Tropical Health Matters

The introduction of Artesunate-Amodiaquine in M’lomp village, Senegal has been monitored over time by Sarrassat and colleagues.Their efforts were motivated by experiences in Thailand, South Africa and Zanzibar, where a decrease in malaria morbidity was observed following the introduction of artemisinin-based combination therapy (ACT).

Decreased incidence has been postulated as an effect of artemisinin-based medicines’ ability to kill gametocytes and reduce transmission (Drakeley et al.; Nosten et al.; Carrara et al.; Barnes et al.; Battarai et al.).

Sarrassat’s team also observed a decrease in the incidence rate and repetitiveness between 2001 and 2002. They were worried that lower rainfall might also have contributed to the findings, especially since treatment coverage was less than ideal.

Ultimately Sarrassat et al. concluded that, “In sub-Saharan countries, in order to optimize the impact on malaria morbidity, ACT deployment must be supported, on the one hand, by a strengthening of public health system to ensure a high ACT coverage and, on the other hand, by others measures, such vector control measures.”

A home management strategy has been one recommendation to improve the ability of health systems to increase ACT coverage. Generally though timely procurement and supply procedures are required to make ACTs available for the whole population at risk. In order to do this, health systems need strengthing as Sarrassat suggests.

BBC is featuring community medicine distributors in Uganda as part of its series on ‘Survival TV’. While the video starts with how things were in a Ugandan community with a funeral of a child who died from malaria, the work of two community medicine distributors in combating malaria with readily available packs of Coartem® (arthmether-lumafantrin) and long lasting insecticide treated nets (LLINs) ultimately provides a positive outcome for Ugandan children.

Home management of malaria (HMM) is not new to Uganda. Kolaczinski and colleagues reported, “In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK®) free of charge to caretakers of febrile children.” Caregivers for children were impressed by the safety of the blister packs, and having been guided be the CDDs 95% of them had administered the correct dose of medicine to their children.

The medicines have changed to arthmether-lumafantrin now, but a recent 3-country assessment “provides encouraging data on parasitological outcomes of children treated with ACT in the context of HMM and adds to the evidence base for HMM as a public health strategy as well as for scaling up implementation of HMM with ACTs.” On average correct adherence was 94% across Uganda, Ghana and Nigeria.

The benefits HMM are not just to the individual child and family, but also to the health system. Sievers and colleagues found in Rwanda that “both admissions for malaria and laboratory markers of clinical disease among children may be rapidly reduced following community-based malaria control efforts.” They also cautioned that as malaria cases and hospital admissions became less frequent, “More accurate diagnosis and management of febrile illnesses is critically needed both now and as fever aetiologies change with further reductions in malaria.”

Another effect of properly organized HMM is reflected in the title of a new article appearing in Malaria Journal: “Implementation of home-based management of malaria in children reduces the work load for peripheral health facilities in a rural district of Burkina Faso.” Not only were fewer children with malaria seen at health facilities in the intervention communities, but in fact more children in those communities were actually treated for malaria in those communities.  HMM clearly improved access to correct malaria treatment.

This access issue was demonstrated in a study by the Tropical Disease Research (TDR)project of UNDP, World Bank, WHO and UNICEF. In districts using CDDs for HMM more children were reached. In fact excepting Cameroon where there were policy and logistical challenges to community drug distribution, reaching the RBM targets was seen as feasible through HMM compared to where malaria treatment was made available only through the normal health care system.

The TDR project built on the successful experience spanning over a decade of ivermectin distribution to control onchocerciasis. When community directed distribution started, health workers worried that communities were not capable to taking charge on medicines. Later they learned that not only could communities deliver ivermectin safely and accurately, but that they could maintain good annual treatment coverage. Finally the health workers learned that community directed distribution helped the health system reach ‘people beyond the end of the road’ who otherwise would not have benefitted from services.

HMM empowers the community and enhances the ability of the health system to reach those in need. HMM should be a central strategy in any malaria control program.

Catholic Relief Services describes the life of Rasmané, a day laborer in Burkina Faso, who works at “a plastic chair factory, where he makes about $37 a month. This won’t go far for Rasmané, his four kids, his mother and wife. That’s why they eat baobab leaves and cheap millet (see photo by Lane Hartill/CRS). A sack of rice that would last a few weeks costs about $55.”  According to CRS, “Some 75 percent of people living in or near Burkina’s major cities don’t have enough food to eat.”

Staple food prices have more than doubled. “Rasmané says he has never seen food prices jump like this. A portion of corn last year was 50 cents. Now, it’s $1.15. A portion of millet was 55 cents. Now it’s $1.25. For someone who doesn’t know from one day to the next if he will work, these price swings sting.” CRS notes the contrast: “Residents of Burkina Faso spend about 76 percent of their monthly income on food. Americans, on the other hand, spend only about 10 percent of their income on food a year, according to the USDA.”

The question arises, what if one of those 4 children get malaria?  Kouéta and colleagues found in Burkina that poor nutritional status was one of the key factors associated with increased risk of death in children with malaria.

Burkina had a short-lived Global Fund Malaria Grant in Round 2 and recently started on its Round 7 grant in June 2008. The first objective of the new grant is to “ensure proper treatment of simple malaria cases diagnosed in health facilities.” Public, private and community health workers are to be trained in proper case management. The GFATM expressed concern in the first progress report that there be proper coordination between principle and sub-recipients for full implementation. The need to closely monitor ACT estimations and actual consumption was stressed.

A reading of the Round 7 proposal implies that ACTs may be subject to the overall national strategy of cost recovery.  One wonders if people like Rasmané can really pay for proper malaria treatment for their children?

The New Vision online (Uganda) reports that “The Government is to provide Coartem, an anti-malaria drug, to private health units at a subsidised price, the Ministry of Health announced yesterday.”  These will be sold at ‘affordable prices‘ according to the ministry.

“Primary health care state minister Emmanuel Otaala said the ministry, in conjunction with donors, would provide the drugs at sh200 per dose for children and sh800 for adults.” Normally Coartem costs “between sh12,000 and sh18,000 in private clinics.” In approximate dollar terms this is a difference between a subsidized rate of US $0.12- 0.48 compared to $7.25 – 10.87.

For implementation the devil will be in the details in terms of procurement and supply chain management (PSM) (public vs private) as well as positioning of the subsidized drugs where existing products may offer the shop owners a greater profit margin.

Nigeria is reframing its Round 4 Global Fund Malaria Grant to include the private sector and provides some lessons about the challenges of dual districution channels for ACTs.  The August 2008 grant progress report outlines these issues.

“There was a delay in the approval of the PSM plan because the PR wished to repackage their ACTs in a manner that would differentiate them from those given out by YGC (Yakubu Gowon Center – PR Public Sector), the other malaria PR. That is because SFH (Society for Family Health – PR private sector) is distributing ACT through the private sector with cost recovery and YGC distributes through the public sector for free. As there were no compliant factories in Nigeria, SFH had to change suppliers to one that could package the drugs according to their needs. This delayed the approval of the PSM plan which was finally approved on March 8th 2008. Procurement is now underway andimplementation can begin fully in the next quarter.”

Private sector involvement is crucial for achieving coverage for a number of reasons, least of which are the fact that in Nigeria it was estimated that a monitory of people with malaria get their treatment in medicine shops. One could never achieve 80% prompt treatment with ACTs only in the public sector.  So while the effort is commendable, it is not something that can be embarked upon quickly.

Well thought out logistics and monitoring plans are needed to ensure the subsidized ACTs actually reach their intended population.

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Please note that the World Malaria Report 2008 is now available to download from WHO’s Global Malaria Program.

The Daily Monitor today warns Ugandans about the potential of fake antimalarial drugs in their midst. “According to the Chairman of the National Drug Authority (NDA) Board, Dr Frank Mwesigye, the drugs that are on high demand are the most counterfeited.” Specifically, “Officials at the National Drug Authority, the body charged with ensuring that all drugs coming into the country are of good quality, have now admitted that individuals dealing in counterfeit drugs are maneuvering through the country’s porous borders and selling fake drugs on the local market.”

On the positive side the NDA Chairman “explained that all drugs imports that go through NDA and those manufactured in Uganda are genuine. About 15 per cent of the drugs used in Uganda are manufactured locally.”  Apparently a recent study published in PLoS One stimulated testing by the NDA of 237 different types of drugs, and all were found to be genuine.

NDA staff, speaking to reporters anonymously were not as certain of the effectiveness of the agency and “called for more resources given the additional duties assigned to them. They said they are now required to inspect food stuffs and cosmetics that are imported into and exported out of the country,” in addition to monitoring over 400 pharmacies in the country.

Apparently the NDA believes that most fake drugs would wind up in the private sector. Fortunately patients can make use of quality drugs provided in the public sector through donor efforts like the Global Fund and the US President’s Malaria Initiative, but another story in the Monitor questions whether the country is doing enough:

According to the report released by the UN’s World Health Organisation, expenditure on medicines ranges from $0.04 to $16.30 across least developed countries. Currently, Uganda’s per capita expenditure on drugs is $1.7 (Shs 2771) yet the ideal spending -within in the country’s limits would be $3.7.

Finally, the ability to perform laboratory diagnosis at the Arua Referral Hospital laboratory was curtailed by theft of two microscopes.  “Daily Monitor has learnt that the machines at the hospital are not labelled making it hard for the police to trace them. According to the police, one microscope has been recovered from a casual labourer.”

The lessons from Uganda show that constant vigilance is needed if patients who suffer from malaria expect to receive efficacious and appropriate life saving treatment. It is not enough for donors to provide supplies, commodities and equipment. Each endemic country must have strong infrastructure – both management and regulatory – to protect and deliver these malaria investments.

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A colleague in Bamako – home of the famous Bamako Initiative – shared an experience with one of the staff members in her organization who sought malaria treatment for a sick 3 and 1/2 year old child at a front line community health clinic.  On the first visit the child was prescribed quinine injection for that cost about US 28 cents.  After three days the child was still sick and returned to receive ACTs at a cost of $10.07.

This raised a few questions. Why were RDTs not used? Why were ACTs not the first line of treatment? Why did the family have to pay for the medicines?

One can answer the first question with the concern that children under 5 years can benefit from prompt and presumptive treatment as a life saving measure.  When the presumptive treatment is NOT the first line drug, one senses that the value of prompt treatment may be negated. Even though the Ministry of Health has printed and circulated malaria treatment guidelines, when one looks at the cost differences, one can get an idea of what the health worker might have been thinking – and it was unlikely to be the guidelines.

The Bamako Initiative is a community based and community managed cost recovery mechanism. The program has been working in Mali for over 15 years. This makes sense for inexpensive essential drugs. So why was the family charged what appears to be the cost of an adult dose for a small child? The ultimate answer may be that the community health service has had to buy ACTs for resale because Mali is what one might call “in between grants”.

The Round 1 Global Fund Grant for Malaria wrapped up almost two years ago. The Round 6 Grant is just taking off. PMI support is available, but also in a start-up phase.

Fortunately the child ultimately got the correct ‘presumptive’ treatment, and also fortunately the parents could afford it.  This scenario may repeat itself in other countries. Therefore all partners must coordinate their efforts in a country and work together to close the “ACT gap.”

Although we have been advocating for continued research into new antimalarial drugs, David Smith of the University of Florida’s Emerging Pathogens Institute says that, “We don’t have anything in the pipeline after ACTs, and it’s basically just a matter of time until drug resistance evolves and artemisinin also fails. So the question becomes how do we keep ACTs in our arsenal for as long as effectively possible?”

Smith, a co-author on a study that is scheduled to publish online this week in the Proceedings of the National Academy of Sciences pointed out that, “The models indicate that we can slow the evolution of resistance to current artemisinin-based therapies if nations use them in combination with two or more partner drugs. Currently, most nations don’t do this. They use one therapy at a time, wait for it to fail, and then switch to a different therapy.”

Issues of cost, logistics and policy implementation are at the root of the problem. In Nigeria, for example, monotherapy artemesinin-based drugs are still available in shops, although the National Agency for Food and Drug Administration is no longer granting new licenses for monotherapies. Some of the old licenses have a few years left, unfortunately.  ACTs brought in through donor programs like the Global Fund have been targeted free for children, which leaves the door open for ‘leakage’ to the adult population who may take lower than effective doses and promote drug resistance.

The upcoming article in PNAS will explain that, “The researchers’ models also show that cycling through single drugs accelerated the rate at which malaria parasites evolved drug resistance. Smith said this occurred because cycling a single drug degraded the parasite’s average fitness, which made it easier for drug-resistant genes to spread throughout the parasite population.”

The contrast still persists with free or subsidized ACTs in the public sector, often aimed only at children and expensive ACTs in the private sector for adults. Unless a comprehensive national malaria drug policy can be implemented throughout all elements of the health sector, the threat of developing resistance to aretesinim-based medicines will persist.

From time to time news stories appear that stress the healing powers of common herbs and spices. The value of turmeric (curcumin), the yellow powder used in many Indian dishes, has again been promoted on the web.We have talked about the importance of continued research for new malaria drugs. PubMed offers some studies that have looked at the effect of turmeric on malaria.

In 2005 Reddy and colleagues showed that, “curcumin, a polyphenolic organic molecule derived from turmeric, inhibits chloroquine-resistant Plasmodium falciparum growth in culture in a dose dependent manner … Additionally, oral administration of curcumin to mice infected with malaria parasite (Plasmodium berghei) reduces blood parasitemia by 80-90% and enhances their survival significantly. Thus, curcumin may represent a novel treatment for malarial infection.”

Nandakumar et al. (2006) reported that, “Artemisinin and curcumin show an additive interaction in killing Plasmodium falciparum in culture. In vivo, 3 oral doses of curcumin following a single injection of alpha,beta-arteether to Plasmodium berghei-infected mice are able to prevent recrudescence due to alpha,beta-arteether monotherapy and ensure almost 100% survival of the animals.”

Concern about multi-drug resistant parasites led Cui et al. (2007) to explore the effects of curcumin on malaria. Observing from previous research that, “Among its antiprotozoan activities, curcumin was potent against both chloroquine-sensitive and -resistant Plasmodium falciparum strains,” these authors found curcumin displaying cytotoxicity for malaria parasites.

The most recently reported research by Martinelli and colleagues (2008) put something of a damper on the subject. They report that, “Recent studies have proposed curcumin as a potential partner for artemisinin in artemisinin combination therapies to treat malaria infections. The efficacy of curcumin alone and in combination with artemisinin was evaluated on a clone of Plasmodium chabaudi selected for artemisinin resistance in vivo. The addition of piperine as an enhancer of curcumin activity was also tested. Results indicated that curcumin, both alone and in combination with piperine had only a modest antimalarial effect and was not able to reverse the artemisinin-resistant phenotype or significantly affect growth of the tested clone when used in combination with artemisinin. This is in contrast with previous in vivo work and calls for further experimental evaluation of the antimalarial potential of curcumin.”

Their call for further research should be heeded … and funded.

• Cui L, Miao J, Cui L. Cytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: inhibition of histone acetylation and generation of reactive oxygen species. Antimicrob Agents Chemother. 2007 Feb;51(2):488-94. Epub 2006 Dec 4.
• Martinelli A, Rodrigues LA, Cravo P. Plasmodium chabaudi: efficacy of artemisinin + curcumin combination treatment on a clone selected for artemisinin resistance in mice. Exp Parasitol. 2008 Jun;119(2):304-7. Epub 2008 Mar 7.
• Nandakumar DN, Nagaraj VA, Vathsala PG, Rangarajan P, Padmanaban G.. Curcumin-artemisinin combination therapy for malaria. Antimicrob Agents Chemother. 2006 May;50(5):1859-60.
• Reddy RC, Vatsala PG, Keshamouni VG, Padmanaban G, Rangarajan PN. Curcumin for malaria therapy. Biochem Biophys Res Commun. 2005 Jan 14;326(2):472-4.

The Clinton Foundation is tackling a challenge that faces the world market for artemisinin-based combination therapy (ACT) medicines – the supply, demand and ultimately the price of the basic ingredient. The move by malaria control partners to get countries to switch to ACTS and save lives amid the failing efficacy of chloroquine and sulfadozine-pyrimethamine was relative swift and did not account for the normal market forces involved in introducing new pharmaceutical products, especially when these are provided free or at cost to the end user.

In addressing Kenya’s rapid policy change to ACTs, Zurovac and colleagues concluded that, “Changes in clinical practices at the point of care might take longer than anticipated. Delivery of successful interventions and their scaling up to increase coverage are important during this process; however, this should be accompanied by rigorous research evaluations, corrective actions on existing interventions and testing cost-effectiveness of novel interventions capable of improving and maintaining health worker performance and health systems to deliver artemisinin-based combination therapy in Africa.” They also said that policy makers should be “carefully prepared for a myriad of financial, political and legislative issues that might limit the rapid translation of drug policy change into action.”

According to news reports, “In 2002, Clinton established an HIV/AIDS initiative that sought to negotiate lower prices for anti-retroviral treatments, and he since has expanded his focus to include malaria treatments such as artemisinin-based combination therapies, or ACTs. One of the factors making the price of artemisinin so volatile – fluctuating from $155 to $1,100 per kilogram in recent years – has been a wildly erratic cycle of shortage and excess of the extract.”

Earlier this year, one of the major producers of ACTs, Novartis, announced, “a 20% average reduction in the price of Coartem^® tablets (artemether/lumefantrine 20 mg/120 mg), the state-of-the-art artemisinin-based combination treatment (ACT) for malaria. Starting this Friday, which is World Malaria Day, this price reduction will increase access to Coartem for millions of malaria patients, especially children in low income regions of Africa.”

Of course Novartis, like other producers must not only rely on supplies of this natural product which is subject to the normal risks of agricultural production, but also to the fact that countries who need ACTs do not always order their supplies in a timely and coordinated manner. This is despite the fact that Novartis has had an edge on other ACT manufacturers by being the first WHO prequalified drug, guaranteeing its priority purchase through Global Fund grants.

The AP story goes on to explain that, “Clinton said he has negotiated with six suppliers involved in producing ACTs that have agreed to certain price ceilings that the foundation says will help keep prices constant and not so dependent on the fluctuating cycles.The agreements are with two suppliers at three levels of the supply chain — raw material, processing and final formulation — and the foundation hopes to add more suppliers.”

Previously we have addressed the potential for synthetic artemisinin production as well as the need for continued research into new and alternative malaria drugs. Stabilizing the price of the raw product will certainly have short term benefits. The long term requires increasing the scope of our malaria treatment arsenal.

The process that ensures people in malaria endemic countries get appropriate and timely life saving treatment starts far away from the individual sufferers. Researchers determine safe and efficacious medicines, international agencies issue guidance, national governments develop treatment policies, guidelines and standards, pharmaceutical companies scale up production, funds to purchase drugs are mobilized, orders for medicines are placed and shipped … and after all these steps treatment has still not reached those in need.

Once the medicines are in the country (either produced there or imported) the supply/distribution chain continues through both public and private warehouses and medical stores. In the public sector the debate over who delivers or collects the medicines start – do states, regions, and districts collect from the national stores or are the medical stores responsible for shipping supplies out to the regions and districts. The debate begins again at the district level when individual facilities contemplate how to get their own supplies.

Assuming the appropriate medicines reach the shelves of the frontline clinic or medicine shop, the next step is for clients to obtain these for themselves and their children.  Eligibilty questions come up – are free medicines only for children or everyone.  Finally the medicines reach the home.  Success of malaria control ultimately rests on the last step, taking the full, correct dose of the medicines.  So what do we know about adherence to malaria drug regimes?

In Senegal Souares and colleagues looked at adherence to a regimen of SP-amodiaquine, in use then, as a proxy for adherence to ACTs at the point when this would be introduced, since both had a 3-day regimen. They found that, “35.3% of children did not comply with the recommended doses and 62.3% did not exactly adhere to the drug schedule. Despite the good efficacy of the drugs, adherence to the therapeutic scheme was poor.” Even though efficacy was good, they foresaw a time when poor adherence could lead to drug resistance and recommended training of health workers to improve patient-provider communication about adherence.

We cannot wait for haphazard adherence to lead to ACT failure. ACT performance standards are needed and should be part of the roll out of any government or donor funded malaria treatment program.  Importantly, training on these standards must reach the private and informal sector, too.