Stopping the relapse

Dr Alejandro Llanos, Universidad Peruana Cayetano Heredia, Lima, Peru

The long-held belief that Plasmodium vivax is benign in comparison to Plasmodium falciparum is starting to change. In addition, the dormant liverstage form (hypnozoite) of P. vivax, which can reactivate without warning leading to the feverish symptoms of malaria, remains a challenge to treat.

The only approved medicine able to eliminate hypnozoites and thus provide a radical cure for relapsing P. vivax malaria is primaquine. In practice primaquine is not always efficacious. The reasons for this are not entirely clear, however, the treatment course is 14 days and so compliance is often difficult to achieve. Additionally, it is associated with potentially fatal side effects in patients who are deficient in the enzyme glucose 6-phosphate dehydrogenase (G6PD).

Tafenoquine, the lead contender to replace primaquine, is currently in clinical development with MMV and GlaxoSmithKline (GSK). Studies show tafenoquine could be taken as a 1-day treatment course for liver-stage malaria – a significant improvement on primaquine’s 14-day course. However, the safety of tafenoquine in G6PD-deficient patients is being assessed because it comes from the same chemical family as primaquine. Trials are also underway to determine the safety and efficacy of tafenoquine for the treatment of P. vivax malaria in non- G6PD-deficient patients. This study commenced in 2011 in Peru and Thailand.

1. What is the prevalence of P. vivax in Peru?

In Peru 90% of malaria is caused by P. vivax, with approximately 22,000 cases occurring each year. Clinically speaking, we are only just beginning to understand the differences between P. falciparum and P. vivax and to make the distinction. Previously, we assumed that patients with severe symptoms were suffering from P. falciparum, but in my clinic at least eight of the last 10 patients with symptoms of severe malaria were found to have P. vivax. In fact, more than half the malaria patients we see actually have both.

2. How is P. vivax malaria managed in Peru in terms of diagnosis and treatment?

Malaria diagnosis both for P. vivax and P. falciparum is made based on clinical symptoms; in facilities with a laboratory a smear examination is conducted to identify the parasite. When a patient is diagnosed with P. vivax malaria, chloroquine plus primaquine is administered. For P. falciparum the treatment is artesunate plus mefloquine for 3 days.

3. How can the management of P. vivax malaria be improved in Peru?

With the current primaquine plus chloroquine regimen we eliminate relapse in approximately 80% of cases. In my view that is not adequate. Moreover, this varies with geography as drug resistance appears to be emerging in some areas. This could be a big problem for us in Peru if changes in climate lead to an increase in mosquitoes and therefore in malaria transmission. Additionally, the current regimen in Peru is long, which makes it difficult to ensure adherence. What we need are new medicines that are easier to take and more efficacious at eliminating the P. vivax parasite from the liver for all patients.

4. How is the trial progressing?

The trial is going well. We have already enrolled the majority of patients required by the study, but will continue to recruit for the next few months. We are aiming to determine the correct dose of tafenoquine to move to Phase III. It stands a good chance of being a great alternative to primaquine, but of course we need to wait to see the results.

Dr Alejandro Llanos is the Principal Investigator at the Peruvian trial site to determine the safety and efficacy of tafenoquine.