Julia Kemp

Getting research into policy, or out of practice, in HIV?

In The Lancet today, Antoinette Tshefu and colleagues report a phase 3 trial in children and adults with uncomplicated falciparum malaria treated with pyronaridine-artesunate, a new artemisinin-combination therapy (ACT), developed by the public-private partnership between Shin Poong Pharmaceutical Company Ltd (Korea) and the Medicines for Malaria Venture (Switzerland). This study was a non-inferiority effi cacy and safety comparison with artemether-lumefantrine. The trial was designed to gain registration of pyronaridine-artesunate by the European Medicines Agency, which is refl ected by the choice of analytical approaches and endpoints. The primary endpoint of the study was the PCRcorrected cure rate by day 28. However, the more interesting endpoint for a clinician is parasitological effi cacy beyond 28 days, in view of the diff erent pharmacokinetic properties of the two partner drugs: lumefantrine, a lipophilic fl uorene derivative with a halflife of 3–6 days, and pyronaridine, a water soluble acridine derivative with a longer elimination half-life (16–17 days). But a somewhat confusing mixture is presented: multiple analyses of cure rates at days 28 and 42 of follow-up, PCR-corrected and not, with per-protocol and intention-to-treat populations. In determinate PCR results were counted as failures, which provides an im plausible worst-case scenario. The per-protocol analysis is also less interesting to the clinician because it is a composite of the performance of the trial as well as that of the treatment itself. Unfortunately, analysis of effi cacy by a Kaplan-Meier survival curve is apparently not acceptable by the European Medicines Agency. Nevertheless pyronaridine-artesunate was clearly effi cacious, which confi rms the excellent antimalarial potential of pyronaridine. The effi cacy of the comparator combination might have been compromised by poor absorption of lumefantrine, because fat was not co-administered as is recommended. A small amount (1·2 g per dose) of fat or a little food will increase blood concentrations of lumefantrine and result in better effi cacy. Importantly, pyronaridine-artesunate seemed to have a better post-treatment prophylactic eff ect than did artemether-lumefantrine. A more serious limitation is that the population in the study consisted mainly of older children and adults in African countries. These patients would have been expected to have acquired signifi cant antimalarial immun ity, which would improve treatment outcomes, particularly with partly eff ective drugs. What we really need to know is whether this new drug is eff ective in patients with no signifi cant immunity, such as young children. In this important high-risk group, other antimalarials (such as piperaquine and sulfadoxinepyri methamine) have diff erent pharmacokinetic properties that result in low drug concentrations and poorer effi cacy. Might this also be the case for pyronaridine? Despite provisions in the protocol for blood-level measure ments, no kinetic correlates of effi cacy were reported. In terms of safety, pyronaridine-artesunate was well tolerated, but a slight shadow remains over the risk of hepatotoxicity of pyronaridine: more patients who received pyronaridine-artesunate had raised liver enzymes. Future studies will need to investigate the risk of toxicity to the liver. Tshefu and colleagues’ study is a good example of an important and well-conducted trial of a new treatment for a tropical disease. My criticism is that it might satisfy developed-world regulatory requirements but it provides limited information of value to the clinician in the fi eld.