Repeated Plasmodium vivax malaria relapses in a Peruvian sailor

Primaquine is currently the only FDA approved drug to prevent relapses of P. vivax, as it targets the hypnozoites latent in hepatic cells 1], 2]. Many Ministries of Health in South America recommend a maximum of 30 mg/day for
7 days (210 mg total) establishing a maximum weight of 60 kg and only a week of treatment
as compliance is low for longer time periods 3]. It has been suggested, however, that this total dose may be at the lower edge of
reasonable efficacy and minimally effective 4]. Several studies have demonstrated failure of primaquine due to inadequate dosage
compared to body weight 1], 5]–7]. In this case, the maximum total dose of 210 mg recommended by the Peruvian Ministry
of Health 3] was not effective for this patient. The subject weighed 25 % over the 60 kg weight
limit and therefore received low-dose regimens twice. No more relapses were observed
after a 14-day full dosage treatment. This is of particular importance for the military,
as personnel tend to weigh more than the weight (60 kg) used to calculate the maximum
total dosage of primaquine. Additionally, the rise of obesity in malaria endemic countries
could render standard treatment recommendations ineffective. Higher doses of primaquine
are used in other regions, as current Centers for Disease Control and Prevention (CDC)
standards advise a maximum dosage of 0.5 mg/kg/day capped at 60 kg (max of 30 mg/day)
for no more than 14 days (420 mg total) in G6PD positive individuals 1]. However, compliance remains a critical issue. Tafenoquine, a new drug undergoing
clinical evaluation, has been shown to be significantly effective in a single dose
taken with chloroquine in preventing relapse of vivax malaria 8]. Until the safety and efficacy of tafenoquine can be further determined, the adoption
of CDC recommendations and larger doses of primaquine are the only options to effectively
treat patients and prevent relapse as well as contribute to the elimination of the
parasite in endemic areas.

A key question in this case is whether the patient’s subsequent episodes of malaria
were the result of relapse of dormant hypnozoites or re-infection with a new strain.
After the initial hospitalization, the patient did not travel to any areas with malaria
transmission, making re-infection unlikely. Additionally, the strains from the February
and August blood smears were identical based on molecular analysis. The Amazon Basin
is a region of high P. vivax diversity, and homologous strains would strongly suggest relapse 9]. While whole genomic analysis is necessary in order to completely determine if the
strains are identical and therefore exhibiting relapse 10], re-infection is doubtful due to the low possibility of transmission, homologous
strains between hospitalizations, and high genetic diversity among P. vivax species in this region. P. vivax exhibits geographical variation in relapse patterns 11]. Historically, it has been thought that frequent relapsing strains originate from
the tropics, and that strains with a long latent period originate from temperate regions
12]. However, the Amazon Basin is unique in that it contains both long-latency and frequent
relapsing strains, complicating attempts to characterize the predominant relapse pattern
11], 13]. Recent evidence has demonstrated that the majority of relapses occur within 2–3 months
of infection, with 70 % of relapses occurring within 5 months of initial infection
11], 14]–16]. In addition, characterizing relapse patterns in malaria-endemic areas is inherently
problematic as studies cannot completely distinguish a relapse from a new infection.
True periodicity of relapse can most accurately be determined in patients with single,
short exposure that minimizes the chance of re-infection. Travellers, including the
military, are therefore good populations to study relapse patterns. In this case,
the sailor did not travel to any areas where he could have been re-infected. His recurrent
parasitaemia is most likely due to the reactivation of a latent strain. The two relapses
occurring 3 months apart are most likely representative of the relapse pattern common
in the Amazon Basin.

In conclusion, the frequent incidence of relapse of P. vivax in South America poses an important challenge for elimination. The 60 kg cap on patient
weight and 210 mg maximum primaquine dose recommended in Peru and other South American
nations may limit the efficacy necessary for radical cure in individual patients and
control in the endemic population. This becomes increasingly important during the
current epidemic of obesity, as a heavier patient population could negatively impact
the management of vivax malaria and potentially other diseases, as well as the effectiveness of other anti-malarial
drugs. Until more effective radical cure drugs are licensed 8] or alternative parameters for dosing are explored (e.g. body mass index), clinicians
can better prevent relapses in vivax malaria and support malaria control by using adequate primaquine dosing by weight
and increasing the number of days of treatment up to 14 days if needed.