Dr. Arun Shah
MD, DCH
KALA-AZAR MEDICAL RESEARCH CENTRE, MUZAFFARPUR

Visceral leishmaniasis a vector born disease occurs in 65 countries and has an incidence of approx 5 lacks cases annually. It is endemic in India, Nepal, Bangladesh, Sudan and Brazil. 80% of Global burden in Indian subcontinent. It continues to be a major public health problem in India especially Bihar and adjoining states. Approx 50% of new cases are children. The global standard for diagnosis remains demonstration of parasites in tissue smear. A rapid immunochromatographic strip test using rk39 antigen already commercially available in market is simple, rapid test and has very high sensitivity and specificity. Though it is an excellent test for making diagnosis of Kalaazar its interpretation should always be made with caution against clinical background of patient. Due to sub clinical infection in endemic zone it may be falsely positive in absence of Kalaazar. Further this test cannot be used in predicting response to therapy or relapse as IgG antibodies persist in blood for long time after successful treatment of infection.

The treatment of Kalaazar is still not satisfactory. The safety, efficacy, affordability and compliance are major issue in successful treatment of VL. Most available drugs need to be given parent rally and require prolonged hospitalization and constant monitoring.

Antimonials compound have historically been the first line of treatment for VL. Emergence of resistance against this important drug since early eighties is a major concern especially in north Bihar (upto 60%). Thus is no longer recommended as first line of drug by national expert committee. However there is high clinical response in neighboring states where it is still recommended as first line of drug. Though relatively inexpensive its use is limited by cardiac toxicity and this requires constant cardiac monitoring. Amphotericin-B has emerged as 1st line drug for antimony unresponsive patients in north Bihar. The dose is .75-1 mg/kg by slow I/V infusion over 4-6 hours on alternate day for 15 doses. Response to treatment is excellent with long term cure rate of almost 100%. Major problem with its use are prolonged hospitalization and infusion related side effects. Introduction of lipid formulation of amphotericin-B is most important development in chemotherapy of VL. Currently three formulation are available: 1. Liposomal amphotericin-B (Ambisome) 2. Amphotericin-B lipid complex (ABLCm Abelect) 3. Amphotericin-B cholesterol emulsion (amphocil/amphomul).

These drugs have been extensively evaluated for treatment of VL and can be successful given for a shorter period of time. Total 15 mg/kg in divided doses is most important determinant in the outcome reaching cure rate close to 100%.

Ambisome a wonder drug with minimal or no side effects however is exorbitantly expensive and thus beyond the reach of common man. Amphomul has similar efficacy and infusion related side effects is same as conventional amphotericin-B. This drug is being manufactured in India, is less expensive. A trial with the molecule with different doses schedule in age group of 18-65 years is already undergoing in few centers in Bihar.

Miltefosine originally developed as antineoplastic agent is first oral anti-leishmanial drug above 2 years of age to be approved and registered in India in 2002. Multicentric trial has shown cure rate of 94% in VL. It is a significant advance in the management of VL eliminating need for parental therapy and hospitalization. Its use however is limited by high cost, GIT symptoms like vomiting and diarrhea and consequent non-compliance. Thus need to be given under close medical supervision as DOT to ensure proper compliance. It is teratogenic drug, cannot be used during pregnancy and women of child bearing age must practice contraception for duration of therapy and 2 months after therapy. Sitamaquin a primaquine analogue is another oral anti-leishmanial drug. Many trials in India and other countries have shown high efficacy but unacceptable side effects especially renal complication. Recently a trial in our center with this drug in different dosage and regimen has been conducted. The initial cure rate at the end of treatment is very high. The final cure rate is awaited. This drug was not tested on children below 16 years of age.

Paromomycin (aminosidine) an aminoglycoside is highly promising anti-leishmanial drug as far as efficacy (94.6%) and safety profile is concerned. The drug has been approved for the use by drug controller of India. A phase 4 study to assess the safety and efficacy of this drug in out patient setting is shortly going to be launched at 7 designated satellite clinics in 1500 patients above 2 year of age in various modules. This drug has potential to be important new first line drug for VL in naïve/resistant cases. It is manufactured in India, thus inexpensive can be given by IM route in dose of 11 mg base/kg body wt for 21 day. Emergence of resistance against Kalaazar drugs is major concern thus combination therapy as in tuberculosis, leprosy and HIV infection has been proposed to prevent emergence of resistance and better compliance. In past combination therapy in field trial has yielded better result e.g., use of antimonials with interferon. A recently conducted trial of combination therapy of single dose of ambisome and miltefosine for shorter period has shown highly encouraging result. Initial clinical and parasitological cure rate is close to 100%. Thus there is need to develop combination regimen of short duration to improve compliance and to protect currently available effective drugs from being rendered ineffective and useless. Considering the burden of disease in poorer section of society it is incumbent upon the government to provide free treatment to these patients.