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  IN THIS Article
 ::  Abstract
 ::  The epidemiologi...
 ::  Trends in hiv / ...
 ::  Transmission par...
 ::  People at risk
 ::  Microbiological ...
 ::  Pathogenesis
 ::  Clinical present...
 ::  Diagnostic tools
 ::  Treatment
 ::  Prevention and t...
 ::  Secondary prophy...
 ::  Relapses
 ::  References

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SYMPOSIUM
Year : 2003  |  Volume : 49  |  Issue : 1  |  Page : 39-49

Leishmaniasis in HIV infection.


Internal Medicine Department, Hospital de la Santa Creu i Sant Pau. Av. Sant Antoni Maria Claret 167, 08025 Barcelona. Catalonia. Spain. , Spain

Correspondence Address:
R Paredes
Internal Medicine Department, Hospital de la Santa Creu i Sant Pau. Av. Sant Antoni Maria Claret 167, 08025 Barcelona. Catalonia. Spain.
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.929

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 :: Abstract 

Herein we review the particular aspects of leishmaniasis associated with HIV infection. The data in this review are mainly from papers identified from PubMed searches and from papers in reference lists of reviewed articles and from the authors' personal archives. Epidemiological data of HIV/Leishmania co-infection is discussed, with special focus on the influence of Highly Active Antiretroviral Therapy (HAART) on incidence of leishmaniasis and transmission modalities. Microbiological characteristics, pathogenesis, clinical presentation and specific treatment of the co-infection are also presented.


Keywords: AIDS-Related Opportunistic Infections, diagnosis,drug therapy,epidemiology,parasitology,Animal, Antimony, therapeutic use,Antiprotozoal Agents, therapeutic use,Antiretroviral Therapy, Highly Active, HIV, pathogenicity,HIV Infections, complications,drug therapy,Human, Leishmania, pathogenicity,Leishmaniasis, complications,diagnosis,drug therapy,epidemiology,Risk Factors,


How to cite this article:
Paredes R, Munoz J, Diaz I, Domingo P, Gurgui M, Clotet B. Leishmaniasis in HIV infection. J Postgrad Med 2003;49:39-49

How to cite this URL:
Paredes R, Munoz J, Diaz I, Domingo P, Gurgui M, Clotet B. Leishmaniasis in HIV infection. J Postgrad Med [serial online] 2003 [cited 2023 Jun 8];49:39-49. Available from: https://www.jpgmonline.com/text.asp?2003/49/1/39/929


The outbreak of HIV/AIDS pandemic during the past 20 years has modified the clinical spectrum of infection by Leishmania spp. in co-infected patients at different levels. The purpose of this review is to outline this emerging background as well as to detail the relevant aspects of such co-infections.


  ::   The epidemiological overlap Top


Despite encouraging news coming from economically developed countries,[1],[2] HIV/AIDS pandemic spread is out of control.[3] Visceral leishmaniasis (VL) is the fourth most common opportunistic parasitic disease in HIV-positive individuals in Spain after pneumocystosis, toxoplasmosis, and cryptosporidiosis.[4] VL promotes the development of AIDS defining conditions[5] and clinical progression, as well as diminishes the life expectancy of HIV-infected subjects. On the other hand, HIV infection increases the risk of developing VL by 100-1000 times in endemic areas[5],[6], reduces the likeliness to therapeutic response and enhances the probability of relapse.[5],[6],[8],[9],[10],[11] Both diseases exert cumulative deficiency of the cellular immune response since both agents damage similar immune resources.[10],[12],[13],[14],[15],[16],[17],[18]

According to data from the World Health Organization,[19] the areas where HIV / Leishmania co-infection is distributed are extensive. So far, 33 countries worldwide have reported co-infections. In southern Europe 25% to 70% of adult VL cases are related to HIV and 1.5% to 9% of AIDS cases suffer from newly acquired or reactivated VL. Of the first 1 700 cases of co-infection which have been reported to the WHO up to 1998, 1 440 cases belonged to south-western Europe.[5] Most co-infections in the Americas are reported in Brazil, where the incidence of AIDS has risen from 0.8 cases per 100 000 inhabitants in 1986 to 10.5 cases per 100 000 inhabitants in 1997. In Africa, the number of cases is expected to rise and is further impaired by social adversities like mass migration, displacement, civil unrest, and war. In Asia, co-infections are increasingly being reported from India, Bangladesh and Nepal, countries that are also facing antimonial resistance.[20],[21] The real impact of HIV/Leishmania co-infection is probably being underestimated owing to constraints in surveillance and reporting of cases.


  ::   Trends in hiv / leishmania co-infection in the “haart-for-some” era Top


It is well known that the advent of highly active antiretroviral therapy (HAART) has modified the natural history of HIV infection and its related opportunistic infections and neoplasms.[1],[2] In addition, it has permitted a partial but substantial recovery of many immune functions in HIV-infected patients,[22] allowing withdrawal of secondary prophylaxis.[23],[24],[25],[26] The beneficial effect of HAART has been demonstrated in other parasitic infections such as toxoplasmosis, cryptosporidiosis and microsporidiosis.[12],[27],[28],[29] A recent study[30] demonstrated that the incidence of VL in HIV-infected patients decreased from 11.6 ± 1.2 per 10 000 persons-years before 1996 to 6.3 ± 0.7 per 10000 persons-years after 1996, the year when HAART was initiated in France. Similar data has been reported from Spain[31] and other reports demonstrate that co-infected patients who receive HAART have a significantly longer survival than those who do not.[10] Nevertheless, the benefits of HAART are only available to 5% or less of HIV-infected patients in the World at present.[3] In countries where HAART is not available, the incidence of opportunistic infections like Pneumocystis carinii is increasing.[32] There is no available data regarding HIV/Leishmania co-infection in developing countries, but several authors suggest that it may be increasing as well.[5],[6],[19],[33]


  ::   Transmission particularities Top


Although the geographic distribution of Leishmania infection is restricted to the areas of distribution of the Phebotomus or Lutzomyia sandflies, HIV infection modifies the traditional zoonotic/anthroponotic patterns of Leishmania transmission. The poor therapeutic outcome, the higher rate of relapses, and the poliparasitic nature of VL in HIV-infected persons, as well as the atypical manifestations of the disease that make diagnosis difficult and the impaired access to health-care resources of co-infected patients, make HIV-infected individuals prone to enlarge the number of human reservoirs in areas where transmission of leishmaniasis is already anthroponotic. In addition, these same characteristics help to create a new focus of anthroponotic transmission in areas where the spread of leishmaniasis has traditionally been zoonotic.

Needle sharing by intravenous drug users (IVDUs) has been proposed as providing an alternative, artificial, and anthroponotic cycle for Leishmania transmission.[5] Multiple indirect data support this hypothesis[8].[30],[34],[37],[39] although similar findings have only been described in South-western Europe, and in fact, no single case of direct acquisition of a primary Leishmania infection derived from syringe use has been reported to date.

Very rarely, Leishmania spp. transmission has been described by alternative means that are also shared by HIV-infection, including blood transfusion,[40],[41],[42],[43],[44],[45],[46] congenital transmission,[46],[47],[48],[49],[50] anal intercourse,[51],[52],[53] and laboratory-acquired.[54] Therefore, although no case of HIV/Leishmania co-infection has been described related to these situations, we must be aware of these potential alternative ways of transmission.


  ::   People at risk Top


Worldwide, the majority of cases of leishmaniasis occur in HIV-negative persons. In this setting, leishmaniasis is still considered a childhood disease.[1],[56],[57],[58],[59] The majority of paediatric patients with leishmaniasis in the Mediterranean basin are HIV-negative.[60] The association of Leishmania infection with AIDS has led to a significant shift in the age of people at risk.

In southwestern Europe 75% of HIV-seronegative and 80 to 83% of HIV-positive patients suffering from VL are men.[5],[10],[33] Men may be at higher risk because of occupational exposure and due to a higher likeliness of intravenous drug use. The limited access of women to healthcare due to cultural and social barriers may underestimate the real impact of leishmaniasis in them. Although some experimental murine models suggest that women are less likely to develop the clinical symptoms of VL than exposed men,[56],[61],[62] it is uncertain whether women are constitutionally protected against Leishmania.

In general, overt clinical leishmaniasis occurs in profoundly immunosuppressed HIV-infected patients. It is considered that 33-78% of co-infected patients with a first episode of VL have previously accomplished AIDS criteria.[4],[10],[36],[63],[65],[66] However, VL can be the first HIV-related serious infection in 13 to 47% of patients.[4],[10],[66] Mean CD4 counts are ??200 cells/mm3 in 62-90% and ? 50 cells/mm3 in 42% of co-infected patients.[8],[11] Studies have suggested that the pre-treatment HIV-1 load may be inversely correlated to the response to anti-Leishmania chemotherapy.[67] Also it is clear that those patients who do not receive HAART are more likely to develop overt clinical leishmaniasis, and to present a higher risk for treatment failure and clinical and parasitological relapse.[8],[10],[11]


  ::   Microbiological features Top


In a majority of HIV-positive individuals, VL is commonly caused by L. infantum or L. donovanii[8] Other Leishmania species like L. braziliensis,[68],[69],[70],[71] L. aethiopica,[72] L.tropica,[73],[74] and L. major[75] have been occasionally described related to the geographical locations of such infections. Nevertheless, there are 3 important considerations to be made regarding the microbiology of HIV-Leishmania co-infections:

a. There is a high variability of L. infantum zymodemes affecting co-infected persons. Up to 150 Leishmania isolates and a total of 17 zymodemes had been described in co-infected patients up to 1997.[8] Indeed, several Leishmania zymodemes can be frequently characterised from single infected individuals. It is uncertain whether this zymodeme variability is exclusively found among IVDUs or if, by the contrary, it is also seen in other HIV risk groups.

b. Several new zymodemes have only been found in HIV-positive patients that had not been reported in immunocompetent patients nor in dogs living in the same geographical areas.

c. The anergic state of HIV-positive individuals permits parasite dissemination regardless of the isolate’s zymodemes. Many theoretically “dermotropic” variants of Leishmania infantum as well as L. (Viannia) braziliensis, L. mexicana and L amazonensis have been described to cause visceral disease in HIV-infected patients.[76],[77],[78],[79] In addition, “viscerotropic” Leishmania spp. variants like L. infantum[80] or L. chagasi[81],[82] can be found in cutaneous lesions related or not to leishmaniasis and even in apparently healthy skin.[83]


  ::   Pathogenesis Top


The co-infection by HIV and Leishmania causes reciprocally enhanced immunologic disturbances.[8] Both infections switch the predominant cellular immune response from Th1 or Th0 to Th2 through complex cytokine-mediated mechanisms leading to the predominance of a humoral response that, according to murine BALBc models,[14] confers susceptibility to both infections. Cytokine disturbances inhibit the production of IFN-?. This exerts a defect in the lytic capacity of macrophages,[13] which cannot eliminate intracellular Leishmania amastigotes through the nitric oxide pathway.[84] The effects of viral infection tend to predominate over those of the parasitic infection.[8] HIV-induced immuno-depression predominates over the cellular response caused by the parasite.[8] HIV-related CD4+ T cell depletion implies a lack of T cells able to recognise Leishmania antigens and to stimulate B-lymphocytes. This leads to an oligoclonal B-cell response, which explains the elevated frequency of false negative Leishmania serology results in co-infected patients.[85] HIV-mediated inhibition of proliferative responses to Leishmania spp.[13] favours the dissemination of leishmaniasis, enables atypical locations of Leishmania parasites, and explains the polyparasitic nature of the disease in HIV positive patients and the uselessness of leishmanin tests in co-infectd patients.

Conversely Leishmania infection increases HIV replication, mainly due chronic immune activation,[95],[96] which is one of the main determinants of HIV-1 disease progression.[86] Immune activation facilitates up-regulation of viral co-receptors (CCR5 and CXCR4), decreased ?-chemokine secretion,[16] enhanced viral entry and integration, as well as viral assembly and/or release.[18] It also leads to an increased secretion of TNF-?, IL-2, IL-4, IL-6, IL-10, and affects the cell cycle.[17],[88] It is indeed associated to several degrees of immune dysfunction, hyporesponsiveness and apoptosis, all leading to enhanced progression of immune deficiency and decreased survival.[89],[90],[91],[92],[93],[94] Compared to HIV-infected patients without leishmaniasis, co-infected patients show a cytokine profile with significant elevations in IL-4, IL-10 and IL-2-receptors, and decreased post-stimulation production of IFN-?.[95],[96],[97],[98] It has been shown that Leishmania infantum-derived lypophosphoglycan (LPG) can induce HIV-1 expression in latently infected peripheral blood mononuclear cells,[15] probably mediated by the secretion of TNF-?.[99] The induction of HIV expression has been suggested by the observations of a progressive increase in HIV-1 RNA load in co-infected patients, in parallel to the increase in IL-4, IL-6 and IL-10 levels.[95] Furthermore, successful treatment of cutaneous, mucocutaneous and VL is associated with a decrease in TNF-? levels.[101] In fact, treatment of leishmanias is in the dually infected patients decreases HIV plasma viral load significantly.[67]


  ::   Clinical presentation Top


Although the majority of Leishmania infections in HIV-positive individuals display clinical features of classic kala-azar,[102],[103] cutaneous and mucocutaneous leishmaniasis, as well as VL in many atypical locations have been increasingly reported. HIV-associated leishmaniasis has five major clinical characteristics:

a. Parasitic dissemination, to the skin in diffuse cutaneous leishmaniasis, or throughout the reticuloendothelial system in visceral and visceralizing syndromes. It has been suggested that almost every organ containing phagocytic cells may eventually become infected by L donovani.[104]

b. Atypical locations, as a consequence of this parasitic dissemination and a defect in cell-mediated immunity.

c. A chronic and relapsing course,[102] with each patient typically experiencing two or three relapses despite proper treatment.

d. Poor response to standard therapy.[105]

e. Lack of anti-Leishmania antibodies, which is seen in many endemic areas.[157]

The clinical features of HIV-related VL are comparable to those of classic disease.[63],[65],[102],[103],[107],[108],[109] The incubation period is variable and may be age-related.[8],[110] During any VL episode, other concomitant opportunistic infections are diagnosed in 42 to 68% of HIV-positive patients.[66],[159] Visceral involvement in HIV-related VL seems to be widespread, neither limited to conventionally described infestation areas nor to the reticuloendothelial system. However, most of the considered “atypical” forms of leishmaniasis have been previously described with variable frequency in immunocompetent individuals,[111],[112],[113],[114] so the term “atypical manifestations” has been challenged.[10]

Systemic Symptoms and Signs

Most patients are male, intravenous drug users with advanced HIV infection and have fever, hepatomegaly and/or splenomegaly, hypergammaglobulinemia, and pancytopenia.[4],[110] Characteristically, splenomegaly is less frequent in HIV-infected patients. Cytopenia is significantly more frequent in HIV-positive patients.[10] Hypergammaglobulinaemia has a limited diagnostic value, because not only it is a frequent finding in VL, but also in HIV-infection per se and in other chronic infections. Constitutional symptoms (asthenia, anorexia and loss of weight) are seen in approximately 50-70% of co-infected patients, and lymphadenopathy ranges 15-60%. The disease tends to disseminate to the skin and other organs, and presentation outside the reticuloendothelial system may mislead the clinician.[110] Frequently, VL is diagnosed during the assessment of a fever of uncertain origin.[115],[116],[117] Seven to 17 percent of fevers of uncertain origin in HIV-positive patients withhold VL, whereas up to 45% of HIV-infected patients who are diagnosed of VL present as fever of unknown origin.[10] It is not uncommon to find Leishmania infection along with other opportunistic infections such as mycobacterioses, pneumonia, cytomegalovirus infections, or AIDS-related neoplasms.

Gastrointestinal Symptoms

Gastrointestinal symptoms are among the most frequent complaints in individuals infected with HIV.[118],[119] Leishmania donovani has been identified in the digestive tracts of 50 percent of HIV-negative patients with VL,[113] and it is increasingly being reported in HIV-positive patients. Any portion of the gastrointestinal tract can undergo parasitisation;[113],[120],[121],[122],[123],[124],[125],[126],[127],[128] jejunal involvement has most frequently been found on biopsies.[120] In HIV-negative patients, the major digestive symptoms of VL include diarrhoea, malabsorption, hypoalbuminemia and weight loss. Unfortunately, these symptoms are non-specific in the patient with AIDS, and thus, other causes must be ruled out.[129] In addition, Leishmania parasites may coexist with many other pathogens or neoplasms in a single digestive area.[105] Therefore, endoscopy and routine biopsy are the best diagnostic tools in HIV-positive patients presenting with unexplained gastrointestinal symptoms.[105],[120],[121],[122],[130] Endoscopy examination shows many variable features, such as normal mucosa, diffuse erythematous oesophageal mucosa with extensive ulceration, erosive gastroduodenitis, gastric ulcers, and multiple reddish colonic lesions.[105],[120] Leishmania parasites have been described coexisting inside Kaposi’s Sarcoma lesions, cytomegalovirus ulcers, or beneath Candida or herpes simplex esophagitis.[105],[120] Therefore, even if the mucosa appears to be normal, multiple random biopsy specimens should be obtained.[105]

Cutaneous Symptoms

Cutaneous involvement of VL is a rare finding,[131] but it is characteristic of HIV-related VL. It is seen in 2–12% of patients with HIV/Leishmania co-infection.[132] It is not infrequent that “viscerotropic” Leishmania species may affect the skin,[131],[133],[134] causing a variable spectrum of lesions. Such lesions may occur simultaneously with visceral involvement and can be papular, maculopapular or nodular. Leishmania amastigotes have been also found in apparently normal skin, infestating sweat ducts,[131] or co-existing with other cutaneous lesions like Kaposi’s sarcoma,[135],[137] herpes simplex and herpes zoster.[138] Sometimes, Leishmania is associated with changes attributable to other dermatological processes like dermatofibromas, psoriasis, Reiter’s syndrome, bacillary angiomatosis, cryptococcosis and oral aphtae, although its presence does not imply a causative role.[80] Unusual skin lesions like linear brown macules on the fingers and palms of the hands, a skin biopsy of a fibrous histiocytoma or even an elevated tattoo, all containing Leishmania amastigotes, have been reported.[139] Leishmaniasis also appeared as a dermatomyositis-like eruption,[140] mucocutaneous and mucosal leishmaniasis, [134] generalised cutaneous leishmaniasis, and post-kala-azar dermal leishmaniasis.[140] As well, primary cutaneous lesions can visceralise in severely immunodepressed patients.[76],[77],[78],[79] Specimens from skin lesions should be obtained whenever there is a suspicion of leishmaniasis in HIV-infected patients. Unless otherwise demonstrated, any cutaneous specimen yielding Leishmania amastigotes in an HIV-infected patient should be considered, in the first place, as a disseminated form of VL rather than a primary cutaneous leishmaniasis.

Respiratory Tract Involvement

Leishmania amastigotes have been found in alveoli and pulmonary septa in up to 75% of HIV/Leishmania co-infected patients in anatomo-pathological studies.[112] However, the clinical significance of this finding remains to be discerned, because the frequent lung involvement usually is not accompanied by symptoms or clinical complications and, when they occur, it is difficult to differentiate the role of Leishmania from other more frequent lung infections.

Renal Involvement and Acute Renal Failure

Renal insufficiency is a rare presentation of leishmaniasis in humans. However, a case of acute renal failure has been recently described as the initial presentation of VL in an HIV-1 infected patient.[142] Glomerulopathy is only associated with visceral disease and not with cutaneous or mucocutaneous forms. Mild proteinuria with benign changes in the urinary sediment (microscopic haematuria and leucocituria) has been reported in up to 60% of HIV-negative patients with kala-azar followed prospectively,[143] although the frequency is unknown for the HIV co-infected. The pathological findings include a glomerulonephritis ranging from purely mesangioproliferative to membranoproliferative, sometimes associated with focal and segmental collapse of capillary loops.[144] Tubulointerstitial damage is usually present.

Miscellaneous Sites of Leishmania Infection

Atypical clinical findings in HIV-related VL suggest that immune failure may facilitate parasitemia and hematogenous spread[145] of leishmanias from typical locations to every part of the body. A retrospective French study found amastigotes in atypical locations in 34% of HIV-infected patients with VL, and these atypical locations where the only diagnostic clue in 15% of cases.[146] Pancreatic,[147] pulmonary,[112] pleural,[148] laryngeal,[104] adrenal,[122] pericardic,[149] myocardic,[122] and lingual[150] leishmanial infections have been described. Importantly, atypical locations can be the first clinical manifestation of VL in the immunodepressed patient.

Mucocutaneous Leishmaniasis in HIV-positive Patients

Mucocutaneous leishmaniasis (MCL) appears in 2 to 3% of all cases of HIV-Leishmania co-infection.[151] Practically all of the Leishmania species can be responsible for MCL lesions. Although the nasal septum and the soft palate are usually affected by MCL due to metastasis from a primary lesion, it can also appear as a primary lesion.[152] Nasal biopsy specimens are commonly needed to elucidate a definitive diagnosis of MCL.


  ::   Diagnostic tools Top


Immune-based Diagnosis

HIV/Leishmania-induced deficit in host’s humoral and cellular responses makes both serological and delayed type IV hypersensitivity-based tests of limited use in co-infected patients. Only about 40-50% of HIV/Leishmania co-infected patients have a positive Leishmania serology.[4],[153] This percentage is inversely correlated with the degree of CD4 T-cell depletion. Anti-Leishmania antibodies in AIDS patients are 50 times lower than in those with an intact immune system.[154] Therefore, with the serological methods many false-negative serology results should be expected in HIV-infected individuals. More sensitive techniques like immunoblotting are being applied which may reach a sensitivity of 70% and a specificity of 73%.[155] However, such serological tests have not been well standarised and there is substantial non-specific cross-reactivity.[156],[157] Hence, it is useful for first diagnosis of leishmaniasis as well as for excluding leishmaniasis when antigenuria is negative, but it is not useful for follow-up, to monitor treatment response of to detect relapses.

Antigen Detection

The polyparasitic nature of leishmaniasis in HIV-1 infected patients permits the detection of Leishmania amastigotes and antigens in peripheral blood, which is unusual in immunocompetent individuals. The direct examination of amastigotes in peripheral blood has permitted the diagnosis of up to 50% of co-infected patients[35],[107] and if the buffy coat is cultured in Novy–McNeal–Nicolle medium, sensitivity may increase to near 70%.[145] In addition to blood samples, methods for detecting Leishmania antigens by Western Blot in urine samples are being implemented. Leishmania antigenuria can persist for several months after the first infection. Hence, it is useful for first diagnosis of leishmaniasis as well as for excluding leishmaniasis when leishmanuria is negative, but it is not useful for follow-up, monitoring, or detecting.

Polymerase Chain Reaction

Although initial PCR techniques requiring tissue samples, had a limited sensitivity and were time consuming,[160],[161],[162],[163],[164] new methods detecting the highly variable regions of the kinetoplast DNA mini-circles improved the sensitivity, specificity and the speed of diagnosis.[165],[166] Such techniques have been combined with ELISA[166] and direct agglutination tests (DAT)[168] with very satisfactory results. Of all the different PCR techniques available, nested-PCR assay is probably the best non-invasive way of diagnosing VL, with a sensitivity of 95.45% in peripheral blood and 100% in bone marrow.[169] Nested-PCR has been useful for monitoring the efficacy of treatment. Relapses after treatment, were predicted 5 months earlier than when predicted using classical diagnostic techniques. Other studies have yielded similar results.[170] However, the cost precludes use of PCR-based tests in underdeveloped countries.

Tissular Parasite Isolation and Culture

The gold standard for the diagnosis of leishmaniasis in HIV-infected patients remains the isolation or identification of the parasite. Up to 10 to 30% of cases of VL in HIV-infected patients are diagnosed from tissue isolates obtained from leishmaniasis in atypical locations. An accurate description of the procedures was provided by Evans.[110] The two most common media utilized in culture are the modified Novy-McNeal-Nicolle medium and a foetal calf serum-supplemented Schneider’s Drosophilla medium.[171],[172] BMAs can yield false-negative results due to various reasons such as the very low number of Leishmania cells in bone marrow or because of haemodiluted samples, or pentamidine or amphotericin B (AMB) given for treatment of pneumocystosis or mycosis.[166] Culture of Leishmania cells from BMAs may improve the direct diagnosis of VL in such patients.[147]


  ::   Treatment Top


Despite the prevalence, clinical implications and epidemiological impact of HIV/Leishmania co-infection, surprisingly scarce data is available regarding the treatment of leishmaniasis in HIV-infected people. The optimal therapy, duration and dosages and particularly, the most adequate treatment and prophylaxis of relapses remain to be established. Overall, treatment approaches are comparable[176] to those of HIV-negative patients with 5 important differences:

a) While the duration of antimonial therapy in HIV-negative patients is 21 days, treatment of co-infected patients should be prolonged until 4 weeks.

b) Treatment of VL is characterised by a low rate of clinical and parasitological response, and frequent relapses. Only about 60% of patients respond clinically or parasitologically to therapy regardless of the regimen used [amphotericin B (AMB) or antimonials], whereas 25-60% of patients experience relapses during the first year after treatment completion.[4],[5],[8],[10],[173]

c) HIV-infected patients are more likely to suffer treatment-related adverse events than the HIV-negative population.[174],[175]

d) There is a role for combining antimonials with allopurinol of IFN-?, which act synergistically with the former compounds, at least in refractory cases and/or relapses. However, there is not enough clinical experience for recommending their use systematically.

e) If available, treatment of HIV-infection with HAART approaches should be stressed.

At present, pentavalent antimonials remain the treatment of choice for HIV-associated VL because their therapeutic efficacy and the rate of adverse events are comparable to those of AMB deoxycolate with less cost. Meglumine antimoniate (20 mg/Kg/day) has demonstrated similar efficacy and toxicity rates than AMB deoxycolate (0.7 mg/Kg/day) both given for 28 days.[173] Generic sodium stibogluconate was comparable to the propietary drug and is substantially cheaper.[175] Due to the emergence of parasite resistance in India,[20] AMB is the treatment of choice in this region. Although lipid formulations are fairly less toxic, antimonials are, in general, considered to be more cost-effective than lipid AMB formulations. Whenever used, allopurinol and IFN-? should be combined with antimonials, and special care should be taken when administering IFN-? to HIV-infected patients suspected of having Kaposi’s sarcoma (KS), since IFN-? could promote the progression of KS lesions. Pentamidine should only be used when no other options are available, specially as a maintenance therapy in co-infection, due to the annoying adverse event profile and an expected lower efficacy. Nevertheless, the high cost at present makes these efficient agents of almost no practical value in less developed countries,[5] so alternative approaches must urgently be developed. Oral miltefosine[21],[177] is a promising alternative for the treatment of Indian VL, but has not been tested yet in HIV/Leishmania co-infected patients.


  ::   Prevention and treatment of relapses Top


Despite its elevated frequency, no specific studies are available comparing the different alternatives to prevent or to treat relapses of VL in HIV co-infected patients. This is an important issue because after “successful” treatment, the parasite persists quiescent in several organs, and continuous exposure to inadequate drug dosages may promote the development of resistance.[8] Up to 7% of VL reactivations in the Mediterranean basin may correspond to re-infections.[178]


  ::   Secondary prophylaxis Top


At present, there is no role for primary prophylaxis against Leishmania infection in HIV-infected patients. Regarding secondary prophylaxis, the most accepted approach includes the monthly administration of 20 mg/Kg meglumine antimoniate or sodium stibogluconate, intravenously or intramuscularly. This is the only strategy that has shown in a non-randomised retrospective trial, some degree of evidence of efficacy.[179] Other alternatives include pentamidine every three or four weeks,[115],[180] liposomal AMB every two weeks,[115],[180] or allopurinol and itraconazole.[115],[182] Further research should clarify the indications and dosages of these regimens. In addition, 2 other important questions remain to be solved. The first is whether HAART mediated immune reconstitution may reduce the likeliness to relapse. Divergent results exist coming from small studies.[10],[183] The second is whether Leishmania prophylaxis can be withdrawn when CD4+ counts surpass 200 cells/mm.[3] However, in daily clinical practice, Leishmania secondary prophylaxis is being withdrawn with CD4 of counts ³ 200 cells/mm3 and, in our clinical experience, no new relapses are being encountered.


  ::   Relapses Top


Relapses have been treated with either antimonials or AMB at standard doses with similar efficacy rates in the clinical setting (personal communication), sometimes during more prolonged periods than usual. Since no specific comparative studies exist, the election of a regimen should be guided by the toxicity profile and patient’s comorbidity.

 
 :: References Top

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2.Mocroft A, Vella S, Benfield T L, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 1998;352:1725-30.  Back to cited text no. 2    
3.UNAIDS: AIDS Epidemic Update 2002. www.unaids.org.  Back to cited text no. 3    
4.Montalban C, Calleja JL, Erice A, Laguna F, Clotet B, Podzamczer D, et al. Visceral leishmaniasis in patients infected with human immunodeficiency virus. Co-operative Group for the Study of Leishmaniasis in AIDS. J Infect 1990;21:261-70.  Back to cited text no. 4    
5.Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002;2:494-501.  Back to cited text no. 5    
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Antimicrobial Agents and Chemotherapy. 2004; 48(3): 852
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56 Challenges and new discoveries in the treatment of leishmaniasis
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57 Challenges and new discoveries in the treatment of leishmaniasis
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58 In vitro assays for evaluation of drug activity against Leishmania spp.
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59 In vitro assays for evaluation of drug activity against Leishmania spp.
Fumarola L, Spinelli R, Brandonisio O
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60 Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes
Paris C, Loiseau PM, Bories C, Breard J
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61 Leishmania - From the bite to the disease
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62 Cutaneous leishmaniasis: current and future management
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[VIEW] | [DOI]



 

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Online since 12th February '04
© 2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow