**2. Biology of** *Plasmodium vivax*

global distribution most heavily weighing upon South and Southeast Asia (SEA) [1]. In most endemic countries, chloroquine (CQ) remains the first-line therapy for acute vivax malaria after more than 70 years of continuous use. CQ-resistant *P. vivax*, documented nearly 30 years ago, now commonly occurs across much of SEA [4, 5]. Unlike the other dominant species causing human malaria, *P. falciparum*, some sporozoites (called bradysporozoites) of *P. vivax* develop into dormant forms in the liver called hypnozoites. This single feature latency—defines and distinguishes the prevention, treatment, and control of vivax malaria. Other sporozoites (called tachysporozoites) immediately develop into actively dividing hepatic schizonts over the 7-day to 18-day incubation period and cause the primary parasitemia and acute attack of patent vivax malaria. Hypnozoites activate weeks, months, or even

In natural endemic settings, it may not be known if any given patient presenting with patent acute vivax malaria is experiencing a tachysporozoite-borne primary attack or a bradysporozoite-borne relapse. This uncertainty poses a fundamental problem of interpretation of parasitemia that may follow therapy [5–8]. The origin of the parasitemia may be a consequence of new primary attack (reinfection), therapeutic failure against blood stages (recrudescence), or renewed latent malaria (relapse). These ambiguities may not be addressed by molecular genotyping techniques because relapses may be either homologous or heterologous to the primary infection event [9, 10]. Estimating the efficacy of blood schizonticidal therapy may thus be

Another drug, a hypnozoitocide, is necessary to treat latent vivax malaria and prevent future attacks. Primaquine (PQ) has been the only available therapeutic option to kill hypnozoites since 1952. A single dose of 30 mg PQ within 48 hours of infection appears sufficient to kill stages of *P. vivax* or *P. falciparum* attempting to develop into hepatic schizonts or hypnozoites [12]. Beyond that period, presumably after formation of dormant hypnozoites, relatively large doses totaling 210 to 420 mg of PQ (delivered over 7 to 56 days) are required to prevent

years later, causing a renewed clinical attack called relapses [6].

complex and difficult [11].

78 Towards Malaria Elimination - A Leap Forward

**Figure 1.** Distribution of *Plasmodium vivax* malaria in the world.

The broad and prolonged neglect of research on *P. vivax* has been highlighted by many researchers [17–20]. Although this lack of research certainly derives from complex and multiple factors, the misperception of this species as intrinsically benign perhaps dominates among them [21]. Today, we accept that a diagnosis of vivax malaria is sometimes associated with severe disease syndromes associated with fatal outcomes [16, 22]. The manner in which *P. vivax* threatens life with such typically low-grade parasitemias (usually tenfold lower than *P. falciparum*) is an important and relatively new question. Nonetheless, some researchers suggest that vivax malaria may be primarily an infection of hematopoietic tissues rather than of the vascular sinuses *per se* [21, 23, 24]. If most *P. vivax* biomass in the human host resides within tissues of the bone marrow and spleen, it would have far-reaching scientific, clinical, and public health implications with respect to measuring and combatting the threats imposed.

We already know the likely importance of the latent hypnozoite reservoir and sub-patent/ asymptomatic parasitemias [25–27]. Adding an as-yet unacknowledged sequestered trophozoite reservoir—very few or no asexual parasites in vascular sinuses but many in the extravascular spaces of erythropoietic tissues—would greatly amplify concerns regarding the effectiveness of diagnosis and treatment in control and elimination. It is possible that most *P. vivax* parasites—certainly hypnozoites but perhaps also trophozoites—occur beyond the vascular sinuses in both asymptomatic and acutely ill patients and, therefore, also beyond the reach of standard diagnostics.

Although the Duffy antigen on the surface of the red blood cell has long been considered essential to *P. vivax* invasion—and its absence in many African populations thought to explain the relative rarity of *P. vivax* on that continent—recent evidence from a variety of African locales has shown patent *P. vivax* parasitemia in patients who are negative for that molecule [28]. Moreover, *P. vivax* has been shown to be present in parts of Africa where it is not prevalent [29] and is indeed prevalent in other areas of that continent like Madagascar, the Horn, and across the northern Sahel [30].

Safe access to PQ for radical cure of vivax malaria may require access to point-of-care diagnostics for G6PD deficiency [37]. Even with such testing, however, there remains the problem of treating those diagnosed as G6PD-deficient, pregnant or lactating women, and infants below the age of 6 months [38]. There are no optimized or validated means of preventing relapse without 8-aminoquinoline drugs, e.g., by chemopreventive or presumptive periodic preventive therapeutic strategies [39, 40]. The 8-aminoquinoline drug, called tafenoquine, is in late clinical development and will likely soon offer a single-dose option to PQ, virtually eliminating the

Challenges in the Control and Elimination of *Plasmodium vivax* Malaria

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Another potential problem in the human host may be the inability to metabolize PQ to its active hypnozoite-killing metabolite by cytochrome P450 2D6 (CYP2D6) [43]. Natural polymorphism in the gene expressing CYP2D6 leads to a range of metabolic activities ranging anywhere between far above normal and null. Patients in need of PQ anti-relapse therapy and having significantly impaired or null CYP2D6 activity may relapse even with full compliance to good quality drug. We do not yet know the extent of this problem with regard to the frequencies of CYP2D6 alleles associated with PQ therapeutic failure, but the significantly impaired CYP2D6 \*10 allele (a particular genetic variant of CYP2D6 gene) is relatively common among Southeast Asians, at about 35% frequency [44]. It may be that many Asians will be unable to adequately metabolize PQ and achieve successful radical

The ambiguity of geographically variable frequency and timing of relapse—along with reinfection and recrudescence in recurrent *P. vivax* malaria after PQ therapy—makes estimating PQ efficacy in endemic settings very difficult. This is true even with directly observed therapy using high-quality drug. After decades of recommending a 5-day regimen of PQ against relapse, on the basis of observed low rates of relapse following therapy, investigators in India ultimately included a relapse control group (placebo) and discovered that efficacy to be nil [46]—the low rate of relapse was naturally occurring. John et al. [47] systematically reviewed recurrence rates after standard 0.25 mg/kg daily for 14-day regimen with rates of recurrence averaging about 8% at 1 month, 10% at 2–3 months, 14% at 4–6 months, and 20% at 7–12 months. In two randomized controlled trials of PQ given at high dose (0.5 mg/kg) to 257 Indonesian soldiers infected by *P. vivax* in eastern Indonesia and followed for a year where reinfection was not possible, 35 (14%) experienced at least one relapse [32, 33]. Among the 21 subjects whose CYP2D6 genotype and phenotype were examined, 20 showed evidence of

Evidence supports the notion of providing presumptive anti-relapse therapy to all patients diagnosed with any species of malaria agents, especially *P. falciparum*. In a retrospective analysis of over 10,000 research subjects naturally infected by *P. falciparum* in Thailand or Myanmar, 912 were treated with rapidly excreted blood schizonticides, and within 2 months, just over 50% experienced a *P. vivax* attack [49]. The people infected by one species in any given community must be considered at high risk of harboring latent and perhaps sub-patent infections of the other co-endemic species. Species-specific therapies, especially in an age of dominant CQ resistance among the plasmodia, may not be sensible in an elimination

important adherence problem with that therapy [41, 42].

significant functional impairment of CYP2D6 [48].

cure [45].

context.
