Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria.

Artemisinin-based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs. The study was carried out in health care facilities spread across Nigeria. From the database of over 10,000 patients recruited into an initial cohort, data for 1000 patients with comorbidities was extracted and matched with a control group of 1000 randomly selected patients with no comorbidity. There were 1105 adverse drug reactions in all, of which 66.2% were recorded in patients with comorbidity, and 34% are patients without comorbidity. The mean age of patients with comorbidities was 38.3 ± 17.5 years and 23.8 ± 17.2 for those without comorbidity. Out of the 979 patients with comorbidity, 36% were hypertensive, 2.2% hypertensive-diabetes, 16.4% peptic ulcer disease, 10.4% HIV/AIDS, 4.4% diabetes and 4.3% were asthmatic. Patients with comorbidity were three times more likely to have adverse drug reaction than those without comorbidity (Odds ration = 2.96; 95% CI = 2.23-3.93). HIV/AIDS and osteoarthritis were significantly associated with development of adverse drug reactions. Probability was <0.0001. Age, weight, and height of patients were also found to be risk factor for development of adverse drug reactions.

Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers.

AIMS: To investigate the effect of tetracycline co-administration on the pharmacokinetics of halofantrine in healthy subjects. METHODS: Eight healthy males were each given 500 mg single oral doses of halofantrine alone, or with tetracycline (500 mg 12 hourly for 7 days), in a crossover fashion. Blood samples collected at predetermined intervals were analyzed for halofantrine and its major metabolite, desbutylhalofantrine (HFM), using a validated HPLC method. RESULTS: Co-administration of tetracycline and halofantrine resulted in a significant increase (P < 0.05) in the maximum plasma concentration (C(max)), total area under the concentration-time curve (AUC), and terminal elimination half-life (t(1/2,z)), compared with halofantrine alone. (C(max) 0.43 +/- 0.14 vs 1.06 +/- 0.44 microg ml(-1) (95% CI on the difference 0.30, 0.95); AUC 32.0 +/- 13.6 vs 63.7 +/- 20.1 microg ml(-1) h (95% CI 14.2, 49.1); t(1/2,z:) 90.8 +/- 17.9 vs 157.4 +/- 57.4 h (95% CI 21.7, 111.5)). Similarly, tetracycline caused a significant increase (P < 0.05) in the AUC and C(max) of HFM. CONCLUSIONS: Tetracycline co-administration significantly increases the plasma concentrations of halofantrine and its major metabolite.