A review of clinical trials of treatments for visceral leishmaniasis in the Indian subcontinent (India, Bangladesh and Nepal)

. Abstract India, Bangladesh and Nepal share nearly 60% of the global burden of the 500,000 annual cases of visceral leishmaniasis (VL, kala-azar). In 2005, the three countries and the World Health Organization (WHO) signed an agreement to eliminate VL as a public health problem from this region by 2015. Objectives To conduct a review of clinical trials of the treatment of VL in India, Bangladesh and Nepal, in order to contribute to the evidence base for the treatment options to be used in the VL elimination programme. Methods We searched PubMed and trial registry databases and contacted clinical investigators to identify published and unpublished comparative, non-comparative and dose-finding trials of amphotericin deoxycholate or liposomal (AmBisome®), miltefosine, paromomycin, sodium stibogluconate and paromomycin + sodium stibogluconate for the treatment of VL in the three countries. Efficacy evaluation was based on final cure at six months of follow up or longer. We reviewed reported serious adverse effects or adverse effects and laboratory changes. The methodological quality of studies was assessed. Six-month success rates were recalculated with 95% confidence intervals (95%CI) on both an intention-to-treat (ITT) and a per-protocol (PP) basis. Relative risks (RR, fixed effect) with 95%CI for failure were calculated for comparative studies. Main results Twenty-three (23) clinical trials enrolling 5,730 patients met the inclusion criteria: 11 comparative, four non-comparative, eight dose-finding. Both plain and liposomal amphotericin B (AmBisome®) were effective in these trials. Miltefosine is as effective as amphotericin B and is the only drug that has been tested in a Phase 4 study; in these conditions, effectiveness was lower than efficacy. Paromomycin is effective both alone and combined with sodium stibogluconate, and was shown not to be different from amphotericin B using a non-inferiority trial design. Sodium stibogluconate is lost to parasite resistance in Bihar; recent data from other areas were not available. The major adverse events were cardiotoxicity with sodium stibogluconate; ototoxicity and nephrotoxicity for paromomycin; vomiting and diarrhoea for miltefosine; nephrotoxicity, vomiting and diarrhoea for amphotericin B deoxycholate and infusion-related fever and chills with AmBisome. Conclusions AmBisome, miltefosine and paromomycin are effective options for treatment of VL in the Indian subcontinent. Other factors, such as costs, and practicalities of care and delivery need to be considered for policy decisions. The majority of available evidence was from Bihar, India with very limited evidence from Bangladesh and Nepal, except on sodium stibogluconate. More studies are needed in these countries to test the efficacy, safety and effectiveness of the various treatment options.