Certain malaria parasites have the ability to form a dormant liver stage, known as the hypnozoite – from the Greek words “hypnos” (sleep) and “zoon” (animal). In human malaria, some of the Plasmodium vivax and P. ovale sporozoites entering the blood from the bite of an infected Anopheles mosquito will remain behind in the liver as hypnozoites (the others develop into schizonts within liver cells, which upon rupture release trophozoites into the blood stream that replicate and eventually cause the disease manifestations of malaria). Hypnozoites may reactivate in the future – varying from 17 days to 9 years depending on the strain of malaria parasite – by turning into schizonts that release trophozoites into the blood again,  This is an interesting survival strategy for the parasites that maximises their chances of reaching the mosquito vector for the sexual reproduction stage of their life cycle, particularly in places where the winters are long and the mosquito population waxes and wanes.

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Screenshot from the 1982 British Medical Bulletin article on the life cycle of the malaria parasite by RS Bray and  PCC Garnham.

For P. vivax and P. ovale, the presence of hypnozoites translates into malaria relapses in humans, as the vast majority of drugs used for treating malaria target the bloodstream parasites (trophozoites) and have no effect on hypnozoites. This became a major problem for western countries during the Pacific battles of World War II, and great efforts were made to develop a well tolerated drug for eliminating hypnozoites – although the 8-aminoquinoline drug pamaquine had been known to prevent malaria relapses since 1931, its frequent side effects (anorexia, methaemoglobinemia, haemolytic anaemia, etc) made it intolerable for widespread use. Four compounds were developed out of the initial research (pentaquine, isopentaquine, SN-3883, and primaquine), and were variously tested in humans until it was concluded that primaquine was both the most effective and best tolerated of the lot.

As a digression, the testing of primaquine and the subsequent choice of dosing and duration makes for interesting reading. Note that we now have strict ethical regulations for experimentation in prisoners and soldiers (both considered “dependent” populations) that were not in place during those years.

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Image of Illinois Stateville Penitentiary, from Wikipedia

Most of the initial studies were done by Dr Alf Alving in Illinois Stateville Penitentiary in the late 1940s, with many prisoners serving as volunteers (serving as human subjects had as one prominent incentive reduced prison time) and maintaining the Chesson strain of P. vivax in a long chain of induced transmission. Certain prisoners, the most famous being child murderer Nathan Leopold, even took on other roles such as recruitment of other subjects, observing the experiments and dissecting mosquitoes. Dr Alving discovered that the maximum tolerated dose of primaquine by African-Americans was 15 mg once a day, above which many of the subjects developed haemolytic anaemia (as a consequence of this, he was subsequently able to discover the cause, which was G6PD deficiency). Although this dose (15 mg) worked for the most part against most P. vivax strains, the minimum dose of primaquine required for “radical cure” of the Chesson strain of P. vivax was found by Dr Alving to be 22.5 mg once daily over 2 weeks.

The subsequent large scale clinical trial of primaquine was also unique, organised mainly by Dr Alf Alving, Major John Arnold and Major Donald Robinson. In September 1951, two troop ships USNS Sergeant Sylvester Antolak and USNS Marine Phoenix departed Sasebo, Japan for Seattle, USA. Aboard these ships, a medically unsupervised trial took place where 1,493 and 2,060 Korean War veterans respectively were randomly assigned to placebo or 15 mg of once daily primaquine for 2 weeks. Despite the trips being made in particularly stormy conditions, the rates of sea-sickness (and other adverse effects – in particular, only 1 episode of haemolysis among the >300 African American veterans in the treatment arm) were low, confirming the safety – and subsequently the efficacy – of primaquine for preventing P. vivax relapses.

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The USNS Sergeant Sylvester Antolak. Image from Navsource.org

After these and other studies, the US Army administered primaquine en masse to all returning veterans from the Korean War without major mishaps, and the FDA approved primaquine for the terminal prophylaxis of vivax malaria (but initially only at the dose of 15 mg daily for 14 days – a story in itself as the regulatory body was already aware of the high rates of failure against the Chesson strain of P. vivax).

And things have largely remained unchanged for the past 60 over years until Monday, when GlaxoSmithKline (GSK) and Medicines for Malaria Ventures announced at the International Conference for Plasmodium vivax Research in Brazil that a single dose of tafenoquine was as effective as 14 days of primaquine in preventing P. vivax relapse. Tafenoquine is another 8-aminoquinolone developed by the US Walter Reed Army Research Institute (in response to another war – the Vietnam War) and produced by GSK with a long half-life of 2-3 weeks (hence justifying the single dose use). There was a bunch of studies done in the 1990s and 2000s showing the safety and efficacy of the drug, but it was never submitted for FDA regulatory approval. The two Phase III studies whose results were announced above, “GATHER” and “DETECTIVE”, were conducted across a large number of countries in Asia, Africa and South America.

It is a matter of local pride that the lead investigator for the Phase III tafenoquine studies is a Singaporean infectious diseases physician – Dr Gavin Koh – who is currently Director of Clinical Development for Diseases of the Developing World at GSK.

 

 

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