IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

• Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01818258
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 52
• Locations: 5
• Arms: 2
• Actual Duration (Months): 23.1
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Children living with HIV from sub-Saharan Africa often present with severe malnutrition. In severe malnutrition, metabolic and/or gut structural derangement may lead to inadequate antiretroviral (ARV) absorption and/or erratic drug levels. The greater surface area to weight ratio in severely malnourished children could also place them at higher risk of under dosing compared to children with mild to moderate malnutrition. However, limited data are available on the pharmacokinetics of ARVs in severely malnourished children. This study addressed this critical gap in knowledge by evaluating the PK of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in severely malnourished children living with HIV, compared to children with normal nutrition to mild malnutrition living with HIV.

Condition or Disease	Intervention/Treatment	Phase
HIV Positive; Malnourished	Drug: ZDV+3TC+LPV/r	Phase 4

Detailed Description

P1092 was a prospective, non-randomized Phase IV open label study of antiretroviral drugs zidovudine (ZDV), lamivudine (3TC), and ritonavir boosted lopinavir (LPV/r) in children living with HIV aged 6 to less than 36 months grouped by nutritional status. The study's primary objectives were to characterize the pharmacokinetics (PK), safety, and tolerability of antiretroviral (ARV) regimens in severely acute malnourished (SAM) children following the initiation of nutritional rehabilitation and compare results to mildly malnourished or normally nourished children in order to determine if current recommended doses are optimal in severely malnourished children.

Two cohorts of children were enrolled based on nutritional status at screening: severely acute malnourished children and children with mild malnutrition or normal nutrition (non-SAM cohort). SAM participants were recruited from nutritional rehabilitation clinics while non-SAM participants were enrolled from HIV treatment centers. SAM participants were required to complete a 10 to 18 day nutritional rehabilitation program before entering the study. A World Health Organization (WHO, 2013) approach to management of SAM was used. All participants were to receive an antiretroviral regimen of ZDV+3TC+LPV/r. ARVs were dosed based on WHO weight band dosing and were to be administered twice per day in a pediatric liquid formulation. ZDV was allowed to be replaced with abacavir at the discretion of the site investigator/clinician in cases of grade 3 or higher hematologic toxicity on a ZDV-inclusive regimen or ZDV intolerance. Participants were followed for 48 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: IMPAACT 1092: Phase IV Evaluation Of The Steady State Pharmacokinetics Of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in Severely Malnourished HIV-1-Infected Children
• Actual Study Start Date: Oct 26, 2015
• Actual Primary Completion Date: Apr 11, 2017
• Actual Study Completion Date: Sep 29, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Severe Malnutrition ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks	Drug: ZDV+3TC+LPV/r; Other Names: Zidovudine Retrovir Lamivudine Epivir Lopinavir/ritonavir Kaletra
Active Comparator: Normal Nutrition/Mild Malnutrition ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks	Drug: ZDV+3TC+LPV/r; Other Names: Zidovudine Retrovir Lamivudine Epivir Lopinavir/ritonavir Kaletra

Outcome Measures

Primary Outcome Measures

1. Grade 3 or Higher Adverse Events Through 24 Weeks [From week 0 to week 24]

   Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs.

2. Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24 [From week 0 to week 24]

   Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs

3. Steady-state Lopinavir Area Under the Curve [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state area under the curve (AUC) for Lopinavir (LPV)

4. Plasma Clearance of Lopinavir [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state plasma clearance (CL/F) of LPV

5. Steady-state Ritonavir Area Under the Curve [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state area under the curve (AUC) for Ritonavir (RTV)

6. Plasma Clearance of Ritonavir [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state plasma clearance (CL/F) of RTV

7. Steady-state Lamivudine Area Under the Curve [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state area under the curve (AUC) of Lamivudine (3TC)

8. Plasma Clearance of Lamivudine [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state plasma clearance (CL/F) of Lamivudine (3TC)

9. Steady-state Zidovudine Area Under the Curve [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

   Steady-state area under the curve (AUC) of zidovudine (ZDV)

10. Plasma Clearance of Zidovudine [0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry]

    Steady-state plasma clearance (CL/F) of Zidovudine (ZDV)

Secondary Outcome Measures

1. Minimum Trough Concentration (Ctrough) of Lopinavir [Measured 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 4, 8, 12, 16, 24, 36 and 48 weeks following study entry]

   Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir >= 1 ug/mL

2. Free Fraction of LPV at Hour 2 Post Dose [Weeks 1, 12 and 24]

   Free fraction of steady-state lopinavir at 2 hours post dose

3. Change in HIV Viral Load From Baseline [Weeks 0, 12, 24, 36 and 48]

   Change from baseline in plasma HIV RNA viral load

4. HIV Viral Load <400 Copies/mL [Baseline and weeks 12, 24, and 48]

   Count (%) of participants with plasma HIV RNA viral load <400 copies/mL

5. Change in CD4 Percent [Weeks 0, 12, 24, 36 and 48]

   Change in CD4 percent from baseline

6. Change in WHO Weight-for-height Z-score [Weeks 0, 24, and 48]

   Change in WHO weight-for-height Z-score from entry. A Z-score indicates the number of standard deviations the measurement is away from the mean. A Z-score of 0 is equal to the mean of the reference population. Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. The reference population was determined by the World Health Organization for children from 0 up to 5 years.

7. Change in Mid-upper Arm Circumference [Weeks 0, 24, and 48]

   Change in mid-upper arm circumference (MUAC) from entry

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 36 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documentation of HIV-1 infection defined as positive results from two samples collected at different time points, using protocol-specified tests

• Meets WHO classification for severe malnutrition, normal nutrition status, or mild malnutrition

• Eligible for HAART defined by WHO 2013 pediatric guidelines

• Parent or legal guardian able and willing to provide signed informed consent, remain within the study area during the study period and agree to have subject followed at the clinical site

• Qualifying hematology and chemistry laboratory values obtained from specimens collected within the study-specific screening period

• For severely malnourished children: An inpatient in a nutrition rehabilitation unit. Clinical improvement after 10-18 days on nutrition rehabilitation defined as: Appetite returned and eating better - child shows interest in food even if does not complete amount given:

• No further weight loss

• Normalized sodium and potassium defined as severity grade 1 or lower

• No evidence of cardiac failure

• Loss of apathy and starting to play

• No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C (non-axillary) or

34.4 to <37.4° C (axillary)

For children with normal - mild malnutrition, clinical stability will be indicated by:

• Good appetite

• Normalized sodium and potassium defined as severity grade 1 or lower

• No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C (non-axillary) or

34.4 to <37.4° C (axillary)

Exclusion Criteria:

• Edematous malnutrition at the time of study entry

• ≥ Grade 3 respiratory distress or presence of cardio respiratory compromise within 3 days prior to entry

• Chemotherapy for malignancy

• Acute infection for which the child has received appropriate antimicrobial treatment for <5 days

• Tuberculosis disease

• Clinic hepatitis as evidenced by jaundice and hepatomegaly

• Taking any disallowed medications

• Any condition, situation, or clinical finding that in the opinion of the investigator would place the child at an unacceptable level of risk for injury, or render the child/caregiver(s) unable to meet the requirements of the study, interfere with study participation, or in the interpretation of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Blantyre CRS (30301)	Blantyre		Malawi
2	Malawi CRS (12001)	Lilongwe		Malawi
3	Kilimanjaro Christian Medical Centre (5118)	Moshi		Tanzania
4	Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)	Kampala		Uganda
5	Harare Family Care (31890)	Harare		Zimbabwe

Sponsors and Collaborators

• International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• National Institute of Allergy and Infectious Diseases (NIAID)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Institute of Mental Health (NIMH)

Investigators

• Study Chair: Maxensia O Owor, MBChB, MMED, MPH, International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Study Documents (Full-Text)

• Study Protocol and Informed Consent Form - Aug 3, 2017
• Statistical Analysis Plan - Aug 20, 2018

More Information

Additional Information:

• Signs/symptoms, laboratory events, and diagnoses were graded using the Division of AIDS (DAIDS) Table for Grading Severity of Adult and Pediatric Adverse Events, Corrected Version 2.0, November 2014.
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Publications

None provided.

• Responsible Party: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01818258
• Other Study ID Numbers: IMPAACT P1092; U01AI068632; 11689
• First Posted: Mar 26, 2013
• Last Update Posted: Aug 12, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group: HIV; Children; HAART; Malnourished
• Additional relevant MeSH terms: HIV Seropositivity; Malnutrition; Ritonavir; Lopinavir; Lamivudine; Zidovudine

Study Results

Participant Flow

Recruitment Details	A total of 52 participants, 25 in the Severe Acute Malnutrition (SAM) cohort and 27 in the non-SAM cohort, enrolled over a period of 12 months between October 26, 2015 and October 21, 2016. The SAM cohort was slower to enroll. Participants were enrolled from 5 sites in 4 African countries: Malawi, Tanzania, Uganda, and Zimbabwe.
Pre-assignment Detail	Children with severe acute malnutrition (SAM) during the screening period were enrolled into the study 10-18 days after starting nutritional rehabilitation, and were required to show clinical improvement. SAM/non-SAM cohort assignments were determined during screening.

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Period Title: Overall Study
STARTED	25	27
COMPLETED	22	24
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort	Total
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r	Total of all reporting groups
Overall Participants	25	27	52
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	19.4 (8.0)	19.1 (8.5)	19.2 (8.2)
Sex: Female, Male (Count of Participants)
Female	9 36%	14 51.9%	23 44.2%
Male	16 64%	13 48.1%	29 55.8%
Race/Ethnicity, Customized (Count of Participants)
Black Non-Hispanic	25 100%	27 100%	52 100%
Region of Enrollment (Count of Participants)
Tanzania	7 28%	9 33.3%	16 30.8%
Uganda	1 4%	1 3.7%	2 3.8%
Zimbabwe	5 20%	12 44.4%	17 32.7%
Malawi	12 48%	5 18.5%	17 32.7%
World Health Organization (WHO) Weight-for-Height Z-Score (Z-Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z-Score]	-3.4 (0.8)	-0.7 (1.2)	-2.0 (1.7)
Mid-Upper Arm Circumference (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	11.1 (1.1)	14.2 (1.6)	12.7 (2.1)
Log10 Plasma HIV RNA Viral Load (log 10 copies/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log 10 copies/mL]	4.8 (1.2)	5.2 (1.3)	5.0 (1.3)
CD4 Percent (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	15.5 (8.8)	24.5 (11.3)	20.2 (11.1)
Nutritional Cohort Subgroup (Count of Participants)
Severe Malnutrition	25 100%	0 0%	25 48.1%
Mild Malnutrition	0 0%	15 55.6%	15 28.8%
Normal Nutrition	0 0%	12 44.4%	12 23.1%

Outcome Measures

1. Primary Outcome

Title	Grade 3 or Higher Adverse Events Through 24 Weeks
Description	Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs.
Time Frame	From week 0 to week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment (ZDV, 3TC, and LPV/r)

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	25	27
Count of Participants [Participants]	13 52%	10 37%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Comparison for number who experienced at least one grade 3 or higher adverse event. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24
Description	Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs
Time Frame	From week 0 to week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment (ZDV, 3TC, and LPV/r)

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	25	27
Count of Participants [Participants]	6 24%	7 25.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Comparison for number who experienced at least one grade 3 or higher adverse event related to study treatment. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

3. Primary Outcome

Title	Steady-state Lopinavir Area Under the Curve
Description	Steady-state area under the curve (AUC) for Lopinavir (LPV)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with LPV AUC data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	22	23
Week 1	49.8	64.8
Week 12	53.0	83.4
Week 24	64.6	79.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.3 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

4. Primary Outcome

Title	Plasma Clearance of Lopinavir
Description	Steady-state plasma clearance (CL/F) of LPV
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with LPV CL/F data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	22	23
LPV CL/F at Week 1	2.2	2.0
LPV CL/F at Week 12	2.3	1.6
LPV CL/F at Week 24	2.1	1.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 Comparison of LPV Clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.5 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 Comparison of LPV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 0.7 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 Comparison of LPV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.5 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

5. Primary Outcome

Title	Steady-state Ritonavir Area Under the Curve
Description	Steady-state area under the curve (AUC) for Ritonavir (RTV)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with RTV AUC data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	22	23
RTV AUC Week 1	1.6	2.1
RTV AUC Week 12	1.8	3.0
RTV AUC Week 24	2.3	3.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 Comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

6. Primary Outcome

Title	Plasma Clearance of Ritonavir
Description	Steady-state plasma clearance (CL/F) of RTV
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with RTV CL/F data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	22	23
RTV CL/F at Week 1	16.9	15.8
RTV CL/F at Week 12	17.3	11.2
RTV CL/F at Week 24	14.8	11.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.5 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 0.8 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.7 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

7. Primary Outcome

Title	Steady-state Lamivudine Area Under the Curve
Description	Steady-state area under the curve (AUC) of Lamivudine (3TC)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with 3TC AUC data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	21	21
3TC AUC at Week 1	4,245.0	5,520.2
3TC AUC at Week 12	4,365.5	7,233.0
3TC AUC at Week 24	6,359.0	5,849.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.6 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

8. Primary Outcome

Title	Plasma Clearance of Lamivudine
Description	Steady-state plasma clearance (CL/F) of Lamivudine (3TC)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with 3TC CL/F data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	21	21
3TC CL/F at Week 1	8.7	8.4
3TC CL/F at Week 12	9.5	6.8
3TC CL/F at Week 24	7.5	8.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 95%; 0.8 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

9. Primary Outcome

Title	Steady-state Zidovudine Area Under the Curve
Description	Steady-state area under the curve (AUC) of zidovudine (ZDV)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with ZDV AUC data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	15	16
ZDV AUC at Week 1	2,261.0	1,774.0
ZDV AUC at Week 12	1,826.0	1,335.7
ZDV AUC at Week 24	2,449.7	1,609.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 0.7 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.6 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 1.2 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

10. Primary Outcome

Title	Plasma Clearance of Zidovudine
Description	Steady-state plasma clearance (CL/F) of Zidovudine (ZDV)
Time Frame	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with ZDV CL/F data at week 1 and at week 12 or 24

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	15	16
ZDV CL/F at Week 1	34.8	58.3
ZDV CL/F at Week 12	48.8	81.8
ZDV CL/F at Week 24	40.8	64.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.5 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 24 Geometric Mean Ratio of Severe Malnutrition/Normal Nutrition/Mild Malnutrition

11. Secondary Outcome

Title	Minimum Trough Concentration (Ctrough) of Lopinavir
Description	Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir >= 1 ug/mL
Time Frame	Measured 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 4, 8, 12, 16, 24, 36 and 48 weeks following study entry

Outcome Measure Data

Analysis Population Description

Participants with minimum trough concentration of LPV data

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	24	25
Week 1	12 48%	21 77.8%
Week 4	14 56%	18 66.7%
Week 8	13 52%	18 66.7%
Week 12	17 68%	18 66.7%
Week 16	11 44%	15 55.6%
Week 24	14 56%	19 70.4%
Week 36	16 64%	19 70.4%
Week 48	16 64%	18 66.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Odds ratio (SAM/non-SAM) of Ctrough >=1 ug/mL from entry through 48 weeks from repeated measures mixed model, with the null hypothesis that the odds ratio is equal to zero (no difference between cohorts in odds of Ctrough >=1 ug/mL).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.22 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio (SAM/non-SAM) for Lopinavir Ctrough >= 1 ug/mL through 48 weeks

12. Secondary Outcome

Title	Free Fraction of LPV at Hour 2 Post Dose
Description	Free fraction of steady-state lopinavir at 2 hours post dose
Time Frame	Weeks 1, 12 and 24

Outcome Measure Data

Analysis Population Description

Participants with LPV free fraction data available

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	9	14
Week 1	0.8 (0.8)	3.2 (2.3)
Week 12	2.2 (1.0)	6.0 (3.8)
Week 24	3.1 (2.8)	2.1 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 1 comparison of LPV free faction. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -3.9 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Severe Malnutrition Cohort - Normal Nutrition/Mild Malnutrition for Week 1 Free Fraction (%) of LPV

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 comparison of LPV free faction. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95%; -6.6 to -1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Severe Malnutrition - Normal Nutrition/Mild Malnutrition for Week 12 Free Fraction (%) of LPV

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 comparison of LPV free faction. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -2.4 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Severe Malnutrition - Normal Nutrition/Mild Malnutrition for Week 24 Free Fraction (%) of LPV

13. Secondary Outcome

Title	Change in HIV Viral Load From Baseline
Description	Change from baseline in plasma HIV RNA viral load
Time Frame	Weeks 0, 12, 24, 36 and 48

Outcome Measure Data

Analysis Population Description

Participants with data at baseline and timepoint of interest (week 12, 24, 36, or 48)

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	22	23
Change in Log10 Viral Load between Baseline and Week 12	-1.4	-2.1
Change in Log10 Viral Load between Baseline and Week 24	-1.7	-2.5
Change in Log10 Viral Load between Baseline and Week 36	-1.8	-2.5
Change in Log10 Viral Load between Baseline and Week 48	-1.8	-2.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 12. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -0.3 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 24. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 36. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -0.2 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 48. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

14. Secondary Outcome

Title	HIV Viral Load <400 Copies/mL
Description	Count (%) of participants with plasma HIV RNA viral load <400 copies/mL
Time Frame	Baseline and weeks 12, 24, and 48

Outcome Measure Data

Analysis Population Description

Participants with data at baseline and timepoint of interest (week 12, 24, or 48)

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	25	27
Baseline	2 8%	2 7.4%
Week 12	8 32%	14 51.9%
Week 24	11 44%	18 66.7%
Week 48	11 44%	18 66.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Baseline Comparison, with null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 12 Comparison, with null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 24 Comparison, with null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Week 48 Comparison, with null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments
	Method	Fisher Exact
	Comments

15. Secondary Outcome

Title	Change in CD4 Percent
Description	Change in CD4 percent from baseline
Time Frame	Weeks 0, 12, 24, 36 and 48

Outcome Measure Data

Analysis Population Description

Participants with CD4 percent data at baseline and timepoint of interest (week 12, 24, 36, or 48)

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	23	24
Change in CD4 Percent at Week 12	3.3	3.0
Change in CD4 Percent at Week 24	9.3	6.8
Change in CD4 Percent at Week 36	10.3	7.1
Change in CD4 Percent at Week 48	12.7	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in CD4 percent from baseline to week 12. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -3.9 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in CD4 percent from baseline to week 24. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -2.5 to 7.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference in cohorts of change in CD4 percent from baseline to week 36. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -1.5 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort, Normal Nutrition/Mild Malnutrition Cohort
	Comments	Difference between cohorts of change in CD4 percent from baseline to week 48. Null hypothesis of no difference between cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 95%; 1.1 to 11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of comparison: Severe Malnutrition - Normal Nutrition/Mild Malnutrition

16. Secondary Outcome

Title	Change in WHO Weight-for-height Z-score
Description	Change in WHO weight-for-height Z-score from entry. A Z-score indicates the number of standard deviations the measurement is away from the mean. A Z-score of 0 is equal to the mean of the reference population. Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. The reference population was determined by the World Health Organization for children from 0 up to 5 years.
Time Frame	Weeks 0, 24, and 48

Outcome Measure Data

Analysis Population Description

Participants with weight and height data available

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	25	27
Week 24	2.3	0.1
Week 48	2.7	0.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort
	Comments	Null hypothesis: change in WHO weight-for-height Z-score from entry to week 24 equal to 0
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean
	Estimated Value	2.34
	Confidence Interval	(2-Sided) 95%; 1.77 to 2.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort
	Comments	Null hypothesis: change in WHO weight-for-height Z-score from entry to week 48 equal to 0
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean
	Estimated Value	2.73
	Confidence Interval	(2-Sided) 95%; 2.09 to 3.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change in Mid-upper Arm Circumference
Description	Change in mid-upper arm circumference (MUAC) from entry
Time Frame	Weeks 0, 24, and 48

Outcome Measure Data

Analysis Population Description

Participants with MUAC data available

Arm/Group Title	Severe Malnutrition Cohort	Normal Nutrition/Mild Malnutrition Cohort
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r	Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
Measure Participants	23	24
Week 24	2.6	1.2
Week 48	3.5	1.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort
	Comments	Null hypothesis: change in MUAC from entry to week 24 equal to 0
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean
	Estimated Value	2.63
	Confidence Interval	(2-Sided) 95%; 1.96 to 3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe Malnutrition Cohort
	Comments	Null hypothesis: change in MUAC from entry to week 48 equal to 0
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean
	Estimated Value	3.53
	Confidence Interval	(2-Sided) 95%; 2.83 to 4.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From study entry to study completion at Week 48 or premature study discontinuation
Adverse Event Reporting Description	Serious Adverse Event (SAE) Reporting Category [v2.0 of the DAIDS expedited adverse event Manual] was used. Study agents for which relationship assessments were required: ZDV, 3TC, LPV/r and abacavir. Other events reported in an expedited fashion included malignancies, seizures and Grade 3/4 hepatotoxicities, and Grade 3/4 related toxicities where a relationship to study drug could not be ruled out. Events were summarized if onset was on or after entry.
Arm/Group Title	Severe Malnutrition		Normal Nutrition/Mild Malnutrition
Arm/Group Description	Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r		Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r
All Cause Mortality
	Severe Malnutrition		Normal Nutrition/Mild Malnutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/25 (12%)		0/27 (0%)
Serious Adverse Events
	Severe Malnutrition		Normal Nutrition/Mild Malnutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/25 (36%)		5/27 (18.5%)
Blood and lymphatic system disorders
Anaemia	1/25 (4%)		1/27 (3.7%)
Neutropenia	0/25 (0%)		2/27 (7.4%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/25 (4%)		0/27 (0%)
Infections and infestations
Gastroenteritis	1/25 (4%)		0/27 (0%)
Pneumonia	3/25 (12%)		2/27 (7.4%)
Pulmonary tuberculosis	1/25 (4%)		0/27 (0%)
Investigations
Haemoglobin decreased	2/25 (8%)		0/27 (0%)
Neutrophil count decreased	3/25 (12%)		0/27 (0%)
Metabolism and nutrition disorders
Malnutrition	2/25 (8%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Severe Malnutrition		Normal Nutrition/Mild Malnutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/25 (100%)		25/27 (92.6%)
Blood and lymphatic system disorders
Anaemia	5/25 (20%)		3/27 (11.1%)
Iron deficiency anaemia	3/25 (12%)		4/27 (14.8%)
Lymphadenopathy	4/25 (16%)		5/27 (18.5%)
Splenomegaly	2/25 (8%)		1/27 (3.7%)
Ear and labyrinth disorders
Otorrhoea	4/25 (16%)		3/27 (11.1%)
Tympanic membrane hyperaemia	4/25 (16%)		3/27 (11.1%)
Eye disorders
Eye discharge	4/25 (16%)		5/27 (18.5%)
Ocular hyperaemia	2/25 (8%)		2/27 (7.4%)
Gastrointestinal disorders
Abdominal distension	2/25 (8%)		0/27 (0%)
Diarrhoea	11/25 (44%)		6/27 (22.2%)
Oral disorder	2/25 (8%)		0/27 (0%)
Stomatitis	5/25 (20%)		1/27 (3.7%)
Vomiting	8/25 (32%)		5/27 (18.5%)
General disorders
Pyrexia	11/25 (44%)		10/27 (37%)
Infections and infestations
Conjunctivitis	3/25 (12%)		3/27 (11.1%)
Gastroenteritis	5/25 (20%)		2/27 (7.4%)
Impetigo	4/25 (16%)		0/27 (0%)
Oral candidiasis	6/25 (24%)		1/27 (3.7%)
Otitis media acute	6/25 (24%)		5/27 (18.5%)
Plasmodium falciparum infection	6/25 (24%)		5/27 (18.5%)
Pneumonia bacterial	3/25 (12%)		5/27 (18.5%)
Tinea faciei	2/25 (8%)		0/27 (0%)
Upper respiratory tract infection	5/25 (20%)		2/27 (7.4%)
Investigations
Alanine aminotransferase increased	5/25 (20%)		3/27 (11.1%)
Aspartate aminotransferase increased	6/25 (24%)		3/27 (11.1%)
Blood albumin decreased	16/25 (64%)		10/27 (37%)
Blood bicarbonate decreased	23/25 (92%)		20/27 (74.1%)
Blood cholesterol increased	3/25 (12%)		2/27 (7.4%)
Blood glucose decreased	5/25 (20%)		4/27 (14.8%)
Blood glucose increased	2/25 (8%)		1/27 (3.7%)
Blood potassium decreased	2/25 (8%)		0/27 (0%)
Blood potassium increased	10/25 (40%)		8/27 (29.6%)
Blood sodium decreased	12/25 (48%)		15/27 (55.6%)
Blood triglycerides increased	1/25 (4%)		4/27 (14.8%)
Haemoglobin decreased	22/25 (88%)		21/27 (77.8%)
Neutrophil count decreased	7/25 (28%)		17/27 (63%)
Platelet count decreased	3/25 (12%)		3/27 (11.1%)
Weight decreased	7/25 (28%)		0/27 (0%)
Metabolism and nutrition disorders
Decreased appetite	4/25 (16%)		2/27 (7.4%)
Dehydration	2/25 (8%)		0/27 (0%)
Failure to thrive	2/25 (8%)		0/27 (0%)
Malnutrition	21/25 (84%)		6/27 (22.2%)
Poor feeding infant	5/25 (20%)		1/27 (3.7%)
Underweight	6/25 (24%)		0/27 (0%)
Psychiatric disorders
Selective eating disorder	2/25 (8%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	17/25 (68%)		14/27 (51.9%)
Dyspnoea	3/25 (12%)		1/27 (3.7%)
Rales	2/25 (8%)		0/27 (0%)
Rhinorrhoea	8/25 (32%)		7/27 (25.9%)
Sneezing	1/25 (4%)		3/27 (11.1%)
Tachypnoea	2/25 (8%)		0/27 (0%)
Use of accessory respiratory muscles	3/25 (12%)		0/27 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/25 (8%)		0/27 (0%)
Erythema	0/25 (0%)		2/27 (7.4%)
Papule	4/25 (16%)		2/27 (7.4%)
Rash	4/25 (16%)		3/27 (11.1%)
Rash generalised	1/25 (4%)		2/27 (7.4%)
Rash papular	2/25 (8%)		3/27 (11.1%)
Vascular disorders
Pallor	2/25 (8%)		0/27 (0%)

Limitations/Caveats

Children with moderate malnutrition were not enrolled in the study by design

More Information

Certain Agreements

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

In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights