Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial

Abstract

BackgroundThe World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.MethodsA randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged ≥1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection.ResultsOverall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection.ConclusionThe new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania.Trial registration number NCT02090036Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1430-3) contains supplementary material, which is available to authorized users.

Sustained High Cure Rate of Artemether–Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania

“…25 The PQ arm was included since there was no statistically significant difference in the cure rate between AL and AL + PQ arm. 26 The first study was conducted 6 months before implementation of AL treatment policy, whereas the second, third, and fourth studies were conducted 1, 6, and 8 years after the implementation of AL in Bagamoyo district, respectively. The subjects inclusion and exclusion criteria are described elsewhere.…”

Evaluation of residual submicroscopic Plasmodium falciparum parasites 3 days after initiation of treatment with artemisinin-based combination therapy

“…Residual PCR-determined submicroscopic malaria parasites include both asexual and sexual parasites remaining days after initiation of antimalarial treatment. ACT has continued to achieve rapid microscopy-determined parasitological clearance across SSA, with a majority of treated patients being cleared of asexual parasites within 48 h of treatment initiation [3,35,[45][46][47]. More precisely, over 90% of patients are being microscopically parasite negative by day 2 and 99% by day 3 post-initiation of ACT [35,46,47].…”

“…ACT has continued to achieve rapid microscopy-determined parasitological clearance across SSA, with a majority of treated patients being cleared of asexual parasites within 48 h of treatment initiation [3,35,[45][46][47]. More precisely, over 90% of patients are being microscopically parasite negative by day 2 and 99% by day 3 post-initiation of ACT [35,46,47]. The PCR on the other hand, has revealed the presence in SSA of P. falciparum genotypes that are probably more likely to survive ACT at submicroscopic level (Table 1), and probably contribute to an onward transmission and subsequent patient recrudescence [17,[19][20][21]48].…”

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa

“…Despite this, there is an increasing body of evidence that SLDPQ is tolerated well by both malaria patients and healthy individuals with good pre-treatment haemoglobin (Hb) concentrations in both Southeast Asia [ 12 ] and SSA [ 13 ] (SAFEPRIM I and II, and PQSAFETY studies; ClinicalTrials.gov identifiers NCT02174900, NCT02654730, and NCT02535767). Moreover, pilot work has demonstrated the feasibility of deploying SLDPQ in Swaziland’s health system [ 14 ].…”

“…Dicko et al . reported overall rates of mild abdominal pain of 10% and mild vomiting of 1.3% across all arms but no one required repeat dosing [ 31 ] whilst acutely infected falciparum patients of all ages (median 10 years) from Tanzania had identical rates of abdominal pain and vomiting of 6.4% (7/110) and 5.5% (6/110), respectively, in the AL-alone and the AL + SLDPQ arms [ 13 ].…”