**4. Latent and sub-patent** *P. vivax*

The latent and sub-patent parasitemia caused by *P. vivax* is difficult or impractical to detect using available technologies. These unnoticed or invisible infections probably represent a dominant majority in most endemic settings. Thus, the primary blow to therapeutic effectiveness (the proportion of patients needing a particular therapy and receiving high-quality drug in a full and adequately absorbed dose) is simply the inability to identify those in need of therapy.

The human host also imposes important barriers to the effectiveness of antimalarial therapies in the real world. Clinical contraindications, patient adherence, provider prescribing practices, provider and patient access to the drug, and its quality and availability; all further chip away the realizable effectiveness of any given antimalarial agent. The contraindications are particularly important in the case of *P. vivax* and the crucial therapy against relapses with PQ, the only current therapeutic option for that clinical indication. Primaquine (and all other 8-aminoquinoline compounds evaluated) invariably provokes an acute hemolytic anemia in patients receiving therapeutic doses against relapse and having an inherited X chromosome-linked deficiency in glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity [35]. This abnormality affects approximately 400 million people or 8% of people residing in malaria endemic countries [36]. 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 important adherence problem with that therapy [41, 42].

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,

Resistance to CQ by the asexual stages of *P. vivax* has been documented in most endemic regions [4, 5]. Resistant strains dominate the malarious Western Pacific and Indonesian archipelago and nations there have adopted highly efficacious ACTs [11] as first-line therapy. With the possible exception of artesunate combined with sulfadoxine-pyrimethamine, all ACTs have shown superb efficacy in killing asexual blood stages of *P. vivax* [31]. The safety and efficacy of PQ against relapse when combined with partner blood schizonticides other than CQ, quinine, or dihydroartemisinin-piperaquine [32, 33] require validation in clinical trials [14]. Elsewhere, for now, resistance appears sporadically and at relatively low frequencies. Despite substantial efforts to identify molecular markers of *P. vivax* resistance to antimalarial drugs, none have yet been validated. *In vivo* testing in patients or relatively difficult *ex vivo* drug testing procedures remain necessary [34]. The monitoring of antimalarial efficacy offers possible relief from risk of failure due to parasite resistance to specific therapies, but this is

The latent and sub-patent parasitemia caused by *P. vivax* is difficult or impractical to detect using available technologies. These unnoticed or invisible infections probably represent a dominant majority in most endemic settings. Thus, the primary blow to therapeutic effectiveness (the proportion of patients needing a particular therapy and receiving high-quality drug in a full and adequately absorbed dose) is simply the inability to identify those in need

The human host also imposes important barriers to the effectiveness of antimalarial therapies in the real world. Clinical contraindications, patient adherence, provider prescribing practices, provider and patient access to the drug, and its quality and availability; all further chip away the realizable effectiveness of any given antimalarial agent. The contraindications are particularly important in the case of *P. vivax* and the crucial therapy against relapses with PQ, the only current therapeutic option for that clinical indication. Primaquine (and all other 8-aminoquinoline compounds evaluated) invariably provokes an acute hemolytic anemia in patients receiving therapeutic doses against relapse and having an inherited X chromosome-linked deficiency in glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity [35]. This abnormality affects approximately 400 million people or 8% of people residing in malaria endemic countries [36].

and across the northern Sahel [30].

80 Towards Malaria Elimination - A Leap Forward

carried out relatively infrequently.

of therapy.

**4. Latent and sub-patent** *P. vivax*

**3. Chloroquine-resistant acute** *P. vivax*

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 cure [45].

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 significant functional impairment of CYP2D6 [48].

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 context.

Effective diagnosis and treatment represents the cornerstone of current control and elimination strategies, and the obstacles described here require consideration in realizing gains against this tenacious endemic problem. Indeed, such gains have been achieved both historically and recently. At the turn of the twentieth century, endemic vivax malaria occurred across much of southeastern North America, northern and southern Europe, the Middle East, and northern Australia—areas where it no longer appears. Much of this success was achieved applying environmental modifications against local *Anopheles* vectors, but more recent elimination successes using principally diagnosis and treatment strategy have occurred in nations like Turkey, Azerbaijan, and Sri Lanka, as examples [50]. The same had been achieved on the Korean Peninsula during the 1970s, but endemic vivax malaria transmission reappeared during the 1990s and persists today [51]. Post-elimination vigilance that includes not only diagnosis and treatment services but also vector control may be essential to protecting and sustaining the elimination of endemic vivax malaria [50].

indoor residual spraying (IRS) of insecticides interventions may not offer full protection or have reached their efficacy limits—especially in areas with residual transmission or in areas where elimination may be considered feasible. Control of disease in these areas will require new approaches, and possibly spatial repellency would be practical and effective [62, 63]. SRs may be useful as stand-alone tools of personal or household protection where other interventions may not reach. Also, they may be combined with conventional interventions to augment

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

http://dx.doi.org/10.5772/intechopen.77082

83

Another vector control strategy for eliminating *P. vivax* in the Asian-Pacific region may be the method of environmental modification called "species sanitation." This approach offers prevention independently of the myriad problems and challenges of diagnosis and treatment or the limitations of insecticidal strategies. Species sanitation is simply sanitizing the environment against specific incriminated vector species by exploiting detailed knowledge of their bionomics (behavior and ecology) [64]. Malcolm Watson in British Malaya, along with Nicholas Swellengrebel and Raden Soesilo in the East Indies, invented, optimized, and validated species sanitation in malaria control [65]. A systematic analysis of 16 such interventions (most conducted before 1945) showed an average 88% reduction of malaria burden [66]. As new cases occur by relapse, reinfection, or importation, making the subsequent infection of mosquitoes improbable (by simply reducing their numbers) eventually suffocates

Although the implementation of LLIN, IRS, and species sanitation in different environmental settings rendered significant success rates [67], it is evident that the key determining factors for the success of any vector intervention selected is a thorough knowledge of the vector bionomics, local malaria transmission dynamics, and residual efficacy of choice insecticide. Knowledge of vector bionomics includes ascertaining breeding and resting preferences and feeding behavior of incriminated vector species. Transmission dynamics include information related to entomological inoculation rates, sibling species composition of vectors (based on reliable PCR identification assays), seasonality of malaria prevalence, and risk factors that may support the human-mosquito contact, while suitable insecticide means any available insecticide that renders knockdown effect and/or mortality to the incriminated vector

Another important issue to be considered is the ability of the *Anopheles* mosquitoes to adapt to the ongoing vector interventions by changing host-seeking behavior, such as from indoor to outdoor or *vice versa*, and selection of insecticide-resistant strain [68]. With current trends in globalization and population migration, deforestation, and resettlement of populations, reintroduction of malaria into areas that have been declared free from transmission is a clear and present risk. Therefore, no single intervention method may guarantee long-term efficacy; thus, regular monitoring of vector density and behavior should be a routine operation wherever this risk occurs. Most malaria control programs no longer have the entomological expertise needed to carry out these important tasks—addressing this problem may be the greatest and most important challenge within the context of a malaria

their impacts.

transmission.

population.

elimination agenda.

#### **5. Vector control in vivax malaria**

Vector control of endemic vivax malaria may not have immediate impacts due to the hypnozoite reservoir contributing >80% of acute attacks of vivax malaria in low or high endemic settings [52, 53]. Success in reducing malaria incidence and local transmission to zero in a malaria endemic area, particularly where sympatric *P. falciparum* and *P. vivax* occur, may require greater sustainability of vector control measures. Vivax malaria transmission will outlast falciparum malaria, and reestablishment of local transmission may occur without imported cases, i.e., by local hypnozoites. Prevention of the seeding of new hypnozoites in liver cells by biting *Anopheles* mosquitoes obviously may contribute positively to the control and elimination of vivax malaria in the long term, but no randomized controlled trials yet affirm this. In one large cluster-randomized trial in Myanmar, insecticide-treated bed netting (ITN) had no impact whatsoever on the risk of malaria [54], an outcome attributed to the dominant *Anopheles* vector, *A. dirus* s.s., feeding predominantly outdoors and early in evening or morning [55]. Relatively modest effects were reported from a similarly cluster-randomized trial in Vietnam, again attributed to mosquito behaviors unfavorable to control by this means [56]. The main Asian vector species tend to feed early in the evening and outdoors where they also rest [57], minimizing their exposure to household insecticides. In other studies of strategies for minimizing exposure to *Anopheles,* much greater impacts against falciparum malaria were demonstrated relative to those against vivax malaria [58–60].

Over the last decade, attempts of using spatial repellents (SRs) to minimize exposure to biting insects have shown some success in diverse settings [61]. Repellency is distinct from the killing action of insecticides in more than one way, i.e., no direct contact is required, and lacking lethality does not select for resistance. SRs are effective irrespective of indoor or late-night feeding and resting behavior like conventional netting or indoor spraying. SRs should be evaluated for added benefit in areas where traditional long-lasting insecticidal net (LLIN) or indoor residual spraying (IRS) of insecticides interventions may not offer full protection or have reached their efficacy limits—especially in areas with residual transmission or in areas where elimination may be considered feasible. Control of disease in these areas will require new approaches, and possibly spatial repellency would be practical and effective [62, 63]. SRs may be useful as stand-alone tools of personal or household protection where other interventions may not reach. Also, they may be combined with conventional interventions to augment their impacts.

Effective diagnosis and treatment represents the cornerstone of current control and elimination strategies, and the obstacles described here require consideration in realizing gains against this tenacious endemic problem. Indeed, such gains have been achieved both historically and recently. At the turn of the twentieth century, endemic vivax malaria occurred across much of southeastern North America, northern and southern Europe, the Middle East, and northern Australia—areas where it no longer appears. Much of this success was achieved applying environmental modifications against local *Anopheles* vectors, but more recent elimination successes using principally diagnosis and treatment strategy have occurred in nations like Turkey, Azerbaijan, and Sri Lanka, as examples [50]. The same had been achieved on the Korean Peninsula during the 1970s, but endemic vivax malaria transmission reappeared during the 1990s and persists today [51]. Post-elimination vigilance that includes not only diagnosis and treatment services but also vector control may be essential to protecting and

Vector control of endemic vivax malaria may not have immediate impacts due to the hypnozoite reservoir contributing >80% of acute attacks of vivax malaria in low or high endemic settings [52, 53]. Success in reducing malaria incidence and local transmission to zero in a malaria endemic area, particularly where sympatric *P. falciparum* and *P. vivax* occur, may require greater sustainability of vector control measures. Vivax malaria transmission will outlast falciparum malaria, and reestablishment of local transmission may occur without imported cases, i.e., by local hypnozoites. Prevention of the seeding of new hypnozoites in liver cells by biting *Anopheles* mosquitoes obviously may contribute positively to the control and elimination of vivax malaria in the long term, but no randomized controlled trials yet affirm this. In one large cluster-randomized trial in Myanmar, insecticide-treated bed netting (ITN) had no impact whatsoever on the risk of malaria [54], an outcome attributed to the dominant *Anopheles* vector, *A. dirus* s.s., feeding predominantly outdoors and early in evening or morning [55]. Relatively modest effects were reported from a similarly cluster-randomized trial in Vietnam, again attributed to mosquito behaviors unfavorable to control by this means [56]. The main Asian vector species tend to feed early in the evening and outdoors where they also rest [57], minimizing their exposure to household insecticides. In other studies of strategies for minimizing exposure to *Anopheles,* much greater impacts against falciparum

malaria were demonstrated relative to those against vivax malaria [58–60].

Over the last decade, attempts of using spatial repellents (SRs) to minimize exposure to biting insects have shown some success in diverse settings [61]. Repellency is distinct from the killing action of insecticides in more than one way, i.e., no direct contact is required, and lacking lethality does not select for resistance. SRs are effective irrespective of indoor or late-night feeding and resting behavior like conventional netting or indoor spraying. SRs should be evaluated for added benefit in areas where traditional long-lasting insecticidal net (LLIN) or

sustaining the elimination of endemic vivax malaria [50].

**5. Vector control in vivax malaria**

82 Towards Malaria Elimination - A Leap Forward

Another vector control strategy for eliminating *P. vivax* in the Asian-Pacific region may be the method of environmental modification called "species sanitation." This approach offers prevention independently of the myriad problems and challenges of diagnosis and treatment or the limitations of insecticidal strategies. Species sanitation is simply sanitizing the environment against specific incriminated vector species by exploiting detailed knowledge of their bionomics (behavior and ecology) [64]. Malcolm Watson in British Malaya, along with Nicholas Swellengrebel and Raden Soesilo in the East Indies, invented, optimized, and validated species sanitation in malaria control [65]. A systematic analysis of 16 such interventions (most conducted before 1945) showed an average 88% reduction of malaria burden [66]. As new cases occur by relapse, reinfection, or importation, making the subsequent infection of mosquitoes improbable (by simply reducing their numbers) eventually suffocates transmission.

Although the implementation of LLIN, IRS, and species sanitation in different environmental settings rendered significant success rates [67], it is evident that the key determining factors for the success of any vector intervention selected is a thorough knowledge of the vector bionomics, local malaria transmission dynamics, and residual efficacy of choice insecticide. Knowledge of vector bionomics includes ascertaining breeding and resting preferences and feeding behavior of incriminated vector species. Transmission dynamics include information related to entomological inoculation rates, sibling species composition of vectors (based on reliable PCR identification assays), seasonality of malaria prevalence, and risk factors that may support the human-mosquito contact, while suitable insecticide means any available insecticide that renders knockdown effect and/or mortality to the incriminated vector population.

Another important issue to be considered is the ability of the *Anopheles* mosquitoes to adapt to the ongoing vector interventions by changing host-seeking behavior, such as from indoor to outdoor or *vice versa*, and selection of insecticide-resistant strain [68]. With current trends in globalization and population migration, deforestation, and resettlement of populations, reintroduction of malaria into areas that have been declared free from transmission is a clear and present risk. Therefore, no single intervention method may guarantee long-term efficacy; thus, regular monitoring of vector density and behavior should be a routine operation wherever this risk occurs. Most malaria control programs no longer have the entomological expertise needed to carry out these important tasks—addressing this problem may be the greatest and most important challenge within the context of a malaria elimination agenda.
