Research from Washington University School of Medicine in St. Louis over the past decade has helped advance a global campaign led by the World Health Organization (WHO) to eliminate two neglected tropical diseases that have left tens of millions of people permanently disabled or disfigured.
Now, an international team led by Gary Weil, MD, professor of medicine and of molecular microbiology – with the assistance of up to $24.7 million in new grant funding from the Bill & Melinda Gates Foundation – plans to conduct clinical trials and related studies in Africa and Oceania that could help speed the elimination of these diseases as a public health problem. About $6 million already has been committed to the project, with additional funding dependent on the results of the first wave of studies.
One of those diseases is lymphatic filariasis, which in severe cases causes elephantiasis, painfully swollen limbs that make it difficult to walk and carry out the tasks of daily life. The second disease is river blindness, known more formally as onchocerciasis, which leads to blindness and severe skin disease. Both are caused by parasitic worms that are transmitted by biting insects.
“Globally, enormous progress has been made in reducing lymphatic filariasis and river blindness, but it will take decades to achieve full elimination with current treatment strategies,” said Weil, the principal investigator of the long-running Death to Onchocerciasis and Lymphatic Filariasis Project (DOLF), funded by the Gates Foundation. “So there is an urgent need to develop new tools and approaches to speed the elimination of both diseases.”
A major focus of the new effort will be on lymphatic filariasis. The WHO launched a global campaign in 2000 to eliminate the disease by 2020. While this program has successfully cut the number of people at risk of disease nearly in half – from 1.4 billion to 800 million – completely ridding communities of the microscopic worms that cause the disease has proven more difficult than expected. Better treatment regimens could accelerate the elimination process.
Lymphatic filariasis is spread by mosquitoes that carry larvae from one person to the next. Once inside a person’s body, the adult worms migrate to lymphatic vessels that drain excess fluid from tissues and return it to the bloodstream. By blocking the drainage routes, worms cause swelling in the lower limbs. Adult worms can live for years in the lymphatics, producing millions of young that travel to the bloodstream, where they are picked up by the next mosquito that bites.
The WHO’s strategy has been to break the cycle of transmission by administering worm medication on a massive scale to everyone who lives where the parasites are found, regardless of whether they are infected. In prior studies in six countries in Asia, Africa, Oceania and the Americas, DOLF researchers found that a triple cocktail of drugs – ivermectin, diethylcarbamazine and albendazole, collectively known as IDA – was safe and more effective than two-drug combinations the WHO had recommended for mass treatment campaigns in most countries. While the two-drug regimens kill the larvae, their effect is incomplete and temporary. Permanently ending transmission requires treating entire communities repeatedly until the adult worms become too old to reproduce, which can take up to seven years. The three-drug combination, however, sterilizes or kills the adult worms. Based on these results, the WHO changed its policy in 2017 to recommend the three-drug combination for filariasis elimination in many places, a shift that could vastly accelerate the pace of elimination.
The WHO does not recommend the triple-drug combination in places where both lymphatic filariasis and river blindness are endemic. The parasites that cause both diseases are susceptible to some of the same medications, so conceivably, both diseases could be eliminated with the same mass treatment strategy. The problem is that the worms that cause river blindness can live in the eye – which is why they trigger vision problems – and when they are killed by medication, the worms release toxic byproducts that can cause blindness.
“With the new funding from the Gates Foundation, we will test IDA in places where some people are co-infected with the worms that cause lymphatic filariasis and onchocerciasis,” Weil said. “Our strategy is to pre-treat people with ivermectin to remove the parasites from the eyes and then, several months later, deliver IDA, which should then be safe.”
The strategy will first be tested in Ghana. Success there will lead to larger studies in other countries in Africa. If successful, 18 countries with overlapping areas of endemic river blindness and lymphatic filariasis – all located in Africa – will have a much more powerful weapon in their fight against parasitic diseases.
The grant also will allow the researchers to test other drug combinations with a goal of finding more treatment regimens that quickly and effectively kill the worms while also being safe and acceptable to the people who have to swallow the drugs. Some of these studies will include a newly approved drug called moxidectin. Moxidectin is similar to ivermectin but lasts longer in the body. It has been shown to be effective for clearing onchocerciasis parasites from the skin for at least one year.
Weil and the DOLF team also will tackle the question of why mass treatment for lymphatic filariasis is not always as effective as hoped. They will look for differences among people – such as history of prior treatment and ability to metabolize medications – and among the parasites – such as genomic variations and signs of drug resistance – that could explain why mass treatment for lymphatic filariasis works better in some people and regions than others.
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