EDCTP Alumni Network

Fostering excellence and collaboration in the next generation of researchers

Call Senior Fellowship (SF)
Programme EDCTP2
Start Date 2019-04-01
End Date 2024-03-31
Project Code TMA2017SF-1943
Status Active

Title

Optimizing Malaria Treatment for HIV-Malaria co-infected Individuals by Addressing Drug Interactions between Artemisinin-based Combination Therapies and Antiretroviral Drugs (OPTIMAL)

Host Organisation

Institution Country
Infectious Diseases Institute Limited (IDI) Uganda
Call Senior Fellowship (SF)
Programme EDCTP1
Start Date 2011-03-14
End Date 2013-09-30
Project Code TA.2009.40200.020
Status Completed

Title

Comparison of efficacy, safety and pharmacokinetics of intravenous artesunate and intravenous quinine followed by oral artemisinin combination therapy for severe malaria treatment in Uganda AND evaluation of pharmacokinetic drug interactions of artesunate, quinine, lumefantrine and piperaquine with antiretroviral drugs

Objectives

To evaluate the effectiveness of IV artesunate plus ACT and IV quinine plus ACT as well as to study the pharmacokinetics of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treatment of severe malaria in adults and children in Tororo district hospital, Uganda. 1. To compare treatment outcome (measured as risk of recurrent parasitaemia and risk of recurrent symptomatic malaria) following treatment with IV quinine followed by oral ACT (Artemether-Lumefantrine or Dihydroartemisinin-piperaquine) and IV artesunate followed by oral ACT (AL or DP) for treatment of severe malaria in Ugandan patients 2. To compare parasite clearance time following treatment with IV quinine followed by oral ACT (AL or DP) and IV artesunate followed by oral ACT (AL or DP) for treatment of severe malaria in Ugandan patients 3. To investigate the pharmacokinetic parameters of IV quinine, IV artesunate, oral AL and oral DP during severe malaria treatment in Ugandan patients and correlate these with treatment outcome 4. To investigate the pharmacokinetic drug interactions of quinine, artesunate, lumefantrine and piperaquine with the antiretroviral drugs (Nevirapine, Efavirenz, Lopinavir/ritonavir) in Ugandan patients.

Host Organisation

Institution Country
Makerere University College Of Health Sciences Uganda
Makerere University Uganda

Participants

Name Institution Country
Jane Achan Makerere University Uganda
Moses R. Kamya Makerere University Uganda
Elly Katabira Makerere University Uganda
Noah Kiwanuka Makerere University Uganda
Mohammed Lamorde Makerere University Uganda
Harriet Mayanja-Kizza Makerere University Uganda
Concepta Merry Makerere University, Uganda/Trinity College, Ireland Uganda

Study Design

PK and drug interaction studies

Sites

Makerere University
Infectious Diseases Institute
Mulago Hospital

Students Supervised

Type Name Title University Start Date End Date
Masters in Medicine Afizi Kibuuka Dr Makerere University 2011 2014
Masters in Medicine Kambale Kasonia Dr Makerere University 2013 2016
Masters of Science in Clinical Epidemiology and Biostatistics Ritah Bakesiima Ms Makerere University 2015 2017

Results & Outcomes

Follow-up of 274 study participants sucessfully completed. Samples for genotyping successfully analysed at the Mulago Molecular Biology laboratory. Samples for drug assays shipped to Mahidol Clinical Pharmacology Laboratory, Thailand. Preliminary results: 1. Rate of achieving failure among patients who received IV Artesunate is higher than in patients who received IV Quinine. 2. Rate of achieving recrudescence is higher among patients who received IV Quinine, compared to those that received IV Artesurate. 3. Probability of acquiring recrudescence is highest among the patients that received IV Quinine + DP.

Grants

Grant Code:
Source of funding:
Merck Master Service Agreement.
Amount:
300000
Role:
Principal Investigator
Start Date:
2018-01-01
End Date:
2020-01-01
Grant Code:
EDCTP-CSA-Ethics-863-CREDU
Source of funding:
Amount:
299406.25
Role:
Start Date:
2017-01-01
End Date:
2019-01-01
Grant Code:
4207128
Source of funding:
NIH
Amount:
275818
Role:
Principal Investigator
Start Date:
2019-01-01
End Date:
2022-01-01

Publications

Authors:
Byakika-Kibwika P, Nyakato P, Lamorde M, Kiragga AN. , Byakika-Kibwika et al.,
Date:
2018-08-30
Journal:
Malar J.
Content:

BACKGROUND:

Malaria control largely depends on availability of highly efficacious drugs, however, over the years, has been threatened by emergence of drug resistance. It is, therefore, important to monitor the impact of recurrent anti-malarial treatment on the long-term efficacy of anti-malarial regimens, especially in sub-Saharan African countries with high malaria transmission. Evaluation of parasite clearance following treatment of severe malaria with intravenous artesunate among patients in Eastern Uganda, was performed, as a contribution to monitoring anti-malarial effectiveness.

METHODS:

Parasite clearance data obtained from a clinical trial whose objective was to evaluate the 42-day parasitological treatment outcomes and safety following treatment of severe malaria with intravenous artesunate plus artemisinin-based combination therapy among patients attending Tororo District Hospital in Eastern Uganda, were analysed. Serial blood smears were performed at 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 h, followed by 6-hourly blood smears post start of treatment until 6 h post the first negative blood smear when parasite clearance was achieved. Study endpoints were; parasite clearance half-life (the time required for parasitaemia to decrease by 50% based on the linear portion of the parasite clearance slope) and parasite clearance time (time required for complete clearance of initial parasitaemia).

RESULTS:

One hundred and fifty participants with severe malaria were enrolled. All participants were treated with intravenous artesunate. All study participants tolerated artesunate well with rapid recovery from symptoms and ability to take oral mediation within 24 h. No immediate adverse events were recorded. The median (IQR) number of days to complete parasite clearance was of 2 (1-2). The median (IQR) time to clear 50% and 99% parasites was 4.8 (3.61-7.10) and 17.55 (14.66-20.66) h, respectively. The median estimated clearance rate constant per hour was 0.32. The median (IQR) slope half-life was 2.15 (1.64, 2.61) h.

CONCLUSION:

Parasite clearance following treatment with intravenous artesunate was rapid and adequate. This finding provides supportive evidence that resistance to artemisinins is unlikely to have emerged in this study area. Continuous monitoring of artemisinin effectiveness for malaria treatment should be established in high malaria transmission areas in sub-Saharan Africa where spread of resistance would be disastrous. Trial registration The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). Registered 7th October 2011, http://www.pactr.org/ ).

Identifiers:
Authors:
Bakesiima R1, Byakika-Kibwika P2, Tumwine JK3, Kalyango JN1, Nabaasa G1, Najjingo I1, Nabaggala GS1, Olweny F1, Karamagi C3.
Date:
2018-08-18
Journal:
BMJ Open.
Content:

OBJECTIVE:

To determine the prevalence and factors associated with dyslipidaemias in women using hormonal contraceptives.

DESIGN:

Cross-sectional study SETTING: Mulago Hospital, Kampala, Uganda PARTICIPANTS: Three hundred and eighty-four consenting women, aged 18-49 years, who had used hormonal contraceptives for at least 3 months prior to the study.

STUDY OUTCOME:

Dyslipidaemias (defined as derangements in lipid profile levels which included total cholesterol ≥200 mg/dL, high-density lipoprotein <40 mg/dL, triglyceride >150 mg/dL or low-density lipoprotein ≥160 mg/dL) for which the prevalence and associated factors were obtained.

RESULTS:

The prevalence of dyslipidaemias was 63.3% (95% CI: 58.4 to 68.1). Body mass index (BMI) (PR=1.33, 95% CI: 1.15 to 1.54, p<0.001) and use of antiretroviral therapy (ART) (PR=1.21, 95% CI: 1.03 to 1.42, p=0.020) were the factors significantly associated with dyslipidaemias.

CONCLUSION:

Dyslipidaemias were present in more than half the participants, and this puts them at risk for cardiovascular diseases. The high-risk groups were women with a BMI greater than 25 Kg/m2 and those who were on ART. Therefore, lipid profiles should be assessed in women using hormonal contraceptives in order to manage them better.

Identifiers:
Authors:
Date:
2019-08-29
Journal:
Antimicrob Agents Chemother.
Content:

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).

Copyright © 2019

Identifiers:

Projects

Fellow:
Pauline Byakika-Kibwika
Collaborators:
Name Country Institution
750 Uganda MAKERERE UNIVERSITY
Objectives:
1. To determine the safety of a standard dose of artemether-lumefantrine compared to double of the standard dose for weight and a 5-day course of artemether-lumefantrine for treatment of uncomplicated malaria in HIV-Malaria co-infected individuals receiving efavirenz-based ART. 2. To determine the steady-state pharmacokinetics of a standard dose of artemether-lumefantrine compared to double of the standard dose for weight and a 5-day course of artemether-lumefantrine for treatment of uncomplicated malaria in HIV-Malaria co-infected individuals receiving efavirenz-based ART. 3. To determine the 42-day treatment outcome and correlate it with the pharmacokinetics of a standard dose of artemether-lumefantrine compared to double of the standard dose for weight and a 5-day course of artemether-lumefantrine for treatment of uncomplicated malaria in HIV-Malaria co-infected individuals receiving efavirenz-based ART. 4. To build Research Capacity through doctoral and Masters Training at Makerere University College of Health Sciences.
Sites:
Infectious Diseases Institute
Study Design:
RCT
Subjects:
HIV-malaria infected individuals
Start Date:
2019-04-01
End Date:
2024-03-31

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