NTDs: Diseases of the bottom billion

What do the world’s “bottom billion” — the approximate number of the world’s citizens earning less than $1.25 USD per day — have in common? Aside from poor living conditions, malnutrition, and political voicelessness, they are also all more likely to suffer from so-called neglected tropical diseases (NTDs), scourges that have become a hallmark of extreme poverty in the world. The World Health Organization has grouped these seventeen diseases (see Table 1) on the basis of their prevalence in the world’s poorest regions and their destructive impact on patients’ lives and local economies. These diseases, neglected by the public eye and in research agendas, actually account for over half a million deaths per year and debilitate over a billion people [].

NTDs disable their victims and prevent people from leading productive lives, locking the afflicted in a vicious cycle that keeps the poorest poor. Many NTDs stunt the physical and mental development of children, especially the intestinal worm infections that especially impact this population. Some NTDs, like blinding trachoma, are transmitted from mother to child and cripple humans from the moment of birth. Others, like elephantiasis, Buruli ulcer, or the historically well-known plague of leprosy, are disfiguring and lead to ostracism and isolation. Together, NTDs debilitate individuals, families and — in countries where they are especially prevalent — entire economies.

Why are the NTDs neglected?

Despite their enormous impact, the NTDs have remained neglected for three key reasons. First, the affected populations are the most politically and economically disenfranchised people on Earth. These patients live in isolated, remote areas, far from not only medical care and sanitation but also from contact with the media and from the more empowered members of the general public. While the global reach of HIV/AIDS and tuberculosis (TB) has put these diseases on national agendas, the silent toll of NTDs on more isolated communities has been easier to ignore. Second, the inability of these patients to pay provides a powerful disincentive for companies developing diagnostics, drugs, and vaccines to venture into research and development of medical products for these diseases. Third, while they maim and debilitate, these chronic diseases rarely cause death, unlike their better-known counterparts of malaria, TB, and HIV/AIDS. Both public and private funding agencies have traditionally found it easier to rally the public around diseases with a high death toll. In terms of both life and productivity lost due to disease, the global disease burden of thirteen of the NTDs is approximately the same as that of HIV/AIDS, and is greater than that of either malaria or TB []. However, research and development funding allotted for all the NTDs together is eightfold less than that for the “big three” of HIV/AIDS, TB, and malaria []

Research needs and the 1/99 gap

As a result of decades-long neglect, the advances in medical science that have revolutionized the prevention and treatment of developed-world diseases have not extended to NTDs. While nearly 3 billion people are at risk for contracting NTDs, we know little about the biology of the diseases or how to treat them. As a result, available treatments are often outdated, toxic, expensive, and/or poorly adapted for the impoverished areas where they are needed most. For example, one of the front-line drugs to treat African sleeping sickness, melarsoprol, needs to be given intravenously by a skilled medical practitioner – something virtually nonexistent in the remote communities where NTDs flourish. Once administered, the drug causes a toxic reaction that kills 1 out of every 20 people that take it [].

Out of 1393 new drugs approved in the United States between 1975-1999, only 15 targeted NTDs; in the past decade, the total so far is 1 [5,6]. Meanwhile, studies show that effective implementation of medicines for NTDs, when they exist, has one of the highest benefit-to-cost ratios for any medical intervention []. The need for robust research funding to develop safer and more effective treatments for NTDs is urgent.

Understanding these diseases will also help reduce the sky-high risk of co-infection with HIV, TB, and malaria, and to manage the other effects the NTDs have on the human body. No one knows, for example, why chronic, persistent worm infections leave children stunted mentally. Insights into these problems could guide intervention to better help those who are at-risk.

The success of the AIDS research community, which, in the span of 15 years, unearthed the causative virus (HIV) and started developing a treatment for the disease, demonstrates the potential for new discoveries when researchers have the requisite resources. So who will pay for the research that can help rehabilitate over a billion of the world’s poorest people? The well-known Gates Foundation has changed the game in global health by providing a substantial portion of funding, but private philanthropy alone cannot solve the problem: governmental contributions around the world have been essential to addressing NTDs []. The National Institutes of Health in the USA, a major source of funding for many academic labs like those here at Harvard, has recently named “global health” as one of its top five priorities. This is an opportunity for universities to establish and strengthen NTD research programs. The UN and World Bank-supported Special Programme for Research and Training in Tropical Diseases (TDR) of the World Health Organization funds drug development, community-based interventions, and control of disease-transmitting insects.

These moves by the US and other developed countries have a charitable element, but also serve foreign and security policies. NTDs slash the impact of the foreign development dollar by locking aid recipients into disability and poverty. Accordingly, the US Agency for International Development has been a major funder of NTD research []. Furthermore, NTDs are prevalent in many regions of military importance, such as the war-torn regions of Africa (including Sudan, Congo, and Angola), Iraq, and Afghanistan []. In response, military agencies in the US, United Kingdom, India, and other countries have established laboratories for research and diagnosis of NTDs. A striking, recent success by the US Army has been the development of a vaccine for Japanese encephalitis, a mosquito-borne infection that endangers both local populations and travelers in Asia [].

Still, more funding is desperately needed. The “10/90 gap,” coined in 1990 to indicate that 90% of research funding was aimed at diseases that afflict 10% of the world’s population (including HIV/AIDS, TB, and malaria), shrinks to a “1/99 gap” to reflect the funding available for the NTDs alone [].

Getting treatments to those who need them

Surprisingly, some of the NTDs can be safely diagnosed and treated, yet the medicines remain out of reach for millions. Sometimes, a drug is just too expensive, especially in the case of branded drugs under patent. For example, liposomal amphotericin B, the existing drug to treat visceral leishmaniasis (a deadly disease transmitted through the bite of the sand fly) costs about $450-$2,500 USD per patient, but the patients who need it typically earn less than $2 per day. More often, the drug may not be sold or provided in the patient’s community, or there may not be any doctors, nurses, or other healthcare providers to diagnose the disease and prescribe treatment. A cheap, generic single-dose pill to treat intestinal worm diseases, for example, has been available for years, but disease eradication is frustrated by reinfection, isolation, and extreme poverty — some patients cannot even buy shoes, which help prevent the transmission of hookworm. Recently, though, long-term programs that integrate education, prevention, and elimination have begun to capitalize on the potential presented by affordable drugs. After an aggressive campaign by local health workers and the global public health community, the Guinea worm parasite is on the verge of eradication; the number of identified cases has decreased from nearly one million in 1989s to 3190 in 2009 []. Still, new drugs are needed to address the specter of emerging drug resistance, especially in areas of mass drug administration.

In rare cases, drug companies donate essential medicines for NTDs, and these treatments can have a significant impact if integrated into local public health and distribution networks. The most well-known example is the standing commitment since 1987 by drug giant Merck to provide the drug ivermectin for river blindness (onchocerciasis) wherever it is needed. By working with communities, governments, NGOs and development agencies, the program has treated over 700 million people and has succeeded in eliminating the disease in several African and Latin American countries [].

The road ahead

An exciting new approach to alleviating and eliminating the suffering caused by NTDs lies in product development partnerships (PDPs), which match funding agencies, such as the Gates Foundation or the government, with academic research labs that will develop treatments, diagnostics, and vaccines, as well as with pharmaceutical companies that have the ability to perfect, manufacture, and distribute these products. PDPs for the “big three” diseases of HIV, malaria and TB are well established (e.g., International AIDS Vaccine Initiative, Medicines for Malaria Venture, Global Alliance for TB Drug Development). NTD-specific PDPs such as the Human Hookworm Vaccine Institute and The Drugs for Neglected Diseases initiative have been set up and are making strides. Notably, the Institute for OneWorld Health, in collaboration with the TDR, has successfully brought an intramuscular injection drug for visceral leishmaniasis to market in developing countries []. Another innovative mechanism to encourage companies that make and market medical technologies is the priority review voucher []. As an incentive to bringing drugs and vaccines for NTDs to market, a company would be entitled to tax credits, and a speedier FDA approval process (shortened by about one year) for another, more profitable product. This idea, first proposed by economists and public health professionals at Duke University, was introduced to lawmakers by a bipartisan Senate coalition and implemented in 2008; it remains to be seen whether the incentives are powerful enough.

After decades of neglect, it seems the time for a new focus on NTDs may finally be at hand. One sign that the NTDs are beginning to step into the scientific limelight is the launch of an NTD-specific journal, PLoS NTDs, from a well-respected publisher. It is becoming more widely recognized that these diseases undermine human rights, global security, and prosperity. Successes so far show the way for all sectors of society: for the general public, to keep up the pressure for increased support of NTD funding; for universities, to train and nurture NTD researchers; for scientists and public health workers, to address these diseases; for companies and entrepreneurs, to seek out public-private PDPs and to pursue NTD-related incentives that have recently emerged. With three billion people at risk and over one billion infected, the world cannot endure the neglect any longer.

– Karolina Maciag is at Harvard Medical School/MIT-HST. Jason Zhang is at Harvard Medical School.

Both are members of Universities Allied for Essential Medicines, an international nonprofit organization of university students that seeks to ensure that academic research is responsive and accessible to the world’s population.

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