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Kala Azar
Since it first began working with kala azar patients, MSF has treated more than 100,000 people for the disease, which is also known as visceral leishmanaisis. A neglected tropical disease (NTD) spread by the bite of a sand fly, kala azar is fatal if not treated, so it’s fair to say the patients MSF tended to were the better for the care they received. The largest groups have been in Sudan and South Sudan, but MSF has also treated the disease in Ethiopia, Kenya, Somalia, Uganda, India, Bangladesh, Georgia, and Yemen. MSF first encountered kala azar in 1988, when the organization responded to an outbreak of the disease in camps for displaced southern Sudanese in Khartoum. The patients had fled from the war-torn Western Upper Nile region, where, in addition to the misery caused by conflict, the disease was exacting a huge toll in its own right. People were presenting with prolonged fevers, extreme weight loss, anemia, and enlarged spleens, and their mortality rate was alarmingly high. After it became clear what teams were seeing, MSF started specifically targeting kala azar and went on to treat 19,000 patients between 1989 and 1995 in what is now South Sudan. The problem has persisted, however, and it is not contained to one country. Kala azar is in fact endemic in 76 countries, putting approximately 200 million people at risk of infection. The Drugs for Neglected Diseases initiative (DNDi) estimates that there are 400,000 new cases of kala azar each year and that 40,000 die from the disease annually. The disease often affects the poorest populations. Epidemics associated with high mortality are frequent where conditions such as complex emergencies, mass migration, high rates of HIV/AIDS, and poor nutritional status accelerate the development and spread of the disease, and where many patients do not have access to treatment. Though there is no vaccine for kala azar and more research and development is needed to find more effective treatment options, the disease can be treated with therapies that are available today. Treatment can be a severe financial burden for the extremely poor, however, and is often not available in endemic areas. MSF therefore continues to run several projects that treat kala azar, adapting its treatment protocols to the particular strain found in a given area because different strains of the disease predominate in different parts of the world. Additionally, MSF’s Access Campaign, along with DNDi, has consistently lobbied for greater funding and more research and development initiatives to be directed towards kala azar and other NTDs. Contraction and DiagnosisHumans contract kala azar when bitten by sand flies that carry the pathogen L. donovani. Sand flies occupy damp, dark places like soil and tree bark. They usually bite at night. Kala azar outbreaks have often coincided with periods of war and civil unrest. For example, during the Sudanese war in the 1980s and 1990s, people fleeing their homes would sleep in bushes or forests where they were more susceptible to bites from pathogen-carrying sand flies. After an individual is bitten, the incubation period can range from ten days to two years, but it is generally between two and four months. Patients suspected of having kala azar can be tested in a variety of ways. Spleen or bone marrow aspiration is the gold standard method, but aspiration requires acute surgical precision and is not available or feasible in most endemic areas. The rK39 and direct agglutination test (DAT) are serological alternatives that do not require a surgical procedure. The specificity and sensitivity of the tests vary depending on the region. In addition to screening for kala azar, the DAT serves as a diagnostic tool, meaning that it can determine the strength of an immune response and not just whether a patient tests positive or negative. Given that kala azar is almost always fatal if left untreated, false negatives are especially dangerous for patients with the disease. As a result, patients in endemic areas who present with symptoms of kala azar yet test negative should be tested again. Patients co-infected with HIV are more likely to receive false-negatives for kala azar compared to patients who have no co-infections. In general, tests for kala azar strains are less accurate in Africa than they are in India and other areas. Once a doctor diagnoses a patient with kala azar, different treatment options are available (see below). Cured patients may experience post-kala azar dermal leishmaniasis (PKLD), which is a complication of kala azar. PKLD affects 2 percent to 5 percent of cured kala azar patients, and symptoms generally appear 3 to 8 years after the patient finishes treatment for kala azar. The disease starts as a rash around the mouth and then spreads. Severe cases of PKLD can disfigure a patient, but the disease is not fatal and can be treated. Kala Azar TreatmentThe cure rate for treated kala azar patients is high, but the treatments themselves can be costly and toxic. The most available and widely-used treatment options are sodium stibogluconate (SSG), paromomycin (PM), miltefosine (INN), and liposomal amphotericin B (L-AmB). Developed in the 1930's, SSG is an intramuscular injection administered over the course of 30 days. Pentostam and Glucantime are brand name versions of the drug, but generic options are also available. Though SSG has high cure rates, the injections are painful and can be fatally toxic, especially for patients co-infected with HIV. Since the drug must be administered by a medical practitioner, patients must remain in a hospital for the full course of treatment. Resistance to the drug is a growing problem, especially in India, where as many as 65 percent of patients are resistant. Relative to SSG, INN is usually well-tolerated by patients. If used alone, the course of treatment lasts 28 days. However, the drug is often used in combination with other treatments to help avoid drug resistance. Pregnant women should not take INN, and the drug is less effective in HIV co-infected patients. PM is an antibiotic that was originally developed to fight cutaneous leishmaniasis. Clinical trials during the 1990s found the antibiotic to be effective in treating its sister disease, kala azar, as well. For kala azar patients, PM is administered intramuscularly for 21 days. It is the cheapest treatment option available. L-AmB (which is marketed by Gilead as AmBisome) is considered the fastest and safest option, but it is also the most expensive. It can be administered over a course of five injections, and a single shot has also proven to be equally efficacious and safe. Given L-AmB’s relatively high price, it is often used as a back-up option if another treatment option first fails. For already impoverished patients afflicted with the disease, treatment can be a significant financial burden. According to a report from OneWorld Health, 87 percent of kala azar patients need to take out loans to pay for treatment. In addition to assuming debt, households reduce their budgets for food, which makes them more susceptible to malnutrition and other diseases. When including the cost of missed work days to receive treatment, a complete course of treatment generally costs 75 percent of the average spent on a family member in a year. Currently, there is no available vaccine for kala azar. In February 2012 a potential vaccine for kala azar began phase one of its clinical trial. Because individuals infected with kala azar can develop resistance to current treatment options, a vaccine would be far more effective in limiting deaths by kala azar.
South SudanOver the past two decades, protracted epidemics in what is now South Sudan have shown that kala azar can cause astonishingly high mortality and infection rates. The epidemiology of these outbreaks has been shaped and enabled by years of armed conflict and the complex humanitarian emergencies that ensued. These include the mass displacement of the population, widespread malnutrition, the absence of health services and infrastructure, and, more recently, an influx of non-immune returnees. The most recent epidemic wave hit South Sudan’s Jonglei and Upper Nile states in 2009 and 2010; through the middle of 2011 more than 10,000 cases were treated (4,500 of them by MSF). This latest outbreak is considered to be the beginning of a multiyear epidemic wave that tends to last three to five years and to occur every eight to ten years. In 2011 and into 2012, case numbers have remained high and the epidemic area has expanded geographically to other areas. In 2002, MSF teams in South Sudan began implementing a combination treatment that involved 17 days of SSG (pentavalent antimony) and PM. This combination regimen has recently been officially adopted by South Sudan as the first-line regimen, a decision that was influenced by DNDi-sponsored multi-country studies of its efficacy and the recommendations of WHO Expert Committee’s. Previously, treatment with SSG monotherapy had taken 30 days. The shorter treatment duration reduces the burden on patients and staff and frees up space in the congested programs, although severely ill, pregnant, and elderly patients, who do not respond as well to SSG, are given L-AmB. MSF’s strategic response to the epidemic has been to decentralize diagnostic and treatment services. This improves access, facilitates early diagnosis and treatment and thereby saves more lives. Even with decentralized services, however, many patients still have to walk for days to reach a treatment facility in a country that is largely without a functional health system, passable roads or basic services. South AsiaIn South Asia, kala azar has a relatively milder presentation than in East Africa and is more sensitive to drugs other than antimonials. In 2005, the governments of Bangladesh, India and Nepal, supported by the WHO, joined forces and presented an ambitious plan to eliminate the disease from the region by 2015. To be feasible, this will require substantial and sustained action. MSF works in the areas with the highest kala azar prevalences in India (Bihar State) and Bangladesh (Mymensingh district). Prior to MSF’s involvement, few people had access to kala azar care in these areas. Treatment was expensive and it required more than 30 days of hospitalization and painful daily injections of SSG or infusions of conventional amphotericin B, which is toxic. Over the past five years, MSF teams in India treated more than 8,000 kala azar patients with a short-course regimen of L-AmB, many of them as outpatients, with an initial cure rate over 98 percent. In Bangladesh, MSF’s strategy combines active case finding using digital mapping and spatial risk factor analysis and treatment based on three doses of L-AmB. The initial cure rate is 99.6 percent, and the final cure rate at six months is 98.6 percent. In both places, MSF is working with DNDi in hopes of making treatment more streamlined and efficacious for patients. Together with DNDi, MSF will soon start clinical studies that evaluate the effectiveness, pharmacovigilance, feasibility, and cost-effectiveness of different short-course regimens involving liposomal amphotericin B, miltefosine, and a combination regimen of miltefosine and paromomycin (for more specifics on these regimens, see MSF’s report, Fighting Neglect). The WHO is conducting trials on different treatment protocols as well, building on past recommendations that the national programs in India, Bangladesh and Nepal have not yet implemented, relying instead on miltefosine monotherapy as first-line treatment in their national elimination guidelines. Despite its convenience as an oral treatment, however, miltefosine is not the ideal drug. It requires 28 days of treatment, and it is teratogenic, and therefore contra-indicated in pregnancy and unusable in women of child bearing age without strict contraception up to four months after treatment. Because of its long half-life, the drug, when given as a monotherapy, can also lead to drug resistance, especially if adherence is poor. Co-InfectionWherever it appears, kala azar is especially difficult to detect and treat in patients co-infected with HIV. The two diseases also influence each other to the detriment of patients. HIV patients are more susceptible to developing kala azar, and kala azar accelerates the onset of full-blown AIDS. Both diseases weaken the immune system. Treatment failure for co-infected patients is high, regardless of the drugs used. Patients must receive antiretroviral therapy in addition to kala azar treatment in order to survive. Additionally, the presence of co-infected patients can worsen the scale of kala azar epidemics, because their blood harbors numerous parasites and thus becomes a source of infection for the insect vector. Future of Kala Azar In early 2012, MSF released a report about NTDs entitled “Fatal Neglect.” In the section about kala azar, MSF made the following recommendations:
FOR SOUTH ASIA To move in this direction, MSF calls upon:
Eliminating kala azar in South Asia is a feasible goal that was recently endorsed once more by WHO. The required tools are there—a very good RDT, a highly effective drug (even as singledose), vector control and a political commitment expressed on paper. The next step is to tap this potential and make it reality. To this end, MSF calls upon:
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