DPART Study: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy
Phase: PHASE4
Conditions: Drug-Drug Interaction, HIV Infection
Sponsor: University of California, San Francisco

DPART STUDY: DIHYDROARTEMISININ-PIPERAQUINE IN THE CONTEXT OF 
ANTIRETROVIRAL THERAPY
A UCSF/ YALE/
INFECTIOUS DISEASES RESEARCH COLLABORATION (IDRC)
 Sponsored by: 
The National Institute of Child Health and Human Development 
Principal UCSF Investigator: 
Francesca Aweeka, Pharm.D.
University of California, San Francisco
Principal Yale Investigator:
Sunil Parikh, M.D., MPH
Yale School of Public Health
Principal MU Investigator:  
Norah Mwebaza, MBChB, DPPM, PhD.
Makerere University
Study Co-Chairs:  
Sunil Parikh, M.D., MPH
Yale School of Public Health
Norah Mwebaza, MBChB, DPPM, PhD.
Makerere University
Francesca Aweeka, Pharm.D.
University of California, San Francisco
Adeodata Kekitiinwa, MBChB, MMED, DPPM
Baylor College of Medicine Children’s 
Foundation Uganda.
Protocol Number:  
National Clinical Trial (NCT) Number:
Version Number: v.1.1
Version Date: April 22, 2019

Table of Contents
PROTOCOL TEAM ROSTER..................................................................................................................4
GLOSSARY................................................................................................................................................6
DPART STUDY SCHEMA........................................................................................................................8
I.0 INTRODUCTION................................................................................................................................11
1.1 Background ....................................................................................................................................11
1.2 Rationale.........................................................................................................................................15
2.0 STUDY OBJECTIVES......................................................................................................................18
2.1 Primary Objectives:.......................................................................................................................18
2.2 Secondary Objectives:..................................................................................................................18
3.0 STUDY DESIGN................................................................................................................................18
3.1 Overview of Pharmacokinetic Sampling Design.......................................................................19
3.2 Overview of study groups.............................................................................................................21
3.3 Study sites......................................................................................................................................22
4.0 SELECTION AND ENROLLMENT OF SUBJECTS.....................................................................22
4.1 Inclusion Criteria............................................................................................................................22
4.2 Exclusion Criteria ..........................................................................................................................23
4.3 Identification and recruitment of study participants..................................................................23
4.4 Screening .......................................................................................................................................24
4.5 Study informed consent and enrollment ....................................................................................24
5.0 MALARIA STUDY DRUG: DIHYDROARTEMISININ-PIPERAQUINE ......................................25
6.0 CLINICAL AND LABORATORY EVALUATIONS.........................................................................29
6.1 Schedule of Evaluations...............................................................................................................29
6.2 Management of malaria or non-malarial illness........................................................................29
6.3 Unscheduled or After-hours Visits ..............................................................................................30
6.4 Missed or late visits.......................................................................................................................30
6.5 Clinical and Laboratory Studies ..................................................................................................30
6.6 ECG studies...................................................................................................................................30
6.7 Pharmacology Laboratory Studies..............................................................................................31
6.8 PK Sample collection and handling............................................................................................33

7.0 TOXICITY AND DATA AND SAFETY MONITORING PLAN (DSMP) ......................................34
7.1 Overview and Summary...............................................................................................................34
7.2 Communication Plan.....................................................................................................................34
7.7 Toxicity management by grade ...................................................................................................39
8.0 STATISTICAL CONSIDERATIONS ...............................................................................................39
8.1 General Design Issues.................................................................................................................40
8.2 Outcome Measures.......................................................................................................................40
8.3 Nutritional Status ...........................................................................................................................41
8.4 Intensive PK study ........................................................................................................................41
9.0 DATA COLLECTION AND MONITORING....................................................................................43
9.1 Record Keeping.............................................................................................................................43
9.2 Data Quality Assurance and Monitoring ....................................................................................44
10.0 HUMAN SUBJECTS.......................................................................................................................44
10.1 Risks and Benefits ......................................................................................................................44
10.2 Treatment and Compensation for Injury ..................................................................................45
10.3 Costs to the Subjects..................................................................................................................45
10.4 Reimbursement of Subjects ......................................................................................................45
10.5 Institutional Review Board (IRB) Review and Informed Consent.........................................45
10.6 Study Discontinuation.................................................................................................................46
10.7 Definition of Parent/Guardianship.............................................................................................46
11.0 PUBLICATION OF RESEARCH FINDINGS...............................................................................46
12.0 BIOHAZARD CONTAINMENT......................................................................................................46
14.0 REFERENCES................................................................................................................................48
APPENDIX A. SCHEDULE OF EVALUATIONS: L1 & C1 ARMS....................................................57
APPENDIX A. SCHEDULE OF EVALUATIONS: D3, E3, L3 & C3 ARMS .....................................59
APPENDIX B. INFORMATION SHEET................................................................................................61
APPENDIX C. WHO CRITERIA FOR SEVERE MALARIA/DANGER SIGNS................................62
APPENDIX D. GUIDELINES FOR ADVERSE EVENT GRADING (DAIDS AE GRADING 
TABLE)......................................................................................................................................................63
APPENDIX E. HIV-INFECTED CHILDREN CONSENT ....................................................................64
APPENDIX F. HIV-UNINFECTED CHILDREN CONSENT...............................................................64
APPENDIX G. ASSENT..........................................................................................................................64

APPENDIX H. FUTURE USE OF BIOLOGICAL SPECIMENS CONSENT....................................64
PROTOCOL TEAM ROSTER
Investigators:
Principal UCSF Investigator: 
Francesca Aweeka, Pharm.D, Department of Clinical Pharmacy, University of 
California, San Francisco
Address:  Parnassus Avenue Box 0622, San Francisco, CA 94143, U.S.A.
Phone Number: 01-415 476-0339; Fax Number:  415 476-0307
Email:  fran.aweeka@ucsf.edu 
Principal Yale Investigator: 
Sunil Parikh, M.D., MPH, Yale School of Public Health
Address: Laboratory of Epidemiology and Public Health, 60 College Street, Room 724
Phone Number: 01-203-737-7906; Fax Number: 01-203-737-1662
Email: sunil.parikh@yale.edu 
Principal MU Investigator:  
Norah Mwebaza, MBChB, DPPM, PhD, Makerere University, Kampala, Uganda
Address:  Department of Pharmacology and Therapeutics
Phone Number: +256782589889
Email: mwebno@yahoo.com 
Study Co-Investigators:
Liusheng Huang, Ph.D. Department of Clinical Pharmacy, University of California, San 
Francisco
Address:  Parnassus Avenue Box 0622, San Francisco, CA 94143, U.S.A.
Phone Number: 01-415 502-2594; Fax Number:  415 476-0307
Email:  Liusheng.huang@ucsf.edu 
Arthur Mpimbaza, MBChB, MMed; Assistant Lecturer
Address: Department of Pediatrics and Child Health, Faculty of Medicine. 
Makerere University
Email: ampimbaza@idrc-uganda.org or arthurwakg@yahoo.com]
Richard Kajubi, MBChB, DPPM, Infectious Diseases Research Collaboration (IDRC)
Address:  IDRC, 2C Nakasero Hill Road, P.O. Box 7475, Kampala, Uganda
Phone Number: +256776211591
Email: rkajubi@gmail.com 

Grace Paul Kisitu, MBChB, MPH, Baylor College of Medicine Children’s Foundation of 
Uganda
Address: P.O BOX 72052, Clock Tower, Kampala Uganda
Phone Number: +256772749154
Email: gkisitu@baylor-uganda.org
Rogers Sekabira, BPHARM, MHSR, MPS, Baylor College of Medicine Children’s 
Foundation of Uganda
Address: P.O BOX 72052, Clock Tower, Kampala Uganda
Phone Number: +256779394136
Email: rsekabira@baylor-uganda.org
Meghan Whalen, Pharm.D. PhD candidate, Department of Clinical Pharmacy, 
University of California, San Francisco
Address:  Parnassus Avenue Box 0622, San Francisco, CA 94143, U.S.A.
Phone number:
Email: meghan.whalen@ucsf.edu
Danh Huynh, PharmD Candidate, Department of Clinical Pharmacy
University of California, San Francisco
Address:  Parnassus Avenue, Box 0622, San Francisco, CA 94143 USA
Email: danh.huynh@ucsf.edu
Sponsor:
NICHD Sponsoring Investigator:  Nahida Chakhtoura, M.D.
Address:  6710B ROCKLEDGE DRIVE Room 2155, MSC 7002
Bethesda, MD 20817
For Fed-Ex use: Rockville, MD  20852
Phone:  301-435-6872 
Email: nahida.chakhtoura@nih.gov  

GLOSSARY
ACT
Artemisinin-combination therapy
AE
Adverse event 
AL 
Artemether-lumefantrine 
ALT 
Alanine transaminase (SGPT) 
ART 
Antiretroviral therapy 
AS-AQ
Artesunate-amodiaquine
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
BIPAI
Baylor College of Medicine International AIDS Initiative
BID 
Twice a day 
CBC 
Complete blood count 
CDC 
Center for Disease Control 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentration of a drug 
Cmin 
Trough serum concentration of a drug 
CoE
College of Excellence
Cr 
Creatinine 
CRF 
Case report form 
CYP
Cytochrome p450
CYP3A4
Cytochrome p450 3A4 
DAIDS 
Division of AIDS 
DHA
Dihydroartemisinin
DMC 
Data Management Centre 
DP
Dihydroartemisinin-piperaquine
DTG
Dolutegravir
ECG
Electrocardiogram
EFV
Efavirenz 
H 
Hour 
HFA
Height for age
Hg 
Hemoglobin 
HIV 
Human Immunodeficiency Virus
HRPP
Human Research Protection Program 
HIC
Human Investigation Committee
HS-RDT 
High sensitive rapid diagnostic test
IDRC
Infectious Disease Research Center
IPT 
Intermittent preventive therapy (for malaria) 
IRB 
Institutional review board 
ITN 
Insecticide treated net
JCRC-REC
Joint Clinical Research Center Research Ethics Committee
LAMP
Loop-mediated isothermal amplification
LBW 
Low birth weight (<2500g) 
LPV 
Lopinavir 
LPV/r 
Lopinavir/ritonavir
LR
Lumefantrine 

MOH 
Ministry of Health 
MU 
Makerere University 
NDA 
Uganda National Drug Authority 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NLME
Non-linear mixed effects
NNRTI 
Nonnucleoside reverse transcriptase inhibitor 
NRTI 
Nucleoside reverse transcriptase inhibitor 
NVP 
Nevirapine 
OR 
Odds ratio 
PCR 
Polymerase chain reaction
PD
Pharmacodynamics 
PI 
Protease inhibitor 
PK
Pharmacokinetics
PO 
Oral 
PQ
Piperaquine
PROMOTE
Prevention of Malaria and HIV Disease in Tororo
Q
Every 
QD 
Once every day 
RR 
Relative Risk 
SBSHDREC School of Biomedical Sciences Higher Degree Regulatory Ethics 
   
           Committee
SD 
Single dose 
SP 
Sulfadoxine-pyrimethamine 
TS 
Trimethoprim-sulfamethoxazole 
UCSF 
University of California, San Francisco 
UGT
Uridine diphosphate-glucuronosyltransferase
ULN
Upper limit of normal
UNAIDS 
Joint United Nations Program of HIV AIDS
UNCST 
Ugandan National Council for Science and Technology 
WFA
Weight for age
WFH
Weight for height
WHO 
World Health Organization 

DPART STUDY SCHEMA
DESIGN: 
Open-label prospective intensive pharmacokinetic study of dihydroartemisinin-piperaquine (DP) 
in HIV-infected children on efavirenz (EFV)-, lopinavir/ritonavir (LPV/r)-, or dolutegravir (DTG)-
based antiretroviral therapy (ART) and HIV-uninfected children not on ART.  All children will be 
malaria-uninfected at the time of enrolment.
SAMPLE SIZE: 
Total sample size (all arms): up to 190 children, depending on the number of children who are 
sequentially enrolled in the single dose and 3-dose DP arms.
Intervention groups: 
1) HIV-infected children age 3 - 10 years on LPV/r-based ART
 
20 children receiving single dose DP (Group L1)

30 children receiving 3-dose DP (Group L3)
Note that the same children from L1 can be re-enrolled into L3 following a washout 
period of 42 days
2) HIV-infected children age 3 - 10 years on EFV-based ART

30 children receiving 3-dose DP (Group E3) 
3) HIV-infected children age 11 - 17 years on DTG-based ART

30 children/adolescents receiving 3-dose DP*¥ (Group D3)
Control groups:
1) HIV-uninfected children age 3-10 years

20 children receiving 3-dose DP (with PK taken after the 1st DP dose ONLY) – 
control for group L1 (Group C1)

30 children receiving 3-dose DP – controls for groups E3 and L3 (Group C3a) 
2) HIV-uninfected children age 11-17 years

30 children receiving 3-dose DP – controls for group D3 (Group C3b)
POPULATION: 
HIV-infected participants will be enrolled from the Baylor Uganda Center of Excellence on the 
Mulago Hospital Complex, Kampala, Uganda. HIV-uninfected participants will be enrolled from 
Masafu General Hospital (MGH) complex in Busia, and other clinics in the surrounding area.
For Group D3, HIV-infected females age 13-17 who are pregnant or of childbearing potential 
and do not agree to consistent and reliable contraception will be excluded from enrollment due 
to potential risks of dolutegravir during 1st trimester.

STUDY REGIMENS FOR PARTICIPANTS: 
DP weight-based dosing will follow World Health Organization Treatment Guidelines for 
uncomplicated malaria (April 2015). Three-dose once daily DP has also been extensively 
studied for chemoprevention in children and pregnant women. 
1) ALL HIV-infected participants must be stabilized (i.e. no change in regimen for at 
least 10 days) on EFV, LPV/r, or DTG + 2 nucleoside reverse transcriptase inhibitors 
(NRTI).
2) HIV-infected children on LPV/r will be enrolled in two Phases. Phase I results will 
inform Phase II dosing, as a lower dose of DP over 3 days may be warranted. Phase 
II will not begin until PK and safety results from Phase I are evaluated. Participants in 
L1 and L3 will be encouraged to participate sequentially in Phase I and Phase II 
separated by a minimum 42-day washout period; however different children may be 
enrolled for the 2 phases.

Phase I participants (Group L1) will receive a single dose of DP to determine 
the magnitude (PK and safety) of the interaction before 3 doses are 
evaluated

Phase II participants (Group L3) will receive a 3-dose DP regimen (which 
consists of 3 days of a once daily DP dose)
3) HIV-infected children on EFV-based or DTG-based ART groups will be studied only 
in the context of the standard 3-dose DP (Groups E3 and D3).
4) HIV-uninfected children (controls) will only be studied in the context of standard 3-
dose DP. However, 20 children will undergo intensive sampling around the 1st dose 
(Group C1) and 30 children will undergo intensive sampling around the 3rd dose 
(Groups C3a and C3b).  
STUDY DURATION: 

Children in Groups L3, E3, D3, and C3 will be followed for 42 days.

Children in Group L1 will be followed for 28 days

Children in Group C1 will be followed for 14 days
HYPOTHESES:
1) Single and 3-dose DP in HIV-infected LPV/r-treated children will provide greater DP PK 
exposure when compared to single and 3-dose DP in HIV-uninfected children not on 
ART.
2) 3-dose DP in HIV-infected EFV-treated children will provide lower PK exposure when 
compared to 3-dose DP in HIV-uninfected children not on ART.
3) 3-dose DP in HIV-infected DTG-treated children will provide comparable PK exposure 
to 3-dose DP in HIV-uninfected children not on ART. 
PRIMARY OBJECTIVES: 

1) To evaluate and compare the PK exposure and safety of single dose DP in HIV-infected 
children on LPV/r-based ART to HIV-uninfected children not on ART (Group L1 vs C1)
2) To evaluate and compare the PK exposure and safety of 3-dose DP in HIV-infected 
children on LPV/r-based ART to HIV-uninfected children not on ART (Group L3 vs C3a)
3) To evaluate and compare the PK exposure of 3-dose DP in HIV-infected children on 
EFV-based ART and HIV-uninfected children not on ART (Group E3 vs C3a). 
4) To evaluate and compare the PK exposure of 3-dose DP in HIV-infected children on 
DTG-based ART and HIV-uninfected children not on ART (Group D3 vs C3b). 
SECONDARY OBJECTIVES: 
1) The effects of DP on antiretroviral PK in the above 3-dose arms (EFV, DTG, LPV/r and 
controls)
2) To evaluate the association of anthropomorphic indicators of malnutrition on PK 
exposure of DP in HIV-infected and HIV-uninfected children
3) Assess auto-induction of DHA from single dose to 3-dose
4) To assess the prevalence of pharmacogenetic variants in key metabolic enzymes, 
including UGT1A1, CYP2B6, CYP3A4, and ABCB1, and the impact of these variants on 
ACT and ART PK.

I.0 INTRODUCTION
1.1 Background
1.1.1 Malaria and artemisinin-combination therapy in sub-Saharan Africa. 
Plasmodium falciparum malaria in Africa remains one of the most challenging infectious 
diseases in the world. According to the latest World Malaria Report, there were 219 
million cases of malaria in 2017, up from 217 million cases in 2016. The estimated 
number of malaria deaths stood at 435 000 in 2017, an improvement from the previous 
year (451 000)(1). Sub-Saharan Africa has the heaviest burden, bearing >90% of 
deaths, primarily in young children <5 years of age for whom antimalarial dosing 
guidelines are not yet optimized.(2) Treatment of uncomplicated malaria in children 
relies solely upon the artemisinin-combination therapies (ACTs).(2, 3) The artemisinins 
rapidly reduce parasite load while the long-acting partner drugs eliminate residual 
parasites and protect against artemisinin resistance and recurrent infection. In 2013 
alone, an estimated 392 million ACT courses were procured by malaria-endemic 
countries(2) with artemether-lumefantrine (AL), artesunate-amodiaquine (AS-AQ), and 
dihydroartemisinin-piperaquine (DP) stipulated as first-line according to the World 
Health Organization (WHO).(4) While AL is the most widely utilized ACT, DP use is on 
the rise as it protects best against recurrent infections, due to the longer half-life of 
piperaquine (PQ; 1 month) as compared to lumefantrine (3 to 5 days).(4, 5) Thus, DP is 
being used both for treatment (2, 6-9) and is under study as intermittent prevention 
therapy for children and pregnant women.(10-13) In addition, given widespread 
resistance to SP, a commonly used IPT, in parts of Africa, many are considering the use 
of DHA/PQ, which provides rapid killing of most parasites by DHA and protection for 
weeks after therapy due to the long half-life of PQ.(14)In Uganda, directly observed 
monthly DHA/PQ administered to school children 6–14 years of age for 1 year had a 
protective efficacy of 96 %.(14, 15)t
1.1.2 HIV and antiretroviral treatment (ART) in sub-Saharan Africa. Sub-Saharan 
Africa is also home to 25 million people with HIV; 2.9 million of whom are children <15 
years,(16-19) and all of whom are eligible for ART under new WHO guidelines.(20) 
First-line ART includes lopinavir/ritonavir (LPV/r)-based ART for children <3 years, and 
efavirenz (EFV)-based ART for children >3 years(20-22) with 86% of 58 WHO focus 
countries adopting EFV-based ART as their preferred 1st-line regimen. (23) As of 2018, 
WHO has recommended dolutegravir (DTG), an integrase inhibitor, as alternative first-
line therapy for children >6 years weighing at least 15kg (24). The recommended dose 
for adolescence and adults is 50mg once daily.(23) There have been many initiatives to 
transition eligible patients from the traditional EFV-based therapy to DTG-based 
regimen due to its high potency, high genetic resistance barrier, and low toxicity 
risks.(25)  We will study the antimalarial DP, given as single and/or 3 consecutive daily 
doses in 4 populations: HIV-uninfected children and HIV-infected children stabilized on 
LPV/r-, EFV-, or DTG-based ART—to further elucidate the PK effects and safety 
profiles of drug-drug interactions between HIV and anti-malarial medications.(26) Due to 
reports in May 2018 of a potential increased risk of neural tube defects in women 
exposed to DTG during the 1st trimester, we will exclude any females on DTG-based 

ART, age 13-17 from participation in our study who are pregnant, or of childbearing 
potential and do not agree to consistent and reliable contraception.(27) 
1.1.3 Malaria and HIV in Uganda. Uganda bears a heavy burden of both malaria and 
HIV. Although malaria prevention and control programs have reduced infections and 
mortality overall, Uganda still has one of the highest malaria transmission intensities in 
the world.(23) In Tororo, children experience up to 2 to 6 malaria episodes per year, 
despite usage of bed nets and trimethoprim-sulfamethoxazole (TS) for those HIV-
infected.(2, 28) For HIV, Uganda is lauded for prior success in stemming the HIV 
epidemic, but new infections are now on the rise.(28-32) It is estimated that 2 million 
HIV-infected children will reside in sub-Saharan African in 2020.(20) Thus, HIV-malaria 
co-infection remains common, with treatment complicated by multiple pharmacological 
factors that require field-based studies.
1.1.4 Significant drug interactions occur between ART and ACT. 
Both components of AL and DP undergo metabolism. 
Dihydroartemisinin (DHA) undergoes metabolism via 
uridine diphosphate-glucuronosyltransferases 
(UGT).(20, 33) Our group has also recently reported on 
the major pathway for PQ metabolism.(34-36) More 
specifically, our group studied the metabolism of PQ in 
vitro and reported inhibition was highest (83%) with 
ketoconazole, a selective CYP3A4 inhibitor, suggesting 
a primary role for CYP3A4 in PQ metabolism. Notably, 
with regards to ART, ritonavir and EFV cause potent 
CYP3A4 inhibition and induction, respectively.(37-39) 
DTG is primarily metabolized by UGT1A1, with a small 
contribution by CYP3A4.(40)
For AL, we have recently demonstrated a marked 
increase in lumefantrine exposure (defined by the area 
under the concentration curve, AUC) occurred during 
LPV/r-based ART co-administration, contrasting with a 
highly significant decrease in artemether, DHA, and 
lumefantrine when given with EFV-based ART, resulting 
in a 10-fold variance in lumefantrine exposure in HIV-infected children with malaria.(41-
43) The resulting change in AL exposure with EFV-based ART was associated with a 
~4-fold higher risk of recurrent malaria compared to the change in AL exposure with 
LPV/r. These results, and our earlier findings of unexpected toxicity with AS-AQ and 
EFV, have impacted HIV and malaria treatment guidelines; specifically, AQ and EFV co-
administration is to be avoided and AL and EFV co-administration should be used with 
caution.(6, 44-46)

 Table 1.  Impact of pregnancy and EFV-based ART on the pharmacokinetics of piperaquine
During pregnancy
After pregnancy
Ratio
HIV uninfected  
(no ART)
HIV infected    
(EFV)
HIV uninfected   
pregnant/non-pregnant (HIV 
uninfected)
EFV/no ART (all 
pregnant)
EFV and 
pregnant/non-
pregnant
n=30***
n=26¥
n=30
Paired (n=27)
All subjects
Cmax, ng/mL
391 (323, 474)
342 (285, 411)
499 (393, 633)
0.82 (0.12)
0.78 (0.08)
0.88 (0.13)
0.69 (0.001)
Tmax, hr
3.11 (3.00, 4.03)
3.99 (2.03, 5.98)
3.06 (2.07, 4.03)
1.01 (0.91)
1.02 (0.62)
1.28 (0.84)
1.30 (0.64)
t1/2, hr
161 (143, 183)
124 (104, 149)
208 (187, 232)*
0.79 (0.012)**
0.77 (0.003)
0.77 (0.01)
0.60 (<0.0001)
AUC0-d21,  hr·µg/mL
10.6 (8.84, 12.7)
6.60 (5.57, 7.83)
17.6 (15.1, 20.7)
0.61 (0.0001)
0.60 (<0.0001)
0.62 (0.0001)
0.38 (<0.0001)
C7d, ng/mL
30.5 (25.9, 36.0)
15.1 (13.0, 17.6)
39.0 (32.3, 47.2)
0.79 (0.03)
0.78 (0.07)
0.50 (<0.0001)
0.39 (<0.0001)
C14d, ng/mL
15.0 (12.4, 18.1)
6.67(5.44, 8.19)
22.6 (18.7, 27.3)
0.68 (0.004)
0.66 (0.007)
0.45 (<0.0001)
0.30 (<0.0001)
C21d, ng/mL
11.8 (10.2, 13.6)
3.75 (2.77, 5.08)
14.5 (12.2, 17.1)
0.83 (0.05)
0.81 (0.02)
0.32 (<0.0001)
0.26 (<0.0001)
Note: ART, antiretroviral therapy; EFV, efavirenz-based ART;  Cmax, maximal concentration, Tmax, time to reach maximal concentration, t1/2, drug 
elimination half life, AUC, area under concentration-time curve,  AUC was calculated using piperaquine concentrations from venous plasma with 
conversion of capillary to venous plasma concentrations when necessary; C7d, C14d, and C21d are actual capillary plasma concentrations at day 7, 
14, and 21 post the 3rd dose. Data are presented as geometric mean (95% confidence interval) except for Tmax, which is reported as median 
(interquartile range). P-value is calculated with Stata® 12.1 using Wilcoxon rank sum test (or signed rank test for paired analysis) Significance 
level: alpha=0.017(0.05/3); . *n=29. **n=26. Paired represents same HIV uninfected women enrolled antepartum and postpartum.***one subject 
excluded since missing day 21 PK sample. ¥ one subject excluded since missing day 14 and 21 samples

For DP, data on the interaction with ART in vivo is limited. There is one study in malaria 
uninfected adults (Banda CG et al 2018) that evaluated DP in the context of EFV-, 
LPV/r-, and nevirapine-based ART regimens. Banda et al. found that there was a 
significance decrease in DP exposure in the EFV-based ART group and did not find a 
significant difference in DP exposure between non-HIV infected adults and adults on 
LPV/r-based ART (albeit this arm only completed the half-dose phase of the study). Our 
group also recently demonstrated a reduction in DHA and PQ exposure in the setting of 
EFV-based ART in pregnant women (Figure 1; Table 1).(4, 45, 47-49)  No data are 
available on the interaction of DP and ART in children, nor on the impact of ART on 
clinical outcomes in the setting of the EFV-, LPV/r-, or DTG-based ART so that 
optimized treatment guidelines can be developed. 
1.1.5 Piperaquine is well tolerated but has been associated with prolongation of 
the QT interval. Overall, DP is very well tolerated, but concern exists over the potential 
for QT prolongation.(50) Myint, et al. conducted a systematic review of DP efficacy and 
safety for treatment of malaria using data from 14 clinical trials involving adults and 
children.(17, 51, 52) There were 2636 study participants treated with DP in 13 trials in 
which safety data were reported. Overall, DP was associated with fewer adverse events 
compared to comparator medications. With regards to QT prolongation, a randomized 
study of a compressed, 2-day regimen of DP for malaria prevention in Cambodian male 
adults found that 4 of 47 individuals in developed QTcF prolongation of >500 msec, 
leading to premature study termination.(52) In comparison to individuals receiving 
placebo, those receiving the compressed regimen had a mean increase in QTcF of 46 
msec post-treatment; a change that was correlated with piperaquine peak 
concentrations. Of note, in our group’s recently published study of DP PK in the setting 
of EFV in pregnant women, there was no significant correlation of PQ PK parameters 
and QT prolongation, and not QTcF >450 msec were observed, although peaks were 
lower than those seen in Cambodian adults.(51) Thus, data are conflicting regarding the 
risk of QT prolongation with PQ, as it remains unclear whether the observed 
prolongation is due to recovery from malaria (shortening of QT occurs during disease) 
and/or a direct effect of PQ.(50) Given concerns that higher PQ levels may lead to QT 
prolongation, and the likelihood of PQ-ART interactions in children, PK data for DP with 
concomitant ART is urgently needed.
1.1.6 ACT PK exposure is also affected by childhood development. The PK 
disposition of drugs in children differs substantially from that in adults.(51, 53-57) For 
metabolism, UGTs mature from 0-6 months of age while CYPs mature over 12 months 
of age.(58-60) Children >1 year from resource-rich settings often exhibit higher drug 
clearance compared to adults, which can reduce PK exposure and warrant higher 
doses (per kg).(61, 62) For DP, Ugandan children <2 years had PQ exposure ~33% 
lower than children 2-10 yrs,(63-65) and a Worldwide Antimalarial Resistance Network 
(WWARN) pooled analyses reported that children <5 yrs are at the highest risk of 
receiving suboptimal DP doses, differences that again may be attributed to higher drug 
clearance in young children.(10, 66-69) Importantly, as a result of work by our group 
and others, the WHO recently revised its dosing of DP in young children to improve PK 
exposure.(19)

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1.1.7 Suboptimum dosing of ACTs in the context of EFV-based ART has important 
implications for the emergence and spread of ACT resistance. Systematic under-
dosing, whether due to ART, malnutrition or other factors, is a concerning factor in the 
development and spread of antimalarial drug resistance.(4) This was suggested for 
sulfadoxine-pyrimethamine,(70) and recently for DP, where 36% of patients in 
Cambodia who failed to clear infection had PQ concentrations below in vitro target 
levels.(70, 71)  We have now shown that a) EFV-treated children have ~2-fold reduced 
exposure to AL, b) EFV-treated pregnant women have a significantly reduced exposure 
to DP. For the ~3 million sub-Saharan African children with HIV, EFV is first-line (when 
>3years).(51) For sub-Saharan African children with malaria, DP use is increasing, both 
for treatment and for chemoprevention. Thus, with the spread of artemisinin and DP 
resistance in Southeast Asia,(20) and emerging concerns for Africa,(72-75) there is 
mounting concern that suboptimal DP dosing in HIV-infected children on EFV-based 
ART or children will contribute to the emergence and selection of DP-resistant 
parasites.(76, 77) 
1.1.8 Genetic polymorphism in metabolic enzymes can alter both ACT and ART 
drug exposure. Antiretrovirals and ACT long-acting partner drugs are metabolized by 
enzymes that display genetic variation. Variants in these enzymes (CYP2B6, CYP3A4 / 
CYP3A5, ABCB1, and UGT1A1) have been shown to impact metabolism of drugs that 
are substrates of these pathways. For example, Maganda et al. found that individuals 
with a CYP2B6*6 genotype had increased EFV exposure, which was then linked to a 
significant reduction in lumefantrine exposure compared to individuals who were not 
taking concomitant EFV (78). As both lumefantrine and PQ are metabolized by 
CYP3A4, there could be a similar reduction in PQ exposure in CYP2B6*6 children 
taking concomitant EFV. We will also explore if there are other instances where 
pharmacogenomics could play a role in drug exposure by investigating the other CYPs 
and UGTs listed above that are key pathways for drugs studied in this proposal
1.2 Rationale
This study is designed to directly address antimalarial PK and safety objectives in 
children, primarily HIV-infected children, one of the most vulnerable populations to 
malaria in the world. This study will focus on the pharmacology of one of the WHO first-
line options for antimalarial treatment, DP. DP has also been studied for its use in 
chemoprevention of malaria, both in children and in pregnant women, and in settings of 
mass drug administration, although it is not yet been recommended for prevention of 
malaria in WHO guidelines. Our study will be conducted in healthy HIV-infected children 
on EFV-, LPV/r- or DTG-based ART, as well as in HIV-uninfected children who will 
serve as a control group. Children in the study will not have malaria. The primary goal of 
the study is to assess the PK and safety of DP in the setting of co-administration with 
first-line ART regimens. 
The ACTs are the most important drugs for the treatment of uncomplicated malaria and 
could have a vital role in the setting of chemoprevention in the upcoming years. Despite 
their widespread use globally, fundamental questions remain for assuring their optimal 

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use in our most vulnerable populations, especially for children in the context of 
interacting medications. Our results on ACT drug interactions are striking and reveal 
that HIV-infected children treated with AL have a wide range of antimalarial exposure 
depending on their ART. Compared to no ART, lopinavir/ritonavir (LPV/r)-based ART 
increased lumefantrine PK exposure >2-fold, while efavirenz (EFV)-based ART, first-line 
for children >3 years of age, dramatically reduced exposure to artemether, DHA, and 
lumefantrine. Importantly, these PK changes were associated with a 4-fold higher risk of 
recurrent malaria after treatment with AL in children receiving EFV compared to those 
receiving LPV/r. 
For DP, our group has demonstrated that PQ is metabolized in vitro by CYP3A4, 
suggesting that it may be subject to similar drug-drug interactions. These findings were 
supported by a ~38% lower PQ concentration in pregnant women on EFV versus HIV-
uninfected pregnant women.(70) Data on the interaction of EFV and DP in children are 
lacking, and if a similar reduction in DP exposure is seen, may be a risk for reduced 
efficacy and the selection of resistant parasites. Similarly, no data exists on the 
interaction of LPV/r-based ART and DP, the concern being that an increase in PQ 
concentrations may be a risk for QT prolongation. Additionally, there is no data on the 
interaction of DTG and DP in children and adolescents despite the high potential for 
DTG usage given the WHO’s recent initiative to encourage clinicians to transition 
eligible patients to DTG due to its high genetic resistance barrier, potency, and relatively 
low toxicity.
QT prolongation is safety concern with piperaquine. Based on our groups prior work, we 
know that piperaquine is a substrate of CYP3A4, and therefore piperaquine levels are 
anticipated to increase with concomitate LPV/r administration, a known CYP3A4 
inhibitor. Given concerns for cardiotoxicity, for the LPV/r-based arm ONLY, we will start 
with a single dose of DP in a group of HIV-infected children on LPV/r-based ART and a 
control group of single dose DP in HIV-uninfected children, to determine the magnitude 
and safety of the interaction, as well as to monitor QT intervals via ECGs (Phase I). 
Following the assessment of the PK and ECG-based safety data from the single dose 
DP groups, we will proceed with one of three different options: 1) no further study of 
LPV/r with DP due to safety concerns, 2) a reduced mg/kg dose of 3-dose DP in the 
context of LPV/r, or 3) standard mg/kg dosing of 3-dose DP in the context of LPV/r-
based ART (Phase II).  ECGs will be performed in participants in all study groups to 
ensure safety, and to provide data on QT intervals across the age spectrum.
  
We will conduct our study in HIV-infected children without malaria living in the urban 
setting of Kampala, Uganda, where our team has had previous experience in directing 
PK/PD studies, and where the largest pediatric HIV clinic in Uganda is located, and has 
long-standing established cohorts. For HIV-uninfected children without malaria, we will 
conduct our study in the malaria-endemic region of Eastern Uganda in Busia where our 
team has long standing experience directing field-based PK/PD studies in the most 
relevant populations.  We will utilize state-of-the-art intensive PK designs and drug 
assay methods to determine drug exposure and safety parameters. 

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Rationale for this study is summarized below:

Dosing guidelines for children have historically relied on studies carried out in adults 
despite knowledge that children exhibit distinct physiological characteristics that 
impact how drugs are handled by their body

Insufficient dosing may compromise care of acute infection but more importantly 
contribute to development of resistance

Excess PK exposure to PQ may be associated with a risk of QT prolongation

We have shown that PQ is metabolized by CYP3A4, and that pregnant women on 
EFV-based ART have significant decreases in DP exposure.

Administration of DP with LPV/r-based ART is expected to increase PQ exposure, 
with a concern for a risk of QT prolongation.

Despite the increase in DTG-usage in recent years, there is limited safety and PK 
exposure data in the setting of DTG-based ART and ACT co-administration. 

Given the above, the study of drug-drug interactions between DP and ART are best 
carried out in healthy malaria-uninfected children prior to larger studies to assess PK 
and PD in the setting of malaria infection. 

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2.0 STUDY OBJECTIVES
2.1 Primary Objectives: 
1) To evaluate and compare the PK exposure and safety of single dose DP in HIV-
infected children on LPV/r-based ART to HIV-uninfected children not on ART 
(Group L1 vs C1)
2) To evaluate and compare the PK exposure and safety of 3-dose DP in HIV-
infected children on LPV/r-based ART to HIV-uninfected children not on ART 
(Group L3 vs C3a)
3) To evaluate and compare the PK exposure of 3-dose DP in HIV-infected children 
on EFV-based ART and HIV-uninfected children not on ART (Group E3 vs C3a). 
4) To evaluate and compare the PK exposure of 3-dose DP in HIV-infected children 
on DTG-based ART and HIV-uninfected children not on ART (Group D3 vs 
C3b). 
2.2 Secondary Objectives: 
1) The effects of DP on antiretroviral PK in the above 3-dose arms (EFV, DTG, 
LPV/r and controls)
2) To evaluate the association of anthropomorphic indicators of malnutrition on PK 
exposure of DP in HIV-infected and HIV-uninfected children
3) Assess auto-induction of DHA from single dose to 3-dose
4) To assess the prevalence of pharmacogenetic variants in key metabolic 
enzymes, including UGT1A1, CYP2B6, CYP3A4, and ABCB1, and the impact of 
these variants on ACT and ART PK.
3.0 STUDY DESIGN
This is an open-label prospective pharmacokinetic and safety study of DP and 3 
different ART regimens in non-malaria-infected 1) HIV-infected children and 2) HIV-
uninfected controls not on ART. DP is a WHO approved first-line treatment for malaria 
and is increasingly being studied for its use in malaria chemoprevention. No change in 
standard of care treatment regimens will be made as part of this protocol. Figure 2 
summarizes the design. This study will enroll a) HIV-infected children, and b) HIV-
uninfected children. HIV-infected participants will be enrolled through the Baylor College 
of Medicine Children’s Foundation Uganda (Baylor-Uganda) Center of Excellence (CoE) 
in Kampala and the HIV-uninfected participants will be enrolled through the Masafu 
General Hospital (MGH) in Busia, or other referral centers in the area. Baylor-Uganda is 
a not for profit child health and development organization affiliated with the Baylor 
College of Medicine International AIDS Initiative (BIPAI).  All HIV care will be managed 
by the participant’s primary HIV providers.

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3.1 Overview of Pharmacokinetic Sampling Design
Subjects will undergo an intensive PK study sampling design, which entails multiple 
venous blood collections in a smaller sample of individuals to accurately estimate drug 
exposure over time. These studies will be conducted in both HIV-infected and HIV-
uninfected participants and will allow us to investigate DP PK exposure in the context of 
EFV-, LPV/r- and DTG-based ART in HIV-uninfected children. Comparisons will be 
based on an intensive PK design for DP AUC estimations. A sample size of 20 
children/adolescents will be needed in groups L1 and C1. A sample size of 30 will be 
needed for each of the other arms (D3, E3, L3, C3a, and C3b). Sampling will occur up 
to day 42 in the 3-dose groups given the long half-life of PQ and for 14 or 28 days in the 
single dose groups. The generation of an AUC will permit robust comparisons so that 
results will inform treatment guidelines and policy.  
Figure 2—Overview of Study Design

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3.2 Overview of study groups
HIV-infected children will be enrolled primarily through the Baylor-Uganda CoE located 
on the Mulago Hospital Complex. HIV-uninfected children will be enrolled from Masafu 
General Hospital in the Busia District and other referral clinics in the area. 
Table 2. Summary of Study Groups
Group
HIV 
status
ART regimen
DP 
regimen
Age range
(years)
Duration 
follow-up
(days)
Sample 
Size
E3
Infected
EFV-based ART
3-dose
3 - 10
42
30
D3
Infected
DTG-based ART
3-dose
11 - 17
42
30
L1*
Infected
LPV/r-based ART
Single 
dose 
3  - 10
28
20
L3
Infected
LPV/r-based ART
3-dose
3 - 10
42
30
C1**
Uninfected
None
3 -dose
3 - 10
14
20
C3a
Uninfected
None
3-dose
3 - 10
42
30
C3b
Uninfected
None
3-dose
11 - 17
42
30
* Single dose group L1 may be sequentially re-enrolled into 3-dose DP groups L3
provided there is a 42-day washout period in between phases.
** Group C1 will have intensive PK performed after the 1st dose of DP only to minimize
blood volumes
All sample sizes refer to “evaluable” PK participants, in other words, those that have 
completed follow-up sufficiently to obtain all required PK study samples. If a child does 
not complete PK sampling procedures for the intensive study for any reason (they are 
not “evaluable”), the child may be re-enrolled in the intensive PK study if they meet 
eligibility requirements. More than 2 missing PK samples will permit a child to repeat the 
study after a 42-day washout period from the last dose of DP.
3.2.1   HIV-infected participants 
This protocol will study the clinical pharmacology of DP in HIV-infected participants on 
EFV-, LPV/r- and DTG-based ART regimens. Children and adolescents in the study will 
be between 3 - 17 years. 30 children will be enrolled for intensive PK studies in each 
ART regimen and followed for up to 42 days (groups E3, D3, L3). For group L1, 20 
children will be enrolled, and PK will be assessed after a single dose, with children 
followed for 28 days.
3.2.2   HIV-uninfected participants
This protocol will also study the clinical pharmacology of DP in HIV-uninfected children 
aged 3 - 17 years. Up to 60 HIV-uninfected subjects will be enrolled for intensive PK 
studies of 3-dose DP and followed for up to 42 days (groups C3a and C3b). For group 
C1, 20 children will be enrolled, and PK will be assessed after the 1st dose of a 3-dose 
regimen, with children followed for 14 days. HIV-uninfected children will primarily serve 
as controls for PK comparison with HIV-infected children. 

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3.3 Study sites
The primary study site for recruitment of HIV-infected children is the Baylor-Uganda 
CoE on the Mulago Hospital Complex in Kampala, Uganda. The Baylor College of 
Medicine Children’s Foundation Uganda has been in operation since 2003 and delivers 
HIV/AIDS care and treatment to over 8500 HIV-infected children and family members, 
with many additional patients seen at affiliated outreach sites (https://bipai.org/uganda). 
All HIV-related care will be provided during the study by the child’s usual provider at the 
Baylor clinic.  
The primary study site for recruitment of HIV-uninfected children is at the Masafu 
General Hospital (MGH) campus situated in the Busia District, in Eastern Uganda. The 
study clinic in Busia will remain open 7 days a week from 8 a.m. to 5 p.m. HIV-
uninfected participants will be recruited from the community surrounding the MGH in the 
Busia District and all study procedures for the HIV-negative children will be conducted 
at the MGH study site. If non-study related medical care is needed for HIV-uninfected 
participants, parents/guardians/participants will be instructed to go to the MGH  and 
request that a study physician on-call be contacted. 
Similar to our previous PK studies, we will allow for referrals from neighboring health 
centers in the Busia districts, provided that entry criteria are met.
4.0 SELECTION AND ENROLLMENT OF SUBJECTS
4.1 Inclusion Criteria
4.1.1   All participants:
1) Agreement to come to clinic for all follow-up PK and safety evaluations
2) Provision of informed consent
4.1.2   HIV-infected participants: 
1) Residency within 30km of Mulago Hospital
2) Confirmed HIV infection (confirmed positive rapid HIV test or HIV RNA as per
Ugandan guidelines)
3) On stable EFV-, LPV/r- or DTG-based ART for at least 10 days prior to
enrollment
4) Age 3 - 10 years if on EFV-based ART or LPV/r-based ART
5) Age 11 - 17 years if on DTG-based ART
4.1.3   HIV-uninfected participants: 

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1) Residency within 30km of Masafu General Hospital
2) Confirmed HIV negative test (confirmed positive rapid HIV test or HIV RNA as
per Ugandan guidelines)
3) Age 3 - 17 years
4.2 Exclusion Criteria
1) History of significant comorbidities such as malignancy, active tuberculosis or
other active WHO stage 4 disease
2) Receipt of any medications known to affect CYP450 metabolism (except ART)
within 14 days of study enrolment (see 4.2.1)
3) Hemoglobin < 7.0 g/dL
4) Current malaria infection or recent treatment with antimalarials within 28 days of
enrolment.
5) Asymptomatic parasitemia detected by microscopy or RDT
6) History of side effects with DP
7) Prior history of cardiac disease (personal or family), baseline QTc >450msec, or
receipt of any cardiotoxic drugs or those known to prolong QT intervals History of
significant comorbidities such as malignancy, active tuberculosis or other WHO
stage 4 disease
8) Weight < 6kg
9) HIV-infected females on DTG-based ART and age 13-17 years who are pregnant
or of childbearing potential and do not agree to consistent and reliable
contraception
4.2.1 Disallowed Medication Guidelines
The following medications are disallowed within 3 weeks prior to receiving study drug:
•
Carbamazepine
•
Clarithromycin
•
Erythromycin (oral)
•
Ketoconazole
•
Phenobarbital
•
Phenytoin
•
Rifabutin
•
Rifampicin
•
Halofantrine
•
Any other medication known to significantly affect CYP450 metabolism.
•
Grapefruit juice should be avoided during the study due to its potential
effects on CYP3A4.
4.3 Identification and recruitment of study participants
HIV-infected children will be enrolled from sites listed above (Section 3.3). 
Parents/guardians of children will be approached for their willingness to participate in 
the PK study. Children will undergo up to 42 days of follow-up for which they will have 

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PK sampling carried out. Participants may be recruited through multiple referral 
mechanisms including those primary sites described below.
4.4 Screening 
HIV-infected and HIV-uninfected children will be screened for study eligibility at the time 
they present to the Baylor-Uganda CoE, MGH, or other referral sites. Parents/guardians 
will be asked about their willingness to have their child participate in the PK study 
involving up to a 42-day follow-up. If the initial verbal screening criteria assessed by 
interview are met, the child and parent or guardian will be asked to provide informed 
consent for laboratory screening and study participation (see Section 4.5). Consenting 
for PK procedures and future use of biologic specimens will be on two separate consent 
forms. Assent will be obtained following guidelines stipulated by the Uganda National 
Council for Science and Technology.  All laboratory procedures, including those for 
screening, will only be conducted after informed consent/assent have been 
obtained.
4.4.1   Laboratory Screening
1. Confirmation of negative malaria status. Will be done by either RDT or thick
smear. Blood will be obtained from a finger prick (in very young children, heel
sticks may be substituted for finger pricks). Thick smears will be read (and
counted if necessary) by the laboratory technicians at the time of presentation.
Smears will be considered negative when examination of 100 high-power fields
does not reveal parasites. If the thick blood smear is positive, participants will
either be managed by study physicians, or referred for care to adjacent clinics,
and treated as per standard of care.
2. Pregnancy testing. All females, age 13 and above will undergo pregnancy
testing. All pregnant females will be excluded from participation.
3. Hemoglobin testing. Will be performed by capillary finger-prick. Those with Hb<
7g/dL will be excluded.
4. HIV testing of HIV-uninfected children. HIV counseling and testing will be done
on all HIV-uninfected children as part of study enrollment screening.  Based on
results of testing, children will be referred appropriately to study staff and clinical
care (in the event they test positive for HIV for the first time).
4.5 Study informed consent and enrollment
Study physicians will conduct the informed consent discussion in the study clinic in the 
appropriate language for the adult or the parents/guardians; translators will be used if 
necessary. Children who are on LPV/r-based ART participating in the single dose 
intensive evaluations may be consented for both the single dose and 3-dose 
evaluations at the time of enrollment depending on the study enrollment needs. 
Following the informed consent discussion, parents/guardians/participants will be asked 

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by the study physicians to sign a research participation informed consent form or assent 
form (Appendices) approved by the UCSF Human Research Protection Program (UCSF 
HRPP), Yale Human Investigations Committee (Yale HIC), Baylor College of Medicine 
IRB, Joint Clinical Research Centre - Research Ethics Committee (JCRC-REC), the 
National Drug Authority in Uganda and the Uganda National Council for Science and 
Technology (UNCST) that will be available in 3 languages (Luganda, Samia, English). 
The informed consent forms will contain information and permission for specimen 
banking and future use of biological specimens. If the parent/guardian/participant is 
unable to read or write, their fingerprint will substitute for a signature, and a signature 
from a witness to the informed consent procedures will be obtained. The witness may 
be a family member, clinic staff not conducting the informed consent discussions, or a 
translator. Assent will be obtained for those children 8-17 years, according to Ugandan 
guidelines.
5.0 MALARIA STUDY DRUG: DIHYDROARTEMISININ-PIPERAQUINE
Participants enrolling in the study will receive DP as oral tablets which will be dosed 
based on the child’s weight and WHO recommendation. DP is a first-line treatment for 
malaria by the WHO and is being studied for possible use as chemoprevention. 
Importantly, children with malaria in Uganda may receive DP at no charge by the 
Ugandan Ministry of Health when presenting for care with malaria. Dosing in children is 
primarily based on weight-based adjustments to adult dosing. Overall, DP is very well 
tolerated, but concern exists over the potential for QT prolongation.(50) Myint, et al. 
conducted a systematic review of DP efficacy and safety for treatment of malaria using 
data from 14 clinical trials involving adults and children.(17, 51, 52) There were 2636 
study participants treated with DP in 13 trials in which safety data were reported. 
Overall, DP was associated with fewer adverse events compared to comparator 
medications. The most common adverse events were dizziness, nausea and vomiting, 
though generally the medication was well tolerated by both adults and children. Of note, 
the only serious adverse events in these 14 studies included 5 deaths (2 adults, 3 
children) that were thought unrelated to DP.
Lwin, et al. conducted a randomized controlled trial of monthly versus bimonthly DP IPT 
among 961 adults at high risk of malaria at the Northwest border of Thailand.(52) 
Overall, 69% of the participants included in the final analysis reported at least one 
adverse event. There was no difference in the proportion of those reporting at least one 
adverse event among participants in the monthly versus bimonthly versus placebo 
arms. There was an increased risk of joint pain among participants randomized to the 
placebo arm, but otherwise there was no difference noted in adverse events by study 
arm. There was only one serious adverse event, which was not related to the use of DP.
5.1 DP and QT prolongation. In 2016, the WHO convened an Evidence Review Group 
(ERG) to assess the cardiac safety of antimalarials, with particular focus on the QT 
interval.(17) The QT interval is associated with the risk of drug-induced torsades de 
pointes (TdP), a potentially lethal arrhythmia. The review followed the “ICH E14: The 

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clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-
antiarrhythmic drugs”, guidelines set forth by the Food and Drug Administration (FDA). 
According to E14 guidelines, QT intervals should be corrected for heart rate, and 
Fridericia’s correction is considered sufficient (QTc = QT/RR0.5). In addition, an increase 
in QT or QTc > 500ms or >60ms above baseline are considered thresholds of particular 
concern. Categorical analysis and AE reporting are also recommended with absolute 
QT/QTc intervals of >450, >480, and >500, or increases of >30ms, and >60ms above 
baseline.
According to the review, there have been 19 deaths recorded for participants receiving 
DP in the context of mass drug administration studies, with one case of sudden death 
and the other 18 deaths not deemed related to cardiac causes. In conclusion, the 
committee stated that “among ~200 000 treated individuals with close follow-up, one 
possible sudden cardiac death associated with DP was reported. This finding is 
consistent with the risk of fatal cardiotoxicity associated with other QT/QTc-prolonging 
medicines in current use”. In addition, “Review of pharmacovigilance, clinical and 
preclinical data, along with preliminary results of PK/PD modelling, reveals no evidence 
of a significant difference in the risks of cardiotoxicity following exposure to piperaquine, 
chloroquine or amodiaquine at the current recommended doses. The risks of 
cardiotoxicity of piperaquine-containing medicines are probably similar for healthy 
volunteers and malaria patients.”(79)
A randomized study of a compressed, 2-day regimen of DP for malaria prevention in 
Cambodian male adults found that 4 of 47 individuals in developed QTcF prolongation 
of >500 msec, leading to premature study termination.(80) In comparison to individuals 
receiving placebo, those receiving the compressed regimen had a mean increase in 
QTcF of 46 msec post-treatment; a change that was correlated with piperaquine peak 
concentrations. 
Recently, a large directly relevant study utilizing the previous WHO DP dosing regimen 
was published, providing additional safety data for DP.(81) A prospective, observational, 
longitudinal, multi-center study of 10,925 participants with uncomplicated malaria 
treated with DP, and monitored for adverse events, including a nested cohort of 1002 
patients receiving serial ECG’s was reported. A total of 797 adverse events were 
reported. No patients had a QTcF >500msec prior to the last dose, and 3 had post-last 
dose QTcF>500msec which returned to <500msec by day 7. Pre- vs post-last dose 
QTcF >60msec occurred in 70 and 89 participants, respectively, but all returned to near 
baseline levels by day 7.
Relevant to this protocol was an open label randomized clinical trial being conducted by 
investigators of the Infectious Diseases Research Collaboration (IDRC) evaluating the 
protective efficacy of 3 different chemoprevention regimens against malaria compared 
to the current standard of care of no chemoprevention (R. Kajubi, personal 
communication). This study evaluated the safety of DP when used as chemoprevention 
in infants. Final results have been generated and show DP to be very well-tolerated and 
associated with a significantly lower rate of all grade 3-4 adverse events, elevated 

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temperature, anemia, and thrombocytopenia compared to the control arms. In addition, 
145 ECGs performed on 19 study participants randomized to DP have documented QTc 
intervals to be within normal limits.
5.2 Dihydroartemisinin. The artemisinins (dihydroartemisinin in the case of DP) are 
generally well tolerated in humans.  In a clinical safety review of 108 studies including 
9241 patients, no serious adverse events or significant toxicities were reported (51).  Of 
minimal concern is the potential for artemisinin associated auditory toxicity. However, in 
a study based in Thailand, there was no evidence of auditory toxicity reported(82). 
5.3   Dosing schedule for DP
Of note, in malaria studies, it is standard practice to refer to the 1st day of treatment as 
study day 0. This nomenclature is used universally in the clinical care of malaria 
patients and has been the standard for all our studies in Uganda. We will use the study 
day nomenclature throughout this protocol.
The primary focus of the intensive PK studies involves PK sampling around the last 
dose of the DP regimen. Standard DP treatment consists of 3 consecutive once-daily 
doses. All participants on DTG- and EFV-based ART, and their controls, will receive the 
standard 3 consecutive once-daily doses. For children in the LPV/r-based ART and 
respective control group, the study will be conducted in 2 phases. Phase I participants 
on LPV/r-based ART will receive a single dose of DP (L1) and a control group of HIV 
uninfected children (C1) will receive 3 consecutive once-daily doses of DP but will 
undergo intensive sampling ONLY following the first dose. Following PK and safety 
evaluation of Phase I participants, we will determine if halting or dose adjustment are 
needed in the before proceeding to Phase II (3 consecutive once-daily dosing in those 
on LPV/r-based ART (Group L3). Group C3a will serve as controls for L3 and will 
receive 3 consecutive once-daily doses. 
5.4   Drug Administration
Every dose of DP will be administered with only water, three hours before or after food 
to minimize risk of adverse side effects such as QT prolongation. Doses will be 
administered observed by a study nurse and time of dosing will be recorded. Due to risk 
of increase exposure of DP and QT prolongation, especially in the presence of a 
CYP3A4 inhibitor, children on LPV/r-based regimen will be given a single dose to inform 
DP dosing for the 3 consecutive once daily regimen. Weight-based dosing will be as 
below (Table 3 for HIV-infected children on EFV-based and DTG-based ART and HIV-
uninfected children.
Table 3. Weight-based daily dosing following 2015 WHO guidelines for DP(4)
Weight (kg)
Dihydroartemisinin + Piperaquine dose (mg)
5 to <8
20 + 160
8 to <11
30 + 240

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11 to <17
40 + 320
17 to <25
60 + 480
25 to <36
80 + 640
36 to <60
120 + 960
60 to <80
160 + 1280
>80
200 + 1600
Efavirenz-, lopinavir/r-, dolutegravir-based ART. This study will not initiate ART 
treatment. Initiating and management of ART use will be carried out through the study 
subjects’ usual clinic (Baylor CoE). HIV-infected children will receive ART as per 
prescription through their primary HIV clinic. No changes in ART will be made for the 
purposes of this protocol.  While receiving DP, ART administration in the morning will 
occur at the same time as DP administration (with the exception of EFV, which is taken 
at night) and the timing will be documented. In order to meet eligibility, children will need 
to have been maintained on ART for at least 10 days prior to enrollment.  
5.5   Missed Doses of DP
Missed doses due to vomiting:

If the episode of vomiting occurs ≤30 minutes post-administration of DP,
participants will be counseled to repeat the dose.  PK sampling will only continue
if the subject can be re-dosed with a full dose and vomiting occurred ≤30 minutes
post-administration of DP.

If the vomiting occurs more than 30 minutes but less than 2 hours post-
administration of DP, redosing of 50% of the dose should occur. The redosing
will be carefully noted on the study case report forms.

Any patient who vomits repeatedly (> 3 times) will be withdrawn from the study.
Missed or late doses due to other reasons:  

If a DP dose was missed or late for any other reason, the dose needs to be taken
as soon as remembered.

If a dose is deemed too many hours late by the study team, the patient will be
withdrawn from the study and PK sampling will not occur.
5.6   Drug supply and distribution
Dihydroartemisinin-piperaquine 
DP is a first-line malaria treatment option in Uganda and is readily available in 
pharmacies and clinics throughout the country. However, to ensure consistency in drug 
preparation, this study will supply the DP for all participants, and will be purchased 
through Ugandan suppliers of the Duocotexin product (as per program pharmacist), 
which is brand name DP. All doses will be provided by and observed in the study clinic.
LPV/r-, EFV-, and DTG based antiretroviral therapy

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LPV/r-based ART is the WHO first-line ART regimen for all children under 3 years of 
age and EFV-based ART is the WHO first-line ART regimen for all children > 3 years of 
age, adolescents, and adults.(83) DTG-based ART is a new regimen recommended by 
WHO as alternative first-line therapy for adolescents over 6 years (and weighing at least 
15kg) and adults. As of June 2017, DTG has been approved by the FDA for use among 
children 6 years and older (weighing at least 30 kg), and by the European Medicines 
Agency for children weighing more than 15 kg (24). ART for HIV-infected participants 
will be administered and managed through their usual clinic.  Those who are not yet 
followed by a clinic will be referred to the appropriate HIV clinic for follow-up of HIV. This 
study will maintain a supply of ART, either provided by Baylor Uganda CoE, the Uganda 
Ministry of Health or purchased by the study, to provide to study participants as 
necessary.  
5.7   Drug Accountability
The study pharmacist will maintain complete records of all study-related medications 
received in the study pharmacy. Lot number and number of pills given to each 
participant at each visit will be recorded. Patients will be requested to return all empty 
drug bottles and to bring any bottles in use to the clinic at follow-up visits. A registry of 
all medications, current product labels, and Certificates of Analysis, provided by 
suppliers will be maintained within the regulatory binder for the study. The date 
received, lot number, expiration date, and date used will be recorded for each of the 
medications. Monthly inventory of all medications will be conducted and a record log of 
medications will be kept at the study clinic. All unused drugs will be returned to the drug 
dispensaries after the study is completed or terminated.
6.0 CLINICAL AND LABORATORY EVALUATIONS
6.1 Schedule of Evaluations
See Appendix A for Schedule of Evaluation (SOE) Table
6.2 Management of malaria or non-malarial illness
If a participant is diagnosed with uncomplicated malaria he or she will receive treatment 
with either AL or other antimalarials in the clinic, as per standard of care. Participants 
will not be treated with DP as it will be assumed that the current infection was not 
prevented by DP given to the participant earlier in the study. If a patient is diagnosed 
with severe malaria, he or she will be referred to Mulago or Masafu General Hospital to 
receive quinine or artesunate following standard MoH treatment guidelines. In both 
cases, participants will be followed up in our clinic for 7 days to ensure proper response 
to malaria treatment and to obtain safety follow-up laboratories as part of the study. 
Participants presenting to clinic for non-malarial illness will managed in clinic or referred 
as necessary to Mulago or MGH.

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6.3 Unscheduled or After-hours Visits
Parents/guardians will be encouraged to visit the study clinic when urgent care is 
needed for her or his child outside of study clinic hours. Parents/guardians will be 
instructed to inform hospital personnel of their child’s involvement in the study at the 
time of registration and to visit the study clinic on the following day. If a patient is 
diagnosed with uncomplicated malaria outside of clinic hours, he or she will receive 
treatment at the local hospital (either Mulago or MGH) and the doctors will be instructed 
to refer patients to our study clinic when it opens at 8 am the following day. Participants 
will be instructed to request treatment with antimalarials other than DP when presenting 
with malaria outside of clinic hours. If a patient is diagnosed with severe malaria, he or 
she will receive quinine or artesunate following standard MoH treatment guidelines. In 
both cases, participants will be followed up in our clinic for 7 days to ensure proper 
response to malaria treatment and to obtain safety follow-up laboratories as part of the 
study. Patients with non-malarial illnesses will be managed at the discretion of the 
hospital/clinic staff. 
6.4 Missed or late visits. 
Parents/guardians/participants will be instructed to return on specified follow-up days in 
all studies. If a participant fails to return on the appropriate follow-up day, a home visitor 
will be sent to assist them in returning to the clinic as soon as possible for follow-up.
6.5 Clinical and Laboratory Studies
Scheduled and unscheduled visits will include a detailed history and physical 
examination, measurement of temperature, height, and weight. Blood will be collected 
on Study Day 0, 14, 28, and 42 for CBC, differential, and liver function tests (LFTs; AST, 
ALT) for groups D3, L3, E3, C3a, and C3b. For groups L1 and C1, blood will be 
collected on Study Day -1, 14, 28 (L1 only) for CBC, differential, and liver function tests 
(LFTs; AST, ALT).  Additional venipunctures may be performed, as appropriate, for 
laboratory testing to evaluate non-malarial medical illnesses at the discretion of study 
physicians. Results will be made available to study physicians for patient management 
decision-making. 1 mL of additional blood will be collected on Day 0 for testing of 
pharmacogenetic variants for groups E3 and D3.
HIV-uninfected children will have HIV serostatus documented through rapid testing, and 
will follow Ugandan MoH guidelines. All positive test results generated for the purpose 
of this study will be confirmed through Western Blot or HIV RNA. If needed, HIV 
counseling and referral will be made. Children will not be notified of HIV testing results. 
Parents and guardians will be notified, and provided post-test counseling, and referred 
to the appropriate HIV clinic for care.  HIV infected children will be expected to have HIV 
status confirmed through their clinic and will be required to be stabilized on at least 10 
days of ART to meet enrollment criteria.
6.6 ECG studies

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The expected peak of piperaquine is 4-6 hours post-last dose. Based on the expected 
directionality of drug-drug interactions, elevated piperaquine concentrations are ONLY 
expected in those children receiving lopinavir-ritonavir (LPV/r).  However, in an effort to 
ensure safety for all children, ECGs will be carried out in all participants. This will also 
allow us to assess the potential impact of age on QT interval changes since we will 
have data from participants ages 3 to 17 years. All ECGs will be performed in triplicate 
and central tendency used as the analysis measure. Additional ECGs may be 
performed for safety follow-up, as needed. All ECG results will be reviewed by two 
experienced ECG readers. Both ECG readers will be experienced in reading pediatric 
ECGs, and will be blinded to each other’s reading. One of the readers will be a non-
study team member. All ECGs with discrepancies between two readers will be re-
evaluated. 
Timing of ECGs:
1) Group L1 (single dose DP in the context of LPV/r-based ART)

Day -1: baseline ECG

Day 0: ~ 4 to 6 hours post-dose (corresponding to peak piperaquine 
concentrations)

Day 7 
2) Groups E3, D3, L3, C1*, C3a, and C3b (all of these groups receive 3-dose 
DP).

Day -1: baseline ECG

Day 2: ~ 4 to 6 hours post-last dose (corresponding to peak 
piperaquine concentrations in a 3-dose regimen)

Day 7

Day 42
*Note – for Group C1, ECG will also be performed approximately 4 to 6 hours post-
dosing on Day 0 (corresponding to peak piperaquine concentrations) so that single dose 
QT impacts can be compared to group L1
6.7 Pharmacology Laboratory Studies
6.7.1 PK sampling for 3-dose study groups (E3, D3, L3, C3a, C3b)
DP administration will be on Study Days 0, 1, and 2. PK samples for DHA and PQ will 
be collected on Study Days 0-4, 7, 14, 21, 28, 35, and 42. 
Sampling for DHA Quantitation
Capillary samples (200 μL each*) will be collected by finger stick at approximately 2 and 
4 hours post- each morning DP dose (Day 0-1). An additional capillary sample will be 
collected pre-dosing on Day 1.
Intensive venous sampling will occur precisely at the same times as per the single dose 
PK evaluations except it will occur post-administration of the 3rd dose of DP. 
Participants will remain in the clinic until completion of the 8-hour blood sampling on 

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Study Day 2 and discharged home. They will then return to the clinic the next morning 
for the 24 hours sample (Study Day 3). 
Sampling for Piperaquine Quantitation
A pre-1st dose sample will also be collected to confirm no residual antimalarial drug is 
detectable. Intensive sampling on Day 2 (as for DHA) will also be used for piperaquine 
analysis. Participants will be asked to return to the clinic on Study Days 3, 4, 7, 14, 21, 
28, 35, and 42 (venous or capillary sampling, 200-500 uL each*). 
For all evaluations, samples up to 24 hours will be used to measure DHA while all 
samples collected will be analyzed for PQ. PK sampling will be discontinued in patients 
who do not meet laboratory eligibility criteria or do not complete DP dosing. 
Correlation Sampling
For groups C3a and C3b, a simultaneous venous and capillary sample will be collected 
on Day 0 (4 hours post-dose), Day 2 (4 hours post-dose), Day 3 (24 hour post last 
dose), Day 7, and Day 14 to correlate venous and capillary concentrations of 
artemisinins and piperaquine.
For groups D3, E3, and L3 a simultaneous venous and capillary sample will be collected 
on Day 14 to correlate venous and capillary concentrations of piperaquine.
Sampling for Antiretrovirals*
A pre-dose venous sample on day 0, day 2, and day 3 will be collected to obtain a 
trough or mid-level of lopinavir/ritonavir, dolutegravir, and efavirenz. In addition, venous 
samples will be collected on Day 2 in the E3 group at 2-, 4-, and 8-hour post-DP dosing. 
This will allow for the comparison of trough antiretroviral PK levels in the 
absence/presence of DP and AUC differences of EFV between pharmacogenetic 
variants. 
*Sample volumes will be as listed above, except for except for day 0, day 2, and day 3 
which will be approximately 1 mL (to allow for antiretroviral PK measurement).
6.7.2 PK sampling for single dose study groups (L1 and C1)
For Phase I, intensive sampling will be conducted after a single DP dose only 
(administered on Day 0). However, C1 participants will get two additional doses of DP 
(2nd dose on Day 1 and 3rd dose on Day 2). 
L1: PK samples will be collected on Study Days 0-2, 7, 14, 21, and 28. 
C1: PK samples will be collected on Day 0 and Day 1. 
Sampling for DHA Quantitation

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Intensive venous sampling will occur via an indwelling catheter prior to and 0.5 1, 2, 3, 
4, 6 and 8 hours post-administration of the Day 0 dose of DP for the determination of 
DHA (and PQ) concentrations in plasma (500 µL each. Participants will remain in the 
clinic until completion of the 8-hour blood sampling on Study Day 0 and be discharged 
home. They will return to the clinic the next morning for the 24-hour sample (Study Day 
1). 
Sampling for Piperaquine Quantitation
A pre-1st dose venous sample of 500 uL will be collected to confirm no residual 
piperaquine is detectable. Intensive sampling on Day 0 (as for DHA) will also be used 
for piperaquine analysis.  C1 participants will have their final PK sample collected the 
next morning for the 24-hour sample (Study Day 1). L1 participants will return on Study 
Days 1, 2, 7, 14, 21, and 28 (venous or capillary sampling, 200-500 μL each). 
For all evaluations, samples up to 24 hours will be used to measure DHA while all 
samples collected will be analyzed for PQ. PK sampling will be discontinued in patients 
who do not meet laboratory eligibility criteria or do not complete DP dosing. 
Pharmacogenetic studies
1 mL of venous blood will be collected on Day 0 in the E3 and D3 groups to genotype 
CYP2B6, CYP3A4 / CYP3A5, UGT1A1, ABCB1 and to investigate connections between 
pharmacogenetic variation and EFV, DTG, and DP PK.
6.8 PK Sample collection and handling
For consistency, blood samples will be obtained from capillary or venous sources, as 
specified. However, if venous PK samples cannot be obtained at desired times due to 
technical or other limitations, technicians may obtain blood from a capillary site. 200 µL 
capillary samples will be collected by finger prick and can be used to measure both 
analytes but without the ability to do repeat analysis if necessary. 500 µL and 1 mL 
venous samples permits repeat analysis as needed. All samples will be immediately 
placed on dry ice, processed for plasma, transferred to liquid nitrogen, and shipped at a 
later date on dry ice to our laboratory for analysis. Liquid nitrogen will be obtained from 
Kampala.
6.8.1 Assays for DHA, Piperaquine and Antiretrovirals
DHA, piperaquine, efavirenz, lopinavir/ritonavir, and dolutegravir will be measured using 
optimized methods validated in our laboratory. All methods will utilize liquid 
chromatography tandem mass spectrometry.

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7.0 TOXICITY AND DATA AND SAFETY MONITORING PLAN (DSMP)
7.1 Overview and Summary
An adverse event is defined as "unfavorable changes in health, including abnormal 
laboratory findings that occur in study participants during the study or within a specified 
period following the study”.  All of the medications in the study have been approved in 
Uganda for treatment of HIV and malaria, and dihydroartemisinin-piperaquine is actively 
being studied around the world for possible use as malaria chemoprevention. DP has 
been studied for chemoprevention, using standard treatment dosing regimens, with 
many clinical studies supporting its use, though it is not standard of care. The drugs 
used in this study are also provided by the Ministry of Health free of charge outside of 
this study. Data regarding the tolerance of DP will be recorded. Study clinicians will 
assess patients at each scheduled and unscheduled visit to the clinic according to a 
standardized clinical record form using scales developed by the NIH Division of AIDS 
Adult and Pediatric Toxicity Tables version 2.1, March 2017.
7.2 Communication Plan 
The study team will have weekly calls on Thursday to discuss the study and review 
newly enrolled participants, participants’ labs, adherence to the protocol, any comments 
or concerns, etc. In addition, if there are any urgent matters (e.g. adverse events, Grade 
3 / 4 lab abnormalities, protocol deviations, etc.) this will be communicated to the team 
immediately via email or phone communication. Incidents requiring reporting will then 
be reported as per the guidelines below.
7.3 Reporting
Guidelines for reporting of adverse events due to study participation provided by UCSF 
HRPP & HIC, Yale HIC, Baylor College of Medicine IRB, NICHD, JCRC-REC, NDA and 
UNCST will be followed as described below. 
Sunil Parikh will be responsible for reporting any adverse events, protocol violations, 
protocol deviations, etc. to Yale University. Fran Aweeka will be responsible for 
reporting any adverse events, protocol violations, protocol deviations, etc. to UCSF and 
NICHD. Norah Mwebaza will be responsible for reporting any adverse events, protocol 
violations, protocol deviations, etc. to UNCST, NDA, and JCRC-REC. Grace Paul Kisitu 
will be responsible for reporting any adverse events, protocol violations, protocol 
deviations, etc. to Baylor College of Medicine.
Per UCSF HRPP & HIC guidelines as found on website updated April 2017: Adverse 
events which are definitely, probably, or possibly related to study procedures or study 
participation AND serious
 or unexpected will be reported. AEs which do not meet those 
criteria will be documented, referenced, and retained in the study files for follow-up. Per 
UCSF HRPP & HIC guidelines, the following definitions for serious or unexpected 
adverse events will be followed:
*Serious Adverse Event (SAE) is any AE that results in any of the following outcomes:
• Death,

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• Life-threatening adverse experience,
• Inpatient hospitalization or prolongation of existing hospitalization,
• Persistent or significant disability/incapacity,
• Congenital anomaly/birth defect, or cancer, or
• Any other experience that suggests a significant hazard, contraindication, side 
effect or precaution that may require medical or surgical intervention to prevent 
one of the outcomes listed above,
• Event occurring in a gene therapy study
• Event that changes the risk/benefit ratio of the study.
±Unexpected Adverse Event. An adverse event is defined as being unexpected if the 
event exceeds the nature, severity, or frequency described in the protocol, consent form 
and investigator brochure (when applicable). An unexpected AE also includes any AE 
that meets any of the following criteria:
• Results in subject withdrawal from study participation,
• Due to an overdose of study medication, or
• Due to a deviation from the study protocol
Per Yale HIC Policy 710, dated April 15, 2017: Any incident, experience or outcome that 
is unexpected AND related or possibly related to participation in the research, AND 
unexpected should be reported to the IRB as an “RNI” within 5 calendar days of the 
Principal Investigator becoming aware of the event. 
Events that may require a temporary or permanent interruption of study activities by the 
Principal Investigator or Sponsor to avoid potential harm to subjects should be reported 
to the Yale IRB immediately (if possible), followed by a written report to the IRB as an 
“RNI” in the online IRES regulatory system no more than 5 calendar days after the Yale 
Principal Investigator becomes aware of the event. 
All related internal and external events involving risk but not meeting the prompt 
reporting requirements should be reported to the IRB in summary form at the time of 
continuing review. 
Per UNCST National guidelines March 2007: “These guidelines give criteria for prompt 
reporting of certain categories of adverse events to an IRC and the UNCST.” “An 
adverse event is any unfavorable and unintended sign, symptom or condition temporally 
associated with the administration of a health-related intervention, whether or not 
considered related to the intervention. The requirement to report adverse events to 
regulatory authorities shall not apply to events that are observed among participants 
who are in observational studies in which no health-related intervention is being 
administered.” However, for consistency, we will report adverse events which are 
definitely, probably, or possibly related to study procedures or study participation AND 
serious
 or unexpected similarly to UNCST and the School of Biomedical Sciences.

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Table 4. Guidelines for reporting adverse events related to study participation
Institution
Type of Adverse Events
When to Report
NICHD

Definitely, Probably, or 
Possibly related AND 
Serious or Unexpected

Within 10 working days 
of awareness
UCSF-
HRPP&IRB

Definitely, Probably, or 
Possibly related AND 
Serious or Unexpected

Within 5 working days of 
awareness

Internal, related deaths 
and life-threatening 
events: report 
immediately
Yale-HIC

Definitely, Probably or 
Possibly related to 
participation in the research 
AND Serious AND 
Unexpected (in terms of 
nature, specificity, severity, 
or frequency)

Within 5 days of 
awareness

Related Events not 
meeting prompt reporting 
requirements are 
reportable in summary 
form at time of continuing 
review
JCRC-REC

All Serious and Unexpected 
events irrespective of 
relationship;

All serious adverse 
events and unexpected 
events must be reported 
within 7 calendar days of 
awareness

All other reportable 
events should be 
reported within 14 
calendar days 
National 
Drug 
Authority

All Serious and Unexpected 
events irrespective of 
relationship;

All serious adverse 
events and unexpected 
events must be reported 
within 7 calendar days of 
awareness.
UNCST

All Serious and Unexpected 
events irrespective of 
relationship;
 

Death and Life-
threatening events within 
48-hours with written 
report within 7-calendar 
days of awareness

All other reportable 
events within 15-calendar 
days of awareness

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7.4 Antiretroviral Toxicity & Management
For HIV-infected children, ART will be managed through the participant’s primary clinic. 
This study is not designed to initiate ART treatment for study subjects. No changes will 
be made to the ART regimens during this study, unless directed by the primary HIV 
provider. ART regimens permitted for this study include EFV-, LPV/r-, DTG-based 
regimens. Issues related solely to a participant’s ART will be managed by the 
participant’s primary HIV clinic. If the clinic is closed, participants will be referred to the 
local hospital.
Dolutegravir is now part of the WHO options for the management of HIV. A report in 
May 2018 suggests a possible increased risk of neural tube defects in women exposed 
to DTG during the 1st trimester. As such, we will not enroll any pregnant women or 
woman of potential childbearing age on DTG-based ART (age 13-17) who do not agree 
to consistent and reliable contraception. This is due to unknown interaction of DTG and 
DP at the time of this study. While DTG has recently been approved by the WHO for 
children as young as 6 years of age, as of submission of this protocol, the Ugandan 
MoH has not yet adopted this policy. If the Ugandan MoH guidelines are changed over 
the course of the study, protocol modifications will be implemented as feasible.
7.5 Dihydroartemisinin-Piperaquine (DP) Toxicity & Management:
DP is a WHO recommended first-line treatment for malaria and is being studied for 
possible use as chemoprevention. DP given as 3 consecutive once daily doses is the 
standard of care for treatment of uncomplicated malaria. While not standard of care, this 
same regimen has also been studied in numerous published clinical trials as 
chemoprevention for malaria in children and pregnant women. Thus, we will be 
evaluating this regimen for possible interactions with ART as these medications are 
often co-administered in clinical practice. We will be assessing and recording data in 
relation to how participants tolerate DP. 
We will be recording participants’ tolerance of DP using the NIH Division of AIDS Adult 
and Pediatric Toxicity Tables (version 2.1, March 2017; https://rsc.tech-
res.com/docs/default-source/safety/daids-ae-grading-table-mar2017.pdf).  This will be 
used to screen for eligibility and to evaluate adverse events for children. Study staff will 
receive extensive training in the identification and management of adverse events. In 
addition, participants will be informed by the study team about potential adverse events 
associated with DP and will be encouraged to present to the study clinic for all potential 
adverse events. The Baylor Uganda CoE study clinic will remain open 5 days a week 
and the Busia clinic will be open 7 days a week. For events occurring outside clinic 
hours, HIV-infected participants will be informed to report to the Mulago Hospital, which 
is on-campus, while HIV-uninfected participants will be told to go to Masafu General 
Hospital. The participants will be instructed to notify the study clinician/nurse about their 
admission/presentation. The monitoring, reporting, and management of adverse events 
will follow guidelines set forth by each respective institution.

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7.6 Cardiotoxicity Concerns & ECGs
As noted in Section 1.1.5, PQ is a CYP3A4 substrate and LPV/r is a CYP450-inhibitor, 
and thus an interaction can raise levels of PQ thus, increasing risk of PQ toxicity. PQ 
toxicity related to peak PQ concentrations and focuses on QT interval prolongation.
7.6.1 LPV/r-Based ART regimen
Dose Adjustment: Given concerns for cardiotoxicity, for the LPV/r-based arm ONLY, we 
will start with a single dose of DP in a group of HIV-infected children on LPV/r-based 
ART and a control group of single dose DP in HIV-uninfected children, to determine the 
magnitude and safety of the interaction, as well as to monitor QT intervals via ECGs 
(Phase I). Following the assessment of the PK and ECG-based safety data from the 
single dose DP groups, we will proceed with one of three different options: 1) no further 
study of LPV/r with DP due to safety concerns, 2) a reduced mg/kg dose of 3-dose DP 
in the context of LPV/r, or 3) standard mg/kg dosing of 3-dose DP in the context of 
LPV/r-based ART (Phase II).  
If the magnitude of the effect of LPV/r on the AUC of PQ during Phase I is:
•
<40% increase, there will be no adjustment in DP dose for Phase II and 
Phase II can begin
•
40-75% increase, there will be a 50% reduction in DP dose for Phase II
•
>75% increase, further evaluation will be completed for Phase I so that a 
specific dose for Phase II can be determined to compensate for the 
magnitude of the change or we will recommend that LPV/r and DP not be 
taken concomitantly.
7.6.2 All Study Arms
ECGs will be performed in participants in all study groups to ensure safety, and to 
provide data on QT intervals across the age spectrum. The expected peak of 
piperaquine is 4-6 hours post-last dose. Based on the expected directionality of drug-
drug interactions, elevated piperaquine concentrations are ONLY expected in those 
children receiving lopinavir-ritonavir (LPV/r).  However, in an effort to ensure safety for 
all children, ECGs will be carried out in all participants. This will also allow us to assess 
the potential impact of age on QT interval changes since we will have data from 
participants ages 3 to 17 years. 
All ECGs will be performed in triplicate and central tendency used as the analysis 
measure. Additional ECGs may be performed for safety follow-up, as needed. All ECGs 
will be read the same day as they are collected. All ECG results will be reviewed by two 
experienced ECG readers. Both ECG readers will be experienced in reading pediatric 
ECGs, and will be blinded to each other’s reading. All ECGs with discrepancies 
between two readers will be re-evaluated. One of these ECG readers will be an 

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individual outside of the main study team and will be a pediatric cardiologist. At any 
point, if QTc prolongation of >500 msec or >60 msec from baseline are noted, 
dosing will be stopped, and the study will be halted until data can be reviewed by 
the study investigators.
7.7 Toxicity management by grade
Alternate explanations for clinical and laboratory abnormalities will be sought. 
Laboratory normal values will be those provided by the clinical laboratory used for this 
study. For each adverse event identified as grade 3 or higher AND serious or 
unexpected (See Section 8.0), an adverse event report form will be completed. Adverse 
events will be followed until they resolve to below a grade 3. 
Grade 1 and 2:
It is anticipated that some subjects, particularly HIV-infected children/adolescents, may 
enter this study with grade 1 or 2 abnormalities already present (e.g. due to ART 
management). The site physicians will manage the grade 1 or 2 events according to 
standard practice. An adverse event report form will not be completed for events 
classified as grade 1 or 2, as these events are common and difficult to distinguish from 
common childhood illnesses.
Grade 3 or 4 (non-life threatening):

Notify the study team.

Repeat observation within 72 hours; notify study team of results.

Subjects may continue taking DP pending clinic visit or repeat laboratory 
tests.  The clinician has the option of immediately stopping the DP if the subject 
cannot be examined in clinic, if a repeat laboratory test cannot be performed 
within 72 hours, or if the clinician determines that continuation of DP is unsafe 
while awaiting clinic exam or test results.

Work-up to exclude other causes. 

For all confirmed Grade 3 or 4 toxicities supported by repeat clinical exam or 
laboratory test results, stop DP until toxicity resolves to < Grade 3.

If drug is restarted with resolution of toxicity and toxicity recurs on re-challenge, 
study drugs will be permanently discontinued.  If DP is discontinued the 
participant will be withdrawn from the study.
Grade 4 life threatening:

Notify study team.

If still receiving DP, DP should be permanently discontinued.

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8.0 STATISTICAL CONSIDERATIONS
8.1 General Design Issues. 
This is a prospective study to evaluate the PK of DP in the context of EFV-, LPV/r- and 
DTG-based ART in HIV-infected children and adolescents compared to the HIV-
uninfected children and adolescents. The study will be conducted in Uganda. 
The current proposal will study the PK of DP in HIV-infected children and adolescents 
on EFV-, LPV/r-, and DTG-based ART and matched HIV-uninfected children and 
adolescents not on ART who will be enrolled through Baylor-Uganda CoE/Busia clinic at 
the Masafu General Hospital. In addition, we will compare the PK of single dose DP with 
3-dose DP in HIV-infected children on LPV/r-based ART and HIV-uninfected children 
not on ART. Comparisons will be based on an intensive PK design for DP AUC 
estimations in 20 subjects for groups L1 and C1 and for 30 subjects in each of the other 
study groups. Study group comparisons will be controlled for age. The proposal will also 
study the impact of DP on ART pharmacokinetics. Table 5 shows the primary PK 
comparison groups for the study.
Table 5. Primary PK objectives and comparator groups
Primary Objectives
Groups
Sample sizes and age 
groups
Impact of LPV/r on single dose DP PK and safety in 
HIV-infected children on LPV/r vs “single dose” DP 
HIV-uninfected children
L1 
vs
C1
L1 (n=20, age 3-10years)
vs.
C1 (n=20, age 3-10 years)
Impact of LPV/r on 3-dose DP PK and safety in HIV-
infected children on LPV/r vs 3-dose DP HIV-
uninfected children
L3
vs
C3a
L3 (n=30, age 3-10years), 
vs.
C3a (n=30, age 3-10 years).
Impact of EFV on DP PK and safety in HIV-infected 
children on EFV-based ART vs 3-dose DP HIV-
uninfected children
E3
vs
C3a
E3 (n=30, age 3-10years),
vs.
C3a (n=30, age 3-10 years).
Impact of DTG on DP PK and safety in HIV-infected 
children on DTG-based ART vs 3-dose DP HIV-
uninfected children
D3
vs
C3b
D3 (n=30, age 11-17 years), 
vs.
C3b (n=30, age 11-17 years).
Safety of DP will be primarily assessed via within-person change in QTc (QT intervals 
will be corrected for heart rate using Fridericia’s correction (QTc = QT/RR0.5))
Although certain children (20 HIV-positive children on LPV/r-based ART) are eligible to 
enroll in both the single-dose DP intensive PK study and the 3-dose DP PK study 
following a washout period of 42 days, there is no assurance that the same child will 
contribute to both study components. Thus, it is possible that the total number of 
subjects for all groups may be as high as 190.

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8.2 Outcome Measures
8.2.1 Primary outcomes 
1) Area under the plasma concentration versus time curve for all drug analytes
2) Safety of single dose DP in HIV-infected children on LPV/r-based ART 
determined via assessment of mean change in QT intervals from baseline
3) Safety of 3-dose DP regimens determined via assessment of mean change in QT 
intervals from baseline
8.2.2 Secondary outcomes
1) The effects of DP on antiretroviral pharmacokinetics in the above 3 dose arms 
(EFV, DTG, LPV/r and controls)
2) The association of anthropomorphic indicators of malnutrition on PK exposure of 
DP in HIV-infected and HIV-uninfected children
3) Assess auto-induction of DHA from single dose to 3-doses
4) To assess the prevalence of UGT1A1 pharmacogenetic variants and their impact 
on DTG PK.
5) To assess prevalence of CYP2B6 pharmacogenetic variants and their impact of 
EFV PK
6) To assess prevalence of CYP3A4 pharmacogenetic variants and their impact of 
EFV and piperaquine PK
7) To assess prevalence of ABCB1 pharmacogenetic variants and their impact of 
EFV PK
8.3 Nutritional Status
Using anthropometric measurements and for a secondary study aim to relate nutritional 
status to PK and clinical outcomes, children will be characterized as a) “stunted” but not 
underweight [i.e. height for age (HFA) z-score ≤-2 and weight for age (WFA) z-score>-
2); b) underweight, but not stunted (WFA z-score ≤-2 and HFA z-score>-2); or c) of 
normal nutritional status (WFA and HFA z-scores >-1)  
8.4 Intensive PK study
8.4.1   Sample Size
Using measures of mean AUC and its coefficients of variation (CV) from our studies and 
the literature, the intensive arms of the study are powered to detect differences in ACT 
AUC between all study groups with n=30 for groups E3, D3, and L3 of HIV-infected 
children and n=20 for group L1. To assure adequate age-matched HIV-uninfected 
controls for the single and 3 dose PK evaluations, n=30 in two different age groups each 
(3-10 years and 11-17 years) is used for the group of HIV-uninfected children and 
adolescents.  Figure 2 and Table 5. 
For unpaired comparisons where n=20 in both groups, there will be 80% power to 
detect a difference in AUC of 40% or more for both the single and 3-dose evaluations, 

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given an overall Type I error of 0.05, a Bonferroni correction for multiple comparisons, 
and with assumption that the coefficient of variation (CV) for all AUC’s is 35-38%.
For unpaired comparisons where n=30 in both groups, there will be 80% power to 
detect a difference in AUC of 30-35% or more for both the single and 3 day DP 
evaluations, given an overall Type I error of 0.05, a Bonferroni correction for multiple 
comparisons, and with assumption that the coefficient of variation (CV) for all AUC’s is 
35-38%. Although many children are likely to be studied for both the single dose DP and 
3-dose DP regimens, it is not likely that all children will provide results for both. Thus, 
unpaired comparisons will be utilized.  In the event the vast majority of children provide 
results for both single dose and 3-dose DP, a paired analysis will be utilized.
8.4.2 Dose adjustment based on single dose results from Phase I (LPV/r only):  20 
children in each “single dose” DP groups (L1 and C1) must be enrolled in Phase I with 
PK results evaluated before enrollment into 3 dose DP groups (L3 and C3a; Phase II) 
can be initiated. The results for these 20 children in each single dose group will be 
compared to one another determine the impact of LPV/r on DP PK exposure prior to 
any children being given 3 doses of DP in the context of LPV/r. 
If the magnitude of the effect of LPV/r on the AUC of PQ during Phase I is:

<40% increase, there will be no adjustment in DP dose for Phase II and Phase II 
can begin

40-75% increase, there will be a 50% reduction in DP dose for Phase II

>75% increase, further evaluation will be completed for Phase I so that a specific 
dose for Phase II can be determined to compensate for the magnitude of the 
change or we will recommend that LPV/r and DP not be taken concomitantly.
8.4.3 Sample size for ECG studies
Primary outcome:  Difference in paired mean QT change (6hrs compared with 
baseline within person) 
Assumptions: two-sided alpha=0.05, sample size =30, paired t-test
Table 6. Power/sample size calculations for ECG studies
Mean of paired differences                   
(Time 6hrs-Baseline) (msec)
SD of the differences (msec)
Power %
10
>95%
15
>95%
10
20
>95%
10
>95%
15
>95%
15
20
>95%
10
>95%
15
>95%
20
20
>95%
10
>95%
25
15
>95%

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20
>95%
10
>95%
15
>95%
30
20
>95%
A sample size of 30 achieves >95% power to detect a mean of paired differences of 
10.0 msec between the null hypothesis mean of paired differences of 0.0 and the 
alternative hypothesis mean of paired differences of 10.0 msec with an estimated 
standard deviation of the difference 10.0 msec and with a significance level (alpha) of 
0.05. In addition, for the group receiving single dose DP (L1) and its comparator (C1), 
samples sizes of n=20 maintains the same power (>95%) to detect the above 
differences.
8.4.2   Intensive PK Analysis
PK parameters for each subject will be estimated using non-compartmental analysis 
(NONCMP) and follow a linear up-log down trapezoidal rule in conjunction with first-
order input (WinNonlin). PK parameters, including the elimination rate constant λz and 
t1/2 will be estimated, with t1/2 calculated as ln2/λz. AUC will be estimated as the AUC0-8h 
or AUC0-24h (as results permit) for DHA and the sum of AUClast (AUC to the end of the 
sampling period) and AUClast-  (from the end of sampling to infinity) for PQ. PK 
parameters will be compared between groups of interest (Figure 2 and Table 5) using a 
two-sided unpaired t-test for two-group comparisons, and ANOVA for multi-group 
comparisons. If PK parameters are found to have skewed distributions and data 
transformations do not induce symmetry, rank-based tests will be used. The following 
groups will be compared:
8.5   Exposure-Response Analysis of DP PK and EKG results. Population PK/PD 
analysis may be employed utilizing data for both HIV infected and HIV uninfected 
children to evaluate associations between PQ exposure and EKG changes. Covariate 
analysis may be performed to identify the impact of covariates on the PK of DP with 
special focus on the impact of markers of malnutrition, as measured by weight, BMI, 
and various Z scores and mid-arm circumference. Other covariates will include age, 
body size (weight, height), concomitant medications, hematocrit, and CD4 count (for 
HIV-infected children). We will test for a significant relationship between drug exposure 
and the primary safety outcome (QT interval prolongation). We will also investigate if 
there is any potential impact of indices of malnutrition, HIV status, age and other 
covariates on safety parameters.  We will identify appropriate dosing for DP in the 
context of ART with the goal of matching the DP exposure seen in non-HIV infected 
patients. Population PK methods may be used to simulate different DP dosing 
approaches to identify optimized regimens that ensure concentrations are achieved in 
the context of ART that match exposure seen in HIV uninfected control participants.
9.0 DATA COLLECTION AND MONITORING

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9.1 Record Keeping
All clinical data will be recorded onto standardized case record forms (CRFs) by study 
physicians. Laboratory data will be recorded in a laboratory record book by the study 
laboratory technologists and then transferred to the case record forms by study 
coordinators, who will review the case record forms frequently for completeness and 
accuracy. Data will be entered directly from CRFs into a computerized database or 
transferred from the CRFs onto standardized data extraction forms and then into a 
computerized database. All computerized data will be double entered to verify accuracy 
of entry. Electronic data including all study databases and supporting electronic 
documentation will be archived to large-scale digital tape on a daily basis. On a monthly 
basis, a complete backup tape will be transported off-site to the Kampala Data 
Management Center (DMC) for rotating secure storage. In addition, the database from 
the backup will be placed onto one of the Kampala DMC servers as a data mirror for 
read-only access in the event that the web-site becomes temporary unavailable. All data 
will be maintained and kept indefinitely. The medical records for the study will be kept in 
a locked office and will only be able to be seen by study staff. The online database will 
be password protected and only the study staff will have access to it. The parent and 
child’s name will not be written in any published reports based on this research and 
genetic data will be de-identified and will not be put into the permanent medical record 
to ensure participant privacy.
9.2 Data Quality Assurance and Monitoring
In order to insure data quality, an initial daily QC level 1 will be conducted, followed by a 
1 month QC, followed by a quarterly data quality audit by the study Data Manager. For 
this audit a 1% random sample of study forms entered into the data management 
system from the previous 2 weeks will be selected and compared for accuracy with the 
original case-report forms and source documents. In addition, the study the Data 
Manager will perform monthly reviews of the 100% double data entry data verification 
logs and the data management system audit trail log to identify potential data quality 
issues.
10.0 HUMAN SUBJECTS
10.1 Risks and Benefits
There are minimal direct benefits to the study subject for participation in the study. 
These are limited to testing for malaria and anemia in all participants, HIV testing in 
HIV-infected children, ECG testing, and a month of possible protection from malaria 
infection. The risks have been reduced to a minimum. For children, we have 
consciously considered the guidelines set forth by the UCSF Committee on Human 
Subjects’ Research (CHR) of 3ml/kg for blood sample collection and have optimized all 
assay requirements for accurate quantification of drug concentrations using the lowest 
amount of blood.  We have also consulted other recommendations.  The most 
conservative recommendations suggest no more than 2.5% (~2 mL/kg) of total blood 

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volume within a 24-hour period or 5% (~4 mL/kg) within a 30-day period.  The NIH 
guidelines state that no more than 3 mL/kg are to be drawn in a single blood draw (24-
hour period) and no more than 9.5 mL/kg are to be drawn over any eight-week period 
for the purposes of research in children. We feel it is unlikely the participant would be 
harmed by taking the amount of blood required in this study.  For the total amount 
collected over 42 days of follow-up the amount of blood that will be drawn will not 
exceed 5.4 mL/kg (no more than 30 mLs or 6 teaspoons will be drawn), which are well 
within these limits.   
There is small chance of infection from performing blood draws.  Additional risks include 
anxiety from the blood draws, HIV testing and learning of testing results. We have 
attempted to minimize the number of needle pokes as much as possible and 
participants will be counseled regarding test results and referred for medical care if 
necessary.  
10.2 Treatment and Compensation for Injury
If the participant is injured as a result of being in this study, treatment will be available 
through Baylor College of Medicine Children’s Foundation—Uganda, Mulago Hospital, 
and Masafu General Hospital. 
Makerere University, UCSF, Yale, Baylor CoE, and NICHD do not normally provide any 
other form of compensation for injury.
10.3 Costs to the Subjects
There will be no cost to the participant or their parents/guardians/participants for 
participation in this study.
10.4 Reimbursement of Subjects
Participants will not be paid for their participation in the study. We will provide all routine 
medical care, including evaluations, and medications available in our clinic. We will 
reimburse for transport and compensate caretakers for the time spent (work hours lost) 
on PK study follow-up days. On certain days, participants will have to be in the clinic for 
several hours. On those days, we will provide food and drink to participants (breakfast, 
dinner, and/or snacks) to ensure their well-being. In addition, we will reimburse the cost 
of consultation for referrals made by study physicians to other clinics and services within 
Mulago Hospital using available funds when available. However, reimbursement of all 
diagnostic tests and treatment recommended outside the study clinic cannot be 
guaranteed in all circumstances. 
10.5 Institutional Review Board (IRB) Review and Informed Consent
This protocol, all procedures and consent forms, and any subsequent modifications 
must be reviewed and approved by the IRBs of participating institutions in both the U.S. 
and in Uganda. This includes the UCSF HRPP/IRB, the Yale HIC, Baylor College of 

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Medicine IRB, the JCRC-REC, the National Drug Authority and the Uganda National 
Council of Science and Technology (UNCST).
All consent forms will be translated into the local languages and back-translated into 
English to ensure correct use of language. Consent forms will be read aloud to parents 
by trained study interviewers. The informed consent will describe the purpose of the 
study, all the procedures involved, and the risks and benefits of participation. 
Interviewers will ask parents/guardians/participants to summarize the study and explain 
the reasons why they want to participate. Either a signature or a thumbprint (for 
parents/guardians who cannot read) will be acceptable to confirm informed consent for 
participation in the study.
10.6 Study Discontinuation
This study may be discontinued at any time by the NIH, respective IRBs or other 
Governmental agencies in the United States or Uganda as part of their duties to ensure 
that research subjects are protected
10.7 Definition of Parent/Guardianship
For this project, we will define a parent as someone who attests that he/she is the 
biological parent of the potential participant. However, it has been found in Uganda that 
a high number of the HIV-infected children have lost one or both parents. These 
children live with caretakers who do not have documented formal guardianship status 
because there is no formal, legal guardian system in Uganda. In Uganda, orphan 
children are customarily cared for by one or more relatives; a single individual family 
member is not usually identified as the sole guardian or custodian of the child. We will 
define a guardian as someone who identifies him/herself as the primary caregiver who 
is able to make all health care decisions for the potential participant. A guardian must be 
at least 18 years of age, however; a parent may be less than 18 years of age. These 
definitions are currently approved for use in current research projects conducted in 
Uganda following extensive discussion with the Ugandan Ministry of Justice, the 
Uganda National Council of Science, the JCRC-REC, and the NIH in 2006.
11.0 PUBLICATION OF RESEARCH FINDINGS
The findings from this study may be published in a medical journal. No individual 
identities will be used in any reports or publications resulting from the study. The 
researchers will publish results of the trial in accordance with NICHD, UNCST, UCSF, 
Yale, Baylor College of Medicine Children’s Foundation-Uganda, and JCRC-REC 
guidelines.

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12.0 BIOHAZARD CONTAINMENT
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel involved in the drawing of blood, 
exposure to blood and secretions, and shipping and handling of all specimens for this 
study. We will follow the current guidelines set forth by the Centers for Disease Control 
and Prevention and the NIH. All infectious specimens will be transported using 
packaging mandated in the Federal Code of Regulations, CDC 42 CFR Part 72.

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APPENDIX A. SCHEDULE OF EVALUATIONS: L1 & C1 ARMS
STUDY DAY
-11
02
1
2
7
14
21
28
Other 
visit10
ENROLLMENT PROCEDURES
Screening and informed consent 
X
HIV testing, counseling and referral if 
necessary3
50uL
Rapid Diagnostic Test and Blood Smear
200uL
X10
Collect locator information
X
CLINICAL AND LABORATORY 
EVALUATIONS
History and Physical Examination4
Will be performed on each day the child is in clinic (for PK blood draws, CBC, Chemistries, etc.)
Hematology and Chemistries5
4mL
4mL
4mL
X10
Electrocardiogram (ECG)6
X
X
X
X
X10
DRUG ADMINISTRATION
DP dosing for all study subjects7
X
X8
X8
Antiretroviral dosing for HIV- infected subjects9
X
X
X
X
X
X
X
X
X
INTENSIVE PK STUDY SAMPLING9
L1: Single dose DP regimen + LPV/r 11
 
500 μL
(0, 0.5, 1, 2, 3, 4, 6 & 8 
hrs)
200μL
(24rs)
200μL
(48hrs)
200μL
(168 hrs)
500μL
(336 hrs)
200μL
(504 hrs)
500uL
(672 hrs)
200uL10
APPROXIMATE TOTAL BLOOD VOLUME 
(mL) 12
4.20
4
0.2
0.2
0.2
4.5
0.2
4.5
0.2
C1: “Single” dose DP –
 Intensive sampling after 1st dose DP11
500 μL
(0, 0.5, 1, 2, 3, 4, 6 & 8 
hrs)
200μL
(24rs / Pre DP 
dose)
APPROXIMATE TOTAL BLOOD VOLUME 
(mL)12
4.25
4
0.2
4
0.2

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Explanation of Intensive PK schedule of events (Appendix A):
1
Study Day -1, will be enrollment day where we will perform baseline ECG, HIV screening, malaria screening and CBC tests on all potential participants
2
As is standard practice in malaria research, study Day 0 refers to the day DP dosing is initiated. 
3
Applies only to HIV-negative patients 
4
History will include general medical history, diagnosis, medication (including ingestion of herbs), allergies, and current symptoms. Physical examination 
will include weight, height, and viral signs (temperature, pulse, blood pressure, respiratory rate), lymphadenopathy, hepatomegaly, splenomegaly, 
infections in ears, mouth, pharynx or skin and pulmonary, cardiac, neurologic or skeletal abnormalities and anthropometric assessments.  Mid-upper 
arm circumference will also be collected at time of first enrollment.
5
Hematology/chemistry draws entail a 4mL venous sample for CBC, differential, ALT/AST, and creatinine. AST is incorporated as part of chemistries 
at all blood draws. 
6
Both groups will receive ECGs. ECGs will be performed at baseline on Day-1 (before the administration of first dose), 4-6 hours post- dose on Day 0. 
On Day 2, ECGs will be performed for the C1 group only pre-last dose and 2-4 hours post-last dose of DP. On Day 7, ECG will be performed for L1 
group only.
7
For L1 and C1, intensive PK sampling will occur following the first dose of DP. However, for C1 group, they will receive additional doses of DP and 
Days 1 and 2 to complete the 3 day course to maximize benefit of DP.
8
DP dosing will occur in C1 arm only on this date
9
For L1 arm only, we will ask for child to take their morning dose of LPV/r in the clinic.
10
Participants may present for unscheduled visits. Study team may perform these tests at the discretion of the team member.
11
Follow up for L1 will be through Day 28 and follow up for C1 will be through Day 14
12
Total blood volume in either arm is between 5-6 teaspoons for the scheduled follow-up visits of up to 28 days.

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APPENDIX A. SCHEDULE OF EVALUATIONS: D3, E3, L3 & C3 ARMS
STUDY DAY
-1
01
1
2
3
4
7
14
21
28
35
42
Other 
visit15
ENROLLMENT 
PROCEDURES
Screening and informed 
consent 
X
HIV testing, counseling and 
referral if necessary2
50uL
Rapid Diagnostic Test and 
Blood Smear
200uL
X15
Collect locator information
X
CLINICAL & 
LABORATORY 
EVALUATIONS
History and Physical 
Examination3
Will be performed on each day the child is in clinic (for PK blood draws, CBC, chemistries)
Hematology and 
Chemistries4
4mL
4mL
4mL
4mL
X15
Pharmacogenomic Sample
1mL17
Electrocardiogram (ECG)5
X5
X
X
X
X15
DRUG ADMINISTRATION
DP dosing for all study 
subjects6
X
X
X
Antiretroviral dosing for 
HIV- infected subjects7
X
X
X
X
X
X
X
X
X
X
X
X
INTENSIVE PK STUDY 
SAMPLING
3 day DP regimen
D3, E3, L3 (HIV+ children)
 1.5mL
(Pre-DP, Pre 
ART)8,9
200uL (2hr, 4 hrs 
post-DP dose)
200μL
Pre DP, 
2 & 4 
hrs 
post-DP
1mL (Pre-ART)9,
500 μL
(0, 0.5, 1, 2, 3, 4, 6 & 
8hrs)
E310: 500uL (2, 4 & 8 hr)
1mL 
(Pre-ART)9
200μL
(24hrs)
200μL
(48hrs
)
200μL
(120 hrs)
500μL
(288 hrs)
200μL
(288 hrs)
200μL
(456 
hrs)
500μL
(624 hrs)
200μL
(792 hrs)
500μL
(960 hrs)
200uL15
APPROXIMATE TOTAL 
BLOOD VOLUME (mL)15
0.20
L3: 5.9
D3 & E3: 6.9
0.6
5.0
E3: 6.5
1.2
0.2
0.2
4.7
0.2
4.5
0.2
4.5
0.2
3 day DP regimen
C3a & C3b (HIV uninfected 
children)
 500uL
(Pre-DP)9
200uL 2hr, 4hr 
500uL 4 hrs12 post-
DP dose
200μL
Pre DP, 
2 & 4 
hrs 
post-DP
500 μL
(0, 0.5, 1, 2, 3, 4, 6 & 
8hrs)
200uL 4hr 12
500uL13 
(24hrs)
200μL
(24hrs)
200μL  
(48hrs
)
500uL13 
(120hrs)
200μL
(120 hrs)
500uL 14 
(288 hrs)
200μL
(288 hrs)
200μL
(456 
hrs)
500μL
(624 hrs)
200μL
(792 hrs)
500μL
(960 hrs)
200uL15
APPROXIMATE TOTAL 
BLOOD VOLUME (mL)16
0.25
5.4
0.6
4.2
0.7
0.2
0.7
4.7
0.2
4.5
0.2
4.5
0.2

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Explanation of Intensive PK schedule of events (Appendix A):
1.
As is standard practice in malaria research, study Day 0 refers to the day DP dosing is initiated.  We will perform baseline ECG, HIV screening, and 
malaria screening on all potential participants on Day -1. To minimize needle pricks to the child, CBC and chemistries will be drawn on Day 0, along 
with Pre-DP level and Pre-ART (for D3, E3, L3)
2.
Applies only to HIV-negative patients
3.
History will include general medical history, diagnosis, medication (including ingestion of herbs), allergies, and current symptoms. Physical 
examination will include weight, height, and viral signs (temperature, pulse, blood pressure, respiratory rate), lymphadenopathy, hepatomegaly, 
splenomegaly, infections in ears, mouth, pharynx or skin and pulmonary, cardiac, neurologic or skeletal abnormalities and anthropometric 
assessments. Mid-upper arm circumference will also be collected at time of first enrollment.
4.
Hematology/chemistry draws entail a 4mL venous sample for CBC, differential, ALT/AST, and creatinine. AST is incorporated as part of chemistries at 
all blood draws. 
5.
ECGs will be performed at baseline (on Day -1), prior to and 4-6 hours post-last dose, Day 7, and Day 42.
6.
All participants will receive a total of 3 doses of DP given over 3 days (Day 0, Day 1, and Day 2)
7.
Children on ART will be ask to take their morning doses of LPV/r or DTG in clinic when instructed by study staff. For children on EFV, they can take 
their doses at home, at bedtime, and record the time of administration.
8.
To minimize number of pokes to the child, Pre-ART and Pre-DP levels should be drawn at the same time as CBC, chemistries, and 
pharmacogenetics biomarker (for a total of 6.5mL venous blood)
9.
Pre-ART sample to quantify trough of LPV/r, DTG and mid-level of EFV, sampled collected via venipuncture on Day 0, 2, & 3 to allow for 
comparisons of ART level
10. For EFV (E3) arm, at 2, 4, and 8 hours during intensive sampling, we will draw additional 500uL samples via venipuncture to characterize EFV PK 
curves. This will be drawn at the same time as DP, therefore, minimizing number of blood draws.
11. For controls (C3a & C3b) only, at 4 hours on Day 0, an additional 500µL will be drawn via a venipuncture to permit correlation of venous and capillary 
concentrations.
12. For controls (C3a & C3b) only, at 4 hours on Day 2, an additional 200µL will be drawn via a capillary stick to permit correlation of venous and capillary 
concentrations.
13. For controls (C3a & C3b) only, on Day 3, and Day 7 an additional 500µL will be drawn via a venipuncture to permit correlation of venous and capillary 
concentrations.
14. For all 3 day arms, on 14, an additional 500µL will be drawn via venipuncture to permit correlation of venous and capillary concentrations.
15. Participants may present for unscheduled visits. Study team may perform these tests at the discretion of the team member.
16. Total blood volume in either arm is between 5-6 teaspoons over 42-days of follow-up for scheduled visits 
17. 1mL of venous blood is collected on day 0 for testing of pharmacogenetic variants for children on DTG and EFV- based regimens.

APPENDIX B. INFORMATION SHEET                  
                                                                        
Information Sheet
A study on Antimalarial Pharmacology in HIV-infected and HIV-
uninfected individuals
Makerere University, University of California, San Francisco, Yale University, and Baylor 
Center of Excellence are carrying out a study on the malaria medicine, dihydroartemisinin-
piperaquine, and how it is taken up by the body in HIV-infected (receiving anti-HIV 
medications) and HIV-uninfected children.

Our clinics are located at the Mulago Hospital Complex, Baylor Center of Excellence, 
and Masafu General Hospital

We want the following to participate
o
HIV-infected (HIV+) children aged 3 -17 years that are taking either efavirenz, 
dolutegravir, or lopinavir/ritonavir as part of their HIV regimens
o
HIV-uninfected (HIV-) children aged 3 - 17 years

Participants in this study will receive medical care during the course of the study at 
the study clinic

We will provide transport to and from our clinic if needed

The Baylor clinic is open every day from Monday to Friday, 8am to 5pm; Makerere 
College of Pharmacology and Therapeutics Clinic is open 7 days per week from 8am 
to 5pm; the Masafu General Hospital clinic is open 7 days per week from 8am to 
5pm.
For more information, come to Baylor Center of Excellence, Makerere College of 
Pharmacology and Therapeutics, or Masafu General Hospital and ask for the malaria 
children’s clinic. The doctors will be happy to talk with you. 
UCSF

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APPENDIX C. WHO CRITERIA FOR SEVERE MALARIA/DANGER SIGNS 
Criteria for severe malaria 

Cerebral malaria - defined as unarousable coma not attributable to any 
other cause in a patient with falciparum malaria 

Generalized convulsions (> 3 convulsions over 24 hours period) 

Severe normocytic anemia (Hb < 5 gm/dL) 

Hypoglycemia 

Metabolic acidosis with respiratory distress 

Fluid and electrolyte disturbances 

Acute renal failure 

Acute pulmonary edema and adult respiratory distress syndrome (ARDS) 

Circulatory collapse, shock, septicemia ("algid malaria") 

Abnormal bleeding 

Jaundice 
Danger signs 

1-2 convulsions over a 24 hour period 

Inability to sit up or stand 

Vomiting everything 

Unable to breastfeed or drink 

Lethargy 

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APPENDIX D. GUIDELINES FOR ADVERSE EVENT GRADING (DAIDS 
AE GRADING TABLE)
Estimating Severity Grade
If the need arises to grade a clinical AE that is not identified in the DAIDS AE grading 
table, use the category “Estimating Severity Grade”.
Grading Adult and Pediatric AEs
The DAIDS AE grading table includes parameters for grading both Adult and Pediatric 
AEs. When a single set of parameters is not appropriate for grading specific types of AEs 
for both Adult and Pediatric populations, separate sets of parameters for Adult and/or 
Pediatric populations (with specified respective age ranges) are given in the table. If there 
is no distinction in the table between Adult and Pediatric values for a type of AE, then the 
single set of parameters listed is to be used for grading the severity of both Adult and 
Pediatric events of that type.
Determining Severity Grade
If the severity of an AE could fall under either one of two grades (e.g., the severity of an 
AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE.
Definitions
Basic Self-care Functions
Adult
Activities 
such 
as 
bathing, 
dressing, 
toileting, 
transfer/movement, continence, and feeding.
Young Children
Activities that are age and culturally appropriate (e.g., 
feeding self with culturally appropriate eating implement).
LLN
Lower limit of normal
Medical Intervention
Use of pharmacologic or biologic agent(s) for treatment of 
an AE.
NA
Not Applicable
Operative Intervention
Surgical OR other invasive mechanical procedures.
ULN
Upper limit of normal

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APPENDIX E. HIV-INFECTED CHILDREN CONSENT
APPENDIX F. HIV-UNINFECTED CHILDREN CONSENT
APPENDIX G. ASSENT
APPENDIX H. FUTURE USE OF BIOLOGICAL SPECIMENS CONSENT

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