Why's malaria taking its toll?

avaged by malaria, Assam is struggling to control the dis-ease. Like in most other parts of the country, the health infrastructure is in a state of terminal decay. Forget the  remote villages, even the district health centres are in shambles.

Check out Lakhimpur district — a microcosm of Assam, if not the whole country. Hollow-eyed patients lie in rows on the mud floor of an unfinished rural school building. Saline drips are strung across a dark room. At the door, a small group of patients and their families wait their turn, with the two harried

doctors in charge of the peripheral malaria ‘hospital’, a makeshift unit housed in Rampur ME

School, at sea. So far, over 200 villagers have been brought to the school in the remote interior of Lakhimpur to have their blood tested and, if lucky, get the right treatment. Pathologists from the Union health and family welfare department conducting rapid blood tests said 100 per cent of those who tested positive for malaria

carried the deadly variant of the pathogen that causes the dis-ease —Plasmodium falciparum(Pf). 

The doctors are despairing. “We have been sent here with only 16 ampoules of quinine. It’s horrible,” says U N Dutta, one of the two doctors at the emergency hospital. “We don’t have enough doctors or paramedic staff or medicines,” adds Dutta, who is also the joint director of health services, Lakhimpur district. Yet, some 370 km away, sitting in his air- conditioned office at Dispur, a senior health official says casu-ally, “There is no shortage of either medicine or doctors.” Emergency health camps like these, set up around the dis- trict and other malaria-affected regions across the state, rely on NGOs like Jan Kalyan, Voluntary Health Association of Assam, and Medecins Sans Frontieres (MSF) for doctors, drugs and ambulance services. 

 The situation isn’t much better at Lakhimpur Civil Hospital in Khelmati town. Malaria patients line hospital cor-ridors, some on metal beds, some on rags laid out on the floor. The 200-bed hospital is scrambling to deal with an influx of nearly 500 patients, most suffering from malaria. More arrive in droves everyday from surrounding villages. The official malaria death toll in Lakhimpur, which appears to be worst affected this year, was 60 as of May 16. Statewide the toll was pegged at 138. The figures are based on the number of reported deaths at the civil and peripheral hospitals.

But Dutta and Jan Kalyan workers, who have been treating patients in villages since April, say at least 300 people had succumbed to the disease in Lakhimpur. They cite late, poor quality testing as possible reasons for the low official fig-ures. According to government guidelines, only patients test-ing positive for the Pf parasite at time of death are listed as malaria victims. “Government hospitals cannot test the blood samples in time,” says Irshad Ali of Jan Kalyan, Lakhimpur. “Hundreds of samples are still lying at the hospitals. By the time they are tested, who knows how many patients will have died of Pf .”

Besides, says Dutta, “once Pf enters vital organs like the liver and brain, it can’t be found in the blood anymore. Blood smear tests conducted at this stage won’t show he parasite.” And of course, there are people in remote areas who don’t even make it within sniffing distance of a medical facility. Unhealthy system Malaria has been endemic to Assam and other northeastern states for long. Excessive rainfall and humidity in the region spawns large mosquito populations. Official estimates say the

disease claims about 500 lives annually. In Assam, the official toll last year was 230. Independent estimates, however, say the figure probably runs into a few housands. 

In most northeastern states, Pf is already resistant to chloroquine, the first-line drug prescribed against malaria. There are also areas where Pf is resistant to the second-line drug sp. The situation persists in other parts of the country.

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For example, a study published in 2004 by National Institute of Malaria Research (nimr), Jabalpur, shows that the dynamics of Pv and Pf in central India have changed over a 27-year period. The study, conducted in the tribal forested belt of Chhattisgarh, revealed that in 1975 Pv was the predominant species (58 per cent) but since 1979, Pf has shown a steady upward trend. Between 1986 and 2000, Pf cases reported by the National Anti Malaria Programme (now rechristened the National Vector Borne Disease Control Programme, nvbdcp) increased 500 per cent, and the death graph also showed a steep upward curve. Since then the number of malaria cases and deaths has declined sharply due to the use of new drugs, but the proportion of Pf has remained at a steady level.

Resistant strain
While it is true that new drugs have succeeded in checking the spread of malaria, pharmaceutical research is struggling to come up with newer drugs because Pf keeps developing drug resistance. The history of the pathogen worldwide shows how difficult the war against malaria can be.

For instance, Pf was first seen to have developed resistance to chloroquine, for long the first-line drug against malaria, almost simultaneously in Colombia and the border between Thailand and Cambodia. In Asia, chloroquine resistance was initially confined to the Indochinese peninsula until the 1970s, when it spread westwards and towards the neighbouring islands in the south and east. The advent of chloroquine resistance in Africa occurred much later, taking a decade to cross the continent. Today, only countries in Central America, north of the Panama Canal, and the island of Hispaniola have not documented chloroquine-resistant Pf malaria.

In India, the first case of chloroquine-resistant Pf was identified in Karbi Anglong in 1973 (see table: Pockets of resistance). Official reports of the nvbdcp directorate, under the directorate general of health services, show that Pf has now developed resistance against chloroquine in 237 primary health centres (phcs) in 52 districts in 19 states. There have been reports that 12 phcs in seven states get cases of malaria resistant to sp, the recommended second-line drug.

Pf has developed resistance to almost all drugs available to counter it. For instance sp which was used as a replacement for chloroquine in most countries, became ineffective in Thailand and its neighbouring countries by the beginning of the 1980s. Resistance to this drug has spread to South America. It has also spread to the African continent. In 1993, Malawi was the first country in East Africa to change from chloroquine to sp as the first-line drug, and other African countries followed this example in the late 1990s. But extensive use of this drug rendered it ineffective.

Similarly, Pf has become resistant to mefloquine, another drug used to treat this parasite. Sporadic cases of prophylactic failure of mefloquine in travellers and therapeutic failure have been reported in Africa, Asian countries and South America. The pathogen has also developed resistance against amodiaquine and quinine.

Assam, a case in point

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Assam demonstrates clearly the obsolescence of the old malaria drugs. msf carried out a study in 2001 using four anti-malarial drugs against uncomplicated Pf in two districts in Assam. They assessed a total of 387 people in Sonitpur and Karbi Anglong districts, studying chloroquine resistance in Pf between 1979 and 1989.

They found that the Centre had recommended sp as the first-line of treatment, but the drug was generally not available. msf tested different anti-malarials and found that failure rates against chloroquine was as high as 96 per cent, and around 57 per cent against sp in Sonitpur.

Similarly, in Karbi Anglong district, they found a 66 per cent resistance to chloroquine , while the figure for resistance to sp was 39 per cent . The group used an sp -artesunate combination (which uses an Artemisia -derivative with an older drug) therapy to treat malaria patients, successfully. In the year 2004, they used this combination in Chirang district on 150 Pf patients. There was a 92.5 per cent success rate.

Mutant parasite
The pathogen becomes drug resistant through spontaneous mutations. Sometimes mutations destroy the pathogen. If that does not happen, the parasite usually develops resistance to the environment it is in -- meaning the drug that is being administered.

As most of the anti-malarial drugs being used are closely related chemically, development of resistance to one facilitates development of resistance to others. For example, chloroquine and amodiaquine are related, so are mefloquine, halofantrine and quinine. Experts also suggest that development of resistance to a number of anti-malarial drugs makes the falciparum parasite genetically plastic and allows it to adapt to a new drug, even when it is not chemically related to drugs previously experienced. The long half-life of drugs like sp and mefloquine also increase the likelihood of resistance developing as these stay in the body for long periods.

Reliance on presumptive treatment also facilitates the development of anti-malarial drug resistance. Once a certain drug environment expands, the pathogen that has mutated to survive that environment is naturally selected and its population keeps growing, making it necessary to create new drugs to create different, hostile environments.

Inferior drugs, which do not have sufficient quantities of active ingredients, also help in promoting resistance.

The way out, most experts agree, is using a combination of drugs, which makes developing resistance difficult. A P Dash, director, nimr, Delhi, says combination therapy should be used in the country. Falciparum malaria has developed resistance to chloroquine due to a mutation in the Pfcrt gene, which is responsible for the parasite's membrane functions.

The mutation is rampant in the country, making combination therapy essential. Bhawna Sharma of Drugs for Neglected Diseases initiative, a subsidiary of msf, and V P Sharma, former director of nimr, also stress the importance of combination therapy.

Unfortunately, as we will see, the drug regimes followed in this country have been utterly misconceived.

Latest reports suggest that resistance has to be countered by using combination therapy involving the Chinese cutting edge drug -- artemisinin. This strategy has problems -- apart, of course, from bureaucratic inertia -- related mostly to finance and availability.

The demand for artemisinin has been continuously on the rise, both in India and worldwide. The drug is derived from a plant found mainly in China -- Artemisia annua (see box: Disease stymied). Artemisinin is considered as of now to be the only effective drug against Pf, which has developed a resistance to it only in stray cases, invariably when it has been used in monotherapy. Experts warn, therefore, that unless it is used in combination this might well happen.

Most manufacturers of artemisinin derivatives in India import a semi-synthetic version of the drug, called artesunate, from China and Vietnam. Industry observers say that if, or when, the health bureaucracy moves to a universal combination regime, pharmaceutical companies may be forced to grow A annua. One company, Ipca Laboratories Limited, Mumbai, has already started doing this.

The government has also taken fitful stabs at promoting the cultivation of A annua. Various institutes have taken up projects for the development of artemisinin-based drugs. In India, the Central Drug Research Institute, Lucknow, in collaboration with the Central Institute of Medicinal and Aromatic Plants (cimap) has developed arteether, a semi-synthetic derivative of artemisinin, the active component of the plant A annua. Themis Medicare, Ltd, Mumbai, has been given a contract to manufacture the drug, christened emal. The National Institute of Pharmaceutical Research, Mohali, Punjab, is also working on a project to cultivate A annua and isolate artemisinin.

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Recently, cimap has developed a new high artemisinin-yielding variety, ' cim -Arogya'. Besides, an improved process for isolating artemisinin from the herb has cut costs of producing artemisinin from Rs 40,000 per kg to about Rs 15,000 per kg. Six companies have contracted farmers to cultivate the plant, which they will buy back to produce artemisinin-related compounds. Under the new arrangement, farmers will stand to make a profit of about Rs 40,000 per hectare for a single season of five months, the Centre claims.

Whose initiative
While there are such sporadic initiatives, the government has made no real attempt to shift to a more rational drug regime, despite promptings from who.

who has been suggesting for a long time that all countries where Pf has shown more than 10 per cent resistance to chloroquine, amodiaquine or sp, should use combination therapies, preferably containing artemisinin derivatives. These are known as artemisinin combination therapies (acts).

act has to be administered for two to three days compared to seven days of artemisinin as monotherapy. And since the pathogen is removed quickly, the chances of it developing resistance are further reduced.

On the northwestern border of Thailand, there was a 47 per cent reduction in the incidence of Pf infections in the 12 months after acts containing artesunate and mefloquine were introduced, without vector control programmes. Over the next 10 years, there was a six-fold reduction in malaria transmission. Similarly in Vietnam, use of acts has led to a substantial drop in malaria incidence. And in KwaZulu Natal, South Africa, a reduction in malaria cases, and fatalities, of more than 90 per cent has been sustained over the past three years after vector control programmes were introduced along with acts.

Supply side

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All available evidence suggests a shift to act is necessary to ensure there are effective drugs that can be used in the combination. To ensure that artemisinin derivatives are not used as monotherapy, who reached an agreement, in May, 2006, with 13 pharmaceutical companies to stop producing single-drug artemisinin medicines. A total of 23 companies make the drug. The remaining 10 have said that they are willing to collaborate with who.

While who is promoting the use of artemisinin derivatives -- artesunate, artemether and dihydroartemisinin -- it is likely that if more is used, there could be a raw material shortfall. In 2004, global production capacity was estimated to be around 25-50 million courses. That was way behind demand, which in 2005 was estimated at around 131-219 million. To meet this demand, who has been promoting cultivation of the herb. Besides, promotion of artemisinin is likely to suffer from crippling cost constraints. Globally act costs us $2.40 (a little over Rs 90) per course, which is the price at which Novartis is selling the drug right now, compared to just us $0.10 (roughly Rs 4.50) for chloroquine. msf estimates that for all Asia Pacific countries, act would cost about us $10.7 million a year. Given that malaria occurs in the poorer countries, a shift to act would require massive funding from donor agencies. The Global Fund to fight aids, Tuberculosis and Malaria (gfatm) is the largest financer of act s. So far, it has given enough to fund six million courses a year, which, obviously, is peanuts. Donors like dfid and Aus aid have not yet reached a firm conclusion on funding strategy and are still pushing the old treatment.

Since 2001, 56 countries have followed who 's recommendation in favour of act as the first-line treatment for malaria, which has created a surge in demand -- from two million courses in 2003 to at least 25 million in 2004. Countries are expected to place orders for at least 130 million courses in 2006. Technically supply can be ratcheted up to meet the demand, but the cost constraints have to be overcome through injection of funds by donors. This will give industry the signal that production should be increased.

Already, for instance, gfatm disbursements have sparked positive responses within the pharmaceutical industry. Novartis has announced that it will produce 210 million courses of acts soon. At an average price of us $1.5 (Rs 68.25) per treatment, when sold in bulk, this works out to purchases worth us $315 million (Rs 1,433.25 crore) over two years. This means that Novartis will be producing in excess of gfatm- financed demand. Novartis can meet the shortfall by selling to the private sector or other funding agencies. Sanofi will produce up to 15 million artesunate/amodiaquine courses in 2006. Ipca is producing 2 million courses per month, while Cipla is also into production of a generic version of the only combination approved by who. gfatm, established in 2002, is the largest funder of acts. In the first four rounds of funding, a total of us $230 million (Rs 1,046.5 crore) has been approved over the first two years, mostly for African countries. In a report, the Institute of Medicine in the us has recommended that combination therapies be sold to both governments and private wholesalers at the same price as chloroquine. Globally, this would cost donors and development agencies us $150-200 million (between Rs 682.5-910 crore) a year.

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Efforts have also been made to step up production of artemisinin. A annua has been cultivated in several countries since 2004-2005. While the largest producers are still China and Vietnam, East African countries (Kenya, Uganda and Tanzania) are also scaling up production and are expected to account for about 20 per cent of world production by the end of 2006. Cultivation of the plant requires a minimum of six to eight months from planting to harvesting, and extraction, processing and manufacturing of the final products require at least two to five months.

There is more hope though. Research into anti-malarial drugs is uncovering substitutes for artemisinin. One of the most advanced products being developed by Medicines for Malaria Venture (mmv), an ngo, is oz 277/ rbx 11160. Ranbaxy is the commercial partner for this drug. The product has entered phase- ii of clinical development and is likely to be in the market by 2009.

This drug too will have to be used in combination therapy because of concerns related to Pf acquiring resistance. "The future of malaria treatment is going to be very different in the next 10 years. mmv is funding 21 projects that are expected to provide a new drug every five years," says P Venugopal, mmv' s international operations director.

With 105 proposals on the list, research input is guaranteed. Researchers in the us are also experimenting with artemisinin culture in yeast cultures (see 'Malaria in a ferment', Down To Earth, May 15, 2006). The hunt for artemisinin is on, but without appropriate cost-effective technology not much can be expected.

Despite these initiatives, India has to import A annua and drugs derived from it. As a result, artemisinin-based drugs cost more in India than in the global market -- recently India bought combination drugs from Indian manufacturers (who are hampered by cost problems) for Rs 110 per course.

But all this will make sense only when the government gets out of denial mode and starts looking seriously at combination therapy.

The National Vector Borne Disease C ontrol P rogramme is in the process of changing the country's drug policy. A meeting was held in March 2006 to discuss new directions but the final policy has not yet been determined. In October 2005, a workshop was held by nimr to discuss the drug policy and come to a consensus regarding treatment of both Pv and Pf. The group suggested that oral artemisinin derivatives should be used only in combinations to ensure that resistance against them is not developed.

But the process of change can be described as too little, too late. As of now, treatment is presumptive, which helps pathogens to become increasingly drug-resistant. Moreover, the government does not seem to be particularly interested in shifting to artemisinin-based therapies. A sample of the denial mode comes from P L Joshi, director, nvbdcp. "We have changed the policy wherever there is a resistance problem. All Pf is not resistant to chloroquine and sp. In Assam, response to chloroquine is very good. Implementation is a problem. There is a need to give the full dose. Only then, one should say that it is not working. Health is a state subject -- they have to ensure that they control it," was his comment on the situation.

Besides, the Centre's treatment protocol stipulates giving chloroquine as a first line treatment where resistance has not been proved. In case this drug doesn't work, sp is given as a second line of treatment. And in areas where chloroquine resistance has been proved sp is administered as a first line treatment and act is the second line treatment. " States have to persuade the Centre to change this protocol. As of now, the protocol has been changed and implemented only in areas where there is resistance. There is no logic in doing this in patches," says Nana Zarkua, medical coordinator, msf, Delhi. Vectors do not respect the government's boundaries.

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" who has clearly established a protocol, based on scientific information, that all Pf cases should be treated with act. The Indian government cannot say that they will treat Pf cases with act only if resistance to chloroquine or sp is proved," says Leena Menghaney, project manager, India, Campaign for Access to Essential Medicines, msf. The problem, she says, is that there is a huge resistance to change and there is no public pressure on the government to change. act just costs around us $2 (Rs 90 approximately) to treat one patient. The price is likely to go down further if industry sees that the government is interested in act. "The fact that people in malaria-prone areas are dying is an indication that the current drug regimes are not working," she adds.

That's one of the big problems. Reporting on malaria is bad. While a 10 per cent annual blood examination rate is considered adequate to reflect the ground situation, data from 2004 shows that many states -- Arunachal Pradesh, Assam, Bihar, Jammu and Kashmir, Jharkhand, Kerala, Manipur, Meghalaya, Nagaland, Sikkim, Tripura, Uttaranchal, Uttar Pradesh and West Bengal -- do not adhere to specified testing procedures. While estimates prepared by who suggest that every year there are around 15 million cases and 20,000 deaths in the country, nvbdcp reports around 2 million cases and 1,000 deaths. Medical certification of cause of death data for 1998 shows that only around 15 per cent of certificates gave a reason for death. Of this, around 4,531 were certified as malaria deaths (data for j & k, Bihar, Assam, Mizoram, Uttar Pradesh, West Bengal and Chandigarh not included). If this statistic is extrapolated, approximately 49,746 people died of malaria in 1998.
nvbdcp is responsible for monitoring drug resistance in the Pf pathogen. It was given the responsibility in 1978. But, at present, there are only 13 monitoring teams in 11 regional offices countrywide. The northeast has only one. The data they collect is used to map areas with pathogens resistant to chloroquine and create a database for the national drug policy. Joshi says areas where doctors report treatment failure are assessed regularly. Given the fact that complete treatment is seldom provided in government facilities, this claim is far-fetched.

That reporting is in tatters is also reflected in basic infrastructure lacunae. To ensure that chloroquine is not used as a presumptive treatment, use of rapid diagnostic kits has been recommended to distinguish between Pv and Pf. nvbdcp started providing limited numbers in 2005 after procuring 965,000 kits. In 2006, it has procured 236,000 kits and will order 5,900,000 more in three months. This is not enough.

Bureaucratic sloth is a metaphor for the government's resistance to change, which mirrors the falciparum's resistance to drugs. Unfortunately, the government cannot mimic as easily the pathogen's plastic response to its environment.