Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

Research on antimetabolites of nucleic acid purines led to drugs for the treatment of acute leukemia (6-mercaptopurine and thioguanine), gout and hyperuricemia (allopurinol), and herpesvirus infections (acyclovir), and for the prevention of organ transplant rejection (azathioprine).

https://science.sciencemag.org/content/sci/244/4900/41.full.pdf

The purine path to chemotherapy

The 1980s have seen significant advances in the treatment of cutaneous, mucosal, and visceral leishmaniasis. Safe regimens of pentavalent antimony in the form of Pentostam (Wellcome Foundation, London; 20 mg of antimony/[kg.d] for 20-30 days) have produced initial cure rates of greater than 90% in these diseases. Biochemical investigations have demonstrated at least three parasite-specific features relevant to the mechanism of action of chemotherapeutic agents: (1) Organization of glycolytic enzymes and some enzymes of fatty acid catabolism into organelles (glycosomes) occurs in Leishmania but not in mammalian cells. Since antimony inhibits both amastigote catabolism of glucose via glycolytic enzymes and catabolism of fatty acids, the mechanism of action of antimony may relate to alteration of glycosomal structure or function. (2) Purine analogues can be utilized by the salvage pathway of purine biosynthesis in amastigotes to a greater extent than in mammalian cells, and allopurinol and allopurinol ribonucleoside are metabolized into presumably toxic nucleotides by these means. (3) Amastigote sterol biosynthesis is akin to that of such fungi as Candida in that the major demethylated sterol is of the ergostane series and in that ketoconazole inhibits its synthesis. Preliminary clinical studies suggest that the purines and the sterol inhibitors may have clinical utility as oral agents against cutaneous leishmaniasis. Possible treatment strategies for the classic and experimental agents have been proposed.

Chemotherapy for Leishmaniasis: Biochemical Mechanisms, Clinical Efficacy, and Future Strategies

It is important to realize that leishmaniasis guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA and ASTMH consider adherence to these guidelines to be voluntary, with the ultimate determinations regarding their application to be made by the physician in the light of each patient's individual circumstances.

Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)

Cutaneous leishmaniasis treatment

Allopurinol was used in the treatment of 10 patients with kala-azar. Of six patients who had previously failed to respond satisfactorily to Pentostam, "cures" were achieved in four. However, it was necessary to add Pentostam to the allopurinol in one, and another relapsed after apparent "cure" but again responded to allopurinol. The response of four patients who had had no previous treatment for kala-azar was less satisfactory.

Allopurinol in the treatment of visceral leishmaniasis

Sixty four Kenyan patients with visceral leishmaniasis were treated with sodium stibogluconate (Pentostam) (40 patients) or various combinations of Pentostam and allopurinol (24 patients). Three patients, initially considered cured after Pentostam, relapsed but responded to further treatment. Sixty two were cured and two patients died. The treatment and the clinical, haematological and parasitological response to treatment are described in detail. If follow up is impossible or unlikely it is advised to continue treatment until parasitological cure is obtained. Prolonged courses of Pentostam, which were required in some patients, resulted in cures and apparently were non toxic. Consideration is to be given to extended treatment with Pentostam before more toxic drugs such as pentamidine and amphotericin B are given.

Clinical, haematological and parasitological response to treatment of visceral leishmaniasis in Kenya. A study of 64 patients.

Clinical and laboratory findings of a series of 64 consecutive patients with visceral leishmaniasis are presented. The diagnosis was established by demonstration of parasites in splenic aspirates. Findings are discussed in comparison with those of former reports from Kenya and elsewhere.

Lyerly Wh

Papers

Allopurinol in the treatment of visceral leishmaniasis

Clinical, haematological and parasitological response to treatment of visceral leishmaniasis in Kenya. A study of 64 patients.

Clinical presentation of visceral leishmaniasis in Kenya: a prospective study of 64 patients.