Category Archives: Resistance

Malaria News Today 2020-09-17

Leading off our news update are findings from eastern Kenya about a genetic blood grouping that may help prevent malaria. While government leaders in the Asia-Pacific region committed to eliminating malaria, a report from the Gates Foundation explains how COVID-19 has set progress back and without new tools it may take more than 25 years to rid the world of the disease. In that light, Novartis is staking its finances on being able to make medicines that will be accessible and fight malaria. More details and the Gates video can be seen by clicking the links below.

How Dantu Blood Group protects against malaria

The secret of how the Dantu genetic blood variant helps to protect against malaria has been revealed for the first time by scientists at the Wellcome Sanger Institute, the University of Cambridge and the KEMRI-Wellcome Trust Research Programme, Kenya. The team found that red blood cells in people with the rare Dantu blood variant have a higher surface tension that prevents them from being invaded by the world’s deadliest malaria parasite, Plasmodium falciparum. The findings were published in Nature and could be significant in the wider battle against malaria.

In 2017, researchers discovered that the rare Dantu blood variant, which is found regularly only in parts of East Africa, provides some degree of protection against severe malaria. The intention behind this new study was to explain why. Red blood cell samples were collected from 42 healthy children in Kilifi, Kenya, who had either one, two or zero copies of the Dantu gene. The Dantu variant created cells with a higher surface tension—like a drum with a tighter skin. At a certain tension, malaria parasites were no longer able to enter the cell.

Novartis ties bond sale to malaria treatment access in sustainability push

Novartis raised 1.85 billion euros on Wednesday from the sale of a bond on which interest payments will rise if the drugmaker fails to expand access to medicines and programmes to combat malaria and leprosy in a number of developing countries.

Investors are increasingly pushing companies to improve their track record on environmental, social and governance (ESG) issues while sustainable investing grows in popularity, spurring an increase in sustainable debt issuance year after year. Novartis’ bond is only the third issue to date to link payments to creditors to company-wide sustainable development targets. By Yoruk Bahceli

Commitment to make Asia Pacific a malaria free region

Government officials from across Asia Pacific have come together during virtual Malaria Week 2020, to reaffirm their commitment to eliminating malaria and strengthening health systems to keep the region safe from health threats. Embracing the theme of “Inclusion. Integration. Innovation.”, officials called for increased collaboration and action to accelerate towards the goal of ending malaria in the region by 2030, at a time when major gains and regional progress are under threat due to disruptions caused by Covid-19.

It could take up to 25 years to eradicate malaria from Africa – Bill Gates

Bill Gates said: “Moving to malaria which is a very awful disease not just to the kids it kills but many kids whose brains are permanently damaged, the economic effects you have with malaria. If we don’t have new tools like vaccines or new ways of killing mosquitoes, it would probably take more than 25 years to get rid of malaria. If we get the new tools and they work, we think it can be done in under 20 years. So the malaria field is both trying to keep the number of deaths down, and we have to deal with the resistance that comes up, that the mosquitoes develop.”

Gates Foundation Report notes that, “We’ve been set back about 25 years in about 25 weeks.” Extreme poverty increased 7% because of COVID-19. In a video included in the Foundation’s report, Bill Gates explains how COVID-19 disrupts the fight against malaria.

Malaria News Today 2020-09-15

Malaria Journal released three articles ranging from the relation between malaria and agricultural irrigation, artemisinin resistance on the Myanmar-China border, and efforts at costing malaria elimination interventions. PLoS Medicine examined the quality of malaria clinical management in children. Finally, Frontiers in Cellular and Infection Microbiology reported on a new drug against malaria and toxoplasmosis. Click on links to read more details.

Minimal tillage and intermittent flooding farming systems show a potential reduction in the proliferation of Anopheles mosquito larvae in a rice field in Malanville, Northern Benin

Irrigation systems have been identified as one of the factors promoting malaria disease around agricultural farms in sub-Saharan Africa. However, if improved water management strategy is adopted during rice cultivation, it may help to reduce malaria cases among human population living around rice fields.

A clear reduction of larva density was observed with both intermittent flooding systems applied to minimal tillage (MT?+?IF?+?NL) and intermittent flooding applied to deep tillage (DT?+?IF?+?AL), showing that intermittent flooding could reduce the abundance of malaria vector in rice fields. Recommending intermittent flooding technology for rice cultivation may not only be useful for water management but could also be an intentional strategy to control mosquitoes vector-borne diseases around rice farms.

No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China’s plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China–Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance.

DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China–Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.

Costing malaria interventions from pilots to elimination programmes

Malaria programmes in countries with low transmission levels require evidence to optimize deployment of current and new tools to reach elimination with limited resources. Recent pilots of elimination strategies in Ethiopia, Senegal, and Zambia produced evidence of their epidemiological impacts and costs. There is a need to generalize these findings to different epidemiological and health systems contexts. Drawing on experience of implementing partners, operational documents and costing studies from these pilots, reference scenarios were defined for rapid reporting (RR), reactive case detection (RACD), mass drug administration (MDA), and in-door residual spraying (IRS). These generalized interventions from their trial implementation to one typical of programmatic delivery. In doing so, resource use due to interventions was isolated from research activities and was related to the pilot setting. Costing models developed around this reference implementation, standardized the scope of resources costed, the valuation of resource use, and the setting in which interventions were evaluated. Sensitivity analyses were used to inform generalizability of the estimates and model assumptions.

Populated with local prices and resource use from the pilots, the models yielded an average annual economic cost per capita of $0.18 for RR, $0.75 for RACD, $4.28 for MDA (two rounds), and $1.79 for IRS (one round, 50% households). Intervention design and resource use at service delivery were key drivers of variation in costs of RR, MDA, and RACD. Scale was the most important parameter for IRS. Overall price level was a minor contributor, except for MDA where drugs accounted for 70% of the cost. The analyses showed that at implementation scales comparable to health facility catchment area, systematic correlations between model inputs characterizing implementation and setting produce large gradients in costs. Prospective costing models are powerful tools to explore resource and cost implications of policy alternatives. By formalizing translation of operational data into an estimate of intervention cost, these models provide the methodological infrastructure to strengthen capacity gap for economic evaluation in endemic countries. The value of this approach for decision-making is enhanced when primary cost data collection is designed to enable analysis of the efficiency of operational inputs in relation to features of the trial or the setting, thus facilitating transferability.

Quality of clinical management of children diagnosed with malaria: A cross-sectional assessment in 9 sub-Saharan African countries between 2007–2018

Appropriate clinical management of malaria in children is critical for preventing progression to severe disease and for reducing the continued high burden of malaria mortality. This study aimed to assess the quality of care provided to children under 5 diagnosed with malaria across 9 sub-Saharan African countries. We used data from the Service Provision Assessment (SPA) survey. SPAs are nationally representative facility surveys capturing quality of sick-child care, facility readiness, and provider and patient characteristics across 9 countries, including Uganda (2007), Rwanda (2007), Namibia (2009), Kenya (2010), Malawi (2013), Senegal (2013–2017), Ethiopia (2014), Tanzania (2015), and Democratic Republic of the Congo (2018).

In this study, we found that a majority of children diagnosed with malaria across the 9 surveyed sub-Saharan African countries did not receive recommended care. Clinical management is positively correlated with the stocking of essential commodities and is somewhat improved in more recent years, but important quality gaps remain in the countries studied. Continued reductions in malaria mortality will require a bigger push toward quality improvements in clinical care. Despite increases in the distribution of malaria tests and effective antimalarial medications, significant gaps in the quality of care for pediatric malaria are present in these 9 countries. Further improvements in quality of malaria care may require a better understanding of remaining barriers and facilitators to appropriate management.

Novel drug could be a powerful weapon in the fight against malaria and toxoplasmosis

Princeton researchers are making key contributions toward developing a promising new treatment for the widespread and devastating diseases toxoplasmosis and malaria.
The Princeton scientists specialize in preparing the drug compound into a medicine that is both safe and effective for humans and able to reach its intended sites of action in the body in sufficient doses. An international team of scientists found the new drug—designated JAG21—to be highly effective against parasites in cell-based studies in the lab. After the discovery, team representatives contacted Princeton’s Robert Prud’homme for help in translating the JAG21 compound into a deliverable medication. Prud’homme is a co-author of a study, published in June 2020 in Frontiers in Cellular and Infection Microbiology, that describes the compound and its excellent preliminary results in mice.

Malaria News Today 2020-09-03

Various updates were found in newsletters and journal abstracts online today. These looked at mosquitoes – what attracts them to people, how ookinetes move in the midgut, and how perlite from volcanic rock may be a barrier repellent. Nigeria reports that there is no ACT resistance – so far.  And malaria partners join to coordinate actions in Uganda.  Click on links to read details.

Nigeria yet to detect resistance of malaria parasite to ACTs, says ministe

Contrary to reports that Africa has for the first time identified resistance strain of the malaria parasite to the drug of choice, Artemisinin Combination Therapy (ACT), the Minister of Health, Dr. Osagie Emmanuel Ehanire, on Monday said a study conducted in three states of the country showed there is no such phenomenon in Nigeria.  “However, we are still monitoring the situation. We insist that people should conduct a malaria test before using the drug of choice. This we hope will help prevent any kind of resistance of the malaria parasite to ACTs.”

Ministry of Health launches the Malaria Free Uganda Fund

Health Minister Dr Jane Ruth Aceng told journalists in Kampala today that the idea of having this new board was reached after realizing that different entities have been conducting the same malaria control related work. She said that the ministry resolved that mainstreaming responsibility will remove financial and operational bottlenecks that deter them from achieving set targets for elimination of the disease. The fund with a board of 11 members is chaired by Kenneth Wycliffe Mugisha of the Rotarian Malaria Partners-Uganda.

Volcanic Rock Yields a New Kind of Insecticide for Mosquitoes

Insecticide resistance to pesticides has become widespread in mosquito populations, making insecticides less effective over time. Therefore, there is an urgent need for insecticides with alternative modes of action. tested a material derived from volcanic rock, perlite, as a potential non-chemical insecticide against Anopheles gambiae, one of the primary mosquitoes that spreads malaria in Africa. In their new report published in August in the Journal of Medical Entomology, they show that perlite has encouraging potential as a mechanical insecticide. Perlite is believed to act by causing dehydration in the mosquitoes. read more…

Mosquitoes love pregnant, beer-drinking exercisers with Type O blood

Mosquitoes spread Zika, West Nile, Chikungunya, Dengue, and Malaria, resulting in 700 million illnesses a year and a million deaths. Even if you don’t get sick from a mosquito bite, the blood thinner they pump into your flesh before draining your blood causes swelling and itching. This article in Smithsonian Magazine lists the factors that make some people more tempting targets than others to mosquito bites. They include:

  • Blood type: “One study found that in a controlled setting, mosquitoes landed on people with Type O blood nearly twice as often as those with Type A.”
  • Carbon Dioxide: “people who simply exhale more of the gas over time—generally, larger people—have been shown to attract more mosquitoes than others.”
  • Exercise: “mosquitoes find victims at closer range by smelling the lactic acid, uric acid, ammonia and other substances expelled via their sweat”
  • Skin bacteria: “scientists found that having large amounts of a few types of bacteria made skin more appealing to mosquitoes”
  • Beer: “Just a single 12-ounce bottle of beer can make you more attractive to the insects”
  • Pregnancy: “pregnant people exhale about 21 percent more carbon dioxide and are on average about 1.26 degrees Fahrenheit warmer than others”
  • Clothing color: “wearing colors that stand out (black, dark blue or red) may make you easier to find”
  • Genetics: “underlying genetic factors are estimated to account for 85 percent of the variability between people in their attractiveness to mosquitoes”

Live In Vivo Imaging of Plasmodium Invasion of the Mosquito Midgut

Malaria is one of the most devastating parasitic diseases in humans and is transmitted by anopheline mosquitoes. The mosquito midgut is a critical barrier that Plasmodium parasites must overcome to complete their developmental cycle and be transmitted to a new host. Here, we developed a new strategy to visualize Plasmodium ookinetes as they traverse the mosquito midgut and to follow the response of damaged epithelial cells by imaging live mosquitoes. Understanding the spatial and temporal aspects of these interactions is critical when developing novel strategies to disrupt disease transmission.

Malaria News Today 2020-09-01

Today we feature summaries and abstracts concerning Plasmodium malariae, P. knowlesi and monkey models for vaccine testing, clothianidin insecticide resistance, the mosquito immune system and drug interactions between medicines for malaria patients.

Some mosquitoes already have resistance to the latest weapon against malaria

By Munyaradzi Makoni: An insecticide about to be widely deployed inside African homes to combat malaria-carrying mosquitoes is already losing its punch. Two years ago, the World Health Organization (WHO) gave the green light for clothianidin, long used in agriculture to kill crop pests, to be added to the current mainstays of indoor mosquito control, which are losing their effectiveness as the insects develop resistance. Since then, many African countries have been laying plans to spray the walls of homes with the pesticide—it would represent the first new class of chemicals adopted for such use in decades—and looking anxiously for evidence of pre-existing resistance.

Now, scientists at Cameroon’s Centre for Research in Infectious Diseases (CRID) have found it. They recently sampled mosquitoes from rural and urban areas around Yaoundé, the capital, including two key malaria carriers. In one standard susceptibility assay, exposure to clothianidin for 1 hour killed 100% of Anopheles coluzzii. But in some A. gambiae samples as many as 55% of the mosquitoes survived, the group reported in a preprint posted 7 August on the bioRxiv preprint server.

Atlas of Malaria Mosquitoes’ Immune System Assembled

An international team of scientists led by investigators at the Wellcome Sanger Institute and the NIH has created the first cell atlas of mosquito immune cells to understand how the insects fight malaria, as well as other mosquito-borne infections. The mosquito host is essential for the malaria parasite to complete its lifecycle, so any disruption would dramatically reduce the transmission of one of the world’s deadliest diseases.
Findings from the new study—published recently in Science through an article titled “Mosquito cellular immunity at single-cell resolution“—discussed the discovery of new types of mosquito immune cells, including a rare cell type that could be involved in limiting malaria infection. The authors also identified molecular pathways implicated in controlling the malaria parasite.

Genetic analysis of the orthologous crt and mdr1 genes in Plasmodium malariae from Thailand and Myanmar

Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.

Quantification of Plasmodium knowlesi versus Plasmodium falciparum in the rhesus liver: implications for malaria vaccine studies in rhesus models

Rhesus macaques are valuable pre-clinical models for malaria vaccine development. The Plasmodium knowlesi/rhesus and Plasmodium falciparum/rhesus models are two established platforms for malaria vaccine testing… Detection of 18S rRNA in the liver following high dose intravenous PfSPZ confirmed that rhesus are modestly susceptible to wild-type P. falciparum sporozoites. However, comparison of 18S rRNA RT-PCR biomarker signal indicates that the P. falciparum liver burden was 3–5 logs lower than in PkSPZ-infected animals. Quantification of this difference in liver stage burden will help guide and interpret data from pre-clinical studies of live-attenuated sporozoite vaccines in rhesus models.

Potential drug–drug interactions associated with adverse clinical outcomes and abnormal laboratory findings in patients with malaria

Hospitalized patients with malaria often present with comorbidities or associated complications for which a variety of drugs are prescribed. Multiple drug therapy often leads to drug–drug interactions (DDIs). The following drug pairs reported the highest frequency of adverse events associated with the interactions; calcium containing products-ceftriaxone, isoniazid–rifampin, pyrazinamide–rifampin, isoniazid–acetaminophen, and ciprofloxacin–metronidazole.

Malaria News Today 2020-08-31

From time-to-time we will feature a collection of news and abstracts available “today.” Here are five stories available on 31st August 2020.

Med-tech on a leash: The many diseases that can be detected by dogs

Malaria, a parasitic disease, which is transmitted to humans by Anopheles mosquitoes, can also be detected by our canine friends. In 2019, English researchers presented the results of a study conducted in The Gambia, which involved training dogs with socks that had been worn by children infected with malaria, who otherwise had no symptoms.
The experiment proved to be so successful that researchers are now planning on using this method to test for asymptomatic cases of the disease….

New Malaria Transmission Patterns Emerge In Africa.

An international study reveals how future climate change could affect malaria transmission in Africa over the next century. Malaria is a climate sensitive disease; it thrives where it is warm and wet enough to provide surface water suitable for breeding by the mosquitoes that transmit it. For more than two decades now, scientists have suggested that climate change may alter the distribution and length of transmission seasons due to new patterns of temperature and rainfall. The burden of this disease falls primarily on Africa. In 2018, out of an estimated 228 million cases of malaria worldwide, 93% were in the African continent.
Detailed mapping of malaria transmission is vital for the distribution of public health resources and targeted control measures.

In the past, rainfall and temperature observations have been used in malaria climatic suitability models to estimate the distribution and duration of annual transmission, including future projections. But factors affecting how rainfall results in water for mosquito breeding are highly complex, for example how it is absorbed into soil and vegetation, as well as rates of runoff and evaporation. A new study, led by the Universities of Leeds and Lincoln in the UK, for the first time combined a malaria climatic suitability model with a continental-scale hydrological model that represents real-world processes of evaporation, infiltration and flow through rivers. This process-focused approach gives a more in-depth picture of malaria-friendly conditions across Africa….

Covid has spelt a lockdown for routine health services in India

Official data are now available to show the extent to which routine health services in India were unavailable and the scale of its impact. The number of fully immunised children fell by over 15 lakh in the three-month period from April to June compared to the same months last year. The number of institutional deliveries fell by about 13 lakh. The registered number of TB patients undergoing treatment fell to almost half of what it was last year. People seeking cancer treatment as outpatients fell by over 70%. Hard-won progress on several national health goals, including the programme to bring down infant and maternal mortality or those to treat TB, malaria and non-communicable diseases such as heart diseases, diabetes and cancer,

Insecticide resistance in indoor and outdoor-resting Anopheles gambiae in Northern Ghana

The overall results did not establish that there was a significant preference of resistant malaria vectors to solely rest indoors or outdoors, but varied depending on the resistant alleles present. Phenotypic resistance was higher in indoor than outdoor-resting mosquitoes, but genotypic and metabolic resistance levels were higher in outdoor than the indoor populations. Continued monitoring of changes in resting behaviour within An. gambiae s.l. populations is recommended.

Highlighting the burden of malarial infection and disease in the neonatal period: making sense of different concepts

Review of neonates from 14 malaria-endemic countries found pooled prevalence in this specific age group. Importantly, their results suggest a prevalence of congenital malaria of 40.4/1000, and a prevalence of neonatal malaria of 12/1000, Interestingly, the authors also confirmed congenital malaria to be more frequent in settings with unstable malaria transmission, a finding in line with the hypothesis of the importance of the immunity background in the risk of congenital malaria.

Presence of k13 561H artemisinin resistance mutations in Plasmodium falciparum infections from Rwanda

Aline Uwimana, Noella Umulisa, Meera Venkatesan, Eric S. Halsey, Tharcisse Munyaneza, Rafiki Madjid Habimana, Ryan Sandford, Leah F. Moriarty, Emily Piercefield, Zhiyong Zhou, Samaly Souza, Ira Goldman, Naomi Lucchi, Brian Ezema, Eldin Talundzic, Daniel Ngamije, Jean-Louis N Mangala, William Brieger, Venkatachalam Udhayakumar, and Aimable Mbituyumuremyi presented a poster on “Presence of k13 561H artemisinin resistance mutations in Plasmodium falciparum infections from Rwanda” at the 68th Annual Meeting of the American Society of Tropical Medicine and Hygiene. Their findings follow.

Artemisinin-based combination therapy (ACT) is the recommended first-line antimalarial for uncomplicated Plasmodium falciparum infection in Rwanda. With the emergence of artemisinin and partner drug resistance in the Greater Mekong sub-region, it is important to characterize the presence of polymorphisms in k13, a gene associated with artemisinin resistance, and in pfmdr1, a gene associated with susceptibility to partner drugs including lumefantrine.

To date, there have been sporadic reports of validated k13 markers in Africa. Adequate efficacy (94-97%) for the ACT artemether-lumefantrine (AL) was found in a therapeutic efficacy study (TES) conducted in three Rwandan sites (Masaka, Rukara and Bugarama) in 2018. TES clinical results are presented in poster LB-5134. Dried blood spots collected from the 2018 TES were characterized for artemisinin resistance-associated k13 molecular markers and 8 flanking microsatellites to assess genetic profile and diversity, along with mutations in pfmdr1.

Methods: DNA was isolated from day 0 and day of recurrence dried blood spots from a 2018 TES of AL conducted in 3 sites in Rwanda and analyzed by Sanger sequencing for resistance markers in the k13 and pfmdr1 genes.

Prevalence of k13 candidate and validated artemisinin resistance markers was calculated using day 0 samples. Presence of k13 markers post-treatment was determined using samples collected on the day of recurrence. 8 flanking microsatellite markers downstream and upstream of k13 were evaluated and compared with previously published results from samples from Thailand1.

Results of Prevalence of k13 561 were derived from HDNA from 219 of 228 day 0 samples and all 37 post-treatment samples were successfully isolated from dried blood spots. 26 of 219 day 0 samples showed presence of the 561H mutation in the k13 gene, a World Health Organization validated marker of artemisinin resistance (ref). 3 of the 26 were mixed infections with wild type (561R/H).

*WHO definitions2: Suspected endemic artemisinin resistance is defined as

  • • ? 10% of patients with a half-life of the parasite clearance slope ? 5 hours after treatment with ACT or artesunate monotherapy; or
  • • ? 5% of patients carrying k13 resistance-confirmed mutations; or
  • • ? 10% of patients with persistent parasitaemia by microscopy at 72 hours
    Confirmed endemic artemisinin resistance is defined as
  • • ? 5% of patients carrying k13 resistance-confirmed mutations, all of whom have been found to have either persistent parasitaemia by microscopy on day 3 or a half-life of the parasite clearance slope ? 5 hours after treatment

Additional k13 data found 8 of 37 post-treatment samples with k13 561H in 4 recrudescences (all also with 561H on day 0) and in 4 reinfections. Candidate k13 resistance marker 469F found in 3 day 0 samples (2 in Rukara, 1 in Bugarama) Candidate k13 resistance markers 441L and 449A found in 1 day 0 sample each (Masaka and Rukara, respectively)

In conclusion, k13 561H, a validated marker of artemisinin resistance, was found at a prevalence of 1-20% amongst 3 TES sites in Rwanda. This is the highest proportion of artemisinin resistance-confirmed k13 mutations reported to date in Africa. The overall efficacy of AL was high in all sites (>90%; see poster LB-5134). However, parasitemia on day 3, a proxy for delayed parasite clearance, ranged from 0-15% across sites. Together with the presence of k13 561H, our results indicate confirmed artemisinin resistance in one site, Masaka, and suspected resistance in another, Rukara.

Flanking microsatellites indicate that the k13 561H mutation likely arose locally as opposed to being introduced from Southeast Asia. k13 mutations are present against a high background prevalence of pfmdr1 N86 and D1246, associated with reduced susceptibility to lumefantrine4.

These results indicate that although AL remains an effective treatment of uncomplicated malaria in Rwanda, artemisinin resistance may be emerging. Continued monitoring and confirmation of suspected resistance is critical. Future studies will include an expansion of TES sites and frequent parasite sampling to assess parasite clearance rates, in addition to molecular analysis.

References

  1. Talundzic et al 2015. Selection and Spread of Artemisinin-Resistant Alleles in Thailand Prior to the Global Artemisinin Resistance Containment Campaign PLoS Pathogens 11(4)
  2. WHO 2017. Status report on artemisinin and ACT resistance
  3. Ishengoma et al 2019. Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania Malaria Journal 18(1):88.
  4. Venkatesan et al 2014 . Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. AJTMH 91(4)

Contact information: Dr. Aline Uwimana <aline.uwimana@rbc.gov.rw> and Dr. Meera Venkatesan <mvenkatesan@usaid.gov>

Affiliations: Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, Rwanda; Maternal and Child Survival Program/JHPIEGO, Baltimore MD, USA; US President’s Malaria Initiative, Washington DC, USA; US President’s Malaria Initiative, Atlanta, Georgia, USA; Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; National Reference Laboratory, Rwanda Biomedical Centre, Kigali, Rwanda; US Peace Corps, Kigali, Rwanda; US President’s Malaria Initiative, Kigali, Rwanda; WHO Rwanda Office, Malaria and Neglected Tropical Diseases Programs, Kigali, Rwanda; The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA

Biology and Malaria Eradication: Are there Barriers?

During a press conference prior to the release of the executive summary of 3-year study of trends and future projections for the factors and determinants that underpin malaria by its Strategic Advisory Group on Malaria Eradication (SAGme), WHO outlined some hopeful signs emanating from the SAGme including

  1. Lack of biological barriers to malaria eradication
  2. Recognition of the massive social and economic benefits that would provide a return on investment in eradication, and
  3. Megatrends in the areas of factors such as land use, climate, migration, urbanization that could inhibit malaria transmission

Concerning the first point, the executive summary notes that, “We did not identify biological or environmental barriers to malaria eradication. In addition, our review of models accounting for a variety of global trends in the human and biophysical environment over the next three decades suggest that the world of the future will have much less malaria to contend with.”

The group did agree that, “using current tools, we will still have 11 million cases of malaria in Africa in 2050.” So one wonders whether there are biological barriers or not.

Interestingly the group did identify, “Potential biological threats to malaria eradication include development of insecticide and antimalarial drug resistance, vector population dynamics and altered vector behaviour. For example, Anopheles vectors might adapt to breeding in polluted water, and mosquito vector species newly introduced to Africa, such as Anopheles stephensi, could spread more widely into urban settings.”

This discussion harkens back to an important conceptual article by Bruce Aylward and colleagues that raised the question in the American Journal of Public Health, “When Is a Disease Eradicable?” They outlined three important criteria that had been proposed at two international conferences in 1997 and 1998.

  1. biological and technical feasibility
  2. costs and benefits, and
  3. societal and political considerations

Their further expansion on the biological issues using smallpox as an example is instructive. They noted that not only are humans essential for the life cycle of the organism, but that there was no other reservoir for the causative virus, and the virus could not amplify in the environment. In short, there were no vectors, as in the case of malaria. The relatively recent documentation of transmission of malaria between humans and other primates of different plasmodium species is another biological concern. At this point, Malaysia, for example, is reporting more cases of Plasmodium knowlesi in humans that either P vivax or P falciparum.

Another biological issue identified by Aylward and colleagues was the fact that smallpox had one effective and proven intervention, the vaccine. Application of the vaccine could be targeted using photograph disease recognition cards as the signs were quite specific to the disease. Malaria has several effective interventions, but most strategies emphasize the importance of using a combination of these, and implementation is met with a number of management and logistical challenges. The signs and symptoms of malaria are confused with a number of febrile illnesses.

Finally, two other issues raised concern. Insecticide resistance was recognized in the first malaria eradication effort, and is raising its head again, as pointed out by SAGme. Comparing smallpox and yaws, the challenge of latent or sub-clinical/asymptomatic infection was mentioned. Malaria too, is beleaguered with this problem.

Clearly, we must not lose momentum in the marathon (not a race) to eliminate malaria, but we must, as WHO stressed at the press conference, increase our research and development efforts to strengthen existing tools and develop new once to address the biological and logistical challenges.

Tropical Health Update 2019-07-28: Ebola and Malaria Crises

This posting focuses on Malaria and Ebola, both of which have been the recent focus of some disturbing news. The malaria community has been disturbed by the clear documentation of resistance to drugs in Southeast Asia. Those working to contain Ebola in the northeast of the Democratic Republic of Congo saw a change in political leadership even in light of continued violence and potential cross-border spread.

Malaria Drug Resistance

Several sources reported on studies in the Lancet Infectious Diseases concerning the spread of Multidrug-Resistant Malaria in Southeast Asia. Reuters explained that by sing genomic surveillance, researchers concurred that “strains of malaria resistant to two key anti-malarial medicines are becoming more dominant” and “spread aggressively, replacing local malaria parasites,” becoming the dominant strains in Vietnam, Laos and northeastern Thailand.”

The focus was on “the first-line treatment for malaria in many parts of Asia in the last decade has been a combination of dihydroartemisinin and piperaquine, also known as DHA-PPQ,” and resistance had begun to spread in Cambodia between 2007 and 2013. Authors of the study noted that while, “”Other drugs may be effective at the moment, but the situation is extremely fragile, and this study highlights that urgent action is needed.” They further warned of an 9impending Global Health Emergency.

NPR notes that “Malaria drugs are failing at an “alarming” rate in Southeast Asia” and provided some historical context about malaria drug resistance arising in this region since the middle of the 20th century. “Somehow antimalarial drug resistance always starts in that part of the world,” says Arjen Dondorp, who leads malaria research at the Mahidol Oxford Tropical Medicine Research Unit in Bangkok and who was a lead author of the report about the randomized trial. Ironically, “one reason could have something to do with the relatively low levels of malaria there. When resistant parasites emerge, they are not competing against a dominant nonresistant strain of malaria and are possibly able to spread easier.

When we are talking about monitoring resistance in low resource and logistically and politically challenging areas, we need to think of appropriate diagnostic tools at the molecular level. Researchers in Guinea-Bissau conducted a proof of concept study and used malaria rapid diagnostic tests applied for parallel sequencing for surveillance of molecular markers. While they noted that, “Factors such as RDT storage prior to DNA extraction and parasitaemia of the infection are likely to have an effect on whether or not parasite DNA can be successfully analysed … obtaining the necessary data from used RDTs, despite suboptimal output, becomes a feasible, affordable and hence a justifiable method.”

A Look at Insecticide Treated Nets

On a positive note, Voice of America provides more details on the insecticide treated net (ITN) monitoring tool developed called “SmartNet” by Dr Krezanoski in collaboration with the Consortium for Affordable Medical Technologies in Uganda. The net uses strips of conductive fabric to detect when it’s in use. Dr. Krezanoski was happy to find that people given the net used it no differently that if they were not being observed. The test nets made it clear who what using and not using this valuable health investment and when it was in use. Such fine tuning will be deployed to design interventions to educate net users based on their real-life use patterns.

Another important net issue is local beliefs that may influence use. We can find out when people use nets, but we also need to determine why. In Tanzania, researchers found that people think mosquitoes that bite in the early evening when people are outside relaxing are harmless. As one community member said, “I only fear those that bite after midnight. We’ve always been told that malaria is spread by mosquitoes that bite after midnight.”

Even if people do use their ITNs correctly, we still need to worry about insecticide resistance. A study in Afghanistan reported that, “Resistance to different groups of insecticides in the field populations of An. stephensi from Kunar, Laghman and Nangarhar Provinces of Afghanistan is caused by a range of metabolic and site insensitivity mechanisms.” The authors conclude that vector control programs need to be better prepared to implement insecticide resistance management strategies.

Ebola Crisis Becomes (More) Political

Headlines such as “Congo health minister resigns over response to Ebola crisis” confronted the global health community this week. this happened after the DRC’s relatively new president took control of the response. The President set up a new government office to oversee the response to an outbreak outside of the Ministry of Health which was managing the current outbreak and the previous ones. The new board was set up without the knowledge of the Minister who was traveling to the effected provinces at the time.

The former Minister, Dr Oly Ilunga stated on Twitter that, “Suite à la décision de la @Presidence_RDC.  de gérer à son niveau l’épidémie d’#Ebola, j’ai remis ma démission en tant que Ministre de la Santé ce lundi. Ce fut un honneur de pouvoir mettre mon expertise au service de notre Nation pendant ces 2 années importantes de notre Histoire. (Following the decision of the @Presidence_RDC to manage the # Ebola outbreak, I resigned as Minister of Health on Monday. It was an honor to be able to put my expertise at the service of our Nation during these two important years of our History.)

The former Minister also warned that the “Multisectoral Ebola Response Committee would interfere with the ongoing activities of national and international health workers on the ground in North Kivu and Ituri provinces.” Part of the issue may likely have been “pressure to approve a new vaccine in addition to one that has already been used to protect more than 171,000 people.” People had warned about the potential confusion to the public as well as ethical issues if a second vaccine was used, especially one that did not have the strong accumulated evidence from both the current outbreak as well as the previous one in West Africa.

One might have thought that this would be a time when stability was needed since “The WHO earlier this month declared the outbreak a Public Health Emergency of International Concern, a rare step meant to highlight the urgency of the moment that has been used only four times before.” In addition, “the World Bank said it would release $300 million from a special fund set aside for crises like viral outbreaks to help cover the cost of the response.”

Unfortunately one of the msain impediments to successful Ebola control, violence in the region, continues. CIDRAP stated that. “the Allied Democratic Forces (ADF), a rebel group, attacked two villages near Beni, killing 12 people who live in the heart of the Democratic Republic of the Congo’s (DRC’s) ongoing Ebola outbreak. The terrorists killed nine in Eringeti and three in Oicha, according to Reuters. ADF has not publicly pledged allegiance to the Islamic state (ISIL), but that hasn’t stopped ISIL from claiming responsibility for the attacks.” It will take more than a change of structure in Kinshasa to deal with the realities on the ground.

CIDRAP also observed that since the resignation of the Health Minister, “DRC officials have provided no update on the outbreak, including statistics on the number of deaths, health workers infected, or suspected cases.” The last was seen on 21 July 2019.

ReliefWeb reports that, “Adding to the peril, the Ebola-affected provinces share borders with Rwanda and Uganda, with frequent cross-border movement for personal travel and trade, increasing the chance that the virus could spread beyond the DRC. There have already been isolated cases of Ebola reported outside of the outbreak zone.”

These are troubling times when parasites and mosquitoes are becoming more resistant to our interventions and when governments and communities are resistant to a clear and stable path to disease containment and control.

The Need to Prevent the Spread of Malaria Drug Resistance to Africa

Chike Nwangwu is a Monitoring and Evaluation Specialist who is currently working on his Doctor of Public Health (DrPH) degree at the Johns Hopkins Bloomberg School of Public Health. Here he presents an overview of the threat of parasite resistance to first-line antimalarial drugs and the need to prevent the spread of this problem in Africa which beard the greatest burden of the global malaria problem.

Malaria, remains one of the most pervasive and most malicious parasitic infections worldwide.  Malaria is caused by Plasmodium parasites when they enter the human body. There are currently five known plasmodium species that cause malaria in humans- P. falciparum and P. vivax are the most prevalent globallyThese parasites are transmitted through the bites of infected female anopheles mosquitoes “malaria-vectors” which perpetuate the spread of the parasite from human-human or from host- human.

Globally, according to the WHO, an estimated 212 million cases of malaria and 429 000 malaria related deaths occurred in 2015.[1]  The global share of malaria is spread disproportionately across regions; Over 90% of global malaria cases and deaths occurred in the African region, with over 70% of the global burden in one sub region-Sub Saharan Africa. In areas with high transmission of malaria, children under 5 are at the highest risk to infection and death; more than two thirds of all malaria deaths occur in this age group.[2]

Although malaria remains a global concern, malaria is preventable and curable.  Increased efforts in malaria prevention and treatment within the past two decades has led to revolutionary success- 6.8 million lives have been saved globally and malaria mortality cut by 45% since 2001.[3] Globally, within a five-year interval (2010-2015) new malaria transmission and mortality in children under 5 years of age fell by 21% and 29% respectively. This has been the one the greatest public health successes in recent years [4]

The improvement of malaria indices aligns with intensification of efforts, through funding, research, innovation pushing the scale up of key malaria interventions in the malaria prevention- diagnostic- treatment cascade. For example, in Sub-Saharan Africa where malaria is most prevalent, there has been a recorded 48% increment in Insecticide Treated Net (ITN) usage since 2005, 15% rise in chemoprevention in pregnant women and within the same time frame diagnostic testing increased from 40% of suspected malaria cases to 76%.[5]

Treatment/ Emergence of insecticide and drug resistance

Malaria treatment plays a key role in controlling its transmission. First, prompt and effective treatment of malaria prevents progression to severe disease and limits the development of gametocytes, thus blocking transmission of parasites from humans to mosquitoes.[6] Drugs can also be used to prevent malaria in endemic populations, including various strategies of chemoprophylaxis, intermittent preventive therapy, and mass drug administration can be effective.[7] Like other interventions, availability and use of antimalarial has been a success. However, this has also come with some challenges. The emergence of resistance, particularly in P. falciparum and P. vivax to antimalarial-quinine and sulfadoxine-pyrimethamine, has been a major contributor to reported resurgences of malaria in the last three decades.[8]

Distribution of reported resistance to antimalarials. As at 2005, antimalarial resistance was is established in 81 of the 92 countries where the disease was endemic (WHO, 2004)

Falciparum resistance first developed in some areas in Southeast Asia, Oceania, and South America before the 70’s eventually the parasite became resistant to other drugs (sulfadoxine/ pyrimethamine, mefloquine, halofantrine, and quinine. Drug-resistant P. vivax was first identified in 1989 in one region and later spread to other regions of the world.[9] As at 2005, antimalaria resistance to chloroquine and sulfadoxine-pyrimethamine was established in 81 of the 92 countries where the disease was endemic. (Figure 1) In 2005, alongside acetaminophen, antimalarial were among the most commonly abused medications in the African region, with the majority of the population having detectable amounts of chloroquine in the blood.[10]

Antimalarial drug resistance is the decrease in viability of an antimalarial to cure an infection.  Parasite resistance results in a delayed or partial clearance of parasites from the blood when a person is being treated with an antimalarial.[11] Antimalaria resistance occurs as the byproduct of at least one mutation in the genome of the parasite, giving an advantageous capacity to evade the impacts of the drug. Within the human host, drug resistance develops gradually. First, a modest number of drug-resistant parasites survive exposure to the drug whilst the drug-sensitive parasites are eliminated. In the absence of additional drugs and competition from drug-sensitive pathogens, the drug-resistant parasites proliferate and their populace develops. This new population is therefore resistant to additional malaria medications of the same type.

Following the discovery of resistance to quinine and sulfadoxine-pyrimethamine, the development of resistance was initially forestalled by the utilization of a new class of malaria drugs – Artemisinin-derivative combinations. These ACTs (Artemisinin Combination Therapy) work by combining artemisinin and an active partner drug with different mechanisms of action. The WHO, with guidance from extensive drug efficacy tests and research, recommends the use of 5 types of ACTs for treatment of uncomplicated malaria caused by the P. falciparum parasite. By 2014, ACTs have been adopted as first-line treatment policy in 81 countries.[12]

Although ACT use has been a breakthrough in malaria treatment, development of resistance to de novo ACTs poses one of the greatest threats to malaria control efforts. P. falciparum resistance to artemisinin has been detected in five countries of the Greater Mekong sub-region (Lao, Myanmar, Thailand, Cambodia, and Vietnam). To date P. vivax resistance to an ACT has not been detected.

Artemisinin resistance is currently defined within the confines of delayed parasite clearance; it represents partial/relative resistance-i.e. most patients who have delayed parasite clearance do not necessarily have treatment failure. Following treatment with an ACT, infections are still cleared, as long as the partner drug remains effective.  Various factors are believed to contribute to the development and spread of resistance to artemisinin; use of oral artesunate monotherapies (oAMT) inclusive.

A global response has been mounted to curtail the spread of ACT resistance to other regions, especially to regions like Sub-Saharan Africa. Research on the mechanisms of drug resistance has steered efforts in the direction, recently the identification of the PfKelch13 (K13) mutations has allowed for a more refined definition of artemisinin resistance that includes information on the genotype. [13]  In addition, stricter policies have been developed for malaria control; Therapeutic efficacy studies (TES) are conducted and used as the main reference from which national malaria control programmes determine their national treatment policy.[14]  These studies help to ensure the efficacy of treatments with recommendations to ensure that these medicines are monitored through surveillance at least once every 24 months at established sentinel sites and in regions with emerging resistance, the creation of additional sentinel surveillance sites. [15]

Preventing and containing antimalarial drug resistance- Recommendations to countries

As research is being done to fully understand the mechanisms of antimalarial resistance; basic recommendations to limit its spread have been disseminated.[16] First, the production and use of oral artemisinin-based monotherapy should be halted and access to the use of quality-assured ACTs for the treatment of falciparum malaria should be ensured. In countries where antimalarial treatments remain fully efficacious; correct medicine use must be promoted, with weight placed on encouraging diagnostic testing, quality-assured treatment, and good patient adherence to the treatment.  Lastly, to reduce the burden of the disease, and prevent the spread of resistance, in regions where there is still high transmission, intensification of malaria control efforts is key, rapid elimination of falciparum malaria would accelerate efforts.

  • [1] World Malaria Report 2016, World Health Organization, Geneva, 2016
  • [2] ibid
  • [3] CDC, Malaria Fast Facts 2017
  • [4] ibid
  • [5] World Malaria Report, 2016
  • [6] Gosling RD, Okell L, Mosha J, Chandramohan D. The role of antimalarial treatment in the elimination of malaria. Clin Microbiol Infect. 2011;17:1617–1623.
  • [7] Greenwood B. Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas. Malar J. 2010;9
  • [8] White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113:1084–1092
  • [9] CDC, Malaria Fast Facts, 2017
  • [10] White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113:1084–1092.
  • [11] Peter B. Bloland, Drug resistance in malaria, World Health Organization, 2001
  • [12] World Malaria Report, 2016, World Health Organization, Geneva,2016
  • [13] Artemisinin and artemisinin-based combination therapy resistance April 2017,World Health Organization, 2017
  • [14] Responding to antimalarial drug resistance, World Health Organization, 2017: http://www.who.int/malaria/areas/drug_resistance/overview/en/
  • [15] ibid
  • [16] Ibid

Preventing Malaria Drug Resistance in the African Setting …

and Dealing with it Should Resistance Occur

Professor Joseph Ana, Africa Centre for Clinical Governance Research & Patient Safety in Calabar, Nigeria shares his experiences and concerns in this blog.

Drug resistance is one of the biggest challenges facing health care systems in the world today. Around 25,000 people die each year from resistant viral and bacterial infections in Europe, but no new classes of antibiotics have come on the market for more than 25 years. The figures are difficult to obtain for Africa and other developing countries.

Medicine shops may sell inappropriate malaria medicines, thus contributing to resistance

Medicine shops may sell inappropriate malaria medicines, thus contributing to resistance

Drug resistance is considered important in the failure of control and treatment of diseases its consequences, and it is considered to be one of the causes of emergence of new strains of infective organisms and re-emergence of once-controlled diseases. The occurrence and impact of the phenomenon is worse in Africa and parts of Asia for malaria according to WHO and the US CDC. Viral and bacterial diseases are also affected in this region.

Therefore, there is urgent need for global sustained action to prevent drug resistance from happening, and to control it, if it happens. The causes of Drug resistance are varied including lack of or poor implementation of the control of access to drugs, population migration and movement, misdiagnosis, under-treatment and irrational drug prescription and use.

Global Report malaria drug resistanceTo prevent drug resistance, countries need to legislate and implement adequate control of access to drugs, sustain public education on the dangers of drug resistance, educate health workers on and enforce rational drug prescribing and use. Effective monitoring of treatment outcomes is also important to know when drug resistance is occurring. With the global and country by country best efforts drug resistance may still occur because of mutation and adaptation of infective organisms.

For diseases like Malaria for which resistance to the most effective drug today, artemisinin-combination drugs, is being reported from Southeast Asia, the development of new drugs alongside vector control is essential by all countries, particularly in Africa.


Professor Joseph Ana – BM.BCh (UNN), FRCSEd, FRSPH, JtCertRCGP-UK, DFFP (RCOG)-UK, DipUrology-UK, Cert.ClinGov.UK; Lead Consultant Trainer / CEO; joseph ana <jneana@yahoo.co.uk>; Contact: Africa Centre for Clinical Governance Research & Patient Safety; @Health Resources International (HRI WA); Consultants in Clinical Governance & Patient Safety (MDCN Accredited CPD Provider); 8 Amaku Street State Housing  (& 20 Eta Agbor Road UNICAL Road),  Calabar, Nigeria.

Visit Website: www.hriwestafrica.com; email: hriwestafrica@gmail.com    Tel: +2348063600642