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Annals of Tropical Medicine & Parasitology, Vol. 97, Supplement No. 1, S143–S147 (2003)
The impact of highly active antiretroviral therapy
(HAART) on visceral leishmaniasis in Spanish patients
who are co-infected with HIV
R. LÓPEZ-VÉLEZ
Medicina Tropical y Parasitologõ´a Clõ´nica, Servicio de Enfermedades Infecciosas,
Hospital Ramón y Cajal, Apartado 31057, 28034 Madrid, Spain
Received and accepted 30 May 2003
Clinicians in Madrid have been observing and treating HIV-positive patients with visceral leishmaniasis (VL) for
over a decade. As their records cover some of the co-infection cases that occurred before and after highly active
antiretroviral therapy (HAART) was introduced into Spain, retrospective analysis of the records has allowed some
of the eVects of HAART on local VL to be determined. Encouragingly, HAART appears to have decreased the
annual incidence of VL among local AIDS cases, from 4.81 cases/100 to just 0.8 case/100 (P <0.0005), a Ž rst
episode of VL now appearing only when there is obvious HAART failure. Unfortunately, it does not seem to be
very good at preventing VL relapses; within 24 months of antileishmanial treatment, 70% of patients who were
receiving HAART had such relapses. The mean time between antileishmanial treatment and VL relapse was,
however, longer when HAART was used than when it was not (20 v. 13 months). In those receiving HAART,
relapses of the VL often occurred despite increasing CD4+ cell counts and undetectable HIV loads, indicating
that successful treatment of the viral infection is insuYcient to prevent the relapse of the leishmaniasis. These
results are in general agreement with other observations made in Spain. VL relapses are possible and even frequent
in HIV-positives who have no more than 200 CD4+ cells/ml, but secondary prophylaxis to prevent VL relapses
may be safely suspended if a CD4+ count of >200 cells/ml can be maintained using HAART. VL also seems to
hamper the immunological recovery of the HIV-positive, although HAART appears to have little eVect on the
clinical manifestations of VL.
VISCERAL LEISHMANIASIS IN THE
HIV-INFECTED: INCIDENCE
Human infection with Leishmania infantum,
the cause of visceral leishmaniasis (VL) in
Europe, is quite common in the countries
that lie in Mediterranean basin, although it
is not always symptomatic. In the south of
Spain, for example, leishmanial amastigotes
can be found in 6% of bone-marrow biopsies
collected from asymptomatic HIV-positive
patients, although all such patients will
probably develop clinical VL (De la Rosa
et al., 2001). In southern Europe generally,
Reprint requests to: R. López-Vélez.
E-mail: [email protected]; fax: +34
913368792.
© 2003 The Liverpool School of Tropical Medicine
DOI: 10.1179/000349803225002615
2%–9% of AIDS patients will develop VL
(WHO, 1999). During the 1990s, most
(50%–60%) of the adult VL cases recorded
in Spain were co-infected with HIV, and up
to 17% of Spanish HIV-positive patients
with non-viral fever were found to be suVering from VL (Miralles et al., 1995). The
great majority of the new cases of VL
detected in Spain now occur in patients
with late-stage HIV infection (77%–90%,
7%–22% and only 0%–3% of such cases
having <200, 200–500 and >500 CD4+
cells/ml, respectively), and 42%–72% meet
the standard criteria for AIDS before or
during their Ž rst episode of leishmaniasis
(WHO, 1995, 1999; Alvar et al., 1997;
López-Vélez et al., 1998). A review of HIVassociated VL in Spain has recently been
published (Pintado and López-Vélez, 2001).
144
LÓPEZ-VÉLEZ
As VL appears to be an opportunistic
infection of the HIV-positive, the incidence
of new cases in Europe was expected to drop
once the treatment of the HIV-infected with
highly active antiretroviral therapy (HAART)
became common. In Madrid, the numbers of
new cases of VL and of VL/HIV co-infection
seen in 1998 — the year after treatment of
HIV-infected patients with protease inhibitors
(PI) became widespread in Spain — were
at least 40% lower than the annual mean
numbers recorded over the previous 5 years
(Anon., 1999). The annual incidence of
new cases of VL among the AIDS cases
of Madrid fell from 0.48 case/100 before
HAART was introduced to 0.26 case/100
once HAART became routine (López-Vélez
et al., 2001). Similar, HAART-attributable
drops in the incidence of VL among the
HIV-infected have been observed elsewhere
in southern Europe. For example, the annual
incidence of VL among the HIV-positive
(cases/100 HIV-positives) dropped from
0.70 to just 0.13 in Rome (Tumbarello et al.,
2000), from 0.80 to 0.12 in Barcelona
(C. Tortajada, unpubl. obs.), and from 0.95 to
0.15 in Sevilla ( J. A. Pineda, unpubl. obs.).
As HAART is unlikely to aVect the transmission of leishmanial parasites, it is assumed
that the antiretroviral drugs prevent an
asymptomatic infection with L. infantum
from becoming symptomatic, or at least slow
the development of any clinical manifestations
of the leishmanial infection. This assumption
is supported by the results of a recent study by
De la Rosa et al. (2001), who gave HAART
to 11 of 17 HIV-positive patients who
had subclinical infections with L. infantum.
Although none of the 17 patients had
received any antileishmanial drugs, none of
those on HAART (but two of those not on
HAART) developed VL during follow-up.
There has been speculation that L. infantum
may be transmitted to humans not only by
sand ies but also, among intravenous-drug
users (IVDU), on shared needles (Alvar et al.,
1997). As IVDU form the main risk-group
for L. infantum/HIV co-infection, some of
the drop seen recently in the incidence
of new cases of VL among Europeans with
HIV infection could be a side-beneŽ t of
needle-exchange programmes. As the drop
in incidence seen in HIV-positives who are
not IVDU is, however, similar to that seen
in the IVDU, it seems clear that HAART is
largely responsible. Among the patients investigated by Amador et al. (2001), however, the
incidence of VL in the year before HAART
was the same as that in the year after
the patients began antiretroviral treatment
(2.2 cases/100).
PROGNOSIS
VL usually follows a chronic and relapsing
course in HIV-positive patients, the number
of relapses and the mean time between them
being dependent on immunological state.
After a correctly treated initial episode of
VL, 60% of HIV-positives will relapse within
6–9 months and 90% within 12 months, the
mean period between subsequent relapses
becoming ever shorter. Without HAART,
10%–19% of the co-infected patients will
die during their Ž rst episode of VL and up
to 24% will die during the month following
the end of antileishmanial treatment. These
deaths are attributed to the toxicity of
the antileishmanial drugs, to complications
arising during the episode, and/or to further
opportunistic infections. The mean survival
time for a case of L. infantum/HIV co-infection
has been estimated at 4–12 months (Alvar
et al., 1997; Laguna et al., 1997, 1999;
López-Vélez et al., 1998). In terms of
prognosis, the beneŽ ts of PI treatment are
not as clear-cut for leishmaniasis as for
other opportunistic infections. Ridolfo et al.
(2000), for example, observed extensive
disseminated cutaneous leishmaniasis in a
patient 8 months after her Ž rst episode of
VL, even though the patient was receiving
treatment with PI and, at the time of her
relapse, had 157 CD4+ cells/ml and an
undetectable viral load. In the study by
Villanueva et al. (2000), Ž ve of 20 HIVpositive patients receiving PI (but no
HAART AND LEISHMANIASIS IN SPAIN
secondary prophylaxis against VL) were
found to relapse within about 15 months of
their Ž rst episode of VL; the relapses could
not be attributed to failure of the antiretroviral treatment, since all the patients
showed marked immunological improvement
(with a mean CD4+ count of 278 cells/ml
and a mean viral load of <200 copies/ml).
In another, similar study, 10 patients with
one or more previous episodes of VL were
followed for about 2 years, without secondary
prophylaxis but with PI treatment (Casado
et al., 2001). Although all 10 responded well
to the antiretroviral treatment (with a mean
of 230 CD4+ cells/ml and a signiŽ cant drop
in the viral load by the end of the second
year), seven (70%) had VL relapses. The
mean time taken to relapse (20 months)
was, however, signiŽ cantly longer than that
recorded in the patients before they began
PI treatment (13 months). In general, it
appears that, following antileishmanial treatment, the probability of a VL relapse in a
HIV-infected patient is not solely dependent
on the immunocompetence of the host (as
indicated by CD4+ counts) but is aVected
by other factors — perhaps the amastigote
load and location or the virulence and/or
antileishmanial resistance of the infecting
strain of L. infantum (Faraut-Gambarelli
et al., 1997; Kubar et al., 1998; Di Giorgio
et al., 1999). Curiously, the infection of
HIV-positives with L. infantum leads, via a
switch from a Th1 to a Th2 response, to
a drop in CD4+ counts and an increase
in viraemia (Medrano et al., 1998). Leishmanial infection therefore tends to limit the
immunological recovery expected after the
administration of HAART and may increase
viral replication and facilitate the progression
to AIDS (Clerici et al., 1993; Nigro et al.,
1999).
SECONDARY PROPHYLAXIS
AGAINST LEISHMANIASIS
Antileishmanial treatment is usually associated with clinical recovery from the VL
145
but rarely prevents numerous relapses in
those co-infected with HIV. Encouragingly,
the results of several studies now indicate
that secondary prophylaxis can help to prevent the relapses, although most of these
investigations were non-randomized and
carried out without any comparative control
groups (Pérez-Molina et al., 1996; Ribera
et al., 1996; Pintado et al., 2001; F. Pasquau,
unpubl. obs.). Laguna et al. (1997) found
such prophylaxis to have little value but most
of their patients were already seriously ill
and/or had already relapsed several times.
The only prospective and randomized trial
to compare the eVectiveness of secondary
prophylaxis (3 mg amphotericin B lipidic
complex/kg, given every 21 days) with nonprophylaxis, using a 12-month follow-up,
demonstrated that the prophylaxis was beneŽ cial, increasing the probability of being free
of illness at 12 months from 22%, seen in the
control group, to 50% (unpubl. obs.). There
has been a recent report on the beneŽ cial
eVect of the combination of HAART and
monthly secondary prophylaxis, with liposomal amphotericin B, in two co-infected
patients who showed no sign of relapsing
after 10–12 months (Mastroianni et al., 2000).
It therefore seems sensible to use maintenance therapy systematically, beginning
soon after the Ž rst episode of VL, the aim
being to prevent an early relapse and the
associated switch from a Th1- to a Th2type response. Once the patients have fully
recovered their immune function, thanks
to the PI treatment, suspension of the
prophylaxis could be considered. Berenguer
et al. (2000) investigated 15 co-infected
patients who had previously been treated for
at least one episode of VL. When, after these
patients had received monthly prophylaxis
with antimonials or liposomal amphotericin
B as well as HAART for over a year (64–70
weeks), the secondary prophylaxis was suspended, only three relapsed within the next
year (the three relapsing cases had 128–182
CD4+ cells/ml). In another study, neither of
the two VL cases under HAART and monthly
146
LÓPEZ-VÉLEZ
prophylaxis with pentamidine relapsed in 18
months of follow-up after the prophylaxis
was stopped (Soriano et al., 2000).
CLINICAL MANIFESTATIONS
The clinical manifestations of leishmaniasis
in the HIV-infected cover a particularly
wide spectrum. Clinical forms that would
be atypical in the immunocompetent are
quite common in the immunocompromised
and appear unaVected by PI treatment.
Recently, Ž rst episodes of VL were observed
in three very immunodepressed patients
to whom HAART had just begun to be
administered. Although all three had low
CD4+ counts (30–94 cells/ml ) when their
leishmanial infections became symptomatic,
they also had undetectable viral loads, raising
the possibility that their symptoms were
a consequence of PI-attributable immune
restoration ( Jiménez-Expósito et al., 1999).
This phenomenon has not, however, been
detected in any other studies, even those of
patients with proven, subclinical, L. infantum
infection when they commenced HAART
(De la Rosa et al., 2001).
CONCLUSIONS
Currently, there are simply too few data
available to be able to draw many deŽ nitive
conclusions on the impact of HAART on
VL in Spain and elsewhere, especially when
related investigations have given discordant
results. Nevertheless, the data that have been
collected indicate that HAART: (1) decreases
the number of new cases of VL (such cases
generally appearing only when the antiretroviral treatment has failed); (2) delays
but, unless the CD4+ count rises above
200 cells/ml, fails to prevent VL relapses; and
(3) may allow secondary prophylaxis (maintenance therapy) to be safely suspended
once the CD4+ count can be maintained
at >200 cells/ml. They also indicate that
VL negatively in uences the immunological
recovery of patients, although HAART seems
to have little impact on the clinical manifestations of L. infantum infection in the
HIV-positive. Further, prospective and multicentre studies are clearly needed to elucidate
the full impact of HAART on VL.
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