Journal of Marine Medical Society

REVIEW ARTICLE
Year
: 2019  |  Volume : 21  |  Issue : 1  |  Page : 4--8

Artemisinin resistance: Cause for worry?


Anurag Khera1, Reema Mukherjee2,  
1 Commanding Officer, 421 Field Hospital, C/O 99 APO, Pune, Maharashtra, India
2 Department of Community Medicine, Armed Forces Medical College, Pune, Maharashtra, India

Correspondence Address:
Lt Col Reema Mukherjee
Armed Forces Medical College, Pune - 411 040, Maharashtra
India

Abstract

Background: Artemisinin resistance is being reported from certain regions of the world. Globally, the scientific community is engaged in tracing the epidemiology of this resistance while also working on possible interventions to curb the spread. Aim: We reviewed the epidemiology of antimalarial drug resistance, especially artemisinin resistance both globally and in India, and report the possible ways forward. Literature Search: Resistance to all antimalarial drugs developed initially in South East Asia and thereafter spread globally. Artemisinin-based combination treatment (ACT) was formally recommended by the World Health Organisation (WHO) in 2005 to achieve an enhanced barrier to drug resistance. However in 2008, resistance to artemisinin was first reported from Western Cambodia/Thailand. Subsequently, P falciparum chromosome 13 ('kelch' motif or K13) (Pfk 13) was implicated with slow in vivo parasite clearance. As of 2019, artemisinin resistance has been confirmed in six countries of the Greater Mekong Sub-region. The North east states of India have been the portal for entry of anti-malarial drug resistance over the past decades. Though in vitro testing have not shown evidence of decreased artemisinin sensitivity, however, Pfk13 mutations have been reported from India, thus sounding a note of caution and indicating the need for continued genetic, clinical and public health surveillance. Conclusion: Though clinical cure in falciparum malaria infection continues to be elicited through use of ACT even in the countries reporting artemisinin resistance, however a comprehensive framework for combating the resistance has already been put into action by the WHO.



How to cite this article:
Khera A, Mukherjee R. Artemisinin resistance: Cause for worry?.J Mar Med Soc 2019;21:4-8


How to cite this URL:
Khera A, Mukherjee R. Artemisinin resistance: Cause for worry?. J Mar Med Soc [serial online] 2019 [cited 2019 Sep 19 ];21:4-8
Available from: http://www.marinemedicalsociety.in/text.asp?2019/21/1/4/260665


Full Text



 Introduction



Malaria has killed more humans in history than any other disease or war.[1],[2] The genetic changes in the parasite and the vector have outpaced human endeavors to contain them. Southeast Asia (SEA) has been the harbinger of drug-resistant Plasmodium falciparum malaria. Starting with resistance to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now produced parasites resistant to artemisinin.[3],[4] This article reviews the epidemiology of the development of antimalarial drug resistance, especially artemisinin resistance, across the globe and in our country and outlines the global efforts toward containment of its spread.

Antimalarial drug resistance over the decades

Powdered bark from the cinchona tree containing quinine and quinidine were the first antimalarials.[5] Chloroquine fuelled the WHO Global Malaria Eradication Programme in the 1950s and 60s. However, resistance to chloroquine reared its head in SEA in the 1970s. The story unfolded in the small gem mining town of Pailin in Cambodia.[3],[6],[7] The proliferating mining industry attracted thousands of workers from neighboring countries like Thailand, Vietnam, Myanmar, and even Bangladesh. Most of these migrant workers had no immunity to malaria, while Pailin and surrounding areas were hotbeds of malaria transmission.[3] As successive batches of incoming migrants came down with malaria, the health authorities in Pailin distributed chloroquine initially daily then weekly. Later, chloroquine-medicated salts were also used as a treatment/preventive measure.[8] This indiscriminate use of chloroquine in suboptimal treatment dosage in this region, resulted in the emergence of resistance to chloroquine, which then spread through SEA to India and subsequently into Africa, thus severely hampering the malaria control efforts globally.[9] At present, chloroquine resistance occurs almost everywhere that falciparum malaria occurs. Interestingly though, chloroquine efficacy against falciparum was restored to almost 99% within a period of 10–15 years after a switchover from chloroquine to sulfadoxine-pyrimethamine (SP) in the African country of Malawi.[10],[11],[12] This highlights an important difference from the resistance pattern in SEA where despite easing the drug pressure, chloroquine resistance remains at almost 100% even in recently published studies.[13],[14]

Resistance to SP and then mefloquine was first established in Thailand/Cambodia and the 1980s, respectively, and it spread across to SEA, India, and finally Africa. The Thailand-Cambodia border, where most forms of antimalarial resistance emerged, was also the epicente centre of SP resistance in 1980s and mefloquine resistance a few years later. Some of the molecular markers of drug resistance include polymorphisms in Plasmodium falciparum chloroquine resistance transporter (PfCRT) which confer resistance to chloroquine while polymorphisms in pfmdr1 gene is associated with resistance to mefloquine, artesunate, lumefantrine and quinine Polymorphisms in P. falciparum dihydrofolate reductase (DHFR) cause resistance to the antifolate drugs including pyrimethamine.[15]

 Epidemiology of Drug Resistance in Malaria



Antimalarial drug resistance emerges due to a spontaneous genetic change (mutation or gene amplification) in the malaria parasite. This mutation interferes with the parasite's susceptibility to a drug. A single mutation may make the parasite completely resistant as in case of atovaquone, and sometimes, a series of mutations provide the parasite with increased tolerance to higher and higher drug concentrations as in the case of pyrimethamine and chloroquine.[16] However, for this drug resistance to spread, the mere occurrence of mutation is not sufficient. When the drug to which the strain is resistant is being used continuously, the sensitive strains are inhibited, and the drug-resistant strains survive, multiply, and get transmitted to the next host, thus spreading resistance.[16],[17] When exposed to the medicine in question (“drug pressure”), the mutant parasite strains that have a survival advantage are selected in favor of sensitive strains. Migrating populations contribute to the spread of resistance by introducing parasites with resistant mutations in new geographical areas.[18],[19],[20] In areas of high transmission, due to the interplay of factors of host immunity and multiple parasite genotypes in the same individual, the survival probability of individual malaria parasites is highly reduced.[21],[22] Even if the resistant mutant does survive the initial drug treatment and multiplies, the ability to produce sufficient gametocytes for transmission is reduced as a result of immunity. Thus, there is a low probability of de novo selection and transmission of a resistant parasite mutant in a high-transmission area as compared with low-transmission areas.[23],[24]

 Artemisinin Resistance: Global Scenario



ACTs were first used around the 1990s when Thailand and surrounding regions reported resistance to all available antimalarials. Artesunate was then combined with mefloquine for P falciparum malaria in these areas, and this combination reported high cure rates.[25],[26] Artemisinin-based combination treatments (ACT) became the mainstay of treatment for P. falciparum malaria since 2005 when the WHO advocated its use in National Malaria Programmes.[27] The rationale behind ACT is to achieve an improved barrier to drug resistance as multiple simultaneous mutations will be required for the parasite to become resistant. Artemisinins are short-acting and are eliminated from the blood within 1–3 h. They act against the young ring and more mature trophozoites rapidly reducing the parasite biomass, thus bringing prompt symptomatic relief. They are generally paired with a partner drug that has a longer half-life and can “mop-up” any remaining parasites.[28] In 2008, resistance to artemisinin was described in Western Cambodia, however, it did not immediately cause concern as clinical cure continued to occur through at a slower rate. Subsequently, over the next few years, the resistance spread to Thailand, Vietnam, Myanmar, and Laos. In 2013, ACT failed to clear parasites in many parts of Cambodia when dihydropiperaquine was the partner drug being used.[29] Research has revealed that the malarial parasite acquired resistance to both artemisinin and piperaquine around 2008, however, due to lack of drug sensitivity surveillance at that time, this could not be detected then, and the failing piperaquine was introduced as the partner drug in ACT for malaria in Cambodia. Retrospectively, malariologists now propose that this led to a multidrug-resistant parasite lineage rapidly increasing in Cambodia, Thailand, and Vietnam but it was first clinically reported only around 2013. Subsequently, in 2014, genome studies identified a region on P falciparum chromosome 13 that was associated with slow in vivo parasite clearance. The mutated gene encodes a protein containing a “kelch” motif (K13).[30],[31],[32] It is proposed that the artemisinin-resistant parasites acquire the ability to quickly repair the damage caused by the drug. “K13” mutations thus became markers for artemisinin resistance. At present, there are five accepted markers of artemisinin resistance, the therapeutic efficacy of ACT, the proportion of cases which are microscopy positive at day 3, parasite clearance half-life, Ring stage survival assay, and K13 sequencing. The WHO has defined partial resistance as delayed parasite clearance following treatment with an artesunate monotherapy or with ACT. Confirmed endemic artemisinin resistance was defined as >5% of patients carrying K13 resistance confirmed mutation, all of whom have been found to have either persistent parasitemia by microscopy on day 3 or half-life of parasite clearance slope >5 h after treatment. The WHO regularly updates the list of candidate and validated K13 propeller mutations thought to be associated with drug resistance. Till date, around 200 nonsynonymous mutations in K13 gene have been reported. Not all of these indicate the emergence of artemisinin resistance. For a K13 mutation to be validated as a marker for artemisinin resistance, the mutation has to be correlated with slow clearance in clinical studies and reduced in vitro drug sensitivity. And as of 2018, artemisinin resistance has been confirmed in six countries of the Greater Mekong Subregion (GMS): Cambodia, the Lao People's Democratic Republic, Myanmar, Thailand, Vietnam, and People's Republic of China (specifically Yunnan Province and Guangxi Zhuang Autonomous Region). Besides, these six regions, parasites with the incriminated K13 mutations have also been reported from Guyana in South America. Genetic and molecular epidemiology studies have revealed that these mutations arose independently in several of these countries and then spread within the regions. The resistance of the parasite against artemisinin is restricted to the ring stage in humans. Hence, despite the patient being infected with artemisinin resistance strain, if the parasite continues to be sensitive to the partner drug, clinical cure occurs.[33] Treatment failure occurs in the event of the parasite being resistant to both artemisinin and the companion drug. However, the consequences of this “slow clearance” or “partial resistance” to artemisinin are cause for worry; first, it may lead to the development of total artemisinin resistance and therefore loss of artemisinin as a treatment option for falciparum malaria. In addition, the slow parasite clearance may also lead to resistance to the partner drug, especially among patients who have high parasitemia at the time of admission, and this partner drug resistance will, in turn, lead to higher clinical failure with ACT treatment. Researchers have attributed occurrence and spread of this artemisinin resistance to a complex interplay of various factors including improper drug dosing (monotherapy or fake/substandard drugs, incomplete course, and dosing regimen), parasite factors (resistance to the partner drug, hyperparasitemia, and the parasite genetic background), and host factors (poor immunity, nutritional state, infection in children).[33],[34]

 Antimalarial Drug Resistance in India: Past and Present



Chloroquine-resistant P. Falciparum malaria was first reported in India in 1973 from Diphu in the Karbi Anglong district of Assam.[35],[36] It spread to the neighboring Nowgaon district and thereafter toward the West and South, covering almost the entire country within a span of few years.[37] Initial reports of sulfapyrimethamine resistance emerged in 1979, again in Karbi Anglong, Assam. Resistance to mefloquine and quinine have been rarely reported in India.[14] Similarly, only sporadic cases of Plasmodium vivax resistance to chloroquine have been documented.[38],[39] The National Institute of Malaria Research (NIMR) and the National Vector Borne Disease Control Programme in 2008 selected 25 sentinel sites for monitoring of antimalarial resistance. These sites were selected to provide a representative “cross-section of transmission intensities, malaria ecotypes, and geographical regions.”

In vitro testing of antimalarial drugs has not shown decreased sensitivity to artemisinin derivatives in India till date.[27] However, Pfk13 mutations have been reported from India. In a study by NIMR to ascertain artemisinin resistance in India, 384 samples were sequenced and nonsynonymous mutations in the propeller region were found in four patients from the Northeast states. Although their presence did not correlate with ACT treatment failures, this mutation in the parasite sounds a warning bell in India indicating the need for continued genetic, clinical, and public health surveillance.[13] A recent news article reported the detection of partial artemisinin resistance in West Bengal where 20 out of the 365 patients of falciparum malaria who were studied, showed delayed parasite clearance and had to be exhibited with six doses of ACT (ACT AL) for complete clinical cure.[40] Resistance to artemisinin has thus reached the Indian borders. Will history be repeated with artemisinin resistance following the well-defined resistance path to India and further to Africa? Researchers feel that this could well happen, hence there is a reason to be cautious and a pressing need to monitor the situation closely as the occurrence of artemisinin resistance in India, and its further spread would seriously affect global malaria elimination efforts.[41]

India banned Artemisinin monotherapy in 2009. At present, the National Drug Policy recommends that patient is exhibited antimalarial therapy only after parasitological confirmation of the diagnosis. In 2013, ACT SP was the first line of treatment for falciparum malaria in all Indian states except the Northeast, where due to resistance to sulfadoxine-pyrimethamine, ACT AL was recommended for use. However, the recently launched National Strategic Plan for Malaria Elimination (2017–2022) has recommended ACT AL as the first-line drug for the treatment of uncomplicated falciparum malaria in the entire country.[27]

 Global Action for Containing Artemisinin Resistance: the Way Forward



Global plan for artemisinin resistance containment (GPARC) was formulated by the WHO with the goal of eliminating and containing artemisinin resistance in areas where it has already occurred and preventing it from occurring in all other areas. The main tools for global containment can be briefly summarized as:

Monitoring and surveillance

Countries need to monitor the presence and spread of artemisinin and partner drug resistance. As per the WHO recommendations, therapeutic efficacy studies for monitoring the efficacy of the nationally recommended first-line antimalarial chemotherapy need to be carried out every 2 years for both vivax and falciparum malaria. High-resolution genetic surveillance of all malaria cases in vulnerable areas should be established.

Elimination of malaria

The WHO has formulated a strategic plan for the elimination of all species of malaria from the six Greater Mekong subregion countries reporting artemisinin resistance by 2030.[40],[41] In regions where artemisinin resistance has not yet been reported, governments need to escalate malaria control activities to reduce transmission and subsequent risk of emergence and spread of artemisinin or partner drug resistance. It is proposed to combine various strategies to accelerate this elimination drive: targeted mass drug administration to eliminate the parasite reservoir and interrupt transmission, mass screening, and treatment using newer diagnostics such as the new Histidine-rich Protein-2 Plasmodium falciparum Rapid Diagnostic Tests. Role of ivermectin in aiding malaria elimination requires further studies. Preliminary research points to reduced lifespan of mosquitoes which ingest blood meals from persons treated with ivermectin. Other strategies such as vaccination and chemoprophylaxis of high risk groups need to be explored.[42]

Drugs and diagnostics

Universal access to good quality antimalarial as per the national policy, continuous monitoring of drug quality and rapid diagnosis through quality diagnostic services, continue to be the mainstay in preventing the spread of artemisinin resistance. At present, there are five ACTs recommended by the WHO: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine-pyrimethamine, and dihydroartemisinin-piperaquine. The WHO is also considering a sixth ACT, artesunate-pyronaridine.[43] Gametocidal dose of antimalarials has also been stressed upon by the WHO, as infections with artemisinin-resistant parasites show higher gametocyte densities, thus increasing the chances of transmission. Funding for antimalaria initiatives such as long-lasting insecticidal nets, rapid diagnostic tests, and quality assured drugs in the GMS region has increased in response to the emergence of artemisinin resistance.[44]

Newer interventions

Newer interventions are required not only in the development of newer drugs and vector control tools but also in use of the currently available ACTs so as to keep ahead of the rapidly spreading resistance. One of the proposed ways is drug rotation, like in Cambodia where ACT combinations with piperaquine were rotated with mefloquine which is currently effective. It was also observed that areas that reported resistance to mefloquine, subsequently regained mefloquine sensitivity due to the introduction of piperaquine as a partner drug. Some other suggestions proposed by researchers include increasing the treatment duration from the current three days to five 5 or seven 7 days or sequential treatment with two ACT combinations. However, adherence, drug toxicity, and acceptability studies need to be carried out for all such treatment regimens. The Tracking Resistance to Artemisinin Collaboration-II (TRAC-II) is examining the pharmacokinetic, drug interactions, safety, tolerability and efficacy of Triple Artemisinin-based Combination Therapies such as dihydroartemisinin-piperaquine with mefloquine and artemether-lumefantrine with amodiaquine.[45],[46],[47] Arterolane, the first fully synthetic non artemesinin derivate compound with rapid schizonticidal activity has been combined with piperaquine and found to be effective in quick relief of symptoms and also prevention of recrudesces. It has already been registered in India and its efficacy in artemisinin-resistant areas needs to be explored. Patient trials are currently underway on a compound KAF156 which belongs to a new class of antimalarial compounds called imidazolopiperazines. It has the potential to clear malaria infection, including resistant strains, as well as to block the transmission of the malaria parasite. It is presently being tested in combination with lumefantrine.[48]

 Conclusion



Emergence and spread of artemisinin resistance across countries are is alarming. It appears to be following the same path as the drug resistance to other antimalarials. With no new antimalarial in the offing at present, as many newer modalities of treatment and cure still under phase II/III trials, there is need to combine a high level of surveillance for early detection and control of drug resistance. There is a need to focus on integrated control strategies, community engagement and intersectoral coordination to be able to respond to this crisis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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