Malaria, Hiv
Conditions
Brief summary
A longitudinal study with four parallel cohorts with each participant followed for 2 years: two cohorts in Busia (high malaria transmission site) and two cohorts in Kampala (low malaria transmission). Each site will have a cohort of children living with HIV (CLHIV) and HIV- uninfected children and will be age-matched, enrolled in parallel, and followed for two years. All children will be enrolled without malaria infection, as determined by a negative blood smear at baseline.
Detailed description
CLHIV will be maintained on a dolutegravir (DTG) based regimen for \>2 weeks prior to enrolment to ensure steady state. All children in Busia (HIV-infected and HIV-uninfected) will be enrolled and then randomized to receive either artemether- lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) for each episode of malaria which occurs over longitudinal follow-up in year one. During year 1, they will continue to receive the same antimalarial each time they are treated for uncomplicated malaria. In year two, those children randomized to the AL arm will begin to receive an alternating regimen for each subsequent malaria episode (AS-AQ, then AL, then AS-AQ, etc..). If local/national guidelines in Uganda for malaria change during the course of the study, the treatment arms will be altered as applicable. Aim 1: To what extent does DTG impact, BMI, body composition and metabolic changes? Aims 2 and 3: Are there critical drug-drug interactions between DTG and first line artemisinin-based combination therapies (ACTs)? Do these changes impact HIV and malaria outcomes? What is the status of ACT resistance and its relationship to PK exposure? MALARIA CASE DEFINITION: Uncomplicated malaria (all of the following) * Fever (≥ 37.5ºC axillary) or history of fever in the previous 24 hours * Positive thick blood smear (any parasitemia) * Absence of severe malaria Severe malaria * Evidence of severe malaria as per WHO criteria
Interventions
Participants will receive the dispersible formulation of AL with contains 20 mg artemether, 120 mg of lumefantrine
Children will receive the tablet formulations of Artesunate Amodiaquine using weight based dosing
Sponsors
Yale University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Only Busia participants (HIV-infected and HIV-uninfected, Cohorts 3 and 4) will be enrolled and then randomized to receive either artemether- lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) for each episode of malaria which occurs over longitudinal follow-up in year one. During year 1, they will continue to receive the same antimalarial each time they are treated for uncomplicated malaria. In year two, those randomized to the AL arm will begin to receive an alternating regimen for each subsequent malaria episode (AS-AQ, then AL, then AS-AQ, etc..). CLHIV, ages 5-17 years, will be identified from respective registers at Baylor-Uganda (in Kampala) and the Masafu HIV clinic (and nearby clinics) in Busia Uganda. HIV-uninfected children, also ages 5-17 years, will be enrolled from catchment areas at these two sites. Recruitment will be balanced by age and sex.
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
* Agreement to come to the clinic for all follow-up evaluations * Provision of informed consent and assent (as appropriate) * Residency within approximately 30 km of the study clinic * Negative blood smear for malaria (all sites) * For Children and adolescents living with HIV * Confirmed HIV infection * On DTG-based regimen for ≥14 days * For HIV-uninfected children - documentation of HIV-negative status by at least 1 assay
Exclusion criteria
* Significant comorbidities such as malignancy, active TB, chronic/active hepatitis B/C, diabetes, severe acute malnutrition, mitochondrial disorders * Receipt of known CYP interacting drugs at enrolment (except HAART) - see list of disallowed medications * Anemia defined by hemocue (Hb \< 7.0) at the time of enrolment * Signs of uncomplicated or severe malaria at the time of enrollment * Prior intolerance to AL or AS-AQ (for those in Busia only) * Pregnancy at enrolment (testing done at enrollment for all those of child-bearing age) * Concurrent enrolment in another research study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Mass Index (BMI) | baseline and 2 years | Change in BMI from baseline and 2 years in kg/m² (Cohort 1 + 3 vs Cohort 2 + 4) |
| Drug pharmacokinetic (PK) exposure | baseline up to 2 years | Comparison of drug exposure by DTG and anti-malarial regimen using Area under the curve (AUC) (Cohort 1 vs 3) |
| Drug pharmacokinetic exposure | baseline up to 2 years | Comparison of drug exposure by DTG and anti-malarial regimen using Area under the curve (AUC) (Cohort 3 vs 4) |
| Recurrence rate of malaria | 28 days and 42 days | To assess the 28 and 42 day efficacy of AL and AS-AQ for the treatment of uncomplicated malaria in children with and without HIV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average change in glucose sensor readings | every 6 months up to 2 years | Change in average of continuous glucose monitor readings over the last 10 days. (Cohorts 1 vs 2) |
| Change in insulin resistance (HOMA-IR) | baseline and 2 years | Change in HOMA-IR in those living with and without HIV. (Cohorts 1+3 vs 2+4) |
| Change in Body Mass Index (BMI) | baseline and 2 years | Change in BMI in children living with HIV from baseline and 2 years in kg/m² (Cohort 1 vs 3) |
| Pharmacokinetic parameters | immediately post drug exposure (Day 1) | AUC (0-8h) and AUC (last) for lumefantrine and DEAQ. (Cohorts 1 and 3) |
| Change in HIV viral load | every 6 months up to 2 years | Change of HIV viral load suppression in those on DTG vs children not living with HIV. (Cohorts 1 vs 3) |
| Malaria treatment outcome | 28 days and 42 days | 28 and 42 day antimalarial treatment efficacy in those on DTG vs Children not living with HIV, as measured by peripheral blood smears |
| HIV genotypic resistance to DTG | baseline and 2 years | Resistance to DTG (binary measures as yes/no) as measured by HIV molecular genotype (Cohort 1 and 3) |
| Artemisinin PK concentration-time profile | During treatment of malaria episodes over 2 years | Area under the plasma concentration versus time curve (AUC) in those receiving AL vs AS-AQ. (Cohorts 3 and 4) |
| Rate of parasite clearance | During treatment of malaria episodes over 2 years | Parasite clearance half-life in those treated with AL vs AS-AQ. (Cohorts 3 and 4) |
| Rate of parasite clearance and HIV | During treatment of malaria episodes over 2 years | Parasite clearance half-life in those living with HIV and those not living with HIV. (Cohorts 3 and 4) |
| Gametocyte quantity | At the time of presentation with malaria up to 2 years | Quantity of gametocytes in the peripheral blood in those treated artemisinin sensitive vs resistant infections. (Cohorts 3 and 4) |
Countries
Uganda
Contacts
CONTACTSunil Parikh, MD, MPH
PRINCIPAL_INVESTIGATORSunil Parikh, M.D., MPH
Yale School of Public Health
Outcome results
None listed