PROMOTE-PEDS: HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00978068
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 176
• Location: 1
• Arms: 2
• Duration (Months): 40
• Patients Per Site Per Month: 4.4

Study Details

Study Description

Brief Summary

HIV and malaria are major causes of morbidity and mortality in Sub-Saharan Africa and children bear the greatest brunt of both diseases. No single existing intervention is likely to control malaria in Africa. Rather, improvements in malaria prevention are likely to come from strategies that employ multiple proven interventions targeting different populations. HIV-infected children represent one of the most vulnerable subpopulations in these countries. It is possible that the use of protease inhibitor (PI) - based antiretroviral therapy (ART) in HIV-infected children living in areas of high malaria transmission could prevent malaria in this vulnerable population. An effective remedy that offers the possibility to further reduce malaria risk, such as PIs, is highly desirable. This study will determine whether a PI based ART regimen will reduce malaria among children living in a malaria endemic area of Uganda and receiving insecticide-treated bed nets (ITN) and TS. This study will compare two different ART regimens. Children enrolled in the study will start or continue to receive either standard Ugandan first line treatment ART regimen (NNRTI+2 NRTIs) or an ART regimen containing the HIV protease inhibitor (lopinavir/ritonavir +2 NRTIs) and followed for a period of 24 months.

Condition or Disease	Intervention/Treatment	Phase
Malaria; HIV Infections	Drug: Lopinavir/Ritonavir (LPV/r); Drug: Nevirapine (NVP); Drug: Efavirenz (EFV); Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)	Phase 3

Detailed Description

This is an open label, single site, randomized clinical trial comparing PI-based ART to NNRTI-based ART for the prevention of malaria in HIV-infected children. The two ART drug regimens that will be used include: Treatment arm 1. LPV/r + 2 NRTIs and Treatment arm 2. NVP or EFV + 2 NRTIs. The study is designed to test the hypothesis that children receiving a PI-based ART regimen will have lower the incidence of malaria compared to children receiving an NNRTI- based ART regimen. The primary study endpoint of the study is malaria incidence.

The study site will be the Tororo District Hospital campus situated in Eastern Uganda, an area of high malaria transmission. Using convenience sampling, 300 HIV-infected children identified from the Tororo community aged 2 months to <11 years either eligible for ART-initiation or already receiving a first line ART regimen with HIV RNA<400 copies/ml will be evaluated for enrollment.

Eligible children will be randomized at enrollment to receive either a PI- based or an NNRTI-based ART regimen. At enrollment, all study participants will receive a long lasting ITN as part of a basic care package including a safe water vessel and multivitamins and given TS chemoprophylaxis, as per current standard of care for HIV-infected children in Uganda. On the day of ART initiation, patients will be counseled about the importance of adherence to ART and possible ART related toxicities. After 2 weeks, patients will be seen to assess adherence and toxicity to study medications by interview and clinical examination. Apart from this visit at week 2, patients will be seen at 4 week intervals timed from ART-initiation. Assessment of adherence will also be done for TS prophylaxis, ITN use and ART. Assessment of adherence to ART will be done by self report of missed doses and pill counts.

Participants will receive all routine and acute medical care at a designated study clinic open 7 days a week from 8 a.m. to 5 p.m. Parents/guardians will be asked to bring their child to the study clinic for all medical care. If after hours, they will be instructed to bring them to Tororo District Hospital premises (where the study clinic is located) and request that the study physician on-call be contacted. They will be followed for at least 24 months and up to 3 years. They will be seen monthly for routine assessments with laboratory evaluations done at every 3 months. At these visits, the study protocol will be reinforced with discussion regarding the need to come to the study clinic promptly upon the onset of any illness and to avoid use of outside medications. Study participants will also be followed closely for adverse events potentially due to study drugs and for malaria and HIV treatment outcomes. During the follow-up period, all patients presenting to the clinic with a new episode of fever will undergo standard evaluation (history, physical examination) and Giemsa-stained blood smear for the diagnosis of malaria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 176 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Randomized Open Label Trial of HIV Protease Inhibitors for the Prevention of Malaria in HIV-Infected Children
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lopinavir/ritonavir (LPV/r) +2 NRTI Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI)	Drug: Lopinavir/Ritonavir (LPV/r); Other Names: Aluvia ; Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI); The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.
Active Comparator: Nevirapine (NVP) or Efavirenz (EFV) +2 NRTI Nevirapine (NVP) or Efavirenz (EFV) +2 nucleoside reverse transcriptase inhibitor (NRTI)	Drug: Nevirapine (NVP); NVP will be used for children < 3 years of age; Drug: Efavirenz (EFV); EFV for children ≥3 years of age; Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI); The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.

Outcome Measures

Primary Outcome Measures

1. Incidence-density of Malaria Defined as the Number of Incident Episodes of Malaria Per Time at Risk. [Time from randomization to at least 24 months of follow up or until end of the study]

Secondary Outcome Measures

1. Percentage of Uncomplicated Malaria Episodes With Accompanying Adverse Events That Occurred in the 28 Days Following Antimalarial Therapy [28 days after antimalarial therapy]

   The rates of adverse events, defined as severity grade 2 or higher that are possibly, probably or definitely related to study drugs over the course of the 28-day period after antimalarial therapy with artemether-lumefantrine (AL).

2. Incidence-density of Malaria Defined as the Number of Incident Episodes of Complicated Malaria Per Time at Risk. [Time from randomization to at least 24 months of follow up or until end of the study]

3. Estimates of the 6-month Risk of a First Episode of Malaria [Enrollment to 6 months follow up]

   To assess the effect of ART independently of potential interactions with antimalarial therapy after treatment for malaria, we compared the two groups with respect to the time to the first episode of malaria. Cumulative risk was estimated using the Kaplan-Meier product-limit formula.

4. 28-day Risk of Recurrent Parasitemia [28 days after antimalarial therapy]

   To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent parasitemia at 28 days were compared between the two groups.

5. 63-day Risk of Recurrent Malaria [28 days after antimalarial therapy]

   To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent malaria at 63 days were compared between the two groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Age 2 months to < 11 years

2. Confirmed HIV diagnosis. i. Children > 18 months: Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test ii. Children < 18 months: Documentation will be DNA PCR confirmation only along with documentation of testing from the referral entity

3. ART-naïve patients eligible for ART initiation per WHO/Uganda guidelines (see Table 1) or Patients receiving first line ART regimen with NNRTI +2 NRTI with at least one HIV RNA <400 copies/ml within the past 6 months

4. Agreement to come to the study clinic for any febrile episode or other illness

5. Agreement to avoid medications administered outside study protocol

6. Provision of informed consent by parent/guardian and agreement to have child's care at the clinical site

7. Lives within 50 km of study site

Exclusion criteria:

1. ART-naïve children: children or their mothers that have received any dose of Nevirapine in the past 24 months

2. Active medical problem requiring in-patient evaluation at the time of screening or enrollment

3. History of cardiac conduction disorder or known significant cardiac structural defect

4. Children receiving any disallowed medications (see section 4.3)

5. Moderate, Severe or Life-threatening (Grade 2, 3, or 4) AST or ALT found within 4 weeks prior to enrollment:

• AST: >113U/L (>2.5xULN)

• ALT: >113U/L (>2.5xULN)

1. Life-threatening (Grade 4) screening laboratory value found within 4 weeks prior to enrollment for the following:

• Absolute neutrophil count: <500 mm3

• Hemoglobin: <6.5 g/dL

• Creatinine: >3.5xULN

• Platelets: <25,000/mm3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IDRC - Tororo Research Clinic	Tororo		Uganda

Sponsors and Collaborators

• University of California, San Francisco
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Study Director: Diane V Havlir, MD, University of California, San Francisco
• Principal Investigator: Moses R Kamya MBChB, MMed, MPH, Makerere University
• Principal Investigator: Grant Dorsey, MD, PhD, University of California, San Francisco
• Principal Investigator: Ted Ruel, MD, University of California, San Francisco
• Principal Investigator: Jane Achan, MBChB, MPed, Makerere University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00978068
• Other Study ID Numbers: H5747-34097; NIH PO1 HD059454; 2009-114; HS-620; 551/ESR/NDA/DID-08/09; H5741-34097 and 10-00991
• First Posted: Sep 16, 2009
• Last Update Posted: Dec 28, 2018
• Last Verified: Dec 1, 2018

• Keywords provided by University of California, San Francisco: Pediatric HIV; Malaria; Uganda; Nevirapine; Zidovudine; Lamivudine; Lopinavir/ritonavir; Stavudine; Efavirenz; HIV
• Additional relevant MeSH terms: Malaria; Ritonavir; Lopinavir; Nevirapine; Efavirenz; Reverse Transcriptase Inhibitors

Study Results

Participant Flow

Recruitment Details	Children were recruited from September 2009 through July 2011.
Pre-assignment Detail	A total of 404 children were screened for eligibility; 228 were found not to be eligible. The main reasons for ineligibility were: 136 Were not eligible for ART 34 Were on ART with detectable viral load 32 Were HIV- 8 Had not received ART but had prior exposure to nevirapine

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Period Title: Overall Study
STARTED	87	89
Initiated Study Drugs	84	86
COMPLETED	83	80
NOT COMPLETED	4	9

Baseline Characteristics

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs	Total
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.	Total of all reporting groups
Overall Participants	84	86	170
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	2.9	3.1	3.1
Sex: Female, Male (Count of Participants)
Female	41 48.8%	41 47.7%	82 48.2%
Male	43 51.2%	45 52.3%	88 51.8%
Previous ART to Enrollment (participants) [Number]
No Previous ART	57 67.9%	58 67.4%	115 67.6%
Previous ART	27 32.1%	28 32.6%	55 32.4%
WHO Clinical HIV stage (participants) [Number]
Stage I (Asymptomatic)	60 71.4%	66 76.7%	126 74.1%
Stage II (mod. unexplained weight loss)	16 19%	15 17.4%	31 18.2%
Stage III (unexplained severe weight loss)	2 2.4%	1 1.2%	3 1.8%
Stage IV (HIV wasting syndrome)	6 7.1%	4 4.7%	10 5.9%
CD4 Percentage (% of white cells that are CD4 cells) [Median (Full Range) ]
No Previous ART	14	16	16
Previous ART	31	30	30
Viral Load (log10copies/mL) [Median (Full Range) ]
No Previous ART	5.4	5.5	5.5
Previous ART	NA	NA	NA
Hemoglobin (g/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dL]	10.4 (1.3)	10.6 (1.5)	10.5 (1.4)
Result of Baseline Blood Smear for Asexual Parasites (participants) [Number]
Positive	10 11.9%	11 12.8%	21 12.4%
Negative	74 88.1%	75 87.2%	149 87.6%

Outcome Measures

1. Primary Outcome

Title	Incidence-density of Malaria Defined as the Number of Incident Episodes of Malaria Per Time at Risk.
Time Frame	Time from randomization to at least 24 months of follow up or until end of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1: LPV/r + 2 NRTIs	Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
Arm/Group Description	Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number [Episodes/ Person-Yr at Risk]	1.32	2.25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments	We assumed that the incidence of malaria in Group 2 would be 0.70 episodes per person-year and estimated that we would need a sample of 300 participants for the study to have 80% power to show a 35% reduction in the incidence of malaria in Group 1, at a 2-sided significance level of 0.05. We then observed an incidence of malaria in Group 2 that was higher than anticipated (2.19 episodes/person-yr) and revised the sample size to 150 participants, who would be followed for at least 6 months.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Incidence Rate Ratio
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.36 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Group 1 represents the numerator for the rate ratio. Group 2 represents the denominator for the rate ratio.

2. Secondary Outcome

Title	Percentage of Uncomplicated Malaria Episodes With Accompanying Adverse Events That Occurred in the 28 Days Following Antimalarial Therapy
Description	The rates of adverse events, defined as severity grade 2 or higher that are possibly, probably or definitely related to study drugs over the course of the 28-day period after antimalarial therapy with artemether-lumefantrine (AL).
Time Frame	28 days after antimalarial therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number [% uncomplicated malaria episodes w/ AEs]	71.0	79.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Cox Proportional-Hazards
	Comments

3. Secondary Outcome

Title	Incidence-density of Malaria Defined as the Number of Incident Episodes of Complicated Malaria Per Time at Risk.
Time Frame	Time from randomization to at least 24 months of follow up or until end of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1	Group 2
Arm/Group Description	LPV/r + 2 NRTIs LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number [Episodes/ Person-Yr at Risk]	0.024	0.026

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments	We assumed that the incidence of malaria in Group 2 would be 0.70 episodes per person-year and estimated that we would need a sample of 300 participants for the study to have 80% power to show a 35% reduction in the incidence of malaria in Group 1, at a 2-sided significance level of 0.05. We then observed an incidence of malaria in Group 2 that was higher than anticipated (2.19 episodes/person-yr) and revised the sample size to 150 participants, who would be followed for at least 6 months.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Incidence Rate Ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.06 to 11.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Group 1 represents the numerator for the rate ratio. Group 2 represents the denominator for the rate ratio.

4. Secondary Outcome

Title	Estimates of the 6-month Risk of a First Episode of Malaria
Description	To assess the effect of ART independently of potential interactions with antimalarial therapy after treatment for malaria, we compared the two groups with respect to the time to the first episode of malaria. Cumulative risk was estimated using the Kaplan-Meier product-limit formula.
Time Frame	Enrollment to 6 months follow up

Outcome Measure Data

Analysis Population Description

Among patients who were followed for 6 months, malaria did not develop in 34 patients in the NNRTI group and 44 in the lopinavir-ritonavir group; data on 10 patients in the NNRTI group and 7 in the lopinavir-ritonavir group were censored before the 6-month follow-up assessment.

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number (95% Confidence Interval) [Cumulative Risk Percentage]	40.7	52.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Cox Proportional-Hazards
	Comments	Adjustment for repeated measures in the same patient
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Group 1 represents the numerator for the hazard ratio. Group 2 represents the denominator for the hazard ratio.

5. Secondary Outcome

Title	28-day Risk of Recurrent Parasitemia
Description	To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent parasitemia at 28 days were compared between the two groups.
Time Frame	28 days after antimalarial therapy

Outcome Measure Data

Analysis Population Description

The risk of recurrence was assessed among patients who had had uncomplicated malaria that had been treated with artemether-lumefantrine.

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number (95% Confidence Interval) [Cummulative Risk Percentage]	14.0	40.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Cox Proportional-Hazards
	Comments	Adjustment for repeated measures in same participant.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; 0.14 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Group 1 represents the numerator for the hazard ratio. Group 2 represents the denominator for the hazard ratio.

6. Secondary Outcome

Title	63-day Risk of Recurrent Malaria
Description	To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent malaria at 63 days were compared between the two groups.
Time Frame	28 days after antimalarial therapy

Outcome Measure Data

Analysis Population Description

The risk of recurrence was assessed among patients who had had uncomplicated malaria that had been treated with artemether-lumefantrine.

Arm/Group Title	LPV/r + 2 NRTIs	NVP or EFV + 2 NRTIs
Arm/Group Description	LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.	NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
Measure Participants	84	86
Number (95% Confidence Interval) [Cumulative Risk Percentage]	28.1	54.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: LPV/r + 2 NRTIs, Group 2: Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTIs
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Cox Proportional-Hazards
	Comments	Adjustment for repeated measures in the same patient.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Group 1 represents the numerator in the hazard ratio. Group 2 represents the denominator in the hazard ratio.

Adverse Events

Time Frame	Time from randomization to at least 24 months of follow up or until end of the study
Arm/Group Title	Group 1		Group 2
Arm/Group Description	LPV/r + 2 NRTIs LPV/r + 2 NRTIs: Group 1 Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.		NVP or EFV + 2 NRTIs NVP or EFV + 2 NRTIs: Group 2 Nevirapine (NVP) or Efavirenz (EFV) + 2 NRTI NVP will be used for children < 3 years of age and EFV for children ≥3 years of age. The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be stavudine.
All Cause Mortality
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/84 (13.1%)		9/86 (10.5%)
Blood and lymphatic system disorders
Anemia	2/84 (2.4%)		3/86 (3.5%)
Dehydration	0/84 (0%)		1/86 (1.2%)
Neutropenia/Absolute neutrophil count	7/84 (8.3%)		9/86 (10.5%)
Thrombocytopenia Platelets, decreased	3/84 (3.6%)		1/86 (1.2%)
Endocrine disorders
Elevated Temperature/Fever	2/84 (2.4%)		1/86 (1.2%)
Gastrointestinal disorders
Diarrhea	1/84 (1.2%)		1/86 (1.2%)
Vomiting	1/84 (1.2%)		1/86 (1.2%)
Hepatobiliary disorders
Elevated ALT	2/84 (2.4%)		2/86 (2.3%)
Metabolism and nutrition disorders
Malnutrition	1/84 (1.2%)		0/86 (0%)
Unintentional weight loss	0/84 (0%)		1/86 (1.2%)
Nervous system disorders
Seizure	2/84 (2.4%)		1/86 (1.2%)
Psychiatric disorders
Altered mental status	0/84 (0%)		1/86 (1.2%)
Renal and urinary disorders
Hypoglycemia	0/84 (0%)		1/86 (1.2%)
Respiratory, thoracic and mediastinal disorders
Cough	1/84 (1.2%)		0/86 (0%)
Dyspnea/respiratory distress	4/84 (4.8%)		3/86 (3.5%)
Skin and subcutaneous tissue disorders
Stevens-Johnson Syndrome	0/84 (0%)		1/86 (1.2%)
Other (Not Including Serious) Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/84 (48.8%)		43/86 (50%)
Blood and lymphatic system disorders
Anemia	2/84 (2.4%)		4/86 (4.7%)
Neutropenia	24/84 (28.6%)		21/86 (24.4%)
Thrombocytopenia Platelets, decreased	9/84 (10.7%)		6/86 (7%)
WBC, decreased	1/84 (1.2%)		2/86 (2.3%)
Endocrine disorders
Chills	2/84 (2.4%)		0/86 (0%)
Elevated Temperature	19/84 (22.6%)		24/86 (27.9%)
Gastrointestinal disorders
Diarrhea	0/84 (0%)		1/86 (1.2%)
Hepatobiliary disorders
Elevated ALT	2/84 (2.4%)		3/86 (3.5%)
Elevated AST	1/84 (1.2%)		1/86 (1.2%)
Metabolism and nutrition disorders
Severe Malnutrition	0/84 (0%)		1/86 (1.2%)
Unintentional weight loss	1/84 (1.2%)		0/86 (0%)
Skin and subcutaneous tissue disorders
Pallor	0/84 (0%)		1/86 (1.2%)
Rash (non-infectious)	0/84 (0%)		1/86 (1.2%)

Limitations/Caveats

The study has limited statistical power for the comparison of uncommon events and limited evaluation of potential cardiotoxic effects, hence future studies of the safety of coadministration of lopinavir-ritonavir and lumefantrine are warranted.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.