Tropical Health Matters

In villages of southeastern Nigeria, Uguru and colleagues found that mosquitoes do not discriminate by socio-economic status (SES), but SES does influence where people go for treatment once those bites result in malaria. “In one of the villages the most poor, very poor and poor significantly used the services of patent medicine vendors and the least poor visited hospitals.”

Expenditure to treat malaria did not vary by SES group and ranged between US$ 1 – 3, with transport costs being less than a dollar.  The difference therefore, was that the poor paid proportionately more for their treatment than co-villagers who were least poor.  Treatment options sought by each group also introduced possible differences in quality of care, too.

As the World Malaria Report of 2005 observed, “Patterns of malaria transmission and disease vary markedly between regions and even within individual countries. This diversity results from variations (in) … conditions that affect malaria transmission and socioeconomic factors, such as poverty and access to effective health care and prevention services.” Because of this, “Malaria control is increasingly recognized as playing a key role in poverty reduction in high burden countries.”

Clearly, people in the villages studied do not have access to cheap or free appropriate malaria medicines, although Enugu State, where the study occurred, has been included in the Global Fund Round 4 Malaria grant in Nigeria. Initially GFATM malaria medicines covered only children less than five years of age who attended government health facilities.

Nigeria has recognized the weakness of a strictly public sector approach and is now making malaria medicines available through both public and private sector sources, particularly the medicine shops frequented by the poor as described in Uguru’s study.

The Society for Family Health (SFH) in Nigeria, with USAID support, has spearheaded an effort to make quality prepackaged antimalarial drugs available cheaply through private sources, such as medicine shops.  Now that SFH is involved with the Global Fund grant in Nigeria, there is hope that this distribution network can be strengthened to reach more people – especially the poor who find it difficult to access formal health services in either the government or the private sector.
There is still a long way to go to achieve universal treatment coverage among the 140 million plus people in Nigeria, but a mixed sector strategy seems to be a good way to start.

Officials in Cape Verde have yet to sign their Global Fund Round 8 HIV grant. IRIN therefore reported that, “People living with HIV in Cape Verde are worried that the HIV/AIDS programme may be disrupted by a change in funders. The World Bank pulled out in June after supporting the programme for seven years, and a US$5.3 million grant from the Global Fund to Fight AIDS, Tuberculosis and Malaria has not yet arrived.”

Major staff cuts have occurred in HIV programming, but ARVs may be sufficient until the end of the year.  Even if the grant is signed tomorrow, it is not certain how quickly procurement of HIV drugs and supplies can happen.

This HIV grant is the first and only award Cape Verde has ever received from the Global Fund. The country has not applied for a malaria grant, and WHO indicates that malaria transmission is focal: “Limited local malaria transmission exists on Sao Tiago (Santiago) island from September through November. The transmission is unstable and mainly due to Anopheles Arabiensis. Plasmodium falciparum is the main parasite. Cases imported from the continent are reported regularly.”

Gaps between funders and funding cycles is not uncommon. Ghana experienced such a near miss in its Global Fund malaria grants as one was closing out and the RCC process was not rolling smoothly nor was a new Round funding coming on board quickly either.  A clear lesson is that funding processes are far from QUICK, and countries must plan their funding pipeline far in advance.

People in Cape Verde may die if the gap in ARV procurement opens and widens.  Likewise people may die when there are delays in grant signing for malaria programs.  People will resort to ineffective malaria drugs that are still available or not seek care if private sector medicine sources are too expensive.  All GFATM applicants need to take the grant signing demands seriously, if they hope to protect the lives of their citizens.

With reports from Southeast Asia of resistance by malaria parasites to artemisinin-based drugs, the race is on to guarantee adequate supplies of these medicines for appropriate treatment in the most endemic areas of the world.  As PBS phrases it, resistance “now threatens to outfox medicine’s last line of effective drugs.”

According to WHO this could reverse the “Huge strides have been made in the past 10 years to reduce the burden of malaria, one of the world’s major killer diseases.” The challenge, as WHO makes clear, includes providing adequate supplies of artemisinin-based combination therapy (ACT), which are used only on parasitologically confirmed cases of malaria and with guarantees that the full, correct does is consumed.

As a natural product, artemisinin has not been easy to produce and store in quantities needed for large scale control programs.  The BBC recently posted an video on efforts to grow Artemisia annua with enhanced artemisinin content. The video explains techniques that were used to breed the plant far more quickly than traditional methods using “fast track molecular methods.” The new plants are being disseminated for field testing to parts of the world where the plant is being grown commercially.

Keeping ahead of resistance requires not only better and faster supplies of ACTs to the front line.  There is also need for drug response surveillance, health education on correct treatment practices and continued vector control efforts.

We should also remember another approach to artemisinin production. A group at the University of California, Berkeley, “has been refining their method of engineering E. coli and yeast to produce a chemical precursor of artemisinin – the most effective malaria treatment available. Artemisinin is sorely needed in the developing world, but too expensive to produce to be affordable.” Not only could such approaches yield more affordable medicines, but could also eventually engineer a form of medicine for which parasites are not resistant

The race is on – will we be able to disseminate enough ACT supplies to make a major dent in malaria morbidity, mortality and especially prevalence before resistant parasites win their own race across the continents from Asia to Africa has happened with chloroquine and sulfadoxine-pyrimethamine?

The biggest threat may not be drug resistance or insecticide resistance but bureaucratic resistance that threatens timely scale-up and sustained implementation of our available interventions, which are the precursors to malaria elimination.

The Nigerian Tribune reports today that, “A clearing agent(names withheld) has been apprehended by the National Agency for Food, Drug Administration and Control (NAFDAC) over his involvement in the importation of fake malaria drugs (Maloxine and Amalar tablets) worth N32.1million.”

The fake products were produced in China but labelled “Made in India,” according to NAFDAC.  Their lab tests showed that these supposed sulphadoxine-pyrimethamine (SP) products lacked the pyrimethamine.  The Tribune quoted the NAFDAC boss as saying that, “the seizure was significant in view of the emergence of resistance strain of malaria parasites, saying the use of the fake drugs might lead to treatment failure, anaemia and death if no effective drug was given after.”

Ironically, these two SP products should not be imported for treatment, since studies dating back five or more years have shown a growing SP resistance. At present the national malaria drug policy recommends only artemisinin-based combination therapy (ACT) for treatment, while reserving SP for intermittent preventive treatment in pregnancy.  The fact that people are still demanding SP products for treatment shows lack of success in educating providers and consumers about the correct medicines as published in 2005 within the drug policy.

At the other end of the malaria drug spectrum, the Registrar of the Pharmacists Council of Nigeria (PCN) worried that unless patent medicine shops are “fully registered and regulated, the health of the people in the state will continue to be in jeopardy.” The PCN Director said that, “training (of PCN staff), which began in 2004 was informed by the council’s desire to train and retrain its staff on transmission, storage and general management of vital records.” It is not clear when and if PCN actually intends to offer training for the medicine shop owners and clerks.

The Tribune also reports that in an effort to comfort parents whose infants are experiencing what they perceive as ‘teething problems’, makers of commercially sold teething mixtures will include “very low doses of anti-malaria, especially those produced here in Nigeria or in the tropics. They also have pain relievers. However, we do know that malaria is not treated or prevented that way in children.” Since these mixtures may not be registered to treat disease, they may not be adequately regulated – and not surprisingly have led to the deaths of many children recently.

A scoping study by Nigerian researchers from the University of Ibadan has shown that patent medicine vendors (OMV) do need more education on the products that they sell – especially a full orientation on the current national malaria drug policies.  They continue to sell the more of the old first-line drugs, chloroquine and SP, instead of the recommended ATCs in large part because their customers cannot afford the new medicines. The researchers have recently called together key policy makers and donor partners to address the PMV question and find ways to improve their practices. We look forward to learning what was achieved.

In the meantime, Nigeria is among the first applicants to the new Affordable Medicines Facility – malaria (AMFm). AMFm “enable countries to increase the provision of affordable ACTs through the public, private and NGO sectors.” AMFm also “will reduce the manufacturer sales price of ACTs to public, private and not-for-profit sector buyers.” This will be an ideal way to ensure that quality ACTs are available to the public at a price they can afford from whichever outlet is most convenient.  AMFm will not succeed though without proper education and training of all providers, including PMVs and the public at large.

An article in Nigeria’s Daily Trust on Sunday casts doubts about the availability of adequate treatment for malaria in the country with a headline that asks, “What Happened to Funds Sunk Into Anti-Malaria Projects?”  It is true that with Nigeria having the highest burden of malaria on the continent there may not yet be enough money, medicines, nets and other resources – the Minister for Health estimates that the country needs $1.3 billion – but that does not mean that current funds are being squandered as the headline implies.

In fact an irony may be that there are too many different types of drugs. Nigeria’s National Agency for Food Drug Administration and Control (NAFDAC) has registered the following Artemether-Lumafantrine ACTs:

• Actimax
• Actpro
• Arcofan
• Artemef
• Artrin
• Atmal
• Coartem
• Fanterm
• Lonart
• Lumether
• Malagard
• Ogamal

Nearly 100 Artesunate-Amodiaquine ACTs have been registered. Few of these ACTs are prequalified by WHO. Some monotherapy artesunate drugs, which WHO disapproves and whose NAFDAC registration won’t expire until 2012, are still for sale and available in shops.  There are at least 5 Artesunate-Mefloquine brands.  Artesunate-SP is registered in up to 10 brands.

Aside from the above, chloroquine is still common as is sulphadoxine-pyrimethamine, both of which exhibit resistance and are no longer recommended for first line treatment in Nigeria. There is of course quinine needed for treatment of malaria in pregnancy. Overall over 325 different brands of antimalarial drugs are registered.

While there may not be enough free or reduced price pre-qualified antimalarial drugs at the front line primary health care facilities, there is a plethora of questionable drugs on the market. One wonders how anyone could test, let along maintain pharmaco-vigilance, on all these medicines.

We hope Nigeria is successful in getting its Global Fund Round 8 malaria grant signed and has a positive experience in applying for the Affordable Medicines Facility for malaria to strengthen quality and supply of inexpensive drugs in the public and private sectors.  In the meantime, partners at national, state and local levels need to consider how the consumer – which includes local and state government medical stores – can make sense of all the antimalarial drugs out there.  Maybe one day NAFDAC and the National Malaria Control Program can truly work in partnership to ensure rational pharmaceutical practices.

This morning the Daily Monitor of Uganda reported that, “At least 30,000 farmers in the districts of Kabale, Kisoro and Ntungamo who are growers of a medicinal plant that is a raw material for anti-malaria drugs are angry that the company that urged them to grow the plant has closed shop leaving them counting losses.” The artemisinin extracted from these leaves is the base for the current recommended first-line treatment of malaria – artemisinin-based combination therapy (ACTs).

It certainly seemed like a good idea in theory to grow A. annua in endemic countries and involve local farmers and the pharmaceutical industry in ACT production and at the same time promote economic development. But as the Daily Monitor shows, this can be a complicated process.  The leaves need to be harvested at just the right time to get the maximum concentration of the antimalarial drug.  The company complained to the Monitor that they were disappointed with their farmers who adulterated the quality:“Most of our farmers harvested Artemisia leaves before they matured. This lowered the artemisinin content.”

IRIN News explained that “In Kenya, the project is being spearheaded by East African Botanicals, which provides seedlings and supports both large- and small-scale farmers in a bid to rapidly increase the volume of plants.” The company spokesperson described their operations thus –

“By the end of 2005, we will have an estimated 1,200 hectares of the crop growing in Kenya,” explained a representative from the company. “We are also growing in Tanzania and Uganda, but still we cannot meet the demand. I am not able to overstate the shortage of this raw material worldwide. What we are growing is definitely making an impact on the shortage but not on the scale needed at the moment. “Everything we are doing is towards a very rapid scale-up of production: contracting more large- and small-scale farmers; planting more hectares; and finding ways to harvest the crop much faster,” he said.

IRIN also reports on efforts in Indonesia to grow A. annua. A government spokeswoman said, “farmers in Tawangmangu, where the soil was suitable for artemisia annua, traditionally grew vegetables and needed assurances that switching to the herb would bring them more benefit.  She expected Indonesia would be able to produce its own Artemisinin by 2010.” One hopes that these farmers will not be left without food crops or artemisinin profits like their Ugandan counterparts.

To make local production of Artemesia annua work there needs to be planning and coordination among government agencies, farmers, and the pharmaceutical industry. Botanical Extracts EPZ Limited in Kenya does claim to be making a profit from locally grown artemisinin, and so it should be possible for all partners to come together for success. The role of agriculture extension in educating farmers and helping them develop a safety net when A. annua crops fail is essential.

Finally, as we have stressed before, we hope that the eventual production of artemisinin synthetically or through biological processes will not render these farmers’ efforts useless.

Many communities lack access to health facilities due to distance or seasonal rains.  Strategies that ensure residents of these communities get appropriate malaria treatment promptly should be a central part of any country’s national malaria plan. According to WHO the HMM strategic components include –

1. Availability of and access to effective, high-quality, prepacked antimalarial medicines at the community level.
2. Training of community-based service providers to ensure they have the necessary skills and knowledge to manage febrile illness or malaria.
3. An effective communication strategy to ensure correct early care seeking behaviour, and appropriate and effective home care of a febrile illness or malaria.
4. A good mechanism for supervision and monitoring of the community activities.

Elmardi and colleagues describe their efforts to provide home management of malaria in less accessible areas of Sudan, and not only include provision of artemisinin-based combination therapy (ACTs) at the village level but also the training of community volunteers to use rapid diagnostic tests (RDTs).

Research sponsored by WHO/TDR has shown that community volunteers have had an important impact on coverage of appropriate ACT treatment of malaria:

• 77% where there were village volunteers
• 33% through health facilities alone

The Sudan experiment in 20 villages provides some important management lessons. All but one volunteer followed treatment guidelines.  On the other hand only 14 relied on the RDT results when treating, and thus provided ACTs for other febrile conditions.

The importance of supervision to reinforce training was underscored here. Supervision is important even for regular health workers in clinics, let along volunteers in villages, but we know that many health systems do not have or utilize the necessary logistics to carry out supervision on a regular basis. The same rains that make it difficult for villagers to reach clinics may make it difficult for health workers to make supervisory visits.

The community volunteers in Sudan were not much different from health workers in clinics in believing that their judgment is better than RDTs.  This is unfortunate.  The community volunteers were also exposed to pressure from clients who were reluctant to accept that they did not have malaria when they made their complaints.

As mentioned by WHO, home management of malaria needs an effective communication strategy.  Community members have their own perceptions of malaria. Communication must be grounded in an understanding of what the community believes and expects.  Only then will local volunteers be able to convince people on the accuracy of RDTs.

Of course it would help greatly if village volunteers had medicines to treat other common ailments so clients with these complaints will not have to go away empty handed.

The Wall Street Journal quotes Novartis Chief Executive Daniel L. Vasella as saying, “In the end the only drug that matters is the drug that is swallowed.” The article goes on to explain how Novartis has developed a form of Coartem that is “Dispersible, that is small, cherry-flavored and dissolves easily,” as a way to ensure that the dispensed medicine is actually swallowed. The article also addresses other flavors that may be tried.

Much progress has been made in packaging malaria drugs for different age groups, especially children, when before there were only standard adult doses than had to be divided – a challenging task for many parents. The alternatives for children were more expensive syrups that were not always stable in tropical climates.

The article also addresses other challenges to ensuring children get their drugs. “But efficient channels to distribute the products are rare, giving rise to what health workers call ‘pile-up’ of drugs trying to reach villages and health clinics.” Efficient distribution is essential since artemisinin based medications have a relatively short shelf life and can expire within 18 months of arriving in a country.

Another challenge is cost. Medicines bought through Global Fund Grants are generally made available free for children in public or NGO clinics. Pilot programs are underway to see how subsidized price antimalarials can be made available through the private sector which may actually account for 50% or more of actual malaria treatments provided.

Three challenges that are not mentioned in the article include –

• For one, when drugs are made available for free or at reduced cost only for children, there will be leakage into wider use as health workers or medicine shop keepers will provide multiple packets of the child drugs to satisfy their adult clients/customers.
• A second unmentioned challenge is the tendency to overprescribe malaria drugs, especially among adults.  The answer to this is case management that includes diagnosis using a laboratory, but more likely rapid diagnostic tests, which can be used at the primary care level
• Finally there is the issue of compliance.  Artemisinin-based combination therapy generally is taken twice a day for three days. If medicine providers do not counsel clients on the need for full compliance children may swallow only a few doses and not only fail to be cured but also contribute to drug resistance.

Malaria case management is a complicated process that begins with the drug manufacturer and ends in the home. All partners along the way must be vigilent if children’s lives are to be saved.

The BBC reports that, “Around 100 million ACTs were sold in 2006, but forecasters say that demand will at least double over the next four years, potentially growing to over 300 million doses annually.This is partly due to a recent decision by the global malaria community to subsidise the cost of ACTs. There is already expected to be a shortage in 2010 owing to a lack of the Artemisia annua wormwood plant plant, the raw material for ACTs, being grown.”

The Artemisinin Enterprise is planning a three-pronged approach to address the problem as reported in Medical News Today.

• The Centre for Novel Agricultural Products at the University of York is using fast-track plant breeding to increase yields of artemisinin from the medicinal plant.
• The Institute for One World Health is using synthetic biology to produce artemisinin through fermentation and subsequent chemical conversion.
• The Medicines for Malaria Venture is developing novel synthetic artemisinin-like compounds.

RBM explains that, “All three approaches are needed to satisfy projected global demand for ACTs. The projects are collaborating to ensure maximum impact on ACT supply chains and to ensure the new technologies do not enter substandard drug or monotherapy supply chains.” A full report of the recent conference that explored these options can be found at the website of Centre for Novel Agricultural Products.

In the meantime research needs to continue on other natural plant derivatives for curing malaria to avoid the dangers of having only one main tool for achieving and maintaining treatment levels needed to eliminate the disease. Of course, rational use of ACTs now is crucial.

A discrepancy “between the perceived and actual level of transmission intensity” has been observed in the ‘Mosquito River’ area of Tanzania near Arusha by Mwanziva and colleagues. Specifically, they found …

Malaria transmission intensity by serological assessment was equivalent to < 1 infectious bites per person per year. Despite low transmission intensity, >40% of outpatients attending the clinics in 2006-2007 were diagnosed with malaria. Prospective data demonstrated a very high overdiagnosis of malaria. Microscopy was unreliable with <1% of slides regarded as malaria parasite-positive by clinic microscopists being confirmed by trained research microscopists. In addition, many ‘slide negatives’ received anti-malarial treatment. As a result, 99.6% (248/249) of the individuals who were treated with ACT were in fact free of malaria parasites.

A similar experience was found in urban Lagos, Nigeria ten years ago*:

• Blood film investigation of 916 children between the ages of 6 months and 5 years yielded a parasite prevalence rate of 0.9%.
• Night knockdown collections of mosquitoes in rooms yielded only C. quinquefasciatus and A. aegypti
• Very low densities of A. gambiae larvae were found in breeding sites (between 0.3 and 0.7)
• Community members, during focus group discussion identified malaria, in it various culturally defined forms, as a major health problem.
• Among the children examined clinically, 186 (20.3%) reported an illness, which they called “malaria” in the previous two weeks, and 180 had sought treatment for this illness.
• Data obtained from 303 shops in the area documented that a minimum of US $4,000 was spent on purchases of antimalarial drugs in the previous week.

This contrasts with a report from Médecins Sans Frontières (MSF) that “ weak distribution and health systems and a lack of qualified staff” are reasons why poor people in many malaria endemic areas do not receive appropriate treatment.

During a recent visit to Mozambique I observed that antenatal clinic staff had Rapid Diagnostic tests. Some explained that if the test was negative, they would send the client to the lab. If the lab results were negative, they would still treat to be on the sfae side.  This reinforces the conclusion by Mwanziva that “rational drug-prescribing behaviour” must be reinforced. Of course as seen in Lagos, this concern goes well past the behavior of orthodox prescribers.

This malaria treatment gap poses serious threats to both lives and resources.  The shame is that health workers and program planners bear as much of the responsibility as the patients themselves, if not more. This is a challenge may be met through development and enforcement of better treatment performance standards.

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*Brieger WR, Sesay HR, Adesina H, Mosanya ME, Ogunlade PB, Ayodele JO, Orisasona SA. Urban malaria treatment behaviour in the context of low levels of malaria transmission in Lagos, Nigeria. African Journal of Medicine and Medical Sciences 2002; 30(suppl): 7-15.