Leishmaniasis is prevalent in 98 countries spread over 4 continents and is most frequent among the most vulnerable, poorer populations of East Africa, the Indian subcontinent and South America. Leishmaniasis affects the skin, mucosa, or internal organs, resulting in severe disfigurement, disability or death. Twelve million people are infected with Leishmania worldwide and an estimated 350 million people are at risk for infection. There are about 2 million new cases and 50,000 deaths each year from leishmaniasis. Infection in immunocompromised people, especially HIV positive patients, is a growing problem (WHO, 2010).
Leishmaniasis is a vector-borne disease that is caused by obligate intra-macrophage protozoa of the Leishmania species. The disease is endemic in large areas of the tropics, subtropics and the Mediterranean basin. More than 20 leishmanial species can cause various forms of leishmaniasis, which are transmitted to humans by ~30 different species of phlebotomine sandflies (Chappuis et al., 2007). The disease affects the skin, mucosa, or internal organs and results in severe disfigurement, disability or even death dependent on the infecting Leishmania species.
Leishmaniasis consists of four main clinical syndromes:
– cutaneous leishmaniasis (CL);
– muco-cutaneous leishmaniasis (also known as espundia);
– visceral leishmaniasis (VL; also known as kala-azar);
– post-kala-azar dermal leishmaniasis (PKDL).
In cutaneous leishmaniasis, the patient generally presents with one or several ulcer(s) or nodule(s) in the skin (WHO, 2010). Different species of Leishmania, including L. major, L. tropica, L. aethiopica and L. mexicana, can be the causative agent of CL. The parasite infects the macrophages in the dermis, with variable clinical presentations and prognoses. The ulcers heal spontaneously — although slowly — in immunocompetent individuals, but cause disfiguring scars.
In muco-cutaneous leishmaniasis, patients suffer from progressively destructive ulcerations of the mucosa, extending from the nose and mouth to the pharynx and larynx (WHO, 2010). These lesions are not self-healing and are usually seen months or years after a first episode of cutaneous leishmaniasis, when the macrophages of the naso-oropharyngeal mucosa become colonized. Leishmania braziliensis is responsible for most cases of muco-cutaneous leishmaniasis.
Visceral leishmaniasis is a systemic disease that is fatal if left untreated and is caused by the Leishmania donovani complex — L. donovani sensu stricto in East Africa and the Indian subcontinent and Leishmania infantum in Europe, North Africa and Latin America (WHO, 2010). There are two types of VL, which differ in their transmission characteristics: zoonotic VL is transmitted from animal to vector to human and anthroponotic VL is transmitted from human to vector to human. In the former, humans are occasional hosts and animals, mainly dogs, are the reservoir of the parasite. Zoonotic VL is found in areas of L. infantum transmission whereas anthroponotic VL is found in areas of L. donovani transmission.
Post-kala-azar dermal leishmaniasis is characterized by a macular, maculo-papular or nodular rash and is a complication of VL that is frequently observed after treatment in Sudan and more rarely in other East African countries and in the Indian subcontinent (WHO, 2010). It can also occur in immunosuppressed individuals in L. infantum-endemic areas. The interval between treated VL and PKDL is 0–6 months in Sudan and 6 months to 3 years in India. PKDL cases are highly infectious because the nodular lesions contain many parasites, and such cases are the putative reservoir for anthroponotic VL between epidemic cycles.
Leishmania and HIV coinfection
According to WHO, a major threat to control visceral leishmaniasis (VL) is its interaction with HIV infection. VL has emerged as an important opportunistic infection associated with HIV. In areas endemic for VL, many people have asymptomatic infection. A concomitant HIV infection increases the risk of developing active VL by between 100 and 2320 times. In southern Europe, up to 70% of cases of visceral leishmaniasis in adults are associated with HIV infection.
Immunosuppression-associated diffuse cutaneous leishmaniasis caused by other Leishmania species can occur in HIV-coinfected patients and people with other forms of immunosuppression (e.g. transplant recipients). Atypical features such as ulceration can occur (WHO, 2010).
The following rule of thumb is used by the WHO:
- 90% of all visceral leishmaniasis cases occur in Bangladesh, Brazil, India, Nepal and Sudan;
- 90% of mucocutaneous leishmaniasis occurs in Bolivia, Brazil and Peru;
- 90% of cutaneous leishmaniasis cases occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia and Syria.
Currently, the drugs used in leishmaniasis treatment present several problems, including high toxicity and many adverse effects, leading to patients withdrawing from treatment and emergence of resistant strains. In addition to these clinical problems, the high (and increasing) cost of the compounds hampers treatment accessibility, especially in developing countries.
The market needs for drugs against leishmaniasis are manifold:
- affordable drugs;
- drugs with less side effects;
- drugs that can be taken orally;
- drugs that are efficient in HIV patients;
- drugs that are efficient against resistant strains.
Current treatment options are limited as they cause significant side-effects. The chemotherapy currently available for treatment of leishmaniasis is far from satisfactory and presents several problems, including toxicity and unacceptable side effects, high cost, long treatment regimens often requiring hospital setting, and the development of drug resistance.
The only orally bioavailable drug with acceptable efficacy against leishmaniasis is the chemical cousin of D121. The latter is known to have a narrow therapeutic window, mainly due to its side effect profile which may reduce compliance to treatment. As sub-optimal dosage can lead to drug resistance, high compliance is a very important criterion to ensure the longevity of an anti-infective agent.
Oblita Therapeutics intends to develop and commercialize D121 as it shows a significant competitive advantage:
– less side effects
– oral administration -> better compliance
– different strains will be tested in old and new world