Effectiveness Study of Paromomycin IM Injection (PMIM) for the Treatment of Visceral Leishmaniasis (VL) in Bangladesh.

BACKGROUND: This study was conducted in Bangladeshi patients in an outpatient setting to support registration of Paromomycin Intramuscular Injection (PMIM) as a low-cost treatment option in Bangladesh. METHODOLOGY: This Phase IIIb, open-label, multi-center, single-arm trial assessed the efficacy and safety of PMIM administered at 11 mg/kg (paromomycin base) intramuscularly once daily for 21 consecutive days to children and adults with VL in a rural outpatient setting in Bangladesh. Patients ≥5 and ≤55 years were eligible if they had signs and symptoms of VL (intermittent fever, weight loss/decreased appetite, and enlarged spleen), positive rK39 test, and were living in VL-endemic areas. Compliance was the percentage of enrolled patients who received 21 daily injections over no more than 22 days. Efficacy was evaluated by initial clinical response, defined as resolution of fever and reduction of splenomegaly at end of treatment, and final clinical response, defined as the absence of new clinical signs and symptoms of VL 6 months after end of treatment. Safety was assessed by evaluation of adverse events. PRINCIPAL FINDINGS: A total of 120 subjects (49% pediatric) were enrolled. Treatment compliance was 98.3%. Initial clinical response in the Intent-to-Treat population was 98.3%, and final clinical response 6 months after end of treatment was 94.2%. Of the 119 subjects who received ≥1 dose of PMIM, 28.6% reported at least one adverse event. Injection site pain was the most commonly reported adverse event. Reversible renal impairment and/or hearing loss were reported in 2 subjects. CONCLUSIONS/SIGNIFICANCE: PMIM was an effective and safe treatment for VL in Bangladesh. The short treatment duration and lower cost of PMIM compared with other treatment options may make this drug a preferred treatment to be investigated as part of a combination therapy regimen. This study supports the registration of PMIM for use in government health facilities in Bangladesh. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01328457.

Cost-effectiveness analysis of combination therapies for visceral leishmaniasis in the Indian subcontinent.

BACKGROUND: Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost-effective alternative compared to monotherapies. METHODS AND FINDINGS: We assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost-effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range. CONCLUSIONS: Combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available.

Drug combinations for visceral leishmaniasis.

PURPOSE OF REVIEW: Several attempts have been made to combine drugs for treating visceral leishmaniasis, but only recently have effective drugs become available and combinations been tested systematically. RECENT FINDINGS: Sequential treatments with liposomal amphotericin B followed by miltefosine or paromomycin (as short as 7 days), as well as the concomitant administration of miltefosine and paromomycin (for 10 days) are very effective in India (>95%). Sodium stibogluconate plus paromomycin for 17 days is more than 90% effective in East Africa. The shortened combination regimens are cost-effective in India. No combination has been tested so far in Brazil, Nepal and Bangladesh, although studies may be expected in the near future. No cost-effectiveness analysis has been done as yet outside India. SUMMARY: There is evidence of high efficacy and benefits with sequential and co-administration treatments in India. More studies are needed in other endemic areas. Introducing combinations and scaling up their use will be challenging. Experience acquired with malaria may be useful. Proper monitoring of use and effects (efficacy and safety) will be required. Currently there are no options for fixed-dose combination treatments for leishmaniasis.

Cost-effectiveness projections of single and combination therapies for visceral leishmaniasis in Bihar, India.

OBJECTIVES: To assess the cost-effectiveness of current monotherapies and prospective combinations for treating visceral leishmaniasis (VL) in Bihar, India in terms of years of life lost (YLL) averted as well as deaths averted. METHODS: We employed two methods to estimate the number of avertable deaths in our analysis: one using estimated mortality, the other using direct incidence estimates for VL. Costs of care are based on an average private hospital in Bihar, and data on drug costs were obtained both locally and from the World Health Organization. RESULTS: The cost of monotherapies per averted YLL ranged from US$2 for paromomycin in an outpatient setting to US$20-22 for AmBisome at 20 mg/kg. The corresponding costs per death averted ranged from US$53-54 to US$523-527. Combinations ranged US$5-8 per YLL averted and US$124-213 per death averted. CONCLUSION: The available treatments for VL are cost-effective, and our mortality and incidence-based methods produce consistent estimates. The combinations considered here were more cost-effective than most monotherapies. Having multiple treatment options and combining drugs are also likely to reduce drug pressure and prolong the drugs' life-span of effective use.

Anthropometrically derived dosing and drug costing calculations for treating visceral leishmaniasis in Bihar, India.

OBJECTIVE AND METHOD: To estimate drug costs of treating visceral leishmaniasis (VL) based on data on the VL population structure from the high-burden, antimony-resistant area of Northern Bihar, India. RESULTS: Paromomycin is the cheapest option ($7450 to treat 1000 patients). Treating 1000 patients with oral miltefosine would cost $119,250 at the current private market price or $64,383-$75,129 at preferential public sector price depending on the size of the order. With AmBisome it would be $163,600 or $229,500 depending on the dose (10 or 15 mg/kg total). These costs are without considering other direct costs (daily intramuscular injections for 3 weeks for paromomycin; intravenous devices and hospitalization for AmBisome; directly observed treatment if applied for miltefosine) and indirect costs. CONCLUSION: These calculations provide useful basic information for projections.

Progress in the treatment of a neglected infectious disease: visceral leishmaniasis.

Visceral leishmaniasis (kala-azar) is a disseminated intracellular protozoal infection. Most cases (90%) occur in the rural regions of five countries: India, Sudan, Nepal, Bangladesh and Brazil. As with other infectious diseases embedded in high-level poverty, developing and/or delivering new treatments for visceral leishmaniasis had been painfully slow or nonexistent. However, despite persistent unresolved obstacles (e.g., drug affordability), renewed interest in visceral leishmaniasis and numerous successful treatment trials have combined to turn a therapeutic corner in the past 5 years, yielding new alternatives to conventional pentavalent antimony. Advances include the use of low-cost generic pentavalent antimony, rediscovery of amphotericin B, short-course regimens via lipid formulations of amphotericin B, retesting injectible paromyomycin and, of clear-cut importance, identifying miltefosine (Impavido, Zentaris) as the first effective oral therapy for this neglected disease.