Problems with the current treatment

Efficacy and safety of available drugs

The pentavalent antimonials have been in use for over 70 years and they continue to be the first choice in many countries, including Colombia, which responds not so much to their benefits but, rather, to the lack of other safe and effective medicines. To compensate for the reduction in healing rates with pentavalent antimonials, the dose was increased (from 10 m/kg/day for 10 days to 20mg/kg/day during 20 or 30 days), with the consequent increase of serious adverse events, which forced to reverse the dose and put a limit (3 amps=15 mg/kg/day approximately).

Efficiency, security, and availability of systemic alternatives

Miltefosine, pentamidine, and amphotericin B have similar efficacy to pentavalent antimonials. The safety profile of miltefosine is better than that of these compounds and its adverse effects are limited to mild to moderate gastrointestinal symptoms. This is the only oral medication available for the treatment of leishmaniasis, which facilitates treatment in children. Pentamidine and amphotericin B are administered parenterally. The volume to be injected and the number of doses used with pentamidine is lower, which improves adherence. These medications are just being included in the management guidelines of some countries and the main inconveniences are their availability and cost.

Variability of results

The effectiveness of pentavalent antimonials is between 45 and 85%. This variability can be due to many circumstances including differences in susceptibility of the different Leishmania species, differences in the host, type of disease, etc. Another important factor is the wide diversity in the criteria to measure efficacy in research and clinical protocols. All these aspects make it difficult to analyze data, draw conclusions, and design unified guides.

Insufficient evidence

The information obtained from patients seen at hospitals in endemic areas is incomplete and of poor quality. The follow-ups are short and more than 80% of the patients do not return to control visits, so the evidence about the actual result of treatment is very poor. The published clinical trials have methodological deficiencies and lack of uniformity in definitions, measurements, and times. In addition, the follow-ups in research protocols are from 6 to 12 months, which allows detecting recurrences in the short term but not relapses in the long term. The recommendation to conduct controlled clinical trials in each country with all drugs seems reasonable but non-realistic given the circumstances and current resources.

Problems for the development of new medications

There are insufficient interest and limited resources in academic institutions and research centers that do not consider leishmaniasis a priority. Besides, the pharmaceutical companies show little interest to develop new anti-leishmanial drugs, especially for the tegumentary form of the disease, for which more than one therapeutic modality is indispensable. On the other hand, government institutions are aware of the needs but do not have the resources nor the infrastructure to undertake the development of therapeutic alternatives.

Also, the patients with leishmaniasis do not have the power or the political import to exert pressure and demand the provision of medicines and, even less, funds for research. Besides, the lack of adequate preclinical models that allow a more accurate screening and evaluation of the activity of new compounds is a problem as well.

Problems with patient care

The people affected by leishmaniasis generally live in remote areas with limited access to health care centers. They are day laborers or cultivate their own small farms, so if they do not work, they do not have an income. To seek medical assistance they must leave their family and work and travel long distances and all this at their own expenses.

Another difficulty is that there is no simple, accurate, safe and economical diagnostic method, so the patient may have to go to the hospital several times to repeat the only available test at this level or assume the costs and delays for more specialized exams. Patients usually have to go two or three times to the health post: first for the initial consultation, then to receive laboratory results and the prescription of the medication, and, finally, to start the treatment when the drug arrives because, in many places, medications are delivered only after the parasitological diagnosis is performed. Therefore, one to six weeks may elapse between the consultation and the start of the treatment.

The care of patients with leishmaniasis is usually provided by young health professionals with no experience in the disease since they are those sent to provide social service in endemic areas. These professionals have a high turnover and there are no education and training programs to teach them.

In some places, Colombia, for example, care is provided by two different entities: One is responsible for diagnosis and the other for treatment and not always there is good coordination between them.

Laboratory tests to control treatment according to official guidelines are not always available in the first level of health care, which is usually where leishmaniasis patients are seen, and this delays the treatment or makes it more expensive since some patients assume the cost to avoid further delays.

Perspectives

The problems related to the therapy are important, but not necessarily the most important. Issues such as accurate diagnosis, accessibility to health services, and long-term follow-up should also be resolved.

All patients must be treated but not all of them have to receive systemic treatment. We must find the method to identify those who can be treated locally versus those who need systemic therapy because they are at risk of developing more severe disease or of disseminating it or having late complications.

The use of two or more simultaneous therapeutic interventions (antileishmanial drugs, physical therapies, immunomodifiers) seems a logical option and more studies should be done to identify the most appropriate ones always in the idea that combined treatments should be the rule from the beginning and not the alternative when monotherapy fails. Local treatment with creams, physical measures or injections seems a reasonable option for a disease affecting the skin and clinical studies should be continued to refine its use.

The increase of cutaneous leishmaniasis in children and women forces us to look for effective, safe, and easy-to-administer therapeutic approaches in these groups. In addition, cleaning, moisturizing, and protecting the ulcer should be an integral and fundamental part of the management of cutaneous leishmaniasis.

The treatment of patients with mucosal leishmaniasis should include the management of sequelae, the recovery of function, the aesthetic remodeling, and the repair of social and family relationships that may have deteriorated as a result of the disease.

The revision and updating of the official guides in each country should be carried out jointly by representatives of the academy, research centers, and health care institutions, as well as the ministries of health, to consider all points of view and make useful, applicable, feasible, and effective decisions.

It is necessary to organize a mechanism to provide advice, counselling, and support in real time to those young professionals working in endemic areas through centers or experts that can help them face those particular situations out of official guidelines and guide them in the use of approved treatments but also in the use of new medicines when appropriate.

An effective follow-up mechanism must be designed for all the patients to ensure that they were correctly treated and, very important, to obtain long-term data results that allow us to establish real appraisal on the effectiveness of drugs.

There was a time when the process was simple: Diagnosis was made and pentavalent antimonials were administered. Today, the situation has become more complex because there are many factors to consider before administering treatment and several therapeutic options. We have to overcome the idea of monotherapy (whatever the product) and move to safe and effective combinations, but the drugs need to be available. It is unfortunate that we know today that oral miltefosine, paromomycin cream, injectable pentamidine, and liposomal amphotericin B could solve much of the problem, but access is restricted by regulations or market considerations.