Malaria retreatment safe, effective against subsequent episodes
The antimalarial medication Pyramax appeared to be equally safe and efficacious during the first treatment vs. retreatment of subsequent malaria episodes, according to the results of a phase 3b/4 trial.
Four prior phase 3 trials assessing Pyramax (pyronaridine/artesunate, Medicines for Malaria Venture, Shin Poong Pharmaceutical), an oral artemisinin-based combination therapy (ACT) used to treat Plasmodium falciparum and P. vivax malaria, showed the regimen temporarily increased patients’ liver enzymes within the first 28 days of therapy, Issaka Sagara, PhD, of the Malaria Research and Training Center at the University of Science, Techniques and Technologies of Bamako, Mali, and colleagues wrote.
“However, because only a few patients in the phase 3 studies were retreated with pyronaridine-artesunate, it was unclear whether treatment of repeated malaria episodes would exacerbate increases in hepatic enzymes or lead to liver injury,” they wrote.
The researchers analyzed a substudy of patients enrolled in the randomized, multicenter, open-label trial, WANECAM, to determine whether multiple treatments of pyronaridine-artesunate increased the risk for hepatotoxicity, defined as an alanine aminotransferase concentration five times greater than the upper limit of normal (ULN), or an alanine or aspartate aminotransferase concentration three times greater than the ULN in addition to a bilirubin concentration more than twice the ULN.
The analysis included 1,686 patients aged 6 months or older who were treated for malaria at health care facilities in Mali and Guinea between October 2011 and October 2013. The patients were randomly assigned pyronaridine-artesunate (n = 1,015) or first-line ACT comparator Coartem (artemether-lumefantrine, Novartis; n = 671). Pyronaridine-artesunate was dosed once daily for 3 days as a 180-mg/60-mg tablet or 60-mg/20-mg granule sachet, depending on the patient’s bodyweight; and artemether-lumefantrine was dosed twice daily for 3 days as a 20-mg/120-mg tablet. The patients were followed for 2 years. Those who presented with malaria at least 28 days after therapy were retreated with the same regimen.
In the pyronaridine-artesunate arm, 1% of patients with complete data (n = 996) developed hepatotoxicity after the first treatment vs. 1% of patients who were retreated (n = 311). There was no evidence of an increased safety risk of pyronaridine-artesunate retreatment, the researchers wrote.
In addition, the 28-day adequate clinical and parasitological response (ACPR) of pyronaridine-artesunate was similar to the ACPR of artemether-lumefantrine, yielding a crude ACPR of 92.7% (95% CI, 91-94.3) vs. 80.4% (95% CI, 77.8-83).
Further analysis with PCR-confirmed new infections produced similar results. The ACPR was greater than 95% at day 28 and 91% at day 42 in both groups.
In a related commentary, Sabine Bélard, MD, MSc, of the pediatric pneumology and immunology department and Florian Kurth, MD, MSc, of the infectious diseases and pneumology department at the Charité University Hospital in Berlin, said the results are “highly reassuring;” however, the safety of pyronaridine-artesunate needs further examination in patients with liver diseases, those with elevated liver enzymes and patients with HIV.
“More evidence for the safety of pyronaridine-artesunate in susceptible populations will promote the exploitation of the many benefits of pyronaridine-artesunate,” they wrote. “A fixed-dose once-daily regimen including the availability of a granule formulation for children, the absence of a major effect of food intake on bioavailability, a long shelf life, a long posttreatment prophylactic effect and projected low price lend support to pyronaridine-artesunate becoming a powerful new arrow in the quiver for the fight against malaria.” – by Stephanie Viguers
Disclosures: Sagara reports receiving grants from MMV and the European and Developing Countries Clinical Trial Partnership, and funding from the University of Science, Techniques and Technologies of Bamako, Mali. Bélard and Kurth report being involved in phase 2 and 3 clinical trials assessing pyronaridine-artesunate. Please see the full study for a list of all other authors’ relevant financial disclosures.