Radical Cure for Plasmodium Vivax Malaria

By Soy Ty Kheang, URC Cambodia

1. Introduction

Malaria is a major global health problem with over 40% of the world’s population (over 2.4 billion people), exposed to malaria risk in some 100 countries worldwide. Malaria is an important cause of morbidity and mortality in adults and children in tropical countries. Outside of Africa, Plasmodium falciparum almost invariably coexists with P. vivax. The biology of these two parasites is notably different, rendering P. vivax more resilient to conventional malaria control measures. In co-endemic areas, the successful reduction in the burden of P. falciparum often leaves P. vivax as the leading cause of malaria, significantly undermining our aspirations for the elimination of malaria. Unlike P. falciparum, P. vivax infections form dormant liver stages (hypnozoites), which can cause relapses of infection weeks to months after the initial attack.1 Repeated relapses damage the health and development of patients, particularly in children, resulting in chronic and severe anemia, malnutrition, growth retardation and poor school attendance. Regarded at one time as a benign infection, vivax malaria is now recognized as a major cause of morbidity and an important contributor to mortality.2

One of the greatest challenges in the treatment of P. vivax is to achieve radical cure safely and reliably. A radical cure requires the delivery of antimalarial agents targeting both blood stages of infection as well as liver stages preventing both relapse and recrudescence. The only licensed antimalarial with hypnozoitocidal activity is primaquine (PQ), an 8-aminoquinoline drug that can also cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an enzyme deficiency present in 1–40% of the population.3 Current World Health Organization (WHO) guidelines recommend a 14-day PQ regimen primarily for safety concerns, and therefore, the drug can be stopped if significant hemolysis occurs. However, because PQ treatment is usually unsupervised, compliance with such a prolonged course of antimalarials is generally poor, limiting its effectiveness and public health benefit. The main determinant of PQ efficacy is the total dose of PQ administered rather than the duration over which it is delivered.4

Shorter courses with a higher daily dose of PQ have the potential to improve adherence and thus, effectiveness without compromising efficacy although it needs close monitoring of side effect and toxicity.

In most areas where P. vivax is prevalent, malaria transmission rates are low, and the affected populations, therefore, achieve little immunity to this parasite. Consequently, people of all ages are at risk. Among the four species of Plasmodium that affect humans, only P. vivax and P. ovale form hypnozoites, parasite stages in the liver that can result in multiple relapses of infection, weeks to months after the primary infection. Thus, a single infection causes repeated bouts of illness.

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2. The situation of P. vivax relapses (burden of relapses due to P. vivax and health risks)

The individual and public health threats posed by relapses due to untreated P. vivax liver stage infection need to be taken into account when discussing the risks and benefits of PQ therapy. The timing and risk of relapse varies widely across geographic regions as figure 1 showing that the pattern of rapidly relapsing strains in tropical areas of Latin America and Africa is similar to the relapse behavior represented by Chesson-like strains of P. vivax of tropical Southeast Asia and Oceania.

Figure 1: Zones of malaria, surveys used and time to relapse

3. Diagnosis of P. vivax

Diagnosis of P. vivax malaria is based on a rapid diagnostic test (RDT) and microscopy, which is performed by health facility personnel including microscopists. RDTs can be deployed at hotspot zones and village levels by volunteers in their community.

4. Determinant G6PD Status

The WHO therapeutic guidelines recommend that patients should be tested for G6PD deficiency before prescribing PQ. CareStart G6PD rapid diagnostic test (the 3 rd generation) has been manufactured by Access Bio and is being recommended by the WHO during the Malaria Policy Advisory Committee meeting to use for screening in identifying the G6PD status. In addition, Access Bio produces CareStart G6PD Biosensor, which is capable of quantifying total G6PD levels. The Biosensor is quite promising to identify G6PD deficiency in women (figure 2).

Figure 2: G6PD algorithm and treatment decision tree2

4. Recommendations on therapy of uncomplicated vivax Malaria

Chloroquine 25 mg base/kg body weight divided over 3 days, combined with PQ 0.25 mg base/kg body weight, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with PQ for radical cure. In Oceania and South-East Asia, the dose of PQ should be 0.5 mg/kg body weight. The G6PD test should be performed: (a) in moderate G6PD deficiency, PQ 0.75 mg base/kg body weight should be given once a week for 8 weeks, (b) in severe G6PD deficiency, PQ should not be given.

Drugs in the development pipeline, including Tafenoquine (TQ), may provide shorter duration or single-dose treatment for radical cure. However, TQ, as with all 8-aminoquinolines, has similar G6PD safety issues to those seen with PQ.

Remarks on PQ dosing regimens: 14 days versus 8 weeks

Distinction in haemolytic response between daily versus weekly dosing with PQ in the same human subject represented by each of the four panels (figure 3).

Figure 3: Haemolytic response after PQ daily and weekly administration

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Remarks: Some heterozygous females who test as normal or not deficient in qualitative G6PD screening tests have intermediate G6PD activity and can still hemolysis substantially. Intermediate deficiency (30–80% of normal) and normal enzyme activity (>80% of normal) can only be differentiated with a quantitative test. In the absence of quantitative testing, all females should be considered as potentially having intermediate G6PD activity and be given the 14-day regimen of PQ; they should be counselled on how to recognize signs of hemolytic anemia. They should be advised to stop PQ and be told where to seek care should these signs develop.

‣ Non-G6PD-deficiency individuals: 14-day PQ dose of 0.25-0.50mg/kg body weight daily safe and effective.

‣ In people with G6PD deficiency, consider preventing relapse by giving PQ at 0.75 mg/kg once a week for 8 weeks with close medical supervision.

‣ Hemolytic response of the same person after daily and weekly administration of PQ occurs more frequently in daily dosing than in weekly dosing.

5. ContraindicationsThe current guidelines recommend that PQ should not be given to pregnant or lactating women with children aged <6 months, or to children aged <6 months because of safety concerns. These groups are vulnerable to morbidity and mortality caused by P vivax malaria, such as chronic and severe anemia, severe malaria, miscarriage and impaired cognitive development.

6. Monitoring and follow upThere is a minimum of six months to a year follow up needed to determine a cure in vivax malaria and to catch the later relapses. For Cambodia, where you have the more aggressive form of vivax (and ones that are generally less sensitive to PQ, hence the need for 30 mg of PQ) 6 months should be enough (figure 4).

Figure 4: Follow up Pv malaria on PQ radical cureDAY Rec0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 17 3 4 5 6 7 8 3 4 5 6 7 8 9 10 11 12

History of fever, current axillary temperature X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X XFull medical history, vital signs, physical examination

X

Ask about any concomitant medication X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X XSymptom checklist X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X XAssess for any indication for study withdrawal X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

Urine pregnancy test X XMasimo pulse-oximeter - main study X X X X X XMasimo pulse-oximeter - G6PD arm X X X X X X

Drug treatmentCQ or ACT X X X XPQ - main study X X X X X X X X X X X X X X XPQ - G6PDd arm X X X X X X X X X

FBC, G6PD activitiy, genotypeG6PD flourescent spot test XG6PD rapid test XParasite microscopy X X X (X) (X) (X) (X) (X) X X X X X X X X X X X X X X X X XRapid diagnostic test for malaria XHaemoglobin HemoCue* - main study X X X X X X X X X X X X X X X X X X X X XHaemoglobin HemoCue* - G6PDd arm X X X X X X X X X X X X X X X X X X X X X X XDBS for malaria PCR X X X X X X X X X X X X X XParasite genotype X X

WEEK MONTH

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Indeed, diagnostic tests will never be 100% reliable and in practice, are usually unavailable in resource-poor settings. The risk of primaquine-induced hemolysis is dose-dependent; thus, the consequences of unintentionally administering a high-dose primaquine regimen to a G6PD-deficient individual incorrectly diagnosed as G6PD normal will need to be gauged before wider recommendations can be made.

7. Countries policies on PQ anti-relapse therapy and G6PD testing (how are radial cure being introduced in the Mekong region or other countries in Africa)

Most of countries with endemic Pv recommend anti-relapse therapy with PQ in line with WHO recommendations although four countries Algeria, Cambodia, Ethiopia and Somalia do not recommend its use as figure 1. Although mentioned in the National Treatment Guideline, Cambodia has not been used PQ radical cure yet but plans for piloting this anti-relapse therapy. In South-East Asia and Western Pacific regions provide PQ radical cure for Pv malaria except Cambodia and Lao PDR until 2018. In the South-East Asian countries, PQ radical treatment of Pv is recommended with G6PD test before treatment in four countries (Cambodia, Lao PDR, Philippine and Thailand).

Based on the 2017 World Malaria Report, among 31 countries in Africa, PQ is used for radical cure of Pv cases in 8 countries. Of them, only 3 countries are recommended G6PD test before treatment (figure 5).

Figure 5: Policies for Pv radical cure and G6PD testing

The application of these recommendations in patients, most with unknown G6PD status, varies among nations and even within nations among health-care providers. Data on antimalarial tablets suggests that, in some countries where primaquine is recommended without G6PD testing, prescription rates are as low as 10% of vivax cases treated with an antimalarial drug.

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8. Results of the radical cure programs to date about scale up and other aspectsThe governments of the Asia–Pacific nations reconfirmed their commitment to the regional elimination of malaria by 2030. Although major gains in malaria control have been made over the last two decades, these successes have been far less apparent for Plasmodium vivax than for Plasmodium falciparum. Indeed, P vivax malaria is more difficult to eradicate than Plasmodium falciparum because it can form dormant liver stages (hypnozoites) that reactivate periodically, causing recurrent infections (relapses) and further transmission.

Before a large scale implementation, NMCP needs to get information on the following: (1) a clear risk–benefit and cost-effectiveness assessment of G6PD testing, (2) the availability of a robust tests that is reliable in field settings with limited infrastructure, (3) a competitive and affordable price and it friendly use for the test and (4) secured and sustainable the test particularly for training of health care staff and associated quality control processes. In addition, impediments to PQ adherence at the level of the patient and health system and suitable strategies to overcome for Pv radical cure either 14-day or 8-week of PQ treatment.

1. White NJ. Determinants of relapse periodicity in Plasmodium vivax malaria. Malar J. 2011;10:297.[PMC free article] [PubMed]

2. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg. 2007; 77:79–87. [PMC free article] [PubMed]

3. Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis. 2004; 39:1336–1345. [PubMed]

4. John GK, Douglas NM, von Seidlein L, Nosten F, Baird JK, White NJ, Price RN. Primaquine radical cure of Plasmodium vivax: a critical review of the literature. Malar J. 2012; 11:280. [PMC free article][PubMed]

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