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Asymptomatic &Borders &Children &Elimination &Indoor Residual Spraying &IRS &Migration &Mosquitoes &Pharmacovigilence Bill Brieger | 08 Oct 2020

Malaria News Today 2020-10-08: the role of travel, asymptomatic disease and gut microbiome from AJTMH

The American Journal of Tropical Medicine and Hygiene has several new articles on malaria. Abstracts are shared. Two articles examine the role of travel in malaria transmission, both cross-border and rural-urban. Another considers the effect on pharmacokinetics of lumefantrine due to gut bacteria. In Uganda indoor spraying has reduced transmission, but asymptomatic cases remain among children. The challenges of asymptomatic malaria to elimination efforts is also examined in India. Links to the articles are found below.

Evidence of Microbiome–Drug Interaction between the Antimalarial Lumefantrine and Gut Microbiota in Mice

The antimalarial drug lumefantrine exhibits erratic pharmacokinetics. Intersubject variability might be attributed, in part, to differences in gut microbiome–mediated drug metabolism. We assessed lumefantrine disposition in healthy mice stratified by enterotype to explore associations between the gut microbiota and lumefantrine pharmacokinetics. Gut microbiota enterotypes were classified according to abundance and diversity indices from 16S rRNA sequencing. Pharmacokinetic parameters were computed using noncompartmental analysis. Two distinct enterotypes were identified.

Maximal concentration (C max) and total drug exposure measured as the area under the drug concentration–time curve (AUC0–24) differed significantly between the groups. The mean and standard deviation of C max were 660 ± 220 ng/mL versus 390 ± 59 ng/mL (P = 0.02), and AUC0–24 was 9,600 ± 2,800 versus 5,800 ± 810 ng × h/mL (P = 0.01). In healthy mice intragastrically dosed with the antimalarial drug lumefantrine in combination with artemether, lumefantrine exposure was associated with gut bacterial community structure. Studies of xenobiotic–microbiota interactions can inform drug posology and elucidate mechanisms of drug disposition.

Malaria Transmission, Infection, and Disease following Sustained Indoor Residual Spraying of Insecticide in Tororo, Uganda

Tororo, a district in Uganda with historically high malaria transmission intensity, has recently scaled up control interventions, including universal long-lasting insecticidal net distribution in 2013 and 2017, and sustained indoor residual spraying (IRS) of insecticide since December 2014. We describe the burden of malaria in Tororo 5 years following the initiation of IRS. We followed a cohort of 531 participants from 80 randomly selected households in Nagongera subcounty, Tororo district, from October 2017 to October 2019. Mosquitoes were collected every 2 weeks using CDC light traps in all rooms where participants slept, symptomatic malaria was identified by passive surveillance, and microscopic and submicroscopic parasitemia were measured every 4 weeks using active surveillance. Over the 2 years of follow-up, 15,780 female anopheline mosquitos were collected, the majority (98.0%) of which were Anopheles arabiensis.

The daily human biting rate was 2.07, and the annual entomological inoculation rate was 0.43 infective bites/person/year. Only 38 episodes of malaria were diagnosed (incidence 0.04 episodes/person/year), and there were no cases of severe malaria or malarial deaths. The prevalence of microscopic parasitemia was 1.9%, and the combined prevalence of microscopic and submicroscopic parasitemia was 10.4%, each highest in children aged 5–15 years (3.3% and 14.0%, respectively). After 5 years of intensive vector control measures in Tororo, the burden of malaria was reduced to very low transmission levels. However, a significant proportion of the population remained parasitemic, primarily school-aged children with submicroscopic parasitemia, providing a potential reservoir for malaria transmission.

Malaria Diagnosed in an Urban Setting Strongly Associated with Recent Overnight Travel: A Case–Control Study from Kampala, Uganda

Malaria is frequently diagnosed in urban Kampala, despite low transmission intensity. To evaluate the association between recent travel out of Kampala and malaria, we conducted a matched case–control study. Cases were febrile outpatients with a positive malaria test; controls were febrile outpatients with a negative test. For every two cases, five controls were selected, matching on age. Data were collected on recent overnight travel out of Kampala (past 60 days), destination and duration of travel, and behavioral factors, including sleeping under an insecticide-treated net (ITN) during travel. From July to August 2019, 162 cases and 405 controls were enrolled. The locations of residence of cases and controls were similar. More controls were female (62.7% versus 46.3%, P < 0.001). Overall, 158 (27.9%) participants reported recent overnight travel.

Travelers were far more likely to be diagnosed with malaria than those who did not travel (80.4% versus 8.6%, OR 58.9, 95% CI: 23.1–150.1, P < 0.001). Among travelers, traveling to a district not receiving indoor residual spraying of insecticide (OR 35.0, 95% CI: 4.80–254.9, P < 0.001), no ITN use (OR 30.1, 95% CI: 6.37–142.7, P < 0.001), engaging in outdoor activities (OR 22.0, 95% CI: 3.42–141.8, P = 0.001), and age < 16 years (OR 8.36, 95% CI: 2.22–56.2, P = 0.03) were associated with increased odds of malaria. Kampala residents who traveled overnight out of the city were at substantially higher risk of malaria than those who did not travel. For these travelers, personal protection measures, including sleeping under an ITN when traveling, should be advocated.

Prevalence of Asymptomatic Malaria Parasitemia in Odisha, India: A Challenge to Malaria Elimination

The prevalence of malaria in India is decreasing, but it remains a major concern for public health administration. The role of submicroscopic malaria and asymptomatic malaria parasitemia and their persistence is being explored. A cross-sectional survey was conducted in the Kandhamal district of Odisha (India) during May–June 2017. Blood samples were collected from 1897 individuals for screening of asymptomatic parasitemia. Samples were screened using rapid diagnostic tests (RDTs) and examined microscopically for Plasmodium species. Approximately 30% of randomly selected samples (n = 586) were analyzed using real-time PCR (qPCR), and the genetic diversity of Plasmodium falciparum was analyzed.

The prevalence of Plasmodium species among asymptomatic individuals detected using qPCR was 18%, which was significantly higher than that detected by microscopy examination (5.5%) or RDT (7.3%). Of these, 37% had submicroscopic malaria. The species-specific prevalence among asymptomatic malaria-positive cases for P. falciparum, Plasmodium vivax, and mixed infection (P. falciparum and P. vivax) by qPCR was 57%, 29%, and 14%, respectively. The multiplicity of infection was 1.6 and 1.2 for the merozoite surface protein-1 gene (msp1) and (msp2), respectively. Expected heterozygosity was 0.64 and 0.47 for msp1 and msp2, respectively. A significant proportion of the study population, 105/586 (18%), was found to be a reservoir for malaria infection, and identification of this group will help in the development of elimination strategies.

Travel Is a Key Risk Factor for Malaria Transmission in Pre-Elimination Settings in Sub-Saharan Africa: A Review of the Literature and Meta-Analysis

By sustaining transmission or causing malaria outbreaks, imported malaria undermines malaria elimination efforts. Few studies have examined the impact of travel on malaria epidemiology. We conducted a literature review and meta-analysis of studies investigating travel as a risk factor for malaria infection in sub-Saharan Africa using PubMed. We identified 22 studies and calculated a random-effects meta-analysis pooled odds ratio (OR) of 3.77 (95% CI: 2.49–5.70), indicating that travel is a significant risk factor for malaria infection.

Odds ratios were particularly high in urban locations when travel was to rural areas, to more endemic/high transmission areas, and in young children. Although there was substantial heterogeneity in the magnitude of association across the studies, the pooled estimate and directional consistency support travel as an important risk factor for malaria infection.

IRS &Monkeys &Mosquitoes &Pharmacovigilence &Resistance &Vector Control Bill Brieger | 01 Sep 2020

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.

Efficacy &Pharmacovigilence &Treatment Bill Brieger | 17 Sep 2012

Prequalification of Malaria Medicines Needs to be Taken More Seriously

The Leadership newspaper in Nigeria reported on Sunday the launching of a new artemisinin-based combination therapy (ACT) drug knwon by the trade name ‘Artiquick.’  In order to ensure that it is not just another route to ‘profit-quick’, we looked into the WHO prequalification list to see if the Chinese company ArtePharm that makes the drug was listed.

Prequalification is based on a comprehensive evaluation of “the quality, safety and efficacy of medicinal products, based on information submitted by the manufacturers, and inspection of the corresponding manufacturing and clinical sites.” The resulting lists of malaria, TB, and HIV drugs and diagnostics is meant to guide various national and international health agencies in their procurement of medicines.

dscn7285sm.JPGThough not stated and often not practiced, it would be ideal if these lists also guided various drug regulatory agencies in malaria endemic countries. Although it is a somewhat arduous process to get prequalification, it is possible and necessary – two new medicines containing artesunate-mefloquine were just added in 12 September.

The prequalified list as of today contains 25 anti-malaria products from only 10 companies. ArtePharm is not among them.  Yet the manufacturer made it known that, “the   new  drug   which  has  proven  very  effective  since  early  this  year  when  it  underwent additional clinical trials, Nigeria can, thus, be very hopeful, on attaining the Millennium Development Goals (MDGs) target on malaria come 2015.”  In addition the manufacturer mentioned to the press that ACTs generally were recommended by WHO, implying that any ACT, including their own, was approved by WHO.

Finally the ArtePharm representative made it know that their product was tested and approved by Nigeria’s food and drug agency NAFDAC. NAFDAC does ensure that products contain the labeled ingredients in the labeled amounts and that the drug is safe to use. It is important in the fight against counterfeit drugs. But NAFDAC has approved hundreds of ACTs for sale and use in the country. Unlike WHO, NAFDAC and other national agencies do not have the reach to inspect the production processes at the root.

Hopefully ArtePharm will begin the journey of the prequalification process soonest, and that countries where it sells its product will also encourage that company and many others to take the responsible steps needed to ensure we have quality antimalarials that will actually eliminate disease and not just eliminate money from patients’ pockets.

Efficacy &Pharmacovigilence &Treatment Bill Brieger | 26 Feb 2012

Tanzania: fake drugs, wrong drugs, more drugs

Selling malaria medicines in Tanzania and elsewhere in Africa is a big business. The market is not one that is easily dominated by a few brands, although the Affordable Medicines Facility malaria (AMFm) would hope otherwise. It appears that volume of relatively low or lower cost malaria drugs is the path to profit, not sales of a pricey mega-drug.

New from Tanzania is that this vast market is attractive to all sorts of manufacturers, even those making fake drugs. According to The Citizen, “The Tanzania Food and Drugs Authority (TFDA) yesterday issued a public warning against the sham product marketed under the name Eloquine (Quinine Sulphate 300mg USP) and packed in a bottle containing 1,000 tablets each.”

IPP Media reported that, “the authority has seized 155 tins of the fake drugs in Dar es Salaam which were yet to be distributed” and a suspect has been detained. The company headquarters in Nairobi helped point out differences in packaging between their products and the fake ones. A major concern of course is that role the fake drug was supposed to play. Normally quinine would be used in a limited way such as for pregnant women, so it is unclear how the fake drug would have been marketed to make a profit.

All of this comes amid efforts of AMFm to ensure that prequalified anti-malarial drugs reach the market (public and private) at prices people can afford. Cheap fake drugs threaten this effort.  A Tanzania study sponsored by the Clinton Foundation/CHAI, “showed promising results: subsidizing the ACTs at the top of the supply chain successfully increased the stocking of ACTs in drug shops and brought down the price of ACTs significantly.”

Prior to AMFm, but after Tanzania changed its malaria drug policy from SP to ACT, “the saleability of ACT was negligible. SP was best-selling.” Pre-AMFm price differentials between ACTs and cheaper but less effective medicines, put ACTs at a disadvantage.
addo2.pngPart of Tanzania’s approach to improving quality of malaria case management in medicine shops is upgrading the quality of these.  Accredited drug dispensing outlets (ADDOs) are places where the sales people and the products are both upgraded. When Tanzania changed its malaria drug policy from SP to ACT, access to ACTs in the private sector was low, while focus was on the public supply of ACTs.  It appears that with the event of AMFm ACT supplies in ADDO shops and other private outlets, but this does not preclude the presence of inappropriate or substandard drugs in non-accredited shops known as duka la dawa baridi.

Despite improved access to ACTs and improved quality of front line medicine store outlets, Tanzania cannot let up on its pharmacovigilence. As we move closer to malaria elimination – for example in Zanzibar in Tanzania – the importance of appropriate parasitological diagnosis and prompt treatment will increase. We cannot afford to have fake and inappropriate drugs compete with ACTs.

Community &Pharmacovigilence &Treatment Bill Brieger | 22 Dec 2011

Mobile Phones for Monitoring Drug Safety in Rural Ghana

Vida Ami Kukula from Dodowa Health Research Centre, Accra, Ghana, shares her poster presentation from the recently concluded American Society of Tropical Medicine and Hygiene Conference.

dscn6402sm.jpgThe influx of antimalarial drugs remains a great concern for health care providers and regulatory bodies. Monitoring the safety of antimalarial drugs at the community level possess a challenge to effective pharmacovigillance. Though, spontaneous reporting of events has been the easiest way of monitoring drug safety; these reports are not as expected. This method also has shortfall because only few patients report. Cohort event monitoring (CEM) is a more effective way of monitoring as visiting people in their homes is expensive.

The use of mobile phone calls to patients prescribed an antimalarial has not been adequately explored. This paper investigates how mobile phone calls can be used to monitor antimalarial safety in rural Dangme West District. CEM of patients with uncomplicated malaria prescribed an antimalarial from seventeen health providers were enrolled and followed by trained field workers.

A pre- treatment form was administered, patient information such as prior medications taken were recorded. Phone numbers of patients including home addresses was documented. Patients were informed and followed up by phone call or visited at home for patients without phones.

dodowa-logo-sm.jpgFollow ups were made from day three when they were expected to complete their antimalarial, however patients who experienced new events before day three were visited before their scheduled visit date. Post treatment form recorded new events patients experienced after taking the anti- malarial, and any other drug taken during the three days of the antimalarial treatment.

4165 patients were enrolled onto the study, 4144 cohorts were followed. 2630 (63.5%) were successfully interviewed on phone and 1514 (36.5%) by visits. Each call interview lasted an average of 4 minutes. It was observed that patients appreciated the calls made to check on their health.

In conclusion, mobile phone use increased access to cohort members followed up for drug safety monitoring. The use of mobile phones in future clinical monitoring activities is recommended. More studies should be conducted to confirm these findings.

Efficacy &Pharmacovigilence &Treatment Bill Brieger | 23 Sep 2011

Nigeria continues to test malaria drug efficacy

At present artemisinin-based combination therapy medicines for malaria are our best hope for treating malaria and have the added benefit of reducing parasite transmission.  If these drugs lose their power, we are in trouble; hence there is need for continued testing to ensure that drug efficacy remains high.

The Nigeria National Malaria Control Program has just circulated its latest malaria drug testing results. All endemic countries should see this as a model for their own continued monitoring of malaria drugs.

nmcp-nigeria-2.jpgA total of 747 children were enrolled in the two treatment arms – artemether-lumefantrine and artesunate-amodiaquine. The sample was drawn from investigations at seven sites in different geographical settings.  Below we find the main points as summarized in the Executive Summary.

1. The Therapeutic Efficacies of two Artemisinin-based Combination Therapies (ACTs) – Artesunate-Amodiaquine (AA) and Artemether-Lumefantrine (AL) were evaluated in 724 children <5 year-old drawn from 7 sentinel sites; Lagos, South-west, South-east, South-south, North-central, North-west and North-east located in 6 geographical zones of Nigeria.

2. All children recovered clinically from their illness. Fever clearance was significantly faster in children treated with AA than in those treated with AL (1.19 ± 0.49 versus 1.33 ± 0.7 d, P= 0.006).

3. Compared with AL, AA significantly reduced the proportion of children with parasitaemia 1 day after treatment began (P=0.016), but parasite clearance times were similar in AA- and AL- treated children (1.13 ± 0.4 versus 1.11 ± 0.34 d, P= 0.47).

4. Overall, adequate clinical and parasitological response (ACPR) on day 28 was 97.4%, and was similar for both AA (95.1%) and AL (96.3) P=0.108). Early treatment failure occurred in one child treated with AA.

5. Overall, PCR-corrected parasitological cure rate on day 28 was 98% and was significantly higher in AA- than in AL- treated children 99.1% (343/346) versus 96.9% (311/321), P=0.048. The cumulative probability of a reappearance of asexual parasitaemia after treatment with AA or AL were similar (Log-rank statistic = 0.027, P=0.869)

6. Recurrent infections were not age or drug dependent. Overall, recrudescence occurred in 5.3% of the children (38 of 711), and was unrelated to age or drug treatment. Recrudescent infections were significantly more common in the eastern flank (North eastern, North central, South eastern than the western flank (North-western, South-western and Lagos) of the sentinel sites [32 of 311 children (10.3%) versus 6 of 319 children (1.9%), P<0.00001].

7. Overall, gametocyte carriage after treatment with both drugs was significantly lower compared with pre-treatment [16 of 491 children (3.3%) versus 46 of 620 children (7.4%), P=0.005].

8. Anaemia, defined as haematocrit <30%, was present in 294 of 672 children (43.8%) and was significantly more common in the eastern than in the western flank of the sentinel sites. Anaemia resolved completely in all anaemic children within 14 days in 93% of the chilldren.

9. In anaemic children, anaemia resolution time was approximately 10 days for both drugs.

10. In the few sentinel sites where adverse drug reactions were monitored, both drugs were tolerated; the reported adverse drug reactions were indistinguishable from the symptoms of malaria.

11. AA and AL are safe and efficacious treatment of uncomplicated P. falciparum malaria in <5 year old Nigerian children.

The full study will be made available at the NMCP’s website.

Drug Quality &Pharmacovigilence &Private Sector &Treatment Bill Brieger | 14 Jan 2010

Counterfeit

dscn5015sm.JPGBBC’s Focus on Africa has identified Africa as the dumping ground for counterfeit goods. Some are cheap knock-offs of branded luxury goods that consumers know are not the real deal. Electronics are another area where the customer should beware. Others camouflage as the original product with packaging that is indistinguishable from the authentic item.

Toothpaste is a good example where the fake, which retailers call ‘Chinese’ contains a poison known as diethylene glycol which is used in anti-freeze.  The retailers sell both products for about the same price, but the incentive for pushing the fakes is profit.

On the genuine product he has made a 13% mark-up, on the counterfeit an impressive 50%. Fair play to him, some might say – after all it is only toothpaste.

But one cannot say ‘it is only medicine’ when drugs are fake. BBC notes that, “According to the World Health Organization (WHO), 30% of medicines sold in developing countries are fakes, and a major problem is that high numbers of government-owned drugs are being illegally obtained and then sold on for profit in the private sector.” BBC worries that …

… with the rising number of direct trade routes between Africa and China, together with porous border controls, outdated legislation and weak enforcement mechanisms, the continent has become fair game for counterfeiters – and the recession has made it worse.

dscn5837sm.JPGFurthermore, “A UN report published in July 2009 reveals that revenues gained from 45 million counterfeit anti-malarial medicines were worth $438m – more than the annual gross domestic product of Guinea-Bissau.”

SafeMedicines.org keeps an update of fake medicine reports. For example in Ghana, “A citizen brought suspect antimalarial medication to a sentinel site set up by the U.S. Agency for International Development (USAID)’s Drug Quality Information Program (DQI).” This was reported July 22, 2009, and involved a fake of Novartis Pharmaceuticals’ malaria product Coartem.

Researchers at Georgia Tech University shared information on the magnitude of the problem. “The percentage of over-the-counter counterfeit artesunate tablets containing no artesunate apparently increased from 38 to 53 percent in southeast Asia between 1999 and 2004.”

Fake drugs kill directly with dangerous ingredients or indirectly when inadequate or no active ingredients are present. They also may drive legitimate manufacturers out of business.  The threat is real and widespread in its impact.

The new funding program, Affordable Medicines Facility malaria (AMFm) aims to enable countries to place quality low-cost antimalarials into the private sector at prices that will supposedly compete favorably with inappropriate and fake medicines. Careful monitoring will be needed to see if this really happens.

Considering the profit margins mentioned above, the fake drugs may still out-compete the subsidized ones.  In short, nothing can replace a vigorous drug regulatory system and donors need to strengthen technical assistance to countries to regulatory capabilities actually work.

Pharmacovigilence &Resistance &Treatment Bill Brieger | 23 Aug 2009

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.

Pharmacovigilence &Treatment Bill Brieger | 02 Jun 2009

Guarding malaria drug quality in Nigeria – from port to store

The Nigerian Tribune reports today that, “A clearing agent(names withheld) has been apprehended by the National Agency for Food, Drug Administration and Control (NAFDAC) over his involvement in the importation of fake malaria drugs (Maloxine and Amalar tablets) worth N32.1million.”

maloxine-and-amalar.jpgThe fake products were produced in China but labelled “Made in India,” according to NAFDAC.  Their lab tests showed that these supposed sulphadoxine-pyrimethamine (SP) products lacked the pyrimethamine.  The Tribune quoted the NAFDAC boss as saying that, “the seizure was significant in view of the emergence of resistance strain of malaria parasites, saying the use of the fake drugs might lead to treatment failure, anaemia and death if no effective drug was given after.”

Ironically, these two SP products should not be imported for treatment, since studies dating back five or more years have shown a growing SP resistance. At present the national malaria drug policy recommends only artemisinin-based combination therapy (ACT) for treatment, while reserving SP for intermittent preventive treatment in pregnancy.  The fact that people are still demanding SP products for treatment shows lack of success in educating providers and consumers about the correct medicines as published in 2005 within the drug policy.

At the other end of the malaria drug spectrum, the Registrar of the Pharmacists Council of Nigeria (PCN) worried that unless patent medicine shops are “fully registered and regulated, the health of the people in the state will continue to be in jeopardy.” The PCN Director said that, “training (of PCN staff), which began in 2004 was informed by the council’s desire to train and retrain its staff on transmission, storage and general management of vital records.” It is not clear when and if PCN actually intends to offer training for the medicine shop owners and clerks.

The Tribune also reports that in an effort to comfort parents whose infants are experiencing what they perceive as ‘teething problems’, makers of commercially sold teething mixtures will include “very low doses of anti-malaria, especially those produced here in Nigeria or in the tropics. They also have pain relievers. However, we do know that malaria is not treated or prevented that way in children.” Since these mixtures may not be registered to treat disease, they may not be adequately regulated – and not surprisingly have led to the deaths of many children recently.

A scoping study by Nigerian researchers from the University of Ibadan has shown that patent medicine vendors (OMV) do need more education on the products that they sell – especially a full orientation on the current national malaria drug policies.  They continue to sell the more of the old first-line drugs, chloroquine and SP, instead of the recommended ATCs in large part because their customers cannot afford the new medicines. The researchers have recently called together key policy makers and donor partners to address the PMV question and find ways to improve their practices. We look forward to learning what was achieved.

In the meantime, Nigeria is among the first applicants to the new Affordable Medicines Facility – malaria (AMFm). AMFm “enable countries to increase the provision of affordable ACTs through the public, private and NGO sectors.” AMFm also “will reduce the manufacturer sales price of ACTs to public, private and not-for-profit sector buyers.” This will be an ideal way to ensure that quality ACTs are available to the public at a price they can afford from whichever outlet is most convenient.  AMFm will not succeed though without proper education and training of all providers, including PMVs and the public at large.

Drug Quality &Pharmacovigilence Bill Brieger | 29 Nov 2008

Can quick wins become quick losses?

A World AIDS Day approaches people in the field are giving a critical look at efforts to scale up ART. Jeremiah Norris in the Daily Times of Malawi raises the question of drug quality in the push for achieving widespread HIV/AIDS treatment goals. Could these same problems surface in the desire to scale up for impact (SUFI) that Roll Back Malaria partners are promoting? Some excerpts highlight the problem:

While activists have applauded the speed of this “scale-up,” it creates dangers. Many of the copies recommended by WHO are untested so patients cannot be certain that they act on the body in exactly the same way as the original (called bioequivalence). If the level of active ingredient is not absolutely correct, it can accelerate drug resistance and the mutation of the Aids virus. Under Indian law, drugs manufactured for export do not have to prove bioequivalence with the patented original.

Brazil is often held up as the model for universal Aids treatment. It too has based this largely on cheap, untested copy drugs. In July, the government acknowledged that one third of the 190,000 Aids patients under treatment were in what it called “a more advanced stage”–but medical studies had already shown even higher levels of drug-resistance.

new-medicines-appear-all-the-time.jpg Norris worries that, “WHO, the Global Fund and the Clinton Foundation therefore sanctioned a drug that was not only unapproved and potentially sub-standard but also more expensive.” Most donors depend on WHO’s ‘prequalification’ program for ensuring drug quality, but maybe it is possible in the rush to achieve coverage some governments are buying drugs not on the prequalified list.

The pressure is on to scale up malaria treatment. The Global Fund Board has recently approved taking on management of the Affordable Medicine Facility – malaria (AMFm), which will among other things enhance the role of private sector in increasing access to malaria medicines. The Clinton Foundation has been negotiating with pharmaceutical manufacturers about making more lower coast malaria drugs available.

Norris’ concern that, “many poor countries … cannot carry out drug evaluation themselves” applies for malaria drugs as well as ARVs.  Even if a drug appears on a WHO or FDA list, one cannot guarantee that the medicine that found in a district hospital pharmacy or a local medicine shop in a malaria endemic country is actually of the quality required. Quick wins in scaled up medicine distribution can ultimately result in quick loss of life if capacity is not built to monitor drug quality at the front line.

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