraceptive agents, for which 
adequate pregnancy pharmacokinetic data are lacking. Pharmacokinetic parameters will be compared 
during pregnancy and postpartum or prior to and after 6-7 weeks of postpartum contraceptive treatment 
and the potential influence of concomitant medications and drug metabolizing genotype will be assessed. 
For pregnant participants, samples of maternal blood at delivery and of cord blood will be obtained in 
order to allow comparison of maternal and fetal plasma ARV concentrations at birth. Genital secretion 
samples will also be obtained from pregnant participants and compared to simultaneous plasma 
concentrations for ARV during pregnancy. Washout pharmacokinetics of transplacentally acquired drug 
will be determined in infants born to mothers receiving ARV and TB drugs during pregnancy. 
 
9.31 
Laboratory Analysis and Reporting 
 
Site:  All PK samples will be registered in the Lab Data Management System (LDMS) database. The 
study database will be kept up to date by close tracking of samples. Plasma samples will be sent to the 
UCSD Pediatric Clinical Pharmacology Laboratory (PCPL) or other specified pharmacology laboratories 
participating in an ACTG QA/QC Pharmacology program. Such laboratories include but are not limited 
to the IMPAACT Chiang Mai Pharmacology Laboratory and the Pharmacology Laboratory of the 
University of Cape Town. Plasma samples will be assayed for concentrations of ARV drugs, 
antituberculosis drugs and/or hormonal contraceptives. All samples will be destroyed after the primary 
assays have been completed for the pharmacokinetic and protein-binding studies.   
 

 
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Methods to be used:  All methods will be standardized with a filed Methods Report, under Good 
Laboratory Practice (GLP) conditions such as those currently used in the UCSD PCPL, the Chiang Mai 
laboratory and the Pharmacology Laboratory of the University of Cape Town, or will be derived from 
published methods.  
 
Reporting of Assay Data:  For ARVs during pregnancy, assays will be batched by participant PK visits 
aggregated in sufficient participant numbers to provide a routine assay group [n=25-30 samples]. These 
will be performed during each week, and in a reasonable time frame to achieve reporting every week, in 
order of receipt of samples from sites within a week of sample receipt into the laboratory. Participant 
assay data will be reported to the site investigator and to the DMC from the pharmacologist. Initial data 
reports will include estimated AUC and a comparison with a concentration-time profile for the 
appropriate drug derived from non-pregnant adult data for all regimens, which will be reported to the site 
investigator regardless of plasma level. In cases where the PK parameter of interest (AUC or Cmin) is 
below the 10th percentile for that drug, compared to non-pregnant adult values, the assay report will 
enclose a notice to the site investigator that this level may be lower than expected therapeutic levels. This 
notice will advise the site investigator advice may be solicited from a study pharmacologist regarding a 
change in dosing regimen of the drug reported. If so, request is made to the study pharmacologist and 
DAIDS medical officer by e-mail. If any change in the dose of the drug is made to such participants, the 
site investigator may request that a second series of PK plasma samples be analyzed and reported on a 
schedule arranged between the assay laboratory and pharmacologist. The team should be notified by e-
mail of any changes made to the participant’s regimen. These changes will also be recorded on the 
appropriate CRF. 
 
Samples to be assayed for TB drug or hormonal contraceptive assays will be batch shipped to the 
appropriate laboratory at the request of the protocol team. TB drug assay results and initial 
pharmacokinetic interpretation will be reported back to the DMC, the participant and her clinical 
caregiver shortly after completion of the assays. Hormonal contraceptive assay data will not be reported 
back to the participant and her clinical caregiver. 
 
Aggregated data reports for each individual drug will be constructed by the UCSD PCPL and periodically 
reported out to the protocol team and the data management center. 
 
9.32 
PK sampling schedules and analysis 
 
9.321 A limited maternal sampling schedule of 5-6 samples collected over the first half of a 
dosing interval will be used for drugs that have demonstrated linear pharmacokinetics, 
predictable absorption and no significant circadian variability in pre-existing 
pharmacokinetic data from non-pregnant individuals. The concentration data collected for 
these drugs will be analyzed by inspection to determine pre-dose concentration, Tmax, 
Cmax and by Bayesian modeling to estimate AUC. Additional pharmacokinetic 
parameters (Cl/F, V/F, t1/2) will be determined by traditional or population 
pharmacokinetic techniques if there are pre-existing pharmacokinetic data to support the 
analytic approach and if there are sufficient data points available to make the effort 
potentially valuable. Population analysis will be performed using the computer program 
NONMEM.  
 
9.322 A full maternal sampling schedule of 7-8 samples collected throughout an entire dosing 
interval will be used for drugs with known or suspected non-linear pharmacokinetics, 
erratic absorption and/or significant circadian variability. All of the currently available 
protease inhibitors fall into this category. Standard pharmacokinetic analyses using model 
dependent and independent pharmacokinetic approaches will be used to analyze the full 

 
IMPAACT P1026s Version 10.0  
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sampling schedule drug concentration data. These analyses will be carried out by the 
team pharmacologists, or by other IMPAACT pharmacologists, as decided by the 
protocol team. 
 
9.323  Infant washout sampling will be collected as specified in Appendix II. Pharmacokinetic 
analysis will include descriptive statistics of drug concentrations and estimation of 
elimination t ½. 
 
9.324 Aggregate PK Analysis:  Analysis of PK data for all drugs will be performed in the 
UCSD Section on Pediatric pharmacology routinely. Aggregated PK analytical data will 
be reported to the pharmacologists and the data management center routinely. Aggregated 
files of analyzed PK data will be kept at the UCSD laboratory for regular additions and 
management. Reports will be written and distributed as necessary for presentations and 
publications. 
 
• 
Standard pharmacokinetic analyses will be performed when sufficient data are 
accumulated in the aggregate data reports on all drugs studied. Model dependent and 
independent traditional pharmacokinetic approaches will be used to analyze drug 
concentration data on those drugs for which sampling is conducted over the entire 
dosing interval. These analyses will be carried out by the team pharmacologists, or by 
other pharmacologists decided by the protocol team. 
 
• 
Population and physiologic based pharmacokinetic techniques may be used to 
analyze data for those drugs for which sample collections are not gathered over the 
entire dosing interval, if there are sufficient data points available to make this effort 
potentially valuable and if this effort is necessary, at all, in support of other 
pharmacokinetic data in a given drug group. This will be accomplished using Mixed 
Effects Modeling with a computer program such as NONMEM [NONlinear Mixed 
Effects Modeling version VI or later] analyzing data comprised of repeated 
measurements in non-linear systems. Individual variation in drug clearance may be 
explained by individual differences in fixed effects, such as age, weight, pregnancy 
status and pharmacogenics as well as random error. This combination of "fixed" and 
"random" effects makes up the "mixed" effects used in the models. By describing 
these fixed effects, the relationships among the PK parameters and participant 
clinical attributes may be determined. Model development will be performed in 3 
steps, as described by Mandema, et al. (93), with oversight by Dr. Edmund 
Capparelli of the UCSD Pharmacology Laboratory.  
 
Typical concentration-time profiles for each drug will be constructed with Monte 
Carlo simulations of study participants and the final population model, parameters 
and variability. Final parameter estimates and simulations will be compared within 
participants and/or with those from non-pregnant adult populations. 
 
9.325 Statistical approach - See Section 8.0 
 
9.326 Anticipated Outcomes - The data from this study will describe maternal ARV PK 
assessments during and after pregnancy, after starting hormonal contraception 
postpartum, and in the context of TB drugs. Pharmacokinetic parameters during 
pregnancy will be compared to a) historical PK data from non-pregnant adults and b) PK 
data from the same women in these cohorts during the postpartum period. If significantly 
low ARV drug exposure is observed among participants antepartum, these results will be 

 
IMPAACT P1026s Version 10.0  
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reported to the principal investigator of that study site, and if a dosing modification for 
that participant is acted upon, the IMPAACT laboratory will offer post-dosing change PK 
assessments. Such participants will be excluded from the antenatal/postpartum ARV 
comparisons. Based upon comparative data assessments dosing modifications for future 
research studies may be recommended.  
 
The study will also compare antiretroviral and TB drug concentrations of cord blood with 
maternal plasma at delivery and describe the pharmacokinetics of washout elimination of 
transplacentally acquired drugs. 
 
The ratio of unbound to total drug concentrations for selected highly bound ARVs will be 
compared to assess the impact of pregnancy on protein binding. 
 
This study will provide data to compare ARV concentrations in genital tract secretions 
versus plasma in pregnant HIV-infected women. These data should advance our 
knowledge on drug penetration into the female genital tract during pregnancy. 
 
 
10.0 
 
DATA COLLECTION REQUIREMENTS  
 
Note:  For Infants see Appendix II for data collection requirements.  
 
Maternal Medications History: 
 
Prophylaxis and/or treatment of HIV related complications, TB treatment, blood products and 
transfusions, antibiotics, hormonal contraceptives, and other prescription medications are to be recorded 
on the CRFs. Over the counter medications or nutritional and herbal supplements, with the exception of 
prenatal vitamins, should not be recorded. Labor and delivery anesthesia/epidurals and other prescription 
medications given in the intrapartum/postpartum period are to be recorded on the CRFs. Over the counter 
medications given in the intrapartum/postpartum period should not be recorded.  
 
At Entry, all current ARV medications as well as any ARV medications received in the 12 months prior 
to the estimated date of confinement are to be recorded on the CRFs. After study entry, all modifications 
to ARV medications including treatment initiations, modifications, and permanent discontinuation of 
treatment are to be recorded on the CRFs at each visit including antiretroviral medications given in the 
intrapartum period. 
 
Medications that meet the above criteria are to be recorded on CRFs, based on the study arm the 
participant is enrolled, as follows: 
 
• 
HIV-infected pregnant women: At Entry, all medications including ARVs taken during the current 
pregnancy must be recorded. For women on TB treatment, a complete history of TB medications 
taken during the current pregnancy must be recorded. After entry, medications taken since the last 
study visit are to be recorded on the CRFs.  
• 
HIV-uninfected pregnant women on no ARV medications with tuberculosis treatment: At Entry, all 
medications taken during the current pregnancy including a complete history of TB medications must 
be recorded. After entry, medications taken since the last study visit are to be recorded on the CRFs.  
• 
HIV-infected postpartum women on ARV medications and hormonal contraceptives: At Entry, all 
medications that have been taken or administered within 30 days prior to registration to the protocol 
must be recorded. After entry, medications taken since the last study visit are to be recorded on the 
CRFs.  

 
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Maternal Signs and Symptoms:  
 
All ≥Grade 3 nausea, constipation, headache, fatigue, reflux/heartburn must be recorded on the CRFs. In 
addition, all* other ≥ Grade 2 events should be recorded. History of hypertension and proteinuria of 
≥Grade 2, during the current pregnancy, should be recorded on the CRFs for all occurrences prior to 20 
weeks gestation. After 20 weeks gestation, record only if it is clear that the diagnosis of preeclampsia has 
been excluded. If the complete date of sign/symptom is not known, then the date should be estimated 
according to date conventions.  
 
*Note:  It is not necessary to record signs and symptoms that are associated with a diagnosis that has been 
recorded on the Diagnoses CRF. All Grade 3 or 4 events and deaths, and any events that met EAE 
reporting requirements or lead to a change in the treatment for which they are on this study, must be 
further evaluated on the study Event Evaluation Form. 
 
Signs and symptoms that meet the above criteria are to be recorded on the CRFs, based on the study arm 
the participant is enrolled, as follows:  
 
• 
HIV-Infected pregnant women on DRV/r and LPV/r: In addition to other sign and symptom history, 
history of headache, abdominal pain, nausea, diarrhea and other gastrointestinal symptoms ≥ Grade 2 
are to be recorded on the CRFs. 
• 
HIV-infected pregnant women: At Entry, signs and symptoms during the current pregnancy are to be 
recorded on the CRFs. After entry, all signs and symptoms identified since the last visit are to be 
recorded on the CRFs.  
• 
HIV-uninfected pregnant women on no ARV medications with tuberculosis treatment: At Entry, signs 
and symptoms during the current pregnancy are to be recorded on the CRFs. After entry, all signs and 
symptoms identified since the last study visit are to be recorded on the CRFs.   
• 
HIV-infected postpartum women on ARV medications and hormonal contraceptives: At Entry, signs 
and symptoms within 30 days prior to registration to the protocol are to be recorded on the CRFs. 
After entry, all signs and symptoms identified since the last study visit are to be recorded on the 
CRFs.   
 
Diagnosis History:  
• 
HIV-infected pregnant women:  At Entry, a history of any ongoing major HIV related diagnoses and 
lifetime history of major obstetrical related diagnoses, including diagnoses during the current 
pregnancy are to be recorded on the CRFs. After entry, all diagnoses, based on the current Diagnoses 
Appendix (available at fstrf.org), and identified since the last visit are to be recorded on the CRFs.  
• 
Pregnant women receiving tuberculosis treatment:  At Entry, a history of any ongoing major TB 
related diagnoses and lifetime history of major obstetrical related diagnoses including during the 
current pregnancy are to be recorded on the CRFs. After entry,  all diagnoses, based on the current 
Diagnoses Appendix (available at fstrf.org), and identified since the last visit are to be recorded on 
the CRFs   
• 
HIV-infected postpartum women on ARV medications and hormonal contraceptives: At Entry, HIV 
related and obstetrical related diagnosis within 30 days prior to registration to the protocol are to be 
recorded on the CRFs. After entry, all diagnoses based on the current Diagnoses Appendix (available 
at fstrf.org), and identified since the last visit are to be recorded on the CRFs.  
 
 
 
 
 

 
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Hematology and Chemistry history in addition to protocol-required labs listed in Appendix I-A through I-
D and I-AMR:  
 
• 
HIV-infected pregnant women:  
 
Hematology:  All ≥Grade 2 results for CBC with differential and platelets; first and last test results at each 
reportable grade and first normal result afterwards are to be recorded on the CRFs. All HIV-1 RNA 
results and Lymphocyte subsets during the current pregnancy and postpartum are to be recorded on the 
CRFs.  
 
Chemistries: All ≥Grade 2 results for AST, ALT, albumin, BUN, creatinine, and total bilirubin during the 
current pregnancy are to be recorded on CRFs, including during postpartum follow up.  
 
• 
HIV-uninfected pregnant women on no ARV medications with tuberculosis treatment:  
 
Hematology: All ≥Grade 2 results for CBC with differential and platelets; first and last test results at each 
reportable grade and first normal result afterwards.   
 
Chemistries: All ≥Grade 2 during the current pregnancy are to be recorded on CRFs, including during 
postpartum follow up. After delivery, all ≥Grade 2 results for AST, ALT, and lactate are to be recorded 
on the CRFs.  
 
• 
HIV-infected postpartum women on ARV medications and hormonal contraceptives:  
 
Hematology:  All ≥Grade 2 results for CBC with differential and platelets, first and last test results at each 
reportable grade and first normal result afterwards.   
 
Chemistries: All ≥Grade 2 results for AST, ALT, and lactate are to be recorded on the CRFs. At entry, 
results obtained within 30 days prior to registration to the protocol are to be recorded on the CRFs. After 
entry, all results since the last study visit are to be recorded on the CRFs.  
 
 
11.0 
 
HUMAN SUBJECTS  
 
The Division of AIDS has concluded that this protocol does NOT meet Federal requirements governing 
prisoner participation in clinical trials and should NOT be considered by local IRBs for the recruitment of 
prisoners. 
 
11.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol, the informed consent documents (Appendices VI-A through VI-D), and any subsequent 
modifications must be reviewed and approved by the IRB or Ethics Committee (EC) responsible for 
oversight of the study. The mother must give written informed consent for her participation in the study 
and for that of her infant.  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 
mother. 
 
Each site which receives US HHS funding and follows the United States 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 subjects and determines when a study subject must have a consent process which involves a 

 
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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 
resigns the consent. The plan should follow all IRB, local, and state guidelines. Confirmation of such a 
plan at a site should be placed in the site’s regulatory file where it is available for review by site monitors. 
 
11.2 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified only by a coded 
number to maintain subject confidentiality. All records will be kept in a secured area. All computer entry 
and networking programs will be done with coded numbers only. Clinical information will not be 
released without written permission of the subject, except as necessary, for monitoring by the FDA, 
OHRP, the NIAID, or the local or national IRB or Ethics Committee. 
 
11.3 
Study Discontinuation 
 
The study may be discontinued at any time by the NIAID, the FDA, the IRB or EC, or other 
governmental agencies as part of their duties to ensure that research participants are protected. 
 
 
12.0 
 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by IMPAACT policies.    
 
 
13.0 
 
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) as well as specific requirements of the host country 
for specific instructions required for ground transportation within that country. 

 
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14.0 
 
REFERENCES 
 
1. Odagiri E, Ishiwatari N, Abe Y, Jibiki K, Adachi T, Demura R, et al. Hypercortisolism and the 
resistance to dexamethasone suppression during gestation. Endocrinologia japonica. 1988;35(5):685-
90. 
2. Schmucker DL, O'Mahony MS, Vesell ES. Women in clinical drug trials. An update. Clin 
Pharmacokinet. 1994;27(6):411-7. 
3. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. 
Drugs. 1995;50(2):222-39. 
4. Gleiter CH, Gundert-Remy U. Gender differences in pharmacokinetics. EurJ Drug Metab 
Pharmacokinet. 1996;21(2):123-8. 
5. Emini EA. Resistance to anti-human immunodeficiency virus therapeutic agents. AdvExpMedBiol. 
1995;390:187-95. 
6. Vanhove GF, Schapiro JM, Winters MA, Merigan TC, Blaschke TF. Patient compliance and drug 
failure in protease inhibitor monotherapy. Jama. 1996;276(24):1955-6. 
7. Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. 
Pharmacotherapy. 1999;19(6):708-12. 
8. Simone C, Derewlany LO, Koren G. Drug transfer across the placenta. Considerations in treatment 
and research. Clin Perinatol. 1994;21(3):463-81. 
9. Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet. 
1995;28(3):235-69. 
10. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 
1997;62(4):400-7. 
11. Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450-mediated metabolism of the 
HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther. 
1996;277(1):423-31. 
12. Lee PC, Werlin SL. The induction of hepatic cytochrome P450 3A in rats: effects of age. Proc Soc Exp 
Biol Med. 1995;210(2):134-9. 
13. O'Sullivan MJ, Boyer PJ, Scott GB, Parks WP, Weller S, Blum MR, et al. The pharmacokinetics and 
safety of zidovudine in the third trimester of pregnancy for women infected with human 
immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials 
group study (protocol 082). Zidovudine Collaborative Working Group. AmJObstetGynecol. 
1993;168(5):1510-6. 
14. Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, van Leeuwen R, et al. Pharmacokinetics and 
antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human 
immunodeficiency virus type 1-infected pregnant women and their offspring. The Journal of infectious 
diseases. 1998;178(5):1327-33. 
15. Best BM, Mirochnick M, Capparelli EV, Stek A, Burchett SK, Holland DT, et al. Impact of pregnancy 
on abacavir pharmacokinetics. AIDS. 2006;20(4):553-60. 
16. Best B, Stek A, Hu C, Burchett S, Rossi SS, Smith E, et al. High-dose Lopinavir and Standard-dose 
Emtricitabine Pharmacokinetics during Pregnancy and Postpartum. 15th Conference on Retroviruses 
and Opportunistic Infections; Boston, Massachusetts, 2008. 2008. 
17. Best B, Burchett S, Li H, Stek A, Hu C, Wang J, et al. Pharmacokinetics of Tenofovir During 
Pregnancy and Postpartum. HIV Medicine.Submitted for publication. 
18. Zolopa A, Ortiz R, Sax P, Brar I, Elion R, Wang H, et al., editors. Comparative study of tenofovir 
alafenamide vs tenofovir disoproxil fumarate, each with elvitegravir, cobicistat, and emtricitabine, for 
HIV treatment. 20th Conference on Retroviruses and Opportunistic Infections Paper; 2013. 
19. Capparelli EV, Aweeka F, Hitti J, Stek A, Hu C, Burchett SK, et al. Chronic administration of 
nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. 2008;9(4):214-20. 
20. World Health O. Programmatic update: Use of antiretroviral drugs for treating pregnant women and 
preventing HIV infection in infants. Executive Summary April 2012. 2012. 

 
IMPAACT P1026s Version 10.0  
             Page 56 of 107                                        2 February 2016  
 
 
 
21. Department of H, Human S. Public Health Service Task Force recommendations for use of 
antiretroviral drugs in pregnant HIV infected women for maternal health and interventions to reduce 
perinatal HIV transmission in the United States. July 8, 2008. 2008. 
22. Mirochnick M, Stek A, Capparelli E, Best B, Rossi SS, Burchett SK, et al. Atazanavir 
pharmacokinetics with and without tenofovir during pregnancy. The 16th Conference on Retroviruses 
and Opportunistic Infections, Montreal, Canada, February, 2009. 2009. 
23. Stek AM, Mirochnick M, Capparelli E, Best BM, Hu C, Burchett SK, et al. Reduced lopinavir 
exposure during pregnancy. AIDS. 2006;20(15):1931-9. 
24. Read JS, Best BM, Stek AM, Hu C, Capparelli EV, Holland DT, et al. Pharmacokinetics of new 625 
mg nelfinavir formulation during pregnancy and postpartum. HIV Med. 2008;9(10):875-82. 
25. Caparelli E, Best B, Stek A, Rossi S, Burchett S, Kreitchmann Rea, editors. Pharmacokinetics of 
Darunavir Once or Twice Daily During Pregnancy and Postpartum. 3rd International Workshop on 
HIV Pediatrics, Rome, Italy, July 15 - 16, 2011; 2011. 
26. Acosta EP, Bardeguez A, Zorrilla CD, Van Dyke R, Hughes MD, Huang S, et al. Pharmacokinetics of 
saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women. 
Antimicrobial agents and chemotherapy. 2004;48(2):430-6. 
27. Cressey TR, Best BM, Achalapong J, Stek A, Wang J, Chotivanich N, et al. Reduced indinavir 
exposure during pregnancy. British journal of clinical pharmacology. 2013;76(3):475-83. 
28. Capparelli E, Stek A, Best B, Rossi S, Burchett S, Li Hea, editors. Boosted FosAmprenavir 
Pharmacokinetics During Pregnancy. The 17th Conference on Retroviruses and Opportunistic 
Infections; 2010 February; San Francisco. 
29. Mirochnick M, Best BM, Stek AM, Capparelli E, Hu C, Burchett SK, et al. Lopinavir exposure with 
an increased dose during pregnancy. Journal of acquired immune deficiency syndromes (1999). 
2008;49(5):485-91. 
30. Mirochnick M, Stek A, Capparelli E, et.al. Lopinavir exposure with a higher dose during the 3rd 
trimester of pregnancy. 13th Conference on Retroviruses and Opportunistic Infections;. 2006. 
31. Watts DH SA, Best B, Wang J, Capparelli E, Cressey T, Aweeka F, Lizak P, Kreitchmann R, Burchett 
SK, Shapiro D, Hawkins E, Smith E, Mirochnick M. Raltegravir Pharmacokinetics during Pregnancy. 
JAIDS.Submitted for publication. 
32. Centers for Disease C, Prevention. Managing Drug Interactions in the Treatment of HIV-Related 
Tuberculosis. 2007. 
33. Kwara A, Ramachandran G, Swaminathan S. Dose adjustment of the non-nucleoside reverse 
transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not 
fit all. Expert Opin Drug Metab Toxicol. 2010;6(1):55-68. 
34. Kwara A, Lartey M, Sagoe KW, Xexemeku F, Kenu E, Oliver-Commey J, et al. Pharmacokinetics of 
efavirenz when co-administered with rifampin in TB/HIV co-infected patients: pharmacogenetic effect 
of CYP2B6 variation. J ClinPharmacol. 2008;48(9):1032-40. 
35. WHO. Global Tuberculosis Report 2013 Geneva, Switzerland: World Health Organization; 2013. 
36. Nemutlu E, Kir S, Eroglu H, Katlan D, Ozek A, Ozyuncu O, et al. Comparison of pharmacokinetic 
profiles of moxifloxacin in Caesarean versus non-pregnant sectioned women by fully validated HPLC 
with fluorescence detection. Comb Chem High Throughput Screen. 2010;13(6):502-9. 
37. Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, Sfikakis P. Pharmacokinetics of 
three newer quinolones in pregnant and lactating women. Am J Med. 1989;87(5A):49S-51S. 
38. Ozyuncu O, Beksac MS, Nemutlu E, Katlan D, Kir S. Maternal blood and amniotic fluid levels of 
moxifloxacin, levofloxacin and cefixime. J Obstet Gynaecol Res. 2010;36(3):484-7. 
39. Flores-Mercado F, Garcia-Mercado JL, Estopier-Jauregui C, Galindo-Hernandez E, Diaz-Gonzales C. 
Clinical pharmacology of amikacin sulphate: blood, urinary and tissue concentrations in the terminal 
stage of pregnancy. J Int Med Res. 1977;5(4):292-4. 
40. Coyne KM, Pozniak AL, Lamorde M, Boffito M. Pharmacology of second-line antituberculosis drugs 
and potential for interactions with antiretroviral agents. AIDS. 2009;23(4):437-46. 

 
IMPAACT P1026s Version 10.0  
             Page 57 of 107                                        2 February 2016  
 
 
 
41. de Kock L, Sy SK, Rosenkranz B, Diacon AH, Prescott K, Hernandez KR, et al. Pharmacokinetics of 
para-aminosalicylic acid in HIV-uninfected and HIV-coinfected tuberculosis patients receiving 
antiretroviral therapy, managed for multidrug-resistant and extensively drug-resistant tuberculosis. 
Antimicrob Agents Chemother. 2014;58(10):6242-50. 
42. Dooley KE, Park JG, Swindells S, Allen R, Haas DW, Cramer Y, et al. Safety, tolerability, and 
pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in 
healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr. 
2012;59(5):455-62. 
43. Svensson EM, Dooley KE, Karlsson MO. Impact of lopinavir-ritonavir or nevirapine on bedaquiline 
exposures and potential implications for patients with tuberculosis-HIV coinfection. Antimicrob 
Agents Chemother. 2014;58(11):6406-12. 
44. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis EMERGENCY 
UPDATE 2008 2008 [cited 2013 01/03/2013]. Available from: 
whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf. 
45. Kropp R, Jungbluth H, Radenbach KL. Influence of capreomycin on renal function. (Preliminary 
results). Antibiot Chemother. 1970;16:59-68. 
46. Garfield JW, Jones JM, Cohen NL, Daly JF, McClement JH. The auditory, vestibular and renal effects 
of capreomycin in humans. Annals of the New York Academy of Sciences. 1966;135(2):1039-46. 
47. El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of hormonal 
contraceptives. EurJ ContraceptReprodHealth Care. 2008;13(2):123-32. 
48. Curtis KM, Tepper NK, Marchbanks PA. Putting risk into perspective: The US medical eligibility 
criteria for contraceptive use. RevEndocrMetab Disord. 2011. 
49. Bennink HJ. The pharmacokinetics and pharmacodynamics of Implanon, a single-rod etonogestrel 
contraceptive implant. EurJ ContraceptReprodHealth Care. 2000;5 Suppl 2:12-20. 
50. Huber J, Wenzl R. Pharmacokinetics of Implanon. An integrated analysis. Contraception. 1998;58(6 
Suppl):85S-90S. 
51. Graesslin O, Korver T. The contraceptive efficacy of Implanon: a review of clinical trials and 
marketing experience. EurJ ContraceptReprodHealth Care. 2008;13 Suppl 1:4-12. 
52. Darney P, Patel A, Rosen K, Shapiro LS, Kaunitz AM. Safety and efficacy of a single-rod etonogestrel 
implant (Implanon): results from 11 international clinical trials. FertilSteril. 2009;91(5):1646-53. 
53. Harrison-Woolrych M, Hill R. Unintended pregnancies with the etonogestrel implant (Implanon): a 
case series from postmarketing experience in Australia. Contraception. 2005;71(4):306-8. 
54. Kreitchmann R, Innocenti AP, Preussler GMI. Safety and efficacy of contraceptive implants 
(Implanon) in HIV infected women. 6th IAS Conference on HIV Pathogenesis, Treatment and 
PreventionRome, 2011. 2011. 
55. Abbot L. Lopinavir and ritonavir prescribing information, 2011. Accessed on May 23, 2011 2011. 
Available from: http://rxabbott.com/pdf/kaletratabpi.pdf. 
56. Kearney BP, Isaacson E, Sayre J, Cheng AK, editors. Tenofovir DF and oral contraceptives: lack of a 
pharmacokinetic drug interaction In: Program and abstracts for the 43rd Interscience Conference on 
Antimicrobial Agents and Chemotherapy, Chicago, IL, September 14-17, 2003.Washington, DC: 
American Society for Microbiology; 2003.2003. 
57. Zhang J, Chung E, Yones C, Persson A, Mahnke L, Eley T, et al. The effect of atazanavir/ritonavir on 
the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy 
women. AntivirTher. 2011;16(2):157-64. 
58. Matiluko AA, Soundararjan L, Hogston P. Early contraceptive failure of Implanon in an HIV-
seropositive patient on triple antiretroviral therapy with zidovudine, lamivudine and efavirenz. J Fam 
Plann Reprod Health Care. 2007;33(4):277-8. 
59. Lakhi N, Govind A. Implanon failure in patients on antiretroviral medication: the importance of 
disclosure: J Fam Plann Reprod Health Care. 2010 Jul;36(3):181-2. doi: 
10.1783/147118910791749164. 

 
IMPAACT P1026s Version 10.0  
             Page 58 of 107                                        2 February 2016  
 
 
 
60. Leticee N, Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of etonogestrel 
implant in patients treated with antiretrovirals including efavirenz. Contraception. 2012;85(4):425-7. 
61. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle 
implant for women living with HIV in a resource-limited setting: concerns for drug interactions 
leading to unintended pregnancies. Aids. 2014;28(5):791-3. 
62. Carten ML, Kiser JJ, Kwara A, Mawhinney S, Cu-Uvin S. Pharmacokinetic interactions between the 
hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol. 
2012;137192(10):28. 
63. Sevinsky H, Eley T, Persson A, Garner D, Yones C, Nettles R, et al. The effect of efavirenz on the 
pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy 
HIV-negative women. Antivir Ther. 2011;16(2):149-56. 
64. John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A, et al. Correlates 
of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with 
maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. JInfectDis. 
2001;183(2):206-12. 
65. 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(1):E5. 
66. 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 InfectDis. 2003;187(3):375-84. 
67. Vernazza PL, Eron JJ, Fiscus SA, Cohen MS. Sexual transmission of HIV: infectiousness and 
prevention. AIDS. 1999;13(2):155-66. 
68. 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(15):2169-76. 
69. 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 TransmInfect. 2008;84(3):167-70. 
70. 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. EurJ ClinMicrobiolInfectDis. 
2004;23(2):111-5. 
71. 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(9293):1593-601. 
72. 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. EurJ ClinMicrobiolInfectDis. 
2001;20(2):91-6. 
73. 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 
AcquirImmuneDeficSyndr. 2006;42(5):584-7. 
74. 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 AcquirImmuneDeficSyndr. 2007;44(1):38-42. 
75. Si-Mohamed A, Kazatchkine MD, Heard I, Goujon C, Prazuck T, Aymard G, et al. Selection of drug-
resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women 
receiving antiretroviral therapy. J InfectDis. 2000;182(1):112-22. 
76. Launay O, Tod M, Louchahi K, Belarbi L, Bouchaud O, Memain N, et al. Differential diffusions of 
indinavir and lopinavir in genital secretions of human immunodeficiency virus-infected women. 
AntimicrobAgents Chemother. 2004;48(2):632-4. 

 
IMPAACT P1026s Version 10.0  
             Page 59 of 107                                        2 February 2016  
 
 
 
77. Dumond JB, Yeh RF, Patterson KB, Corbett AH, Jung BH, Rezk NL, et al. Antiretroviral drug 
exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS. 
2007;21(14):1899-907. 
78. Min SS, Corbett AH, Rezk N, Cu-Uvin S, Fiscus SA, Petch L, et al. Protease inhibitor and 
nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected 
women. J AcquirImmuneDeficSyndr. 2004;37(5):1577-80. 
79. Kwara A, Delong A, Rezk N, Hogan J, Burtwell H, Chapman S, et al. Antiretroviral drug 
concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly 
active antiretroviral therapy. ClinInfectDis. 2008;46(5):719-25. 
80. Yeh RF, Rezk NL, Kashuba AD, Dumond JB, Tappouni HL, Tien HC, et al. Genital tract, cord blood, 
and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human 
immunodeficiency virus type 1-infected women. AntimicrobAgents Chemother. 2009;53(6):2367-74. 
81. Burger D, van dHI, la PC, van der EM, Groeneveld P, Richter C, et al. Interpatient variability in the 
pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of 
gender, race, and CYP2B6 polymorphism. BrJ ClinPharmacol. 2006;61(2):148-54. 
82. Saitoh A, Fletcher CV, Brundage R, Alvero C, Fenton T, Hsia K, et al. Efavirenz pharmacokinetics in 
HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J 
AcquirImmuneDeficSyndr. 2007;45(3):280-5. 
83. Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbe L, et al. Pharmacogenetics of 
long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids 
Clinical Trials Group Study. J InfectDis. 2005;192(11):1931-42. 
84. Arab-Alameddine M, Di IJ, Buclin T, Rotger M, Lubomirov R, Cavassini M, et al. Pharmacogenetics-
based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. 
ClinPharmacolTher. 2009;85(5):485-94. 
85. Scholler-Gyure M, Kakuda TN, Raoof A, De SG, Hoetelmans RM. Clinical pharmacokinetics and 
pharmacodynamics of etravirine. ClinPharmacokinet. 2009;48(9):561-74. 
86. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical 
impact. Drug Metab Rev. 2009;41(2):89-295. 
87. Siccardi M, D'Avolio A, Baietto L, Gibbons S, Sciandra M, Colucci D, et al. Association of a single-
nucleotide polymorphism in the pregnane X receptor (PXR 63396C-->T) with reduced concentrations 
of unboosted atazanavir. ClinInfectDis. 2008;47(9):1222-5. 
88. Schipani A, Siccardi M, D'Avolio A, Baietto L, Simiele M, Bonora S, et al. Population 
pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism 
and unboosted atazanavir clearance. AntimicrobAgents Chemother. 2010;54(12):5242-50. 
89. Anderson PL, Aquilante CL, Gardner EM, Predhomme J, McDaneld P, Bushman LR, et al. Atazanavir 
pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors. J 
AntimicrobChemother. 2009;64(5):1071-9. 
90. Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D, et al. HIV protease inhibitors 
are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are 
influenced by SLCO1B1 polymorphisms. PharmacogenetGenomics. 2010;20(2):112-20. 
91. Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, et al. Genetic polymorphisms of NAT2 and 
CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with 
pulmonary tuberculosis. Tuberculosis(Edinb). 2007;87(6):551-6. 
92. Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC, Altan AM, et al. Nevirapine-induced 
hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique. 
Pharmacogenomics. 2010;11(1):23-31. 
93. Mandema JW, Verotta D, Sheiner LB. Building population pharmacokinetic--pharmacodynamic 
models. I. Models for covariate effects. J PharmacokinetBiopharm. 1992;20(5):511-28. 
 

 
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TABLE A 
GUIDELINES FOR USING SCHEDULE OF EVALUATIONS AND SAMPLE INFORMED CONSENTS 
 
Participant criteria 
Regimen(s) being studied 
Use this Schedule of Evaluations 
Use this Consent Form 
HIV-infected pregnant women and 
their infants  
ARVs without TB Treatment  
Appendix I-A and I-AMR 
(Maternal) 
Appendix II (Infant) 
Appendix VI-A  
HIV-infected pregnant women and 
their infants  
ARVs with TB Treatment 
(First and Second Line TB 
Treatment) 
Appendix I-B and I-AMR 
(Maternal) 
Appendix II (Infant) 
Appendix VI-B  
HIV-uninfected pregnant women and 
their infants 
No ARVs with TB Treatment 
(First and Second Line TB 
Treatment) 
Appendix I-C (Maternal) 
Appendix II (Infant) 
Appendix VI-C 
HIV-infected postpartum women 
ARVs with Contraceptives 
Appendix I-D (Maternal) 
Appendix VI-D 
 

 
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APPENDIX I-A 
SCHEDULE OF EVALUATIONS FOR WOMEN ON ARV MEDICINES WITHOUT TUBERCULOSIS TREATMENT 
NOTE: ADDITIONAL CLINICAL MONITORING IS REQUIRED FOR WOMEN ON DRV/r.  SEE APPENDIX I-AMR FOR SPECIFIC REQUIREMENTS 
EVALUATION 
2nd Trimester 
(20-26 weeks)9 
3rd Trimester  
(30-38 weeks)9 
 
Delivery 
(+/- 4 days)14 
 
2-3 weeks 
Postpartum 
6-12 weeks 
Postpartum15 
ARMS16 
All 
All 
All 
DRV/r 
EFV, DTG, ELV/Cobi, 
DRV/Cobi, ATV/Cobi, 
TAF(all TAF arms)  
CLINICAL  
Informed Consent 
X 
X 
 
 
 
Documentation of HIV Infection1 
[3 mL] 
[3 mL] 
 
 
 
History/Concomitant Medicines2 
X 
X 
X 
X 
X 
Physical Exam3 
X 
X 
X 
X 
X 
Perinatal Adherence Questionnaire4 
X 
X 
 
X 
X 
Report to ARV Pregnancy Registry 
X 
 
X 
 
 
LABORATORY  
Albumin5 
5 mL 
5 mL 
 
5 mL 
5 mL 
BUN/creatinine/bilirubin5 
X 
X 
2.5 mL 
X 
X 
AST/ALT5 
X 
X 
2.5 mL 
X 
X 
Hgb5 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
Alpha-1 acid glycoprotein6 
X 
X 
 
X 
X 
IMMUNOLOGY 
CD4 cell count 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
VIROLOGY 
HIV RNA 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
Vaginal Swab7  
X 
X 
 
 
X 
PHARMACOLOGY  
Intensive PK sampling7,8  
17-19 mL9 
17-19 mL9 
 
17-19 mL 
17-19 mL 
Vaginal secretions7,10 
X 
X 
 
 
X 
PHARMACOGENETICS 
Genotyping7 
X11 
X11 
 
 
 
OTHER 
Cord Blood12 
 
 
X 
 
 
Maternal Delivery Sample13 
 
 
5 mL 
 
 
TOTAL BLOOD VOLUME 
30-35 mL 
30-35 mL 
18 mL 
30-32 mL 
30-32 mL 
 

 
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APPENDIX I-A FOOTNOTES 
 
1. If there is insufficient documentation of HIV status, as specified in Section 4.15, HIV diagnostic testing is to be done according to the protocol 
definition.  
2. See Section 10, Data Collection Requirements, for history requirements. 
3. Physical exam to include at a minimum weight, height (entry), vital signs, signs and symptoms and diagnoses.  
4. Administer on same days as intensive PK sampling. 
5. Draw at time of PK sampling in second and third trimesters and postpartum. BUN/creatinine/bilirubin and AST/ALT can be assayed from the albumin 
sample if drawn at the same time.  
6. Measured from PK sample; an extra tube is not required. 
7. See the Laboratory Processing Chart (LPC) on the P1026 Protocol Specific Webpage on the IMPAACT Website (http://www.impaactnetwork.org) for 
collection, processing and shipping instructions.  
8. See Appendix III for 12-hour or 24-hour sampling time points depending on the ARV drug evaluated.  
9. Entry may occur at the second or third trimester visit. The participant must be on the medicine of interest for at least 2 weeks prior to PK sampling. PK 
sampling visit should occur within 5 days after enrollment using the Subject Enrollment System. 
10. Collect vaginal secretions for drug levels at pre-dose, and 1, 2, and 4 hours after dosing for all drugs. 
11. Obtain at first PK evaluation. 
12. Draw immediately after the cord is clamped.  
13. Draw at the time the cord is clamped.  
14. Evaluations can be done four days prior to delivery through four days after delivery; day of delivery = day 0 for determining the target dates for 
postpartum evaluations.  
15. Abstract data from participants chart if available within the window for the visit.  
  

 
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APPENDIX I-B 
SCHEDULE OF EVALUATIONS FOR WOMEN ON ARV MEDICINES WITH TUBERCULOSIS TREATMENT 
NOTE:  ADDITIONAL CLINICAL MONITORING IS REQUIRED FOR WOMEN ON LPV/r. SEE APPENDIX I-AMR FOR SPECIFIC REQUIREMENTS. 
EVALUATION 
Second Trimester 
(20-26 weeks)8 
Third Trimester 
(30-38 weeks)8 
 
Delivery 
(+/- 4 days)13 
 
2-8 weeks 
Postpartum16 
ARMS 
ARVs with First or Second Line Tuberculosis Treatment 
CLINICAL 
Informed Consent 
X 
X 
 
 
Documentation of HIV Infection1 
[3 mL] 
[3 mL] 
 
 
History/Concomitant Medicines2 
X 
X 
X 
X 
Physical Exam2 
X 
X 
X 
X 
Perinatal Adherence Questionnaire3 
X 
X 
 
X 
Report to ARV Pregnancy Registry 
X 
 
X 
 
Audiology assessment14 
 
 
X 
LABORATORY 
Albumin4 
5 mL 
5 mL 
 
5 mL 
BUN/creatinine/bilirubin4 
X 
X 
2.5 mL 
X 
AST/ALT4 
X 
X 
2.5 mL 
X 
Hgb4 
1 mL 
1 mL 
1 mL 
1 mL 
Alpha-1 acid glycoprotein5 
X 
X 
 
X 
TSH/fT415 
6 mL 
6 mL 
 
6 mL 
IMMUNOLOGY 
CD4 cell count 
1 mL 
1 mL 
1 mL 
1 mL 
VIROLOGY 
HIV RNA 
6 mL 
6 mL 
6 mL 
6 mL 
PHARMACOLOGY 
Intensive PK Sampling6,7 
31-35 mL8 
31-35 mL8 
 
31-35 mL9 
PHARMACOGENETICS 
Genotyping6 
X10 
X10 
 
 
OTHER 
Cord Blood11 
 
 
X 
 
Maternal Delivery Sample12 
 
 
5 mL 
 
TOTAL BLOOD VOLUME 
44-57 mL 
44-57 mL 
18 mL 
13-54 mL 
 

 
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APPENDIX I-B FOOTNOTES 
 
1. If there is insufficient documentation of HIV status, as specified in Section 4.15, HIV diagnostic testing is to be done according to the protocol 
definition.  
2. Physical exam to include at a minimum weight, height (entry), vital signs, signs and symptoms and diagnoses. See Section 10, Data Collection 
Requirements, for history requirements. 
3. Administer on same days as intensive PK sampling. 
4. Draw at time of PK sampling in second and third trimesters and postpartum. BUN/creatinine/bilirubin and AST/ALT can be assayed from the albumin 
sample if drawn at the same time.  
5. Measured from PK sample; an extra tube is not required. 
6. See the Laboratory Processing Chart (LPC) on the P1026 Protocol Specific Webpage on the IMPAACT Website (http://www.impaactnetwork.org) for 
collection, processing and shipping instructions. 
7. See Appendix III for the number of samples and timing of specimens will vary depending on the ARV/TB drug being evaluated.  
8. Entry may occur at the second or third trimester visit. The participant must be on the medicine of interest for at least 2 weeks prior to PK sampling. PK 
sampling visit should occur within 5 days after enrollment using the Subject Enrollment System. 
9. Obtain PK sampling only if participant is still taking TB drugs. 
10. Obtain at first PK evaluation. 
11. Draw immediately after the cord is clamped. For this arm, collection of cord blood can be omitted if there are circumstances that prohibit collection 
(i.e. delivery at non-study facility, delivery during non-business hours). 
12. Draw at time the cord is clamped. For this arm, collection of maternal delivery sample can be omitted if there are circumstances that prohibit collection 
(i.e. delivery at non-study facility, delivery during non-business hours). 
13. Evaluations can be done four days prior to delivery through four days after delivery; day of delivery = day 0 for determining the target dates for 
postpartum evaluations.  
14. For participants treated with any injectable TB medication the audiology assessment can be from chart abstraction or otherwise can be performed at 
any time during follow-up; refer to the LPC for additional information. 
15. For participants treated with ethionamide and/or para-aminosalicylic acid.  Refer to the LPC for additional information; follow the assay requirements 
of your testing lab.   
16. Abstract data from participants chart if available within the window for the visit.  
 

 
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APPENDIX I-AMR 
ADDITIONAL MONITORING REQUIREMENTS FOR WOMEN ON DRV AND LPV 
 
NOTE:  THESE REQUIREMENTS ARE IN ADDITION TO THOSE SPECIFIED IN APPENDIX IA AND IB. ONLY PERFORM ONCE IN THE 
EVENT OF OVERLAP WITH APPENDIX I-A AND I-B. 
EVALUATION 
Antepartum 
2-3 weeks Postpartum 
 
Entry1 
From Entry to 30 
weeks gestation 
From 30 weeks 
gestation to delivery9 
 
CLINICAL 
History2 
X 
q4 weeks 
q2 weeks 
X 
Physical Exam3 
X 
q4 weeks 
q2 weeks 
X 
Targeted OB Exam (fundal height; fetal 
heart tones) 
X 
q4 weeks 
q2 weeks 
 
Electrocardiogram 
X4 
 
X5 
 
LABORATORY 
Chemistries6 
5 mL 
5 mL 
q4 weeks 
5 mL 
q4 weeks 
5 mL 
 
CBC7 
1 mL 
1 mL 
q4 weeks 
1 mL 
q4 weeks 
1 mL 
 
Gestational Diabetes Screening8 
 
X 
X 
 
TOTAL BLOOD VOLUME 
6 mL 
6 mL 
6 mL 
6 mL 
 
APPENDIX I-AMR FOOTNOTES 
1. Entry visit may occur on the same day as initial PK sampling. 
2. History will include assessment of headache, abdominal pain, nausea, diarrhea and other gastrointestinal symptoms ≥ Grade 2. 
3. Physical exam to include at a minimum weight, height (entry), vital signs, signs and symptoms and diagnoses. 
4. It is acceptable to do the EKG within +/- 2 weeks of entry. 
5. EKG should be done after 30 weeks gestation but prior to delivery. 
6. Chemistries will include ALT, AST, bilirubin, electrolytes, glucose, BUN, creatinine, pancreatic amylase. Lipase is required if pancreatic amylase is ≥ 
Grade 3. If pancreatic amylase is not available, use total amylase.   
7. CBC will include cell differential and platelet count. 
8. Diabetes screening must be done once while on increased dose DRV or LPV/r, between 24 weeks gestation and delivery. May obtain from chart 
abstraction. If not done as part of clinical care, perform gestational diabetes screening, typically using 1-hour 50 gram or 2-hour 75 gram glucose test, 
or using local standard of care test. If results are abnormal, follow-up as per local standard of care.  
 
Note: if diabetes or gestational diabetes diagnosis has already been made, do not perform above tests. 
9. Non-stress test and amniotic fluid index are recommended starting at 34 weeks gestation but are not reported.  
 

 
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APPENDIX I-C 
SCHEDULE OF EVALUATIONS FOR HIV-UNINFECTED WOMEN WITH TUBERCULOSIS TREATMENT 
 
EVALUATION 
Second Trimester 
(20-26 weeks)5 
Third Trimester 
(30-38 weeks)5 
Delivery 
(+/- 4 days)9  
 
2-8 weeks 
Postpartum11 
ARMS 
 
EMB, INH, PZA, RIF, or Second Line TB Treatment 
 
CLINICAL  
Informed Consent 
X 
X 
 
 
History/Concomitant Medicines1 
X 
X 
X 
X 
Physical Exam (weight)1  
X 
X 
X 
X 
Audiology assessment10 
 
 
X 
LABORATORY  
Albumin2 
5 mL 
5 mL 
 
5 mL 
BUN/creatinine/bilirubin2 
X 
X 
2.5 mL 
X 
AST/ALT2 
X 
X 
2.5 mL 
X 
Hgb2 
1 mL 
1 mL 
1 mL 
1 mL 
Alpha-1 acid glycoprotein3 
X 
X 
 
X 
TSH/fT412 
6 mL 
6 mL 
 
6 mL 
PHARMACOLOGY 4 
Intensive PK sampling5  
17 mL6 
17 mL6 
 
17  mL7 
PHARMACOGENETICS4 
 
 
 
 
Genotyping 
X8 
X8 
 
 
TOTAL BLOOD VOLUME 
23-29 mL 
23-29 mL 
6 mL 
6-29 mL 
 

 
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APPENDIX I-C FOOTNOTES 
  
1. Physical exam to include at a minimum weight, height (entry), vital signs, signs and symptoms and diagnoses. See Section 10, Data Collection 
Requirements, for history requirements. 
2. Draw at time of PK sampling in second and third trimesters and postpartum. BUN/creatinine/bilirubin and AST/ALT can be assayed from the albumin 
sample if drawn at the same time. 
3. Measured from PK sample; an extra tube is not required. 
4. See the Laboratory Processing Chart (LPC) on the P1026 Protocol Specific Webpage on the IMPAACT Website (http://www.impaactnetwork.org) for 
collection, processing and shipping instructions. 
5. See Appendix III for 12-hour sampling time points; collect at pre-dose, and at 1, 2, 4, 6, 8, and 12 hours post-dose. 
6. Entry may occur at the second or third trimester visit. The participant must be on the medicine of interest for at least 2 weeks prior to PK sampling. PK 
sampling visit should occur within 5 days after enrollment using the Subject Enrollment System. 
7. Obtain PK sampling only if participant is still taking TB drugs. 
8. Obtain at first PK evaluation. 
9. Evaluations can be done four days prior to delivery through four days after delivery; day of delivery = day 0 for determining the target dates for 
postpartum evaluations.  
10. For participants treated with any injectable TB medication the audiology assessment can be from chart abstraction or otherwise can be performed at 
any time during follow-up; refer to the LPC for additional information. 
11. Abstract data from participants chart if available within the window for the visit. 
12. For participants treated with ethionamide and/or para-aminosalicylic acid.  Refer to the LPC for additional information; follow the assay requirements 
of your testing lab.   

 
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APPENDIX I-D 
SCHEDULE OF EVALUATIONS FOR POSTPARTUM WOMEN ON ARV MEDICINES AND HORMONAL CONTRACEPTIVES 
 
EVALUATION 
2-12 weeks 
Postpartum12 
6-7 weeks after Contraceptive 
Initiation13 
ARMS 
 
EFV or DRV/COBISISTAT or ATV/COBISISTAT WITH ETHINYL ESTRADIOL 
or ETONOGESTREL IMPLANT 
 
CLINICAL 
Informed Consent 
X 
 
Documentation of HIV Infection1 
[3mL] 
 
History/Concomitant Medicines2 
X 
X 
Physical Exam (weight) 2 
X 
X 
Perinatal Adherence Questionnaire3 
X 
X 
LABORATORY 
Hematology4 
1 mL 
1 mL 
Chemistries5 
5 mL 
5 mL 
Pregnancy Test (serum or urine) 
 
X 
Alpha-1 acid glycoprotein6 
X 
X 
IMMUNOLOGY 
CD4 Cell Count 
1 mL 
1 mL 
VIROLOGY 
HIV RNA 
6 mL 
6mL 
PHARMACOLOGY7 
ARV Intensive PK sampling 8 
17-19 mL 
17-19 mL 
Contraceptive Intensive PK sampling (ethinyl 
estradiol and progestin)9   
 
[16 mL] 
Etonogestrel PK10 
 
[4 mL] 
Progesterone 
 
1 mL 
PHARMACOGENETICS7 
Genotyping 
X11 
 
TOTAL BLOOD VOLUME 
30-35 mL 
35 – 49 mL 
 

 
IMPAACT P1026s Version 10.0 
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APPENDIX I-D FOOTNOTES 
 
1. If there is insufficient documentation of HIV status, as specified in Section 4.15, HIV diagnostic testing is to be done according to the protocol 
definition.  
2. Physical exam to include at a minimum weight, height (entry), vital signs, signs and symptoms and diagnoses. See Section 10, Data Collection 
Requirements, for history requirements. 
3. Administer on same day as intensive PK sampling. 
4. Hematology includes CBC with cell differential and platelet count. 
5. Chemistries include ALT, AST, bilirubin, electrolytes, glucose, BUN, creatinine, total amylase. Lipase is required if total amylase is ≥ Grade 3. 
6. Measured from PK sample; an extra tube is not required. 
7. See the Laboratory Processing Chart (LPC) on the P1026 Protocol Specific  Webpage on the IMPAACT Website (http://www.impaactnetwork.org) 
for collection, processing and shipping instructions. 
8. See Appendix III for 12-hour or 24-hour sampling time points depending on ARV being evaluated.  
9. See Appendix III for 24-hour sampling time point. Collect 2 mL at pre-dose, 1, 2, 4, 6, 8, 12 and 24 hours post-dose only on women on oral 
contraceptives. 
10. Collect one 4mL sample only on women with etonogestrel implant. 
11. Obtain at first PK evaluation 
12. The participant must be on the ARV of interest for at least 2 weeks prior to the initial PK sampling and not using any hormonal contraceptive method 
during that time. PK sampling visit should occur within 5 days after enrollment using the Subject Enrollment System. 
13. ARVs and the combined oral contraceptives should be taken at the same time of day on the day of PK sampling and three days before PK sampling. 
 
 

 
IMPAACT P1026s Version 10.0  
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APPENDIX II 
SCHEDULE OF EVALUATIONS FOR INFANTS 
 
EVALUATION 
Birth8  
(through day 3 of 
life) 
 
5-9 days of life 
(infants undergoing 
washout PK only, see 
Section 4.4) 
 
16 – 24 weeks of  
life10 
CLINICAL  
 
Physical Exam1 
X 
X 
X 
HIV Infection Status2 
X 
X 
X 
History/Chart abstraction3 
X 
X 
X 
Audiology assessment9 
X 
PHARMACOLOGY4   
Washout PK Sampling Plasma  
2.25 mL5 
0.75 mL6 
 
Dried Blood Spot 
(for pharmacogenetics) 
 
0.25 mL7 
 
0.25 mL7 
 
 
TOTAL BLOOD VOLUME 
 
0 to 2.5 mL 
 
0 to 1 mL  
 
1. Physical exam should include measurement of length and weight. 
2. Record all HIV test results available. 
3. At birth, record the following results/events that are available since birth. After the birth visit, record 
all available results/events since the last visit. 
Infant feeding status, if available 
Hematology:  All ≥Grade 2 results for CBC with differential and platelets; first and last results at each 
reportable grade and first normal result afterwards. 
Chemistries:  All ≥Grade 2 results for glucose, AST, ALT for all infants. For HIV-infected infants, 
also record ≥Grade 2 electrolytes, BUN, creatinine, total and direct bilirubin, lipase, albumin, total 
protein, triglycerides, cholesterol, CPK, and amylase. 
Signs/Symptoms: All ≥Grade 1 neurologic events, and all other ≥Grade 2 events. 
Diagnoses: Any diagnoses as defined in the Diagnoses Appendix (which can be found at 
www.fstrf.org), including congenital anomalies and mitochondrial disorders.  
Note that all Grade 3 or 4 events and deaths, and all ≥Grade 1 neurologic events must be further 
evaluated on the study Event Evaluation Form. 
Record any concomitant prescription medicines since birth. After the birth visit, record any 
concomitant prescription medicines taken since the last visit. 
4. Collection of PK samples can be omitted, with approval of the protocol team, if there are 
circumstances that prohibit collection (i.e. delivery at non-study facility).  Only infants who meet the 
requirements for infant washout PK will undergo pharmacology evaluations; see protocol Section 4.4 
for infant requirements for washout PK sampling.  
5. Blood samples to be collected at 2-10, 18-28 and 36-72 hours after birth. See Laboratory Processing 
Chart (LPC) for collection, processing and shipping instructions.  
6. Single blood sample to be collected between 5 – 9 days of life. See Laboratory Processing Chart 
(LPC) for collection, processing and shipping instructions.  
7. For infants for which informed consent has been obtained for genetic testing:  Obtain once, at any 
collection, at either the Birth (through day 3 of life) Visit OR at the 5 - 9 days of life visit (if washout 

 
IMPAACT P1026s Version 10.0  
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PK to be collected). See Laboratory Processing Chart (LPC) for collection, processing and shipping 
instructions. 
8. Evaluations can be done from birth through day 3 of life; day of birth = day 0 
9. Only for infant of mothers treated with any injectable TB medication.  The audiology assessment can 
be from chart abstraction or otherwise can be performed at any time during follow-up; refer to the 
LPC for additional information. 
10. Abstract data from the participants chart if available within the window for the visit.  
 

 
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APPENDIX III 
MATERNAL INTENSIVE PK SAMPLING SCHEDULE FOR ARV MEDICINES, 
TUBERCULOSIS TREATMENT AND HORMONAL CONTRACEPTIVES 
 
REGIMEN(S) BEING 
STUDIED 
PHARMACOKINETIC (PK) SAMPLING SCHEDULE 
ARVS WITHOUT TB TREATMENT 
darunavir/ritonavir twice 
daily 
12 hour sampling during optional 2nd trimester, during 3rd trimester and 
6-12 weeks postpartum. If therapy begins prior to 30 weeks gestation, 
women will receive 600/100 mg b.i.d. or 800/100 mg b.i.d. or 900/100 
mg b.i.d. Dose may be adjusted based on results of optional individual 
2nd trimester sampling. Dose will be increased to 800/100 mg b.i.d. or 
900/100 mg b.i.d. at 30 weeks gestation regardless of 2nd trimester 
results. PK sampling will be done no sooner than two weeks after the 
dose increase. After delivery, 800/100 mg b.i.d. or 900/100 mg b.i.d. 
will continue until discharge from the hospital or 3 days postpartum 
whichever is earlier. Postpartum PK sampling will be done 2-3 weeks 
postpartum on 600/100 mg b.i.d. dose. 
dolutegravir  
 
 
 
 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum  
elvitegravir/cobicistat 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
darunavir/cobicistat 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
atazanavir/cobicistat 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
tenofovir alafenamide 
fumarate 25 mg q.d. without 
cobicistat or ritonavir  
 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
tenofovir alafenamide 
fumarate/ 10 mg q.d. with 
cobicistat 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
tenofovir alafenamide 
fumarate 10 mg q.d. with 
ritonavir 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
efavirenz 
24 hour sampling during optional 2nd trimester, during 3rd trimester  
and 6-12 weeks postpartum 
ARVs WITH TB TREATMENT 
efavirenz with TB drugs 
(ethambutol, isoniazid, 
pyrazinamide, rifampicin) 
24 hour sampling during 2nd trimester (if enrolled), during 3rd trimester 
and 2-8 weeks postpartum if still taking TB drugs.  
lopinavir/ritonavir with TB 
drugs (ethambutol, isoniazid, 
pyrazinamide, rifampicin)  
12 hour sampling during 2nd trimester (if enrolled), during 3rd trimester 
and 2-8 weeks postpartum if still taking TB drugs.   
kanamycin, amikacin, 
capreomycin, moxifloxacin, 
levofloxacin, bedaquiline, 
clofazamine, pretomanid, 
ofloxacin, ethionamide/ 
12 hour sampling during 2nd trimester (if enrolled), during 3rd trimester 
and 2-8 weeks postpartum if still taking TB drugs.   

 
IMPAACT P1026s Version 10.0  
  Page 73 of 107 
2 February 2016   
 
REGIMEN(S) BEING 
STUDIED 
PHARMACOKINETIC (PK) SAMPLING SCHEDULE 
prothionamide, 
terizidone/cycloserine, high 
dose INH, delamanid, 
linezolid, para-aminosalicylic 
acid  (PAS) 
NO ARVS WITH TB TREATMENT  
ethambutol, isoniazid, 
pyrazinamide, rifampicin 
12 hour sampling during 2nd trimester (if enrolled), during 3rd trimester 
and 2-8 weeks postpartum if still taking TB drugs.  
ARVS WITH CONTRACEPTIVES 
darunavir/cobicistat or 
atazanavir/cobicistat with 
ethinyl estradiol containing 
contraceptives 
24 hour sampling 2-12 weeks postpartum for ARVs and 24 hour 
sampling 6-7 weeks after contraceptive initiation for both ARVs and 
oral contraceptives 
darunavir/cobicistat or 
atazanavir/cobicistat with 
etonogestrel implant 
24 hour sampling 2-12 weeks postpartum for ARVs and 24 hour 
sampling 6-7 weeks after contraceptive initiation for ARVs and a 
single sample for etonogestrel implant PK. 
efavirenz with ethinyl 
estradiol containing 
contraceptives 
 24 hour sampling 2-12 weeks postpartum for ARVs and 24 hour 
sampling 6-7 weeks after contraceptive initiation for both ARVs and 
oral contraceptives 
atazanavir/ritonavir/tenofovir 
with ethinyl estradiol 
containing contraceptives 
24 hour sampling 2-12 weeks postpartum for ARVs and 24 hour 
sampling 6-7 weeks after contraceptive initiation for both ARVs and 
oral contraceptives 
 
12 hour sampling time points:  Pre-dose, and at 1, 2, 4, 6, 8 and 12 hours post-dose 
24 hour sampling time points:  Pre-dose, and at 1, 2, 4, 6, 8, 12, and 24 hours post-dose 
 
For women who are on multiple arms of  P1026s, doses of medicines should be administered at the same 
time OR additional samples must be drawn to complete the PK evaluation for EACH drug (i.e., samples 
need to be drawn at 1, 2, 4, etc. hours post-dose for each study drug if doses are staggered). In addition, 
single samples will be obtained at delivery from the mother and from the umbilical cord after being 
clamped. 
 

 
IMPAACT P1026s Version 10.0  
  Page 74 of 107 
2 February 2016   
 
APPENDIX IV 
DIETARY RECOMMENDATIONS FOR ANTIRETROVIRAL MEDICINES, TUBERCULOSIS 
MEDICINES AND HORMONAL CONTRACEPTIVES 
 
NRTIs 
• 
Tenofovir alafenamide fumarate (TAF): Take with food. 
 
PIS/COMBINATIONS 
• 
Darunavir/ritonavir twice daily:  Take with food to enhance bioavailability. Studied with meals 
ranging from 240 Kcal (12 grams of fat) to 928 Kcal (56 grams of fat). 
• 
Lopinavir/ritonavir (Alluvia®):  Take with a high fat meal to enhance bioavailability and minimize 
pharmacokinetic variability. (Studied with meals of ~850 Kcal, ~55% from fat.) 
• 
Atazanavir/ritonavir/tenofovir:  For tenofovir, avoid high fat meals two hours before and two hours 
after taking dose. For atazanavir/ritonavir, take with a light meal to enhance bioavailability and 
minimize pharmacokinetic variability. Take at least two hours before or one hour after administration 
of an antacid. 
• 
Atazanavir/cobicistat and darunavir/cobicistat: Take with food. 
 
NNRTIs 
• 
Efavirenz:  Take on an empty stomach (at least one hour before or two hours after a meal). 
 
Integrase Inhibitors 
• 
Dolutegravir: May be taken without regard to meals. 
• 
Elvitegravir/cobicistat: Take with food. 
 
First Line Tuberculosis Medicines: 
If a combination product is used, then it should be administered with food. If administered as separate 
medications: 
• 
Ethambutol: Take with food to minimize stomach upset if needed. 
• 
Isoniazid: Take on an empty stomach (at least one hour before or two hours after a meal) 
• 
Pyrazinamide: May be administered without regard to meals. 
• 
Rifampicin: Take on an empty stomach (at least one hour before or two hours after a meal). 
 
Second Line Tuberculosis Medicines: 
Second Line TB drugs can be given without regards for meals, with the exception of delamanid 
and bedaquiline which should be administered with meals. 
 
Hormonal Contraceptives: 
• 
May be taken without regard to meals. 

 
IMPAACT P1026s Version 10.0                                   Page 75 of 107 
  
 
 
2 February 2016   
 
APPENDIX V 
MATERNAL PHARMACOKINETIC PARAMETER TARGETS 
Current Open Study Arms: 
ARV Study Drug 
PK 
Parameter 
Non-pregnant 
Typical Value 
(mcg*hr/mL) 
Estimated 
10th percentile 
(mcg*hr/mL) 
Reference 
Atazanavir/cobicistat 
AUC0-24 
46.1 
28.4 
Evotaz™ [package insert] Princeton, NJ; Bristol-Myers Squibb 
Company; 2015. 
Darunavir/cobicistat 
AUC0-24 
100.6 
70.4* 
Tashima K, Crofoot G, Tomaka FL, Kakuda TN, Brochot A, 
Van de Casteele T, et al. Cobicistat-boosted darunavir in HIV-
1-infected adults: week 48 results of a Phase IIIb, open-label 
single-arm trial. AIDS Res Ther. 2014 Dec 1;11:39. 
Elvitegravir/cobicistat 
AUC0-24 
23 
16.1* 
Stribild™ [package insert]  Foster City, CA; Gilead Sciences; 
2013 
Darunavir/ritonavir twice 
daily (800/100 mg b.i.d.) 
AUC0-12 
62.3 
43.6* 
Prezista™ [package insert]  Titusville, NJ; Janssen; 2012 
Dolutegravir 
AUC0-24 
53.6 
37.5* 
Tivicay™ [package insert]  Research Triangle Park, NC; ViiV 
Healthcare; 2014 
Efavirenz 
AUC0-24 
58.1 
40 
SustivaTM [package insert] Princeton, NJ: Bristol-Myers Squibb 
Company; 2004. 
Lopinavir/ritonavir 
AUC0-12 
80 
52 
Murphy R, Brun S, Hicks C, Eron J, Gulick R, King M, et al. 
ABT-378/ritonavir plus stavudine and lamivudine for the 
treatment of antiretroviral-naïve adults with HIV-1 infection: 
48-week results. AIDS 2001;15: 1-9. 
Tenofovir alafenamide 
fumarate (TAF) without 
cobicistat or ritonavir 
AUC0-24 
 
 
To be updated once drug is FDA-approved. 
TAF/cobicistat 
AUC0-24 
 
 
To be updated once drug is FDA-approved. 
TAF/ritonavir 
AUC0-24 
 
 
To be updated once drug is FDA-approved. 
 
 
 

 
IMPAACT P1026s Version 10.0                                   Page 76 of 107 
  
 
 
2 February 2016   
 
TB Study Drug 
PK 
Parameter 
Minimum Cut-off Value 
Reference 
Ethambutol 
Cmax 
Once Daily: < 2 mcg/mL 
Thrice Weekly: < 4 mcg/mL 
Chideya S, et al. CID 2009;48:1685-94. Tappero JW, et al. CID 
2005;41:461-9. Peloquin CA. Drugs 2002;62(15):2169-83. 
Isoniazid 
Cmax 
Once Daily: < 3 mcg/mL 
Thrice Weekly: 8 mcg/mL 
Chideya S, et al. CID 2009;48:1685-94. Tappero JW, et al. CID 
2005;41:461-9. Peloquin CA. Drugs 2002;62(15):2169-83. 
Pyrazinamide 
Cmax 
Once Daily: < 20 mcg/mL 
Thrice Weekly: < 40 mcg/mL 
Chideya S, et al. CID 2009;48:1685-94. Tappero JW, et al. CID 
2005;41:461-9. Peloquin CA. Drugs 2002;62(15):2169-83. 
Rifampicin 
Cmax 
Once Daily or Thrice Weekly: < 8 
mcg/mL 
Chideya S, et al. CID 2009;48:1685-94. Tappero JW, et al. CID 
2005;41:461-9. Peloquin CA. Drugs 2002;62(15):2169-83. 
 
* There are inadequate data for this combination to estimate the 10th percentile. Therefore, a 30% reduction from typical exposure will be used as the minimal acceptable 
exposure. 
 
 

 
IMPAACT P1026s Version 10.0                                   Page 77 of 107 
  
 
 
2 February 2016   
 
Closed Study Arms: 
ARV Study Drug 
PK 
Parameter 
Non-pregnant 
Typical Value 
(mcg*hr/mL) 
Estimated 
10th percentile 
(mcg*hr/mL) 
Reference 
Abacavir 
AUC0-12 
5.8 
4.1 
McDowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose 
pharmacokinetics and pharmacodynamics of abacavir alone and in 
combination with zidovudine in HIV infected adults. Antimicrob Agents 
Chemother. 2000;44:2061-2067. 
Amprenavir 
AUC0-12 
23.9 
13.2 
Falloon J, Piscitelli S, Vogel S, Sadler B, Mitsuya H, Kavlick MF, et al. 
Combination therapy with amprenavir, abacavir, and efavirenz in human 
immunodeficiency virus (HIV)-infected patients failing a protease-
inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. 
Clin Infect Dis 2000;30:313-318. 
Atazanavir/ritonavir 
AUC0-24 
57 
29.4 
ReyatazTM [package insert] Princeton, NJ; BMS Virology; 2003. 
Darunavir/ritonavir once 
daily (800/100 mg. q.d.) 
AUC0-24 
87.854 
56.486 
Prezista™ [package insert] Titusville, NJ; Janssen, 2012 
Didanosine delayed 
release EC  
AUC0-24 
3.10 
2.04 
WangY, Livingston E, Patil S, McKinney RE, Bardeguez AD, Gandia J, 
O’Sullivan MJ, Clax P, Huang S, Unadkat JD. J Infect Dis 1999;180:1536-
41. 
Etravirine 
AU0-12 
4.2 
2.5 
Boffito M, Winston A, Jackson A, Fletcher C, Pozniak A, Nelson M, et al. 
Pharmacokinetics and antiretroviral response to darunavir/ritonavir and 
etravirine combination in patients with high-level resistance. AIDS 
2007;21:1449-1455. 
Fosamprenavir/ritonavir 
AUC0-12 
39.6 
27.7* 
LexivaTM [package insert] Cambridge, MA: Vertex Pharma; 2003  
Indinavir/ritonavir 
AUC0-12 
19.1 
12.9 
Cressey T, Leenasirimakul P, Jourdain G, Tod M, Sukrakanchana P, 
Kunkeaw S, Puttimit C, Lallemant M. Low doses of indinavir-boosted with 
ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and 
tolerability. J Antimicrob Chemother 2005;55:1041-44. 
Maraviroc 
AUC0-12 
2.5 
1.75* 
Selzentry™ [package insert] New York; Pfizer; 2011 
Nelfinavir 
AUC0-12 
26 
18.5 
ViraceptTM [package insert] Agouron Pharmaceuticals; 2004. 
Raltegravir 
Cmin 
55 ng/mL 
1.9 ng/mL 
Isentress™ [package insert] Whitehouse Station, NJ; Merck; 2012 
Rilpivirine 
AUC0-24 
2396 ng*hr/mL 
1609 ng*hr/mL 
EdurantTM [package insert]  Raritan, NJ; Tibotec; 2011 
Tenofovir  
Cpre-dose 
3.7 
2.5 
Havlir D, Cheeseman S, McLaughlin M, Murphy R, Erice A, Spector S. 
High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in 
patients with human immunodeficiency virus infection. JID 1995;171:537-
45. 

 
IMPAACT P1026s Version 10.0                                   Page 78 of 107 
  
 
 
2 February 2016   
 
ARV Study Drug 
PK 
Parameter 
Non-pregnant 
Typical Value 
(mcg*hr/mL) 
Estimated 
10th percentile 
(mcg*hr/mL) 
Reference 
Tipranavir/Ritonavir 
AUC0-12 
476 
333* 
Yong C, Sabo J, Oksala C, MacGregor T, Kohlbrenner V, McCallister S, 
et al. Population pharmacokinetic assessment of systemic steady-state 
tipranavir concentrations for adults administered tipranavir/ritonavir 
500/200 mg twice daily. 12th Conference on Retroviruses and 
Opportunistic Infections 2005; 654 (abstract). 

 
IMPAACT P1026s Version 10.0               Page 79 of 107                                    2 February 2016  
 
APPENDIX VI-A 
SAMPLE CONSENT FORM 
FOR WOMEN ON ARV MEDICINES WITHOUT TUBERCULOSIS TREATMENT 
 
(Note to Sites:  For use with Appendix I-A, I-AMR, and II)  
 
IMPAACT P1026s: Pharmacokinetic Properties of Antiretroviral and Related Drugs During 
Pregnancy and Postpartum, Version, 10.0, dated 2 February 2016   
(International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network) 
 
INTRODUCTION                                
 
You and your baby are being asked to take part in the research study named above because you are 
infected with the Human Immunodeficiency Virus (HIV), the virus that causes AIDS, and you are 
pregnant and are taking one or more of the following HIV medicines during your pregnancy: 
darunavir/ritonavir twice daily, efavirenz, elvitegravir/cobicistat, darunavir/cobicistat, 
atazanavir/cobicistat, dolutegravir, tenofovir alafenamide fumarate (TAF)/cobicistat, TAF/ritonavir, TAF 
alone.  
 
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 take part in 
this study/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? 
 
The correct amount of HIV medicines needed during pregnancy to treat your HIV infection and to protect 
your baby from HIV infection while being safe for you and your baby is not known for all HIV 
medicines. In this study, we will compare levels of HIV medicines in pregnant women to levels in non-
pregnant adults on the same medicines. If it is found that the your blood levels of HIV medicines are too 
low, a new dose may be recommended that is not yet approved by the Food and Drug Administration 
(FDA). We will also see how well the medicines get into vaginal secretions where they may help to keep 
the amount of HIV in the vagina at a lower level. The amount of medicine found in blood from your 
baby’s umbilical cord will be compared to the amount of medicine in your blood at the time of delivery. 
We will also look to see how much of the HIV medicine you took is getting into your baby and how safe 
these medicines are for you and your baby. 
 
This study will be looking at dosing combinations and dose amounts of certain HIV medicines that are 
not yet approved by the FDA and are still being studied.  For example, the higher doses of darunavir 
twice daily is not approved by the FDA. 
 
WHAT DO I /DOES MY BABY HAVE TO DO IF I AM IN THIS STUDY? 
 
You will continue to obtain and take your HIV medicines as you would normally. No HIV medicines are 
supplied by this study. Your doctor may ask your permission to report the medicine you take to a national 
registry, which collects information anonymously on the use of HIV medicine during pregnancy, and any 
effects these medicines may have on infants. This information is completely confidential and your name 
will not be used.  You do not have to agree to be in the registry.  
 
Your doctor will review with you any dietary recommendations related to the HIV medicines that you are 
taking. You will need to be on your HIV medicines for at least 2 weeks before your first study visit. 

 
IMPAACT P1026s Version 10.0               Page 80 of 107                                    2 February 2016  
 
During Pregnancy  
 
• 
You will need to come to the clinic to make sure you are eligible for the study before you enroll. This 
may be done as part of your first study visit when you are 20-26 weeks pregnant or 30-38 weeks 
pregnant, so a separate visit will not be required. We may test you for HIV to confirm your status. At 
each visit, a history and physical exam, and routine blood tests will be done. Blood will also be drawn 
to check how well your body is able to fight infection and to check the amount of HIV in your blood. 
The total amount of blood for these tests is 13 – 16 mL (2½- to 3 ½ teaspoons). At each visit you will 
be asked about taking your HIV medicines.  
   
• 
Checking the Amount of HIV Medicine in Your Blood 
 
Sites outside the U.S. should include:  Blood that is drawn during this study will be sent to doctors in 
laboratories in your country or overseas who have special ways of looking at the amount of HIV medicine 
in the blood. 
 
If you enter the study when you are 20-26 weeks pregnant, repeat blood samples will be taken to 
measure the amount of HIV medicine in your blood. These blood samples will be repeated when 
you are 30-38 weeks pregnant. A small plastic catheter (soft tube) will be placed in a vein in your 
arm during this visit, so that blood can be drawn multiple times, without having to stick you with 
a needle several times. The tube will stay in place until all of the blood samples are drawn. 
Depending on the medicine(s) you are taking and the time you usually take them, 7 blood 
samples over 12 hours, or 8 blood samples over 24 hours will be taken. The total amount of blood 
taken for these tests will be between 17-19 mL (about 3½ to 4 teaspoons). You will be asked to 
provide the times of your previous two doses of medicine and to describe the time and amount of 
your previous two meals. Before these repeat blood samples are taken, the study staff will review 
with you any dietary recommendations related to the HIV medicines you are taking. Once your 
HIV medicine levels have been determined, they will be reported back to you and your doctor as 
soon as possible. If these levels are low compared to those in non-pregnant adults, you and your 
doctor will be told. You may decide, in consultation with your doctor, to adjust the dose of the 
medicine(s). The new dose may be higher than the current FDA approved dose.  If you and your 
doctor choose to increase your dose of medicine, you may choose to have repeat blood sampling 
and drug measurements taken during the pregnancy and after you deliver to assess the levels of 
medicine in your blood on the new dose.  
 
• 
Genetic Testing 
 
Some of your blood collected for other tests will be used for genetic testing. Also, if you agree, between 
birth and 9 days after birth, your baby will have one drop of blood taken for genetic testing of your baby. 
This test is to see if there are differences in specific genes that may affect the levels of some medicines. 
Some people break down medicines differently based on their DNA and this can change the levels of the 
medicines in their bodies. You may decide that you do not want your or your baby’s DNA to be tested 
either now or at another time, by contacting your care provider during the study. You can still participate 
in this study even if you make this decision. This test will be done later in the study so you will not 
receive the results of this test. Please read the following statement carefully and then mark your initials in 
the appropriate space provided:   
 
I agree to allow my DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 

 
IMPAACT P1026s Version 10.0               Page 81 of 107                                    2 February 2016  
 
I agree to allow my baby’s DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 
• 
Checking the Amount of HIV Medicine in Your Vagina 
 
At some of the same times you have blood drawn to check the levels of HIV medicine in your blood, a 
small amount of vaginal fluid (about 1/8 of a teaspoon) will be taken before you take your dose of HIV 
medicine and again one, two, and four hours after your dose to check the amount of medicine in the 
vagina. The samples can be taken by you or your health care provider. Your provider will talk with you 
about the different ways vaginal fluid can be collected so that it is as comfortable as possible for you. 
These drug levels and testing will be done in batches later in the study, so you and your doctor won’t get 
results of these tests. If you have a pregnancy condition such as placenta previa (placenta that is implanted 
in the lower uterus) or broken water bag that would make it unsafe to collect vaginal specimens, they will 
not be collected. 
 
• 
Additional study tests if you are taking darunavir/ritonavir twice daily  
 
If you are taking darunavir/ritonavir twice daily, you will be followed more closely during pregnancy and 
after delivery because these higher dosing combinations are not yet approved by the FDA. You will have 
an electrocardiogram (a quick test that looks at how your heart is beating) when you enter the study and 
again after 30 weeks into your pregnancy. If you have not had a test to check for gestational diabetes done 
as standard of care by your primary care physician, between 24 weeks gestation and delivery, some blood 
will be taken after a sweet drink to check the level of glucose (blood sugar) in your blood. If the tests are 
abnormal, you will be followed by your primary care physician. From the time you enter the study until 
30 weeks into your pregnancy, you will have a medical history, physical examination, and routine blood 
tests done every four weeks. About 6 mL (slightly more than one teaspoon) of blood will be taken for 
these tests. From 30 weeks until delivery, a medical history and physical examination will be done every 
two weeks and routine blood tests will be done every 4 weeks. About 6 mL (slightly more than one 
teaspoon) of blood will be taken for these tests. Two to three weeks after delivery, you will have a 
medical history, physical examination, and routine blood tests done. About 6 mL (slightly more than one 
teaspoon) of blood will be taken for these tests. 
 
During Delivery 
 
At the time of delivery, a history and physical exam and routine blood tests will be done. Blood will also 
be drawn to check how well your body is able to fight infection and to check the amount of HIV in your 
blood. About 18 mL (about 3½ teaspoons) of blood will be drawn. You will be given the results of these 
tests. After your baby is born, a small amount of blood will also be drawn from the umbilical cord that is                             
attached to the placenta after the placenta has been separated from the baby. This blood comes from the 
placenta not your baby.  
 
After Delivery 
 
If you are taking efavirenz, elvitegravir/cobicistat, darunavir/cobicistat, atazanavir/cobicistat, 
dolutegravir, or tenofovir alafenamide fumarate (TAF)/cobicistat, TAF/ritonavir, TAF alone, you will be 
seen in the clinic 6-12 weeks after you deliver your baby. At this visit after delivery, you will have a 
history and physical exam, and routine blood tests. Blood will also be drawn to check how well your body 
is able to fight infection and to check the amount of HIV in your blood. You will be given the results of 
these tests. Repeat blood samples will be taken to check the amount of HIV medicine in your blood. The 
total amount of blood to be drawn at this visit is between 30-32 mL (6 to 6½ teaspoons). A vaginal fluid 

 
IMPAACT P1026s Version 10.0               Page 82 of 107                                    2 February 2016  
 
sample and a vaginal swab will be taken. The vaginal sample can either be collected by you or your 
doctor. This testing will be done in batches later in the study, so you and your doctor won’t get the results 
of these tests.   
  
If you are taking darunavir/ritonavir twice daily you will be seen in the clinic at 2-3 weeks after you 
deliver your baby. At this visit after delivery, you will have a history and physical exam, and routine 
blood tests. Blood will also be drawn to check how well your body is body is able to fight infection and to 
check the amount of HIV in your blood. Repeat blood samples will be taken to check the amount of HIV 
medicine in your blood like what was done during your pregnancy. The total amount of blood to be drawn 
at this visit is between 30-32 mL (6 to 6½ teaspoons). At each visit you will be asked about taking your 
HIV medicines. 
  
Study Visits for Your Baby  
After your baby is born, your baby will be examined 3 times during the study: from birth to 3 days after 
birth, 5-9 days after birth, and again at 4-6 months of age. During these visits, your baby will be weighed 
and measured and information about your baby’s health will be recorded from his/her medical records. 
Your baby, if able, will have blood samples taken to determine how much of the antiretroviral medication 
you took during pregnancy got into your baby and how long it takes to go away. Your baby will have 
blood samples taken at three time points between birth and 3 days after birth and a fourth sample taken 
between 5 and 9 days after birth. About 1 mL, or less than ¼ teaspoon (sites-add locally relevant 
description of blood volume) of blood will be taken for each sample. The total amount of blood taken for 
these tests will be around 3 – 4 mL, about 1 teaspoon (sites-add locally relevant description of blood 
volume). 
 
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? 
 
The study will enroll 25 women per drug/drug combination and their babies. 
 
HOW LONG WILL YOU/YOUR BABY BE IN THIS STUDY? 
 
You and your baby will be in this study until 24 weeks after you deliver your baby. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you and your baby off the study early without your permission if: 
 
• 
The study is cancelled by the IMPAACT network, U.S. Food and Drug Administration (FDA), 
National Institutes of Health (NIH), the Office for Human Research Protections (OHRP), other local 
or national regulatory agencies, or the site’s Institutional Review Board (IRB) or Ethics Committee 
(EC). An IRB and EC are committees that watches over the safety and rights of research subjects. 
• 
You are/your baby is not able to attend the study visits as required by the study. 
• 
You need a treatment that you may not take while on study. 
• 
You are not able to take the HIV medicine(s) required by the study. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
WHAT ARE THE RISKS OF THE STUDY? 

 
IMPAACT P1026s Version 10.0               Page 83 of 107                                    2 February 2016  
 
 
The medicines used in this study may have side effects. Your doctor will explain the possible side effects 
of the medicines you are taking. 
 
Any time a medicine dose is used (both approved and not approved by the FDA), unexpected side effects 
may occur. If you have any questions concerning the possible side effects of the medicines that you are 
taking, please ask the medical staff at your site to review them with you.  
 
Risks of Drawing Blood 
 
Blood drawing may cause fainting or lightheadedness or some discomfort. Other risks include bleeding or 
bruising where the needle enters the body. A small blood clot may form where the needle enters the body 
or swelling of the surrounding skin may occur. There is also a small risk of a minor infection at the blood 
draw site. Blood drawing from your baby can also be done by heel stick. Heel stick may cause some 
discomfort, bleeding or bruising at the site of the heel stick. There is a small risk of infection at the site of 
the heel stick.  
 
Risks of Collecting Vaginal Fluid and Vaginal Swabs 
 
You may feel slight discomfort when collecting vaginal fluid. This should be minimal.  
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be made. You 
may benefit from having the levels of HIV medicine(s) in your blood measured and having your blood 
checked for safety effects. If these levels are low compared to those in non-pregnant adults, you and your 
clinician may decide to increase the dose of the medicine(s). Information learned from this study may 
help others who have HIV. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For US Sites 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to 
disclose information that may identify you/your baby, 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/your baby, 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 U.S. Food and Drug Administration 
(FDA). 
 
People who may review your/your baby’s records include: the U.S. Food and Drug Administration 
(FDA), (insert Name of Site) IRB, National Institutes of Health (NIH), the Office for Human Research 
Protection, study staff, and study monitors. Any publication of this study will not use your/your baby’s 
name or identify you/your baby personally. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you/your baby or your/your baby’s participation in 
this research. If an insurer, employer, or other person obtains your written consent to receive research 

 
IMPAACT P1026s Version 10.0               Page 84 of 107                                    2 February 2016  
 
information, then the researchers may not use the Certificate of Confidentiality to withhold that 
information. 
 
For sites outside the U.S 
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 Ministry of Public Health in your country, the FDA, 
the Office of Human Research Protections (OHRP), the NIH, (insert name of site) IRB, Ethics Committee 
(EC), study staff, and study monitors. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost for the study-related clinic visits, examinations, and laboratory tests in this study. Any 
medical costs for your treatment outside this study, including your prescribed medicines for HIV, will be 
charged to you or your health insurance company. This study will not cover any cost related to your 
pregnancy and delivery or care of your baby. You will not receive payment for your participation in this 
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/your baby’s 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 National 
Institutes of Health (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 SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part/allow your baby to 
take part in this study or leave this study at any time. Your decision will not have any impact on 
your/your baby’s participation in other studies conducted by NIH and will not result in any penalty or loss 
of benefits to which you are/your baby is 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 subject, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site 
• 
telephone number of above   
 
SIGNATURE PAGE   

 
IMPAACT P1026s Version 10.0               Page 85 of 107                                    2 February 2016  
 
 
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/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 
 
 

 
IMPAACT P1026s Version 10.0               Page 86 of 107                                    2 February 2016  
 
APPENDIX VI-B 
SAMPLE CONSENT FORM 
FOR WOMEN ON ARV MEDICINES WITH TUBERCULOSIS TREATMENT (FIRST LINE 
AND SECOND LINE) 
 
 (Note to Sites:  For use with Appendix I-B, I-AMR, and II)  
 
IMPAACT P1026s: Pharmacokinetic Properties of Antiretroviral and Related Drugs during 
Pregnancy and Postpartum, Version, 10.0, dated 2 February 2016  
(International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network) 
 
INTRODUCTION                                
 
You and your baby are being asked to take part in the research study named above because you are 
infected with the Human Immunodeficiency Virus (HIV), the virus that causes AIDS and you are 
pregnant and are taking HIV medicines and tuberculosis medications as described in one of the tables 
below.  
 
One of the following HIV medications: 
Efavirenz 
Lopinavir/ritonavir 
At least one of the following additional TB 
medications: 
rifampicin 
ethambutol  
isoniazid 
pyrazinamide  
 
Or 
 
HIV medications:  
Any 
 
Two of the following TB medications: 
kanamycin 
amikacin 
capreomycin 
moxifloxacin  
levofloxacin 
ofloxacin 
ethionamide/prothionamide 
terizidone/cycloserine 
para-aminosalicylic acid  (PAS) 
isoniazid  
bedaquiline 
clofazamine 
delamanid 
linezolid 
pretomanid 
  
 
 
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 take part in 
this study/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? 

 
IMPAACT P1026s Version 10.0               Page 87 of 107                                    2 February 2016  
 
 
The correct amount of tuberculosis medicines needed during pregnancy to treat tuberculosis infection is 
not known. When tuberculosis medicines are taken together with HIV medicines TB medicines may 
decrease the amount of the HIV medicines in the blood, so that the correct doses of the these HIV 
medicines to protect your baby from HIV infection while being safe for you and your baby is not known. 
In this study, we will measure levels of tuberculosis medicines and these HIV medicines in HIV-infected 
pregnant women. We will compare the levels of tuberculosis medicines to those in HIV-uninfected 
pregnant women on the same tuberculosis medicines. We will also compare the levels of HIV medicines 
to those in non-pregnant adults without tuberculosis on the same HIV medicines. If it is found that the 
your blood levels of the HIV medicines are too low, a new dose may be recommended that is not yet 
approved by the Food and Drug Administration (FDA). The amount of medicine found in blood from 
your baby’s umbilical cord will be compared to the amount of medicine in your blood at the time of 
delivery. We will also look to see how much of the HIV medicines you took are getting into your baby 
and how safe these medicines are for you and your baby.  
 
This study will be looking at dosing combinations and dose amounts of certain HIV medicines that are 
not yet approved by the FDA and are still being studied. For example, the higher doses of 
lopinavir/ritonavir and efavirenz being studied are not approved by the FDA. 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
You will continue to obtain and take your HIV and tuberculosis medicines as you would normally. No 
HIV or tuberculosis medicines are supplied by this study. Your doctor may ask your permission to report 
the medicine you take to a national registry, which collects information anonymously on the use of HIV 
medicine during pregnancy, and any effects these medicines may have on infants. This information is 
completely confidential and your name will not be used. You do not have to agree to be in the registry.  
 
Your doctor will review with you any dietary recommendations related to the HIV and tuberculosis 
medicines that you taking. You will need to be on your HIV and tuberculosis medicines for at least 2 
weeks before your first study visit. 
 
During Pregnancy  
 
• 
You will need to come to the clinic to make sure you are eligible for the study before you enroll. This 
may be done as part of your first study visit when you are 20-26 weeks pregnant or 30-38 weeks 
pregnant, so a separate visit will not be required. We may test you for HIV to confirm your status. At 
each of these visits you will have a history and physical exam, and routine blood tests. Blood will also 
be drawn to check how well your body is able to fight infection and to check the amount of HIV in 
your blood. The total amount of blood for these tests is 13 - 22 mL (slightly more than 4 teaspoons).  
At each visit you will be asked about taking your HIV medicines.  
 
• 
Checking the Amount of HIV and Tuberculosis Medicines in Your Blood 
 
If you enter the study when you are 20-26 weeks pregnant, repeat blood samples will be taken to 
measure the amount of HIV and tuberculosis medicines in your blood. These blood samples will be 
repeated when you are 30-38 weeks pregnant. A small plastic catheter (soft tube) will be placed in a 
vein in your arm for an extended period of time, so that blood can be drawn multiple times, without 
having to stick you with a needle several times. The tube will stay in place until all of the blood 
samples are drawn. Depending on the medicine(s) you are taking and the time you usually take them, 
7 blood samples over 12 hours, or 8 blood samples over 24 hours will be taken. The total amount of 
blood taken for these tests will be between 31-35 mL (about 7 teaspoons). You will be asked to 

 
IMPAACT P1026s Version 10.0               Page 88 of 107                                    2 February 2016  
 
provide the times of your previous two doses of medicine and to describe the time and amount of 
your previous two meals. Before these repeat blood samples are taken, the study staff will review 
with you any dietary recommendations related to the HIV medicines you are taking. Your HIV 
medicine level will be reported back to you and your doctor as soon as possible. If the level is low 
compared to those in non-pregnant adults, you and your doctor will be told. You may decide, in 
consultation with your doctor, to adjust the dose of the medicine(s). The new dose may be higher than 
the current FDA approved dose.  If you and your doctor choose to increase your dose of medicine, 
you may choose to have repeat blood sampling and drug measurements taken during the pregnancy 
and after you deliver to assess the levels of medicine in your blood on the new dose. The tuberculosis 
drug levels and testing will be done in batches later in the study, so you and your doctor won’t get 
results of these tests. 
 
• 
Genetic Testing 
 
Some of your blood collected for other tests will be used for genetic testing. Also, if you agree, between 
birth and 9 days after birth, your baby will have one drop of blood taken for genetic testing of your baby. 
This test is to see if there are differences in specific genes that may affect the levels of some medicines. 
Some people break down medicines differently based on their DNA and this can change the levels of the 
medicines in their bodies. You may decide that you do not want your or your baby’s DNA to be tested 
either now or at another time, by contacting your care provider during the study. You can still participate 
in this study even if you make this decision. This test will be done later in the study so you will not 
receive the results of this test. Please read the following statement carefully and then mark your initials in 
the appropriate space provided:   
 
I agree to allow my DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 
I agree to allow my baby’s DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 
    
• 
Additional study tests if you are taking lopinavir/ritonavir  
 
If you are taking an increased dose of lopinavir/ritonavir, you will be followed more closely during 
pregnancy and after delivery because this higher dosing combination is not yet approved by the FDA. 
You will have an electrocardiogram (a quick test that looks at how your heart is beating) when you enter 
the study and again after 30 weeks into your pregnancy. If you have not had a test to check for gestational 
diabetes done as standard of care by your primary care physician, between 24 weeks gestation and 
delivery, some blood will be taken after a sweet drink to check the level of glucose (blood sugar) in your 
blood. If the tests are abnormal, you will be followed by your primary care physician. From the time you 
enter the study until 30 weeks into your pregnancy, you will have a medical history, physical 
examination, and routine blood tests done every four weeks. About 6 mL (slightly more than one 
teaspoon) of blood will be taken for these tests. From 30 weeks until delivery, a medical history and 
physical examination will be done every two weeks and routine blood tests will be done every 4 weeks. 
About 6 mL (slightly more than one teaspoon) of blood will be taken for these tests. Two to three weeks 
after delivery, you will have a medical history, physical examination, and routine blood tests done. About 
6 mL (slightly more than one teaspoon) of blood will be taken for these tests. 
 
During Delivery 

 
IMPAACT P1026s Version 10.0               Page 89 of 107                                    2 February 2016  
 
 
At the time of delivery, a history and physical exam and routine blood tests will be done. Blood will also 
be drawn to check how well your body is body is able to fight infection and to check the amount of HIV 
in your blood. You will be given the results of these tests. About 18 mL (about 3½ teaspoons) of blood 
will be drawn. After your baby is born, a small amount of blood will also be drawn from the umbilical 
cord that is attached to the placenta after the placenta has been separated from the baby. This blood comes 
from the placenta not your baby.  
 
After Delivery 
 
You will be seen in the clinic 2-8 weeks after you deliver your baby. At this visit after delivery, you will 
have a history and physical exam, and routine blood tests. Blood will also be drawn to check how well 
your body is body is able to fight infection and to check the amount of HIV in your blood. You will be 
given the results of these tests. If you received injectable TB drugs you will have a hearing test. This 
hearing test can be scheduled on any day after you deliver. If you are still taking tuberculosis medicines, 
repeat blood samples will be taken to check the amount of HIV medicine and tuberculosis medicine in 
your blood. The total amount of blood to be drawn for these tests is between 13-54 mL (about 3 to 11 
teaspoons) depending on the tests that will be done. At each visit you will be asked about taking your 
HIV medicines.  
 
 
Study Visits for Your Baby: 
 
After your baby is born, your baby will be examined 3 times during the study: from birth to 3 days after 
birth, 5-9 days after birth, and again at 4-6 months of age. During these visits, your baby will be weighed 
and measured and information about your baby’s health will be recorded from his/her medical records. If 
you received injectable TB drugs your baby will have a hearing test.  This hearing test can be scheduled 
on any day. Your baby, if able, will have blood samples taken to determine how much of the antiretroviral 
medication you took during pregnancy got into your baby and how long it takes to go away. Your baby 
will have blood samples taken at three time points between birth and 3 days after birth and a fourth 
sample taken between 5 and 9 days after birth. About 1 mL, or less than ¼ teaspoon (sites-add locally 
relevant description of blood volume) of blood will be taken for each sample. The total amount of blood 
taken for these tests will be around 3 – 4 mL, about 1 teaspoon (sites-add locally relevant description of 
blood volume). 
 
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? 
 
The study will enroll 25 women per HIV medicine/tuberculosis medicine combination and their babies. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You and your baby will be in this study until 24 weeks after you deliver your baby. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you and your baby off the study early without your permission if: 
 
• 
The study is cancelled by the IMPAACT network, U.S. Food and Drug Administration (FDA), 
National Institutes of Health (NIH), the Office for Human Research Protections (OHRP), other local 

 
IMPAACT P1026s Version 10.0               Page 90 of 107                                    2 February 2016  
 
or 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 subjects. 
• 
You are/your baby is not able to attend the study visits as required by the study. 
• 
You need a treatment that you may not take while on study. 
• 
You are not able to take the HIV or TB medicine(s) required by the study. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The medicines used in this study may have side effects. Your doctor will explain the possible side effects 
of the medicines you are taking. 
 
Any time a medicine dose is used (both approved and not approved by the FDA), unexpected side effects 
may occur. If you have any questions concerning the possible side effects of the medicines that you are 
taking, please ask the medical staff at your site to review them with you.  
 
Risks of Drawing Blood 
 
Blood drawing may cause fainting or lightheadedness or some discomfort. Other risks include bleeding or 
bruising where the needle enters the body. A small blood clot may form where the needle enters the body 
or swelling of the surrounding skin may occur. There is also a small risk of a minor infection at the blood 
draw site. Blood drawing from your baby can also be done by heel stick. Heel stick may cause some 
discomfort, bleeding or bruising at the site of the heel stick. There is a small risk of infection at the site of 
the heel stick. 
 
  
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be made. You 
may benefit from having the levels of HIV and TB medicine in your blood measured and having your 
blood checked for safety effects. If these levels are low compared to those in non-pregnant adults, you 
and your clinician may decide to increase the dose of the medicine(s). Information learned from this study 
may help others who have HIV and TB. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
U.S. sites: 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that 
may identify you/your baby, 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/your baby, 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 U.S. Food and Drug Administration (FDA).  
 
People who may review your/your baby’s records include the U.S. Food and Drug Administration, the 
site IRB or Ethics Committee, other national regulatory agencies, the National Institutes of Health, the 

 
IMPAACT P1026s Version 10.0               Page 91 of 107                                    2 February 2016  
 
Office for Human Research Protections, study staff, and study monitors. Any publication of this study 
will not use your/your baby’s name or identify you/your baby personally 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you/your baby or your/your baby’s 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. 
 
For sites outside the U.S. 
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 Ministry of Public Health in your country, the FDA, 
the Office of Human Research Protections (OHRP), the NIH, (insert name of site) IRB, Ethics Committee 
(EC), study staff, and study monitors. 
 
WHAT ARE THE COSTS TO ME? 
There is no cost for the study-related clinic visits, examinations, and laboratory tests in this study. Any 
medical costs for your/your baby’s treatment outside this study, including your prescribed medicines for 
HIV and tuberculosis will be charged to you or your health insurance company. This study will not cover 
any cost related to your pregnancy and delivery or care of your baby. You will not receive payment for 
your participation in this study. 
 
WHAT HAPPENS IF I AM 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/your baby’s 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 National 
Institutes of Health (NIH). You will not be giving up any of your/your baby’s legal rights by signing this 
consent form. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study/allow 
your baby to take part in this study or leave this study at any time. Your decision will not have any impact 
on your/your baby’s participation in other studies conducted by NIH and will not result in any penalty or 
loss of benefits to which you are/your baby is 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 subject, contact: 

 
IMPAACT P1026s Version 10.0               Page 92 of 107                                    2 February 2016  
 
• 
name or title of person on the Institutional Review Board (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 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 
 
 
 

 
IMPAACT P1026s Version 10.0               Page 93 of 107                                    2 February 2016  
 
APPENDIX VI-C 
SAMPLE CONSENT FORM 
FOR HIV-UNINFECTED PREGNANT WOMEN ON NO ARV MEDICINES WITH 
TUBERCULOSIS TREATMENT 
 
(Note to Sites:  For use with Appendix I-C and II)  
 
IMPAACT P1026s: Pharmacokinetic Properties of Antiretroviral and Related Drugs During 
Pregnancy and Postpartum, Version, 10.0, dated 2 February 2016   
(International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network) 
 
INTRODUCTION                                
 
You and your baby are being asked to take part in the research study named above because you are 
pregnant and are taking tuberculosis medicines during your pregnancy as described in one of the tables 
below.  
 
At least one of the following TB medications: 
rifampicin 
ethambutol  
isoniazid 
pyrazinamide  
 
or 
 
Two of the following TB medications: 
- 
kanamycin 
- 
amikacin 
- 
capreomycin 
- 
moxifloxacin  
- 
levofloxacin 
- 
ofloxacin 
- 
ethionamide/prothionamide 
- 
terizidone/cycloserine 
- 
para-aminosalicylic acid  (PAS) 
- 
isoniazid  
- 
bedaquiline 
- 
clofazamine 
- 
delamanid 
- 
linezolid 
- 
pretomanid 
  
 
 
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 take part in 
this study/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? 
 

 
IMPAACT P1026s Version 10.0               Page 94 of 107                                    2 February 2016  
 
The correct amount of tuberculosis medicines needed during pregnancy to treat tuberculosis infection is 
not known. In this study, we will measure the levels of tuberculosis medicines in the blood of women 
before and after delivery. We will also look to see how safe these medicines are. .  
 
WHAT DO I/MY BABY HAVE TO DO IF I AM IN THIS STUDY? 
 
You will continue to obtain and take your tuberculosis medicines as you would normally. No tuberculosis 
medicines are supplied by this study. Your doctor will review with you any dietary recommendations 
related to the tuberculosis medicines that you are taking. You will need to be on your tuberculosis 
medicines for at least 2 weeks before your first study visit. 
 
During Pregnancy  
 
You will need to come to the clinic to make sure you are eligible for the study before you enroll. This 
may be done as part of your first study visit when you are 20-26 weeks pregnant or 30-38 weeks pregnant, 
so a separate visit will not be required. At each of these visits you will have a history and physical exam, 
and routine blood tests. You will be given the results of these tests. About 6 - 12 mL (slightly more than 2 
teaspoon) of blood will be drawn at each visit depending on what TB drugs you are taking. 
 
• 
Checking the Amount of Tuberculosis Medicine in Your Blood 
 
At 20-26 weeks and 30-38 weeks of your pregnancy, blood samples will be taken to measure the amount 
of tuberculosis medicine in your blood. A small plastic catheter (soft tube) will be placed in a vein in your 
arm and will stay there for about a half a day, so that blood can be drawn about 7 times, without having to 
stick you with a needle more than about once. . The tube will stay in place until all of the blood samples 
are drawn. Seven (7) blood samples will be taken over 12 hours. The total amount of blood taken for 
these tests will be about 17 mL (about 3 ½ teaspoons) depending on the number of tuberculosis medicines 
you are taking. You will be asked for the times and amounts of your previous two doses of medicine and 
last two meals. The study staff will review with you the best diet for the tuberculosis medicines you are 
taking. The tuberculosis drug levels will be done in batches later in the study, so you and your doctor 
won’t get results of these tests until about the end of the study.  
 
During Delivery 
 
At the time of your delivery, a history and physical exam and routine blood tests will be done. About 6 
mL (slightly more than one teaspoon) of blood will be taken. You will be given the results of these tests. 
 
After Delivery 
 
You will be seen in the clinic 2-8 weeks after you deliver your baby. At this visit you will have a history 
and physical exam, and routine blood tests.  If you received injectable TB drugs you will have a hearing 
test. This hearing test can be scheduled for any time after you deliver.  If you are still taking tuberculosis 
medicines, repeat blood samples will be taken to determine the amount of TB medicine in your blood. 
The total amount of blood to be drawn for these tests is between 6 and 29 mL (about 1 to 6 teaspoons) 
depending on the tests to be done.  
 
Study Visits for Your Baby 
 
After your baby is born, your baby, will be examined 2 times during the study: from birth to 3 days after 
birth and again at 4 – 6 months of age. During these visits, your baby will be weighed and measured and 

 
IMPAACT P1026s Version 10.0               Page 95 of 107                                    2 February 2016  
 
information about your baby’s health will be recorded from his/her medical records. If you received 
injectable TB drugs your baby will have a hearing test. This hearing test can be scheduled on any day.  
 
Each of your baby’s study visits will last about [sites add local information about time for study visits].  
 
Genetic Testing 
 
 
Some of your blood collected for other tests will be used for genetic testing to help understand how your 
body handles your medications based on your genes and DNA. Also, if you agree, between birth and 3 
days of age, your baby will have one drop of blood taken for genetic testing of your baby. You may 
decide that you do not want your or your baby’s genes to be tested. Tell your health care provider if you 
decide this. You can still participate in this study even if you make this decision. This test will be done 
later in the study so you will not receive the results of this test. Please read the following statement 
carefully and then mark your initials in the appropriate space provided:   
 
 
I agree to allow my DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 
I agree to allow my baby’s DNA to be tested. 
 
 
Yes_______      No_________ Initials ________ Date ________ 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
The study will enroll 25 women for each tuberculosis treatment and their babies. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You and your baby will be in this study until 24 weeks after you deliver your baby. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
The study is cancelled by the IMPAACT network, U.S. Food and Drug Administration (FDA), 
National Institutes of Health (NIH), the Office for Human Research Protections (OHRP), other local 
or 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 subjects. 
• 
You are/your baby is not able to attend the study visits as required by the study. 
• 
You need a treatment that you may not take while on study. 
• 
You are not able to take the tuberculosis medicine(s) required by the study. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 

 
IMPAACT P1026s Version 10.0               Page 96 of 107                                    2 February 2016  
 
The medicines used in this study may have side effects. Your doctor will explain the possible side effects 
of the medicines you are taking. If you have any questions concerning the possible side effects of the 
medicines that you are taking, please ask the medical staff at your site to review them with you.  
 
Risks of Drawing Blood 
 
Blood drawing may cause fainting or lightheadedness or some discomfort. Other risks include bleeding or 
bruising where the needle enters the body. A small blood clot may form where the needle enters the body 
or swelling of the surrounding skin may occur. There is also a small risk of an infection at the blood draw 
site. Blood drawing from your baby can also be done by heel stick. Heel stick may cause some 
discomfort, bleeding or bruising at the site of the heel stick. There is a small risk of infection at the site of 
the heel stick. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be no direct benefit to you but you will have more doctor visits 
where you can be checked that your medicines are safe. Information learned from this study may help 
others who are pregnant and have tuberculosis. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For US Sites: 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. 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 for 
information that would identify you or your baby, 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 U.S. Food and Drug Administration (FDA). 
 
People who may review your/your baby’s records include: the U.S. Food and Drug Administration 
(FDA), (insert Name of Site) IRB, National Institutes of Health (NIH), the Office for Human Research 
Protection, study staff, and study monitors. Any publication of this study will not use your/your baby’s 
name or identify you/your baby personally. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you/your baby or your/your baby’s 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. 
 
(For sites outside the U.S.) 
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. 
 

 
IMPAACT P1026s Version 10.0               Page 97 of 107                                    2 February 2016  
 
Your/your baby’s records may be reviewed by the Ministry of Public Health in your country, the FDA, 
the Office of Human Research Protections (OHRP), the NIH, (insert name of site) IRB, Ethics Committee 
(EC), study staff, and study monitors. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost for the study-related clinic visits, examinations, and laboratory tests in this study. Any 
medical costs for your/your baby’s treatment outside this study, including your prescribed medicines for 
tuberculosis, will be charged to you or your health insurance company. This study will not cover any cost 
related to your pregnancy and delivery or care of your baby. You will not receive payment for your 
participation in this 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 insurance company.  
There is no program for compensation either through this institution or the National Institutes of Health 
(NIH). You will not be giving up any of your/your baby’s legal rights by signing this consent form. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part/allow your baby to 
take part in this study or leave this study at any time. Your decision will not have any impact on 
your/your baby’s participation in other studies conducted by NIH and will not result in any penalty or loss 
of benefits to which you/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 subject, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site 
• 
telephone number of above   
 
 
 
 

 
IMPAACT P1026s Version 10.0               Page 98 of 107                                    2 February 2016  
 
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/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 
 
 
 

 
IMPAACT P1026s Version 10.0               Page 99 of 107                                    2 February 2016  
 
APPENDIX VI-D 
SAMPLE CONSENT FORM 
FOR POSTPARTUM WOMEN ON ANTIRETROVIRAL MEDICINES AND HORMONAL 
CONTRACEPTIVES 
 
(Note to Sites:  For use with Appendix I-D)  
 
IMPAACT P1026s: Pharmacokinetic Properties of Antiretroviral and Related Drugs During 
Pregnancy and Postpartum, Version, 10.0, dated 2 February 2016   
(International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network) 
 
INTRODUCTION 
 
You are being asked to take part in the research study named above because you are infected with the 
Human Immunodeficiency Virus (HIV), the virus that causes AIDS and are taking the HIV medicines, 
efavirenz or atazanavir/ritonavir/tenofovir or darunavir/cobicistat or atazanavir/cobicistat, and plan to 
start using an oral contraceptive pill containing ethinyl estradiol, or an etonogestrel implant after you 
deliver your baby. 
 
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 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? 
 
Some HIV medicines interact with hormonal birth control, potentially changing the levels of the birth 
control (increasing the chance of side effects or of pregnancy) or of the HIV drug (increasing side effects 
or decreasing HIV activity). We want to study whether oral contraceptive pills containing the estrogen 
agent ethinyl estradiol or the contraceptive etonogestrel implant have significant interactions with 
darunavir/cobicistat, atazanavir/cobicistat, efavirenz or atazanavir/ritonavir/tenofovir . We want to look at 
the levels of these medicines  in your blood before you start one of the two types of hormonal birth 
control. Then we will measure the levels of these medicines again after you have been on birth control for 
several weeks and see if the levels have changed. We will also measure the levels of the hormones in your 
blood from the birth control and compare those levels to results from women using the same birth control 
but not taking antiretroviral medicines. We can see if the hormones and antiretroviral (ARV) medicines 
interact or not and see if hormonal birth control should work as well in women on certain ARV drugs. We 
will also look to see how safe these medicines are for you.   
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
You will continue to obtain and take your HIV medicines as you would normally. No HIV medicines or 
hormonal contraceptives are supplied by this study. Your doctor will review with you any dietary 
recommendations related to the HIV medicines that you are taking. You will need to be on the same dose 
of your HIV medicines for at least 2 weeks before your first study visit. 
 
2-12 weeks after you deliver your baby 
 
You will need to come to the clinic to make sure you are eligible for the study before you enroll. This 
may be done as part of your first study visit, so a separate visit will not be required. We may test you for 
HIV to confirm your status. You will have a history and physical exam, and routine blood tests to see if it 
is safe for you to be in the study.  You will be asked about taking your HIV medicines.  Blood will be 

 
IMPAACT P1026s Version 10.0               Page 100 of 107                                    2 February 2016  
 
drawn to check how well your body is able to fight infection and to check the amount of HIV in your 
blood. The total amount of blood taken from these tests will be 13 – 16 mL (about 2½ to 3 ½ teaspoons). 
You will be given the results of these tests. You will be asked to sign this consent form. 
 
If you are able to be in this study, blood tests will be done to measure the amount of HIV medicine in 
your blood. A small plastic catheter (soft tube) will be placed in a vein in your arm and stay there for 
about a half a day so that blood can be drawn about 7 -8 times, without having to stick you more than 
about once.  Depending on the medicine(s) you are taking, 7 blood samples over 12 hours, or 8 blood 
samples over 24 hours will be taken. The total amount of blood taken for these tests will be 17-19 mL 
(about 4 teaspoons). You will be asked to provide the times and amounts of your last two doses of 
medicine and last two meals. Before these blood samples are taken, the study staff will review with you 
any food recommendations related to the HIV medicines you are taking. After these blood tests are taken, 
you will start the oral contraceptive pills as prescribed by your regular doctor or have the etonogestrel 
implant inserted by your doctor.  
 
6 to7 weeks after you have started hormonal contraceptives  
 
You will come to the clinic 6-7 weeks after you have started hormonal contraceptives and 
the same tests that were done 2-12 weeks after you delivered your baby will be repeated. We will ask you 
questions about how you are taking your medicines. A pregnancy test will also be done. You will take 
your HIV medicine at the same time of day you take your hormonal contraceptives three days before you 
have repeat blood samples drawn and on the day you have repeat blood samples drawn to check the levels 
of hormone and HIV medicine in your blood. If you are using the etonogestrel implant 4mL (about one 
teaspoon) of blood will be taken from you. If you are using oral contraceptives eight (8) blood samples 
(about 3 teaspoons) will be taken over 24 hours. The total amount of blood taken for all these tests will be 
between 35-49 mL (about 7 to 10 teaspoons) depending on which contraceptive method you are using. 
This testing will be done in batches later in the study, so you and your doctor won’t get the results of 
these tests until the end of the study. You will be asked about taking your HIV medicines.   
 
Genetic Testing 
 
 
Some of your blood collected for other tests will be used for genetic testing to help understand how your 
body handles your medications based on your genes and DNA. You may decide that you do not want 
your genes to be tested. Tell your health care provider if you decide this. You can still participate in this 
study even if you make this decision. This test will be done later in the study so you will not receive the 
results of this test. Please read the following statement carefully and then mark your initials in the 
appropriate space provided:   
 
    
I agree to allow my DNA to be tested. 
 
Yes_______      No_________ Initials ________ Date ________ 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
The study will enroll 100 women; 25 women per HIV medicine/hormonal contraceptive combination. 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study until 6-7 weeks after you start taking hormonal contraceptives. 
 

 
IMPAACT P1026s Version 10.0               Page 101 of 107                                    2 February 2016  
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
The study is cancelled by the IMPAACT network, U.S. Food and Drug Administration (FDA), 
National Institutes of Health (NIH), the Office for Human Research Protections (OHRP), other local 
or 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 subjects. 
• 
You are not able to attend the study visits as required by the study. 
• 
You need a treatment that you may not take while on study. 
• 
You are not able to take the HIV medicines or hormonal contraceptives required by the study. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The medicines used in this study may have side effects. Your doctor will explain the possible side effects 
of the medicines you are taking. If you have any questions concerning the possible side effects of the 
medicines that you are taking, please ask the medical staff at your site to review them with you.  
 
Risks of Drawing Blood 
 
You may feel faint or lightheaded or feel some discomfort when blood is drawn for this study. Other risks 
include bleeding or bruising where the needle enters the body. A small blood clot may form where the 
needle enters the body or swelling of the surrounding skin may occur. There is also a small risk of a 
minor infection at the blood draw site. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be no direct benefit to you but you will have more doctor visits 
where you can be checked for safety on your medications. Information learned from this study may help 
others who are taking HIV medicines and want to use hormonal contraceptives. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For US Sites 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. 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 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 U.S. Food and Drug Administration (FDA). 
 
People who may review your records include: the U.S. Food and Drug Administration (FDA), (insert 
Name of Site) IRB, National Institutes of Health (NIH), the Office for Human Research Protection, study 
staff, and study monitors. Any publication of this study will not use your name or identify you personally. 
 

 
IMPAACT P1026s Version 10.0               Page 102 of 107                                    2 February 2016  
 
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. 
 
(For sites outside the U.S.) 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name of identify you personally. 
 
Your records may be reviewed by the Ministry of Public Health in your country, the FDA, the Office of 
Human Research Protections (OHRP), the NIH, (insert name of site) IRB, Ethics Committee (EC), study 
staff, and study monitors. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost for the study-related clinic visits, examinations, and laboratory tests in this study. Any 
medical costs for your treatment outside this study, including your prescribed HIV medicines or hormonal 
contraceptives will be charged to you or your health insurance company. This study will not cover any 
cost related to your pregnancy and delivery or care of your baby. You will not receive payment for your 
participation in this study. 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you 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 National Institutes of Health (NIH). You 
will not be giving up any of your legal rights by signing this consent form. 
 
WHAT ARE MY RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study or leave 
this study at any time. Your decision will not have any impact on your participation in other studies 
conducted by NIH and will not result in any penalty or loss of benefits to which you are otherwise 
entitled. 
 
We will tell you about new information from this or other studies that may affect your health, welfare or 
willingness to stay in this study. If you want the results of the study, let the study staffs 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 rights as a research subject, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization appropriate 
for the site 
• 
telephone number of above   
 

 
IMPAACT P1026s Version 10.0               Page 103 of 107                                    2 February 2016  
 
 
 
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 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 
  
 
 

 
IMPAACT P1026s Version 10.0               Page 104 of 107                                    2 February 2016  
 
APPENDIX VII 
HISTORY OF VERSION 1.0 TO VERSION 9.0 
 
Versions 1.0 and 6.0 of P1026s never opened to enrollment.  
 
Version 2.0 opened on March 17, 2003 and included 5 study arms:  
• 
nevirapine 200 mg twice a day  
• 
amprenavir 1200 mg twice a day 
• 
abacavir 300 mg twice a day 
• 
lopinavir/ritonavir (Kaletra) 400/100 mg twice a day 
• 
indinavir/ritonavir 800/100 mg twice a day 
 
Version 3.0 opened on May 19, 2004 and included 8 study arms:  
• 
The nevirapine arm was discontinued as there are sufficient pharmacokinetic data between 
P1026s and P1022. 
• 
The indinavir/ritonavir arm was discontinued due to lack of enrollment. 
• 
The amprenavir arm was replaced with fosamprenavir/ritonavir 700/100 mg twice a day. 
• 
abacavir 300 mg twice a day 
• 
increased dose of Kaletra 400/100 mg twice a day until 30 weeks gestation, then 533/133 mg 
twice a day until results of postpartum PK evaluation were available 
• 
atazanavir/ritonavir 300/100 mg once a day 
• 
didanosine delayed release (Videx® EC) 400 mg once a day  if weight > 60 kg; 250 mg once a 
day if weight < 60 kg 
• 
emtricitabine 200 mg once a day  
• 
tenofovir (300 mg once a day 
• 
tenofovir/atazanavir/ritonavir 300/300/100 mg once a day 
 
Version 4.0 opened on May 17, 2005 and included 10 study arms:    
• 
lopinavir/ritonavir (Kaletra®) 400/100 mg twice a day until 30 weeks gestation, then 533/133 mg 
twice a day until results of postpartum PK evaluation were available 
• 
fosamprenavir/ritonavir 700/100 mg twice a day 
• 
atazanavir/ritonavir 300/100 mg once a day  
• 
didanosine delayed release (Videx® EC) 400 mg once a day if weight > 60 kg; 250 mg once a 
day if weight < 60 kg 
• 
emtricitabine 200 mg once a day 
• 
tenofovir 300 mg once a day 
• 
tenofovir/atazanavir/ritonavir 300/300/100 mg once a day 
• 
nelfinavir [625 mg tablets] 1250 mg twice a day 
• 
efavirenz 600 mg once a day 
• 
tipranavir/ritonavir 500/200 mg twice a day 
 
Version 5.0 opened on February 6, 2006 and included 10 study arms: 
• 
lopinavir/ritonavir (Kaletra®) tablets 400/100 mg [2 tablets] twice a day  until 30 weeks 
gestation, then 600/150 mg [3 tablets] twice a day until postpartum hospital discharge; and 
400/100 mg [2 tablets] twice a day  after postpartum hospital discharge, until 2 week postpartum 
PK sample is drawn 
• 
fosamprenavir/ritonavir 700/100 mg twice a day 
• 
atazanavir/ritonavir 300/100 mg once a day 

 
IMPAACT P1026s Version 10.0               Page 105 of 107                                    2 February 2016  
 
• 
didanosine delayed release (Videx® EC) 400 mg once a day if weight > 60 kg; 250 mg once a 
day if weight < 60 kg 
• 
emtricitabine 200 mg once a day  
• 
tenofovir (300 mg once a day  
• 
tenofovir/atazanavir/ritonavir 300/300/100 mg once a day  
• 
nelfinavir (625 mg tablets)  1250 mg twice a day  
• 
efavirenz 600 mg once a day 
• 
tipranavir/ritonavir 500/200 mg twice a day  
  
Version 7.0 opened on May 12, 2009 and included 14 study arms 
• 
The lopinavir/ritonavir, standard dose atazanavir/ritonavir, emtricitabine, tenofovir, standard dose 
tenofovir/atazanavir/ritonavir, and standard dose nelfinavir arms were closed.  
• 
fosamprenavir/ritonavir 700/100 mg twice a day 
• 
didanosine delayed release (Videx® EC) 400 mg once a day if weight > 60 kg; 250 mg once a 
day if weight < 60 kg 
• 
efavirenz 600 mg once a day 
• 
tipranavir/ritonavir 500/200 mg twice a day  
• 
raltegravir 400 mg twice a day 
• 
etravirine 200 mg twice a day 
• 
maraviroc 150 mg or 300 mg twice a day 
• 
darunavir/ritonavir 800/100 mg once a day  
• 
darunavir/ritonavir 600/100 mg twice a day 
• 
atazanavir/ritonavir 300/100 mg once a day until 30 weeks gestation then 400/100 mg once a day 
until postpartum hospital discharge; then 300/100 mg once a day after postpartum hospital 
discharge until 2 week postpartum PK samples drawn 
• 
tenofovir/atazanavir/ritonavir 300/300/100 mg once a day until 30 weeks gestation; then 
300/400/100 mg once a day until postpartum hospital discharge; then 300/300/100 mg once a day 
after postpartum hospital discharge until 2 week postpartum PK samples drawn 
• 
nelfinavir [625 mg tablets] 1250 mg twice a day until 30 weeks gestation; then 1875 mg twice a 
day until postpartum hospital discharge; then 1250 mg twice a day after postpartum hospital 
discharge until 2 week postpartum PK samples drawn 
• 
indinavir/ritonavir 400/100 mg twice a day only to participants enrolling in Thailand 
• 
lopinavir/ritonavir (Alluvia tablets) 400/100 mg [2 tablets] twice  day until 30 weeks gestation; 
then 600/150 mg [3 tablets] twice a day until postpartum hospital discharge; then 400/100 mg [2 
tablets] twice a day after postpartum hospital discharge until 2 week postpartum PK sample 
drawn only to participants enrolling in Uganda 
 
Version 8.0 opened on April 18, 2013 and included 18 study arms: 
 
➢ Antiretrovirals without TB treatment (10 arms): 
• 
darunavir/ritonavir twice daily (600/100 mg b.i.d. or 800/100 mg b.i.d. until 30 weeks gestation; 
then 800/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after 
postpartum hospital discharge until 2 week postpartum PK samples are drawn) 
• 
darunavir/ritonavir twice daily (600/100 mg b.i.d. or 900/100 mg b.i.d. until 30 weeks gestation; 
then 900/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after 
postpartum hospital discharge until 2 week postpartum PK samples are drawn) 
• 
didanosine delayed release (Videx® EC) (400 mg q.d. if weight > 60 kg; 250 mg q.d. if weight < 
60 kg) 
• 
etravirine (200 mg b.i.d.)  

 
IMPAACT P1026s Version 10.0               Page 106 of 107                                    2 February 2016  
 
• 
maraviroc (150 mg b.i.d. or 300 mg b.i.d.) 
• 
nelfinavir 625 mg tablets (1250 mg b.i.d. until 30 weeks gestation; then 1875 mg b.i.d. until 
postpartum hospital discharge; then 1250 mg b.i.d. after postpartum hospital discharge until 2 
week postpartum PK samples are drawn)  
• 
rilpivirine (25 mg q.d.) 
• 
tipranavir/ritonavir (500/200mg b.i.d.)  
• 
efavirenz (600 mg q.d.) (sites outside of Thailand) 
• 
lopinavir/ritonavir (Alluvia®) tablets (400/100 mg [2 tablets] b.i.d. until 30 weeks gestation, then 
600/150 mg [3 tablets] b.i.d. until postpartum hospital discharge; and 400/100 mg [2 tablets] b.i.d. 
after postpartum hospital discharge, until 2 week postpartum PK samples are drawn) (African 
sites only) 
 
➢ Antiretrovirals with Tuberculosis Treatment (3 study arms) (Receiving one of the following ARV 
drug drugs/drug combinations and rifampicin containing TB treatment with at least one of the 
following TB drugs.):  
• 
efavirenz 600 mg q.d. 
• 
lopinavir/ritonavir 800/200 mg b.i.d. 
• 
nevirapine 200 mg b.i.d 
 
TB drugs: 
- 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. and at least 
one of the following drugs: 
- 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
- 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
- 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
➢ HIV-uninfected women - No Antiretrovirals with Tuberculosis Treatment (1 study arm) 
 
➢ Antiretrovirals with Postpartum Contraceptives (4 study arms): 
• 
lopinavir/ritonavir 400/100 b.i.d. postpartum and starting combined oral contraceptives 
formulated with 30-35 µg ethinyl estradiol 
• 
atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting combined oral 
contraceptives formulated with 30-35 µg ethinyl estradiol 
• 
lopinavir/ritonavir 400/100 b.i.d. postpartum and starting etonogestrel implant. 
• 
atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting etonogestrel implant. 
 
Version 9.0 opened on September 30, 2014 and included 16 study arms: 
 
➢ Antiretrovirals without TB treatment (8 arms): 
• 
darunavir/ritonavir twice daily (600/100 mg b.i.d. or 800/100 mg b.i.d. until 30 weeks gestation; 
then 800/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after 
postpartum hospital discharge until 2 week postpartum PK samples are drawn) 
• 
darunavir/ritonavir twice daily (600/100 mg b.i.d. or 900/100 mg b.i.d. until 30 weeks gestation; 
then 900/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after 
postpartum hospital discharge until 2 week postpartum PK samples are drawn) 
• 
etravirine 200 mg b.i.d.  
• 
elvitegravir/cobicistat 150/150 mg q.d. 
• 
dolutegravir 50 mg q.d. 
• 
tenofovir alafenamide fumarate (TAF) 10 mg q.d. 

 
IMPAACT P1026s Version 10.0               Page 107 of 107                                    2 February 2016  
 
• 
 efavirenz 600 mg q.d. (Sites outside of Thailand only) 
• 
lopinavir/ritonavir (Alluvia®) tablets (400/100 mg [2 tablets] b.i.d. until 30 weeks gestation, then 
600/150 mg [3 tablets] b.i.d. until postpartum hospital discharge; and 400/100 mg [2 tablets] b.i.d. 
after postpartum hospital discharge, until 2 week postpartum PK samples are drawn) (African 
Sites Only) 
 
➢ Antiretrovirals with Tuberculosis Treatment (3 study arms) (Receiving one of the following ARV 
drug drugs/drug combinations and rifampicin containing TB treatment with at least one of the 
following TB drugs.):  
• 
efavirenz 600 mg q.d. 
• 
lopinavir/ritonavir 800/200 mg b.i.d. 
• 
nevirapine 200 mg b.i.d 
 
TB drugs: 
- 
rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. and at least 
one of the following drugs: 
- 
ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. 
- 
isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. 
- 
pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. 
 
➢ HIV-uninfected women - No Antiretrovirals with Tuberculosis Treatment (1 study arm) 
 
➢ Antiretrovirals with Postpartum Contraceptives (4 study arms): 
 
• 
atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting combined oral 
contraceptives formulated with 30-35 µg ethinyl estradiol 
• 
efavirenz 600mg q.d. postpartum and starting combined oral contraceptives formulated with 30-
35 µg ethinyl estradiol 
• 
atazanavir/ritonavir/tenofovir 300/100/300 mg q.d. postpartum and starting etonogestrel implant. 
• 
efavirenz 600mg q.d. postpartum and starting etonogestrel implant