Malaria succumbs to drug combo
A combination drug that pairs pyronaridine with artesunate (Pyramax) for treatment of Plasmodium falciparum malaria was at least as effective as giving mefloquine (Lariam) plus artesunate in a large international trial.
Among 1,271 patients in Africa and Asia on a per-protocol basis, adequate clinical and parasitologic responses were seen in 99.2% of patients receiving pyronaridine-artesunate (95% CI 98.3% to 99.7%), compared with 97.8% of those treated with mefloquine and artesunate (95% CI 95.8% to 99.1%), reported Isabelle Borghini-Fuhrer, PhD, of the Medicines for Malaria Venture (MMV) in Geneva, Switzerland, and colleagues.
Efficacy was lower but nearly identical in the two study arms on an intention-to-treat basis, the researchers indicated in the April 5 issue of the New England Journal of Medicine.
However, they also noted some geographic variation in time to response and in recrudescence rates that supported earlier suggestions of growing resistance to artemisinin-based drugs in Cambodia.
Pyronaridine is an existing anti-malarial drug that is mainly used in China, while artesunate and similar artemisinin-based agents are mainstays for malaria treatment in many endemic areas.
MMV, a public-private nonprofit partnership, believes that combining the two agents may be helpful in regions where artemisinin resistance in Plasmodium parasites is on the rise -- at least until effective non-artemisinin drugs become available.
The current trial was part of a larger program sponsored by MMV and Shin Poong Pharmaceutical Co., a South Korean company that has developed a single-tablet combination of 180 mg of pyronaridine and 60 mg of artesunate.
Patients with microscopically confirmed, active, uncomplicated P. falciparum malaria were randomized 2:1 to receive the pyronaridine-artesunate combination or mefloquine at 250 mg plus artesunate at 100 mg in separate pills.
Severely ill patients and those with significant comorbidities were excluded from the trial.
About 15% of both treatment arms failed to complete the study. About 40% of dropouts simply disappeared; most of the others showed reappearance of P. falciparum infection or were found to be infected with other Plasmodium species. Fewer than 1% of patients in both arms had adverse events that led to withdrawal from the study.
The primary study endpoint was noninferiority in clinical and parasitological response at day 42 for the pyronaridine-artesunate combination pill relative to the other arm on a per-protocol basis. About 88% of the pyronaridine-artesunate arm and 87% of those assigned to mefloquine and artesunate had enough data to be included in this analysis.
Of 749 in the pyronaridine-artesunate group, 743 had adequate responses, compared with 360 of 368 in the mefloquine-artesunate arm (percentage difference 1.4% favoring pyronaridine-artesunate, 95% CI 0.0% to 3.5%), thus easily meeting the noninferiority standard.
On an intention-to-treat basis, adequate responses were registered in 83.1% of the pyronaridine-artesunate group versus 83.9% of the mefloquine-artesunate group (difference not significant).
But there were some downsides for the pyronaridine-artesunate combination drug: rates of recrudescence were significantly higher (P=0.02) as were late (after day 28) infections with P. falciparum (P=0.02) and P. vivax (P<0.001). Late infections with each of these organisms affected more than 20% of patients in the pyronaridine-artesunate arm.
Borghini-Fuhrer and colleagues found that most of these differences from the mefloquine-artesunate arm were in the 211 patients from Cambodia, in whom parasite clearance times with both treatments were about double those seen in other participants.
The researchers suggested that artemisinin resistance in the region, combined with a longer half-life of mefloquine in circulation relative to pyronaridine (3 weeks versus 2 weeks), might account for the increase in late infections with pyronaridine-artesunate.
"If the parasiticidal effect of artemisinin is attenuated by pharmacodynamic resistance, there is greater dependence on the patient's immune system and the partner drug to eradicate residual parasites," they wrote.
The researchers also noted that the region is a low-transmission area for P. falciparum, meaning that its residents are less likely than those elsewhere to be immune to the parasite.
Borghini-Fuhrer and colleagues concluded that "pyronaridine-artesunate has potential for the treatment of P. falciparum malaria."
The study was funded by Shin Poong Pharmaceutical Co. and the Medicines for Malaria Venture.
One author was an employee of Shin Poong. Two including Borghini-Fuhrer were employees of the Medicines for Malaria Venture. Others indicated they had no relationships with commercial entities.
By John Gever
Primary source: New England Journal of Medicine Source reference: Rueangweerayut R, et al "Pyronaridine–artesunate versus mefloquine plus artesunate for malaria" N Engl J Med 2012; 366: 1298-1309.
Source: MedPage Today