Tropical Health Matters

The World Health Organization reminds us today that, “Antimicrobial resistance is not a new problem but one that is becoming more dangerous; urgent and consolidated efforts are needed to avoid regressing to the pre-antibiotic era.”  It is not just antibiotics that are in trouble, but other microbial agents including malaria drugs.

In the malaria community we are also worried about insecticide resistance.  Growing resistance to DDT was one of the reasons that earlier efforts to eradicate the disease were not globally successful.

WHO explains clearly that human behavior (patients, providers, health service managers and drug manufacturers) plays a big role in developing antimicrobial resistance:

Antimicrobial resistance is facilitated by the inappropriate use of medicines, for example, when taking substandard doses or not finishing a prescribed course of treatment. Low-quality medicines, wrong prescriptions and poor infection control also encourage the development and spread of drug resistance. Lack of government commitment to address these issues, poor surveillance and a diminishing arsenal of tools to diagnose, treat and prevent also hinder the control of drug resistance.

Scientific American this month has two timely articles on antibiotic resistance that also highlight how human behavior exacerbates the problem.  Agricultural use of antibiotics is one major problem. Another revolves around infection prevention procedures (or the lack thereof) in hospitals.

The use of combination drug treatments was expected to slow or prevent the emergence of resistance to another class of anti-malaria drugs, but prior and continued use of monotherapy artesunate drugs in Southeast Asia has raised the specter of resistance developing there and spreading throughout the world following the patterns of chloroquine and sulphadoxine-pyrimethamine. The following steps are designed to help:

• Treatment only with combination therapies where there is no demonstrable resistance for either component of the combination
• Treatment based only on positive results of parasitological tests thus avoiding indiscriminant use of malaria drugs
• Regular/frequent drug efficacy testing using WHO protocols
• Pharmacovigilence/Surveillance

Donors and National Malaria Control Programs must recognize and fund surveillance activities as one of the central interventions in efforts to eliminate malaria. As this year’s World Health Day theme clearly states: no action today, no cure tomorrow.

For many years after the launching of the Roll Back Malaria Partnership, the malaria community had been putting the cart before the horse.  As malaria drug policy changed to artemisinin-based combination therapy (ACT) rolled across the African continent in the wake of resistance to chloroquine and sulphadoxine-pyrimethamine, basic diagnostic criteria at the front line clinics still relied on clinical diagnosis, often through well accepted algorithms.

Health workers of all stripes from physicians to clinic aids trusted in their clinical judgement and prescribed ACTs in nearly all cases of febrile illness. This was justified to some extent by the deadly nature of malaria in small children.

Eventually two issues called into question the validity of algorithms and clinical judgement if malaria were to be eliminated.  First, if we actually went to scale in providing malaria treatment for all suspected cases of malaria, we might never find adequate funding to buy all the needed ACTs, which cost upwards to 10 times that of the predecessors.

Secondly, if we were ever to gain a true picture of the malaria situation as interventions were scaled up and prevalence decreased, we could no longer base our health information systems on clinical or suspected cases.

Rapid diagnostic tests (RDTs) were a long time in coming and in many places have still not reached the front lines. Even when RDTs become available, they have not always been used correctly.  Just last year we assessed RDT implementation in Burkina Faso, for example, and found most cases of paludism simple (uncomplicated malaria) were treated with ACTs without testing. The only encouraging note was that following the national sick child algorithm, cases with fever ANCDcough were treated as acute respiratory illness.

Cascade training had been rolled out to teach health workers in Burkina Faso to use RDTs, but nearly expired unused RDT stocks were found in their clinics.  Not all RDTs were stored properly to protect against high tempaerature and humidity.

Even when RDTs were used, the existing clinic records systems did not provide a clear space to record RDT results. Some health workers were creative and addre red RDT+ and RDT- notations in their registers where space allowed.  Findings of this assessment are being used to improve training.

Now comes an encouraging study from Tanzania that shows health workers not only can learn to use RDTs correctly. The researchers also found reductions of ACT use in lower transmission areas where previously clinical judgement had resulted in high proportions of febrile patients receiving ACTs.

The Tanzania experience shows the neet for both clear government policies supporting RDT use and well supervised dissemination of these policies out to the front line clinic. Both Rwanda and Mozambique have shown that RDTs can even be effectively used beyond the clinic walls by community health workers. Accurate diagnosis is a key step in th elimination of malaria.

Obinna Onwujekwe and colleagues have documented a major problems with health seeking behavior surveys – people do not always give valid responses. This is not to say that people lie, but the interview situation can be a complex social interaction in which things are not always as they seem. In Onwujekwe’s study while respondents indicated that their preferred source of care for malaria illness were public and private clinics, their main actual source of care for recent malaria episodes were the patent medicine dealers.

Perceptions of what are ideal and expected behaviors often differ from what people actually do. For example with guinea worm 75% of residents in rural southwestern Nigeria said that clinics offered the best treatment for the disease. Examination of clinic records during the same time found that only about 3% of actual sufferers attended a clinic.

When asked why, villagers complained that guinea worm could not be cured with western medicine and that treatment which included bandaging the open ulcer agnered the worm and made the disease worse. In fact a fair number of people who were treated at clinic actually attended for another reason, and the health worker just happened to notice the guinea worm ulcer.

Another issue is gender. in Onwujekwe’s survey a majority of the respondents were female. Women in health surveys have been found to give ‘don’t know’ responses more often than men. The interview is a formal social situation with a visitor to the home. Sometimes women may not feel comfortable giving opinions on behalf of their households.

The key lesson from these experiences is that while we urgently need data on whether people are actually gaining universal access to malaria treatment services, we need to take caution in how we approach interviewees and how they believe they should answer us. Interview techniques that set people at ease and find several different ays to ask the same question about treatment choices can help improve data collection. Only with valid responses, will we learn if our services are reaching people and where improvements are needed.

Recently in a small provisions shop in Abuja I bought a box of ‘Anti Malarial Tea’ bags. The 20 bags/sachets weighed 2 grams each. The instructions were to use “3 times daily, one bag each time.” The only ingredient listed was “Herba artemisiae annuae.”

Indications for the use of this dried herb product were as follows: “The Product can be used to eliminate plasmodium agamous body. It can also be used to control symptom and kill plasmodium. It has similar effect on resist virulent chloroquine malarias.”

The manufacturing date was blank, but the espiry date was listed as ‘2014.’ Storage was recommended as “Store in shade, light-avoided and airproofed.” In fact the tea bags were sealed in a silver colored bag.

This product was obviously not moving fast, and there was little likelihood that it was competing with orthodox antimalarial drugs. Still one might be concerned about monotherapy and drug resistance.

A recent article in the journal Molecules did address the potency of artemisia annua in different forms of extraction. The researchers found that …

… the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice.

Here again one wonders if using the dried herb as tea would contribute to parasite resistance.  Another group of researchers tested the tea on malaria in mice and found that, “The tea does not decrease the parasitaemia fast enough.”

Herbal medicines form the base for many remedies throughout the world. Although a website for the actual company named on the box, Xiamen Jianxi Health Product Co., Ltd., was not found, another site listed 70 different teas including –

• Eye Bright Tea
• Kidney & Liver Mind/Care/Flush Tea
• Anti-Hypertensive Tea
• Anti Malarial Tea
• Refreshment & Heat Clearing Tea
• Cough Sputum Removing Tea
• Stomach & Heart Burn Relieving Tea

In our quest for universal access to and appropriate use of ACTs, we forget that people still have many treatment alternatives.  Until we can make quality ACTs cheaply and easily available in endemic countries, people who suspect they have malaria will make all efforts – whether teas, antibiotics, analgesics, inefficacious malaria drugs and the like – to address their problems.

In wondering whether Nigeria’s health system is non-existent, Seyi Abimbola suggested that, “It is safe to assume that every country has a health system, no matter how dysfunctional.”  Seyi also addresses the potential role of patent medicine vendors whose neighborhood shops have become ‘trusted’ institutions.  But let’s take this one step further beyond the shop.

The other evening after food, I was sitting with friends out on an Abuja back street having drinks when a man came buy with a straw tray on his head selling medicines.  These ‘drug hawkers’ specialize in what the Yoruba term pa’se po, a combination of pills and capsules, often sold in a small clear nylon bag that taken at once should relieve one of a particular ailment. Some actually say this mix that literally ‘combines or brings together the work of all’ can be formulated to treat all kinds of diseases in one. Colorful mixes of analgesics, antibiotics and even valium have been common.

One person at a nearby table began to explain his aches and pains and was given a mix of pain killers and vitamins.  I called the guy over and asked what he had for malaria and was given the mix pictured here – sulphadoxine-pyrimethamine, paracetamol and big multi-vitamin caplet.  These two mixes cost only 100 Naira (about 67 US cents) each.  Like many, this man had mixtures for both chronic and infectious illnesses.

This hawker was a bit more sophistocated than most in that he sold the medicines still in their blister pack, and the malaria medicine, though no longer approved as a treatment in Nigeria, at least was not expired.  Of course when he walks around the neighbourhoods during the day, the tray on his head is explosed to the sun!

Nigeria has long fought a battle against illegal sales of medicines, which often include fake or expired drugs. For example in 2007 the Federal Government “called for sanctions to be to put in place against persons who engage in unauthorised distribution, sale and dispensing of medicine or controlled substances.” While this article bemoaned the fact that, “Nigeria is one of the few developing countries in the world where medicines of all categories are sold in open market stalls, roadside kiosks, peddled in buses and hawked in basket along the streets,” the press from other countries also carry such stories as seen below from The Gambia …

“… it is still a common practice for some people who have taken the sales of these drugs as a livelihood. This is no doubt a dreadful act and should be discouraged. It is sad to not e that the people who are hawking these drugs don’t even know the essence of the drugs, their indication, dosage, side effects or even their contra-indications. They just carry them in a transparent plastic bag and move with them from place to place particularly around the ferry crossing terminals.”

Efforts to bring down the cost of appropriate and approved malaria medicines such as those by the Clinton Foundation and the Global Fund’s new Affordable Medicines Facility for malaria, may not compete with the convenience and price of the drug hawkers. More regulation in a non-existent system will not do the trick. Maybe a more clever market-oriented consumer education approach would help? Let’s hawk ideas not expired medicines.

Tarry Asoka, a medical doctor and health development consultant, provides us a perspective on why health insurance is needed to meet malaria treatment gaps. Tarry is  Publisher/Editor of Health Insurance Affairs and Malaria Bytes…

All across sub-Saharan Africa the poor utilization of modern health services usually reverses and begins to improve, reaching a tipping point as soon as there is confirmed indication that ‘treatment charges’ in health facilities have been removed. And politicians in the sub region are very quick to take good note of this phenomenon – often taking full advantage to develop populist ‘free health campaigns’ that are often not sustainable.

The lack of continuity is not usually the result of faulty design but due to poor execution as many of these are mostly ad hoc initiatives rather than enduring programmes. But the fact that these campaigns continue to be popular especially among poorer citizens despite their lack of permanence and irrespective of who is organising it – government, NGOs or private – should give health planners some worry that something is not quite right.

Curiously, malaria is still the most common condition recorded by health professionals during such health jamborees. A recent free medical check-up drive to promote a new community-based health care programme in a high density area in Port Harcourt, Rivers State, Nigeria – noted that close to 30% of those who were seen had classical symptoms and signs of malaria that have not been treated for at least 2 days.

So what could have happened to such persons especially children if this event did not take place at that particular point in time? Your guess is as good mine.

But one fact is clear – the payments that are needed to be made at the point of accessing health services prevent large majority of the population from seeking medical care. A recent survey in Kenya, for example, found that “61.5% of individuals who did not seek (malaria) treatment reported that cash shortage was the main barrier.” Others coped by borrowing, selling household possessions, or buying cheap drugs from shops.

Therefore, any mechanism that enables people to access care ‘free at the point of delivery’ will improve treatment for life-threatening conditions such as malaria and save lives.

This is ‘no-brainier’, and does not require elaborate plans to be put in place. Apart from informal and community-based health insurance, which has been quite challenging to set up, other approaches such as vouchers and coupons have also proved to be useful alternatives.

The task now is to scale-up these options to achieve universal coverage.

Malaria Journal published a few days ago an article comparing the costs of treating children and adults for malaria at a Nigerian hospital based on clinical diagnosis versus treating only when microscopy was positive for parasites. Normally we would pass abstracts from such articles on to members of our listserve (see link at right), but comments from a colleague in Nigeria gave pause.

He rightly pointed out that normally any research that helps us consider the factors involved in proper malaria diagnosis and treatment is welcome as we move toward universal coverage and elimination. His concern was that the researchers, who conducted their study in 2009, had not followed national malaria treatment policy and guidelines, which had been promulgated in 2005 based on the alarming growth of resistance of malaria parasites to the common, though cheap, antimalarials such as chloroquine and sulphadoxine-pyrimethamine (SP).

First the cost findings from the team at Bowen University Teaching Hospital (aka Baptist Medical Center, Ogbomosho) –

• For children, testing all but treating only Giemsa positives was $6.04/child
• Empiric treatment of all children clinically diagnosed was $4.49/child
• For adults, treating only Giemsa positives was $4.84/adult for treatment option one and $4.97/adult for option two
• Empiric treatment for adults was $4.14/adult for option one and $4.63/adult for option 2

In spite of the cost findings, the researchers did point out the drawbacks of empirical or clinical diagnosis in terms of accuracy and potentials for promoting drug resistance and called for scale up of rapid diagnostic tests (RDTs) to address these concerns.

The treatment regimens in this study included …

• Pediatric patients: artesunate (6-9 tablets of 3 mg/kg on day one and 1.5 mg/kg for the next four days) plus amodiaquine (10 mg/kg on days one to two and 5 mg/kg on day three in suspension)
• Adult option one: four and one-half 50 mg artesunate tablets on day one and nine additional artesunate tablets over the next four days, plus three 500 mg sulphadoxine/25 mg pyrimethamine tablets
• Adult option two: four and one-half 50 mg artesunate tablets on day one and nine additional artesunate tablets for the next four days plus nine 200 mg tablets of amodiaquine at a dose of 10 mg/kg on day one to two and 5 mg/kg on day three

National treatment guidelines specifically stress use of artemisinin-based combination therapy (ACT) for basic, uncomplicated malaria treatment.These guidelines are undergoing further revision with a stronger emphasis on ACT use based on RDTs and microscopy where available and recognition of the dangers of monotherapy drugs like chloroquine, SP and even artesunate itself.

The researchers from Ogbomosho are rightly concerned about cost issues, and being a private/NGO university and hospital, they do witness the direct effects of medication costs on patients that health staff in the public sector may not see.

This is still no excuse for not following national treatment guidelines when these drugs were available for their procurement in 2009. Now with the advent of the Affordable Medicine Facility malaria (AMFm) in Nigeria all health facilities, especially NGO hospitals like Ogbomosho, have no reason not to buy and dispense the correct medicines.

To re-emphasize this point, a press release from November 2010 clearly states –

“The Federal Government has directed all medical doctors and other health officials in the country to henceforth start using Artemisinin-based Combined Therapy (ACT) for the treatment of malaria disease in the country. Minister of Health, Prof. Onyebuchi Chukwu, gave the directive yesterday in Abuja during the ministerial press briefing on Affordable Medicines Facility (AMF) for malaria programme. According to the minister, the spread of malaria had become so critical that everyone in the country was now involved.”

We hope health workers in all sectors get the word! Hopefully national authorities will step up their efforts to disseminate guidelines to all front line health workers whether in public, private or NGO sectors.

According to the World Health Organization, its “Prequalification Programme aims to make quality priority medicines available for the benefit of those in need.” The results is a “list of prequalified medicinal products used for HIV/AIDS, malaria, tuberculosis and for reproductive health.” The list is supposed to guide purchasing decisions of all UN and development partner agencies.

The Global Fund is one of the international agencies that encourages its recipient countries to buy from the prequalified list, and through the Affordable Medicines Facility, malaria (AMFm) intends that not only good quality is promoted, but reduced prices. Interestingly, this development has raised concern in Nigeria, the biggest market for malaria drugs in Africa.  As Soyombo Opeyemi explains in the Daily Independent …

The proposed intervention by The Global Fund to drastically reduce prices of Artemisinin Combined Therapies (ACTs) through its Affordable Medicines for Malaria programme (AMFm), which will see ACTs from six foreign companies sell from September 2010 at a monitored price regime of between N60 and N70 a dose [between US $ 0.40-0.47], as against the current average price of N350 for most ACTs produced or marketed in Nigeria, has generated a rumpus in the last few weeks in the media.

The controversy arises over two competing development goals – making high quality medicines available to those in need at affordable prices vs strengthening local industrial capacity. As seen in the Table below, many of the manufacturing sites are in ‘developing’ countries, but as Abdullahi Mohammed points out in This Day …

(These manufacturers) also have access to cheap credit, enjoy tax reliefs and export incentives, among other forms of official assistance. All this makes it difficult for Nigerian manufacturers, who currently have practically no access to bank credit and are stuck with providing their own infrastructural requirements, to compete with their foreign counterparts.

The Nigerian malaria drug market is vast. There are dozens of Arthemeter-Lumefantine ACTs approved for sale and over 100 Artesunate-Amodiaquine formulations. Some of these are produced by actual Nigerian manufacturers while others are imported by a Nigerian Company from India and elsewhere. It would be important to identify the actual indigenous manufacturers who are losing out to the six big international pharmaceutical producers.

It is not clear whether there are actual foreign assistance efforts aimed at building the capacity of malaria endemic countries in Africa to produce their own pharmaceutical products.  If such a longer term project were started in parallel with efforts like AMFm, there may be more acceptance for temporary set backs in the local market, knowing that in good faith, the international community is trying to strengthen countries’ abilities to fight malaria into the future.

the challenge though is which aid program can address the infrastructural problems facing Nigerian manufacturers – lack of reliable electricity, water supply and roads – as well as a legal framework that protects intellectual property and gives the local companies a fair chance to compete.

Not all fevers are malaria. This should not be an earth shaking statement, but national treatment guidelines in malaria endemic countries often stress presumptive treatment for malaria, especially when children present with fever. Irin explains that even the World Health Organization has been hard pressed to recommend otherwise when accurate parasitological diagnostic resources are unavailable.

The concern about over-diagnosis of malaria is hitting home though because the current first line treatment, artemisinin-based combination therapy (ACT) is quite expensive, and additionally, health experts are concerned that overuse or misuse of these drugs may foster parasite resistance. To make this point even stronger Peter Gething and colleagues found that, “Of the 183 million children with malaria symptoms treated by public health clinics in 2007, only 43 percent were diagnosed with malaria, but many more most likely received anti-malarial medication (IRIN News).”

A variety of febrile illnesses, especially from mosquito-borne diseases, occur in the same community. A news report from Vapi, India states that, “During the (previous week), 13 cases of chikungunya, six of dengue and 25 of malaria have been reported from in and around Vapi with Nehru Street being the most affected. The outbreak of mosquito transmitted diseases has made the health officials in the district rush to the city to initiate measures for vector control.”

A serological-epidemiological household survey in Sudan after a yellow fever outbreak found, “serologic evidence of recent or prior chikungunya virus, dengue virus, West Nile virus, and Sindbis virus infections.”

Källander and colleagues stressed the challenges of clinical diagnosis to differentiate malaria and pneumonia and reported that, “Of 3671 Ugandan under-fives at 14 health centres, 30% had symptoms compatible both with malaria and pneumonia, necessitating dual treatment. Of 2944 ‘malaria’ cases, 37% also had ‘pneumonia’.”

Gething’s group did find that 72% of those febrile cases that actually were malaria were found in locations that had higher parasite prevalence. Possibly clinicians in more highly endemic areas can presume correctly more often that a fever is malaria, but this still does not stop the wastage of ACTs, which will continue until the parasitological testing gap is closed with adequate supplies of rapid diagnostic tests and microscopes (and the skills to use these).

Gething and colleagues stress the need for countries to develop appropriate strategies by adapting the statistical models they developed with more country based data. They sadly conclude that, “Unfortunately, inadequacies in national health management information systems across Africa are in part a cause of the present imperfections in essential  commodity demand and burden estimation.”

It would be even sadder if much of the treatment commodity supplies distributed in 2010 to achieve universal coverage of malaria interventions were wasted on non-malaria fevers.

Forty-four Ministers of Health of the African continent (as well as Brazil and India) or their representatives congregated at a special ministerial session of the 18^th Roll Back Malaria (RBM) Partnership Board meeting and on the last day, 14^th May 2010, signed a document in which they, “Express(ed) our governments’ engagement, with support from our development partners, to eliminate (ban and enforce) oral artemisinin-based malaria monotherapies and substandard ACTs from the market through tangible policies, strategies and regulatory measure within the next 12 months.” Hopefully these words will lead to action and soon.

The World Health Organization has been pressing this issue strongly for several years, and as far back as 2001 a WHO publication, “Use of Antimalarial Drugs” (pg. 72), specifically stated that artemisinin should preferably be administered in combination with another effective blood schizonticide. A press release in early 2006 WHO called for an immediate halt to provision of single-drug artemisinin malaria pills, and was issued in concert new malaria treatment guidelines issued by WHO.  In another press release later in 2006 WHO announced that some pharmaceutical companies agreed to stop marketing single-drug artemisinin malaria pills, specifically the press release explained that …

“In January 2006, WHO appealed to all companies to stop marketing oral artemisinin monotherapies and to re-direct their production efforts towards ACTs. Following the January appeal, an additional 23 companies were identified and informed of WHO’s recommendation. 13 companies said they would comply with the WHO guidance. Additional companies have said they are willing to collaborate with WHO in this endeavour.”

It is not clear that WHO’s warning was heeded, because another WHO press release on 25 February 2009 stated that, “WHO today said that the emergence of parasites resistant to artemisinin at the Thai-Cambodia border could seriously undermine the success of the global malaria control efforts.” While outright resistance was not declared, Dondorp and colleagues found in 2009 that, “P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia.”

Reuters reported earlier this year that, “Pailin (Cambodia) is the origin of three drug-resistant malaria parasites over the past five decades. Thanks to prolonged civil conflict, dense jungles and movement of mass migrants in the gem mines in the 1980s and 90s, the strains multiplied and dispersed through Myanmar, India and two eventually reached Africa.” The situation is made worse by illegal pharmacies that sell counterfeit medicines. MediaGlobal stated earlier this month that, “the government (of Cambodia) has shut down 65 percent of illegal pharmacies. The number of illegal pharmacies has decreased from 1,081 in November 2009 to 379 in March 2010.”

Action by the 44 African Ministers of Health is not too late, but it could have come sooner. The Ministers pledged to “Report on progress in eliminating oral artemisinin-based monotherapies in May 2011,” as they signed up “to the commitment against the use of oral artemisinin-based monotheraples for malaria control.”

Nigeria, with the highest malaria burden in Africa, was one of the countries that apparently missed the meeting. Onwujekwe and co-researchers recently documented the sales or provision of monotherapy artesunate drugs in most of the public and private hospitals as well as pharmacies they studied in Anambra State. Nigeria’s policy concerning monotherapy artemisinin drugs was to all those already on the market to continue until their license ran out.

As we reported previously, some of those licenses will not expire until 2012.  We hope Nigeria and all other malaria endemic countries will act sooner than later and be able to report the complete removal of monotherapy artemisinin drugs my May 2011.  We want to eliminate malaria, not eliminate the effectiveness of ACTs.