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| ID | Type | Description | Link |
|---|---|---|---|
| 2R01HD068174-11A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
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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.
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)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CLHIV on DTG- Kampala (Cohort 1) | Experimental | CLHIV on DTG living in the low transmission malaria setting of Kampala |
|
| HIV-uninfected children- Kampala (Cohort 2) | No Intervention | HIV-uninfected children living in the low malaria transmission site of Kampala (control) | |
| CLHIV on DTG- Busia (Cohort 3) | Experimental | CLHIV on DTG living in the high malaria transmission site of Busia |
|
| HIV-uninfected children- Busia (Cohort 4) | No Intervention | HIV-uninfected children living in high malaria transmission site of Busia (control) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Artemether-lumefantrine (AL) | Drug | Participants will receive the dispersible formulation of AL with contains 20 mg artemether, 120 mg of lumefantrine |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Body Mass Index (BMI) | Change in BMI from baseline and 2 years in kg/m² (Cohort 1 + 3 vs Cohort 2 + 4) | baseline and 2 years |
| Drug pharmacokinetic (PK) exposure | Comparison of drug exposure by DTG and anti-malarial regimen using Area under the curve (AUC) (Cohort 1 vs 3) | baseline up to 2 years |
| Drug pharmacokinetic exposure | Comparison of drug exposure by DTG and anti-malarial regimen using Area under the curve (AUC) (Cohort 3 vs 4) | baseline up to 2 years |
| Recurrence rate of malaria | 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. | 28 days and 42 days |
| Measure | Description | Time Frame |
|---|---|---|
| Average change in glucose sensor readings | Change in average of continuous glucose monitor readings over the last 10 days. (Cohorts 1 vs 2) | every 6 months up to 2 years |
| Change in insulin resistance (HOMA-IR) |
| Measure | Description | Time Frame |
|---|---|---|
| Time to resistance | Time to resistance mutation in days. (Cohort 3 and 4) | up to 2 years |
| K13 mutations | Rate of K13 mutation and Artemisinin partial resistance. (Cohort 3 and 4) |
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
For HIV-uninfected children - documentation of HIV-negative status by at least 1 assay
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Sunil Parikh, MD, MPH | Contact | 1-203-737-7906 | sunil.parikh@yale.edu |
| Name | Affiliation | Role |
|---|---|---|
| Sunil Parikh, M.D., MPH | Yale School of Public Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Baylor- Uganda | Recruiting | Kampala | Uganda |
Data will be de-identified, and shared on clinepidb.org upon conclusion of the study
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| ID | Term |
|---|---|
| D008288 | Malaria |
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
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| ID | Term |
|---|---|
| D000077611 | Artemether, Lumefantrine Drug Combination |
| C515299 | amodiaquine, artesunate drug combination |
| ID | Term |
|---|---|
| D000077549 | Artemether |
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
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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.
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| artesunate-amodiaquine (AS-AQ) | Drug | Children will receive the tablet formulations of Artesunate Amodiaquine using weight based dosing |
|
Change in HOMA-IR in those living with and without HIV. (Cohorts 1+3 vs 2+4)
| baseline and 2 years |
| Change in Body Mass Index (BMI) | Change in BMI in children living with HIV from baseline and 2 years in kg/m² (Cohort 1 vs 3) | baseline and 2 years |
| Pharmacokinetic parameters | AUC (0-8h) and AUC (last) for lumefantrine and DEAQ. (Cohorts 1 and 3) | immediately post drug exposure (Day 1) |
| Change in HIV viral load | Change of HIV viral load suppression in those on DTG vs children not living with HIV. (Cohorts 1 vs 3) | every 6 months up to 2 years |
| Malaria treatment outcome | 28 and 42 day antimalarial treatment efficacy in those on DTG vs Children not living with HIV, as measured by peripheral blood smears | 28 days and 42 days |
| HIV genotypic resistance to DTG | Resistance to DTG (binary measures as yes/no) as measured by HIV molecular genotype (Cohort 1 and 3) | baseline and 2 years |
| Artemisinin PK concentration-time profile | Area under the plasma concentration versus time curve (AUC) in those receiving AL vs AS-AQ. (Cohorts 3 and 4) | During treatment of malaria episodes over 2 years |
| Rate of parasite clearance | Parasite clearance half-life in those treated with AL vs AS-AQ. (Cohorts 3 and 4) | During treatment of malaria episodes over 2 years |
| Rate of parasite clearance and HIV | Parasite clearance half-life in those living with HIV and those not living with HIV. (Cohorts 3 and 4) | During treatment of malaria episodes over 2 years |
| Gametocyte quantity | Quantity of gametocytes in the peripheral blood in those treated artemisinin sensitive vs resistant infections. (Cohorts 3 and 4) | At the time of presentation with malaria up to 2 years |
| up to 2 years |
| Prevalence of mutations in malaria transporters | Change in mutation prevalence of pfcrt and pfmdr1 in those treated with AL vs AS-AQ for malaria.(Cohort 3 and 4) | During treatment of malaria episodes over 2 years |
| Infectious Disease Research Collaboration (IDRC) | Recruiting | Kampala | Uganda |
|
| D000079426 |
| Vector Borne Diseases |
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D007287 |
| Inorganic Chemicals |
| D009930 | Organic Chemicals |
| D000078102 | Lumefantrine |
| D005449 | Fluorenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D011083 | Polycyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |