HIV Positive, Malnourished
Conditions
Keywords
HIV, Children, HAART, Malnourished
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.
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.
Interventions
DRUGZDV+3TC+LPV/r
Sponsors
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)
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 36 Months
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
| 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. |
| 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 |
| 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) |
| 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 |
| 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) |
| 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 |
| 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) |
| 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Change in HIV Viral Load From Baseline | Weeks 0, 12, 24, 36 and 48 | Change from baseline in plasma HIV RNA viral load |
| 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 |
| Change in CD4 Percent | Weeks 0, 12, 24, 36 and 48 | Change in CD4 percent from baseline |
| 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. |
| Change in Mid-upper Arm Circumference | Weeks 0, 24, and 48 | Change in mid-upper arm circumference (MUAC) from entry |
| 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 |
Countries
Malawi, Tanzania, Uganda, Zimbabwe
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Severe Malnutrition Cohort Severe Acute Malnutrition at Entry ZDV+3TC+LPV/r | 25 |
| Normal Nutrition/Mild Malnutrition Cohort Normal Nutrition or Mild Malnutrition at Entry ZDV+3TC+LPV/r | 27 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Unable to Travel to Clinic | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Normal Nutrition/Mild Malnutrition Cohort | Total | Severe Malnutrition Cohort |
|---|---|---|---|
| Age, Continuous | 19.1 months STANDARD_DEVIATION 8.5 | 19.2 months STANDARD_DEVIATION 8.2 | 19.4 months STANDARD_DEVIATION 8 |
| CD4 Percent | 24.5 percent STANDARD_DEVIATION 11.3 | 20.2 percent STANDARD_DEVIATION 11.1 | 15.5 percent STANDARD_DEVIATION 8.8 |
| Log10 Plasma HIV RNA Viral Load | 5.2 log 10 copies/mL STANDARD_DEVIATION 1.3 | 5.0 log 10 copies/mL STANDARD_DEVIATION 1.3 | 4.8 log 10 copies/mL STANDARD_DEVIATION 1.2 |
| Mid-Upper Arm Circumference | 14.2 centimeters STANDARD_DEVIATION 1.6 | 12.7 centimeters STANDARD_DEVIATION 2.1 | 11.1 centimeters STANDARD_DEVIATION 1.1 |
| Nutritional Cohort Subgroup Mild Malnutrition | 15 Participants | 15 Participants | 0 Participants |
| Nutritional Cohort Subgroup Normal Nutrition | 12 Participants | 12 Participants | 0 Participants |
| Nutritional Cohort Subgroup Severe Malnutrition | 0 Participants | 25 Participants | 25 Participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 27 Participants | 52 Participants | 25 Participants |
| Region of Enrollment Malawi | 5 Participants | 17 Participants | 12 Participants |
| Region of Enrollment Tanzania | 9 Participants | 16 Participants | 7 Participants |
| Region of Enrollment Uganda | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Zimbabwe | 12 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Female | 14 Participants | 23 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 29 Participants | 16 Participants |
| World Health Organization (WHO) Weight-for-Height Z-Score | -0.7 Z-Score STANDARD_DEVIATION 1.2 | -2.0 Z-Score STANDARD_DEVIATION 1.7 | -3.4 Z-Score STANDARD_DEVIATION 0.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 25 | 0 / 27 |
| other Total, other adverse events | 25 / 25 | 25 / 27 |
| serious Total, serious adverse events | 9 / 25 | 5 / 27 |
Outcome results
Primary
Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24
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
Population: All participants who received at least one dose of study treatment (ZDV, 3TC, and LPV/r)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Severe Malnutrition Cohort | Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24 | 6 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24 | 7 Participants |
Comparison: 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.p-value: >0.999Fisher Exact
Primary
Grade 3 or Higher Adverse Events Through 24 Weeks
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
Population: All participants who received at least one dose of study treatment (ZDV, 3TC, and LPV/r)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Severe Malnutrition Cohort | Grade 3 or Higher Adverse Events Through 24 Weeks | 13 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Grade 3 or Higher Adverse Events Through 24 Weeks | 10 Participants |
Comparison: Comparison for number who experienced at least one grade 3 or higher adverse event. Null hypothesis of no difference between cohorts.p-value: 0.4Fisher Exact
Primary
Plasma Clearance of Lamivudine
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
Population: Participants with 3TC CL/F data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 1 | 8.7 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 12 | 9.5 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 24 | 7.5 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 1 | 8.4 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 12 | 6.8 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lamivudine | 3TC CL/F at Week 24 | 8.8 L/hours |
Comparison: Week 1 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.8995% CI: [-0.4, 0.5]t-test, 2 sided
Comparison: Week 12 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.1895% CI: [0.8, 2.3]t-test, 2 sided
Comparison: Week 24 comparison of 3TC clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.5395% CI: [0.5, 1.4]t-test, 2 sided
Primary
Plasma Clearance of Lopinavir
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
Population: Participants with LPV CL/F data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 1 | 2.2 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 12 | 2.3 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 24 | 2.1 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 1 | 2.0 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 12 | 1.6 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Lopinavir | LPV CL/F at Week 24 | 1.7 L/hours |
Comparison: Week 1 Comparison of LPV Clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.8995% CI: [0.5, 2.3]t-test, 2 sided
Comparison: Week 12 Comparison of LPV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.3795% CI: [0.7, 3.1]t-test, 2 sided
Comparison: Week 24 Comparison of LPV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.6395% CI: [0.5, 2.9]t-test, 2 sided
Primary
Plasma Clearance of Ritonavir
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
Population: Participants with RTV CL/F data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 1 | 16.9 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 12 | 17.3 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 24 | 14.8 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 1 | 15.8 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 12 | 11.2 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Ritonavir | RTV CL/F at Week 24 | 11.5 L/hours |
Comparison: Week 1 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.8495% CI: [0.5, 2.2]t-test, 2 sided
Comparison: Week 12 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.2195% CI: [0.8, 3.1]t-test, 2 sided
Comparison: Week 24 comparison of RTV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.4495% CI: [0.7, 2.5]t-test, 2 sided
Primary
Plasma Clearance of Zidovudine
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
Population: Participants with ZDV CL/F data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 1 | 34.8 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 12 | 48.8 L/hours |
| Severe Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 24 | 40.8 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 1 | 58.3 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 12 | 81.8 L/hours |
| Normal Nutrition/Mild Malnutrition Cohort | Plasma Clearance of Zidovudine | ZDV CL/F at Week 24 | 64.0 L/hours |
Comparison: Week 1 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.0995% CI: [0.3, 1.1]t-test, 2 sided
Comparison: Week 12 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.2395% CI: [0.3, 1.4]t-test, 2 sided
Comparison: Week 24 comparison of ZDV clearance between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.000395% CI: [0.5, 0.8]t-test, 2 sided
Primary
Steady-state Lamivudine Area Under the Curve
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
Population: Participants with 3TC AUC data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 1 | 4,245.0 ng*hours/mL |
| Severe Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 12 | 4,365.5 ng*hours/mL |
| Severe Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 24 | 6,359.0 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 1 | 5,520.2 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 12 | 7,233.0 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lamivudine Area Under the Curve | 3TC AUC at Week 24 | 5,849.2 ng*hours/mL |
Comparison: Week 1 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.2795% CI: [0.5, 1.2]t-test, 2 sided
Comparison: Week 12 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.04795% CI: [0.4, 1]t-test, 2 sided
Comparison: Week 24 comparison of 3TC AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.7695% CI: [0.6, 1.9]t-test, 2 sided
Primary
Steady-state Lopinavir Area Under the Curve
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
Population: Participants with LPV AUC data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 1 | 49.8 ug*hours/mL |
| Severe Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 12 | 53.0 ug*hours/mL |
| Severe Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 24 | 64.6 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 1 | 64.8 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 12 | 83.4 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Lopinavir Area Under the Curve | Week 24 | 79.4 ug*hours/mL |
Comparison: Week 1 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.4995% CI: [0.4, 1.6]t-test, 2 sided
Comparison: Week 12 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.2395% CI: [0.3, 1.4]t-test, 2 sided
Comparison: Week 24 Comparison of LPV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.6395% CI: [0.3, 2]t-test, 2 sided
Primary
Steady-state Ritonavir Area Under the Curve
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
Population: Participants with RTV AUC data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 1 | 1.6 ug*hours/mL |
| Severe Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 12 | 1.8 ug*hours/mL |
| Severe Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 24 | 2.3 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 1 | 2.1 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 12 | 3.0 ug*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Ritonavir Area Under the Curve | RTV AUC Week 24 | 3.0 ug*hours/mL |
Comparison: Week 1 Comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.4295% CI: [0.4, 1.5]t-test, 2 sided
Comparison: Week 12 comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.1195% CI: [0.3, 1.1]t-test, 2 sided
Comparison: Week 24 comparison of RTV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.4495% CI: [0.4, 1.5]t-test, 2 sided
Primary
Steady-state Zidovudine Area Under the Curve
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
Population: Participants with ZDV AUC data at week 1 and at week 12 or 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 1 | 2,261.0 ng*hours/mL |
| Severe Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 12 | 1,826.0 ng*hours/mL |
| Severe Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 24 | 2,449.7 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 1 | 1,774.0 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 12 | 1,335.7 ng*hours/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Steady-state Zidovudine Area Under the Curve | ZDV AUC at Week 24 | 1,609.3 ng*hours/mL |
Comparison: Week 1 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.3995% CI: [0.7, 2.2]t-test, 2 sided
Comparison: Week 12 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.4395% CI: [0.6, 3]t-test, 2 sided
Comparison: Week 24 comparison of ZDV AUC between cohorts. Null hypothesis of no difference between cohorts.p-value: 0.00395% CI: [1.2, 2]t-test, 2 sided
Secondary
Change in CD4 Percent
Change in CD4 percent from baseline
Time frame: Weeks 0, 12, 24, 36 and 48
Population: Participants with CD4 percent data at baseline and timepoint of interest (week 12, 24, 36, or 48)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 12 | 3.3 percent |
| Severe Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 24 | 9.3 percent |
| Severe Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 36 | 10.3 percent |
| Severe Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 48 | 12.7 percent |
| Normal Nutrition/Mild Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 48 | 6.7 percent |
| Normal Nutrition/Mild Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 12 | 3.0 percent |
| Normal Nutrition/Mild Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 36 | 7.1 percent |
| Normal Nutrition/Mild Malnutrition Cohort | Change in CD4 Percent | Change in CD4 Percent at Week 24 | 6.8 percent |
Comparison: Difference in cohorts of change in CD4 percent from baseline to week 12. Null hypothesis of no difference between cohorts.p-value: 0.8995% CI: [-3.9, 4.4]t-test, 2 sided
Comparison: Difference in cohorts of change in CD4 percent from baseline to week 24. Null hypothesis of no difference between cohorts.p-value: 0.3195% CI: [-2.5, 7.6]t-test, 2 sided
Comparison: Difference in cohorts of change in CD4 percent from baseline to week 36. Null hypothesis of no difference between cohorts.p-value: 0.1895% CI: [-1.5, 7.8]t-test, 2 sided
Comparison: Difference between cohorts of change in CD4 percent from baseline to week 48. Null hypothesis of no difference between cohorts.p-value: 0.01895% CI: [1.1, 11]t-test, 2 sided
Secondary
Change in HIV Viral Load From Baseline
Change from baseline in plasma HIV RNA viral load
Time frame: Weeks 0, 12, 24, 36 and 48
Population: Participants with data at baseline and timepoint of interest (week 12, 24, 36, or 48)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 12 | -1.4 log10 copies/mL |
| Severe Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 24 | -1.7 log10 copies/mL |
| Severe Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 36 | -1.8 log10 copies/mL |
| Severe Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 48 | -1.8 log10 copies/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 48 | -2.6 log10 copies/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 12 | -2.1 log10 copies/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 36 | -2.5 log10 copies/mL |
| Normal Nutrition/Mild Malnutrition Cohort | Change in HIV Viral Load From Baseline | Change in Log10 Viral Load between Baseline and Week 24 | -2.5 log10 copies/mL |
Comparison: Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 12. Null hypothesis of no difference between cohorts.p-value: 0.1595% CI: [-0.3, 1.7]t-test, 2 sided
Comparison: Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 24. Null hypothesis of no difference between cohorts.p-value: 0.295% CI: [-0.4, 1.8]t-test, 2 sided
Comparison: Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 36. Null hypothesis of no difference between cohorts.p-value: 0.1395% CI: [-0.2, 1.8]t-test, 2 sided
Comparison: Difference in cohorts of change in log10 plasma HIV viral load from baseline to week 48. Null hypothesis of no difference between cohorts.p-value: 0.08995% CI: [-0.1, 1.8]t-test, 2 sided
Secondary
Change in Mid-upper Arm Circumference
Change in mid-upper arm circumference (MUAC) from entry
Time frame: Weeks 0, 24, and 48
Population: Participants with MUAC data available
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Change in Mid-upper Arm Circumference | Week 24 | 2.6 centimeters |
| Severe Malnutrition Cohort | Change in Mid-upper Arm Circumference | Week 48 | 3.5 centimeters |
| Normal Nutrition/Mild Malnutrition Cohort | Change in Mid-upper Arm Circumference | Week 24 | 1.2 centimeters |
| Normal Nutrition/Mild Malnutrition Cohort | Change in Mid-upper Arm Circumference | Week 48 | 1.6 centimeters |
Comparison: Null hypothesis: change in MUAC from entry to week 24 equal to 0p-value: <0.000195% CI: [1.96, 3.28]t-test, 2 sided
Comparison: Null hypothesis: change in MUAC from entry to week 48 equal to 0p-value: <0.000195% CI: [2.83, 4.24]t-test, 2 sided
Secondary
Change in WHO Weight-for-height Z-score
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
Population: Participants with weight and height data available
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Severe Malnutrition Cohort | Change in WHO Weight-for-height Z-score | Week 24 | 2.3 Z-Score |
| Severe Malnutrition Cohort | Change in WHO Weight-for-height Z-score | Week 48 | 2.7 Z-Score |
| Normal Nutrition/Mild Malnutrition Cohort | Change in WHO Weight-for-height Z-score | Week 24 | 0.1 Z-Score |
| Normal Nutrition/Mild Malnutrition Cohort | Change in WHO Weight-for-height Z-score | Week 48 | 0.4 Z-Score |
Comparison: Null hypothesis: change in WHO weight-for-height Z-score from entry to week 24 equal to 0p-value: <0.000195% CI: [1.77, 2.91]t-test, 2 sided
Comparison: Null hypothesis: change in WHO weight-for-height Z-score from entry to week 48 equal to 0p-value: <0.000195% CI: [2.09, 3.37]t-test, 2 sided
Secondary
Free Fraction of LPV at Hour 2 Post Dose
Free fraction of steady-state lopinavir at 2 hours post dose
Time frame: Weeks 1, 12 and 24
Population: Participants with LPV free fraction data available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 1 | 0.8 Percent of Unbound LPV | Standard Deviation 0.8 |
| Severe Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 12 | 2.2 Percent of Unbound LPV | Standard Deviation 1 |
| Severe Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 24 | 3.1 Percent of Unbound LPV | Standard Deviation 2.8 |
| Normal Nutrition/Mild Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 1 | 3.2 Percent of Unbound LPV | Standard Deviation 2.3 |
| Normal Nutrition/Mild Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 12 | 6.0 Percent of Unbound LPV | Standard Deviation 3.8 |
| Normal Nutrition/Mild Malnutrition Cohort | Free Fraction of LPV at Hour 2 Post Dose | Week 24 | 2.1 Percent of Unbound LPV | Standard Deviation 0.6 |
Comparison: Week 1 comparison of LPV free faction. Null hypothesis of no difference between cohorts.p-value: 0.00395% CI: [-3.9, -0.9]t-test, 2 sided
Comparison: Week 12 comparison of LPV free faction. Null hypothesis of no difference between cohorts.p-value: 0.01195% CI: [-6.6, -1.1]t-test, 2 sided
Comparison: Week 24 comparison of LPV free faction. Null hypothesis of no difference between cohorts.p-value: 0.4695% CI: [-2.4, 4.4]t-test, 2 sided
Secondary
HIV Viral Load <400 Copies/mL
Count (%) of participants with plasma HIV RNA viral load \<400 copies/mL
Time frame: Baseline and weeks 12, 24, and 48
Population: Participants with data at baseline and timepoint of interest (week 12, 24, or 48)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Severe Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Baseline | 2 Participants |
| Severe Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 12 | 8 Participants |
| Severe Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 24 | 11 Participants |
| Severe Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 48 | 11 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 48 | 18 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Baseline | 2 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 24 | 18 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | HIV Viral Load <400 Copies/mL | Week 12 | 14 Participants |
Comparison: Baseline Comparison, with null hypothesis of no difference between cohorts.p-value: >0.999Fisher Exact
Comparison: Week 12 Comparison, with null hypothesis of no difference between cohorts.p-value: 0.15Fisher Exact
Comparison: Week 24 Comparison, with null hypothesis of no difference between cohorts.p-value: 0.065Fisher Exact
Comparison: Week 48 Comparison, with null hypothesis of no difference between cohorts.p-value: 0.065Fisher Exact
Secondary
Minimum Trough Concentration (Ctrough) of Lopinavir
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
Population: Participants with minimum trough concentration of LPV data
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 1 | 12 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 4 | 14 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 8 | 13 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 12 | 17 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 16 | 11 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 24 | 14 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 36 | 16 Participants |
| Severe Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 48 | 16 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 48 | 18 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 1 | 21 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 16 | 15 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 4 | 18 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 36 | 19 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 8 | 18 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 24 | 19 Participants |
| Normal Nutrition/Mild Malnutrition Cohort | Minimum Trough Concentration (Ctrough) of Lopinavir | Week 12 | 18 Participants |
Comparison: 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).p-value: 0.1795% CI: [0.22, 1.29]Mixed Models Analysis