Tropical Health Matters

Providing malaria treatment once a term to Kenyan pupils offers important benefits according to this headline: “Malaria prevention in schools reduces anaemia and improves educational potential in Kenyan school children.” In fact lower rates of anemia and improved classroom attention were achieved. Children do not have to be observably sick from malaria to be affected by the disease – the prevalence of P. falciparum was around 40% in these children at baseline.

The study which is fully described in The Lancet, was “A stratified, cluster-randomised, double-blind, placebo-controlled trial of IPT in 30 primary schools in western Kenya. Schools were randomly assigned to treatment (sulfadoxine-pyrimethamine [SP] in combination with amodiaquine or dual placebo) by use of a computer-generated list. Children aged 5–18 years received three treatments at 4-month intervals (IPT n=3535, placebo n=3223). The primary endpoint was the prevalence of anaemia, defined as a haemoglobin concentration below 110 g/L. This outcome was assessed through cross-sectional surveys 12 months post-intervention.”

Here is an example where Millennium Development Goals for health and education goals can be achieved through a common intervention.

Of course the benefits of a school-based health program are based on the levels of school attendance, and as reported, “School-age children represent 26% of Africa’s population where 94% of children go to school.”  It should be stressed that this figure is for primary school students.

Interestingly the average age of the study pupils was almost 14 years, likely reflecting late start for education possibly due to family financial problems. The implication for community level malaria control is that there may be a large number of 5-8 year old children who are not yet in school, but are hopefully protected by ITNs at home.

While WHO’s Global Malaria Program (GMP) acknowledges the existence of a now quite extensive body of research on intermittent preventive treatment for infants, it has yet to endorse the practice. The fact that the current study on school children was “funded by the Gates Malaria Partnership which is supported by a grant from the Bill & Melinda Gates Foundation (with) additional funding … provided by the Norwegian Education Trust Fund and multi-donor Education Development Programme Fund of the World Bank; DBL Centre for Health Research and Development; and the Wellcome Trust,” is unlikely to sway opinion at GMP, which has been critical of Gates’ involvement in malaria control and research.

While some may question the use of SP as part of the IPT regimen for these children, the overall concept of IPT for primary school pupils is valuable. One cannot assume that because they don’t look sick that these children are in fact healthy and are not part of the malaria transmission process – it would be a mistake to neglect school children. Partners need to work together to increase available interventions that can reach this group so that endemic countries will ultimately benefit not only from their improved educational attainments, but also from their enhanced economic potential as adults.

Two new articles stress the role of community volunteers, local alternative providers and household members in controlling malaria.

Ajayi and colleagues trained volunteer community medicine distributors (CMDs) to provide arthmether-lumefantrine (AL) in selected villages near Ibadan, Nigeria. They elarned that, “the use of AL at home and community level is feasible with adequate training of community medicine distributors and caregivers. Community members perceived AL to be effective thus fostering acceptability. The negative attitudes of the health workers and issue of incentives to CMDs need to be addressed for successful scaling-up of ACT use at community level.” Parents in these villages had not heard of AL before, but after one year of intervention they were happy with the results of using AL and with the performance of the CMDs. Challenges learned from this field experience included uncertainties of regula medicine supplies, continued supervision of the CMDs, CMD desires for incentives and negative attitudes of formal health workers.

Mbonye et al. have produced another in their series of articles concerning community distribution of intermittent preventive treatment for pregnant women (IPTp) in Uganda. This time they looked at cost and cost effectiveness of community distributors comparent to health facility based provision of IPTp. They had drawn on a variety of existing people to serve as distributors including traditional birth attendants, drug-shop vendors, community health workers and peer mobilizers. Although it cost slightly more to deliver IPTp in the community (due in part to one time training costs), the cost-effectiveness was greater because of reductions in severe anemia and fewer low birth weight babies. The challenges here are common with pilot or experimental programs – that of linking with the formal health system to guarantee ongoing supervision and support, but this can be built into future efforts.

More effort is needed to test the generalizability of these interventions, but the key message is that the community needs to be actively involved in malaria control efforts. Another key factor is that the health system (whether public, private or NGO) needs to ensure that malaria commodity procurement and supply systems reach the community in a sustained way.

McRobert and colleagues have published promising findings in PLoS Biology on enzymes needed for malaria parasites to produce gametocytes. They explain that, “Our data predict that in addition to targeting asexual erythrocytic stages, a drug inhibiting Plasmodium PKG could also block parasite transmission to the mosquito, a highly desirable property that would help limit the spread of any drug-resistant parasites. Transmission-blocking drugs would be a powerful tool for reducing the malaria burden in areas endemic for P. falciparum.”

David Baker, a co-author, noted in a press release from the London School of Hygiene and Tropical Medicine that, “The enzyme we have discovered, a protein kinasea, is essential for the development of malaria parasite gametes. Working with genetically modified parasites, in combination with inhibitors of this enzyme, we have demonstrated that it is feasible to block the sexual stage of the life cycle of the malaria parasite. This has exciting implications in terms of improving how we go about tackling malaria. If a drug can be developed that targets this stage of the life cycle, and combined with a curative drug, it would be an important new approach for controlling malaria transmission and the spread of drug resistance.

A 2-in-1 drug that not only treats the disease but prevents transmission would be a most valuable addition to the malaria arsenal. And while the time from drug discovery to a drug on the market may take years, it is important to keep the research pipeline flowing in order to keep ahead of drug resistance. For example, researchers are looking far and wide, and Prudhomme et al. suggest that a “source of marine natural products (may be) marine microorganisms.” Simultaneously it is also important to evaluate continually possible resistance of malaria parasites to existing drugs.

We cannot afford to rest on the laurels of ACTs or sit back in hopes of the perfect vaccine. Research funding for all aspects of malaria control must be boosted.

In Mali, ‘shocking levels’ of malaria misdiagnosis are being reported. “The discrepancy between real and assumed cases has reached “shocking” levels all over Africa … Malaria diagnostics in Mali rely on expensive equipment which most health clinics, particularly in rural areas, cannot afford and do not have the trained staff to use … As a result most doctors “make assumptions based on suspicion,” he said, leading to over-treatment of malaria cases … most people who develop a fever in Mali do not visit a health clinic at all either because they live too far away, or are unwilling to pay up to US$0.95 for a consultation.”

They self diagnose and treat instead.” IRIN reports that, “Up to 70 percent of cases of feverish illness in children are diagnosed and treated at home.” In contrast, “Laboratories the gold standard. Mali needs more and better-equipped laboratories to combat mass misdiagnosis.”

Although the news release about Mali does not give numbers, they may be quite substantial. Two years ago a medical officer working for a major corporation in Nigeria discussed the experiences from their company’s employee/family clinics and showed that without laboratory tests at least 75% of patients whom clinicians diagnosed as having malaria were free of parasites. The company thought that lab tests resulted in a major savings for the company in terms of malaria pharmaceuticals.

Many diseases present with malaria-like symptoms, including dengue fever, which is poorly recognized in Africa. Nordstrand et al. (2007) report that in the absence of laboratory diagnosis, tickborne relapsing fever is treated as malaria in Togo.

There are concerns about the cost of laboratory diagnosis. Rapid Diagnostic Tests (RDTs), though not without expense, are a solution in low resource settings. Hopkins et al. (2008) report that “Based on the high PPV (positive predictive value: 93%) and NPV (negative predictive value: >97%), HRP2(histidine-rich protein 2)-based RDTs are likely to be the best diagnostic choice for areas with medium-to-high malaria transmission rates in Africa.”

Even when laboratory diagnosis is available, it may not be used. As Polage and colleagues observed in Ghana, “Perhaps the most significant barrier to laboratory use was physicians’ reliance on clinical judgment.”

A lesson here is that clinical diagnosis may be no better that self-diagnosis. An interesting question is by how much would the world’s burden of malaria be reduced simply by performing an accurate diagnosis in a laboratory or with RDTs?

The Swiss Pharmaceutical giant, Novartis, has announced further cuts in the price of its artemether-lumefantrine (AL) anti-malarial drug, Coartem®. According to AFP, ” The new price of 37 cents (0.23 euros) for children’s doses will start from Friday which is World Malaria Day.” This reflects a 20% reduction in price. This announcement not only comes two before World malaria Day, but two days after Novartis announced for the first quarter of 2008 that, “Net income up 10% to USD 2.3 billion.”

The Novartis press release goes on to say that Coartem is “the only fixed-dose ACT that has been approved by a stringent, internationally-recognized health authority.” This refers to WHO’s pre-qualification efforts to ensure safe and effective medicines for major donor program use. The current list does now include other artemisinin-based combination therapy products such as artesunate-amodiaquine (AA) and artesunate-mefloquine, but WHO still favors Coartem and assists countries apply for Coartem at cost.

Ghana for one has chosen AA as its first line antimalarial drug, and is in the process of updating its national malaria drug policy and guidelines to reflect this and possibly include AL and atovaquone-proguanil as second line choices for people who may react to amodiaquine. Generally though, most countries are in lockstep with Coartem. While Novartis is optimistic about its “ability to satisfy Coartem production requirements in 2008 or the future,” it also issued a disclaimer about future uncertainties. It is just such uncertainties that require countries to consider alternatives, as in Ghana.

Ultimately if in the future donors do not persist in providing funding for buying anti-malarial drugs at cost, there needs to other mechanisms to bring costs in line with what countries can afford. Greater commercial availability of different types of malaria drugs that also bear WHO’s seal of approval will hopefully also bring down prices across the board for all such products and make it easier for countries to buy their own medicines as needed.

World Malaria Day means that the malaria situation in more countries outside Africa will be getting attention. The Daily Times of Pakistan has observed that “Pakistan reported 3.5 million suspected malaria cases in 2007 and 0.13 million of them were later confirmed, says an official of Directorate of Malaria Control (DOMC),” but also expressed concern that WHO “claims that high incidence of suspected malaria cases is exaggerated and the figure couldn’t be more than 1.6 million because malaria has yet not reached epidemic proportions in Pakistan.”

Better data are needed. The website ‘fitfortravel‘ can compose a map to guide travelers on the need for antimalarials, but this is not intended as an accurate picture of the country’s malaria situation. That said, malaria is obviously a recognized problem in the country because the Global Fund to fight AIDS, TB and Malaria has awarded Pakistan three grants to fight the disease.

The Round 3 proposal to Global Fund explained that, “The plasmodium falciparum is on the rise and in 2001 as many as 25 districts had a P. falciparum ratio of more that 30 percent. The parasite has developed RI & RII level resistance to chloroquine in many areas.” The proposal also reports that the annual parasite incidence reaches 18 per 1000 in certain districts, but also says that only abouy 21% of the population use government health facilities were data could be collected. Therefiore it is not surprising that the Daily Times reports that, “The DOMC official said only 20 percent of the total population had access to malaria treatment.”

Some published data comes from hospitals, which of course would not reflect the general situation in the population, but at least is a step in the direction of documentation. Idris et al. from the Ayub Medical College in Abbotabad studied nearly 2000 febrile patients and found that over 7% had malaria parasites. While most cases were P. vivax, 24% were P. Falcuparun and 3% were mixed. In Karachi, Beg et al. documented among over 500 patients hospitalized that P. vivax and P. falciparun were found in almost equal measure (52% and 46%). They expressed concern that many were treated with inappropriate medicines, showing a need for updating pre-service and in-service training.

Bhatti et al., looked at malaria in pregnancy in Karachi. The findings they reported included the following: “Two patients had an abortion. One of the following complications including, threatened abortion, preterm labour, ARDS or Cerebral malaria, was observed in one patient each. Mean weight of babies born to cases was 2.8 kg (range 1.4-3.8) and of control babies was 3.2 kg (range 2.5-4.0 kg).” P. falciparum was identified as one of the risk factors for poor pregnancy outcome.

Among the 28 malaria Global Fund grants approved for Round 7, half came from regions outside Africa. As international attention is turning more to malaria all over the world, it is important for all endemic countries to seek better population based data about their malaria situation so that appropriate interventions can be targeted most effectively.

National Public Radio reported this morning that Viagra, Pfizer’s erectile dysfunction drug, has now been on the market for ten years, NPR explained that, “In Viagra’s first month on the market, doctors wrote more than 500,000 prescriptions. Former presidential candidate Bob Dole once plugged the pill in TV commercials. The drug has been a long-term boost for Pfizer’s profits. Last year, it brought the pharmaceutical giant more than $1.7 billion.”

Nearly a year ago, NPR also reported that, “The male impotence drug Viagra may have a new use. It could be helpful in battling jet lag. A scientific journal carried that finding. Scientists came up with it after feeding Viagra to hamsters. The hamsters then had the lights turned off and on in ways that simulate jet lag. The hamsters on Viagra recovered from jet lag up to fifty-percent faster than those without.”  No studies have shown that Viagra cures malaria.

So what is Pfizer doing about malaria? Doubtless a new malaria product will not net $1.7 billion in a year. Is there any incentive for big pharmaceutical companies to get involved in solving the malaria problem?

Pfizer is undertaking some drug trials. “Through our Zithromax®/chloroquine clinical trial program, Pfizer scientists are developing a potential malaria treatment based on our widely used antibiotic, Zithromax®. Dosed in combination with chloroquine, Zithromax® demonstrated positive results in the treatment of adults with malaria in Africa. Currently, clinical studies are ongoing at centers in South America, India and Africa.”  Usually though, WHO does not making combination therapy for malaria that contains a drug for which there is already widespread resistance like chloroquine.

On a more practical basis, Pfizer is sponsoring ‘Mobilize Against Malaria‘, which is “A five year, three country initiative that engages and educates treatment providers and patients to improve the utilization and effectiveness of malaria treatment and patient adherence” in Ghana, Kenya and Senegal. Hopefully Pfizer will do more to address challenges of malaria drug potency with the profits it makes from male impotency.

The Daily Times of Malawi has reported that, “The Malaria Control Program has said the new malaria drug, artemisinin combination therapy (ACT)—commonly known as LA—is the best drug against malaria, even though patients have complained of unpleasant side effects. Some patients have complained of persistent headaches and itching whilst others have said some of their body parts swell after taking the drug.” One assumes that “LA” means lumefantrine-arthemeter. In contrast in neighboring Zambia researchers found that after the new treatment policy of ACTs was introduced there were high levels of acceptability, and “it was not surprising to see high levels of compliance.”

Itching and fatigue have definitely been associated with amodiaquine. But according to Malawi’s Global Fund Round 7 Malaria Proposal, “AL (artemether- lumefantrine) was chosen over other ACTs due to its co-formulation which is expected to improve compliance while artesunate+amodiaquine (AA) was chosen as second line for the management of the uncomplicated malaria.” A recent review of ACTs by Nosten and White reported that, “except for occasional hypersensitivity reactions, the artemisinin derivatives are safe and remarkably well tolerated. The adverse effect profiles of the artemisinin-based combination treatments are determined by the partner drug.”

Just because a drug is effective, it may not be acceptable. As was found with AA in Ghana in 2005, first the drug needs to be formulated correctly. Various other factors affect acceptability including cost, packaging, provider-client communication and drug color in addition to side-effects. It is quite important to test all these factors with consumers, not just drug efficacy.

Perceived problems with drugs do interfere with compliance, and poor compliance will lead to development of drug resistance. Monitoring of acceptability and compliance must be an integral part of any malaria control program.

In the meantime there is need to keep searching for new anti-malarial drugs. That is why the news is sad that after nearly a decade’s work put into developing LapDap, the drug was ultimately pulled from the market because of links with anemia. This was a good example of public-private collaboration, and hopefully such ventures will continue.

Coming into the immigration office in Bukavu, Democratic Republic of Congo, one is welcomed by a 2008 calendar that features chloroquine products made by Pharmakina, a company that has set up production in DRC. Another copy of the calendar is seen in the provincial office of the national AIDS coordinating agency. According to the company “PHARMAKINA combats malaria supplying drugs of natural origin. PHARMAKINA cultivates 1,200 hectares of quinquina that guarantees the stocks of barks for a LONG-TERM production.”

While it is admirable that local botanical production is being promoted, the sale of chloroquine when drug resistance is rendering this anti-malaria drug useless in most of Africa is questionable. [see comment for correction] The East African Network for Monitoring Antimalarial Treatment observed that “Between 1998 and 2001, Kenya, Uganda, Tanzania, Zanzibar, Rwanda and Burundi changed antimalarial drug policy, in the face of widespread chloroquine resistance.” Specifically in DRC researchers reported that CQ is no longer efficacious in the treatment of malaria.

Furthermore DRC’s malaria grant from the Global Fund remarks on the change of national malaria drug policy to use artesunate-amodiaquine as first line treatment. The August 2007 progress report on that grant observed that there was, “Concern with the impact of the switch from chloroquine to ACTs on the program’s Phase 2 targets on the Principal Recipient’s ability to purchase sufficient drugs to enable it to reach targets and the CCM’s proposal in the Phase 2 request to reduce the program’s timeline from 5 to 4 years.” Maybe this is why CQ is still popular?

Local production of malaria drugs does have the potential to reduce costs and increase access. Just as Pharmakina is promoting local cultivation of quinine, other companies and countries are promoting growing of artemisinin. The principle is the same, but the drugs are not. The challenge is producing the most efficacious drugs that come in combination form. Following WHO malaria treatment guidelines is a good place to start.

Last year we reported on the second year results of the UNICEF/UNDP/World Bank/WHO Tropical Disease Research (TDR) Program’s Community Directed Intervention (CDI) Multi-Country study. CDI was originally developed for annual distribution of ivermectin as part of the African Program for Onchocerciasis Control. The current study tested whether the community and the volunteer distributors selected by the community could manage additional health interventions. Included in the trial were ITNs for children and pregnant women, home management of malaria with Coartem, Vitamin A and TB case detection.

At the end of the second year of the study “Malaria home management coverage doubled, Bednet coverage doubled to quadrupled, Vitamin A coverage was significantly higher, and TB case detection rate doubled.” One of the seven research team leaders, Richard Ndyomugyenyi of Uganda, explained that, “… if we involve them (the community) as stakeholders right from the beginning, and they are following up what you are doing, it becomes easy for them to implement, because those results would also be theirs.”

Richard further noted that, “The main reason this works seems to be that this process [CDI] empowers the communities to own the process and the programme. So they actively participate in deciding how these interventions should be delivered – so they take an interest in their own program, and it increases coverage”

According to Elizabeth Elhassan, the team leader from Kaduna, Nigeria, “Once you empower people, and they realise it is for their own benefit, it becomes a priority for the communities.” Of course community participation must be coupled with availability of commodities. “The study went well, particularly in 2006 as we had a reasonable supply of materials: nets, antimalarials, and vitamin A, to both the study and the comparison arms,” Elizabeth told RealHealthNews.

The seven teams from Nigeria, Cameroon and Uganda just completed their third year and final data analysis last week in Douala.  Interventions were added to the existing ivermectin distribution each year to observe how communities could handle the extra responsibilities. In control arms normal ivermectin distribution occurred but the other interventions were provided to the district health authorities to distribute through their ‘normal’ channels. The CDI process used in the research is described on the TDR website where a short video clip from the team that worked in Taraba State, Nigeria can be found.
The accompanying graphs show that the results have maintained a positive direction.  The study arms that received the malaria interventions by the second year had higher coverage than those in the other two arms in year two and by the third year those who had received the interventions in either year did better than the control districts/arms.  ITN coverage for pregnant women and home management of malaria showed the best results.  The improvements in ITN coverage for children were still below RBM targets, and qualitative results indicated that better follow-up by the volunteer distributors in reminding people to use the nets is needed.

Clearly the community directed participatory approach can help get basic health commodities to people living in remote and rural areas. Qualitative results found that the malaria interventions were particularly successful because communities see malaria as a serious problem that affects everybody.

The research teams are now planning advocacy meetings with policy makers in their countries, while TDR staff are sharing the results internationally to encourage other countries and donors to adopt the CDI approach.