Malaria Falciparum

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Elizabeth A Ashley - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic study of artemether lumefantrine given once daily for the treatment of uncomplicated multidrug resistant Falciparum Malaria
    Tropical Medicine & International Health, 2007
    Co-Authors: Rose Mcgready, Elizabeth A Ashley, Kasia Stepniewska, Niklas Lindegardh, Anna Annerberg, Robert Hutagalung
    Abstract:

    Summary Background  Adherence to antiMalarial drug regimens is improved by simple dosing. If the fixed antiMalarial drug combination artemether–lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. Methods  In an open randomized study, 43 patients with uncomplicated Falciparum Malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration–time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Results  Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC(0∞) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114–5781) μg/ml h, compared with 432 (308–992) μg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84–100) in the six-dose arm and 85% (70–100) in the three-dose arm (P = 0.3). Conclusion  Artemether–lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antiMalarial should be given twice daily in a 3-day regimen, with food containing fat. Donnees de base  La compliance aux traitements a base d'antimalariques est amelioree par des doses simples. Si la combinaison a dose fixe d'antimalariques artemether–lumefantrine pouvait etre administree une fois par jour, cela devrait ameliorer la compliance et donc l'efficacite, et reduire le risque de selection de resistance. Methodes  dans une etude randomisee ouverte, 43 patients presentant une Malaria Falciparum non compliquee ont recu des doses equivalentes d'artemether–lumefantrine avec 200 ml de lait aromatise, selon le regime conventionnel i.e: deux fois par jour ou selon un regime a une seule dose quotidienne pendant 3 jours. L'objectif final primaire etait la comparaison des aires sous la courbe (AUC) de la concentration plasmatique de lumefantrine en fonction du temps. Les objectifs secondaires etaient la mesure des taux de guerison ajustes par les resultats de la reaction en chaine de la polymerase (PCR) au jour 42ieme et les profils de tolerance. Resultats  Les profils pharmacocinetiques de lumefantrine ont ete obtenus pour 36 patients. Les AUC(0∞) dans le regime ‘‘une fois par jour’’etait 30% inferieur a celles dans le regime conventionnel (p = 0,011) avec une valeur mediane de 306 (114–5781) μg/ml h comparea 432 (308–992) μg/ml h. Il n'y avait aucune difference significative dans les concentrations plasmatiques maximales atteintes. Les taux de guerison ajustes par la PCR au 42ieme jour du suivi etaient de 94% (IC95%: 84–100) dans le groupe a 6 doses et 85% (IC95%: 70–100) dans le groupe a 3 doses (p = 0,3). Conclusion  L'efficacite de l'Artemether–lumefantrine est reduite dans le regime ‘'une fois par jour‘’ parce que l'absorption du lumefantrine est dose dependante. Aux doses recommandees actuellement, cet antimalarique devrait etre administre deux fois par jour dans un regime de trois jours, avec la nourriture contenant la matiere grasse. Antecedentes  La adherencia al tratamiento con antimalaricos mejora si se simplifica la dosificacion. Si se pudiese dar la combinacion fija de antimalaricos artemeter–lumefantrina (AL) en una dosis unica por dia, deberia mejorar la adherencia y por lo tanto la efectividad del tratamiento, habiendo un menor riesgo de seleccion de cepas resistentes. Metodos  En un ensayo abierto, aleatorizado, en el que 43 pacientes con Malaria no complicada por Falciparum recibieron durante tres dias dosis equivalentes de AL con 200ml de leche, bien bajo el regimen convencional de dos veces al dia o en una dosis unica cada dia. El criterio principal de valoracion fue una comparacion de las areas bajo las curvas de la concentracion de lumefantrina en plasma a lo largo del tiempo (ABC). Los criterios secundarios de valoracion fueron las PCR del dia 42, las tasas de curacion ajustadas y los perfiles de tolerabilidad. Resultados  Se obtuvieron los perfiles farmacocineticos de la lumefantrina para 36 pacientes. El ABC (0∞) del regimen unico al dia era un 30% mas bajo que el regimen convencional (p = 0.011) con una media (rango) de 306 (114–5781) μg/ml h comparado con 432 (308–992) μg/ml h. No habia una diferencia significativa entre las maximas concentraciones de plasma alcanzadas. Las tasas de curacion ajustadas por PCR a los 42 dias de seguimiento fueron 94% (95%CI 84–100) para el grupo con 6 dosis y 85% (70–100) para los que recibieron 3 dosis (p = 0.3). Conclusion  La eficacia de artemeter–lumefantrina se reduce al dar una dosis unica, puesto que la absorcion de la lumefantrina esta limitada por la dosis. En las dosis recomendadas en la actualidad, este antimalarico deberia darse dos veces al dia en un regimen de tres dias, acompa,nado con alimentos que contengan grasas.

  • a randomized open study to assess the efficacy and tolerability of dihydroartemisinin piperaquine for the treatment of uncomplicated Falciparum Malaria in cambodia
    Tropical Medicine & International Health, 2007
    Co-Authors: Bart Janssens, Duong Socheat, Elizabeth A Ashley, M Van Herp, L Goubert, S Chan, S Uong, S Nong, A Brockman, W Van Damme
    Abstract:

    Summary Objectives  To compare the efficacy and tolerability of dihydroartemisinin–piperaquine (DHA–PQP) with that of a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated Falciparum Malaria in Cambodia. Method  Randomized open-label non-inferiority study over 64 days. Results  Four hundred and sixty-four patients were included in the study. The polymerase chain reaction genotyping-adjusted cure rates on day 63 were 97.5% (95% confidence interval, CI, 93.8–99.3) for DHA–PQP and 97.5% (95% CI, 93.8–99.3) for MAS3, P = 1. There were no serious adverse events, but significantly more episodes of vomiting (P = 0.03), dizziness (P = 0.002), palpitations (P = 0.04), and sleep disorders (P = 0.03) reported in the MAS3 treatment group, consistent with the side-effect profile of mefloquine. Conclusions  DHA–PQP was as efficacious as MAS3, but much better tolerated, making it more appropriate for use in a routine programme setting. This highly efficacious, safe and more affordable fixed-dose combination could become the treatment of choice for Plasmodium Falciparum Malaria in Cambodia. Objectifs  Comparer l'efficacite et la tolerance du dihydroartemisinine-piperaquine (DHA–PQP) a celles d'un regime a base de mefloquine de trois jours (MAS3) pour le traitement de la Malaria Falciparum non compliquee au Cambodge. Methode  Etude Randomisee ouverte de non inferiorite sur 64 jours. Resultats  464 patients ont ete inclus dans l’etude. Les taux guerison au jour 63 ajustes par les resultats du genotypage par la reaction en chaine de la polymerase etaient de 97,5% (IC95%: 93.8–99.3) pour le DHA–PQP et de 97,5% (IC95%: 93,8–99,3) pour le MAS3, P = 1. Il n'y avait aucun effet adverse serieux, mais de facon significative, des episodes de vomissement (P = 0,03), des vertiges (P = 0,002), des palpitations (P = 0,04), et des troubles de sommeil (P = 0.03) ont ete rapportes dans le groupe du traitement au MAS3, ce qui etait consistant avec les profiles d'effets secondaires du mefloquine. Conclusion  le DHA–PQP etait aussi efficace que le MAS3, mais bien mieux tolere, le rendant ainsi plus approprie pour l'usage en routine dans le cadre d'un programme. Cette combinaison a dose fixe de grande efficacite, sure et plus accessible pourrait devenir le traitement de choix pour la Malaria aPlasmodium Falciparum au Cambodge. Objetivos  Comparar la eficacia y la tolerabilidad de la dihidroartemisinina-piperaquina (DHA–PQP) con la de un regimen de 3 dias de mefloquina (MAS3), para el tratamiento de la Malaria no complicada por Falciparum en Cambodia Metodo  Estudio aleatorizado, abierto, de no-inferioridad, durante 64 dias. Resultados  Se incluyeron 464 pacientes en el estudio. Las tasas de curacion en el dia 63, ajustadas por genotipaje mediante PCR, fueron del 97.5% (95% IC: 93.8–99.3) para DHA–PQP y del 97.5% (95%IC: 93.8–99.3) para MAS3, P = 1. No se observaron eventos adversos serios, pero si se reporto un numero significativo de episodios de vomitos (P = 0.03), mareos (P = 0.002), palpitaciones (P = 0.04), y desordenes del sue,no (P = 0.03) entre el grupo de tratamiento con MAS3, algo consistente con el perfil de efectos secundarios de la mefloquina. Conclusiones  La DHA–PQP fue tan eficaz como la MAS3, ademas de ser mejor tolerada, siendo mas apropiada para el uso dentro del marco de un programa de rutina. Esta combinacion de dosis fija, altamente eficaz, segura y mas asequible, podria convertirse en el tratamiento de eleccion para Malaria por Plasmodium Falciparum en Cambodia.

  • an open label randomized comparison of mefloquine artesunate as separate tablets vs a new co formulated combination for the treatment of uncomplicated multidrug resistant Falciparum Malaria in thailand
    Tropical Medicine & International Health, 2006
    Co-Authors: Rose Mcgready, Elizabeth A Ashley, Khin Maung Lwin, Win Htay Simon, Lucy Phaiphun, Stephane Proux, Nantawan Wangseang, Walter R J Taylor
    Abstract:

    Summary Background  Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium Falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant Falciparum Malaria. Methods  On the north-western border of Thailand 500 adults and children with uncomplicated Falciparum Malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. Results  The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2–95.6) in the fixed combination group and 89.2% (85.0–93.4) in the loose tablets group (P = 0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. Conclusion  This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer. Keywords  artemisinin , fixed combination , Malaria , mefloquine Donnees de base  L'administration de medicaments en combinaison fixee est essentielle pour le succes des strategies de traitement a base d'artemisine en combinaison. Cela evite qu'un des medicaments ne soit pris en l'absence de la protection de l'autre, reduisant ainsi les chances d’emergence et de propagation de souches multiresistantes de Plasmodium Falciparum. La reduction du nombre de comprimes devrait egalement favoriser la compliance au traitement. Une nouvelle combinaison a dose fixee de mefloquine et d'artesunate a ete developpee. Elle a ete comparee au regime conventionnel utilisant des comprimes separes pour le traitement de la Malaria Falciparum multiresistante non compliquee. Methodes  500 adultes avec une Malaria Falciparum non compliquee dans la region a la frontiere nord-ouest de la Thailande ont ete randomises pour recevoir soit la nouvelle combinaison a dose fixee, soit les comprimes separes. Ils ont ensuite ete suivis hebdomadairement pendant 63 jours. Resultats  Les taux de guerison au jour 63, ajustes par les resultats PCR, etaient de 91.9% (IC95%: 88.2–95.6) pour le groupe recevant la combinaison fixee et 89.2% (IC95%: 85.0–93.4) pour le groupe recevant les comprimes separes (P = 0.3). Les cas de vomissements observes au debut du traitement etaient moins eleves dans le groupe recevant la combinaison fixee. Conclusion  La nouvelle combinaison a base de mefloquine et d'artesunate etait efficace, bien toleree et facile a administrer. Mots cles  artemisinine , combinaison fixee , Malaria , mefloquine Antecedentes  Dar medicamentos en una combinacion fija es esencial para el exito de la estrategia de una terapia de combinacion basada en la artemisinina. Esto previene que un medicamento se tome sin la proteccion de otro, reduciendo la probabilidad del surgimiento y la propagacion de cepas resistentes de Plasmodium Falciparum. Una menor carga de comprimidos tambien deberia facilitar el cumplimiento del tratamiento. Se ha desarrollado una nueva combinacion fija de mefloquina mas artesunato. Esta se ha comparado con el regimen convencional en comprimidos separados para el tratamiento de Malaria por Falciparum no complicada y multiresistente. Metodos  En la frontera noroeste de Tailandia, se aleatorizaron 500 adultos y ninos con Malaria por Falciparum no complicada para recibir la nueva combinacion fija o los comprimidos por separado. El seguimiento se realizo semanalmente durante 63 dias. Resultados  La tasa de curacion en el dia 63, ajustada por PCR, fue de 91.9% [95%IC 88.2–95.6] en el grupo con combinacion fija y de 89.2% [85.0–93.4] en el grupo con dos comprimidos (P = 0.3). Se observo una menor incidencia en vomitos tempranos en el grupo que recibio la combinacion fija. Conclusion  La nueva combinacion fija de mefloquina mas artesunato fue eficaz, bien tolerada y conveniente a la hora de administrarla. Palabras clave  artemisinina , combinacion fija , Malaria , mefloquina

Paul Garner - One of the best experts on this subject based on the ideXlab platform.

  • primaquine or other 8 aminoquinolines for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Patricia M Graves, Leslie Choi, Hellen Gelband, Paul Garner
    Abstract:

    Background The 8-aminoquinoline (8AQ) drugs act on Plasmodium Falciparum gametocytes, which transmit Malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to Malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. Falciparum Malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘Malaria*', ‘Falciparum', ‘primaquine', ‘8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials evaluating community effects on Malaria transmission met the inclusion criteria. With artemisinin treatment Low dose PQ Infectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence). Moderate dose PQ Infectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups. High dose PQ Infectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis. With non-artemisinin treatment Trials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis. Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). Authors' conclusions A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for Malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce Malaria transmission at community level.

  • primaquine or other 8 aminoquinoline for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2015
    Co-Authors: Patricia M Graves, Hellen Gelband, Paul Garner
    Abstract:

    Background: Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium Falciparum gametocytes are sensitive to 8-aminoquinolines (8AQ), and consequently these drugs could prevent parasite transmission from infected people to mosquitoes and reduce the incidence of Malaria. However, when used in this way, these drugs will not directly benefit the individual. In 2010, the World Health Organization (WHO) recommended a single dose of primaquine (PQ) at 0.75 mg/kg alongside treatment for P. Falciparum Malaria to reduce transmission in areas approaching Malaria elimination. In 2013, the WHO revised this to 0.25 mg/kg to reduce risk of harms in people with G6PD deficiency. Objectives: To assess the effects of PQ (or an alternative 8AQ) given alongside treatment for P. Falciparum Malaria on Malaria transmission and on the occurrence of adverse events. Search methods: We searched the following databases up to 5 January 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 1, 2015); MEDLINE (1966 to 5 January 2015); EMBASE (1980 to 5 January 2015); LILACS (1982 to 5 January 2015); metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'Malaria*', 'Falciparum', 'primaquine', 8-aminoquinoline and eight individual 8AQ drug names as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, comparing PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria, with the same Malaria treatment given without PQ/8AQ. Data collection and analysis: Two review authors independently screened all abstracts, applied inclusion criteria and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, asexual parasite clearance time and recrudescence. We stratified the analysis by artemisinin and non-artemisinin treatments; and by PQ dose (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg). We used the GRADE approach to assess evidence quality. Main results: We included 17 RCTs and one quasi-RCT. Eight trials tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining 10 trials either did not report on whether they tested (eight trials), or reported that they did not test (two trials). Nine trials included study arms with artemisinin-based treatments and eleven included study arms with non-artemisinin-based treatments. Only one trial evaluated PQ given as a single dose of less than 0.4 mg/kg. PQ with artemisinin-based treatments: No trials evaluated effects on Malaria transmission directly (incidence, prevalence or entomological inoculation rate) and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two-thirds with the high dose PQ category (RR 0.29, 95% confidence interval (CI) 0.22 to 0.37; seven trials, 1380 participants, high quality evidence) and the medium dose PQ category (RR 0.30, 95% CI 0.16 to 0.56; one trial, 219 participants, moderate quality evidence). For the low dose category, the effect size was smaller and the 95% CIs include the possibility of no effect (dose: 0.1 mg/kg: RR 0.67, 95% CI 0.44 to 1.02; one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on Malaria transmission directly. Two small trials from the same laboratory in China evaluated infectiousness to mosquitoes, and reported that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by three-fifths with high dose PQ category (RR 0.39, 95% CI 0.25 to 0.62; four trials, 186 participants, high quality evidence), and by around two-fifths with medium dose category (RR 0.60, 95% CI 0.49 to 0.75; one trial, 216 participants, high quality evidence), with no trial in the low dose PQ category reporting this outcome. Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (N = 112) preclude a definite conclusion. Authors' conclusions: In individual patients, PQ added to Malaria treatments reduces gametocyte prevalence, but this is based on trials using doses of more than 0.4 mg/kg. Whether this translates into preventing people transmitting Malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community Malaria transmission. For the currently recommended low dose regimen, there is currently little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved, or that it is safe in people with G6PD deficiency.

Rose Mcgready - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic study of artemether lumefantrine given once daily for the treatment of uncomplicated multidrug resistant Falciparum Malaria
    Tropical Medicine & International Health, 2007
    Co-Authors: Rose Mcgready, Elizabeth A Ashley, Kasia Stepniewska, Niklas Lindegardh, Anna Annerberg, Robert Hutagalung
    Abstract:

    Summary Background  Adherence to antiMalarial drug regimens is improved by simple dosing. If the fixed antiMalarial drug combination artemether–lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. Methods  In an open randomized study, 43 patients with uncomplicated Falciparum Malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration–time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Results  Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC(0∞) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114–5781) μg/ml h, compared with 432 (308–992) μg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84–100) in the six-dose arm and 85% (70–100) in the three-dose arm (P = 0.3). Conclusion  Artemether–lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antiMalarial should be given twice daily in a 3-day regimen, with food containing fat. Donnees de base  La compliance aux traitements a base d'antimalariques est amelioree par des doses simples. Si la combinaison a dose fixe d'antimalariques artemether–lumefantrine pouvait etre administree une fois par jour, cela devrait ameliorer la compliance et donc l'efficacite, et reduire le risque de selection de resistance. Methodes  dans une etude randomisee ouverte, 43 patients presentant une Malaria Falciparum non compliquee ont recu des doses equivalentes d'artemether–lumefantrine avec 200 ml de lait aromatise, selon le regime conventionnel i.e: deux fois par jour ou selon un regime a une seule dose quotidienne pendant 3 jours. L'objectif final primaire etait la comparaison des aires sous la courbe (AUC) de la concentration plasmatique de lumefantrine en fonction du temps. Les objectifs secondaires etaient la mesure des taux de guerison ajustes par les resultats de la reaction en chaine de la polymerase (PCR) au jour 42ieme et les profils de tolerance. Resultats  Les profils pharmacocinetiques de lumefantrine ont ete obtenus pour 36 patients. Les AUC(0∞) dans le regime ‘‘une fois par jour’’etait 30% inferieur a celles dans le regime conventionnel (p = 0,011) avec une valeur mediane de 306 (114–5781) μg/ml h comparea 432 (308–992) μg/ml h. Il n'y avait aucune difference significative dans les concentrations plasmatiques maximales atteintes. Les taux de guerison ajustes par la PCR au 42ieme jour du suivi etaient de 94% (IC95%: 84–100) dans le groupe a 6 doses et 85% (IC95%: 70–100) dans le groupe a 3 doses (p = 0,3). Conclusion  L'efficacite de l'Artemether–lumefantrine est reduite dans le regime ‘'une fois par jour‘’ parce que l'absorption du lumefantrine est dose dependante. Aux doses recommandees actuellement, cet antimalarique devrait etre administre deux fois par jour dans un regime de trois jours, avec la nourriture contenant la matiere grasse. Antecedentes  La adherencia al tratamiento con antimalaricos mejora si se simplifica la dosificacion. Si se pudiese dar la combinacion fija de antimalaricos artemeter–lumefantrina (AL) en una dosis unica por dia, deberia mejorar la adherencia y por lo tanto la efectividad del tratamiento, habiendo un menor riesgo de seleccion de cepas resistentes. Metodos  En un ensayo abierto, aleatorizado, en el que 43 pacientes con Malaria no complicada por Falciparum recibieron durante tres dias dosis equivalentes de AL con 200ml de leche, bien bajo el regimen convencional de dos veces al dia o en una dosis unica cada dia. El criterio principal de valoracion fue una comparacion de las areas bajo las curvas de la concentracion de lumefantrina en plasma a lo largo del tiempo (ABC). Los criterios secundarios de valoracion fueron las PCR del dia 42, las tasas de curacion ajustadas y los perfiles de tolerabilidad. Resultados  Se obtuvieron los perfiles farmacocineticos de la lumefantrina para 36 pacientes. El ABC (0∞) del regimen unico al dia era un 30% mas bajo que el regimen convencional (p = 0.011) con una media (rango) de 306 (114–5781) μg/ml h comparado con 432 (308–992) μg/ml h. No habia una diferencia significativa entre las maximas concentraciones de plasma alcanzadas. Las tasas de curacion ajustadas por PCR a los 42 dias de seguimiento fueron 94% (95%CI 84–100) para el grupo con 6 dosis y 85% (70–100) para los que recibieron 3 dosis (p = 0.3). Conclusion  La eficacia de artemeter–lumefantrina se reduce al dar una dosis unica, puesto que la absorcion de la lumefantrina esta limitada por la dosis. En las dosis recomendadas en la actualidad, este antimalarico deberia darse dos veces al dia en un regimen de tres dias, acompa,nado con alimentos que contengan grasas.

  • an open label randomized comparison of mefloquine artesunate as separate tablets vs a new co formulated combination for the treatment of uncomplicated multidrug resistant Falciparum Malaria in thailand
    Tropical Medicine & International Health, 2006
    Co-Authors: Rose Mcgready, Elizabeth A Ashley, Khin Maung Lwin, Win Htay Simon, Lucy Phaiphun, Stephane Proux, Nantawan Wangseang, Walter R J Taylor
    Abstract:

    Summary Background  Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium Falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant Falciparum Malaria. Methods  On the north-western border of Thailand 500 adults and children with uncomplicated Falciparum Malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. Results  The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2–95.6) in the fixed combination group and 89.2% (85.0–93.4) in the loose tablets group (P = 0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. Conclusion  This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer. Keywords  artemisinin , fixed combination , Malaria , mefloquine Donnees de base  L'administration de medicaments en combinaison fixee est essentielle pour le succes des strategies de traitement a base d'artemisine en combinaison. Cela evite qu'un des medicaments ne soit pris en l'absence de la protection de l'autre, reduisant ainsi les chances d’emergence et de propagation de souches multiresistantes de Plasmodium Falciparum. La reduction du nombre de comprimes devrait egalement favoriser la compliance au traitement. Une nouvelle combinaison a dose fixee de mefloquine et d'artesunate a ete developpee. Elle a ete comparee au regime conventionnel utilisant des comprimes separes pour le traitement de la Malaria Falciparum multiresistante non compliquee. Methodes  500 adultes avec une Malaria Falciparum non compliquee dans la region a la frontiere nord-ouest de la Thailande ont ete randomises pour recevoir soit la nouvelle combinaison a dose fixee, soit les comprimes separes. Ils ont ensuite ete suivis hebdomadairement pendant 63 jours. Resultats  Les taux de guerison au jour 63, ajustes par les resultats PCR, etaient de 91.9% (IC95%: 88.2–95.6) pour le groupe recevant la combinaison fixee et 89.2% (IC95%: 85.0–93.4) pour le groupe recevant les comprimes separes (P = 0.3). Les cas de vomissements observes au debut du traitement etaient moins eleves dans le groupe recevant la combinaison fixee. Conclusion  La nouvelle combinaison a base de mefloquine et d'artesunate etait efficace, bien toleree et facile a administrer. Mots cles  artemisinine , combinaison fixee , Malaria , mefloquine Antecedentes  Dar medicamentos en una combinacion fija es esencial para el exito de la estrategia de una terapia de combinacion basada en la artemisinina. Esto previene que un medicamento se tome sin la proteccion de otro, reduciendo la probabilidad del surgimiento y la propagacion de cepas resistentes de Plasmodium Falciparum. Una menor carga de comprimidos tambien deberia facilitar el cumplimiento del tratamiento. Se ha desarrollado una nueva combinacion fija de mefloquina mas artesunato. Esta se ha comparado con el regimen convencional en comprimidos separados para el tratamiento de Malaria por Falciparum no complicada y multiresistente. Metodos  En la frontera noroeste de Tailandia, se aleatorizaron 500 adultos y ninos con Malaria por Falciparum no complicada para recibir la nueva combinacion fija o los comprimidos por separado. El seguimiento se realizo semanalmente durante 63 dias. Resultados  La tasa de curacion en el dia 63, ajustada por PCR, fue de 91.9% [95%IC 88.2–95.6] en el grupo con combinacion fija y de 89.2% [85.0–93.4] en el grupo con dos comprimidos (P = 0.3). Se observo una menor incidencia en vomitos tempranos en el grupo que recibio la combinacion fija. Conclusion  La nueva combinacion fija de mefloquina mas artesunato fue eficaz, bien tolerada y conveniente a la hora de administrarla. Palabras clave  artemisinina , combinacion fija , Malaria , mefloquina

Patricia M Graves - One of the best experts on this subject based on the ideXlab platform.

  • primaquine or other 8 aminoquinolines for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Patricia M Graves, Leslie Choi, Hellen Gelband, Paul Garner
    Abstract:

    Background The 8-aminoquinoline (8AQ) drugs act on Plasmodium Falciparum gametocytes, which transmit Malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to Malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. Falciparum Malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘Malaria*', ‘Falciparum', ‘primaquine', ‘8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials evaluating community effects on Malaria transmission met the inclusion criteria. With artemisinin treatment Low dose PQ Infectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence). Moderate dose PQ Infectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups. High dose PQ Infectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis. With non-artemisinin treatment Trials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis. Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). Authors' conclusions A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for Malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce Malaria transmission at community level.

  • primaquine or other 8 aminoquinoline for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2015
    Co-Authors: Patricia M Graves, Hellen Gelband, Paul Garner
    Abstract:

    Background: Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium Falciparum gametocytes are sensitive to 8-aminoquinolines (8AQ), and consequently these drugs could prevent parasite transmission from infected people to mosquitoes and reduce the incidence of Malaria. However, when used in this way, these drugs will not directly benefit the individual. In 2010, the World Health Organization (WHO) recommended a single dose of primaquine (PQ) at 0.75 mg/kg alongside treatment for P. Falciparum Malaria to reduce transmission in areas approaching Malaria elimination. In 2013, the WHO revised this to 0.25 mg/kg to reduce risk of harms in people with G6PD deficiency. Objectives: To assess the effects of PQ (or an alternative 8AQ) given alongside treatment for P. Falciparum Malaria on Malaria transmission and on the occurrence of adverse events. Search methods: We searched the following databases up to 5 January 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 1, 2015); MEDLINE (1966 to 5 January 2015); EMBASE (1980 to 5 January 2015); LILACS (1982 to 5 January 2015); metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'Malaria*', 'Falciparum', 'primaquine', 8-aminoquinoline and eight individual 8AQ drug names as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, comparing PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria, with the same Malaria treatment given without PQ/8AQ. Data collection and analysis: Two review authors independently screened all abstracts, applied inclusion criteria and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, asexual parasite clearance time and recrudescence. We stratified the analysis by artemisinin and non-artemisinin treatments; and by PQ dose (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg). We used the GRADE approach to assess evidence quality. Main results: We included 17 RCTs and one quasi-RCT. Eight trials tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining 10 trials either did not report on whether they tested (eight trials), or reported that they did not test (two trials). Nine trials included study arms with artemisinin-based treatments and eleven included study arms with non-artemisinin-based treatments. Only one trial evaluated PQ given as a single dose of less than 0.4 mg/kg. PQ with artemisinin-based treatments: No trials evaluated effects on Malaria transmission directly (incidence, prevalence or entomological inoculation rate) and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two-thirds with the high dose PQ category (RR 0.29, 95% confidence interval (CI) 0.22 to 0.37; seven trials, 1380 participants, high quality evidence) and the medium dose PQ category (RR 0.30, 95% CI 0.16 to 0.56; one trial, 219 participants, moderate quality evidence). For the low dose category, the effect size was smaller and the 95% CIs include the possibility of no effect (dose: 0.1 mg/kg: RR 0.67, 95% CI 0.44 to 1.02; one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on Malaria transmission directly. Two small trials from the same laboratory in China evaluated infectiousness to mosquitoes, and reported that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by three-fifths with high dose PQ category (RR 0.39, 95% CI 0.25 to 0.62; four trials, 186 participants, high quality evidence), and by around two-fifths with medium dose category (RR 0.60, 95% CI 0.49 to 0.75; one trial, 216 participants, high quality evidence), with no trial in the low dose PQ category reporting this outcome. Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (N = 112) preclude a definite conclusion. Authors' conclusions: In individual patients, PQ added to Malaria treatments reduces gametocyte prevalence, but this is based on trials using doses of more than 0.4 mg/kg. Whether this translates into preventing people transmitting Malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community Malaria transmission. For the currently recommended low dose regimen, there is currently little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved, or that it is safe in people with G6PD deficiency.

Hellen Gelband - One of the best experts on this subject based on the ideXlab platform.

  • primaquine or other 8 aminoquinolines for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Patricia M Graves, Leslie Choi, Hellen Gelband, Paul Garner
    Abstract:

    Background The 8-aminoquinoline (8AQ) drugs act on Plasmodium Falciparum gametocytes, which transmit Malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to Malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. Falciparum Malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘Malaria*', ‘Falciparum', ‘primaquine', ‘8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials evaluating community effects on Malaria transmission met the inclusion criteria. With artemisinin treatment Low dose PQ Infectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence). Moderate dose PQ Infectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups. High dose PQ Infectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis. With non-artemisinin treatment Trials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis. Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). Authors' conclusions A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for Malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce Malaria transmission at community level.

  • primaquine or other 8 aminoquinoline for reducing plasmodium Falciparum transmission
    Cochrane Database of Systematic Reviews, 2015
    Co-Authors: Patricia M Graves, Hellen Gelband, Paul Garner
    Abstract:

    Background: Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium Falciparum gametocytes are sensitive to 8-aminoquinolines (8AQ), and consequently these drugs could prevent parasite transmission from infected people to mosquitoes and reduce the incidence of Malaria. However, when used in this way, these drugs will not directly benefit the individual. In 2010, the World Health Organization (WHO) recommended a single dose of primaquine (PQ) at 0.75 mg/kg alongside treatment for P. Falciparum Malaria to reduce transmission in areas approaching Malaria elimination. In 2013, the WHO revised this to 0.25 mg/kg to reduce risk of harms in people with G6PD deficiency. Objectives: To assess the effects of PQ (or an alternative 8AQ) given alongside treatment for P. Falciparum Malaria on Malaria transmission and on the occurrence of adverse events. Search methods: We searched the following databases up to 5 January 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 1, 2015); MEDLINE (1966 to 5 January 2015); EMBASE (1980 to 5 January 2015); LILACS (1982 to 5 January 2015); metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'Malaria*', 'Falciparum', 'primaquine', 8-aminoquinoline and eight individual 8AQ drug names as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, comparing PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. Falciparum Malaria, with the same Malaria treatment given without PQ/8AQ. Data collection and analysis: Two review authors independently screened all abstracts, applied inclusion criteria and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, asexual parasite clearance time and recrudescence. We stratified the analysis by artemisinin and non-artemisinin treatments; and by PQ dose (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg). We used the GRADE approach to assess evidence quality. Main results: We included 17 RCTs and one quasi-RCT. Eight trials tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining 10 trials either did not report on whether they tested (eight trials), or reported that they did not test (two trials). Nine trials included study arms with artemisinin-based treatments and eleven included study arms with non-artemisinin-based treatments. Only one trial evaluated PQ given as a single dose of less than 0.4 mg/kg. PQ with artemisinin-based treatments: No trials evaluated effects on Malaria transmission directly (incidence, prevalence or entomological inoculation rate) and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two-thirds with the high dose PQ category (RR 0.29, 95% confidence interval (CI) 0.22 to 0.37; seven trials, 1380 participants, high quality evidence) and the medium dose PQ category (RR 0.30, 95% CI 0.16 to 0.56; one trial, 219 participants, moderate quality evidence). For the low dose category, the effect size was smaller and the 95% CIs include the possibility of no effect (dose: 0.1 mg/kg: RR 0.67, 95% CI 0.44 to 1.02; one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on Malaria transmission directly. Two small trials from the same laboratory in China evaluated infectiousness to mosquitoes, and reported that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by three-fifths with high dose PQ category (RR 0.39, 95% CI 0.25 to 0.62; four trials, 186 participants, high quality evidence), and by around two-fifths with medium dose category (RR 0.60, 95% CI 0.49 to 0.75; one trial, 216 participants, high quality evidence), with no trial in the low dose PQ category reporting this outcome. Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (N = 112) preclude a definite conclusion. Authors' conclusions: In individual patients, PQ added to Malaria treatments reduces gametocyte prevalence, but this is based on trials using doses of more than 0.4 mg/kg. Whether this translates into preventing people transmitting Malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community Malaria transmission. For the currently recommended low dose regimen, there is currently little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved, or that it is safe in people with G6PD deficiency.

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