Treatment: Visceral Leishmaniasis

Visceral leishmaniasis (VL), also known as kala-azar, black fever, and Dumdum fever,[1]:426 is the most severe form of leishmaniasis. Leishmaniasis is a disease caused by protozoan parasites of the Leishmania genus. This disease is the second-largest parasitic killer in the world (aftermalaria), responsible for an estimated 500,000 cases each year worldwide.[2] The parasite migrates to the internal organs such as liver, spleen (hence 'visceral') and bone marrow, and, if left untreated, will almost always result in the death of the host. Signs and symptoms include fever, weight loss,mucosal ulcers, fatigue, anemia and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization(WHO), is the emerging problem of HIV/VL co-infection.[3] General Considerations Severe anemia should be corrected by blood transfusion, and other comorbid conditions should be managed promptly. Treatment of VL is complex, as the optimal drug, dosage, and duration vary with the endemic region. In spite of completing recommended treatment, some patients experience relapse (most often within 6 months), and prolonged follow-up is recommended. A pentavalent antimonial is the drug of choice in most endemic regions of the world, but there is widespread resistance to antimony in the Indian state of Bihar, where either amphotericin B (AmB) deoxycholate or miltefosine is preferred. Dose requirements for AmB are lower in India than in the Americas, Africa, or the Mediterranean region. In Mediterranean countries, where cost is seldom an issue, liposomal AmB is the drug of choice. In immunocompetent patients, relapses are uncommon with AmB in its deoxycholate and lipid formulations. Antileishmanial therapy has recently evolved as new drugs and delivery systems have become available and resistance to antimonial compounds has emerged. Except for AmB (deoxycholate and lipid formulations), antileishmanial drugs are available in the United States only from the Centers for Disease Control and Prevention. Pentavalent Antimonial Compounds Two pentavalent antimonial (SbV) preparations are available: sodium stibogluconate (100 mg of SbV/mL) and meglumine antimonate (85 mg of SbV/mL). The daily dose is 20 mg/kg by rapid IV infusion or IM injection, and therapy continues for 2830 days. Cure rates exceed 90% in Africa, the Americas, and most of the Old World but are <50% in Bihar, India, as a result of resistance. Adverse reactions to SbV treatment are common and include arthralgia, myalgia, and elevated serum levels of aminotransferases. Electrocardiographic changes are common. Concave ST segment elevation is not significant, but prolongation of QTc to >0.5 s may herald ventricular arrhythmia and sudden death. Chemical pancreatitis is common but usually does not require discontinuation of treatment; severe clinical pancreatitis occurs in immunosuppressed patients. Amphotericin B AmB is currently used as a first-line drug in Bihar. In others parts of the world, it is used when initial antimonial treatment fails. Conventional AmB deoxycholate is administered in doses of

0.751.0 mg/kg on alternate days for a total of 15 infusions. Fever with chills is an almost universal adverse reaction to AmB infusions. Nausea and vomiting are also common, as is thrombophlebitis in the infused veins. Acute toxicities can be minimized by administration of antihistamines like chlorpheniramine and antipyretic agents like acetaminophen before each infusion. AmB can cause renal dysfunction and hypokalemia and in rare instances elicits hypersensitivity reactions, bone marrow suppression, and myocarditis, all of which can be fatal. The several lipid formulations of AmB developed to replace the deoxycholate formulation are preferentially taken up by reticuloendothelial tissues. Because very little free drug is available to cause toxicity, a large amount of drug can be delivered over a short period. Liposomal AmB has been used extensively to treat VL in all parts of the world. With a terminal half-life of 150 h, liposomal AmB can be detected in the liver and spleen of animals for several weeks after a single dose. This is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of VL; the regimen is 3 mg/kg daily on days 15, 14, and 21 (total dose, 21 mg/kg). However, the total dose requirement for different regions of the world varies widely. In Asia, it is 1015 mg/kg; in Africa, 18 mg/kg; and in Mediterranean/American regions, not less than 20 mg/kg. The daily dose is flexible (110 mg/kg). In a study in India, a single dose of 10 mg/kg cured infection in 96% of patients. Adverse effects of liposomal AmB are usually mild and include infusion reactions, backache, and occasional reversible nephrotoxicity. Paromomycin Paromomycin (aminosidine) is an aminocyclitol-aminoglycoside antibiotic with antileishmanial activity. Its mechanism of action against Leishmania has yet to be established. Paromomycin is approved in India for the treatment of VL at an IM dose of 11 mg of base/kg daily for 21 days; this regimen produces a cure rate of 95%. However, the optimal dose has not been established in other endemic regions. Paromomycin is a relatively safe drug, but some patients develop hepatotoxicity, reversible ototoxicity, and (in rare instances) nephrotoxicity and tetany. Miltefosine Miltefosine, an alkylphosphocholine, is the first oral compound approved for the treatment of leishmaniasis. This drug has a long half-life (150200 h); its mechanism of action is not clearly understood. The recommended therapeutic regimens for patients on the Indian subcontinent are a daily dose of 50 mg for 28 days for patients weighing <25 kg, a twice-daily dose of 50 mg for 28 days for patients weighing 25 kg, and 2.5 mg/kg for 28 days for children 211 years of age. These regimens result in a cure rate of 94% in India. Doses in other regions remain to be established. Because of its long half-life, miltefosine is prone to induce resistance in Leishmania. Its adverse effects include mild to moderate vomiting and diarrhea in 40% and 20% of patients, respectively; these reactions usually clear spontaneously after a few days. Rare cases of severe allergic dermatitis, hepatotoxicity, and nephrotoxicity have been reported. Because miltefosine is expensive and is associated with significant adverse events, it is best administered as directly observed therapy to ensure completion of treatment and to minimize the risk of resistance induction. Because miltefosine is teratogenic in rats, its use is contraindicated during pregnancy

and (unless contraceptive measures are strictly adhered to for at least 3 months after treatment) in women of childbearing age. Multidrug Therapy Multidrug therapy for leishmaniasis is likely to be preferred in the future. Its potential advantages in VL include (1) better compliance and lower costs associated with shorter treatment courses and decreased hospitalization, (2) less toxicity due to lower drug doses and/or shorter duration of treatment, and (3) a reduced likelihood that resistance to either agent will develop. Trials of multidrug therapy are under way in Asia and Africa. Prognosis of Treated VL Patients Recovery from VL is quick. Within a week of the start of treatment, defervescence, regression of splenomegaly, weight gain, and recovery of hematologicparameters are evident. With effective treatment, no parasites are recovered from tissue aspirates at the posttreatment evaluation. Continued clinical improvement over 612 months is suggestive of cure. A small percentage of patients (with the exact figure depending on the regimen used) relapse but respond well to treatment with AmB deoxycholate or lipid formulations. VL in the Immunocompromised Host HIV/VL co-infection has been reported from 35 countries. VL behaves as an opportunistic infection in HIV-1-infected patients where both infections are endemic. HIV infection can increase the risk of developing VL severalfold in endemic areas. Co-infected patients usually show the classic signs of VL, but they may present with atypical features due to loss of immunity and involvement of unusual anatomic locations, with, for example, infiltration of the skin, oral mucosa, gastrointestinal tract, lungs, and other organs. Serodiagnostic tests are commonly negative. Parasites can be recovered from unusual sites such as bronchoalveolar lavage fluid and buffy coat. Liposomal AmB is the drug of choice for HIV/VL co-infectionboth for primary treatment and for treatment of relapses. A total dose of 40 mg/kg, administered as 4 mg/kg on days 15, 10, 17, 24, 31, and 38, is considered optimal and is approved by the FDA, but most patients relapse within 1 year. Pentavalent antimonials and AmB deoxycholate can also be used where liposomal AmB is not accessible. Reconstitution of patients' immunity by antiretroviral therapy has led to a dramatic decline in the incidence of co-infection in the Mediterranean basin. In contrast, HIV/VL co-infection is on the rise in African and Asian countries. Ethiopia is worst affected: up to 30% of VL patients are also infected with HIV. Since restoration of the CD4+ T cell count to >200/microL does decrease the frequency of relapse, antiretroviral therapy (in addition to antileishmanial therapy) is a cornerstone for the management of HIV/VL coinfection. Secondary prophylaxis with liposomal AmB has been shown to delay relapses, but no regimen has been established as optimal.