Tuesday, 7 February 2012

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

Michael Regnier 7 Feb, 2012
Neglected tropical diseases: Control, elimination or eradication?
 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 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.

Breeding site for Simulium (blackfly) species 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.

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 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.”

Vector control: insecticide-treated mosquito nets 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, Benin Collecting water from an unprotected pond in Benin


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 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.

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