|Call||Senior Fellowship (SF)|
Optimizing Malaria Treatment for HIV-Malaria co-infected Individuals by Addressing Drug Interactions between Artemisinin-based Combination Therapies and Antiretroviral Drugs (OPTIMAL)
|Infectious Diseases Institute Limited (IDI)||Uganda|
|Call||Senior Fellowship (SF)|
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
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.
|Makerere University College Of Health Sciences||Uganda|
|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|
PK and drug interaction studies
|Infectious Diseases Institute|
|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|
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.
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.
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).
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.
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/ ).
To determine the prevalence and factors associated with dyslipidaemias in women using hormonal contraceptives.
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.
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.
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.
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.
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.).
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