Thursday, April 26, 2012

Are We Treating Malaria?

  • Prompt and effective treatment makes the difference between life and death for malaria patients
  • Large majority of malaria patients in Africa, SE Asia and India may not be receiving any treatment
  • For most patients of malaria, who are poor and who live in remote areas, treatment is inaccessible, ineffective, insufficient, improper and incomplete.
  • The resources and political will evidently available for a moon mission are clearly lacking for malaria control.

Our Priority: Moon Over Man
By Dr. BS Kakkilaya, Mangalore
Malaria Day, April 25, 2012.
It’s World Malaria Day yet again and it’s time for one more slogan. After ‘malaria - a disease without borders’ (2008), ‘counting malaria out’ (2009, 2010) and ‘achieving progress and impact’ (2011), it is time to ‘Sustain Gains, Save Lives and Invest in Malaria’ in 2012. First observed on April 25, 2008, following the decision of the World Health Assembly at its 60th session in May 2007,[1] World Malaria Day marks the anniversary of the historic African Summit on Roll Back Malaria held in Abuja, Nigeria on the 25th of April 2000 and the Abuja Declaration signed there by 44 African malaria-endemic countries.[2] World Malaria Day intends to be the culmination of year-long implementation of national malaria-control strategies, including community-based activities for malaria prevention and treatment in endemic areas, and is the occasion to inform the general public of the obstacles encountered and progress achieved in controlling malaria.[1]
The Million Murdering Challenge:
Hundreds of years after using qing hao and cinchona; 115 years after Sir Ronald Ross’s discovery of the mode of transmission through mosquitoes and the methods to control it; and fourteen years after the Roll Back Malaria (RBM) movement, announced by the WHO in 1998 with the goal of halving malaria deaths by 2010, and halving again by 2015, malaria continues to kill millions, as it did in the past. (See Table 1)

Table 1: Malaria Mortality 1900-2010
19003 19903 2010
Population 1616m 5388m 6892m4
Malaria Mortality 3.13m 0.9m 1.23m5
Deaths/10000 19.4 1.6 1.78
Population 94m 532m 990m4
Malaria Mortality 0.21m 0.787m 1.13m5
Deaths/10000 22.3 14.8 11.41
Population 277m 843m 1189m4
Malaria Mortality 0.08m 0.0003m 0.045m5
Deaths/10000 2.88 0.003 0.84

Most of the malaria cases and deaths occur in sub Saharan Africa. According to the World Malaria Report 2011, 81% of the total malaria burden is from this region, with P. falciparum accounting for 81% of cases. Nine out of ten malaria deaths occur in Africa, with 86% deaths occurring in children below the age of 5 years, i.e., about 3000 child deaths every day. [6] Africa was inexplicably excluded from the malaria control efforts initiated by the WHO in the 1950s[7] and to this day continues to suffer from malaria and all its ill effects on health and economy. India too has a large burden of malaria, particularly in the tribal belts of Jharkhand, Orissa, Chhattisgarh, Madhya Pradesh, Maharashtra and the north eastern states, with an estimated 25 million (or even more) cases and nearly 2 lakh deaths annually.[8-12] (Table 2)

Table 2: Malaria in India
Source Total cases Deaths
NVBDCP8 1.59 million 1018
Expert Committee9 9.7 million 46800
WHO10 25 million >30000
Dhingra N et al11 >200000
Brooks et al12 180 million

The million murdering seeds of malaria, so named by Sir Ross, can be wiped out by just three days of treatment yet continue to kill millions even in this twenty first century, mocking at our collective ability to conquer simple diseases. Malaria continues to be our greatest challenge, not just parasitological, but also social, cultural, political and economical challenge that we have to overcome by all means.
But why have we failed so far?
Early and accurate diagnosis and prompt and effective treatment form the cornerstone of malaria control and make the difference between life and death for malaria patients.[13] But our biggest problem has been getting the right drugs for the right people at the right time.[14] Is the treatment accessible to the patients suffering from malaria? Is the accessible treatment really effective? Is the effective treatment available in sufficient quantities? Is there enough awareness among the suffering public and treating doctors about the diagnosis and treatment of malaria?
Treatment is Inaccessible:
It is increasingly becoming clear that those who have malaria do not get the treatment and those who get the treatment often do not have malaria at all. And it is a double jeopardy, especially for the poor: many cannot access the health facility that provides free drugs and most cannot access drugs from nearby private clinics owing to the high costs. [14] What is free is not accessible and what is accessible is expensive and thus not available.
Studies show overwhelming evidence for the fact that the majority of those with malaria, particularly in Africa, do not get antimalarials effectively.[14,15] Most malaria deaths in Africa, South East Asia and India occur at home, without confirmation of the diagnosis. Many patients struggle, often unsuccessfully, to access even basic health care and for those that succeed, the care they receive may be of dubious quality, improper and ineffective.[14,15] Distance from health services, costs of transport and of treatment, limitations in the household budget to cater to all members if they fall sick concurrently, and other logistical problems prevent many patients from being effectively treated.[14] With such severe constraints in accessing even basic healthcare and antimalaria drugs, nothing more needs to be mentioned about access to life saving facilities, blood transfusion and other supportive care that are essential for patients suffering from severe malaria.
Without treatment, malaria cannot be controlled. And the governments of most of the malarious countries are unable to help their people suffering from malaria. Compared to 1900s, malaria has disappeared from much of Europe and the United States, but continues to be the biggest bane of the poverty stricken countries in Africa, southern America and Asia.[16] This co-existence of malaria and poverty is mutually worsening. Many of the malaria endemic countries have the lowest GDP and spend the least on public health. These countries also have the lowest ratios of physicians and nurses to general public.[17] [Table 3]

Table 3: Healthcare standards in malarious countries and US
Country %GDP Per capita on health Doctors/ 10000 Nurses/ 10000
Africa 6.0 146 2.3 10.9
India 4.2 122 6 13
US 15.2 7164 26.7 98.2

Most of these countries have very poor infrastructure. Dilapidated buildings, lack of proper roads, lack of electricity, lack of drugs and essential supplies and non-functional equipment at health facilities[18] adversely affect accessibility and healthcare delivery. The urban-rural divide (in India, 88% towns have healthcare facilities v/s 24% villages and 66% medical professionals are in urban areas), income inequity, gender inequity and social inequity[18] further compound the problem.
Is there malaria control so expensive? It is estimated that the annual costs of malaria in Africa alone amount to US$12 billion-100 billion, whereas ~$3.4 billion per annum is needed for drugs and $4.7 billion is estimated to be needed for R&D until 2015.[19-21] For India, costs of malaria have been estimated at US$1.2 billion (or more) annually, and its control would need about US$ 80million; thus it has been estimated that every rupee invested in control would result in a return at least Rs. 20.[22] Yet there are no takers for malaria control; Ross’s sanitary axiom written in 1910 ringing to be so true yet again: “For economic reasons alone, governments are justified in spending for the prevention [of malaria] a sum of money equal to the loss which the diseases inflict on the people”, but “it is the rule to grudge spending a hundred pounds for a disease which costs thousands..”[19,23]
Treatment is Ineffective:
As of now, malaria parasites, particularly the more virulent P. falciparum that causes almost all the deaths, have developed resistance to all the available antimalaria drugs and no new drugs are visible in the near future. Prof. Nicholas White, Chairman, Wellcome-Trust South East Asian Tropical Medicine Research Units and Professor of Clinical Tropical Medicine at the Mahidol University, Thailand wrote in the New England Journal of Medicine dated 12 Sep., 1996: "Mother Nature gave us the cinchona alkaloids and qinghaosu. World War II led to the introduction of chloroquine, chloroguanide (proguanil), and eventually amodiaquine and pyrimethamine. The war in Vietnam brought mefloquine and halofantrine. These drugs are all we have available now to treat malaria. It is difficult to see where the next generation of antimalarial drugs will come from....there is little pharmaceutical industry interest in developing new antimalarial drugs; the risks are great, but the returns on investment are low....If drug resistance in P. falciparum continues to increase at the current rate, malaria may become untreatable in parts of Southeast Asia by the beginning of the next millennium."[24] With the latest reports from Thai-Burmese border suggesting fast spreading resistance against artemisinin, his prophecy appears to be coming true.[25] While natural products such as quinine and artemisinin have taken decades to succumb to resistance, synthetic drugs have perished within a few months to years.[26-28](See Table 4)

Table 4: Development of Resistance to Antimalaia Drugs
Drug Introduced First Reported Resistance Effectiveness (years)
Quinine 1632 1910 278
Chloroquine 1945 1957 12
Proguanil 1948 1949 1
Sulfa/Pyrimeth 1967 1967 <1
Mefloquine 1977 1982 5
Atovaquone 1996 1996 <1
Artemisinin 1970s 2001 ~30
Most strains of resistant malaria have emerged from SE Asia region and with the latest reports, P. falciparum strains in SE Asia appear to have developed resistance against almost all antimalaria drugs. Resistance to chloroquine in P. falciparum is wide spread across the malarial world, except in central America. Resistance to chloroquine in P. vivax and P. malariae and against primaquine in P. vivax have also been reported in parts of SE Asia.[27-35] (See Table 5)

Table 5: Distribution of Drug Resistance
Species Resistant to Areas
P. falciparum Chloroquine All over except central America
SP SE Asia, South America, Africa
Mefloquine SE Asia, parts of South America and Africa
Quinine Parts of SE Asia and South America
Artemisinin Parts of SE Asia
P. vivax Chloroquine Indonesia, PNG, parts of SE Asia and India
Primaquine Parts of SE Asia
P. malariae Chloroquine Indonesia
Chloroquine resistance in P. falciparum is wide spread in India too, with full 117 districts (i.e 50 high endemic districts of Andhra Pradesh, Chhattisgarh, Jharkhand, Madhya Pradesh & Orissa and 67 in North Eastern States) and 253 PHCs of another 46 districts being declared so by the NVBDCP.[36] There have also been some sporadic reports of chloroquine resistance in P. vivax from India.[32,33]
Resistance to antimalaria drugs has therapeutic, diagnostic and economic implications in the management of malaria. With chloroquine and sulfa/pyrimethamine, the most commonly used and cheapest antimalaria drugs, becoming ineffective in most parts of the world, there has been an urgent need to change to new drug/s, preferably a combination therapy to prevent further development of resistance. With new drug/s being more expensive, initiating treatment on the basis of clinical diagnosis alone would mean unnecessary wastage of precious and expensive drugs and therefore, new approaches and guidelines for malaria diagnosis have been necessitated. With the available alternatives 50-700% more expensive compared to chloroquine and SP, any new drug regimen would also mean a heavy economic burden on the already impoverished countries. Increasing resistance to all available drugs also necessitates urgent funding for the development of new drugs against malaria.[26,37,38]
WHO now advocates Artemisinin Combination Therapy for the treatment of P. falciparum malaria all over the world where resistance to chloroquine and SP is established.[29] Combinations of artesunate with either sulfa/pyrimethamine, mefloquine, amodiaquine or pyronaridine; artemether with lumefantrine or dihydroartemisinin with piperaquine are now in use in different parts of the world. The NVBDCP in India also recommends artesunate+SP (or other ACTs) for the treatment of P. falciparum malaria all across the country.[39]
As these drugs are expensive, presumptive treatment or treatment on the basis of clinical diagnosis are no more encouraged. Instead, in situations where microscopic diagnosis of malaria is not possible, WHO and NVBDCP now recommend the use of Rapid Diagnostic Tests (RDTs) to confirm malaria before initiating specific treatment.[29,39] But RDTs are not without problems. Many RDTs have poor sensitivity at low parasitemia and also at high parasitemia (due to prozone phenomenon). These tests are also known to cross react with other malaria species or with auto antibodies, resulting in false positive tests and making species identification difficult. Long lasting antigenemia may result in false positive tests even after full treatment. Therefore, the results of the RDTs, though looking simple, may need to be interpreted with care.[40] Despite these recommendations against presumptive treatment, it is quite common for ACT to be used on the basis of clinical diagnosis alone and there is good evidence from across Africa and increasingly from Asia that, in most formal healthcare settings where ACT are provided, a substantial proportion, and often the majority of antimalarials, are given to children and adults who have no parasites and, therefore, do not have malaria.[14]
Are the effective drugs available in sufficient quantities?
There are many reasons why the needy would not get the effective drugs in sufficient quantities. With the new, effective drugs being far more expensive than chloroquine and SP, governments are unlikely to be able to finance adequate supplies and private sector prices may be out of reach for many. This may influence choice of regimen and create market for fake and substandard drugs, increasing further the risks of mortality and drug resistance.[14,41]
It has been estimated that with 215-374 million cases of falciparum malaria annually, about 113 to 314.5 million adult treatments would be needed, requiring US$1.6 billion-US$3.4 billion per annum for providing ACT.[20,21]

Table 6: ACT Demand Estimates 2010-2012
Year 2010 2011 2012
Doses 217m 287m 295m
Public buy 182m 176m 178m
Total distributed in 2010
Where Global Africa Rest
Doses 117m 110m 7m
80 million doses worth $70million bought with support from Affordable Medicines Facility – Malaria (AMFm) of The Global Fund
From Table 6 it is clear that the global supply of ACT doses do not match the estimated demand and the funding support by agencies such as the Affordable Medicines Facility – Malaria (AMFm) of The Global Fund is also quite inadequate. [6,41-43] Amir Attaran and others have been over the years closely following the funding patterns of the Global Fund and other aid agencies. In a paper published in The Lancet in 2004, Attaran et al were highly critical of the manner in which WHO and the Global Fund extended support to the poor African nations fighting malaria.[13] In Africa, Global Fund for AIDS, Tuberculosis, and Malaria (GFATM) and other aid agencies supported the use of chloroquine and SP for years after WHO advocated ACT and by approving this aid, the WHO violated its own policy of abandoning chloroquine. As chloroquine ($0·13) and SP ($0·14) cost far less than ACT ($1·00–3·00), this decision allowed the aid agencies to provide ‘treatment’ (of chloroquine and SP) to ten times more patients than with ACT. Attaran et al called these decisions as indefensible and wrote that at the least this would have wasted precious international aid money, and at the most, killed patients who had malaria and tens of thousands of children might have died every year as a direct result.[13] Another survey by Richard Tren and others for the Africa Fighting Malaria found unintended, but not unforeseen, worrying consequences of the subsidy provided by AMFm.[44] These orders for ACTs for four countries, Ghana, Kenya, Nigeria and Tanzania, accounted for 80% of global ACT production capacity, thereby depriving other deserving countries of their supply of ACTs. It was found that Zanzibar, with zero malaria transmission, also ordered 240000 AMFm treatments. Seventy percent orders were for adult doses, while children were in fact mostly in need of these drugs in Africa. Three manufacturers were also buyers in Africa, thereby suggesting conflicts of interest in these transactions.[44] And with the Global Fund announcing a halt to all new funding until 2014, even this level of support may not be continued in the coming years.[45,46]
It is not just the funds that are hard to find. The global production of artemisinin is also lagging behind the demand generated by the new treatment policy of using ACT everywhere. There are six major producers of raw artemisinin (3 in Viet Nam, 2 in India, 1 in China). As against the demand of about 80 tonnes of artemisinin in the year 2011, only about 50 tonnes were available. With increasing demand, there will be a need for significant scale-up of artemisinin production.[47,48]
Inadequate supply and high cost of artemisinin are driving consumers to cheaper brands, most of which are either fake or substandard. It has been estimated that 38-52% of ACT in SE Asia and Africa may be fake and that ~15% of ACT brands from legal manufacturers may be substandard. Such fake and substandard drugs increase the risk of death from severe malaria, tantamount to murder, and substandard drugs also increase the risks of drug resistance.[49-52] Although WHO demanded a halt to artemisinin monotherapy in 2007, it continues to be available in India, SE Asia and Africa, increasing the risk of ineffective therapy and drug resistance.[44,53-56]
Efforts to increase the production of effective drugs through new technologies are also not making much headway. Although synthetic and semisynthetic artemisinin analogs (OZ277/RBx11160, OZ439, CDRI97/78, PA1103/SAR114262, artemisone) have been developed and sequencing of the Artemisia annua genome has opened up of the possibilities of fast breeding and high-yielding varieties of the plant and genetically engineered semisynthetic artemisinin, the production for clinical use is still awaited.[57-61]
The latest efforts at the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany where production of artemisinin from dihydroartemisinic acid (unused by-product from the isolation of artemisinin from sweet wormwood; also easily produced in genetically modified yeast) by incorporating endoperoxide structure by photochemistry using UV light have shown some promise, with claims that 800 photo-reactors should suffice to cover the global requirement for artemisinin.[62]
Entirely new classes of drugs against malaria seem to be distant dreams as yet. Of the 1556 new drugs developed between 1975 and 2004, only 8 were anti-malarials. Although hundreds of new drug targets on the acidocalcisome, vestigial mitochondrion, apicoplast, digestive vacuole, unusual ion channels, proteases, kinases etc., have been identified following the decoding of the Plasmodial genome in Oct. 2002, it may take years and cost quite a lot before these molecules are available for clinical use.[58,63,64]
These efforts, therefore, appear strong in initiatives but weak in novelty of mechanism of action; many of the so called new drugs being analogs of the existing molecules, they may not circumvent resistance.[65,66] On the other, funding for new drug research may also be inadequate. Even though the global spending on malaria R&D has gone up to $612 million in 2009, of which $182.5 million (30.7%) was spent on drug development, more would be needed.[67,68]

Ignorance adds to the woes:
Lack of awareness among patients as well as medical professionals regarding timely diagnosis and treatment is also a major obstacle in successfully treating and controlling malaria.[69] Ignorance, belief patterns and customs may keep the patients away from diagnosis and treatment of malaria. Concerns about the safety and efficacy of conventional medicines; belief that a child with convulsions could die if given an injection or taken to hospital; reliance on traditional healing methods, including consultation with traditional healers, use of herbal remedies, sponging and bathing, and various forms of fumigation; and stopping medications once symptoms had ceased, often as a means of rationing pills to preserve a supply for future illness episodes have all been found to be common among malaria patients and their relatives.[70] The awareness among doctors regarding timely diagnosis and latest treatment guidelines is also reported to be low. [71]
Are we treating malaria at all?
Considering all these, it is clear that malaria treatment is inaccessible for most patients, quality malaria treatment is not sufficiently available and some of the treatment that is available may be ineffective, and ignorance compounds the problem further by making the treatment inaccessible, improper and incomplete. Then, are we treating malaria at all? Are these reasons not enough for malaria that can be treated in 3 days, to kill 12300000 a year?
Dr Margaret Chan, Director-General of WHO in her inaugural address in 2006 pointed out that lack of resources and too little political commitment were the true “killers”.[72] It is no secret that lack of funding is driving malaria resurgence and all its related deaths.[73]
We have conquered the moon long ago, but not yet the tiny mosquito. We have had enough money for the first one, but not for the second one. Malaria in India can be controlled with the same amount that was spent on Chandrayan I.[22,74] But our political priorities are very clear. Moon over man.


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