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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 49, Num. 1, 2003, pp. 39-49
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Journal of Postgraduate Medicine, Vol. 49,
No. 1, Jan-March, 2003, pp.
39-49
Symposium
Leishmaniasis in HIV Infection
Paredes R, Muñoz J, Díaz I, Domingo P, Gurgui M, Clotet B
Infectious Disease Unit and Internal Medicine Department. Hospital de la Santa
Creu i Sant Pau. Barcelona. and HIV Clinical Unit and irsi Caixa Retrovirology
Unit. Hospital Universitari Germans Trias i Pujol. Badalona. Catalonia. Spain.
Address for Correspondence: Roger Paredes
i Deiros, MD. Internal Medicine Department, Hospital de la Santa Creu i Sant
Pau. Av. Sant Antoni Maria Claret 167, 08025 Barcelona. Catalonia. Spain. E-mail:
34120rpd@comb.es Code Number: jp03009
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. (J Postgrad Med 2003;49:39-49)
Key Words: Leishmaniasis, HIV, AIDS, hepatitis, interferon.
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
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 conditions5 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 areas5,6, reduces the likeliness to therapeutic
response and enhances the probability of relapse.5,6,8-11 Both diseases
exert cumulative deficiency of the cellular immune response since both agents
damage similar immune resources.10,12-18
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
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.23-26 The beneficial effect
of HAART has been demonstrated in other parasitic infections such as toxoplasmosis,
cryptosporidiosis and microsporidiosis.12,27-29 A recent study30 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 Spain31 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
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 hypothesis8.30,34,37,39 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,40-46 congenital
transmission,46-50 anal intercourse,51-53 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
Worldwide, the majority of cases of leishmaniasis occur in HIV-negative persons.
In this setting, leishmaniasis is still considered a childhood disease.1,56-59 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
In a majority of HIV-positive individuals, VL is commonly caused by L.
infantum or L. donovanii8 Other Leishmania species
like L. braziliensis,68-71 L. aethiopica,72 L.tropica,73,74 and L.
major75 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.76-79 In addition, "viscerotropic" Leishmania spp.
variants like L.
infantum80 or L.
chagasi81,82 can be found in cutaneous lesions related or not
to leishmaniasis and even in apparently healthy
skin.83
Pathogenesis
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-γ. 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 b-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-α, 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.89-94 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-γ.95-98 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-α.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-α levels.101 In fact, treatment of leishmanias is in
the dually infected patients decreases HIV plasma viral load significantly.67
Clinical Presentation
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.63,65,102,103,107-109 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,111-114 so
the term "atypical manifestations" has been challenged.10
The majority of Leishmania infections in HIV-positive individuals display clinical
features of classic kala-azar. Splenomegaly is less frequent in HIV-infected
patients than in
immunocompetent individuals.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.115-117 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;113,120-128 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.105,120-122,130 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 212% 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.76-79 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 spread145 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
lingual150 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
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 patients35,107 and if the buffy coat is cultured in
NovyMcNealNicolle 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,160-164 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 ELISA166 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
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 comparable176 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-γ, 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-γ should
be combined with antimonials, and special care should be taken when administering
IFN-γ to HIV-infected
patients suspected of having Kaposi's sarcoma (KS), since IFN-γ 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 miltefosine21,177 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
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
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
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.
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