Tropical Health Matters

Last week Dora Akunyili, Director General of Nigeria’s National Agency for Food and Drug Administration (NAFDAC) called on faith based organizations to join the fight against counterfeit malaria drugs in Nigeria. She explained that with the faded efficacy of chloroquine and sulfadoxine-pyrimethamine (SP) Nigeria must be vigilant in protecting the efficacy of ACTs.

NAFDAC does take action as seen in a recent newspaper notice seen in part here that warns the public about unregistered and potentially dangerous drugs. NAFDAC has taken other recent helpful actions. For example, the Agency has asked producers of SP to remove the warning that this drug is contraindicated in pregnancy so that SP can be used for IPTp during the second and third trimesters (but still not the first).

Some challenges remain. Many monotherapy artesunate drugs had been registered over the past 5 years, and although NAFDAC agrees with WHO that such drugs can lead to resistance and should not be sold, NAFDAC has taken a more conservative approach and is simply allowing the licenses on those products to expire. The monotherapy drugs are still in abundance in the medicine and pharmacy shops, particularly in urban areas, and some state pharmacy stores do stock them. While it would mean financial loss to companies, businesses and clinics if monotherapy artemisinin drugs were abruptly withdrawn, the longer term costs of developing resistance to artemisinin-based drugs would be enormous both in terms of lives and finance.

Nigeria is not the only country that should pay attention to its malaria drug supply. Recently I purchased an artesunate-SP combination in a registered pharmacy shop in Entebbe, Uganda as seen in the photo. Again, combinations of artesunate and drugs like chloroquine and SP that have reduced efficacy is dangerous in terms of speeding up development of parasite resistance to the artesunates. WHO expects that this combination “will fail rapidly.”

The time to act to protect ACTs in Africa in now.

[Note that photos of pharmaceutical products do NOT constitute an endorsement.]

Ghana, like other countries in the region, is reported to be revising its national malaria strategy. Most countries developed a new strategy document around 2001, at the beginning of the Roll Back Malaria Partnership, that reflected the goals of achieving 60% coverage of the core interventions (ITNs, IPT and appropriate and timely case management).  This level was supposed to have been achieved by 2005, and then new targets of 80% coverage took effect for the 5-year period starting 2006.  Many changes occurred between 2001 and 2006 including the availability of artemisinin-based combination therapy (ACT), long-lasting insecticide treated nets (LLINs), and the re-emergence of indoor residual spraying (IRS).

Some shifts in policy have occurred, and it is natural for a new strategy to be developed to account for these. The Global Fund for Fighting AIDS, TB and Malaria (GFATM) noted that Ghana switched to ACTs, and now the country needs to embody this in their malaria strategy. Ghana was given permission to use artesunate-amodiaquine as its ACT rather than the pre-qualified drug artemether-lumefantrine.  Drug quality issues resulted in serious side effects that eroded the public trust. The Food and Drugs Board took action, and as the GFATM noted, the PR worked hard “to overcome the bad publicity around the launch of ACTs.” Therefore the new malaria strategy needs a strong health education component to overcome and remaining public skepticism about the intentions and quality of the national malaria control effort.

Another challenge of the new malaria strategy will be to prevent the diversion of nets into the private sector. This problem likely arose in part due to the fact that cost was a major issue that prohibited net ownership before the start of the GFATM grant.

Ghana is also considering IRS, which is possible now that Ghana has been designated a PMI country. The challenge with IRS is determining the appropriate insecticide because of varying resistance of vectors in different regions of the country.

Overall the biggest challenge in revising the malaria strategy is determining Ghana’s own national malaria control needs and then coordinating the input of donors to meet those needs rather than developing a strategy based solely on what the donors expect.

A few years ago a colleague who works for a large corporation in Nigeria showed me malaria diagnosis laboratory results from their company clinics.  The company was able to test workers and family members in their labs after a clinical diagnosis of malaria and before dispensing drugs. Over a span of 5 years only 20-25% of patients were found to be parasitaemic, and without the tests, most people would have been given malaria treatment.  Those were the days when the company was still dispensing cheap chloroquine. Today with ACTs that cost 10-50 times more than chloroquine, these lab tests are even more important.

Zurovac et al. (2006) found that when both clinical and laboratory skills were improved, major cost savings resulted in malaria treatment. Ochola et al. (2006) concluded that dipsticks can perform better than standard microscopy in clinical (field) settings in endemic areas.  Rennie et al. (2006) reported that community health workers can be trained to perform rapid diagnostic tests.

Reyburn et al. (2007) compared RDTs with microscopy in Tanzania among clinic attenders.  Patients were assigned equally to receive one or the other form of test.  In both groups approximately 80% of patients had complained of fever within 48 hours.  Fourteen percent of patients in the microscopy group were found to have malaria parasites, while 16% in the RDT group tested positive. Clinical diagnosis might have overestimated the proportion of malaria case by three or four times.

The reality is that few front line health facilities in malaria-endemic have laboratory services, and thus rapid diagnostic tests are being considered. RDTs are estimated to cost between US$0.60 – $1.00, and as implied from research mentioned above, the cost savings from reducing over-prescribed ACTs could be substantial and might offset these costs.   The question is whether malaria control programs will be able to adopt, buy and distribute rapid test materials to front line facilities. Hopefully financial resources like GFATM and PMI can help address this question.

The current Newsletter of the Tropical Disease Research (TDR) Program highlights the role home management of fever/malaria can have in reducing the deaths of over one million children annually. TDR notes the value of having child doses prepackaged in order to enhance provision of the correct amount of medicine to children.  The Newsletter quotes Professor Umberto D’Alessandro from the Prince Leopold Institute of Tropical Medicine in Antwerp, Belgium, who said, “There are no data available on the effects of ACT when it is given by mothers to their children without proper diagnosis. It should reduce mortality, but we simply don’t know if it does.”  This has led TDR to support Studies using ACTs in home management settings in Benin, Burkina Faso, Cameroon, Ethiopia, Malawi, Nigeria, Uganda and the United Republic of Tanzania.

Some encouraging preliminary results were published last year from independent work in Ghana. An article by Gyapong et al. reported that, “Adherence of agents and caregivers to the treatment (with Coartem) was 308/334 (92.5%). Delay in seeking care was reduced from 3 to 2 days. No serious adverse drug reactions were reported. Community members were enthusiastic about the performance of the agents.”

Turning research into practice, and thereby making ACTs available in the home, will require several steps.  There are at least two effective strategies for getting malaria medicines for prompt care of children into the home.  One is training and supplying community volunteers, while the second is selling antimalarials in licensed shops, often at subsidized prices. For these strategies to save children’s lives, policy decisions are needed concerning whether ACTs will remain prescription drugs or whether they can be sold in the licensed medicine shops which are near the home.

An article by Mokuolu et al. in the January 2007 issue of the American Journal of Tropical Medicine and Hygiene, reports on changes in malaria drug sales before and after the issuance of the new national antimalarials drug policy. Data come from doctors’ prescriptions at University of Ilorin Teaching Hospital pharmacy in Kwara State.  The Federal Ministry of Health, with support from WHO conducted two rounds of malaria drug efficacy trials, and based on these a new policy promoting Artemisinin-based Combination Therapy (ACT) was drafted in 2004. The policy was not officially inaugurated until May of 2005.  Data from Ilorin examine both 2004 and 2005.

The hospital pharmacy operates a revolving fund with prices pegged just above cost. Sales of drugs containing artemisinin increased by 300% in just one year.  Also, as a percentage of total malaria drug doses sold, medicines containing artemisinin rose from 18% in 2004 to 49% in 2005.  The proportion of sales of chloroquine, the former first line drug, dropped from 73% to 27% in the same period.  These changes occurred in spite of the fact that the cost of a course of chloroquine tablets was about 12 US cents compared to between US $2.30 and $7.20 for a tablets containing artemisinin.  It appears that prescribers are adopting the new policy, and consumers are paying the price.

Three issues of concern arise from the findings.  In 2005, over two-thirds of the drugs containing artemisinin were not ACTs, but artemisinin monotherapy formulations (see photo above). WHO has demanded that sales on monotherapy drugs be halted in order to prevent the spread to resistance to artemisinin. The current approach of the Nigerian Agency for Food and Drug Administration (NAFDAC) has taken the approach of not intending to renew the license of monotherapy drugs when these expire, but not in pulling the drugs off the shelves.  A second concern is the fact that a small (~7%) but notable portion of drugs were sold in syrup form which is not only more expensive but also less stable. Child dose packets of ACT tablets are available (see photo below). Finally sulphadoxine-pyramethamine (SP) continues to be a large portion of total sales (23% in 2005) in spite of the fact that SP, according to national policy, should be reserved for Intermittent Preventive Treatment in pregnancy and not used for curative purposes.

 

Hopefully the authors will continue to monitor malaria drug prescribing and branch out into the state and local governments as well as into the private sector to learn more about response to the new national ACT policy. Learning about compliance with the new policy in the private sector is crucial, because this is where the bulk of malaria drugs are sold and where the bulk of controversy about drug quality exists. (Note that pictures of malaria medicines herein do NOT constitute an endorsement.)

The Tropical Disease Research (TDR) program of UNDP/World Bank/WHO/UNICEF piloted Community Directed Intervention (CDI) for ivermectin distribution for onchocerciasis (river blindness) control in 1995, and found that it provided greater coverage than distribution efforts organized by only the health authority. With CDI communities made decisions when and how to collect their annual ivermectin supplies, about the preferred mode of distribution (house-to-house, central), and days when distribution would occur, and who would be their volunteer Community Directed Distributors (CDDs). This model was adopted by the African Program for Onchocerciasis Control (APOC) and has become possibly the largest community participatory disease control mechanism in Africa, and possibly the world, reaching millions residents in isolated villages who often rarely see the formal health service. While the health system provides training, supervision and commodities, it is the villagers themselves that organize their own ivermectin distribution.

Two years ago, TDR embarked on new research that tested whether other health interventions could be integrated within the CDI model. Thus, in selected districts in Cameroon, Nigeria, Tanzania and Uganda CDDs are also promoting home management of fever with antimalarials drugs, distributing insecticide treated nets, undertaking case detection for TB, and giving Vitamin A, in addition to annual ivermectin doses. One new intervention was introduced at each site in each of four trial districts, while the fifth serviced as control (offering only ivermectin as usual). A second intervention was added in year two. In the third and final year, all five interventions will be taking place in the four study districts at each site. Effort was made to ensure that the district health departments had supplies of all commodities, but only in the intervention districts were the commodities made available through the CDI approach.

The research teams recently completed a data analysis workshop on progress made by year two. ITN ownership, net use and timely and appropriate home management of malaria episodes in children under five years of age showed significant progress over baseline and compared with the control areas where only ivermectin distribution was provided through the CDI approach.

The key lesson is that even though malaria commodities are supplied to district health services, they do not always reach people unless the community is involved. Some countries are including community volunteers in their malaria strategy, such as Role Model Mothers in Nigeria. We hope that with the preliminary results of TDR’s CDI study, more countries will take seriously the need to get communities actively involved in their own malaria control efforts.

Two recent articles demonstrate how countries, anxious to treat malaria cheaply with the newer artemisinin-based combination therapy (ACT), are exploring ways to grow Artemisia anua locally and feed that into the local pharmaceutical industry. Growing Artemisia anua in Kenya may offer local farmers a chance to ‘triple their income.’ This assumes large scale multinational commercial growers don’t get the edge on production and that more the one current extracting facility begins operation. Likewise in Nigeria laws are being considered that would promote local growing and production. These actions promise a boon for both national health and economic development.

Reliance on the ‘shrub’ that produces artemisinin is a challenging process requiring the right soil and climatic conditions, as well as attention to the relatively short period when the chemical is at optimal levels within the foliage. Success also rests on meeting infrastructural demands such as good quality roads and transport.

A question exists whether a short-term gain in local production might eventually be offset by efforts to synthesize artemisinin. Discover Magazine in its December 2006 issue named Jay Keasling, a Chemical engineer at the University of California at Berkeley, as its scientist of the year (2006) for pioneering ways to use ‘synthetic biology’ to produce artemisinin in the lab (or eventually factory) using genetically engineered bacteria and/or yeast. Keasling’s team has already been working several years on this process and has received awards from the Gates Foundation to advance the effort further. They may have a viable process ready for production by 2010 and bring the cost of a dose down to 10 US cents. Even with major price reductions by one of the major international manufacturers of ACTs, the cost today is at least one US dollar through programs receiving support from the Global Fund to Fight AIDS, TB and Malaria.

While it is good that many approaches are being followed to bring ACTs closer to the people who need it at a cheaper price, synthetic production is the process that in the long run will likely provide the cheapest route. Hopefully governments and pharmaceutical companies are not setting up local farmers in Africa for economic disappointment down the road when the synthetic production of artemisinin becomes viable.

The death knell for chloroquine (CQ), a cheap and relatively long lasting antimalarial drug, have been tolling across the continents in a westerly direction for decades and finally reached West Africa in the 1990s. In southern Africa, Malawi was one of the first countries to officially discontinue use of CQ in 1993. A recent article in the New England Journal of Medicine (NJEM – subscription required) reports that when CQ was no longer available in either the public or private health systems of Malawi, the mutated P. falciparum gene associated with drug resistance disappeared.

The drug is now effective again at treating malaria in parts of Malawi– but before too much excitement develops for the drug that is 1/20th the price of currently recommended artemisinin-based combination therapies (ACTs), the authors of the NJEM article caution that CQ is still available throughout the rest of the continent and will not regain its former strength until it disappears entirely as was the case in Malawi. Only then could CQ be reintroduced, but in combination with other antimalarial drugs to prevent resistance from returning. But what are the chances that CQ will be taken off the shelves any time soon, and what does this say about malaria drug policy in endemic countries?

Nigeria, for example, adopted a new ACT-based drug policy in 2005, which was greeted with the headline “Government bans Chloroquine as first line drug in malaria treatment” in a prominent national daily, which required a response by the Federal Ministry of Health a few days later, “Chloroquine Not Banned, Says Minister”. In this milieu it has been a major challenge to convince state and local government health services to adopt the new national malaria drug policy and use their limited essential drug funds to buy ACTs. Supplies from donors, whether the Global Fund or the World Bank, are not adequate, nor are they intended to cover the ACT needs of the total population.

Not surprisingly, CQ and sulphadoxine-pyramethamine (SP), another cheap antimalarial drug to which parasites are resistant, are available and being used for treatment in local government clinics in the southeastern part of the country, an area where CQ resistance is highest. ACTs are rare or non-existent in these rural settings, even in drug shops whose owners are reluctant to buy these expensive alternatives not knowing whether their customers can pay. It is only in the urban private medicine shops and pharmacies that one sees a plethora of ACTs, and unfortunately also monotherapy artesunate drugs.

So, the pressure remains to buy and sell or dispense CQ. One key factor is education of both public and private providers, many of whom have not heard about the new drug policy. Education will not be enough until, as an accompanying NJEM editorial says, the cost of ACTs is comparable to what people have been paying for CQ and SP.

As a final concern, researchers are finding that CQ may be valuable in the treatment of HIV. HIV and malaria produce some very negative synergies so it is not clear what the practical implications of continued use of CQ for HIV might be, but it does raise the possibility that CQ may not disappear soon, and we may not be able to replicate the Malawi experience after all.

Pregnant women are particularly vulnerable to malaria, which can cause life-threatening anemia, low-birth weight, and even death for the infant. Yet the international public health community seems to be overlooking the risks pregnant women and their unborn children face when infected with malaria. And myths and misperceptions at the country level also hamper effective control of malaria in pregnancy (MIP).

Take a look at the WHO’s Global Malaria Program (GMP) website and you will find that intermittent preventive treatment (IPT) for pregnant women has been replaced by indoor-residual spraying (IRS). Specifically in reference to a new publication on IRS, the website states, “IRS is now one of THREE main interventions promoted by WHO to control malaria,” and a closer reading of that document shows that IPT has been dropped in favor of IRS. Obviously WHO is not dropping MIP interventions, but the fall from grace for IPT in pregnancy is disconcerting when MIP is responsible for morbidity and mortality in both mothers and newborns. This is particularly discouraging since IPT and ITNs for pregnant women have been shown to be highly effective, and are delivered through established ante-natal services, making them an obvious choice for high impact at low cost.

In addition to benign neglect by international health officials, various myths have emerged about MIP interventions at the country level. Front line health workers and mothers in many countries still believe that the drug of choice, sulfadoxine-pyrimethamine (SP), is either unsafe or too strong for pregnant women. A second myth surrounds SP as an appropriate treatment – the news about preventing further drug resistance in the general population by not using SP for curative care has not been heard or heeded, especially when the alternatives, artemisinin-based combination therapy (ACT), is so expensive.

Another myth is that since SP is relatively cheap, there is little need to focus major donor attention on strengthening IPT programming. Finally there is the myth that insecticide-treated nets (ITNs) will certainly reach pregnant women if community campaigns are conducted. Aside from the normal problems of leakage and poor documentation, separating ITN distribution from antenatal care removes an important incentive for women to safeguard their pregnancies through timely prenatal visits.

Recently the Roll Back Malaria Working Group on MIP held its seventh meeting in Abuja, Nigeria. A key recommendation was greater involvement, if not full leadership by the reproductive health (RH) community in the battle against malaria in pregnancy. The close integration of RH and malaria control programs can make sure IPT remains a priority intervention necessary to meet the goals detailed in the Abuja Declaration from 2000.