Lon et al. Malaria Journal 2014, 13:96

Blackwater fever in an uncomplicated Plasmodium falciparum patient treated with dihydroartemisinin-piperaquin

Atovaquone-Proguanil in Combination with Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial

Background: Recent artemisinin-combination therapy failures in Cambodia prompted a search for alternatives. Atovaquone-proguanil (AP), a safe, effective treatment for multidrug-resistant Plasmodium falciparum (P.f.), previously demonstrated additive effects in combination with artesunate (AS). Methods: Patients with P.f. or mixed-species infection (n = 205) in Anlong Veng (AV; n = 157) and Kratie (KT; n = 48), Cambodia, were randomized open-label 1:1 to a fixed-dose 3-day AP regimen +/-3 days of co-administered artesunate (ASAP). Single low-dose primaquine (PQ, 15 mg) was given on day 1 to prevent gametocyte-mediated transmission. Results: Polymerase chain reaction-adjusted adequate clinical and parasitological response at 42 days was 90% for AP (95% confidence interval [CI], 82%-95%) and 92% for ASAP (95% CI, 83%-96%; P =. 73). The median parasite clearance time was 72 hours for ASAP in AV vs 56 hours in KT (P <. 001) and was no different than AP alone. At 1 week postprimaquine, 7% of the ASAP group carried microscopic gametocytes vs 29% for AP alone (P =. 0001). Nearly all P.f. isolates had C580Y K13 propeller artemisinin resistance mutations (AV 99%; KT 88%). Only 1 of 14 treatment failures carried the cytochrome bc1 (Pfcytb) atovaquone resistance mutation, which was not present at baseline. P.f. isolates remained atovaquone sensitive in vitro but cycloguanil resistant, with a triple P.f. dihydrofolate reductase mutation. Conclusions: Atovaquone-proguanil remained marginally effective in Cambodia (≥90%) with minimal Pfcytb mutations observed. Treatment failures in the presence of ex vivo atovaquone sensitivity and adequate plasma levels may be attributable to cycloguanil and/or artemisinin resistance. Artesunate co-administration provided little additional blood-stage efficacy but reduced post-treatment gametocyte carriage in combination with AP beyond single low-dose primaquine

A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of <i>Plasmodium vivax</i> malaria

<div><p>Background</p><p>Tafenoquine is an investigational 8-aminoquinoline for the prevention of <i>Plasmodium vivax</i> relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen.</p><p>Methods</p><p>This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed <i>P</i>. <i>vivax</i> were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120.</p><p>Results</p><p>Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83–98%) with tafenoquine, and 100% (22/22) (90%CI 87–100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92–100%), and 95% (19/20) (90%CI 78–100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4–25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5–5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient.</p><p>Discussion</p><p>Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of <i>P</i>. <i>vivax</i> malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing.</p><p>Trial registration</p><p>Clinicaltrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01290601" target="_blank">NCT01290601</a></p></div

Most common adverse events overall (regardless of causality) occurring in at least two patients in either treatment group (intention-to-treat/safety population).

<p>Most common adverse events overall (regardless of causality) occurring in at least two patients in either treatment group (intention-to-treat/safety population).</p

Dosing schedule.

<p>The planned enrollment for this study was 70 patients in each of two cohorts in order to yield at least 60 evaluable patients in each cohort. Using a 2:1 randomization ratio and assuming a true success rate on treatment of at least 98%, the sample size of 40 evaluable tafenoquine patients provided 90% power to show that the lower limit of the one-sided 95% confidence interval for the day 28 cure rate was above 85%.</p

Per-protocol population analysis of parasite, gametocyte and fever clearance time.

<p>Per-protocol population analysis of parasite, gametocyte and fever clearance time.</p

Study design, patient disposition and main efficacy outcomes.

<p>*The three patients with early treatment failure (at day 7) in the tafenoquine group cleared parasitemia spontaneously on day 8 without additional treatment, and were relapse free for the duration of their follow-up (until day 28 for one patient, day 60 for the second and day 120 for the third).</p

Baseline characteristics of the study participants in intention-to-treat/safety population.

<p>Baseline characteristics of the study participants in intention-to-treat/safety population.</p

Individual patient tafenoquine plasma concentrations.

<p>*The three patients with early treatment failure (at day 7) in the tafenoquine group and slow parasite clearance had similar tafenoquine plasma concentrations to the population that had parasite clearance at day 7.</p