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. Author manuscript; available in PMC: 2012 Jun 1.
Published in final edited form as: Curr Opin Infect Dis. 2011 Dec;24(6):578–585. doi: 10.1097/QCO.0b013e32834c61e3

Plasmodium vivax treatments: what are we looking for?

Ric N Price 1,2,3, Nicholas M Douglas 1,3, Nicholas M Anstey 1,2, Lorenz von Seidlein 1
PMCID: PMC3280893  EMSID: UKMS40442  PMID: 21986614

Abstract

Purpose of Review

For over 50 years the treatment of Plasmodium vivax has relied on a combination of chloroquine plus primaquine, but this strategy is under threat. Chloroquine efficacy is now compromised across much of the vivax endemic world and there are significant operational difficulties in deploying primaquine. We review the recent advances in P. vivax chemotherapy that may influence the future management of this neglected pathogen.

Recent Findings

New generation artemisinin combination therapies (ACTs) have shown potent efficacy against the erythrocytic stages of both drug resistant P. vivax and P. falciparum. Antimalarial regimens containing slowly-eliminated drugs provide a measure of protection against the first, and possibly second, relapse of tropical strains of P. vivax, but reliable radical cure is needed to prevent future relapses. Primaquine is currently the only licensed hypnozoitocidal treatment, but requires long treatment courses and its effectiveness in different endemic settings remains largely unknown.

Summary

In regions coendemic for P. vivax and P. falciparum, a unified treatment policy for malaria of any parasitological cause is likely to confer the greatest individual and public health benefit. Optimizing the safety and effectiveness of primaquine through the development of rapid diagnostic tests for G6PD deficiency and improving drug adherence will be crucial endeavours in the fight against vivax malaria.

Keywords: P. vivax, malaria, drug resistance, antimalarials, primaquine

Introduction

For many centuries vivax malaria has been referred to as ‘benign tertian fever’ because of its 48 hour blood-stage periodicity and perceived lack of life-threatening complications. In the early part of the 20th century, treatment of vivax malaria was reliant on quinine. A major drug discovery program in the 1930s resulted in the identification and development of a variety of potent alternative antimalarials, including the aminoquinoline and antifolate drugs. The Second World War accelerated further drug development driven by the need to deploy military personnel in malarious countries. By the 1950s, chloroquine was established as the preferred blood schizontocidal treatment for P. vivax malaria, with primaquine coadministered to prevent relapses from dormant liver stages of the parasite. The combination of chloroquine plus primaquine has remained the default option for treating vivax malaria for almost 50 years. During this period, malaria researchers and policymakers have focused their efforts on tackling the burden of P. falciparum, the major cause of global malaria mortality. In the shadow of P. falciparum, the development of drugs, diagnostics, and vaccines for P. vivax stalled (1).

The last decade has seen a widespread scale-up of insecticide-treated bed nets and highly effective artemisinin combination therapies (ACTs) for uncomplicated falciparum infections. In many places these interventions have been associated with significant reductions in the overall burden of malaria (2, 3). Outside of Africa, where Plasmodium falciparum and P. vivax invariably co-exist (4), intensive control measures have had a disproportionately greater impact on P. falciparum than P. vivax (5-7). The control and elimination of P. vivax will be far harder than for P. falciparum. The comparative refractoriness of P. vivax to current malaria control interventions is largely attributed to its dormant liver stages (hypnozoites) which cause recurrent blood stage infections (relapses) weeks-months after initial infection, sustaining transmission, even in environments that are hostile to the mosquito vector for much of the year.

Recent estimates suggest that 40% of the world’s population is at risk of P. vivax transmission (8) with between 70 and 390 million clinical episodes of vivax malaria each year (9, 10). The net annual cost of those infections has been estimated to be between US$1.4 and 4 billion (10). Although undoubtedly less pathogenic than P. falciparum, P. vivax infections have been associated with severe and fatal disease (11-13) and substantial morbidity, particularly severe anemia (14, 15). The socioeconomic consequences of vivax malaria are poorly quantified, but likely to be substantial. (10, 16-18).

In this article we review the antimalarial drug treatments available for P. vivax malaria as well as progress in developing new therapeutic options for its control and ultimate elimination (Table 1). Two main aspects of treatment are addressed: removal of erythrocytic parasitemia, and terminal elimination of exoerythocytic hypnozoite stages.

Table 1. Stage specificity of antimalarial agents active against Plasmodium vivax.

Mosquito Sporontocidal DHFR inhibitors
Atovaquone
Primaquine
Tafenoquine
Bulaquine 1
Human
Hypnozoitocidal Primaquine
Tafenoquine
Bulaquine
Blood schizontocidal Artemisinins
Lumefantrine
Atovaquone
DHFR inhibitors
DHPS inhibitors 2
Quinolines 3
Antibiotics
Primaquine
Tafenoquine
Bulaquine 1
Gametocytocidal All drugs with asexual
activity are
gametocytocidal
against Plasmodium vivax
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Abbreviations: DHFR; dihydrofolate reductase, DHPS; dihydropteroate synthetase.

1

Bulaquine is metabolised to primaquine; similar activity inferred.

2

Sulfadoxine has intrinsically weak activity against Plasmodium vivax.

3

Includes quinine, chloroquine, amodiaquine, mefloquine, piperaquine and pyronaridine (excludes hypnozoitocidal quinolines).

Treatment of P. vivax Erythrocytic Stages

The interpretation of clinical studies for relapsing malarias is challenging (14, 19). Recurrent parasitemia following initial treatment can arise from reinfection, relapse from hypnozoite stages or true recrudescence due to parasite resistance or partial / inadequate therapy. Molecular analysis, which has been so important in confirming true recrudescence in clinical trials of P. falciparum, is less helpful in P. vivax studies, since it is currently not possible to distinguish between recrudescence and relapse of the same parasite strain. Pharmacokinetic analysis can help to confirm adequate drug absorption and establish whether recurrent infections occur in the face of blood concentrations known to exceed the minimum inhibitory concentration (MIC) of the parasite. Such analyses are often omitted due to logistical constraints or cost. Most of the available antimalarial drugs recommended for asexual treatment are potent schizontocides but have no activity against hypnozoites, hence the timing and recurrence of parasitemia is primarily a function of the elimination half-life of the initial drug treatment rather than its intrinsic schizontocidal activity.

In clinical trials, antirelapse therapy with primaquine is often administered concomitantly with the schizonticidal study drug. Since the primaquine has both hypnozoitocidal and schizontocidal activity its early administration can augment initial asexual parasite clearance and thus mask early indicators of declining schizontocidal drug efficacy. Vivax malaria drug trials therefore need to be interpreted in light of the concomitant use of primaquine, the timing of recurrence, available molecular data, schizontocidal drug concentrations, entomological inoculation rates and the epidemiology of relapse in the study area.

Chloroquine

Chloroquine (25mg base/kg over three days) remains the treatment of choice for P. vivax malaria in most parts of the world due to its wide availability, familiarity amongst health care staff, low cost, potency against sensitive strains (20) and long terminal elimination half-life. However this default option has become increasingly untenable because of the emergence and spread of chloroquine resistant (CQR) strains of the parasite. Despite the aforementioned difficulties in clinical trial interpretation there is now good evidence that the efficacy of chloroquine against P. vivax is declining in most locations where vivax malaria is endemic (14, 21). The epicentre of P. vivax chloroquine resistance appears to be the island of New Guinea where chloroquine resistance was first discovered and where the majority of individuals with P. vivax infection now fail chloroquine therapy (22-25). Recent reports have provided evidence of declining chloroquine efficacy against P. vivax from Ethiopia (26, 27), Madagascar (28), India (29), Indonesia (Alor and Lampung), (30, 31), South Korea (32), Myanmar (33) and Thailand (34, 35).

Alternative Monotherapies for P. vivax

Most commonly used antimalarial drugs are active against the asexual stages of P. vivax; the exception being the antifolates which act slowly (36) and are vulnerable to the rapid development of drug resistance (37, 38). A range of antimalarial drugs have demonstrated good efficacy against chloroquine-resistant P. vivax in clinical trials including mefloquine (39), atovaquone+proguanil (40), halofantrine (41), piperaquine (42, 43), artesunate (42, 43), and pyronaridine (44). The activity of these drugs against CQR P. vivax has also been confirmed by in vitro studies (45, 46). In vitro and in vivo studies suggest a degree of cross-resistance between chloroquine and amodiaquine (47), and this is likely to have accounted for high recurrence rates in clinical studies from Papua, Indonesia (48) and Papua New Guinea (43).

Artemisinin Combination Therapy for P. vivax Infection

Highly effective artemisinin combination therapies (ACTs) have become the treatment of choice for uncomplicated falciparum malaria, which by 2009 had been adopted by 81 malarious countries as first-line policy (49). Although World Health Organization (WHO) guidelines acknowledge that ACT plus primaquine is an appropriate alternative to chloroquine in regions where chloroquine efficacy is declining (20), there has been limited enthusiasm for such a policy with only The Solomon Islands, Vanuatu, Papua New Guinea (PNG) and Indonesia having adopted ACTs for first-line treatment of vivax malaria by 2009 (49). In general this reflects a lingering perception that ACT is an unnecessary and expensive choice for a disease which can be readily treated in most areas with chloroquine (50). Additional concerns have also been raised regarding the lack of substantial evidence confirming the efficacy of antirelapse regimens when primaquine is administered with schizontocidal drugs other than chloroquine or quinine (51). Despite these caveats there is a growing opinion advocating a unified ACT-based therapy for both P. falciparum and P. vivax in all coendemic regions. As the cost of ACTs falls and their availability increases the advantages of a pragmatic, unified ACT-based treatment protocol for both P. falciparum and P. vivax in all co-endemic regions, becomes compelling (21).

To date there have been 13 published studies of the efficacy of ACT for treating P. vivax monoinfection, including assessments of dihydroartemisinin+piperaquine (DHA+PIP) (42, 43, 48, 52-55), artemether+lumefantrine (AM+LUM) (26, 42, 43, 56, 57), artesunate+amodiaquine (AS+AQ) (48), artesunate+sulfadoxine+pyrimethamine (AS+SP) (38, 43, 58) and pyronaridine with either dihydroartemisinin (59) or artesunate (44). Five of these studies come from the island of New Guinea and all but one of the remaining from other parts of Asia.

In all of these studies parasite clearance was rapid (60), indicative of the potent activity of the artemisinins against all asexual stages of P. vivax (37). However the rates of recurrence within 28-42 days of ACT administration varied considerably. The risk of recurrent parasitemia was greatest in patients treated with artesunate+sulfadoxine+pyrimethamine (67%) (43), artesunate+amodiaquine (48%) (48) and artemether+lumefantrine (57-70%) (42, 43). In the case of AS+SP and AS+AQ this is likely to reflect compromised efficacy of the slowly-eliminated partner drug. In contrast, high rates of treatment failure with AM+LUM are likely to reflect relapsing infections rather than recrudescent infections; as suggested by 2.6% of Thai patients having recurrent parasitaemia following AM+LUM plus primaquine (57) compared to 57-70% of Papuan patients when primaquine was delayed until the end of the study (42, 43).

The Role of Post Treatment Prophylaxis

None of the current ACTs have any efficacy against the hypnozoite stages of P. vivax. Slowly-eliminated drugs, such as piperaquine (half-life ~28 days) and mefloquine (~12 days), provide a clinically significant period of post-treatment prophylaxis (PTP) against blood-stage parasitemia. The duration of this effect depends on the pharmacokinetic profile of the drug, the total dose administered, and the drug susceptibility of the infecting parasites (61). Post-treatment prophylaxis prevents or delays parasite recurrence arising from either new infections (reinfection) or reactivation of dormant liver stages (relapse). The greater the risk of recurrence, the more apparent this prophylactic effect is likely to become. Although transmission intensity tends to be low in most vivax endemic regions, each inoculation with P. vivax has the potential to cause multiple future relapses. The number of relapses can vary considerably. In equatorial regions, 60-90% of patients have recurrent P. vivax malaria within 42 days of the initial infection (more likely to be relapse rather than reinfection) (43, 48, 62). Such rates of recurrence are comparable to P. falciparum reinfections in high transmission settings in Africa (63).

The delay in relapse and reinfections conferred by the use of slowly-eliminated antimalarial drugs for P. vivax provides a longer period free from symptomatic malaria, allowing a greater length of time for haematological recovery which in turn reduces the risk of anaemia (42, 48). Reducing recurrent P. vivax infections may also impact upon transmission potential to the mosquito vector by decreasing overall gametocyte carriage (34). The risk of relapse and benefits of PTP are not restricted to patients with acute P. vivax monoinfection. In regions co-endemic for P. vivax and P. falciparum the treatment of pure falciparum malaria is followed by P. vivax parasitemia in over half of all patients treated with a rapidly-eliminated antimalarial drug by 9 weeks of follow-up (62). Similar to the treatment of P. vivax monoinfections, the use of slowly-eliminated antimalarials such as mefloquine or piperaquine reduces markedly the risk of these early heterologous relapses (43, 62, 64-66).

The long-term benefits of prolonged post-exposure prophylaxis are unclear. A single P. vivax sporozoite infection can prime the liver with multiple hypnozoites. Although slowly eliminated antimalarials will suppress the first, and possibly the second, relapse in equatorial regions, it remains to be shown whether this will reduce the total number of relapses or simply delay the occurrence of the next one. If the total number of relapses can be reduced then the PTP will impact upon gametocyte carriage and hence transmissibility.

Severe Vivax Malaria

Severe and fatal vivax malaria has been reported from Indonesia (11, 13), Papua New Guinea (67), India (68) and Brazil (69, 70). The main manifestations are anemia and respiratory distress (13, 67, 71-73). Series of patients with coma, shock and renal and hepatic dysfunction associated with vivax malaria have been described, but may be confounded by comorbidities (68-70, 74). In the absence of comparative drug trials, physicians have tended to adopt a similar treatment approach for severe vivax malaria as for severe falciparum malaria (20), namely administration of parenteral quinine or artesunate, along with broad spectrum antibiotic cover and supportive care.

The SEAQUAMAT and AQUAMAT studies have demonstrated clear superiority of intravenous artesunate over quinine in reducing case-fatality in severe falciparum malaria (75, 76). Intravenous artesunate also leads to a rapid clinical response in patients with severe vivax malaria (13, 74), but there have been no clinical trials comparing the mortality of intravenous artesunate versus quinine for severe P. vivax infection. P. vivax has a lower infecting parasite biomass compared with P. falciparum and does not cause major red blood cell sequestration in the deep vasculature, hence superior efficacy of artesunate over quinine cannot be assumed. Several studies have suggested artemisinin derivatives may result in haematopoietic suppression (77, 78). Since severe anaemia accounts for the greatest proportion of severe manifestations in vivax malaria, it will be important to ensure that artesunate is at least as efficacious as quinine in reducing mortality in severely anaemic patients, as was shown to be the case in children with severe anaemia due to falciparum malaria (76). However given the importance of initiating highly effective schizontocidal treatment as quickly as possible in severe falciparum malaria, the magnitude of the benefit of artesunate compared to quinine in severe falciparum malaria and the difficulties of discriminating between P. vivax and P. falciparum, a unified policy of intravenous artesunate seems pragmatic and appropriate, although further clinical studies are warranted.

Treatment of P. vivax Exoerythrocytic Stages

Relapsing infections from the exoerythrocytic liver stages are the most important impediment to the success of P. vivax control programmes (21, 79). Hypnozoites are insensitive to most schizontocidal drugs and even to agents that are active against liver stage schizonts such as atovaquone+proguanil. Hypnozoites are sensitive to 8-aminoquinoline antimalarial drugs at nanomolar concentrations, although only primaquine is currently licensed (80). Two other 8-aminoquinolines, bulaquine and tafenoquine, are in clinical development (81, 82), but there are very few other hypnozoitocidal candidates from other classes of compounds (83).

The World Health Organization recommends a dose of 0.25-0.5mg/kg primaquine daily for 14 days for radical cure of vivax malaria (20). Primaquine can cause upper gastrointestinal discomfort and life-threatening hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. In the most recent WHO malaria treatment guidelines primaquine is reported to be contraindicated in children <4 years of age and pregnant women (20) (page 52), the patient groups at greatest risk of morbidity associated with recurrent vivax infections. The risk-benefit of primaquine is unclear especially in young children, where a paucity of safety data rather than overt toxicity, is quoted as a rationale for withholding antirelapse therapy. In practice national malaria control programs often advocate deployment of 14 days primaquine in children as young as one year old, but studies are urgently needed to demonstrate primaquine safety in children particularly in infants, and those with mild and moderate G6PD deficiency.

There are as yet no reliable bedside tests for G6PD deficiency. Many health care providers therefore elect to administer primaquine without G6PD testing or simply adopt a blanket policy to omit the prescription of antirelapse therapy altogether. Adherence to standard primaquine regimens in some studies has been reported to be acceptable (84) but outside of study settings is almost certainly poor (85). The latter represents perhaps the greatest pragmatic challenge to the successful deployment of radically curative therapy. Outside of Oceania, a short course of directly observed, high-dose primaquine (1mg/kg/day) administered over 7 days has been shown to be well-tolerated and can reduce relapses by day 28 from 50% to 4% (86, 87). If the tolerability and safety of short-course, high-dose primaquine regimens can be assured in other population groups, a new primaquine regimen could be of great benefit in improving adherence to and thus effectiveness of antirelapse therapy. Education campaigns and routine direct observation of therapy may also be beneficial and warrant further investigation.

The 8-aminoquinolines, primaquine and pamaquine, are more effective when co-administered with chloroquine or quinine than when given alone (88). The reasons for this apparent potentiation of effect are not clear. There is a hypothetical concern that schizontocidal drugs other than quinine and chloroquine may not have this potentiating effect (51). Definitive evidence for a difference in potentiation will require large, randomized studies with supervised drug administration and long-term follow-up.

Once radical cure of P. vivax can be reliably and safely ensured, novel deployment strategies can be considered to reduce the overall burden of vivax malaria. Individuals infected with hypnozoites and/or undetectable or asymptomatic asexual parasitemia, constitute a major reservoir of infection – most obviously manifested by high rates of P. vivax recurrence following treatment for supposedly pure P. falciparum infections (62). Two potential strategies for reducing the transmission potential of these individuals are worthy of intensive investigation. The first is to provide primaquine therapy as part of mass schizontocidal drug treatment campaigns in co-endemic regions. The second is to provide effective anti-hypnozoite treatment to all patients with malaria in co-endemic regions rather than just those with P. vivax infections (62).

Conclusions

The chemotherapy of P. vivax has changed little over the last 50 years and there are few novel interventions on the horizon. This situation is totally unacceptable in an era when funding for malaria research is at an all-time high. Several high priority areas of research (outlined in Box 1) must be addressed if we are to have a realistic chance of eliminating vivax malaria.

Box 1 Research Priority Areas for the Treatment of P. vivax infection.

Treatment of Erythrocytic Stages

  • Investigate the relative advantages and disadvantages of an extended period of post-treatment prophylaxis provided by slowly eliminated drugs.

  • Investigate the impact of intermittent preventive treatment on vivax malaria in infancy, childhood and pregnancy.

  • Establish the overall cost-effectiveness of a unified ACT-based treatment strategy for vivax and falciparum malaria in co-endemic regions.

  • Establish the efficacy, safety and haematological effects of intravenous artesunate for the treatment of patients with severe vivax malaria.

  • Investigate the efficacy of novel schizonticidal agents against both multidrug-resistant falciparum and vivax malaria.

Treatment of Exoerythrocytic Stages

  • Develop robust, accurate and affordable point-of-care diagnostics for G6PD deficiency.

  • Develop new compounds for the eradication of P. vivax hypnozoites.

  • Assess the efficacy, effectiveness and safety of novel approaches to deliver primaquine treatment regimens (e.g. short-course / high-dose regimens, directly observed therapy, patient education campaigns).

  • Assess the impact of routine use of effective anti-relapse therapy in high transmission settings

  • Establish the safety profile of primaquine in patients with different degrees of G6PD deficiency.

  • Assess the utility of primaquine radical cure for P. vivax, following falciparum as well as vivax malaria in co-endemic regions.

  • Confirm the efficacy of primaquine when co-administered with different artemisinin combination therapies.

  • Investigate the impact of primaquine prescription as part of mass drug administration for reducing P. vivax transmission.

Plasmodium falciparum is resistant to chloroquine in most endemic regions and although slower to appear, chloroquine-resistant P. vivax strains are spreading throughout the world. In regions where P. vivax and P. falciparum cohabit, a unified treatment policy for malaria of any parasitological cause is likely to confer the greatest individual and public health benefit. Artemisinin combination therapies are highly efficacious against both species (except for parts of Cambodia) and are therefore prime candidates for unified treatment. Slowly-eliminated ACTs can suppress the first relapse of tropical strains of P. vivax, but whether this reduces transmission in the long term remains to be proven. The most important potential chemotherapeutic means of interrupting transmission of vivax malaria will be radical cure and thus prevention of all future relapses by using hypnozoitocidal medication. Primaquine is the only licensed drug for this purpose, but there are significant operational challenges in its use. The hypnozoitocidal drug discovery pipeline is virtually bare, hence optimizing the safety and effectiveness of primaquine through development of rapid diagnostic tests for G6PD deficiency and improving drug adherence are high priorities in the fight against vivax malaria.

Key Points.

  • A unified treatment policy for malaria of any parasitological cause will confer significant individual, public health and operational benefits in regions coendemic for P. falciparum and P. vivax.

  • Slowly-eliminated ACTs offer post treatment prophylaxis against the first relapse of tropical strains of P. vivax, which in the short term reduces the risk of anaemia and the transmissibility of the parasite.

  • Ensuring adherence to a complete course of primaquine is the greatest challenge in the control of P. vivax malaria, and may be achieved by adopting short-course, high-dose regimens.

  • A robust bedside test for G6PD deficiency is urgently needed to define the toxicity profile of primaquine and facilitate the safe deployment of antirelapse therapy.

Acknowledgements

We thank Nick White, Francois Nosten, Dennis Shanks, Kevin Baird and the members of the Vivax Working Group of the Asia Pacific Malaria Elimination Network (APMEN) for informative discussions that have shaped this opinion piece. RNP is a Wellcome Trust Senior Fellow in Clinical Science, NMD is funded by the Rhodes Trust, NMA is supported by an NHMRC Practitioner Fellowship and LvS by the AusAID-funded Asia-Pacific Malaria Elimination Network.

Funding Source: Wellcome Trust (UK), the Rhodes Trust (UK) and National Health & Medical Research Council (Australia)

Abbreviations

CQR

chloroquine resistance

Footnotes

No conflict of interests declared.

“The treatment of P. vivax”

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References

  • 1.Baird JK. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev. 2009 Jul;22(3):508–34. doi: 10.1128/CMR.00008-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Ceesay SJ, Casals-Pascual C, Erskine J, Anya SE, Duah NO, Fulford AJ, et al. Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet. 2008 Nov 1;372(9649):1545–54. doi: 10.1016/S0140-6736(08)61654-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.O’Meara WP, Bejon P, Mwangi TW, Okiro EA, Peshu N, Snow RW, et al. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet. 2008 Nov 1;372(9649):1555–62. doi: 10.1016/S0140-6736(08)61655-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hay SI, Guerra CA, Tatem AJ, Noor AM, Snow RW. The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis. 2004 Jun;4(6):327–36. doi: 10.1016/S1473-3099(04)01043-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet. 2000 Jul 22;356(9226):297–302. doi: 10.1016/s0140-6736(00)02505-8. [DOI] [PubMed] [Google Scholar]
  • 6.Sattabongkot J, Tsuboi T, Zollner GE, Sirichaisinthop J, Cui L. Plasmodium vivax transmission: chances for control? Trends in parasitology. 2004 Apr;20(4):192–8. doi: 10.1016/j.pt.2004.02.001. [DOI] [PubMed] [Google Scholar]
  • 7.Oliveira-Ferreira J, Lacerda MV, Brasil P, Ladislau JL, Tauil PL, Daniel-Ribeiro CT. Malaria in Brazil: an overview. Malar J. 2010;9:115. doi: 10.1186/1475-2875-9-115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, Temperley WH, et al. The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis. 2010;4(8):e774. doi: 10.1371/journal.pntd.0000774. [DOI] [PMC free article] [PubMed] [Google Scholar]; ** First map of the global burden and transmission of vivax malaria from the Malaria Atlas Project (MAP).
  • 9.Mendis K, Sina BJ, Marchesini P, Carter R. The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg. 2001;64(1-2 Suppl):97–106. doi: 10.4269/ajtmh.2001.64.97. [DOI] [PubMed] [Google Scholar]
  • 10.Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):79–87. [PMC free article] [PubMed] [Google Scholar]
  • 11.Barcus MJ, Basri H, Picarima H, Manyakori C, Sekartuti, Elyazar I, et al. Demographic risk factors for severe and fatal vivax and falciparum malaria among hospital admissions in northeastern indonesian papua. Am J Trop Med Hyg. 2007 Nov;77(5):984–91. [PubMed] [Google Scholar]
  • 12.Rodriguez-Morales AJ, Benitez JA, Arria M. Malaria Mortality in Venezuela: Focus on Deaths due to Plasmodium vivax in Children. Journal of tropical pediatrics. 2008 Apr;54(2):94–101. doi: 10.1093/tropej/fmm074. [DOI] [PubMed] [Google Scholar]
  • 13.Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, et al. Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia. PLoS medicine. 2008 Jun 17;5(6):e128. doi: 10.1371/journal.pmed.0050128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Price RN, Douglas NM, Anstey NM. New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Current opinion in infectious diseases. 2009 Jun 29; doi: 10.1097/QCO.0b013e32832f14c1. [DOI] [PubMed] [Google Scholar]
  • 15.Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Hasanuddin A, Warikar N, et al. Vivax Malaria: A Major Cause of Morbidity in Early Infancy. Clin Infect Dis. 2009 Jun 15;48(12):1704–12. doi: 10.1086/599041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, et al. The effects of mefloquine treatment in pregnancy. Clin Infect Dis. 1999 Apr;28(4):808–15. doi: 10.1086/515183. [DOI] [PubMed] [Google Scholar]
  • 17.Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, et al. Adverse pregnancy outcomes in an area where multidrug-resistant plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis. 2008 May 1;46(9):1374–81. doi: 10.1086/586743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Attanayake N, Fox-Rushby J, Mills A. Household costs of ‘malaria’ morbidity: a study in Matale district, Sri Lanka. Trop Med Int Health. 2000 Sep;5(9):595–606. doi: 10.1046/j.1365-3156.2000.00612.x. [DOI] [PubMed] [Google Scholar]
  • 19.Baird JK. Chloroquine resistance in Plasmodium vivax. Antimicrob Agents Chemother. 2004 Nov;48(11):4075–83. doi: 10.1128/AAC.48.11.4075-4083.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.World Health Organisation Guidelines for the treatment of malaria2010 [Google Scholar]
  • 21.Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN. Artemisinin combination therapy for vivax malaria. Lancet Infect Dis. 2010 Jun;10(6):405–16. doi: 10.1016/S1473-3099(10)70079-7. [DOI] [PMC free article] [PubMed] [Google Scholar]; * A comprehensive review of the role of artemisinin combination therapy for the treatment of P. vivax
  • 22.Rieckmann KH, Davis DR, Hutton DC. Plasmodium vivax resistance to chloroquine? Lancet. 1989;2(8673):1183–4. doi: 10.1016/s0140-6736(89)91792-3. [DOI] [PubMed] [Google Scholar]
  • 23.Baird JK, Basri H, Purnomo, Bangs MJ, Subianto B, Patchen LC, et al. Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am J Trop Med Hyg. 1991 May;44(5):547–52. doi: 10.4269/ajtmh.1991.44.547. [DOI] [PubMed] [Google Scholar]
  • 24.Sumawinata IW, Bernadeta, Leksana B, Sutamihardja A, Purnomo, Subianto B, et al. Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in Indonesian Papua. Am J Trop Med Hyg. 2003 Apr;68(4):416–20. [PubMed] [Google Scholar]
  • 25.Ratcliff A, Siswantoro H, Kenangalem E, Wuwung M, Brockman A, Edstein MD, et al. Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2007 Apr;101(4):351–9. doi: 10.1016/j.trstmh.2006.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Yohannes AM, Teklehaimanot A, Bergqvist Y, Ringwald P. Confirmed vivax resistance to chloroquine and effectiveness of artemether-lumefantrine for the treatment of vivax malaria in Ethiopia. Am J Trop Med Hyg. 2011 Jan;84(1):137–40. doi: 10.4269/ajtmh.2011.09-0723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ketema T, Getahun K, Bacha K. Therapeutic efficacy of chloroquine for treatment of Plasmodium vivax malaria cases in Halaba district, South Ethiopia. Parasit Vectors. 2011;4(1):46. doi: 10.1186/1756-3305-4-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Barnadas C, Ratsimbasoa A, Tichit M, Bouchier C, Jahevitra M, Picot S, et al. Plasmodium vivax resistance to chloroquine in Madagascar: clinical efficacy and polymorphisms in pvmdr1 and pvcrt-o genes. Antimicrob Agents Chemother. 2008 Dec;52(12):4233–40. doi: 10.1128/AAC.00578-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Srivastava HC, Yadav RS, Joshi H, Valecha N, Mallick PK, Prajapati SK, et al. Therapeutic responses of Plasmodium vivax and P. falciparum to chloroquine, in an area of western India where P. vivax predominates. Annals of tropical medicine and parasitology. 2008 Sep;102(6):471–80. doi: 10.1179/136485908X311759. [DOI] [PubMed] [Google Scholar]
  • 30.Sutanto I, Suprijanto S, Nurhayati, Manoempil P, Baird JK. Resistance to chloroquine by Plasmodium vivax at Alor in the Lesser Sundas Archipelago in eastern Indonesia. Am J Trop Med Hyg. 2009 Aug;81(2):338–42. [PubMed] [Google Scholar]
  • 31.Sutanto I, Endawati D, Ling LH, Laihad F, Setiabudy R, Baird JK. Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia. Malar J. 2010;9:52. doi: 10.1186/1475-2875-9-52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Lee SW, Lee M, Lee DD, Kim C, Kim YJ, Kim JY, et al. Biological resistance of hydroxychloroquine for Plasmodium vivax malaria in the Republic of Korea. Am J Trop Med Hyg. 2009 Oct;81(4):600–4. doi: 10.4269/ajtmh.2009.09-0102. [DOI] [PubMed] [Google Scholar]
  • 33.Guthmann JP, Pittet A, Lesage A, Imwong M, Lindegardh N, Min Lwin M, et al. Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar. Trop Med Int Health. 2008 Jan;13(1):91–8. doi: 10.1111/j.1365-3156.2007.01978.x. [DOI] [PubMed] [Google Scholar]
  • 34.Phyo AP, Lwin KM, Price RN, Ashley EA, Russell B, Sriprawat K, et al. Dihydroartemisinin-piperaquine versus chloroquine in the treatment of P.vivax malaria in Thailand: a randomized controlled trial. Clin Infect Dis. 2011 doi: 10.1093/cid/cir631. In Press. [DOI] [PMC free article] [PubMed] [Google Scholar]; * One of the largest randomized controled trials of schizonticidal drugs for P. vivax, highlighting the presence of chloroquine resistance in Thailand and the role of parasite stage on clinical response.
  • 35.Rijken MJ, Boel ME, Russell B, Imwong M, Leimanis ML, Phyo AP, et al. Chloroquine resistant vivax malaria in a pregnant woman on the western border of Thailand. Malar J. 2011;10:113. doi: 10.1186/1475-2875-10-113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Darlow B, Vrbova H, Gibney S, Jolley D, Stace J, Alpers M. Sulfadoxine-pyrimethamine for the treatment of acute malaria in children of Papua New Guinea. II. Plasmodium vivax. Am J Trop Med Hyg. 1982 Jan;31(1):10–3. doi: 10.4269/ajtmh.1982.31.10. [DOI] [PubMed] [Google Scholar]
  • 37.Pukrittayakamee S, Chantra A, Simpson JA, Vanijanonta S, Clemens R, Looareesuwan S, et al. Therapeutic responses to different antimalarial drugs in vivax malaria. Antimicrob Agents Chemother. 2000 Jun;44(6):1680–5. doi: 10.1128/aac.44.6.1680-1685.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Tjitra E, Baker J, Suprianto S, Cheng Q, Anstey NM. Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations. Antimicrob Agents Chemother. 2002 Dec;46(12):3947–53. doi: 10.1128/AAC.46.12.3947-3953.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Maguire JD, Krisin, Marwoto H, Richie TL, Fryauff DJ, Baird JK. Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia. Clin Infect Dis. 2006 Apr 15;42(8):1067–72. doi: 10.1086/501357. [DOI] [PubMed] [Google Scholar]
  • 40.Lacy MD, Maguire JD, Barcus MJ, Ling J, Bangs MJ, Gramzinski R, et al. Atovaquone/proguanil therapy for Plasmodium falciparum and Plasmodium vivax malaria in Indonesians who lack clinical immunity. Clin Infect Dis. 2002;35(9):e92–5. doi: 10.1086/343750. [DOI] [PubMed] [Google Scholar]
  • 41.Baird JK, Basri H, Subianto B, Fryauff DJ, McElroy PD, Leksana B, et al. Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine. The Journal of infectious diseases. 1995 Jun;171(6):1678–82. doi: 10.1093/infdis/171.6.1678. [DOI] [PubMed] [Google Scholar]
  • 42.Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung RM, Laihad F, et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007 Mar 3;369(9563):757–65. doi: 10.1016/S0140-6736(07)60160-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Karunajeewa HA, Mueller I, Senn M, Lin E, Law I, Gomorrai PS, et al. A trial of combination antimalarial therapies in children from Papua New Guinea. The New England journal of medicine. 2008 Dec 11;359(24):2545–57. doi: 10.1056/NEJMoa0804915. [DOI] [PubMed] [Google Scholar]
  • 44.Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, et al. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One. 2011;6(1):e14501. doi: 10.1371/journal.pone.0014501. [DOI] [PMC free article] [PubMed] [Google Scholar]; * A prospective multicenter clinical study of a novel fixed dose artemisinin combination for the treatment of P. vivax.
  • 45.Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, et al. In vitro activity of pyronaridine against multidrug resistant Plasmodium falciparum and P. vivax. Antimicrob Agents Chemother. 2010 Sep 27; doi: 10.1128/AAC.00801-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Russell B, Chalfein F, Prasetyorini B, Kenangalem E, Piera K, Suwanarusk R, et al. Determinants of in vitro drug susceptibility testing of Plasmodium vivax. Antimicrob Agents Chemother. 2008 Mar;52(3):1040–5. doi: 10.1128/AAC.01334-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Hasugian AR, Tjitra E, Ratcliff A, Siswantoro H, Kenangalem E, Wuwung RM, et al. In vivo and in vitro efficacy of amodiaquine monotherapy for treatment of infection by chloroquine-resistant Plasmodium vivax. Antimicrob Agents Chemother. 2009 Mar;53(3):1094–9. doi: 10.1128/AAC.01511-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Hasugian AR, Purba HL, Kenangalem E, Wuwung RM, Ebsworth EP, Maristela R, et al. Dihydroartemisinin-Piperaquine versus Artesunate-Amodiaquine: Superior Efficacy and Posttreatment Prophylaxis against Multidrug-Resistant Plasmodium falciparum and Plasmodium vivax Malaria. Clin Infect Dis. 2007 Apr 15;44(8):1067–74. doi: 10.1086/512677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.World Health Organisation World Malaria Report. 2009 [Google Scholar]
  • 50.Whitty CJM, Chandler C, Ansah E, Leslie T, Staedke SG. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities. Mal J. 2008;7:S7. doi: 10.1186/1475-2875-7-S1-S7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Baird JK. Resistance to chloroquine unhinges vivax malaria therapeutics. Antimicrob Agents Chemother. 2011 May;55(5):1827–30. doi: 10.1128/AAC.01296-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Hung TY, Davis TM, Ilett KF, Karunajeewa H, Hewitt S, Denis MB, et al. Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol. 2004 Mar;57(3):253–62. doi: 10.1046/j.1365-2125.2003.02004.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Karunajeewa H, Lim C, Hung TY, Ilett KF, Denis MB, Socheat D, et al. Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin) in Cambodian children and adults with malaria. Br J Clin Pharmacol. 2004 Jan;57(1):93–9. doi: 10.1046/j.1365-2125.2003.01962.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Awab GR, Pukrittayakamee S, Imwong M, Dondorp AM, Woodrow CJ, Lee SJ, et al. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial. Malar J. 2010;9:105. doi: 10.1186/1475-2875-9-105. [DOI] [PMC free article] [PubMed] [Google Scholar]; * A large randomised control trial which, although highlighting chloroquine sensitivity, demonstrated reduced incidence of malaria in patients receiving treatment with a long acting ACT (dihydroartemisinin-piperaquine).
  • 55.Karunajeewa HA, Ilett KF, Mueller I, Siba P, Law I, Page-Sharp M, et al. Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob Agents Chemother. 2008 Jan;52(1):237–43. doi: 10.1128/AAC.00555-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Li X, Li C, Che L, Liu X, Li Z, Huang D, et al. [Observation on efficacy of artemether compound against vivax malaria] Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 1999;17(3):175–7. [PubMed] [Google Scholar]
  • 57.Krudsood S, Tangpukdee N, Muangnoicharoen S, Thanachartwet V, Luplertlop N, Srivilairit S, et al. Clinical efficacy of chloroquine versus artemether-lumefantrine for Plasmodium vivax treatment in Thailand. Korean J Parasitol. 2007 Jun;45(2):111–4. doi: 10.3347/kjp.2007.45.2.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Kolaczinski K, Durrani N, Rahim S, Rowland M. Sulfadoxine-pyrimethamine plus artesunate compared with chloroquine for the treatment of vivax malaria in areas co-endemic for Plasmodium falciparum and P. vivax: a randomised non-inferiority trial in eastern Afghanistan. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2007 Nov;101(11):1081–7. doi: 10.1016/j.trstmh.2007.06.015. [DOI] [PubMed] [Google Scholar]
  • 59.LeYuan S, QingXia H. Observation on effi cacy of pyronaridine phosphate and combined with dihydroartemisinin for treatment of malaria in Eritrea, Africa. Chin J Parasitic Dis Control. 2001;14(R382.31) [Google Scholar]
  • 60.Sinclair D, Gogtay N, Brand F, Olliaro P. Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. Cochrane Database Syst Rev. 2011;7:CD008492. doi: 10.1002/14651858.CD008492.pub2. [DOI] [PubMed] [Google Scholar]
  • 61.White NJ. How antimalarial drug resistance affects post-treatment prophylaxis. Malar J. 2008;7:9. doi: 10.1186/1475-2875-7-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Douglas NM, Nosten F, Ashley EA, Phaiphun L, van Vugt M, Singhasivanon P, et al. Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics. Clin Infect Dis. 2011 Mar;52(5):612–20. doi: 10.1093/cid/ciq249. [DOI] [PMC free article] [PubMed] [Google Scholar]; ** A retrospective analysis of a series of clinical trials of falciparum malaria, highlighting that the greatest risk of parasitaemia within 63 days is actually recurrence of P. vivax rather than P. falciparum.
  • 63.Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. Clin Infect Dis. 2009 Dec 1;49(11):1629–37. doi: 10.1086/647946. [DOI] [PubMed] [Google Scholar]
  • 64.Mayxay M, Thongpraseuth V, Khanthavong M, Lindegardh N, Barends M, Keola S, et al. An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People’s Democratic Republic (Laos) Trop Med Int Health. 2006 Aug;11(8):1157–65. doi: 10.1111/j.1365-3156.2006.01671.x. [DOI] [PubMed] [Google Scholar]
  • 65.Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet. 2006 Jun 24;367(9528):2075–85. doi: 10.1016/S0140-6736(06)68931-9. [DOI] [PubMed] [Google Scholar]
  • 66.Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010 Oct;10(10):673–81. doi: 10.1016/S1473-3099(10)70187-0. [DOI] [PMC free article] [PubMed] [Google Scholar]; * A large clinical trial confirming that recurrence rates of P. vivax after P. falciparum vary according to the half life of the initial antimalarial treatment.
  • 67.Genton B, D’Acremont V, Rare L, Baea K, Reeder JC, Alpers MP, et al. Plasmodium vivax and mixed infections are associated with severe malaria in children: a prospective cohort study from Papua New Guinea. PLoS medicine. 2008 Jun 17;5(6):e127. doi: 10.1371/journal.pmed.0050127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009 Feb;80(2):194–8. [PubMed] [Google Scholar]
  • 69.Alexandre MA, Ferreira CO, Siqueira AM, Magalhaes BL, Mourao MP, Lacerda MV, et al. Severe Plasmodium vivax malaria, Brazilian Amazon. Emerging infectious diseases. 2010 Oct;16(10):1611–4. doi: 10.3201/eid1610.100685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Andrade BB, Reis-Filho A, Souza-Neto SM, Clarencio J, Camargo LM, Barral A, et al. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar J. 2010;9:13. doi: 10.1186/1475-2875-9-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Price L, Planche T, Rayner C, Krishna S. Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2007 Jul;101(7):655–9. doi: 10.1016/j.trstmh.2007.02.014. [DOI] [PubMed] [Google Scholar]
  • 72.Anstey NM, Russell B, Yeo TW, Price RN. The pathophysiology of vivax malaria. Trends in parasitology. 2009 May;25(5):220–7. doi: 10.1016/j.pt.2009.02.003. [DOI] [PubMed] [Google Scholar]
  • 73.Tan LK, Yacoub S, Scott S, Bhagani S, Jacobs M. Acute lung injury and other serious complications of Plasmodium vivax malaria. Lancet Infect Dis. 2008 Jul;8(7):449–54. doi: 10.1016/S1473-3099(08)70153-1. [DOI] [PubMed] [Google Scholar]
  • 74.Lampah DA, Yeo TW, Hardianto SO, Tjitra E, Kenangalem E, Sugiarto P, et al. Coma Associated with Microscopy-Diagnosed Plasmodium vivax: A Prospective Study in Papua, Indonesia. PLoS Negl Trop Dis. 2011 Jun;5(6):e1032. doi: 10.1371/journal.pntd.0001032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Dondorp A, Nosten F, Stepniewska K, Day N, White N, Group SS. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005 Aug 27 2;Sep 27 2;366(9487):717–25. doi: 10.1016/S0140-6736(05)67176-0. [DOI] [PubMed] [Google Scholar]
  • 76.Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 13;376(9753):1647–57. doi: 10.1016/S0140-6736(10)61924-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Kongpatanakul S, Chatsiricharoenkul S, Khuhapinant A, Atipas S, Kaewkungwal J. Comparative study of dihydroartemisinin and artesunate safety in healthy Thai volunteers. Int J Clin Pharmacol Ther. 2009 Sep;47(9):579–86. doi: 10.5414/cpp47579. [DOI] [PubMed] [Google Scholar]
  • 78.Finaurini S, Ronzoni L, Colancecco A, Cattaneo A, Cappellini MD, Ward SA, et al. Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation. Toxicology. 2010 Oct 9;276(2):128–34. doi: 10.1016/j.tox.2010.07.016. [DOI] [PubMed] [Google Scholar]
  • 79.Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis. 2004 Nov 1;39(9):1336–45. doi: 10.1086/424663. [DOI] [PubMed] [Google Scholar]
  • 80.Galappaththy GN, Omari AA, Tharyan P. Primaquine for preventing relapses in people with Plasmodium vivax malaria. Cochrane Database Syst Rev. 2007;(1):CD004389. doi: 10.1002/14651858.CD004389.pub2. [DOI] [PubMed] [Google Scholar]
  • 81.Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2008 Nov;102(11):1095–101. doi: 10.1016/j.trstmh.2008.04.024. [DOI] [PubMed] [Google Scholar]
  • 82.Krudsood S, Wilairatana P, Tangpukdee N, Chalermrut K, Srivilairit S, Thanachartwet V, et al. Safety and tolerability of elubaquine (bulaquine, CDRI 80/53) for treatment of Plasmidium vivax malaria in Thailand. Korean J Parasitol. 2006 Sep;44(3):221–8. doi: 10.3347/kjp.2006.44.3.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Wells TN, Burrows JN, Baird JK. Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trends in parasitology. 2010 Mar;26(3):145–51. doi: 10.1016/j.pt.2009.12.005. [DOI] [PubMed] [Google Scholar]
  • 84.Leslie T, Rab MA, Ahmadzai H, Durrani N, Fayaz M, Kolaczinski J, et al. Compliance with 14-day primaquine therapy for radical cure of vivax malaria--a randomized placebo-controlled trial comparing unsupervised with supervised treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2004 Mar;98(3):168–73. doi: 10.1016/s0035-9203(03)00041-5. [DOI] [PubMed] [Google Scholar]
  • 85.Khantikul N, Butraporn P, Kim HS, Leemingsawat S, Tempongko MA, Suwonkerd W. Adherence to antimalarial drug therapy among vivax malaria patients in northern Thailand. Journal of health, population, and nutrition. 2009 Feb;27(1):4–13. doi: 10.3329/jhpn.v27i1.3313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Silachamroon U, Krudsood S, Treeprasertsuk S, Wilairatana P, Chalearmrult K, Mint HY, et al. Clinical trial of oral artesunate with or without high-dose primaquine for the treatment of vivax malaria in Thailand. Am J Trop Med Hyg. 2003 Jul;69(1):14–8. [PMC free article] [PubMed] [Google Scholar]
  • 87.Krudsood S, Tangpukdee N, Wilairatana P, Phophak N, Baird JK, Brittenham GM, et al. High-dose primaquine regimens against relapse of Plasmodium vivax malaria. Am J Trop Med Hyg. 2008 May;78(5):736–40. [PMC free article] [PubMed] [Google Scholar]
  • 88.Alving AS, Arnold J, Hockwald RS, Clayman CB, Dern RJ, Beutler E, et al. Potentiation of the curative action of primaquine in vivax malaria by quinine and chloroquine. J Lab Clin Med. 1955 Aug;46(2):301–6. [PubMed] [Google Scholar]

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