Limited Access to Drug in Malaria Control: Comparison
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Malaria burden has severe impact on the world. Several arsenals, including the use of antimalarials, are in place to curb the malaria burden. Limited access to drugs ensures that patients do not get the right doses of the antimalarials in order to have an effective plasma concentration to kill the malaria parasites, which leads to treatment failure and overall reduction in malaria control via increased transmission rate. 

  • malaria
  • drug-pressure
  • limited-access
  • antimalarials
  • treatment

1. Introduction

The control of malaria has stalled in the last five years [1,2][1][2]. There is need for a continuous review of the control strategies. Antimalarials remain one of the formidable tools in malaria control. Both reduced access to antimalarials by the populace and pressure from these drugs on malaria parasites are important factors that play different roles in the overall malaria control. Limited access to drug and drug pressure are two sides of a coin that can individually and/or collectively lead to treatment failure. While reduced access to drugs negatively impact malaria control via increased spread/transmission, drug pressure facilitates the generation of resistant Plasmodium which results in treatment failures, respectively. Some antimalarials such as chloroquine (CQ) have lost their place in malaria control due to resistance development, and this fate befalls several other antimalarials [3,4][3][4]. Treatment failure can result from drug resistance (often from drug pressure), high baseline parasite density, childhood (age less than five), incorrect dosing, non-compliance with duration of dosing regimen, poor drug quality and drug interactions leading to decreased drug exposure [5]. Other factors that can lead to reduced access may include: cost of the drug, reduced or poor access to health facilities, lack of free drug or functional health insurance scheme, and some socio-cultural as well as religious characteristics of a people (e.g., religious beliefs and traditions).

2. Overview of the Current Antimalarial Portfolio

Before the advent of refined antimalarials, the use of herbs had been the hallmark of treatment, as exemplified by the Cinchona bark from which quinine was extracted and identified in 1820 by the French chemists, J. Pelletier and J. Caventou [6]. Today, several drugs are currently used for the treatment of malaria. These drugs, for convenience, are classified into four major classes: antifolates, quinolines (aryl-amino alcohols, 4-aminoquinolines, bis-quinoline and naphthyridine), hydroxynaphtoquinone and endoperoxides (Table 1). The antifolates interfere with folic acid synthesis which is essential in nucleic acid metabolism [7]. The commonest antifolates in use are pyrimethamine and sulfadoxine. The main mode of action of quinolines and endoperoxides is targeting of the heme detoxification process put in place during the digestion of hemoglobin by the parasite [8,9][8][9]. The quinolines are mainly represented by chloroquine, mefloquine, amodiaquine, lumefantrine and quinine [10]. For the endoperoxides, artemisinin and its derivatives (artemether, artesunate, arteether) are the main examples.
Table 1. Antimalarial portfolio.

Antimalarials

Introduction Date

Resistance Date

Genetic Marker

Mechanism of Action

Mechanism of Resistance

References

Region Used

Region of Reported ACT Failure

Aryl-amino alcohol

  

Artemether-lumefantrine (AL)

Africa, Americas and Middle East

Burkina Faso, Cambodia, Lao People’s Democratic Republic, Thailand and Vietnam

Quinine

Dihydroartemisinin-piperaquine (DHA-PPQ)

1820

1910

Southeast Asia, China and Africa

Pfmdr1

Inhibition of heme detoxification

Gene amplification and mutation leading to drug efflux and/or non-binding to target site

Cambodia, Lao People’s Democratic Republic, Thailand and Vietnam

[16][11]

Mefloquine

1977

1982

Artesunate-amodiaquine (AS-AQ)

West Africa

Indonesia, Cambodia

Pfmdr1

[17][12]

Lumefantrine

Artesunate-mefloquine (AS-MQ)

1976

  

Southeast Asia and Americas

Cambodia, Lao People’s Democratic Republic, Thailand and Vietnam

Pfmdr1

[18][13]

4-aminoquinolines

  

Artesunate-sulfadoxine-pyrimethamine (AS-SP)

Southeast Asia, Middle-East and South America

Northeastern India, Somalia and Sudan

Chloroquine

1945

1957

Pfcrt, Pfmdr

Inhibition of heme detoxification and redox cycling of heme to and fro the cytosol

Artesunate—pyronaridine (AS-PY)

Southeast Asia

Cambodia, Vietnam

Gene mutation: efflux of molecules from food vacuole

[19,20][14][15]

Amodiaquine

1948

1990s

Pfcrt, Pfmdr

[18,21][13][16]

Bis-quinoline

  

Piperaquine

1960s

2010

Pfcrt, Pfplasmepsin 2-3 copy number

Inhibition of heme detoxifica-tion and redox cycling of heme to and fro the cytosol

Gene amplification

[22,23][17][18]

Naphthyridine

  

Pyronaridine

1980

-

  

Inhibition of heme detoxification

  

[24][19]

Antifolates

  

Sulfadoxine

1937

1960s

Pfdhps

Inhibition of folate metabolism and DNA replication

Gene mutation leading to drug binding site modification

[25][20]

Proguanil/cycloguanil

1948

1949

Pfdhfr

[26][21]

Pyrimethamine

1952

1960s

  

Endoperoxide

  

Artemisinin and its derivatives (DHA, ATS, ATM)

1972

2008

PfKelch13
Note: Failure rates of ≥10% were considered according to the WHO therapeutic efficacy studies reports [2].
Prevention is said to be better than cure. Some antimalarials can be used for chemoprevention. This reduces the risk of developing overt malaria signs and symptoms. This also reduces the mortality risk associated with malaria especially in children under five years, pregnant women and travelers, who do not live in malaria endemic countries. Atovaquone/proguanil and sulfadoxine/pyrimethamine are among the antimalarials that can be used in chemoprevention of malaria (Table 1) [14,15][30][31].

3. Limited Access to Drugs

For effective treatment of diseases, access to the right medications is a prerequisite, among several other factors. The availability of quality and affordable drugs in sufficient quantity is an essential element in universal health coverage. Several health agencies including the World Health Organization (WHO) have since their establishment worked to increase access to medications. Unfortunately, these efforts have been frustrated by a number of factors, ranging from economic to sheer wickedness on the part of businessmen.  (Figure 1).
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Figure 1.
Impact of limited drug access and drug pressure on malaria control.

3.1. Counterfeiting/Drug Quality

The quality of drug refers to the suitability of either a drug substance or drug product for its intended use as described during an FDA international conference on Harmonization [35][32]. The quality of a drug is anchored on three features: identity, strength and purity for the intended use [36][33]. The quality of a drug must be assured and maintained until it gets to the end users (patients). Regrettably, there is a great deal of interplay between drug manufacture and delivery to the end users which compromises the drug quality. Such interplay includes but not limited to: compromised drug manufacture (sub-therapeutic active ingredients, non-compatible excipients and lack of good manufacturing practices (GMP)). Inaccessibility and high price of quality ACTs, poor transportation and harsh storage conditions, wrong dispensing (mistakes by dispensers) as well as lack/or inadequate regulation from regulatory agencies, contribute immensely to counterfeiting of antimalarials. The use of poor quality antimalarials can cause a drop in efficacy and reduce parasite clearance, which are characteristics of drug resistance and eventual drug failure [37][34]. Drugs against infectious diseases such as malaria are among the most falsified drugs in the market especially in developing countries, which fall under malaria endemic regions. According to a WHO account, one in every ten drugs in developing countries are either substandard or falsified [38][35]. Quality tests conducted on some artemisinin derivatives in Africa failed the tests [39][36]. This calls for more regulation from the government of these affected countries to ensure strict compliance to GMP.
Even when the drugs meet the required standard after manufacture, the means of transportation to the pharmacies or hospitals are often inadequate. This is mostly the case with drugs that are unstable under certain temperature ranges. The impact of poor quality drugs is huge; about 122,000 deaths were estimated in children under five in sub-Sahara Africa and therefore should be taken seriously [40][37]. The counterfeiting of antimalarials limits the availability of the required amount of drugs for effective treatment and hence can culminate in treatment failure and reduction in malaria control.

3.2. Cost of Drug

Most, if not all, the novel antimalarials hit the market at exorbitant prices as premium brands. This adversely affects the affordability by the deserving masses, thereby limiting access to the drugs. Some patients may attempt to buy some doses. Consequently, there will be an incomplete or non-treatment of malaria across different categories of patients. Incomplete drug regimens can lead to treatment failure on subsequent administration of complete doses. Sometimes, the lack of resources from the patients can result in the use of less effective antimalarials.
Both non-treatment and incomplete treatment continually make the subjects harbors for the malaria parasites, which enhances transmission to other people, worsening malaria control. The WHO considers health insurance as a veritable tool in ameliorating the effect of the cost of essential drugs [41,42][38][39]. Ordinarily in developed countries, the cost burden of drugs are borne by health insurance; however, in most of the low-to-medium income countries (LMIC) where malaria is endemic, health insurance utilization or its awareness is still relatively low [43][40]. Most patients still pay for their drugs out of the pocket. Attention must be paid to the cost of drugs as treatment outcome or efficiency is tightly linked to the cost of prescription. The high cost of some antimalarials, especially ACTs, raises the risk of utilizing counterfeit or sub-standard brands due to switches at the pharmacy because of their cheapness. This can lead to treatment failure which may be progressive, affecting the regimen even when the right drugs are eventually used.
To ameliorate the impact of high cost of novel antimalarials, most malaria endemic countries benefit from antimalarial donations which are made available to malaria subjects free of charge. Increasing access to antimalarials through reduced cost can improve the treatment outcome and reduce transmission significantly. This will reduce overall malaria burden.

3.3. Drug Storage/Transportation

Antimalarials remain viable at certain temperatures. However, this is not the case in the course of movement of these drugs to some rural communities. The drug gets to the end users in a degraded form with reduced efficacy. Improved means of transportation of drugs and storage can therefore retain the quality of drugs as they get to the end users. The right environmental controls such as temperature, light, and humidity, conditions of sanitation, ventilation, and segregation, which affect the drug stability and quality [44][41], must be regulated during drug transit and storage.

3.4. Drug Interactions

The drugs that reach the systemic circulation can be grossly affected by their interaction with substances ingested alongside the drugs. Such interactions affect the absorption, distribution, metabolism, and/or excretion of drugs, which can reduce the clinical efficacy of the drug. The interaction could be additive, synergistic or antagonistic. Such substances are mainly either food (drug-food interaction) or other drugs (drug-drug interaction). Synergistic interactions can improve the efficacy of the index drug. Antagonistic interactions can reduce the drugs available at the site of action, in other words, reducing access to the drug. For example, some antiviral and antibacterial agents administered concurrently with antimalarials result in antimalarial failure [45][42]. While some interactions decrease the availability and activity of some antimalarials, others may increase their activity [46,47][43][44]. For instance, imatinib or other Syk kinase inhibitors which potentiate artemisinin combination therapies [48][45]. Due to the interaction of antimalarials with other drugs or food, patients must seek proper medical counsel before taking any antimalarial with other drugs. The interaction of antimalarials and other substances is shown in Table 3.
Table 3. Drugs interacting with antimalarials.

Food/Drug

Class

Probable Mechanism of Interaction

Consequences

Indinavir, nelfinavir

Antiretroviral

Inhibits CYP3A4

May increase concentrations of ART and LUM

Imatinib

Anticancer

Inhibits Syk, Lyn, Bcr-Abl

Decrease artemisinin concentration and accelerate ART efficacy

Ritonavir

Antiretroviral

Inhibits CYP2D6 and CYP3A4

May increase concentrations of ART and LUM

Ketoconazole

Antifungal

Inhibits CYP3A4

Shown to cause modest increase in concentration of

ART and LUM

Fluconazole

Antifungal

Inhibits CYP3A4

May cause increase in concentration of ART and LUM

Inhibition of heme detoxification and C-C radical formation

Entry into quiescent state

[

27

]

[

22

]

Hydroxynaphtoquinones

  

Atovaquone

1996

1996

Pfcytb

Competitive inhibition of Complex iii of the ETC

Modification of binding site on Complex iii/cytochrome b

[26,28][21][23]

Tetracycline antibiotic

  

Doxycycline

1967

  

SNPs in Pfmdt and PftetQ

Inhibition of protein, nucleotide and deoxynucleotide synthesis

Not yet described

[29,30][24][25]
Note: DHA = dihydroartemisinin, ATS = artesunate, ATM = artemether, SNPs = single nucleotide polymorphism.
In order to avoid the emergence of parasite resistance, drug combinations are strongly advocated for malaria treatment. The recommended combination is artemisinin-based therapy (ACT) (Table 2), although other combinations such as atovaquone/proguanil and sulfadoxine/pyrimethamine are also available. For example, to protect endoperoxide activity and their partner drugs against parasite resistance, since 2001 the WHO has recommended the use of artemisinin derivatives with one or two partner drugs, which are chosen according to the differences in their pharmacokinetic properties. As a result of the failure that has been reported with dihydroartemisinin-piperaquine (DHA-PPQ) and other ACTs in Southeast Asia (Table 2), the use of triple combination therapy has been put forward as a more reliable approach going by the efficacy outcome obtained from atovaquone-proguanil–artesunate [13][26]. However, the cost of the triple combination, atovaquone–proguanil–artesunate, may limit its application in low-to-medium income countries were malaria is endemic.
Table 2. Artemisinin-based combinations therapies (ACTs) against P. falciparum recommended by the WHO [31,32,33][27][28][29].

ACTs

Rifampicin, isoniazid

Anti-tuberculosis

Induces CYP3A4

May decrease concentrations of ART and LUM

Nevirapine, efavirenz

Antiretrovirals

Induces CYP3A4

May decrease concentrations of ART and LUM

Phentytoin/phenobarbital

/carbamazepine

Anticonvulsants

Induces CYP3A4

May decrease concentrations of ART and LUM

Adapted from [46,47,48][43][44][45]. ART = artemisinin, LUM = lumefantrine, CYP = cytochrome P450.

3.5. Use of Antimalarials as Monotherapies

Different antimalarials have different pharmacokinetic properties including short half-lives. The recommended combination is artemisinin-based therapy (ACT) (Table 2), although other combinations such as atovaquone/proguanil and sulfadoxine/pyrimethamine are also available. Atovaquone/proguanil and sulfadoxine/pyrimathamine are used mainly in prophylaxis (malaria chemoprevention) in travelers and pregnant women, respectively [14,15][30][31]. The combination makes up for the shortcomings (such as short half-life of artemisinin) of each drug in the combination, ensuring effective exposure time [49][46]. The currently recommended six ACTs from WHO are: artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (AS-AQ), artesunate-mefloquine (AS-MQ), artesunate-sulfadoxine-pyrimethamine (AS-SP) and artesunate-pyronaridine (AS-PY) [32][28]. Regrettably, in some places and for some reasons, people still use these antimalarials as monotherapies. The exposure of the parasite to only one drug makes it easier for the parasite to develop resistance to such antimalarial drugs, leading to a reduction in malaria control. The effective use of these ACTs is therefore strongly advocated to improve access to drugs.

3.6. Hoarding of Drugs by Corrupt Officials

There are several malaria programs intended to increase access to drugs by different governmental and non-governmental agencies. These agencies either subsidize the drugs or make them entirely free [2]. These drugs go through some middlemen before getting to the intended targets. Regrettably, sometimes the drugs get stockpiled in the hands of these middlemen, who do so for several reasons ranging from profit-making to sheer wickedness. They hoard the drug in order to resell them to make gains. This leaves the poor masses without the usually subsidized or free drugs.

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