Download Influence of Highly Active Antiretroviral Therapy on the Outcome of

BRIEF REPORT
Influence of Highly Active
Antiretroviral Therapy
on the Outcome of Subclinical
Visceral Leishmaniasis in Human
Immunodeficiency Virus–Infected
Patients
Rafael de la Rosa,1 Juan A. Pineda,2 Juan Delgado,1 Juan Macı́as,2
Francisco Morillas,3 Joaquina Martı́n-Sánchez,3 Manuel Leal,1
Armando Sánchez-Quijano,1 and Eduardo Lissen,1
1
Viral Hepatitis and AIDS Study Group, Department of Internal Medicine, Virgen
del Rocı́o University Hospital, 2Viral Hepatitis and AIDS Study Group,
Department of Internal Medicine, Valme University Hospital, Seville,
and 3Department of Parasitology, Facultad de Farmacia, Universidad
de Granada, Granada, Spain
Seventeen human immunodeficiency virus–infected patients
who were harboring untreated subclinical visceral leishmaniasis (VL) were prospectively followed up. None of the 11
patients who received highly active antiretroviral therapy
(HAART) presented with symptomatic VL during follow-up,
whereas 2 out of 6 patients who received therapy other than
HAART had an episode of overt kala-azar. These findings
suggest that HAART does not induce the evolution of latent
VL into symptomatic disease.
The introduction of highly active antiretroviral therapy (HAART)
has modified the course of HIV infection. Because of this therapy,
HIV-infected patients who receive HAART have fewer opportunistic infections and survive longer than do HIV-infected patients who do not receive HAART [1]. However, opportunistic
diseases, such as cryptococcal meningitis [2], cytomegalovirus
retinitis [3], lymphadenitis associated with Mycobacterium avium
complex infection [4], and others, may appear a few weeks after
HAART is started, despite a significant increase in the patient’s
CD41 cell count. This fact has led some researchers to speculate
that recovery of the inflammatory response that is induced by
HAART could uncover latent disorders [5].
Visceral leishmaniasis (VL) occurs frequently in HIV-infected
Received 30 March 2000; revised 11 July 2000; electronically published 6 February 2001.
Reprints or correspondence: Dr. Juan A. Pineda, Urbanización Ntra. Sra. de la Salud, 63,
41510 Mairena del Alcor, Seville, Spain ([email protected]).
Clinical Infectious Diseases 2001; 32:633–5
Q 2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3204-0017$03.00
HIV/AIDS
patients who live in the Mediterranean basin [6]. A significant
proportion of leishmanial infections remain dormant in HIVinfected individuals [7], but some leishmanial infections evolve
into overt kala-azar [7, 8]. To our knowledge, there have been
no studies on the effect of HAART on VL. However, on the
basis of a report of cases of symptomatic VL that appeared in
patients shortly after initiation of HAART [9], we hypothesized
that some patients with latent infections could develop symptoms after initiation of such therapy. In this report, we describe
the evolution of infections in a group of patients with latent
VL who received antiretroviral therapy after VL was diagnosed.
Materials and methods. Three hundred fifty-five HIVinfected patients who attended our institution from January
1993 through August 1998 were invited, regardless of their
symptoms, to participate in a study that aimed to assess the
prevalence of VL in our area [6]. A total of 314 patients (88.5%)
agreed to be studied and underwent sternal bone marrow aspiration. All individuals gave written informed consent to participate in the study. VL was diagnosed when amastigotes were
found on Giemsa-stained slides and/or when promastigotes
were cultured on Evans modified Tobie’s medium. VL was considered subclinical if the patient met the following criteria: no
fever, no splenomegaly, and a hemoglobin level of !9 g/dL. If
there was fever, splenomegaly, or a hemoglobin level of >9 g/
dL, these conditions had to be attributable to another concomitant disease, and they had to have abated with the specific
treatment of the disease, without antileishmanial therapy.
Nineteen (6%) of these patients had subclinical VL. These
patients received antileishmanial therapy according to the discretion of the investigator and the patient’s wishes. Therefore,
2 patients were treated with antileishmanial drugs when the
diagnosis of subclinical VL was made. The remaining 17 subjects were included in the study.
The 17 patients with untreated subclinical VL were prospectively followed up every 12 weeks. At each visit, clinical,
hematological, virological, and immunological evaluations were
performed. At the least, analysis of a bone marrow aspirate for
Leishmania species was performed when patients had unexplained fever, liver or spleen enlargement, or a significant decline in the leukocyte, platelet, or RBC count. When these
symptoms coincided with a finding of Leishmania species in
bone marrow aspirates by use of Giemsa staining and/or culture
with Evans modified Tobie’s medium, a diagnosis of symptomatic VL was made.
Patients received antiretroviral therapy according to the
drugs available at the time of the study and according to inHIV/AIDS • CID 2001:32 (15 February) • 633
ternational recommendations. Protease inhibitors were not
available at our hospital until January 1997. After this time, all
patients who received care at our institution were offered
HAART, a protease inhibitor–based regimen. The reported
compliance rate among the 17 patients included in this study
was 190%.
Results. The characteristics of the study population at the
time of diagnosis of subclinical VL are shown in table 1. The
median duration of follow-up was 29 months (range, 6–66
months). Eleven patients received HAART (i.e., a combination
that includes, at least, a transcriptase inhibitor for which the
patient was naı̈ve plus 1 protease inhibitor) after a diagnosis
of subclinical VL was made. Four of these individuals (patients
3, 4, 5, and 6; figure 1) were given HAART within 4 months
after diagnosis.
For the 11 patients who received HAART, the median CD41
cell count at the start of therapy was 65 cells/mm3 (range, 1–651
cells/mm3). Nine of the 11 patients who received HAART had
increases in CD41 cell counts that were 125% of the CD41 T
cell counts at baseline (the median increase in the CD41 cell
count at week 12 after the start of HAART was 92 cells/mm3
[range, 26–336 cells/mm3]). In addition, 8 of these 11 patients had decreases in plasma virus load levels (at least 1
logarithmic unit below baseline values) 12 weeks after
HAART was started. At this time, 6 patients had plasma
HIV levels of !200 copies/mm3.
None of the patients who received HAART presented with
symptomatic VL. However, 2 of the 6 patients who did not
receive HAART had an episode of overt kala-azar occur at 24
and 26 months after diagnosis of subclinical VL (for patients
1 and 2, respectively; figure 1). These patients had CD41 T cell
counts of 20 cells/mm3 and 82 cells/mm3, respectively, at the
time that HAART was begun. One of the 4 patients who started
receiving HAART within the first few months after being given
Table 1. Characteristics of HIV-infected patients who were
receiving highly active antiretroviral therapy (HAART) at the time
of diagnosis of subclinical visceral leishmaniasis.
Characteristic
Patients
given
HAART
(n p 11)
Patients
not given
HAART
(n p 6)
Men, no. (%)
11 (100)
Age, median y (range)
31 (24–41)
33 (29–41)
5 (83.3)
CD41cell count, median
cells/mm3 (range)
119 (1–1358)
48.5 (20–120)
Duration of follow-up,
median mo (range)
32 (12–66)
28 (6–33)
Patients with risk factor, no. (%)
IDU
8 (72.7)
4 (66.7)
Non IDU
3 (27.3)
2 (33.3)
NOTE.
IDU, injection drug use.
634 • CID 2001:32 (15 February) • HIV/AIDS
Figure 1. Events during follow-up of HIV-infected patients who were
receiving highly active antiretroviral therapy (HAART) after subclinical
visceral leishmaniasis (VL) was diagnosed, month 0. Black bar, duration
without antiretroviral treatment; dark gray bar, duration of antiretroviral
treatment other than HAART; light gray bar, duration of HAART; black
circle, death; white triangle, symptomatic VL; circle with diagonal line,
lost to follow-up.
a diagnosis of subclinical VL had an episode of herpes zoster
2 months later (patient 4; figure 1). Two patients were lost to
follow-up.
Discussion. In this study, none of the 11 HIV-infected
patients with subclinical VL who were receiving HAART developed symptomatic VL, whereas 2 patients who were receiving an antiretroviral regimen other than HAART developed
overt kala-azar during follow-up. Thus, HAART does not appear to induce evolution of latent VL into symptomatic disease.
The present study is limited because of the relatively small
sample size. However, studies about the influence of HAART
on subclinical VL are lacking; to our knowledge, this is the first
report of a prospective study of HIV-infected patients with
latent VL who were receiving HAART.
Antiretroviral therapy other than HAART was not randomly
assigned to the patients that we studied, since antiretroviral
drugs were used according to their availability. This fact might
have introduced some bias. However, CD41 cell counts were
similar for all patients at the start of both regimens, a fact that
serves as an argument against the existence of a selection bias.
Some patients included in this study received HAART more
than 6 months after diagnosis of VL, but since leishmanial
infection has been reported to be a persistent disorder [7, 10,
11], it was probably present in the patients when they began
receiving HAART. In fact, 9 patients included in this study
underwent sequential bone marrow examinations as part of
another investigation; in 5 of these patients, Leishmania amastigotes were found at different times (authors’ unpublished
data). In any case, the effect of HAART on the outcome of
latent VL is undoubtedly shown by the 4 patients who started
receiving HAART within 4 months after diagnosis of VL.
After patients started receiving HAART, the appearance of
symptoms of an established subclinical infection seems to be
a consequence of the recovery of an appropriate inflammatory
response against the pathogen [12]. The lack of evolution of
latent VL into symptomatic VL in our patients should not be
attributed to either a failure to control virus replication or a
lack of increased T cell counts. In fact, significant increases in
CD41 cell counts and decreases in plasma HIV levels were
observed in most patients who were receiving HAART. Moreover, 1 patient had reactivation of an opportunistic disease
(herpes zoster).
In addition to increasing T cell counts and reducing immune
system activation, HAART leads to increased levels of T-helper
type 1 cytokines [13]. This fact could explain why patients who
were receiving HAART did not develop overt kala-azar, since
an adequate T-helper type 1 cytokine response is associated
with control of leishmanial infection [14].
If the effect of HAART on HIV-infected patients with latent
VL, as reported here, is confirmed, a drop in the incidence of
symptomatic VL should be observed in conjunction with the
use of HAART, as has been shown for other opportunistic
disorders [15]. More studies that address this issue are needed.
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