Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 49, Num. 1, 2003, pp. 29-30

Journal of Postgraduate Medicine, Vol. 49, No. 1, Jan-March, 2003, pp. 29-30

Symposium

Indian Kala-azar - Better Tools Needed for Diagnosis and Treatment

Sundar S

Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, India.

Code Number: jp03007

In India, kala-azar (Visceral leishmaniasis; VL) affects millions of people, and the state of Bihar accounts for nearly 90% cases, followed by West Bengal and Eastern Uttar Pradesh. Neighboring countries like Nepal (Terai region) and Bangladesh also report a significant number of cases with VL. Ever since the first reports from North Bihar in the early seventies, there has been a continuous occurrence of the disease with two big epidemics in 1977-78 and 1992-93. Most of the affected population is very poor and illiterate and not aware of the preventive measures. These patients cannot afford expensive diagnosis or treatment.

Demonstration of parasites is the most reliable and conventional method for diagnosing VL. The parasite is commonly found in the splenic or bone marrow aspirate and in the buffy coat of peripheral blood (in HIV co-infection). The sensitivity of splenic aspirate smear is more than 95% and is regarded as the gold standard for the diagnosis of Kala-azar.1 Splenic aspiration carries the risk of severe haemorrhage. The sensitivity of bone marrow smear, the other dragnostic option, is only about 60-85% and the procedure is quite painful. Although several serodiagnostic tests have been developed e.g. ELISA, Indirect fluorescent antibody test; none is in practice because of drawbacks like high cost, need for electricity, complicated technical procedures and unsatisfactory specificity and sensitivity.¹ Direct agglutination test is a cheap, sensitive and specific test and is popular in Africa, but it is associated with drawbacks like batch to batch variation, instability of the antigen, need for incubation and a cumbersome procedure, and thus is not popular in India.¹ A rapid immunochromatographic test based on a 39 aminoacid antigen found in the kinesine region of amastigotes of L chagasi, has recently been developed and is cheap, easy to use, requires no equipment, and has high sensitivity and specificity.² However, like other antibody based tests, it remains positive for long periods after cure, and cannot be used for predicting cure or in relapses. In several studies from the Indian subcontinent, the strip test was 100% sensitive and 93-98% specific.^2,3 Though with a few limitations, rK39 strip test is a very useful diagnostic modality in the field conditions and is being applied increasingly in the Indian subcontinent. Antigen detection is more specific than antibody- based immunodiagnostic tests. Recently, a new latex agglutination test (KATEX) has been developed to detect leishmanial antigen in the urine of patients with kala-azar.⁴ Evaluation of this test is currently underway in India, Sudan, Nepal and Brazil. DNA detection using polymerase chain reaction has also been developed by many laboratories with a high level of accuracy. Unfortunately none of these new tools are field friendly and commercially available.

Treatment of VL has been based on pentavalent antimonial compounds (Sb) for more than 50 years. Until about two decades ago, a small dose of Sb (10 mg/kg for 6-10 days) cured most patients, however, there has been growing refractoriness to this drug in recent years, and in most severely affected VL regions of Bihar, Sb is able to cure only one- third of the patients even when 6-8 times higher dose is used.⁵ Emergence of Sb resistant strains of L donovani, which require 3-5 times higher amount of Sb for similar killing the parasites, is a reality and alternative drugs are urgently needed.⁵ Pentamidine, though reported to be highly effective initially, is now able to cure only ~70% patients, and is highly toxic including a dreaded side-effect i.e. insulin dependent diabetes mellitus. Because of these reasons, its use has been abandoned in India.

The antifungal amphotericin B (AB), a polyene antibiotic, has significant antileishmanial activity and is used for treatment of VL in the Sb-refractory regions of India with excellent results.⁶ In doses of 0.75 mg to 1 mg/kg for 15 to 20 infusions, it cures nearly 100% patients. It is also a toxic drug, and moderate to severe infusion-reactions like fever with rigor and chills are common. Occasionally serious side effects like refractory hypokalemia, nephropathy, myocarditis and death might occur. However, it remains the most important antileishmanial drug for Sb-refractory regions, and has been recommended as first line drug for these areas by the Indian National Expert Committee.⁷ Need for hospitalisation for prolonged periods, high cost, requirement of close monitoring and high incidence of adverse events (occasionally serious) are important hindrances in the use of amphotericin B and these have prevented its usage at the primary health care level in Bihar.

To improve the tolerance and widen the narrow therapeutic window, lipid formulations of AB have been developed. These are taken up by the macrophages and very little free drug is available. This has led to a markedly improved toxicity profile and it has become possible to deliver a large quantity of AB over a short time. Three formulations are commercially available; first of these to be used in India was amphotericin B lipid complex (ABLC; Abelcet). Through several studies it was demonstrated that successful treatment of VL could be done using a total dose of 10-15 mg/kg administered over 5 days.⁸ No significant side effects were noted. Liposomal AB (AmBisome) was next to be evaluated, a total dose of 3.75, 7.5 and 15.0 mg/kg delivered over five consecutive days, cured 89%, 93%, and 97%, respectively.⁹ In another study with this drug, a single total dose (5 mg) infusion of AmBisome cured 91% patients.¹⁰ Amongst all lipid ABs, AmBisome has the best safety profile, and only minor side effects in small proportion of patients were noted. Application of single dose treatment makes it possible to treat large number of patients over a very short time with minimum hospital costs. Unfortunately because of their extremely high cost, most deserving and needy patients are deprived of these highly attractive drugs. An indigenous cheaper liposomal preparation of AB has been developed at KEM Hospital by Dr NA Kshirsagar, but commercial-scale availability is yet to be ensured for this very promising compound.

An aminoglycoside, paromomycin (PA), has been combined with antimony or used alone in the treatment of VL with good results. In a phase II study, daily intramuscular injections of paromomycin alone in a dose of 16 mg/kg for 21 days cured 93% patients.¹¹ Though phase II studies were done several years ago, final phase III trials could not be done as the only manufacturer Pharmacia stopped production of PA. Now its production has been started by another company and phase III trials are expected to commence soon. This drug could be an ideal replacement for Sb as a first line drug.

Oral drugs have obvious advantages over injectibles, and several oral formulations like allopurinol, ketoconazole, fluconazole and atovaquone have been tested, but without much success. Sitamaquine (WR6026) and miltefosine are two promising oral antileishmanial compounds. In a Kenyan trial, sitamaquine at a dose of 1 mg/kg/day for 4 weeks cured 4 of 8 (50%) patients.¹² But recently a report from Brazil showed its relatively poor efficacy compounded with nephrotoxicity. Trials are underway in India to evaluate this compound. Miltefosine, an alkyl phospholipids, developed as an antitumor agent, is the first oral compound which has been successfully developed in India for the treatment of VL. Several studies with oral miltefosine (10, 50 mg capsules, Zentaris AG, Germany), led to the following conclusions i) A daily dose of 100-150 mg for four weeks cured >95% patients. ii) Mild to moderate GI side-effects like vomiting is seen in ~40% patients, and iii) mild diarrhoea in 15-20% patients.19,20 Miltefosine has recently been approved in India for the treatment of VL in adults and recommended daily dose is 100 mg for adults weighing more than 25 kg (50 mg for those with <25 kg weight; ~2.5 mg/kg) for four weeks.^13,14 Since L donovani has acquired resistance to several antileishmanial compounds and limited experience with miltefosine in HIV co-infected VL patients indicate appearance of resistance to miltefosine as well, it is important to devise strategies to protect the newly developed drugs from loosing their efficacy in the same way as that of Sb or pentamidine. Combination chemotherapy with multiple drugs, as used in malaria or tuberculosis, needs to be tested and brought to practice if the life and utility of the new drugs are to be prolonged.

References

1. Sundar S, Rai M. Laboratory Diagnosis of Visceral Leishmaniasis. Clin Diag Lab Immunol 2002;9:951-8.
2. Sundar S, Reed SG, Singh VP, Kumar PCK, Murrary HW. Rapid accurate field diagnosis of visceral leishmaniasis. Lancet 1998;351:563-5.
3. Bern C, Jha SN, Joshi AB, Thakur GD, Bista MB. Use of the recombinant k39 dipstick test and the direct agglutination test in a setting endemic for visceral leishmaniasis in Nepal. Am J Trop Med Hyg 2000;63:153-7.
4. Attar ZJ, Chance ML, el-Safi S, Carney J, Azazy A, El-Hadi M, et al. Latex agglutination test for detection of urinary antigens in visceral leishmaniasis. Acta Trop 2001;78:11-6.
5. Sundar S. Drug Resistance in Indian visceral leishmaniasis. Trop Med Int Health 2001;6:849-54.
6. Mishra M, Singh MP, Choudhury D, Singh VP, Khan AP. Amphotericin B for second line treatment of Indian kala-azar (letter). Lancet 1991;37:926.
7. Minutes of the expert group meeting on drug therapy in leishmaniasis held on 29 August 2000. Indian Council of Medical Research, New Delhi.
8. Sundar S, Agrawal NK, Sinha PR, Horwith G, Murray HW. Cure with short-course, low dose amphotericin B lipid complex therapy for Antimony-unresponsive visceral leishmaniasis. Ann Int Med 1997;127:133-7.
9. Sundar S, Jha TK, Thakur CP, Mishra M, Singh VR, Buffels R. Low dose liposomal amphotericin B in refractory Indian visceral leishmaniasis-a multicentre study. Am J Trop Med Hyg 2002;66:143-6.
10. Sundar S, Agrawal G, Rai M, Makharia MK, Murray HW. Treatment of Indian visceral leishmaniasis with single or daily infusion of low dose liposomal amphotericin B:randomised trial. BMJ 2001;323:419-22.
11. Jha TK, Olliaro P, Thakur CP, Kanyok TP, Singhania BL, Singh IJ, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 1998;316:1200-5.
12. Sherwood JA, Gachihi GS, Muigai RK, Skillman DR, Mugo M, Rashid JR, et al. Phase 2 efficacy trial of an oral 8-aminoquinoline (WR6026) for treatment of visceral leishmaniasis. Clin Infect Dis 1994;19:1034-9.
13. Sundar S, Rosenkiamer F, Makharia MK, Mandal AK, Voss A, Hilgard P, Murray HW. Trial of miltefosine for visceral leishmaniasis. Lancet 1998;352:1821-4.
14. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, et al. Oral miltefosine for indian leishmanisis. N Engl J Med 2002;347:1739-46.

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