Safety and tolerability of repeated doses of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a systematic review and an aggregated data meta-analysis of randomized controlled trials.

BACKGROUND: Malaria infection during pregnancy is an important cause of maternal and infant mortality and morbidity with the greatest effect being concentrated in sub-Saharan Africa. In areas of moderate to high malaria transmission, the World Health Organization (WHO) recommends the administration of intermittent preventive treatment of malaria in pregnancy (IPTp) using sulfadoxine-pyrimethamine (SP) to be given to all pregnant women at each scheduled antenatal care visit at monthly intervals. However, there is concern that increased resistance has compromised its effectiveness. This has led to a need for evaluation of alternatives to SP for IPTp with dihydroartemisinin-piperaquine (DP) emerging as a very promising candidate. Thus, this systematic review and aggregated data meta-analysis was conducted to establish the safety and tolerability of repeated doses with DP in IPTp. METHODS: A systematic review and aggregated data meta-analysis of randomized controlled trials (RCTs) was performed by searching electronic databases of PubMed, Science Direct, ClinicalTrials.gov and Google Scholar. RCTs comparing IPTp DP versus recommended standard treatment for IPTp with these outcome measures were analyzed; change in QTc interval, serious adverse events (SAE), grade 3 or 4 adverse events possibly related to study drug and vomiting within 30 min after study drug administration. The search was performed up to 24th June 2023. Data was extracted from eligible studies and an aggregated data meta-analysis was carried out with data pooled as risk ratio (RR) with a 95% confidence interval (CI), using RevMan software (5.4). This study is registered with PROSPERO, CRD42022310041. RESULTS: Six RCTs involving 7969 participants were included in this systematic review and aggregated data meta-analysis. The pooled analysis showed that DP was associated with a change from baseline of the QTc interval although this change was not associated with cardiotoxicity. There was no statistically significant difference in the risk of occurrence of SAEs among participants in both treatment groups (RR = 0.80, 95% CI [0.52-1.24], P = 0.32). However, significant difference was observed in grade 3 or 4 AEs possibly related to study drug where analysis showed that subjects on IPT DP were statistically significantly more likely to experience an AE possibly related to study drug than subjects on IPT SP (RR = 6.65, 95% CI [1.18-37.54], P = 0.03) and in vomiting within 30 min after study drug administration where analysis showed that the risk of vomiting is statistically significantly higher in subjects receiving IPT DP than in subjects receiving IPT SP (RR = 1.77, 95% CI [1.02-3.07], P = 0.04). CONCLUSION: DP was associated with a higher risk of grade 3 or 4 AEs possibly related to study drug and a higher risk of vomiting within 30 min after study drug administration. However, these were experienced in a very small percentage of women and did not affect adherence to study drugs. DP was also better tolerated in these studies as compared to most alternatives that have been proposed to replace SP which have proved to be too poorly tolerated in IPTp use.

Patterns of childhood tuberculosis diagnosis in Ethiopia: A multicenter cross-sectional study.

Background: Children share 12% of the global 10 million people infected with tuberculosis (TB) each year. Closing case detection gap in children remains difficult, with 56% of all children and 65% under-five with TB missed each year. We aimed to assess the patterns of childhood TB diagnosis and underlying determinants in Ethiopia when different TB diagnostic platforms are applied. Methods: A multi-site, cross-sectional study was carried out in Ethiopia as part of the larger EXIT-TB study - evidence-based multiple focused integrated intensified TB screening package. Outpatient children aged ≤ 15 with cough of any duration seeking care at four healthcare facilities in Ethiopia were enrolled consecutively. Participants underwent sputum Xpert MTB/RIF and/or smear microscopy and posteroanterior chest X-ray (CXR), and their clinical and sociodemographic data were captured using a structured questionnaire. Data were analyzed using Stata version 23. Multiple regression model was computed to determine the factors that influence TB case detection, with a 95% confidence interval (CI) and p < 0.05 taken as statistically significant. Results: A total of 438 children were enrolled. Of these, 399 had CXR examination of which 55 (13.8%) were suggestive of TB, 270 had Xpert MTB/RIF testing of which 32 (11.9%) were positive, and AFB smear microscopy was done for 51 children of which 2 (3.9%) were positive. Febrile children were more likely to be diagnosed with pulmonary TB than those without fever [aPR = 1.3, 95% CI (1.1-1.4)], and those with a TB contact history were more likely to be diagnosed with pulmonary TB than those with no such contacts [aPR = 1.2, 95% CI (1.1-1.3)]. Children from rural residences were more likely to be diagnosed with TB than those from urban residences [aPR = 1.3, 95% CI (1.1-1.5)]. Conclusion: The findings showed that clinical diagnosis remains an important method of TB diagnosis in children and the preferred choice to avert underdiagnosis. A more sensitive TB diagnostic method for children was symptom screening, followed by CXR and Xpert MTB/RIF assay or smear microscopy. Hence, an algorithm that combines clinical, CXR, and microbiological confirmatory tests can improve the rate of pulmonary TB diagnosis in children till more accurate and cost-effective diagnostic tools are accessible. Fever, weight loss, and TB contact history are highly associated with TB positivity rates in children.