POVERTY: Neglected tropical diseases: Control, elimination or eradication?

Michael Regnier 7 Feb, 2012

 Last week, the world’s pharmaceutical companies announced new and renewed commitments to donating drugs needed to treat neglected tropical diseases (NTDs). Tackling these diseases requires more than providing hospitals and pharmacies with pills – usually, these drugs are actively distributed through mass administration programmes with the aim of controlling disease as well as treating the affected individuals. Michael Regnier spoke to Professor Moses Bockarie of the Liverpool School of Tropical Medicine to find out more about the strategies used.
There are basically three choices when deciding our response to endemic infectious diseases: control, elimination or eradication. On the face of it, it may seem obvious to pick eradication every time, but in all human history we have only managed to eradicate one disease – smallpox. Eradication is not easy, even when the characteristics of the disease in question are favourable. For many neglected tropical diseases (NTDs), control has been the most practical strategy.

Control
Control reduces the impact of a disease in a given area until it is no longer a major public health issue, explains Professor Moses Bockarie, Director of the Centre for Neglected Tropical Diseases at the Liverpool School of Tropical Medicine*. As a prime example, he describes the Onchocerciasis Control Programme (OCP), which was sponsored by four UN agencies including the World Health Organization (WHO) and the World Bank.

 Rivers like this one in West Africa were breeding sites for blackfly

Onchocerciasis, or river blindness, is caused by nematode worms that are passed from blackflies to humans. OCP began in 1974, using helicopter spraying to kill blackfly larvae in the rivers of 11 countries in west Africa. In 1987, the pharmaceutical company Merck Sharpe & Dohme (MSD, known as Merck & Co in North America) started to provide its drug ivermectin free to OCP so that the programme could expand to include a strategy of mass drug administration. The company’s donation continues today and MSD has committed to providing ivermectin free for as long as it is needed.
Bockarie says OCP was one of the most successful efforts of its kind: “It opened up thousands of acres of land for agriculture but the main outcome was it reduced onchocerciasis to a level where it was no longer of public health significance.” By 2002, transmission of onchocerciasis had been drastically reduced – almost stopped – in all of the participating countries except Sierra Leone, which was then in the grip of civil war.
According to the WHO, 600 000 cases of onchocerciasis were prevented by OCP and 18 million children born in areas where the risk of onchocerciasis is now controlled and minimal. OCP was followed by the African Programme for Onchocerciasis Control (APOC), which has extended the mass drug administration of ivermectin to the remaining African countries with endemic onchocerciasis.
The success of OCP was encouraging for similar schemes for other diseases such as lymphatic filariasis and schistosomiasis, although later efforts to implement disease control programmes were often initiated by scientists working in the field rather than international agencies or national governments. That there are several disease control programmes currently in place is a testament to the advocacy and dedication of those scientists, as well as the funders who support them and the national and international agencies that are helping to deliver the programmes on the ground.
A key feature of today’s disease control programmes is the level of coordination between them. “The common features of certain NTDs – their association with poverty, they are easily treated and the drugs are donated by pharmaceutical companies – allows for combination, improved ‘packaging’ to target them all together through preventive chemotherapy,” explains Bockarie. “Funders are happier to support these integrated programmes.”
By 2005/06, a package was in place to treat seven NTDs, saving 50 per cent on the cost of administrating each drug separately. Mass drug administration works for these diseases not only because the drugs are donated or provided at low cost, but also because the drugs can be given orally in a single dose every six or twelve months.

Elimination
Lymphatic filariasis (also called elephantiasis) is one of the diseases being controlled through integrated programmes – it is also treated with ivermectin – but it has already been successfully eliminated from China, Korea and ten African countries. Elimination means stopping transmission in a particular territory.
Elimination of lymphatic filariasis in certain countries has been possible because ivermectin is so effective, but there are other factors working in our favour, according to Bockarie: “The drug is very good, tools for diagnosis are very good. There is no natural reservoir for the parasite, so if you can eliminate it from humans, it is gone. If you reduce the parasite load in the community to less than 1 in 1000, transmission is impossible.”

 Man with elephantiasis of the lower regions, 1904

Like onchocerciasis, lymphatic filariasis is caused by thread-like nematode worms, although the worms that cause lymphatic filariasis are transmitted by mosquitoes rather than blackflies. Infection leads to thickening of the skin and other tissues, and massive swelling, particularly of the legs and male genitals. Of course, there are still many people with lymphatic filariasis in the countries where transmission has been successfully interrupted – it will take many more years for the signs of the disease to disappear.
Since OCP ended, strategies for onchocerciasis have also moved more towards elimination in certain countries. These were prompted, says Bockarie, by the recent upsurge in interest in NTDs generally. “We have the resources to monitor and evaluate progress and there is a bigger workforce available which means we can put in place protocols for effective monitoring.”
In its roadmap for NTDs published last week, the WHO says elimination of onchocerciasis is feasible in Latin America by 2015. In Africa, the WHO estimates the 12 APOC and 11 ex-OPC countries may all have achieved elimination by 2020, out of a total of 31 African countries affected by the disease.
Although onchocerciasis and lymphatic filariasis are treated with the same drug, it will not be simple to eliminate both diseases in all countries. “One of the biggest challenges is co-infection,” says Bockarie. “We can control onchocerciasis and lymphatic filariasis with existing tools but only in certain settings.”
One problem is another parasite called Loa loa, which is also sensitive to ivermectin. Unfortunately, in patients with large numbers of Loa loa parasites in their bodies, treatment with ivermectin can cause serious, potentially fatal, effects when dead Loa loa worms enter the bloodstream. So ivermectin cannot be used to treat onchocerciasis or lymphatic filariasis where Loa loa infections are also prevalent. This does not mean, however, that we have to give up.
“Different strategies are being developed,” says Bockarie, “such as more refined, higher resolution mapping.” Knowing precisely where the diseases are endemic is vital to using resources in the most efficient and effective way. The standard approach for onchocerciasis and lymphatic filariasis has been to go to a district and sample the people. If more than 1 per cent are infected, the whole district is classed as endemic and is eligible for treatment. This does not work in areas with Loa loa – mapping has to be done at the village level if the status of all three infections is to be accurately determined and the right strategy implemented.
In areas with co-infection of Loa loa, the drug albendazole can be used first to reduce the levels of Loa loa infection in order to dampen the adverse effects of treatment with ivermectin that follows. Of course, as with the early days of OCP, control and elimination efforts do not have to focus on drugs. Other approaches include using antibiotics to kill Wolbachia, a bacterium that lives in lymphatic filariasis and onchocerciasis parasites but not in Loa loa. The parasites are dependent on Wolbachia, so killing the bacterium kills the parasites. However, there are other issues with using antibiotics: treatment is over one or two weeks rather than in a single annual dose as with the antiparasitic drugs, which makes it harder to ensure people get the full course of treatment.
Targeting the insects that transmit the parasites – the flies that carry Loa loa, or the mosquitoes that transmit the worms that cause lymphatic filariasis – is called vector control, and it is an approach that Bockarie has been championing for years: “What pushed me into public health and advocacy,” he explains, “was that vector control was being ignored. The lymphatic filariasis control programme had two main objectives: drugs to reduce infection in humans, and reduce or manage morbidity. Vector control was missing. When the lymphatic filariasis programme was developing, there was no space to talk about mosquitoes.”

 Mosquitoes killed by insecticide on a treated net

Bockarie’s early training was in medical entomology – the use of scientific knowledge about insects to understand and address human disease. He began studying malaria but mosquitoes that transmit malaria also transmit lymphatic filariasis and other NTDs, although this sometimes seems to get overlooked: “In the last two to three years, we’ve seen the impact of [insecticide treated] bed nets on malaria,” he says. “But we know bed nets would impact on lymphatic filariasis as much as, if not more than, malaria – what’s happening in lymphatic filariasis?”
While the integrated efforts to control and eliminate various NTDs are growing, it seems there is a need to integrate them further with efforts against the big three infectious diseases – malaria, tuberculosis and HIV/AIDS – as well.

 Collecting water from an unprotected pond in Benin

Eradication

Eradication can be simply defined as global elimination. It was achieved in the 20th century with smallpox and we may be close to eradicating a second disease in the form of dracunculiasis, or Guinea worm disease. How? “Stop people drinking infected water,” says Bockarie. “It’ll completely eradicate it, get rid of the parasite completely.” It sounds simple, although as dracunculiasis is another neglected tropical disease, simple doesn’t necessarily mean easy, but the WHO has set a firm target in its NTDs roadmap to eradicate dracunculiasis by 2015.
Professor David Molyneux, acting chair of the UK Coalition against NTDs and one of the scientists who introduced the term ‘neglected tropical diseases’, has described progress on dracunculiasis so far as remarkable: “The total number of cases has declined from well over three million in the late 1980s to only 1060 reported in 2011. The end is in sight. What is remarkable is that this has been done without a drug or a vaccine. Applying basic public health principles – health education, case containment, surveillance, water filtration and enhanced access to safe water has been critical.
“Success is in sight but as always, the cost remains as we travel down the final mile and need to identify the last infected villages and isolate final cases.”
The Carter Center has been a particularly strong advocate for action against dracunculiasis over the past 25 years and will play a role along with a number of funders including the UK Department for International Development and the Gates Foundation in achieving the 2015 eradication target. Another NTD called yaws is set for eradication by 2020 but for the other NTDs, control and national or regional elimination strategies remain crucial.
 Professor Moses Bockarie

Implementing the strategy
Bockarie is Sierra Leonean. I finish our interview by asking him about science in Africa. Although he recognises the current lack of capacity as an important issue, he is optimistic about the growth of African science and its role in tackling NTDs.
“We have funding to support countries to achieve elimination,” he says. “This includes support for governments to do mass drug administration, operational research and capacity building. In Sierra Leone, just introducing operational research led to an increase in Sierra Leonean-led publications in the last couple of years compared to the 20 years prior to that.
“At the Liverpool School, we have part-time PhD students in Africa, basing their PhD research on the work they’re doing at home; we’ve built regional laboratories.
“We’re also working to take a more scientific approach to evaluating capacity-building,” he adds, “working to measure the effect of such programmes. Capacity-building will lead to sustainability and it will provide the local support and resource to do the required surveillance on which elimination of NTDs depends.”
This is one of a series of blog posts accompanying a Wellcome News feature on neglected tropical diseases. Next week: ‘One Health’ – why looking at human and animal health together can help in the fight against NTDs.

* The Liverpool School for Tropical Medicine and the University of Liverpool are collaborative partners in the Liverpool Wellcome Trust Tropical Centre and in the Wellcome Trust’s Major Overseas Programme in Malawi.
Related resources: The Wellcome Trust website has a number of scientific animations showing the life cycles of many parasites, bacteria and viruses that cause disease including many NTDs such as Lymphatic filariasis.
http://wellcometrust.wordpress.com/2012/02/07/neglected-tropical-diseases-control-elimination-or-eradication/#more-8966

MALARIA: Do we have tools and guidelines for malaria elimination?

Bill Brieger : 07 Dec 2011

Sessions at the current American Society of Tropical Medicine and Hygiene in Philadelphia have focused on progress in the global elimination of lymphatic filariasis (LF). Filariasis and malaria have some elements in common, such as some mosquito vectors, and possibly malaria elimination efforts could learn from LF elimination.
The duration of a typical filariasis elimination program might span around 10 years, much shorter than expected for malaria, where Roll Back Malaria has already been working hard for 13 years. Even with this difference LF elimination has important surveillance tools needed for the end game that can be adapted for malaria. As the figure here shows, the first step is mapping which can take at least a year.
Then there are at least five annual mass drug administrations (MDA) with ivermectin or DEC and albendazole. Monitoring goes along with distribution, and as pointed out at a panel presentation at ASTMH, determines whether the program can enter Step 3 (three rounds of annual surveillance) or complete a few more MDA rounds. Eventually the project site is certified as having eliminated filariasis.
An ASTMH symposium highlighted the challenges: “The decision to implement a mass drug administration (MDA) program for LF is based on convenience sampling to demonstrate that the prevalence of infection is greater than 1% in a selected district or implementation unit. Making the decision to stop MDA has been a challenge for countries,” when prevalence drops below 1%.

Fortunately those involved in LF have tools and guidelines to focus their efforts. These guide initial mapping and choice of diagnostic tools, ongoing program monitoring and endline Transmission Assessment Surveys (TAS) The purpose of the guidelines is …



“Effective monitoring, epidemiological assessment and evaluation are necessary to achieve the aim of interrupting LF transmission. Th is manual is designed to ensure that national elimination programmes have available the best information on methodologies and procedures for (i) monitoring MDA, (ii) appropriately assessing when infection has been reduced to levels where transmission is likely no longer sustainable, (iii) implementing adequate surveillance aft er MDA has ceased to determine whether recrudescence has occurred, and (iv) preparing for verifi cation of the absence of transmission.”
The guideline manual provides general guidance to national programmes but reminds program managers that each program is unique and may require further technical guidance.
Several countries, especially in the Asia-Pacific Region and Southern Africa are working toward malaria elimination. Such tools adapted to malaria program needs are required. One of the challenges for the TAS is that while countries have received donations of medicines to eliminate LF, they have found it harder to find or allocate funds to do the necessary surveillance to know when to stop interventions and verify elimination. This also rings true for malaria - donors and governments should not stop funding malaria elimination until certification has been achieved.
http://www.malariafreefuture.org/blog/?p=1342

MALARIA: Smelly chemicals confuse mosquitoes

1 June 2011 By James Gallagher

 Female mosquitoes follow a trail of carbon dioxide
Chemicals which interfere with a mosquito's ability to sniff out humans have been developed by US scientists, according to research in Nature.

It is hoped they could be used to develop the next generation of mosquito traps and repellents.
A UK expert said the discovery could be a "major step forward" if the chemicals were safe and cheap.
Blood sucking female mosquitoes use carbon dioxide in exhaled breath to track down humans.
They can detect minute changes in the concentration of the gas.
This knowledge is already used in carbon dioxide traps, but requires dry ice or gas cylinders - which mean they are rarely used in developing countries.
Researchers have been looking for chemicals which can disrupt or confuse a mosquito's carbon dioxide sense.

Deception
Scientists at the University of California, Riverside, tested smelly chemicals on three species of mosquito: Anopheles gambiae, which spreads malaria; Culex quinquefasciatus, which spreads filariasis and West Nile virus; and Aedes aegypti which spreads dengue and yellow fever.
The researchers say that these insects combined infect half a billion people each year, some in at risk countries will be infected multiple times in their lifetime, and cause millions of deaths.
The researchers identified three groups of chemicals, which disrupt a mosquito's carbon dioxide receptors.
One mimicked carbon dioxide and could be used as bait in insect traps, another prevented the mosquito from detecting carbon dioxide and the last group tricked the mosquito's brain into thinking it was surrounded by huge quantities of the gas - so it could not pick which way to go.

 

Anopheles gambiae is responsible for the vast majority of malaria cases in Africa Professor Anandasankar Ray, from the University of California, Riverside, said: "These chemicals offer powerful advantages as potential tools for reducing mosquito-human contact, and can lead to the development of new generations of insect repellents and lures.

"The identification of such odour molecules, which can work even at low concentrations, and are therefore economical, could be enormously effective in compromising the ability of mosquitoes to seek humans, thus helping control the spread of mosquito-borne diseases."
Carbon dioxide is not the only way mosquitoes can find their dinner however, as the smell of human sweat and skin can also be used.
Dr James Logan, from the London School of Hygiene and Tropical Medicine, said: "Whilst this is an exciting study, the authors are yet to show that the chemicals are capable of protecting a human being from being bitten.
"Although carbon dioxide is an important cue for mosquitoes, we know that mosquitoes respond differently to a trap releasing carbon dioxide than to a real human being, which releases a complex mixture of many attractive chemicals, heat, visual cues and moisture.
"The key question is - do the 'response modifying odours' actually protect a human being?"
The chemicals also need to be used at high concentrations, which could be hazardous to human health. The researchers say their next step is to develop safer chemicals.
Dr Nikolai Windbichler, from Imperial College London, said work needed to be done to ensure they were safe and could be produced at low cost.
He added: "These compounds have novel and desirable properties because they can confuse the mosquitoes' host seeking behaviour even when the substances are no longer present or the mosquitoes have left the area of application.
"This, if realised, could be a major step forward and could protect large groups of people or large areas, something that is not currently feasible with existing repellents."
Mark Stopfer, from the US National Institutes of Health, said the study offered "a promising line of defence."
http://www.bbc.co.uk/news/health-13614781

POVERTY: KENYA: Elephantiasis thrives amid funding gap

Photo: WHO
Elephantiasis could easily be stopped with the help of just a couple of pills a year
NAIROBI, 11 October 2010 (IRIN) - Stigma has allowed a disfiguring microscopic worm to thrive in Kenya's coastal region, but with adequate funding, the spread of lymphatic filariasis (LF), also known as elephantiasis, could easily be stopped in the east African country with the help of just a couple of pills a year.
Spread by mosquitoes, elephantiasis can cause severe swelling of the limbs, breasts, and scrotum as well as thickening and hardening of the skin.
Some three million people living in Kenya’s Coast Province are “at risk”, a category that includes those who may already have contracted the disease, whose symptoms can take decades to manifest themselves.
"In the larger Kilifi District alone, 460,000 cases have been reported over the years,” Safari Ngowa, programme manager of MAP International, an international NGO that has helped elephantiasis patients in Kenya since 2008, told IRIN.
“A lot of these people perhaps do not know that they can get help at public hospitals," Ngowa said. "MAP International mostly conducts operations for those with swellings in their genitals and provides palliative care for those with swollen limbs."
Shanaz Sharif, director of public health and sanitation in Kenya’s Ministry of Health, said: “Reluctance to come forward and seek treatment also complicates [compiling] figures for the disease. Some of the sufferers have lived with the condition so long they just don't come forward."
He said Kenya was committed to eradicating the disease but budgetary constraints had affected the mass administration of two drugs which, when taken annually for four or five years, halt the transmission of the infecting parasite. The World Health Organization’s (WHO) Global Programme to Eliminate LF is leading this effort.
Elephantiasis affects millions of people worldwide and although it can be prevented, the disease has no cure and access to treatment in the developing world is hampered by stigma and poor health infrastructure.
Mass drug administration
"There was a delay in conducting the mass drug administration (MDA) in 2009 but we did it early this year in the affected districts," Sharif said.
MDA in Kenya was launched in Kilifi district in 2002 and then scaled up to include Malindi and Kwale districts in 2003.
An highly endemic area along River Sabaki in Malindi district has been used for operational research by the Kenya Medical Research Institute (KEMRI) since 2002. Four rounds of MDA given to the communities in this area have led prevalence rates to drop from 21 percent in 2002 to under one percent in 2009, according to KEMRI scientist Sammy Njenga.
“Scaling up [MDA] was supposed to happen every year but we have not been able to do this, or deliver drugs every year, because of financial constraints,” he told IRIN, explaining that the issue was not so much the cost of the drugs themselves, but that of their delivery and correct administration in remote areas.
Njenga described LF as a “hidden disease” that in the past had not been taken as seriously by health officials as malaria, HIV and tuberculosis.
On a more positive note, he said studies had shown that while interrupting MDA in other countries had allowed prevalence to rise, this did not appear to be the case in Kenya.
According to WHO, there are other reasons why less than a third of those at risk of LF in Africa benefit from MDA.
Loa loa
“In over 10 LF-endemic countries in Central Africa, Loa loa, another parasitic disease, is also present. Because people with Loa loa infections are at risk of severe adverse reactions when given ivermectin, traditional MDA for LF cannot be implemented in these areas,” Kazuyu Ichimori, who works with the programme to eliminate LF at WHO’s Department of Control of Neglected Tropical Diseases, told IRIN in an emailed response to questions.
“This is one of the biggest challenges to scaling up the geographical coverage of MDA and research is ongoing to better map the specific areas of overlap and to determine alternative strategies to interrupt transmission,” she added.
“The other major challenges are the 13 countries which have not begun MDA that are in conflict or post-conflict stages as well as logistical problems in implementing MDA (and achieving high coverage) in urban areas,” she wrote.
A WHO strategic plan to eliminate the disease as a public health problem by 2020 discusses “potential of enhanced drug regimens and vector control as a complement or alternative to the traditional MDA approach,” she added.
According to WHO figures, LF affects more than 120 million people worldwide, one-third of whom live in Africa. At least 40 million people around the world are seriously incapacitated and disfigured by the disease. It is endemic in 81 countries.
In 2009, WHO said the MDA programme targeted 496 million people and treated 385 million - a 77 percent coverage rate.
http://www.irinnews.org/report.aspx?ReportID=90739