Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis.

BACKGROUND: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. FINDINGS: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. INTERPRETATION: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Performance of the hematology analyzer XN-31 prototype in the detection of Plasmodium infections in an endemic region of Colombia.

Early and accurate diagnosis is critical in reducing the morbidity and mortality associated with malaria. Microscopy (MI) is the current diagnostic gold standard in the field; however, it requires expert personnel, is time-consuming, and has limited sensitivity. Although rapid diagnostic tests for antigen detection (RDTs) are an alternative to diagnosis, they also have limited sensitivity and produce false positive results in detecting recent past infection. The automated hematology analyzer XN-31 prototype (XN-31p) (Sysmex Corporation, Kobe, Japan) is able to identify plasmodium-infected erythrocytes, count parasitemia and perform complete blood-cell counts within one minute. The performance of the XN-31p in diagnosing malaria was evaluated and compared with real-time polymerase chain reaction (qPCR), MI and RDT in an endemic area of Colombia where Plasmodium falciparum and Plasmodium vivax are present. Acute febrile patients were enrolled from July 2018 to April 2019 in Quibdó, Colombia. Malaria diagnoses were obtained from MI and RDT in the field and later confirmed by qPCR. Venous blood samples in EDTA were processed with an XN-31p in the field. Sensitivity, specificity, positive/negative predictive values, and the likelihood ratios of positive and negative tests were calculated with respect to the results from qPCR, MI and RDT. The intraclass correlation coefficient (ICC) and Bland-Altman plot were used to evaluate the concordance in the parasitemia with respect to MI. A total of 1,754 subjects were enrolled. The mean age was 27.0 years (IQR 14-44); 89.6% were Afro-Colombians, 94.3% lived in urban areas and 0.91% were pregnant. With respect to qPCR, the XN-31p showed a sensitivity of 90% (95% CI 87.24-92.34) and a specificity of 99.83% (95% CI 99.38-99.98) in detecting Plasmodium spp.; both parameters were equivalent to those for MI and RDT. Using MI as the reference, the XN-31p showed a sensitivity of 98.09% (95% CI 96.51-99.08), a specificity of 99.83% (95% CI 99.4-99.98), an ICC of 0.85 (95% CI 0.83-0.87) and an average difference of - 3096 parasites/µL when compared with thick-smear MI and an ICC of 0.98 (95% CI 0.97-0.98) and an average difference of - 0.0013% when compared with thin-smear MI. The XN-31p offers a rapid and accurate alternative method for diagnosing malaria in clinical laboratories in areas where P. falciparum and P. vivax cocirculate.

Malaria in Pregnancy in Endemic Regions of Colombia: High Frequency of Asymptomatic and Peri-Urban Infections in Pregnant Women with Malaria.

Background: Malaria in pregnancy (MiP) has been associated with adverse pregnancy outcomes. There is limited information on MiP in low transmission regions as Colombia. This study aimed to describe the epidemiology of MiP through active surveillance of infections by microscopy and polymerase chain reaction (PCR). Methods: A cross-sectional study was conducted between May 2016 and January 2017 in five municipalities (Apartadó, Turbo, El Bagre, Quibdó, and Tumaco) in Colombia. Pregnant women self-presenting at health centers for antenatal care visits, seeking medical care for suspected malaria, or delivery, were enrolled. Diagnosis of Plasmodium spp was made in peripheral and placental blood samples by microscopy and PCR. Results: A total of 787 pregnant women were enrolled; plasmodial infection was diagnosed by microscopy in 4.2% (95% CI 2.8-5.6; 33/787) or by nPCR in 5.3% (95% CI 3.8-6.9; 42/787) in peripheral blood. Most of the infections were caused by P. falciparum (78.5%), and 46% were afebrile (asymptomatic). Women in the first and second trimester of pregnancy were more likely to be infected (aOR = 3.06, 95%CI = 1.6 - 5.8). To live in the urban/peri-urban area (aOR = 3.04, 95%CI = 1.4 - 6.56), to have a history of malaria during last year (aOR = 5.45, 95%IC = 2.16 - 13.75), and the infrequent bed net usage (aOR = 2.8, 95%CI = 1.31 - 5.97) were associated with the infection. Pregnant infected women had a higher risk of anaemia (aOR = 2.18, 95%CI = 1.15 - 4.12) and fever (aOR = 14.2, 95%CI = 6.89 - 29.8). Conclusion: The screening for malaria during antenatal care in endemic areas of Colombia is highly recommended due to the potential adverse effects of Plasmodium spp. infection in pregnancy and as an important activity for the surveillance of asymptomatic infections in the control of malaria.

Barriers that limit the implementation of thermal fogging for the control of dengue in Colombia: a study of mixed methods.

BACKGROUND: Thermal fogging of Insecticides is a vector control strategy used by the Medellin Secretary of Health to combat dengue. This method is employed during outbreaks to curb populations of potentially infectious adult mosquitoes and interrupt transmission cycles. While this strategy has been used in Medellin since 2007, in some years it has not reduced dengue cases as expected. Difficulties in the implementation of fumigation strategies, such as lack of opportunity for treatment and public perception may be factors that limit its utility. The objective of this study was to identify barriers that hinder the implementation of thermal fogging, as well as attitudes and beliefs that prevent its acceptance. METHODS: We used a cross-sectional observational study of mixed methods carried out in neighborhoods prioritized for fumigation treatment in Medellin, Colombia. First, we assessed the timeliness of treatment by determining the latency period between reported dengue cases and the implementation of fumigation in response to those cases. Next, we administered structured questionnaires to residents in the area of fumigation treatments (n = 4455 homes) to quantify acceptance and rejection, as well as factors associated with rejection. RESULTS: The median time between notification and treatment was 25 days (IQR 20.0-36.5). Fumigators were only able to treat 53.7% of total households scheduled for treatment; 9.6% rejected treatment, and treatment teams were unable to fumigate the remaining 36.7% of homes due to absent residents, no adults being present, and other reasons. The most frequent causes for rejection were residents being busy at the time of treatment (33.1%) and no interest in the treatment (24.5%). Other reasons for rejection include the perceptions that fumigation does not control pests other than mosquitoes (4.3%), that no mosquitoes were present in the home (3.3%), and that fumigation affects human health (3.1%). CONCLUSIONS: The high percentage of houses where it was not possible to perform fumigation limits control of the vector. Future strategies should consider more flexible treatment schedules and incorporate informational messages to educate residents about the safety and importance of treatment.

Challenges for the diagnosis and treatment of malaria in low transmission settings in San Lorenzo, Esmeraldas, Ecuador.

BACKGROUND: Ecuador is on the verge of eliminating malaria according to the World Health Organization criteria. Nevertheless, active transmission foci still persist in the country, and these represent an important challenge for achieving the objectives set out. Diagnosis and treatment are a mainstay in the control and elimination of this disease. This study aimed to explore the barriers hindering the implementation of malaria diagnosis and treatment strategies in a focus of active transmission in the San Lorenzo canton, Ecuador. METHODS: Using a convergent mixed methods design during 2017, the researchers assessed the physical and human resources of the services network at the primary level of care along with the quality assurance activities, patient access to healthcare services and perceptions regarding the care provided to patients with malaria. RESULTS: The programme's administrative transition from the National Service of Vector-borne Diseases to the Ministry of Public Health is perceived from the interviewed participants to have weakened the diagnosis network established in recent years. A mean of 6.4 ± 0.88 months was found for anti-malarial medication shortage at the primary level of care. Likewise, there was high healthcare staff turnover (permanence, Me = 7 months; IQR = 5-16) and a deficit of general knowledge on the disease among the entirety of healthcare staff, as only 29% of physicians were aware of the correct first-line treatment for malaria by Plasmodium falciparum and Plasmodium vivax. It was evidenced that 95.7% of patients were hospitalized to receive anti-malarial treatment. Both patients and healthcare staff considered the area to be difficult to reach due to its geography and the presence of groups outside the law. They also identified the lack of personnel and microscopy posts in this border area as the main barrier. CONCLUSION: The network of diagnostic services for malaria is weak in San Lorenzo, and socio-economic, political and historical factors hinder the implementation of the universal malaria elimination strategy based on diagnosis and treatment.

Prospective Study of Plasmodium vivax Malaria Recurrence after Radical Treatment with a Chloroquine-Primaquine Standard Regimen in Turbo, Colombia.

Plasmodium vivax recurrences help maintain malaria transmission. They are caused by recrudescence, reinfection, or relapse, which are not easily differentiated. A longitudinal observational study took place in Turbo municipality, Colombia. Participants with uncomplicated P. vivax infection received supervised treatment concomitantly with 25 mg/kg chloroquine and 0.25 mg/kg/day primaquine for 14 days. Incidence of recurrence was assessed over 180 days. Samples were genotyped, and origins of recurrences were established. A total of 134 participants were enrolled between February 2012 and July 2013, and 87 were followed for 180 days, during which 29 recurrences were detected. The cumulative incidence of first recurrence was 24.1% (21/87) (95% confidence interval [CI], 14.6 to 33.7%), and 86% (18/21) of these events occurred between days 51 and 110. High genetic diversity of P. vivax strains was found, and 12.5% (16/128) of the infections were polyclonal. Among detected recurrences, 93.1% (27/29) of strains were genotyped as genetically identical to the strain from the previous infection episode, and 65.5% (19/29) of infections were classified as relapses. Our results indicate that there is a high incidence of P. vivax malaria recurrence after treatment in Turbo municipality, Colombia, and that a large majority of these episodes are likely relapses from the previous infection. We attribute this to the primaquine regimen currently used in Colombia, which may be insufficient to eliminate hypnozoites.

Therapeutic efficacy of alternative primaquine regimens to standard treatment in preventing relapses by Plasmodium vivax: A systematic review and meta-analysis / Eficacia terapéutica de esquemas de Primaquina usados como alternativa al tratamiento estándar en la prevención de recaídas por Plasmodium vivax: Una revisión sistemática y meta-análisis

Objective: To compare efficacy and safety of primaquine regimens currently used to prevent relapses by P. vivax. Methods: A systematic review was carried out to identify clinical trials evaluating efficacy and safety to prevent malaria recurrences by P. vivax of primaquine regimen 0.5 mg/kg/day for 7 or 14 days compared to standard regimen of 0.25 mg/kg/day for 14 days. Efficacy of primaquine according to cumulative incidence of recurrences after 28 days was determined. The overall relative risk with fixed-effects meta-analysis was estimated. Results: For the regimen 0.5 mg/kg/day/7 days were identified 7 studies, which showed an incidence of recurrence between 0% and 20% with follow-up 60-210 days; only 4 studies comparing with the standard regimen 0.25 mg/kg/day/14 days and no difference in recurrences between both regimens (RR= 0.977, 95% CI= 0.670 to 1.423) were found. 3 clinical trials using regimen 0.5 mg/kg/day/14 days with an incidence of recurrences between 1.8% and 18.0% during 330-365 days were identified; only one study comparing with the standard regimen (RR= 0.846, 95% CI= 0.484 to 1.477). High risk of bias and differences in handling of included studies were found. Conclusion: Available evidence is insufficient to determine whether currently PQ regimens used as alternative rather than standard treatment have better efficacy and safety in preventing relapse of P. vivax. Clinical trials are required to guide changes in treatment regimen of malaria vivax.

Objetivo: Comparar la eficacia y seguridad de los esquemas de primaquina actualmente usados para prevenir las recaídas de malaria por P. vivax. Métodos: A través de una revisión sistemática se identificaron ensayos clínicos que evaluaran la eficacia y seguridad para prevenir recurrencias por P. vivax del régimen de primaquina 0.5 mg/Kg/día por 7 o 14 días comparado al régimen estándar de 0.25 mg/Kg/día por 14 días. Se determinó la eficacia de primaquina con la incidencia acumulada de recurrencias posterior a 28 días. Se estimó el riesgo relativo global con un meta-análisis de efectos fijos. Resultados: Se identificaron 7 ensayos clínicos para el régimen 0.5 mg/Kg/día/7 días que mostraron una incidencia de recurrencias entre 0% y 20% con un seguimiento de 60 a 210 días; solo 4 estudios compararon con el régimen estándar y no se encontraron diferencias en las recurrencias entre ambos esquemas (RR= 0.977; IC 95%= 0.670-1.423). Se identificaron tres ensayos clínicos que usaron el esquema 0.5 mg/Kg/día/14 días con una incidencia de recurrencias entre 1.8% y 18.0% para 330 a 365 días; solo un estudio comparó con el régimen estándar (RR= 0.846; IC 95%= 0.484-1.477). Se encontró alto riesgo de sesgo y diferencias en la conducción de los estudios incluidos. Conclusión: No hay suficiente evidencia para determinar si los regímenes de primaquina usados como alternativas al tratamiento estándar tienen mejor eficacia para prevenir las recaídas de P. vivax. Se requieren ensayos clínicos para orientar los cambios en el esquema de tratamiento de este tipo de malaria.

Therapeutic efficacy of alternative primaquine regimens to standard treatment in preventing relapses by Plasmodium vivax: A systematic review and meta-analysis.

OBJECTIVE: To compare efficacy and safety of primaquine regimens currently used to prevent relapses by P. vivax. METHODS: A systematic review was carried out to identify clinical trials evaluating efficacy and safety to prevent malaria recurrences by P. vivax of primaquine regimen 0.5 mg/kg/ day for 7 or 14 days compared to standard regimen of 0.25 mg/kg/day for 14 days. Efficacy of primaquine according to cumulative incidence of recurrences after 28 days was determined. The overall relative risk with fixed-effects meta-analysis was estimated. RESULTS: For the regimen 0.5 mg/kg/day/7 days were identified 7 studies, which showed an incidence of recurrence between 0% and 20% with follow-up 60-210 days; only 4 studies comparing with the standard regimen 0.25 mg/kg/day/14 days and no difference in recurrences between both regimens (RR= 0.977, 95% CI= 0.670 to 1.423) were found. 3 clinical trials using regimen 0.5 mg/kg/day/14 days with an incidence of recurrences between 1.8% and 18.0% during 330-365 days were identified; only one study comparing with the standard regimen (RR= 0.846, 95% CI= 0.484 to 1.477). High risk of bias and differences in handling of included studies were found. CONCLUSION: Available evidence is insufficient to determine whether currently PQ regimens used as alternative rather than standard treatment have better efficacy and safety in preventing relapse of P. vivax. Clinical trials are required to guide changes in treatment regimen of malaria vivax.

OBJETIVO: Comparar la eficacia y seguridad de los esquemas de primaquina actualmente usados para prevenir las recaídas de malaria por P. vivax. MÉTODOS: A través de una revisión sistemática se identificaron ensayos clínicos que evaluaran la eficacia y seguridad para prevenir recurrencias por P. vivax del régimen de primaquina 0.5 mg/Kg/día por 7 o 14 días comparado al régimen estándar de 0.25 mg/Kg/día por 14 días. Se determinó la eficacia de primaquina con la incidencia acumulada de recurrencias posterior a 28 días. Se estimó el riesgo relativo global con un meta-análisis de efectos fijos. RESULTADOS: Se identificaron 7 ensayos clínicos para el régimen 0.5 mg/Kg/día/7 días que mostraron una incidencia de recurrencias entre 0% y 20% con un seguimiento de 60 a 210 días; solo 4 estudios compararon con el régimen estándar y no se encontraron diferencias en las recurrencias entre ambos esquemas (RR= 0.977; IC 95%= 0.670-1.423). Se identificaron tres ensayos clínicos que usaron el esquema 0.5 mg/Kg/día/14 días con una incidencia de recurrencias entre 1.8% y 18.0% para 330 a 365 días; solo un estudio comparó con el régimen estándar (RR= 0.846; IC 95%= 0.484-1.477). Se encontró alto riesgo de sesgo y diferencias en la conducción de los estudios incluidos. CONCLUSIÓN: No hay suficiente evidencia para determinar si los regímenes de primaquina usados como alternativas al tratamiento estándar tienen mejor eficacia para prevenir las recaídas de P. vivax. Se requieren ensayos clínicos para orientar los cambios en el esquema de tratamiento de este tipo de malaria.

Validation of a method for the simultaneous quantification of chloroquine, desethylchloroquine and primaquine in plasma by HPLC-DAD.

One of the most important aspects regarding the therapeutic efficacy of antimalarials is its quantification in biologic fluids. The detection and measurement of antimalarial drug levels is important for demonstrating (1) adequate absorption of the drug being given, (2) compliance in taking the full regimen required for treatment and (3) the level of drug in the blood at any time during the test period that parasites reappear. There is a lack of validated methods that simultaneously quantify different antimalarials administered at the same time, such as the use of chloroquine (CQ) and primaquine (PQ) in infections caused by Plasmodium vivax. In this study, a bioanalytical method was validated for the simultaneous quantification of primaquine (PQ), chloroquine (CQ) and desethylchloroquine (DSCQ) in human plasma using liquid-liquid extraction and high performance liquid chromatography with a diode array detector (HPLC-DAD). The PQ was evaluated over a concentration range of 100-3000 nM and the CQ and DSCQ was evaluated over a concentration range of 20-2000 nM. The selectivity of the method was verified by checking for interference by commonly used antimalarials and plasma samples. The accuracy and precision of the method was assessed for drugs spiked into human plasma and recoveries of 83.7%, 92.3%, and 76.5% were obtained for CQ, DSCQ, and PQ, respectively. The applicability of this method was also demonstrated with blood samples from patients with vivax malaria that received combination CQ plus PQ treatment. The simultaneous detection and accurate measurement of CQ, DSCQ, and PQ levels in human plasma provides an important and economical method for validating and monitoring sensitivity/resistance of P. vivax to more common treatment regimen.