Treating cutaneous leishmaniasis by radio-frequency induced heat (RFH) therapy

描述（由申请人提供）：由利什曼原虫属寄生虫引起的感染包括皮肤（CL），粘膜（ML）和内脏利什曼病（VL）。目前有1 200多万人患有利什曼病，每年约有200万新病例，使其成为一个重大的全球健康问题。最近，在美国的犬类以及在伊拉克和阿富汗服役的军队人员中发现了CL。全身五价锑药物，如stiboglusate钠（SSG），是全球范围内推荐的CL治疗方法，但它们是有毒的，并且治疗依从性较差，因为每天注射3周或更长时间。此外，在免疫功能低下的个体中，抗锑治疗与复发有关。我们对安全、易于管理和有效诱导长期治愈的CL的新治疗方法感兴趣。近年来，射频诱导热（RFH）疗法已被用于治疗CL。这种治疗方法在局部麻醉下，将可控和局部的射频送入病变30-60秒。几项短期随访研究（4-5个月）和一项长期随访研究（12个月）涉及在伊拉克感染L. major的美国士兵，发现RFH治疗与全身抗体治疗相当，甚至更好。我们最近发现，RFH治疗对SSG难治性hiv感染患者的CL诱导治愈也是有效的。此外，我们发现RFH治疗可使近98%的免疫功能正常的CL患者在6个月内完全临床治愈，且在长达1年的时间内无复发。这些发现表明，RFH治疗在诱导免疫功能正常和免疫功能低下患者的慢性淋巴细胞白血病的长期治愈方面应该是有效的，因此可能代表一种新的一线治疗方法。然而，需要进行临床试验，以确定治愈率，并确定RFH治疗难以用常规药物治疗的其他利什曼原虫引起的CL的长期疗效，并确定生活在利什曼原虫流行地区的患者的疾病复发风险（如果有的话）。该R34申请的目标是计划一项开放标签III期临床试验来比较长期疗效

DESCRIPTION (provided by applicant): Infections caused by protozoan parasites of the genus Leishmania include cutaneous (CL), mucosal (ML) and visceral leishmaniasis (VL). Over 12 million people are currently suffering from leishmaniasis, and approximately 2 million new cases occur annually, making it a major global health problem. Recently, CL has been seen in canine populations in the US as well as army personnel serving in Iraq and Afghanistan. Systemic pentavalent antimonials such as sodium stibogluconate (SSG) are the recommended treatment for CL world-wide, but they are toxic, and compliance with treatment is poor because daily injections for 3 weeks or longer are required. Furthermore, in immunocompromised individuals antimonial treatment is associated with relapses. We are interested in novel treatments for CL that are safe, easy to administer and effective in inducing long-term cure. Recently, radio-frequency-induced heat (RFH) therapy has been used in the treatment of CL. This treatment delivers controlled and localized radiofrequencies into lesions for 30-60 seconds under local anesthesia. Several short-term follow-up (4-5 months) studies and one long-term follow-up (12 months) study involving US soldiers who were infected with L. major in Iraq found that RFH therapy was comparable, or even better, than systemic antimonial therapy. We recently found that RFH therapy was also effective in inducing cure of CL in HIV-infected patients who were refractory to SSG. Furthermore, we found that RFH therapy induced complete clinical cure in nearly 98% of immunocompetent CL patients by 6 months with no relapses for up to 1 year. These findings suggest that RFH therapy should be effective in inducing long-term cure of CL in immunocompetent as well as immunocompromised patients, and could therefore represent a novel first line of treatment. However, a clinical trial is needed o determine cure rates and establish long-term efficacy of RFH therapy in treatment of CL caused by other Leishmania species that are difficult to treat with conventional drugs, and to determine the risk of disease recurrence (if any) in patients living in Leishmania endemic regions. The goal of this R34 application is to plan an open-label phase III clinical trial to compare the long- term efficacy of RFH therapy versus SSG in the treatment of CL in patients residing in Leishmania endemic regions. We propose to perform this trial in India, Ethiopia, Peru and Guatemala because infections in these regions are caused by different Leishmania species, and they represent clinically diverse forms of CL. This R34 application will allow us to select study team members, identify enrollment sites and local laboratories, and obtain approvals from local regulators and Institutional Review Boards (Aim 1), and to finalize the clinical trial protocol including a statistical analysis plan, data management and safety monitoring plans, and informed consent process and documents (Aim 2). Accomplishing these aims will lay a sound foundation for our multicenter clinical trial. PUBLIC HEALTH RELEVANCE: Cutaneous leishmaniasis is caused by Leishmania parasites. This infection is a global health problem and a neglected tropical disease. This disease has also affected several US Army personnel serving in Iraq and Afghanistan as well as canine populations in the US. Current treatment of CL involves 20 injections of pentavalent antimonial drugs which are toxic and have poor patient compliance. The goal of this proposal is to plan a Phase III open label multicenter clinical trial to compare long-term efficacies of conventional antimonial injection treatment versus a single topical RF-induced heat therapy in treatment of CL in patients living in Leishmania endemic regions of India, Peru, Guatemala and Ethiopia.