**Abstract**

Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated *P. vivax* whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on *P. vivax* resistance to antimalarials and the molecular basis of resistance lags far behind the *P. falciparum* as *in vitro* cultivation of the *P. vivax* has not yet been established. Therefore, data on the *P. vivax* resistance to any antimalarial drugs are generated through *in vivo* studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where *P. falciparum* and *P. vivax* are distributed in sympatry may reflect, although require validation, the status of *P. vivax* resistance. This review focuses on the currently available data that may represent the *state-of-the art* of the *P. vivax* resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.

**Keywords:** *Plasmodium vivax*, antimalarials, resistance status, genetic marker(s)

## **1. Introduction**

*Plasmodium vivax* presents a major challenge to achieving the global effort to eliminate malaria by 2030. The global distribution and factors that are associated with *P. vivax* occurrence in wider geographic regions in tropical, subtropical and temperate zones have extensively been reviewed recently [1, 2]. The ability of this species to undergo dormancy in the form of single-celled hypnozoites in the human liver, a safe haven from immune attack during the long mosquito-free cold seasons contributed to this phenomenon (**Figure 1**) [3]. Currently, *P. vivax* is present in 51 countries across Central and South America, the horn of Africa, Asia and the Pacific islands. Global malaria control and elimination programme successfully brought down the malaria incidence from 238 million cases in 2000 to 229 millions in 2019. The proportion of *P. vivax* cases declined from 7% in 2000 to 3% in 2019 [4]. Between 2000 and 2015, global malaria case incidence declined by 27%, and between 2015 and 2019 it declined by less than 2%, indicating a slowing of the rate of decline since 2015. Different from other human malaria, *P. vivax* uses Duffy antigen as its receptor in human to invade exclusively the young red blood cell (reticulocytes). Therefore, individuals who do not express the Duffy antigen are considered to be genetically resistant to *P. vivax* infection and this is particularly true in the majority of African sub-saharan population [5]. However, evidence for

**Figure 1.** Plasmodium vivax *life cycle [3].*

*P. vivax* infections in Duffy negative patients raise the possibility of an alternative invasion mechanism to Duffy [6, 7].

*Plasmodium vivax* in most geographic regions is distributed in sympatry with *P. falciparum*. This situation requires special attention during diagnosis and before prescription of drugs to the infected people. The biological characteristic of the *P. vivax* exhibit multiple exoerythrocytic cycle (relapses) from a single mosquito inoculation, and coupled with the very early emergence of gametocytes in the course of blood-stage infection, perhaps enables parasite survival and transmit to mosquito vector silently despite relatively low probability of propagation in blood. This propensity presents a unique challenge to the chemotherapeutic intervention against vivax malaria cases in which radical cure to block the reactivation of hypnozoites should be given in addition to blood schizontocide. Although *P. vivax* has been known to be less severe than *P. falciparum*, a growing body of evidence indicates that severe and fatal outcome also occurred in many *P. vivax* cases and necessitate the importance of reversing the historic neglect of this infection [8–10].

Treatment of *P. vivax* currently relies on either chloroquine or ACTs, supplemented both with 14 days primaquine as anti-hypnozoites. The only available drug for radical cure is primaquine but its use in vivax endemic region is limited by its potential serious complication among the people who inherit glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency.

The present review focuses on the recent progress that has been achieved to try to circumvent the problem of drug resistance in *P. vivax*. The global spread of chloroquine-resistant *P. vivax* has forced some countries to adopt artemisinin-based combination therapy (ACTs) to replace chloroquine as the first line drug to treat uncomplicated *P. vivax* and this policy change also impact the use of primaquine, the sole agent for anti-relapse. Many studies and reviews have been exclusively focused to elucidate the basic mechanism(s) of drug resistance in the malarial parasite using *P. falciparum* or other rodent and avian plasmodia as model while *P. vivax*, as usual, is consistently neglected. In discussing the topic, we will review all antimalarial drugs that used to be used or have been used to treat vivax malaria since the early development of quinine to date. Rapid development of resistance to

#### Plasmodium vivax *and Drug Resistance DOI: http://dx.doi.org/10.5772/intechopen.97320*

the antimalarial drug mainstays from the early days to date will also be discussed to provide better perspectives for circumventing the problem of antimalarial drug resistance. The global extent of the drug-resistant *P. vivax* will also be reviewed to determine the appropriate measures based on drug policies that have been adopted by World Health Organisation (WHO) and implemented on local setting by member countries.
