TROPICAL DISEASE

Evidence Shows Combined Common Drugs Can KO Neglected Tropical Infections

It might seem odd that a U.S. geriatrician would publish a paper in a major medical journal on relatively ignored diseases in poor countries where few people live long enough to require specialized aging care.

Graham Ramsay

A majority of the seven most prevalent neglected tropical diseases can be controlled with existing oral medications given simultaneously, according to a systematic review by Madhuri Reddy and her colleagues.

But this year, Madhuri Reddy grabbed the chance to help fight neglected tropical diseases with a study investigating the medical evidence underlying a proposed plan to treat multiple diseases with an inexpensive combination of drugs that have been available for 30 to 40 years.

“People who are experts in this field are aware of these facts, but many in the Western medical community are not,” said Reddy, whose research at the Hebrew Rehabilitation Center focuses on chronic wounds. “Even though these diseases don’t directly affect us, we should know about them. This analysis of the best evidence to date gives us a baseline of where we are now and where to go from here.”

Rapid Impact
The term neglected tropical diseases refers to a group of 13 common chronic infections that strike more than 1 billion people in developing countries. Together, they pose a threat comparable to HIV/AIDS, TB, or malaria, as measured by years of healthy life lost due to disability. They do not usually kill people. They ravage the population more insidiously by corrupting health, especially through developmental delays in children and adverse pregnancy outcomes, and perpetuating the cycle of poverty.

In contrast to the better-known “big three,” many people in developed countries have never heard of infections like roundworm, whipworm, hookworm, or snail fever (see table). Relatively cheap oral treatments already exist for many of the common neglected diseases. A proposed “rapid impact package” to deliver several drugs together once or twice a year would make the remedies an even better bargain.

Earlier this year, Reddy responded to a call for papers on global health and poverty for a theme issue of The Journal of the American Medical Association and recruited other geriatricians she had trained with in Canada. “We had been interested in the neglected tropical diseases and decided this was the time,” she said. “A few people devote their lives to these diseases, but we can all do something.”

The senior author on the paper, Paula Rochon, a senior scientist at Baycrest, the geriatric facility for the University of Toronto, had set a precedent a few years earlier. She looked into the disconnect between the global burden of disease and the published randomized controlled clinical trials. Studies in leading medical journals have little relevance to international health, she found. Rochon’s study was cited in JAMA’s call for papers. (JAMA was one of 230 science and biomedical journals publishing simultaneous global theme issues in October, an event coordinated by the Council of Science Editors.)

In their study, Reddy and her colleagues applied a systematic review, an evidence-analyzing method they know a lot about, to a group of unglamorous diseases they knew almost nothing about. The technique combines a comprehensive search of the literature and additional sources with transparent criteria for evaluating and selecting the top quality studies.

This approach avoids the bias of a narrative review, but it is limited by the rigor of the individual studies and by the potential for publication bias toward positive results, said co-author Sudeep Gill, a geriatrician at Queen’s University in Kingston, Ontario.

At least two of the most prevalent neglected diseases can be treated simultaneously with existing oral drug treatments, the study found, and a single drug combination can control four of the top seven diseases. The authors caution that adverse events are poorly documented, especially in more vulnerable groups such as children and pregnant women.

Integrated Disease Control
“This helps build the evidence base for integrated tropical disease control,” said Peter Hotez, chair of microbiology, immunology, and tropical diseases, and president of the Sabin Vaccine Institute at George Washington University and founding editor-in-chief of a new journal launched in November, PLoS Neglected Tropical Diseases. “These are called neglected diseases for a reason. We don’t have a critical mass of scientists and physicians working on these. Having experts like Madhuri weigh in is helpful.”

Common (Proper Name)	Prevalence of Infection Worldwide	Cause	Usual Transmissions	Clinical Features
Roundworm (ascariasis)	1.2 Billion	Worm (helminth)	Fecal contamination of soil	Impaired growth, physical fitness, and cognitive function; intestinal obstruction, biliary and pancreatic disease
Whipworm (trichuriasis)	795 Million	Worm (helminth	Fecal contamination of soil	Impaired growth, physical fitness, and cognitive function; dysentery, rectal prolapse
Hookworm (necatoriasis, ancylostomiasis)	740 Million	Worm (helminth)	Fecal contamination of soil	Malnutrition and anemia; impaired growth, physical fitness, and cognitive function
Snail fever, bilharzia (schistosomiasis)	200 Million	Worm (helminth)	Skin contact with water containing infected snails	Hematuria, anemia, impaired growth and school performance; bladder cancer; renal, hepatic, and spleen failure
Elephantiasis (lymphatic filariasis)	120 Million	Worm (helminth)	Mosquitos	Disfigured limbs and genitalia
Trachoma	80 Million	Bacteria	Flies or skin contact	Visual impairment and blindness
River blindness (onchocerciasis)	37 Million	Worm (helminth)	Black flies	Eye lesions, dermatitis, subcutaneous nodules, or all three

The top seven neglected tropical diseases are a mystery to many Westerners. This chart provides their names, prevalence, cause, usual transmission route, and clinical features.

Hotez, who advised Reddy on the study, and his colleagues have proposed a theoretical framework for an integrated assault on these diseases and an initial scale-up of integrated control in several sub-Saharan African countries, including Rwanda and Burundi.

“This study highlights the fact that we do have very good tools available today, to treat a lot of people with some really horrid infections, at a very affordable price,” said Nilanthi de Silva, a clinician and a medical parasitologist in Sri Lanka, who also advised Reddy on the study. “This sort of awareness is particularly lacking in the U.S.A., and I think Madhuri’s paper presents the data in a fresh manner that reminds us that a great deal can be done with what is available right now.”

The next level of challenges for neglected tropical diseases involves building the capacity to deliver the drugs, instituting a way to monitor compliance and evaluate outcomes, tracking potential emerging drug resistance, and developing the next generation of new drugs and vaccines. Many of these activities are now being funded by the Bill & Melinda Gates Foundation. The resulting infrastructure can also support other simple disease control tools, such as vitamin A supplements and mosquito bed nets. Even while looking ahead, Hotez said, “when you’re working in developing countries, there’s an ethical imperative to do what you can now.”

—Carol Cruzan Morton

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