Gottfredsson 1999
Gottfredsson 1999
Gottfredsson 1999
CONCISE COMMUNICATIONS
Oropharyngeal candidiasis (OPC), primarily caused by Can- 1–infected persons [5]. It is likely that most of the decrease in
dida albicans, is relatively common in persons infected with the prevalence of opportunistic infections is due to improve-
human immunodeficiency virus (HIV) type 1. The point prev- ments in immune function in patients who receive highly active
alence of OPC in HIV-1–infected persons is 2.2%–7%, and the antiretroviral therapy (HAART) [6]. The improvements in im-
lifetime risk is 190% [1]. The presence of OPC is a predictor mune function in patients responding to HAART are incom-
of poor outcome in HIV-1–infected persons [2]. A statistical pletely understood. They do not appear to be solely reflected
association exists between few CD4 cells and the development by increases in numbers of CD4 lymphocytes, since the rise in
of OPC, but this association is weak [1, 3]. In fact, some HIV- CD4 cells in patients responding to HAART lags behind other
1–infected persons with relatively high CD4 cell counts can have qualitative and quantitative measures of immunity [5].
In order to improve our understanding of how carriage of
OPC, as can some persons with acute HIV-1 infection syndrome
yeast in the oropharynx is determined in HIV-1 disease, we
[4]. Thus, the pathophysiology of OPC remains poorly under-
conducted a cross-sectional study of several clinical factors and
stood, and factors that probably play a role in this disease are
their association with yeast colonization. Our hypothesis was
yet unidentified.
that the presence and amount of yeasts would be correlated
Recent experience suggests that the prevalence of most op-
with both plasma HIV-1 RNA levels (viral load) and peripheral
portunistic infections, including OPC, are declining in HIV-
blood CD4 lymphocyte counts. Furthermore, of these two po-
tential predictors, we believed that plasma HIV-1 RNA would
Received 23 November 1998; revised 8 April 1999; electronically published most closely correlate with yeast colonization.
9 July 1999.
Presented in part: 12th World AIDS Conference, Geneva, June–July 1998
(abstract 22214).
Informed consent was obtained from all patients prior to study partici- Materials and Methods
pation, in compliance with human experimentation guidelines of the US
Department of Health and Human Services. The study was approved by
the Duke Institutional Review Board Committee.
Study design. This cross-sectional study was conducted in an
Grant support: NATO science fellowship (to M.G.). academic medical center outpatient clinic. Baseline clinical varia-
a
Present affiliation: Hospital das Clı́nicas da Faculdade de Medicina da bles and laboratory data were collected prospectively. This clinic
Universidade de São Paulo, Brazil. provides care for 11000 HIV-1–infected patients and serves as the
Reprints or correspondence: Dr. John R. Perfect, Dept. of Medicine,
primary care provider for the vast majority of its patients.
Division of Infectious Diseases and International Health, P.O. Box 3353,
Duke University Medical Center, Durham, NC 27710 ([email protected] Patient evaluations. At enrollment, the study subjects were
.edu). interviewed and examined and asked to swish 20 mL of 0.9% sterile
saline in their mouths for 15 s and to collect the contents into a
The Journal of Infectious Diseases 1999; 180:534–7
q 1999 by the Infectious Diseases Society of America. All rights reserved. sterile container. Subsequently, 1 mL was plated onto CHROM-
0022-1899/99/8002-0042$02.00 agar (Hardy Diagnostics, Santa Maria, CA). After the plates were
JID 1999;180 (August) HIV-1 RNA and Candida Colonization 535
incubated at 307C for 48 h, growth on the plates was quantitated, parametric correlation coefficient. Bivariate and multivariable lo-
and the Candida load was expressed as colony-forming units (cfu) gistic regression analyses were then used to assess these relation-
per milliliter. If a dense growth of yeast was noted after 24 h of ships further. Poisson regression analysis was performed by use of
incubation, the culture was diluted 10-fold and replated. Colonies Candida load as the dependent variable in both bivariate and mul-
with the diagnostic green appearance were assumed to be C. al- tivariable analyses. For the Poisson regression analysis, the Can-
bicans; all other organisms were speciated by use of standard dida load was categorized as follows: no growth, 1–50 cfu/mL,
growth and morphologic criteria as well as sugar assimilation pro- 51–200 cfu/mL, 201–500 cfu/mL, 501–1500 cfu/mL, and 11500 cfu/
files (API 20; BioMerieux, Hazelwood, MO). All enrolled patients mL. Goodness-of-fit was evaluated by Pearson’s x2 test for each
had recent HIV-1 RNA and CD4 cell measurements (!30 days for model, as well as by residual plots. One outlier was identified (1533
plasma HIV-1 RNA and !90 days for CD4 cell count) CD4 cells/mL, CD4/CD8 ratio of 1.13, Candida load !25); this
while on a stable antiretroviral regimen. Most of the patients (64/ subject was influential in the models in which CD4 cell count was
83) had plasma HIV-1 RNA determined by reverse transcriptase– used as an independent variable. Since no other data points were
polymerase chain reaction (Roche Diagnostics, Alameda, CA) and in this range, we chose to delete this subject from the final analysis.
CD4 lymphocyte counts determined by flow cytometry on the same Statistical analysis was performed by use of SAS software (SAS
relation coefficients. As shown in table 2, the only predictor of in the incidence of opportunistic infections in HIV-1–infected
Candida load was plasma HIV-1 RNA (r 5 .35, P 5 .001). persons receiving HAART suggests, however, that partial re-
When only the 58 patients who were colonized with yeasts were constitution of the immune system can result from retroviral
analyzed, the correlation with HIV-1 RNA was even stronger, suppression. We hypothesized that the yeast carriage in patients
and no other potential predictors reached statistical significance with HIV-1 infection was more closely associated with the level
(data not shown). Numbers of yeasts in the oropharynx were of retroviral replication and its effects on mucosal immunity
generally low in patients with a plasma HIV-1 RNA of !4 log10 rather than on peripheral blood CD4 lymphocyte counts. This
copies/mL, but counts rose steeply in persons with higher HIV- hypothesis was based on several observations. Some patients
1 loads (14 log10 copies/mL). can have OPC during acute HIV-1 infection syndrome, when
By bivariate logistic regression analysis, the presence of Can- virus load measurements are generally very high and CD4 cells
dida species in the oropharynx was associated with higher HIV- are usually relatively preserved [4]. Furthermore, antiretroviral
1 loads (odds ratio, 1.9 for each 1 log10 HIV-1 RNA increase; monotherapy is associated with a significant reduction in OPC,
95% confidence interval, 1.12–3.09; P 5 .016). No other patient despite minimal effects on CD4 cell counts [8]. In addition,
presence and number of yeasts, in the final statistical model 2. Selwyn PA, Alcabes P, Hartel D, et al. Clinical manifestations and predictors
of disease progression in drug users with human immunodeficiency virus
(table 2). Improvements in systemic immune function that occur
infection. N Engl J Med 1992; 327:1697–703.
during HAART [5] may by mirrored at the mucosal surfaces,
3. Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis
explaining our findings of an association between HIV-1 load in HIV-infected patients: colonization, infection, treatment, and emer-
and oropharyngeal yeast colonization. Conceivably, the low- gence of fluconazole resistance. Am J Med 1994; 97:339–46.
ering of viral replication in plasma results in stronger mucosal 4. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection.
immunity, but there is no consensus on how to quantitate this N Engl J Med 1998; 339:33–9.
improvement. HIV-1 envelope proteins may directly suppress 5. Powderly WG, Landay A, Lederman MM. Recovery of the immune system
with antiretroviral therapy: the end of opportunism? JAMA 1998; 280:
phagocytosis and intracellular killing of Candida by neutrophils
72–7.
and monocytes [11, 12]. Accordingly, high degrees of viral rep- 6. Detels R, Munoz A, McFarlane G, et al. Effectiveness of potent antiretroviral
lication may facilitate yeast proliferation on the oropharyngeal therapy on time to AIDS and death in men with known HIV infection
mucosal surface by suppressing host responses. Local immune duration: multicenter AIDS cohort study investigators. JAMA 1998; 280:
function therefore may be partially restored by lowering HIV- 1497–503.