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Human African Trypanosomiasis (HAT), or, as it’s better known, sleeping sickness, is a parasitic and potentially fatal neglected tropical disease (NTD) transmitted to humans by the tsetse fly. Historically, sleeping sickness has occurred in the poorest rural areas of Africa, where weak health systems and political instability make disease surveillance and management difficult. Seventeen sub-Saharan African countries reported cases of sleeping sickness to the World Health Organization (WHO) in 2009. The Democratic Republic of Congo (DRC) alone, recorded 74 percent of all cases, and 97 percent of of cases occurred in a total of seven countries. The global estimated caseload for 2012 is 30,000.
Sleeping sickness was long a scourge in Africa, but concerted efforts by the colonial powers last century meant that by the 1960s it was thought to be a plague of the past. However, from the 1970s onwards there was something of a resurgence. Since the 1990s, renewed efforts to actively detect and treat sleeping sickness within specific control programs resulted in a decrease in numbers of reported cases—from more than 26,000 cases in 2000 to fewer than 7,200 cases in 2010. However, “hot spots” still occur in regions of conflict or instability—DRC in particular—and large areas in endemic countries (“blind spots”) are not covered by active surveillance, meaning the real count is likely higher than what’s been recorded.
Nonetheless, decreasing case numbers have spurred speculation that it could be possible to eliminate the disease altogether. But this is far from a given. It is fair to say, however, that for the time being, sleeping sickness can be controlled through widespread screening of at-risk populations and comprehensive treatment of infected patients. Vector control can also help. As with most NTDs, though, the degree to which this can all be effective hinges largely on the amount of resources directed toward the effort.
MSF and HAT/Sleeping Sickness
MSF has been treating patients with sleeping sickness for more than 25 years, since it opened its first project in northern Uganda in 1986. At the beginning of the 1980's, political upheaval in northern Uganda led to the breakdown of health structures and disease control programs. Civil war forced most of the population of the West Nile region, in the country's northwest, to seek refuge in neighboring Sudan, in a region that is now part of South Sudan. Their sanctuary, however, was endemic for sleeping sickness, and beginning in 1985, these refugees, some of them newly infected, started returning to Uganda and resettling on long untilled lands where tsetse flies had proliferated. This led to a major outbreak in the West Nile region. MSF responded by screening almost one million individuals and treating more than 18,000 patients for sleeping sickness from 1987 to 2002.
In July 2007, MSF initiated a sleeping sickness control project in Doruma, in the district of Haut-Uélé in northeastern DRC, near the borders of what is now South Sudan and the Central African Republic (CAR). Screening activities and treatment of infected patients were initiated in the health districts of Doruma and Ango, and started in Bili in January 2009 by a second MSF team.
The prevalence of sleeping sickness averaged 3.6 percent in the villages that could be screened, and 1,570 patients were treated until March 2009, when all activities had to be stopped and the teams evacuated following an attack on the MSF base in Banda by the Lord's Resistance Army militia. The capacities of local public health facilities were too weak for MSF to hand over responsibility for the diagnosis and treatment of the disease, however.
MSF resumed its sleeping sickness activities in Doruma in December 2009 and began them in and around Dingila in September 2010, treating more than 1,800 additional patients in 2010 and 2011.
The complex security environment has severely affected all aspects of sleeping sickness control throughout the region. Moreover, massive displacements of people fleeing the conflict probably contributed to the reemergence of sleeping sickness in Bas-Uélé, and forced MSF (jointly with other partners) to screen refugees from DRC who were seeking sanctuary in South Sudan. Widespread insecurity also interrupted MSF's active screening activities in Batangafo, Central African Republic, in 2011.
In 2012, realizing the need for greater mobility to screen as many targeted populations as possible, MSF implemented a new approach to tackle sleeping sickness—the mobile sleeping sickness team. The international team, made up of a laboratory technician, a medical doctor, two logisticians and a project coordinator, work together with national doctors, nurses, laboratory staff, logisticians, and community outreach workers. The team travels in countries with a high prevalence and/or historical foci of sleeping sickness to implement active village screening and treatment, along with training, surveillance, and advocacy. Having a mobile team means that people who are too old or too sick to reach an MSF clinic can still be screened and addressed. To date, MSF’s mobile team has worked in CAR, Chad, and Republic of Congo.
By 2012, more than 20 MSF programs in seven countries had screened nearly 3 million people and treated approximately 50,000 patients. Considering the paucity of actors committed to combating this neglected disease, MSF also takes on the responsibility of advocating and lobbying for safe, effective, and accessible diagnostics and treatment. It also participates in and leads clinical research projects that are testing better treatment options. This includes, as noted below, two new diagnostic tests and a new oral treatment.
Right now, MSF is a primary actor in the effort to control sleeping sickness and secure better care for those suffering from it. Prevention efforts such as vector control are crucial to MSF’s efforts to keep sleeping sickness at bay. But for many years, the greatest obstacle to fighting the disease has been the lack of new and better diagnostic tools and medicines.
Transmission and Diagnosis
Sleeping sickness is caused by two sub-species of parasites—Trypanosoma brucei (T.b.) gambiense, which is found in western and central Africa, and T.b. rhodesiense, which is present in eastern and southern Africa. A demarcation line of sorts runs through the Rift Valley.
The most common form of sleeping sickness stems from T.b gambiense. The sickness occurs in two stages. The first stage is marked by fever, headache and joint pain. The disease is relatively easy to treat in the first stage, but the lack of specificity in these symptoms makes the disease difficult to diagnose, which often delays the start of treatment.
The second stage, the neurologic phase, occurs when the parasite crosses the blood-brain barrier and infects the central nervous system. The patient can suffer from confusion and reduced coordination, along with bouts of fatigue punctuated with periods of agitation. The sickness makes it so people cannot stay awake during the day (hence the name) but cannot sleep at night. Their mental faculties deteriorate, and they eventually fall into a coma. Without treatment, the disease is fatal. Even after successful treatment, the neurological phase can lead to chronic sequelae.
West African sleeping sickness progresses slowly compared to its East African counterpart, although it is just as lethal. Patients with the West African strain enter Stage II usually within one to two years following the bite; without treatment, the patient can die within three years. East African sleeping sickness progresses more quickly. The parasite crosses the blood-brain barrier within a few weeks after Stage I, marking the start of Stage II. When the central nervous system is infected by the parasite, mental deterioration and other neurological problems ensue. Without treatment, death occurs within months.
Currently the diagnosis and staging of the disease requires a complicated series of tests, including painful and invasive procedures such as lumbar punctures. These existing tests require trained staff and can be difficult to perform in remote areas where the disease occurs. There is a pressing need for better, simpler, and more easily administered diagnostic tools and algorithms.
For that reason, MSF was excited by the news, released in late 2012, that two new rapid screening tests were expected in 2013. Developed with the support of the Foundation for New Innovative Diagnostics and the Institute of Tropical Medicine Antwerp, the new tests are easy-to-use and do not require cold chain, which means more people at risk of the disease could be screened. Additional tests would still be required to confirm suspected cases, but the new screening tests will remove many of the logistical constraints faced today by mobile sleeping sickness teams.
Treatment options for sleeping sickness are different for Stages I and II. While current treatments offer patients a chance at full recovery, none are ideal. Many are quite old. Some are dangerous, some are difficult to administer, and some are not as effective as they need to be.
For Stage I sleeping sickness, treatment options include pentamidine, which was developed in 1940, and suramin, which was developed in the 1920s. Pentamidine requires seven to ten daily intramuscular injections. Apart from the pain of the injections and occasional bouts of hypotension and hypoglycemia, pentamidine is generally well-tolerated and can even be administered at village level during or following active screening sessions. Suramin is also injected intramuscularly and can cause nausea and an urticarial rash. About 50 percent of patients on suramin will develop adrenal cortical damage, which can occasionally be severe enough to require life-long treatment.
Although pentamidine and suramin are potent options for treating Stage I of sleeping sickness, they cannot treat Stage II, when the disease is more often diagnosed. Melarsoprol, eflornithine, nifurtimox, and nifurtimox-eflornithine are the current treatment contenders for curing Stage II sleeping sickness.
Developed in 1949, melarsoprol is a derivative of arsenic. It requires 10 painful daily intravenous injections that are highly toxic. Often described by patients as “fire in the veins,” the medicine kills approximately one in twenty patients who take it. Additionally, some MSF programs have reported up to a 30 percent treatment failure using the drug.
Eflornithine was developed in 1981 and is primarily used as a second line treatment for West African sleeping sickness. It is far safer than melarsoprol and is effective, but it is also resource-intensive and difficult to administer because it requires complex logistics, trained health staff, 56 intravenous (IV) infusions over a period of 14 days, and constant follow up. When it’s used as a monotherapy, there is also the risk that resistance will develop.
Nifurtimox is an oral drug originally developed to combat Chagas disease in the 1970s. It is sometimes used after melarsoprol relapse and has an efficacy rate of approximately 70 percent. Compared to injections, oral drugs like nifurtimox are easy to administer. But the relatively low efficacy rate makes nifurtimox a less-than-ideal option.
Nifurtimox-eflornithine combination therapy (NECT), which involves the above two drugs used, as the name suggests, in combination, is a recent development in sleeping sickness treatment that simplifies and shortens patient care. NECT was developed through a collaboration of MSF, Epicentre, the Drugs for Neglected Diseases initiative (DNDi), the Swiss Tropical and Public Health Institute (Swiss-TPH) and control programs from most affected countries. It combines oral nifurtimox for 10 days and reduces the number of infusions necessitated by eflornithine treatment from 56 over 2 weeks to 14 over 7 days.
The NECT rollout has been very successful in endemic countries since 2010, with an estimated 60 percent of patients receiving the new combination. Following MSF's review of NECT as a preferred sleeping sickness treatment option, in May 2009, the WHO included NECT in its List of Essential Medicines.
While nifurtimox-eflornithine might be the best treatment option on the market today, it is still complicated to administer and requires close patient monitoring—something frequently unavailable in sub-Saharan Africa. When organizations like MSF are present, this is possible, but the ultimate goal would be for local medical systems to have treatments they can offer in whatever setting patients are located. Concerted efforts are thus needed to bring more innovative drugs to the forefront.
MSF and the Access Challenge
Any new advances or sources of hope must be mitigated by the ongoing concern about a lack of funding and support for efforts to fight the disease. Controlling sleeping sickness is especially difficult given that pharmaceutical companies do not find financial benefit in researching or producing better treatment options for neglected diseases. When the population affected with a certain disease cannot afford to pay high prices for a cure, pharmaceutical companies do not see profit in production.
This has slowed advances in sleeping sickness treatment. Notably, doctors and health organizations welcomed eflornithine as a replacement for toxic melarsoprol when eflornithine was discovered to be a viable treatment for sleeping sickness. Despite the registration of eflornithine in Uganda in 1993 and in other African countries in subsequent years, production was discontinued by the original producer (Marion Merrel Dow, which became Hoechst Marion Roussel) because it was not sufficiently profitable. A search by the WHO and MSF to find a third party producer failed.
This was a wholly unacceptable situation—which was pushed into the realm of the absurd when a cosmetic product containing eflornithine and designed to prevent facial hair was later put on the market. In response, MSF's Campaign for Access to Essential Medicines launched an advocacy effort that helped bring about a five-year agreement from 2001 to 2006 between the WHO and Aventis Pharma. This agreement included adequate production of eflornithine for sleeping sickness, donations of key drugs (pentamidine, melarsoprol, and eflornithine), and significant funding to support sleeping sickness control agreements.
In addition to promoting access to sleeping sickness treatment, MSF has responded to pharmaceutical companies' lack of investment by becoming a forerunner in the discovery of new drug options. MSF and Epicentre, MSF's epidemiological arm, have initiated clinical trials to find better treatment options for sleeping sickness patients. Results of MSF's trials have had a major impact on standard protocol for sleeping sickness treatment.
Within the past decade, MSF's clinical work has advanced sleeping sickness treatment strategies. Working with DNDi, Ministries of Health in DRC and the Republic of Congo, and the Swiss Tropical and Public Health institute, MSF honed in on NECT as the best available treatment option for sleeping sickness. Following the trial's discovery, the NECT rollout in endemic countries has been quick and comprehensive. By the end of 2010, only one in ten patients was receiving melarsoprol. Further study has proven NECT to be very safe and effective.
In December 2012, MSF announced that its programs in CAR and DRC would be taking part in clinical trials for fexinidazole, a new oral treatment option developed with the support of DNDi that is ready for field testing. The hope is that fexinidazole could, in the near future, offer a good alternative to the current multiple infusions required to treat advanced sleeping sickness.
All these efforts, however, could stall if they do not get the support they need. “New, better-adapted tools will help simplify the process, which is good for both patients and medical staff to better tackle the disease burden,” said Dr. Anja De Weggheleire, Medical Coordinator at MSF in Kinshasa, in December 2012. “However, just when a united effort is most needed, national control activities are left under-funded and under-resourced. If this does not urgently change, we could lose the opportunity to diagnose and treat people who are not currently being reached and, worse, we risk a resurgence of the disease.”
One example of the potential consequences: In DRC, which is home to nearly three-quarters of all reported cases, the number of people tested for the disease declined significantly in the latter months of 2012, and in June 2013, the primary stream of external funding for the control program is due to cease flowing. Without control mechanisms in place, the country risks a resurgence of sleeping sickness, as has occurred several times in the past when monitoring significantly decreased, even for just short periods of time. “If sustainable funding is not secured soon, the near future will see us with excellent new tools to tackle sleeping sickness, yet no national activities to implement them,” warned Dr. Manica Balasegaram, Executive Director of the MSF Access Campaign, at the end of 2012.
Challenges to Combating Sleeping Sickness
Global control of sleeping sickness is currently constrained by a lack of simple-to-use diagnostic and treatment tools, high disease prevalence in remote and often insecure contexts, a lack of active surveillance in areas where sleeping sickness is potentially endemic, a lack of skilled human resources in remote endemic areas and shrinking international financing of sleeping sickness programs. MSF is concerned by the current optimism that global elimination of sleeping sickness is feasible. Sustainable elimination will not be possible without improved diagnostic and treatment tools and stronger surveillance systems. Moreover, the current donor policy to integrate sleeping sickness diagnosis and treatment into existing health structures is premature and poses a serious risk of leaving out people who live in places with little or no access to health care. These policies could give rise to a neglect of the most at-risk areas and lead to new outbreaks—as has been the case in the past.
MSF is thus calling for: