NTDs require more recognition, resources to be controlled

Worldwide, neglected tropical diseases have infected hundreds of millions of people, and hundreds of millions more are at risk. Despite these numbers, and the significant morbidity associated with them, they remain a major health problem that has garnered little attention and funding.

“These diseases have a certain set of characteristics,” Peter J. Hotez, MD, PhD, founding dean of the National School for Tropical Medicine at Baylor College of Medicine, and president of the Sabin Vaccine Institute, told Infectious Disease News. “They are typically chronic, disabling infections that have a high prevalence, but disproportionately affect people in extreme poverty. We used to say they only affect developing countries, but there is an increasing burden in the United States and other G-20 countries, as well.”

When the term neglected tropical diseases (NTDs) was first reported in the literature, the list included 13 or 14 diseases, according to Hotez. Now, WHO classifies 17 diseases as NTDs. It also estimates that more than 1 billion people worldwide are affected by these diseases, which are endemic in 149 countries.

Peter J. Hotez, MD, PhD, Baylor
College of Medicine, said that
an estimated 1 billion people
worldwide are affected by NTDs.
Photo courtesy of Hotez PJ

Infectious Disease News discussed NTDs with several experts in the field to identify clinical successes, how much more work must be done, and the challenges to implementing programs that target NTDs.

Widespread problem

In 2011, nearly 250 million people required treatment for schistosomiasis, but only about 28 million actually received treatment. Similarly, more than 120 million people are infected with lymphatic filariasis, which is a threat for more than 1.4 billion people in 73 countries. In addition, nearly 1 billion children require treatment for a soil-transmitted helminth infection, the most common being ascariasis, trichuriasis and hookworm.

These five diseases, together with trachoma and onchocerciasis, also known as river blindness, comprise a core group of seven NTDs that can be controlled with pills that are for the most part donated and cost just pennies to deliver, even to remote communities. Three of them, lymphatic filariasis, trachoma and onchocerciasis, can potentially be eliminated for good within a 7-year time frame

These NTDs represent a “low-hanging fruit” that can be controlled or eliminated with existing tools, according to Gary Weil, MD, professor of medicine at Washington University. However, NTD intervention programs have not been fully embraced by public health officials and policymakers because higher priority has been given to the “big three” global infectious diseases: HIV/AIDS, tuberculosis and malaria. Several of the Millennium Development Goals have specific health-related targets, but only the big three are mentioned by name. Other infections, including NTDs, are relegated to the category of “other diseases,” according to Hotez.

“Unlike the big three, we have effective treatments for these seven diseases that costs less than 50 cents a person per year,” Weil said in an interview. “The day that this happens for HIV, TB and malaria will be great, but right now, we are already there for these seven NTDs, and that’s exciting.”

Reasons for neglect

With cheap and easy treatments, some may wonder why these diseases are still considered neglected. There are several reasons. The first is that these diseases do not kill people quickly.

“Many people don’t actually know they’re infected and don’t seek treatment,” Alan Fenwick, PhD, OBE, professor of tropical parasitology at Imperial College London, told Infectious Disease News. “Serious symptoms do not show until later in life when it’s too late because the damage to the internal organs has already been done.”

Another reason, Fenwick said, is that these diseases do not typically occur in urban, developed areas. They are endemic in rural, developing areas, and thus, are unknown to many people, particularly decision makers.

Most do not realize that these diseases existed in the United States until about the 1940s, according to James Kazura, MD, director of the Center for Global Health and Diseases and professor of international health, medicine and pathology at Case Western Reserve University.

“These diseases went away because of industrialization and overall improvement of health,” Kazura said. “But the world is quite different now. For a variety of reasons, it will be decades before developing countries reach the degree of economic development that has unwittingly eliminated these diseases in the developed world.”

In addition, the health impact of NTDs is less apparent to the Western world, but it is well known that malaria and TB kill people, including children, especially in sub-Saharan Africa, Kazura said. In addition, HIV also has a significant effect on communities in developed countries, making it closer to home.

“NTDs are not considered Western diseases,” Kazura said. “This is changing, but it’s still an issue. Even for malaria and tuberculosis, two of the big three, the resources are miniscule if you compare them to diseases like diabetes and cancer.”

Schistosomiasis and women

Although schistosomiasis equally affects women and men, this disease can be especially devastating for women. The classic understanding was that Schistosoma haematobium worms lay eggs that migrate into the bladder and are excreted through the urine. However, studies have shown that up to 75% of women who have S. haematobium infection also have eggs in the genital tract, according to Jennifer Downs, MD, MS, assistant professor of medicine at the Center for Global Health in the division of infectious diseases at Weill Cornell Medical College. The eggs migrate through the tissue of the genital tract and can cause damage to the vagina, cervix and the upper reproductive organs.

“This disease is therefore associated with many reproductive symptoms for women, including infertility, bleeding and painful sexual intercourse,” Downs said in an interview. “It is underdiagnosed and undertreated, and it causes a lot of suffering.”

More recently, research has suggested that women with urogenital schistosomiasis also have a higher risk for acquiring HIV, Downs said. In sub-Saharan Africa, increased susceptibility to HIV infection in women with schistosomiasis has been hypothesized to be a major contributor to the HIV epidemic among women.

There are treatment campaigns that target schistosomiasis in sub-Saharan Africa, and WHO recommends treating entire communities in regions where schistosomiasis is highly endemic. However, when the treatment dollars are scarce, many of these campaigns focus on providing medication to school children, Downs said, meaning that women of reproductive age, remain untreated.

Alan Fenwick

Alan Fenwick

“Schistosomiasis is definitely a neglected tropical disease, but it’s even more neglected among women,” Downs said. “In addition, girls often stop going to school earlier than boys, so even when drug treatment campaigns focus on schools, so the burden remains for women.”

Mass drug administration

Lymphatic filariasis can now be treated with one dose of albendazole (Albenza, GlaxoSmithKline) and one dose of ivermectin (Stromectol, Merck). In addition, schistosomiasis can be treated with one dose of praziquantel (Biltricide, Bayer), trachoma can be treated with one dose of azithromycin (Zithromax, Pfizer) and onchocerciasis can be treated with ivermectin. The three soil-transmitted helminth infections can also be treated with a single pill. This is why these seven infections are targeted with mass drug administration (MDA).

According to Hotez, MDA involves treating the population of entire geographic areas, regardless of whether they have symptoms or confirmed infection. For three of the NTDs, lymphatic filariasis, trachoma and onchocerciasis, there is the possibility for elimination through the implementation of MDA. Albendazole, ivermectin, and azithromycin are being donated, indefinitely, by GlaxoSmithKline, Merck and Pfizer, respectively.

To go even further, a “rapid impact” package delivers these medicines, along with treatments for schistosomiasis and the soil-transmitting helminths, as one mass treatment to be delivered to geographic regions where all seven of these diseases pose a problem. The delivery cost is 50 cents a person per year, Hotez said.

“We have done a lot of advocacy for these packages, now through Sabin’s Global Network for NTDs and its END7 campaign,” Hotez said. “With support of the US Agency for International Development, these packages have now been deployed in more than 20 countries.”

“Congress appropriated about $90 million a year for the rapid impact packages, with additional funding coming from the British government. We can potentially eliminate three of the NTDs with the package, and we can knock down the other four with MDA. It’s one of the most cost-effective initiatives in all of global public health.”

The funds currently available are enough to treat about half of the people that need to be treated are many are now being treated on a regular basis, Fenwick said.

“If the drug donations continue and we continue reaching out to people and delivering these treatments, then the net results will be that the diseases disappear,” Fenwick said.

Potential for elimination

Kazura and Weil both said that the World Health Assembly has resolved that lymphatic filariasis should be eliminated as a public health problem by 2020. Some countries are approaching elimination, but there are still some countries that have not even begun MDA.

“In NTDs, the word ‘elimination’ takes on several meanings,” Kazura said. “The first phase is to control the disease and eliminate it as a public health problem, which many countries have done for lymphatic filariasis. The next phase is completely eliminating the infection in an area, being able to stop repeated treatments because the parasite reservoir has been removed so that transmission is interrupted. That’s a higher bar to reach. We are approaching that in some parts of the world for lymphatic filariasis, but not many.”

Weil said onchocerciasis is also now being targeted for elimination. There have long been programs to control the disease and reduce the frequency, but studies have shown that repeated treatment with ivermectin has eliminated the infection completely in some areas, thus making the disease a candidate for global elimination.

There also is an elimination program in place for trachoma, Weil said, but elimination for that disease is defined differently than it is for lymphatic filariasis and onchocerciasis. Trachoma elimination is defined as less than 5% of children having visible evidence of infection.

“If trachoma is reduced to that level, then new cases of blindness will be uncommon,” Weil said. “It’s a high level of control that reduces the disease to an acceptably low level, but not an absolute elimination program.”

Inadequate infrastructure

The tools to combat some of the most devastating of the NTDs are there. MDA has the potential to be successful, but most of the countries where NTDs are a significant problem do not have the infrastructure needed to deliver the drugs to those who need them.

“In Lagos, Nigeria, for example, a large load of drugs may be delivered, but that doesn’t mean everyone who needs the medication will receive it,” Weil said. “It’s difficult and expensive to distribute these drugs, and many countries simply don’t have the infrastructure and resources to do this.”

The US and British governments have helped many of the countries, but some countries do not have a sponsor yet and have not begun an MDA program. In many countries, it is difficult to convince the ministries of health that NTDs are a priority.

“When you have many children being born with HIV or dying of malaria, NTDs are low on the totem pole,” Weil said. “They may be sympathetic to the issue, but they often lack the resources and the resolve to tackle it, despite the availability of donated drugs.”

According to Hotez, with the exception of the US and British governments, there has not been widespread funding provided by other G-20 countries for NTD control or elimination. However, this may change in the coming years, and now some G-20 countries are supporting research and development efforts for NTDs, he added. Additional funds are being raised privately through the Ending Neglected Disease (END) Fund, he said.

Kazura said some countries, such as Denmark, Sweden, Italy and Australia, have provided significant funding for NTDs on a relative scale, but not as much as the United States because their economies are not nearly as large.

“The United States has supported training of young scientists in the developing world, and now some of those people are taking on leadership roles in research and implementation of programs for NTDs,” Kazura said. “It has been gratifying to see scientists that are indigenous people. They have a much clearer notion of what the challenges are than someone like me.”

Future goals

For schistosomiasis control, MDA can only control the morbidity and the symptoms, Downs said. To eradicate it completely, there must be access to clean water and education, particularly about using latrines. Two villages in China were able to decrease the incidence of schistosomiasis to 1% by providing households with latrines and piped water, replacing cattle with farm machines, and implementing community-wide interventions.

“It was expensive and intense, but it can be done,” Downs said.

Fenwick said that similar schistosomiasis elimination programs are underway in Zanzibar, Burundi and Rwanda.

In general, there must be improvements to the organizational infrastructure within local ministries of health so that programs, such as MDA, can be implemented. There also must be recognition that control of some of the NTDs can be integrated into control programs for malaria and other diseases.

“Bed nets don’t only prevent malaria, they will also help eliminate lymphatic filariasis,” Kazura said. “We’re trying to get people to take a more holistic view of the way health care interventions are delivered to local communities.”

Hotez and the Sabin Vaccine Institute have collaborated with many global partners to develop low-cost vaccines that will prevent some of the diseases, including schistosomiasis, hookworm, leishmaniasis and Chagas disease. To eliminate some diseases, vaccines are critical either because they cannot be targeted by MDA, or MDA alone may not be sufficient for elimination.

“We are seeing a lot of success with MDA and rapid impact packages,” Hotez said. “Now, we’ve got to scale up the research and make vaccines for these diseases, and work for greater global advocacy against these diseases.” – by Emily Shafer

References:

WHO. Weekly epidemiological record. 2013;88:389-400.

For more information:

Alan Fenwick, PhD, can be reached at afenwick@gmail.com
Peter J. Hotez, MD, PhD, can be reached at: hotez@bcm.edu
Jennifer Downs, MD, can be reached at: jna2002@med.cornell.edu.
James Kazura, MD, can be reached at: jxk14@case.edu
Gary Weil, MD, can be reached at: Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8051, St. Louis, MO 63110.

Disclosure: The researchers report no relevant financial disclosures.



How should the funds devoted to neglected tropical diseases be allocated?

POINT

Funding should focus on implementing programs of control in endemic countries.

Frank O. Richards

Money should be going to implementation of treatment programs as opposed to new research for treatments or vaccines. I’m not a researcher: I consider myself a public health practitioner. Right now, the implementation gap, which is the gap between knowing what works and doing what we know works, is much larger than the knowledge gap. I am much more attuned to closing the implementation gap. We know a lot about what we can do to eliminate NTDs, and we should be doing more of that. NTDs are a very large and diverse group of diseases. My focus is on the group of NTDs that can be controlled or eliminated with mass drug administration programs. These have been largely driven by the generosity of pharmaceutical companies. Several of them provide more free medicines that we have the resources to distribute. We need to take advantage of the large donations to distribute free and safe medications to distribute to the poorest of the poor. The donations have gone a long way toward leveraging new resources and good publicity about NTDs. But I feel as though we’ve fallen short of the funding we need to make the most out of this opportunity. We need to develop the infrastructure to deliver the medicine, along with health education and community engagement, so that everyone is on board with the process. The cost of distributing these medicines is less than 50 cents per treatment, but that is only 10% to 15% of the cost of implementing these programs. The opportunity is there and we need to close the implementation gap.

Frank O. Richards, MD, is director of the River Blindness, Lymphatic Filariasis, Schistosomiasis and Malaria Programs at The Carter Center. Disclosure: Richards reports no relevant financial disclosures.

 

COUNTER

Funding should focus on research for new treatments and vaccines, and for surveillance.

Laurence Buxbaum

It would be great if we had tools available right now to solve our problems, but we don’t. We can’t really roll out programs without more research. If we want a long-term strategy to eliminate NTDs, it will require research for vaccines and also treatments for the diseases that don’t have them. There also needs to be surveillance research so we know where to implement treatment programs. We don’t have a magic bullet.

There are NTDs that have excellent treatments available, such as some worm infections. We also may be able to get rid of river blindness and lymphatic filariasis with treatments that we have now. For other NTDs, however, there isn’t a great system. For leishmaniasis, for example, there is a good oral drug that works well in India, but not in South America. You could use the money to roll out a drug program to treat people in India, and that might be effective. But to be effective, there needs to be persistent funding, or you end up accomplishing very little. Vector-borne diseases such as African Sleeping Sickness have come back strongly after programs started by colonial powers disappeared.

To that end, what we really need is a multi-pronged approach in which you implement the established strategies, but also develop new drugs and vaccines to roll out for the next stage. It’s short-sighted to put your money into one thing, unless there is a definitive solution. There are some other diseases, like smallpox, which have been eliminated because of the development of a vaccine, and they’re working on that for other diseases. But we can’t get to vaccines for NTDs without the research.

Laurence Buxbaum, MD, PhD, is director of the Laboratory of Parasitology at Philadelphia Research and Educational Foundation, VA Medical Center, and adjunct assistant professor of Infectious Diseases at University of Pennsylvania School of Medicine. Disclosure: Buxbaum reports no relevant financial disclosures.