Category Archives: Resistance

Keeping up with Malaria – 4 years and 500 postings

This month marks the 4th year for Malaria Matters and our 500th posting. Two of our first postings we examined what happens to chloroquine when it is no longer used as a first line drug,and how malaria proposals fare at the Global Fund.

Chloroquine was valued because it was inexpensive and therefore justifiably used for presumptive treatment. Resistance showed not only that the presumptive treatment approach was likely flawed, but that single drug or mono-therapy treatments were not appropriate. Research today continues to document the spread of chloroquine resistance for example, in vivax and falciparum malaria in Indonesia.

What our 2006 posting addresses was the fact that chloroquine resistance did reduce after the drug is withdrawn as the front line treatment in Malawi. These findings were backed up by a study from Kenya published last year. The Kenya researchers reported “a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower,”ultimately taking twice as long as it did in Malawi – assuming use remains at a low level.

dscn9149-sm.JPGThe practical research question moving into the future toward malaria elimination is whether an inexpensive drug like chloroquine can ever again find a place in the pharmacological arsenal against malaria. The experiences of both increasing and reducing drug efficacy also stress the importance of maintaining strong pharmaco-vigilence as part of any national malaria control effort.

Concerning the Global Fund we expressed disappointment in 2006 that malaria grants performed so poorly in Round 6 allocations in terms of relative proportion of total grants as well as proportion of submitted grants approved. Since that time the Roll Back Malaria Harmonization Working Group has mobilized human resources to strengthen the grant writing process. Since that time malaria grants have been gaining a greater share of total resources and have had better success in being approved.

According to AIDSPAN, this year’s Round 10 allocations may be a mixed bag for malaria. While 79% of submitted malaria proposals were recommended for approval (better than the 50% overall approval rate), only a small number of proposals were submitted (24) and ultimately approved (19) of the 89 from all sources.

This low ‘turnout’ may reflect the economic constraints at the Global Fund where there had even been some doubt earlier that a Round 10 would be issued, but it reflects poorly on the need to scale up and sustain malaria interventions into 2015 and beyond. This also does not reflect changes in Global Fund approaches such as the rolling continuation credit and the potential move toward funding based on national strategy, all of which are changes at the GFATM since 2006.

Overall once can see that in four short years the funding and technical landscape surrounding the control and elimination of malaria are changing quickly. We are closer now to a vaccine, WHO has updated its malaria treatment guidelines, long awaited rapid diagnostics tests are rolling out in larger quantities, and countries, such as those in southern Africa, that need to develop pre-elimination strategies are being identified. We intend that Malaria Matters will help you keep up with these vital changes.

If Myanmar cannot control malaria, what of Burma?

Myanmar has operated only three Global Fund Grants in its history. The Round 3 Malaria grant was terminated at Phase 1 in 2007. Two million dollars was disbursed, but no results were found in the progress report at the Global Fund website. No explanatory notes were offered.

In the meantime, malaria continues unabated. Reports from a remote rural area observe that, “About half of the villagers in this remote corner of Kachin State are suffering from the mosquito-borne disease, but medical supplies provided by the Kachin Baptist Convention (KBC), a Christian group, ran out two weeks ago.”

The website explains that villagers are reluctant to complain because, “In military-ruled Myanmar, saying anything seen as critical of the authorities can have serious consequences.” Instead villagers wait as they lack money needed to reach clinics and thus, resort to indigenous treatments.

Reports from the KBC indicate that they only had the resources to assist about five percent of the Kachin population in the fight against malaria. The mission group complained that, “There are many people we can’t reach, and it’s getting worse. It’s linked to poverty. Most of them can’t even afford mosquito nets.”

Myanmar does have an unsigned Round 9 malaria Global Fund grant pending. One wonders whether performance would be any better than Round 3.

Myanmar is part of the broader Mekong area where fears of malaria drug resistance are a constant concern. IRIN reports that, “Mekong countries of Cambodia, China, Lao PDR, Myanmar, Thailand and Vietnam, show (malaria drug) tolerance … with the drug proving less effective and taking longer than previously to kill the parasite.”

IRIN noted that, “… studies in Myanmar had shown that parasites were still detected in some cases after treatment, taking more than a benchmark three days to be cleared …  This is an indication that there is resistance .” Furthermore, “only around 500,000 ACT courses are available annually – a fraction of what is needed to treat an estimated 8.5 million malaria cases.”
wikimedia-commons-myanmar.jpgAccess to malaria treatment and prevention is not a unique problem. IRIN reminds us that in the wake of a major tropical cyclone in 2008 the Myanmar population in affected areas was threatened with malnutrition and diseases due to lack of adequate access to food and medicine. This health neglect is endemic.

Will new elections help? BBC reports that a group of 15 nations, “known as the Friends of Burma, called for inclusive, participatory and transparent elections. Afterwards the secretary general said he had expressed concern that conditions in Burma do not measure up to what is needed for an inclusive political process.”

Without an inclusive political culture can the political will and accountability exist to control and eventually eliminate malaria? This is not just an issue for the poor and suffering within Myanmar since practices there enhance malaria drug resistance in the region and ultimately the world.  If Myanmar cannot control malaria, one wonders if Burma could.

Will malaria parasites defy elimination?

Three new articles in Malaria Journal plus a news release from the Commonwealth Games in India remind us that like any other organism, the malaria parasite will fight for survival.

Yvonne Lim and colleagues document a rare case of P. ovale imported into Malaysia. They note that local vectors are capable of transmitting this parasite as well as an “exponential increase in the number of visitors from P. ovale endemic regions.”

A Nigerian table tennis player at the Commonwealth Games in India withdrew after coming down with malaria. The Times of India implies that the illness may be a result of “The Capital’s dreaded mosquitoes.” Depending on when he arrived in India, Ekundayo Nasiru could have brought the disease with him. In either case the potential for importing and exporting malaria exists.

Now under way in several pilot countries, “The Affordable Medicines Facility-Malaria (AMFm) is a mechanism to increase access to quality assured ACT.” AMFm hopes that with approved and cheaper artemisinin-based combination therapy (ACT) drugs monotherapies will be driven from the market and the lifespan of ACTs will be prolonged, thus “reducing the likelihood of resistance to artemisinin.”

artequin-child2.jpgUnfortunately, another article in Malaria Journal reviews “Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand.” After identifying cases of recrudescence after treatment, the researchers concluded that …

Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

These experiences show how important it is not only to document drug resistance and imported cases but also to help countries plan “Robust Malaria surveillance systems towards malaria pre-elimination and assessing Roadmaps achievements,” which is the theme of a meeting of the East Africa Regional Network (RBM) underway in Kigali. More technical assistance is needed in “strengthening Malaria surveillance in high and low burden countries,” if elimination goals are ever to be achieved.

Strong words against oral artemisinin monotherapy drugs

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 18th Roll Back Malaria (RBM) Partnership Board meeting and on the last day, 14th 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.

art_drugs_sm.JPGThe 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.

Getting tough on monotherapy artemisinin drugs

In Guyana Stabroek News reports that, “Minister of Health Dr Leslie Ramsammy has thrown down the gauntlet to pharmacies to desist from selling the single dose artemisinin malaria drug by the end of this year or he would instruct officers from the Food & Drugs Department to size the drug from their shelves.” Guyana has been promoting ACTs since 2004.

In Guyana, the coastal areas are considered to be malaria free while the interior areas are considered to be high-risk malaria areas. Guyana therefore, may not me among the most endemic countries for malaria, but all endemic countries need to take the disease seriously, like Guyana’s Minister of Health, in order for global elimination to succeed.

Guyana has seen success in promoting malaria control. In endemic areas bednet use by children under 5 years of age increased from 7% to 70% between 2000 and 2006, according to the Multiple Indicator Cluster Survey.

Guyana’s Round 7 Global Fund proposal also aims to decrease malaria incidence by 70%. Included in the strategies are diagnosis and treatment with the intention that all health facilities (including the private sector) would be appropriately trained and equipped with microscopes and have adequate amounts of drugs and rapid tests. This is why the need for appropriate treatment with ACTs, not monotherapy drugs is being stressed.

As we have mentioned before, Guyana’s malaria control efforts are complicated by migrant miner populations in the endemic areas. It is such populations that may help drive the demand for cheaper, though inappropriate malaria medicines like artemisinin monotherapies.

An interesting irony is that WHO lists Guyana among the 16 countries that have never registered artemisinin monotherapy drugs. This implies that the availability of such medicines in Guyana is truly against the law and also shows how slippery the pharmaceutical import business can be.

WHO as of 16 November 2009, lists 33 endemic countries as not taking adequate steps to stop the sales of monotherapy artemisinin drugs.  Another 29 have “taken regulatory measures to withdraw the marketing authorization of oral artemisinin-based monotherapies after implementing ACT policy.” The approach of these 29 does not mean the immediate withdrawal of monotherapies, as some like Nigeria are simply letting the current registration of these drugs run out – meaning they may be on the market for another 2-3 years.

Unless all endemic countries take action like that proposed in Guyana, we may not be proceeding along the pathway to elimination, but down the road to drug resistance.

When Parasites Travel

Mobile population importation of drug-resistant infections and diseases is a focus of the November 2009 issue of Emerging Infectious Diseases. In that issue, MacPherson and colleagues cite, “Many examples of imported multidrug-resistant (MDR) infectious diseases are associated with migrant populations, e.g., MDR Plasmodium falciparum malaria in immigrants, tourists, and returned foreign-born travelers.”

Parasites travel –

  • According to Monge-Maillo, malaria accounted for nearly 10% “of 2,198 immigrants referred to the Tropical Medicine Unit of Ramón y Cajal Hospital over a 20-year period” in Spain.
  • CDC received reports of 1,324 cases of malaria, including four fatal cases, with an onset of symptoms in 2004 among persons in the United States or one of its territories. This number represents an increase of 3.6% from the 1,278 cases reported for 2003,” as reported in MMWR by Skarbinski and colleagues.
  • In the Netherlands 5043 laboratory cases of imported malaria were confirmed between 2000 and 2003 according to Klein and Bosman.

fly_dscn0185.JPGThe problem is worse when drug-resistant parasites travel. Chan and co-researchers have been examining archival human sera “to explore the origin and evolution of Plasmodium falciparum chloroquine resistance in the Pacific.”

In 2002 Afghan refugees brought malaria into northwestern Pakistan. They experienced a 28% treatment failure rate when chemically substandard locally manufactured sulfadoxine-pyrimethamine was used for routine treatment. This is a potential way of producing drug resistance that could be carried back home by returning refugees

MacPherson and colleagues demand what they call, “Pharmaceutical security systems for standard and quality medicines,” in an effort to combat “commonly substandard or counterfeit” drugs in endemic countries.  Progress in eliminating malaria in Zanzibar, Rwanda and Zambia can easily be threatened if resistant parasites cross their borders. These parasites don’t need passports and visas.

Enhancing artemisinin production – on a fast track

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

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

artemisia-annua-bbc2.jpgAs a natural product, artemisinin has not been easy to produce and store in quantities needed for large scale control programs.  The BBC recently posted an video on efforts to grow Artemisia annua with enhanced artemisinin content. The video explains techniques that were used to breed the plant far more quickly than traditional methods using “fast track molecular methods.” The new plants are being disseminated for field testing to parts of the world where the plant is being grown commercially.

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

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

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

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

Artemisinin – production, resistance, change

The fate of artemisinin in malaria control may be affected from the plant source to the parasites in humans according to two recent web postings.  Some challenges may result from people willing to change quickly, while others may be slow to react.

Sociolingo Africa has provided an update on artemisinin production in Uganda.  The situation of decreasing prices amid increasing demand was seen as puzzling.  The farmers who had begun cash crop production of artemisinin were now seeing ‘leaves rotting in the fields’ and were being encouraged to grow “Davana; Chillies; Fennel; Jasmine Rose; Ginger; Vettiver; Basil; and many more others, most of which are used in the production of essential oils and perfumes” by the Indian companies that were in fact guiding the Ugandan production of artemisinin.

It is possible, considering any commodity market, that diversification is a wise move on the part of the company.  Clearly there are efforts afoot (e.g. AMFm, Clinton Foundation) to reduce to cost that consumers pay in order to make the artemisinin-based combination therapy (ACT) drugs available thus, creating possibly more downward pressure on pricing.

In the early days of ACT promotion prices of the drug were said to be high because of the uncertainties in the procurement processes of endemic countries.  International mechanisms by organizations such as the Global Fund and WHO to coordinate this process while also increasing the supply to reach coverage targets also mean that production could confidently increase while prices of the final product could reduce.

So back to Uganda – there is likely now greater competition among producers of artemisinin in many countries – including the Ugandan farmers – in line with increasing demand projections. These farmers changed in reponse to the companies’ projections. At least in this case if substitute crops are provided, they may not suffer too much, but the fate of such farmers in other endemic countries such as Kenya where artemisinin farming has been introduced may not be so clear.

On the other side of the continent there are worries about parasite resistance to artemisinin.  In Nigeria ASNS News notes that, “Dr. Paul Orhi, Director General of NAFDAC (National Agency for Food and Drug Administration and Control), is quoted in the local press that the main reason for (growing emergence of resistance) was because people were not taking proper doses and that they still use monotherapy instead of combining two drugs appropriately.”

While it may take time for the resistance to spread from Southeast Asia where it has recently been documented, the Nigerian concern is real.  The irony is that there does not need to be worry about monotherapy if NAFDAC were to be bold and withdraw the registration of the numerous artesunate monotherapies currently on the market in Nigeria.

The current policy of NAFDAC is to allow those monotherapy drugs already registered to stay on the market until their registrations expire – some as late as 2012.  If NAFDAC were bold enough to change now and withdraw those registrations, its Director General would have less to worry about.  Proper training of health and pharmacy workers in both public, private and commercial sectors to counsel those receiving ACTs on the proper regimen would also reduce his worry about improper dosing.

Timely and appropriate change is needed to protect and increase the malaria drug supplies we have now, while research continues to find new medicines as the need will most certainly arise.

ACT Treatment Failure – reality today … or tomorrow

The ‘F’ word has appeared in peer reviewed malaria literature. “Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia,” reads the title of a new article in Malaria Journal. The authors concluded that, “It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.”

In narrowing down an explanation for treatment failure, the authors considered the following:

  • Adulterated and counterfeit drugs are on the market, but it was unlikely that these entered into their study
  • Mefloquine dosage ideally varies by weight, and some could have been underdosed, but again analysis shows this was not a factor

The authors also surmised that if resistance to mefloquine is at play, this may expose the patient to only a three-day dose of the artesunate, which then would effectively make artesunate a monotherapy and open to provoking resistance at that dose.

Lim and colleagues consider how resistance to artemisinin drugs could develop in artemether-lumefantrine (AL). coartem-sm.JPG Challenges to absorption of lumefantrine exist and may be related to diet. Here again, the artemisin drug would effectively become 3-day dose of monotherapy, if the partner in the combination was compromised.

Fortunately Premji et al. reported in Africa that “food consumption is adequate post-weaning (and) it appears that only a very small amount of dietary fat is necessary to ensure optimal efficacy with AL and that the fat content of standard meals or breast milk in sub-Saharan Africa is adequate.”

Could home management be a tipping point for ACT resistance.  Data from Ajayi et al. “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.” A strong health education component to home management is still necessary.

After modeling the scenarios for ACT resistance, Pongtavornpinyo and co-researchers offer a prescription for action.  They conclude that, “The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures.”

Pongtavornpinyo also noted that resistance is more likely to develop in low transmission areas such as found in studies from Southeast Asia mentioned above. Even in high transmission areas, “high ACT coverage alone cannot reduce malaria transmission unless it is used together with vector-control measures.”

Unfortunately at present unavailability of ACTs may be a bigger problem in these high transmission areas, such as the frequent stock-outs in Uganda reported by Start News. This is despite several years of Global Fund support for malaria control in Uganda. Purchasing the new ACTs in commercial pharmacies is too expensive for most, and so people resort to buying the older and cheaper drugs for which there is resistance.

Either way – whether resistance to artemisinin develops tomorrow or people are forced to take cheaper but less effective drugs today – the patient suffers.

Malaria warnings from the east

Two news items require greater world-wide attention if current malaria control tools are to remain effective. asks the question, is “Monkey malaria the next bird flu?” The article reports that Dr. McCutchen, “An expert at the NIH, has highlighted the threat of an emergent highly virulent form of malaria, questioning whether the disease has made the jump from animal to man.”

macaque-4509sm.jpgThe news story further states that, “Although at least ten species of Plasmodium can infect humans, only four forms of specifically human malaria are believed to exist. In the case of these four established human malaria types, the parasite is transmissible from one human to another, and a stable transmission cycle is established in the absence of any other vertebrate host. Now Dr McCutchan has raised the question – has a monkey malaria made that switch and become the fifth human malaria?” The full article appears in Future Microbiology and focuses on Borneo.

Dr McCutchan explained that interest was generated because of the severity of the infections and that, “The study of P. knowlesi is extremely significant regardless of whether it has entered humans permanently or represents a zoonosis. In either case, we face a health problem of potentially widespread significance and one that will present new problems for malaria control.”

Two other recent studies have documented the transmission of Plasmodium knowlesi to humans in the Philippines and Singapore. Research by Luchavez et al. (2008) extends the geographic range of known human P. knowlesi infections from Thailand, Myanmar, peninsular Malaysia, and Malaysian Borneo to Palawan Island in the Philippines. Their “report documents autochthonous human cases in the country. Major progress in malaria control has been achieved in many malarious areas in the Philippines. However, P. knowlesi forms a previously unrecognized pool of infections that may be maintained in forested areas through its presence in a simian reservoir, despite control efforts in the human population.”

Ng et al. (2008) in the Singapore example note that the case was originally misdiagnosed as Dengue, which is endemic in the region. They were fortunate that the infection responded to chloroquine.

Finally, another malaria control challenge was reported by Wongsrichanalai and Meshnick (2008) in the form of growing resistance to artesunate-mefloquine on the Cambodia-Thailand border. They suggest that, “These ACT failures might be caused by high-level mefl oquine resistance because mefloquine was used for monotherapy long before the introduction of ACT. This observation raises 2 questions. First, how can existing P. falciparum–resistant strains be controlled? Second, how can the evolution of new ACT- resistant strains be avoided elsewhere, e.g., in Africa?”

Not only does malaria not respect political borders, but now it seems, not even the ‘borders’ between species.