Ethical and cultural implications for conducting verbal autopsies in South and Southeast Asia: a qualitative study.

INTRODUCTION: Causes of deaths often go unrecorded in lower income countries, yet this information is critical. Verbal autopsy is a questionnaire interview with a family member or caregiver to elicit the symptoms and circumstances preceding a death and assign a probable cause. The social and cultural aspects of verbal autopsy have gotten less attention than the technical aspects and have not been widely explored in South and Southeast Asia settings. METHODS: Between October 2021 and March 2023, prior to implementing a verbal autopsy study at rural sites in Bangladesh, Cambodia, Laos, Myanmar and Thailand, focus group discussions were conducted with village heads, religious leaders and community members from varied demographic backgrounds. Thematic analysis elucidated customs and traditional views surrounding death to understand local ethnocultural sensitivities. RESULTS: We found that death rituals varied greatly among religions, ethnicities and by socioeconomic status. Mourning periods were reported to last 3-100 days and related to the cause of death, age and how close the deceased person was to the family. Participants advised that interviews should happen after mourning periods to avoid emotional distress, but not long after so as to avoid recall bias. Interviewers should be introduced to respondents by a trusted local person. To provide reassurance and confidentiality, a family's residence is the preferred interview location. Interview questions require careful local language translation, and community sensitisation is important before data collection. CONCLUSION: Verbal autopsy is acceptable across a wide range of cultural settings in Southeast Asia, provided that local norms are preidentified and followed.

Determinants of Primaquine and Carboxyprimaquine Exposures in Children and Adults with Plasmodium vivax Malaria.

Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Patients with uncomplicated P. vivax malaria and with normal glucose-6-phosphate dehydrogenase were randomized to receive either chloroquine (25 mg base/kg of body weight) or dihydroartemisinin-piperaquine (dihydroartemisinin at 7 mg/kg and piperaquine at 55 mg/kg) plus primaquine, given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Predose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine, and carboxyprimaquine were measured. Methemoglobin levels were measured at frequent intervals. Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the milligram-per-kilogram primaquine daily dose, day of sampling, partner drug, and fever clearance, there was a significant nonlinear relationship between age and trough primaquine and carboxyprimaquine concentrations and daily methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations that were 0.53 (95% confidence interval [CI], 0.39 to 0.73)-fold lower, trough carboxyprimaquine concentrations that were 0.45 (95% CI, 0.35 to 0.55)-fold lower, and day 7 methemoglobin levels that were 0.87 (95% CI, 0.58 to 1.27)-fold lower. Increasing plasma concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine plasma concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Young children have lower primaquine and carboxyprimaquine exposures and lower levels of methemoglobinemia than adults. Young children may need higher weight-adjusted primaquine doses than adults. (This study has been registered at ClinicalTrials.gov under identifier NCT01640574.).

Randomized Controlled Trial of the Electrocardiographic Effects of Four Antimalarials for Pregnant Women with Uncomplicated Malaria on the Thailand-Myanmar Border.

Quinoline antimalarials cause drug-induced electrocardiographic QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria. Pregnant women with microscopy-confirmed parasitemia of any malaria species were enrolled in an open-label randomized controlled trial on the Thailand-Myanmar border from 2010 to 2016. Patients were randomized to the standard regimen of dihydroartemisinin-piperaquine (DP) or artesunate-mefloquine (ASMQ) or an extended regimen of artemether-lumefantrine (AL+). Recurrent Plasmodium vivax infections were treated with chloroquine. Standard 12-lead electrocardiograms were assessed on day 0, 4 to 6 h following the last dose, and day 7. QT was corrected for the heart rate by a linear mixed-effects model-derived population-based correction formula (QTcP = QT/RR0.381). A total of 86 AL+, 82 ASMQ, 88 DP, and 21 chloroquine-treated episodes were included. No patients had an uncorrected QT interval nor QTcP of >480 ms at any time. QTcP corresponding to peak drug concentration was longer in the DP group (adjusted predicted mean difference, 17.84 ms; 95% confidence interval [CI], 11.58 to 24.10; P < 0.001) and chloroquine group (18.31 ms; 95% CI, 8.78 to 27.84; P < 0.001) than in the AL+ group, but not different in the ASMQ group (2.45 ms; 95% CI, -4.20 to 9.10; P = 0.47) by the multivariable linear mixed-effects model. There was no difference between DP and chloroquine (P = 0.91). QTc prolongation resulted mainly from widening of the JT interval. In pregnant women, none of the antimalarial drug treatments exceeded conventional thresholds for an increased risk of torsade de pointes.

Chloroquine Versus Dihydroartemisinin-Piperaquine With Standard High-dose Primaquine Given Either for 7 Days or 14 Days in Plasmodium vivax Malaria.

BACKGROUND: Primaquine is necessary for the radical cure of Plasmodium vivax malaria, but the optimum duration of treatment and best partner drug are uncertain. A randomized controlled trial was performed to compare the tolerability and radical curative efficacy of 7-day versus 14-day high-dose primaquine regimens (total dose 7mg/kg) with either chloroquine or dihydroartemisinin-piperaquine. METHODS: Patients with uncomplicated P. vivax malaria on the Thailand-Myanmar border were randomized to either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine, either 0.5 mg/kg/day for 14 days or 1 mg/kg/day for 7 days. Adverse events within 42 days and 1-year recurrence rates were compared and their relationship with day 6 drug concentrations assessed. RESULTS: Between February 2012 and July 2014, 680 patients were enrolled. P. vivax recurrences (all after day 35) occurred in 80/654 (12%) patients; there was no difference between treatments. Compared to the 7-day primaquine groups the pooled relative risk of recurrence in the 14-day groups was 1.15 (95% confidence interval 0.7 to 1.8). Hematocrit reductions were clinically insignificant except in G6PD female heterozygotes, 2 of whom had hematocrit reductions to <23% requiring blood transfusion. CONCLUSION: Radical cure should be deployed more widely. The radical curative efficacy in vivax malaria of 7-day high-dose primaquine is similar to the standard 14-day high-dose regimen. Chloroquine and dihydroartemisinin-piperaquine are both highly effective treatments of the blood stage infection. Quantitative point of care G6PD testing would ensure safe use of the 7-day high-dose primaquine regimen in G6PD heterozygous females. CLINICAL TRIALS REGISTRATION: NCT01640574.