Treatment of ACL with alternative regimens with meglumine antimoniate: an old solution to an old problem, says Dr. Armando Schubach

INIs experience, currently coordinated by Dr. Maria Inês Fernandes Pimentel, and other authors, both in Brazil and Latin America, has shown good results, even in patients with more than one lesion

Since 1914 antimonials have been used worldwide for the treatment of all forms of leishmaniasis. In the 1940s, the trivalent antimonials, poorly tolerated by patients, were replaced by pentavalent antimonials. Topical paromomycin, cryotherapy, thermotherapy and intralesional pentavalent antimonials have been used for decades to treat cutaneous leishmaniasis (CL) in the Old World where there is no mucosal form of leishmaniasis (ML). In the 1980s, based on successful reports of intralesional treatment in the Middle East, intralesional meglumine antimoniate (IL-MA) was introduced at the Evandro Chagas National Institute of Infectology of the Oswaldo Cruz Foundation (INI/Fiocruz), Rio de January, by Dr Manoel Paes de Oliveira Neto. Initially, to treat patients unable to receive conventional treatment; later, its use was extended to a larger number of patients who were followed for a long time without the development of ML.

In Brazil, the current treatment for American tegumentary leishmaniasis (ATL) is held with one of the three medicines available from the Ministry of Health (MS): meglumine antimoniate, amphotericin B, in the liposomal or deoxycholate presentation, or isethionate of pentamidine, injectable options, which present high toxicity with need of handling of adverse effects and monitoring of the treatment by clinical, laboratory and electrocardiographic examination. According to the infectious diseases physician, Master in Tropical Medicine, Ph.D. in Parasitic Biology, researcher at the National Institute of Infectology Evandro Chagas (INI)/Oswaldo Cruz Foundation (Fiocruz), Dr. Armando Schubach, a matter of concern to the Ministry is the lethality, about 0.5%, reported in cases of ACL in recent years. Since it is not a lethal disease, it is possible that some of these deaths are related to treatment, which is done with potentially toxic drugs and without adequate monitoring, he says. Across the country, ACL treatment is usually performed in basic health units, characterized by the lack of resources and operational difficulties for the management of comorbidities, monitoring of adverse effects and use of second-line drugs such as amphotericin B and pentamidine. Second-line drug treatment is often only available at centers located far from endemic areas, forcing patients to move away from their places of residence and work during the treatment period. Under such conditions, simple, practical and safe therapeutic regimens such as IL-MA are desirable. Therefore, primary health care services must be able to perform it. Unfortunately, this training process has been slow.

In 2010, the World Health Organization (WHO) recognized that CL is not a lethal disease, that serious complications are rare and that the risk of progression to the mucosal form is low. Therefore, its treatment should not jeopardize the lives of patients and, as first choice, should be local, less toxic treatments. In 2013, the Pan American Health Organization (PAHO) also began to recommend intralesional treatment and emphasized the need to incorporate scientific data produced in each country into national control programs. Since 2017, the Ministry of Health introduced IL-MA treatment in Brazil and adopted the technique developed at INI, with minor adaptations to PAHO recommendations: indication for single lesions less than 3 cm in diameter and not located in the head or periarticular regions. Although used for over thirty years, only in December 2016, the technique developed at INI was described and published in the Journal of the Brazilian Society of Tropical Medicine (RSBMT).

According to Dr. Schubach, until recently, the greatest experience with IL-MA treatment had been developed at the INI/Fiocruz, Rio de Janeiro. For more than thirty years, successful use of IL-MA has been reported, including in elderly patients and patients with contraindication, poor response or reactivation after treatment with systemic MA. Aiming to produce new scientific evidence, the treatment with intralesional meglumine antimoniate was first applied by Dr. Maria Cristina de Oliveira Duque in a series of patients with CL attended at a health post, located in the municipality of Timóteo (MG). The efficacy found (90%) was similar to that observed with systemic treatment in the same region, with no patient needing to discontinue treatment due to adverse effects. The patients underwent a 1-year follow up without reactivation of cutaneous lesions nor evolution to ML.

In recent years, another Fiocruz/MG research group, coordinated by Dr. Glaucia Fernandes Cota, has been contributing to the production of scientific evidence related to IL-MA treatment. Systematic reviews on spontaneous healing and on the efficacy of intralesional treatment, a proposal for standardization of the IL-MA application technique, a series of cases and an uncontrolled clinical trial have been published. Researchers from other Latin American countries have also published case series and clinical trials with IL-MA treatment.

A multicenter clinical trial coordinated by Dr Marcelo Rosandiski Lyra of INI, which compares IL-MA with systemic MA at the dose of 20 mg Sb⁵⁺/kg/day, is underway in Brazil, with the support of the Ministry of Health and PAHO. According to Dr. Schubach this essay may give an overview of the effectiveness of IL-AM in different regions of the Country. Another important point is that, certainly, the treatment regimen with IL-MA developed in the INI is not definitive, there being scope for variations of the technique and individual preferences, as well as for the improvement of the method, he says. Still according to the researcher, among the points that can be improved are the number, size and location of the lesions, the need for prior anesthesia, the minimum effective volume of MA, maximum volume per session, the interval between infiltrations, more adequate conduct if no epithelialization is observed after the third infusion (observe without treatment or continue until epithelization), among others.

Currently, there is no way to predict which patient will be permanently cured, which will present reactivation of cutaneous lesions and which will evolve to the mucosal form. The arguments that the spontaneous cure of cutaneous lesions or the use of subdoses and local treatments could be blamed for the poor evolution of the disease, are losing support in the face of contrary evidence resulting from the long-term follow-up of patients with spontaneous cure or those treated with MA in low doses, systemically or IL, says Dr. Schubach. It is believed that more than half of the reactivations and changes in ML occur within two years after initial treatment. Thus, it is recommended that patients with ACL be followed for at least two years after treatment or spontaneous cure. All patients should be advised to seek care in the event of late skin or mucous lesions.

In Brazil, MA is the drug of choice for most cases of ACL. Dr. Schubach recalls that although there are regional differences, resistance to antimonials is not a national problem. He explains that in the endemic areas for Leishmania (Viannia) guyanensis, the drug of choice is pentamidine isethionate and that cases of poor response to AM or pentamidine isethionate should be treated with liposomal amphotericin B. Although amphotericin B is an excellent drug, its use is unfeasible in basic health units, because in addition to the high cost, it needs hospital structure and trained personnel, rarely available in the endemic areas. Unfortunately, there is still insufficient data on the efficacy of IL-MA in areas of Leishmania (Viannia) guyanensis nor in areas where resistance to systemic MA has been reported, he laments. The researcher acknowledges that another promising option in a relatively short time frame is oral miltefosine.

Due to the problems associated with conventional treatment with antimonials, a great diversity of alternative treatments, topical or systemic, have been studied. In this sense, Dr. Schubach emphasizes the systemic MA 5 mg Sb⁵⁺/kg/day, continuous or in series of 10 days, with intervals without medication, and oral miltefosine, already having evidence of the efficacy of both in Brazil, besides the intralesional pentamidine isethionate already tested in the Bolivia, and which appeared to be an effective option and with fewer adverse effects than systemically. For him, it is worth a study in Brazil, particularly in areas of Leishmania (Viannia) guyanensis and thermotherapy, another interesting therapeutic option that deserves more studies in Brazil.

Asked about effectiveness, safety, cost-effectiveness and budget impact of treatments, Dr. Schubach argues that under existing conditions for the treatment of CL in basic health units in Brazil, simple, practical, effective and safe therapeutic regimens such as IL-MA are desirable. It is intuitive to say that IL-MA treatment is cost-effective since it uses fewer inputs and drugs and reduces the number and severity of adverse effects. However, studies on the subject are scarce. I can cite a masters thesis on the use of IL-MA in the Bolivian jungle, published in 2019, an ongoing study conducted at INI and another by the Fiocruz/MG group, he concludes.…