Current HIV Research, 2008, 6, 485-499 485
1570-162X/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.
Oral Candidosis in HIV-Infected Patients
Hiroshi Egusa*,1, Niroshani S. Soysa2, Arjuna N. Ellepola3, Hirofumi Yatani1 and
Lakshman P. Samaranayake4
1Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry, Suita City, Osaka 565-0871, Ja-
pan; 2Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya,
Peradeniya, Sri Lanka; 3Department of Bioclinical Sciences, Faculty of Dentistry, Health Sciences Center, Kuwait Uni-
versity, Kuwait; 4Department of Oral BioSciences, Faculty of Dentistry, University of Hong Kong, Prince Philip Dental
Hospital, Hong Kong SAR, China
Abstract: Oral candidosis (syn. Oral candidiasis; OC), is a collective term given to a group of oral mucosal disorders
caused by the fugal pathogen belonging to the genus Candida. The association of OC with the human immunodeficiency
virus (HIV) infection has been known since the advent of the acquired immune deficiency syndrome (AIDS) pandemic.
OC is one of the earliest manifestations of HIV disease in high risk individuals not undergoing chemotherapy and is also a
strong predictor of the subsequent risk of AIDS-related illness or death. With the advances in HIV therapy, such as highly
active anti-retroviral therapy (HAART), the prevalence and presenting features of OC have changed in HIV-infected indi-
viduals, especially those in industrialized countries. The presence of OC in “controlled” HIV-positive individuals may be
indicative of a patient nonadherence to therapy or possible failure. The factors contributing to the genesis of OC and its
progression in these individuals are poorly understood, but may include an interrelationship between HIV and Candida
and/or a dysfunction in the local immunity, superimposed on weakened cell-mediated immunity and depletion of CD4 T
cells. The dramatic increase in publications on this topic matches the increased importance and awareness of this oppor-
tunistic infection in HIV-infected individuals. In this review we first address the epidemiologic and clinical features of OC
in HIV-infected persons, followed by the current understanding of the pathogenesis of OC in the context of HIV infection
with a concluding section on the current management concepts of OC.
Keywords: Oral candidosis, HIV, epidemiology, pathogenesis, HAART, antimycotics.
1) HIV/AIDS Development and Oral Candidosis
is HIV-1, and the relatively uncommon HIV-2 is
concentrated in West Africa and is rarely found elsewhere
. Both types of HIV cause acquired immune deficiency
syndrome (AIDS) usually accompanied by oral candidosis
(OC). The first documented HIV/AIDS-associated OC in
patients was reported in 1981, among young active homo-
sexual men , and the unexplained OC featured promi-
nently in individuals who eventually developed AIDS. In
1992, the EC-Clearinghouse on oral problems related to HIV
infection and WHO collaborating center on oral manifesta-
tions of HIV revised and drew up a consensus classification
of the oral manifestations in HIV infection and, presumptive
and definitive diagnostic criteria for oral lesions . Accord-
ing to this classification, OC especially psudomembranous
candidosis (PC) and erythematous candidosis (EC) were
considered as group 1 lesions strongly associated with HIV
infection. There is now substantial data, accumulated over a
very short period, emphasizing its prevalence in HIV-
The predominant human immunodeficiency virus (HIV)
signs of OC also increases with advancing HIV-infection
The frequency of isolation of Candida and the clinical
*Address correspondence to this author at the Department of Fixed Prostho-
dontics, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka,
Suita-city, Osaka 565-0871, Japan; Tel: +81-6-6879-2946;
Fax: +81-6-6879-2947; E-mail: email@example.com
[4, 5]. Oropharyngeal candidosis (OPC) has been reported to
occur in from 50 to 95% of all HIV-positive persons at some
point during their progression to full-blown AIDS . In one
study of 62 HIV-infected patients microbiological recovery
of oral Candida albicans isolates was 57.7%, 76.5% and
87.5% for stage 1, 2 and 3 patients, respectively . Consis-
tent with the latter study, a recent report revealed that those
who presented with OC have 2.5 times grater risk of pro-
gression to AIDS than those without .
2) OC Prevalence in HIV-Infected Adults
prevalence of OC in HIV-infected adults in various coun-
tries. The frequency of OC in HIV infected adults reported
after 2001 range from 5.8 to 98.3%. The prevalence in Asia
ranged from 8% (India: 50 HIV-infected patients under
highly active anti-retroviral therapy: HAART ) to 98.3%
(Cambodia: 121 HIV-infected patients unexposed to antimy-
cotics ), while in Africa it ranges from 34.9% in Camer-
oon  to 80% in Kenya . The prevalence of OC in
Latin and South America varies from 28.6% (Brazil: 161
HIV-infected patients, 70.8% of those had anti-retroviral
treatment: ARVT ) to 52% (Venezuela: 75 HIV-infected
patients, 62.7% of those had ARVT ). In other industrial-
ized countries it varies from 5.8% (the US: 294 HIV-infected
adolescents, 45.6% of those had ARVT ) to 84.6% (Rus-
sia: 13 AIDS patients ). The current figures on the preva-
lence of the OC in HIV-infected populations of the develop-
ing countries are similar to those from earlier studies .
On the other hand, the epidemiology of OC in the post-
Table 1 summarizes the recent reports on the global
486 Current HIV Research, 2008, Vol. 6, No. 6 Egusa et al.
HAART era indicates that the prevalence of OC is declining
in populations in industrialized countries with the introduc-
tion of better HIV therapies. For instance Greenspan, et al.
investigated changes in the pattern of oral disease associated
with HAART in a clinical population, and reported a de-
crease in the prevalence of OC during the period 1990-2000
in the US , although OC is still the most common HIV-
related oral condition in various populations world wide
3) Age and OC in HIV Infection
tion between age and the presence of OC. McCarthy, et al.
There is contradictory evidence available on the associa-
reported that OC is twice as likely to occur in patients over
35 years of age in comparison to the younger patients .
Shiboski, et al. investigated 294 HIV-infected adolescents
(13-19 years of age) and reported that the most common
HIV-related oral lesion was OC (5.8%) although its preva-
lence was lower than that reported among both adults and
children . This may be due to a more robust immune
system in HIV-infected adolescents in comparison to HIV-
infected adults as most of the T lymphocytes that populate
the immune system develop in the thymus before its involu-
tion in late adolescence [20, 21]. In addition, the use of den-
tal prostheses is known to increase the frequency of EC,
which often presents as denture stomatitis, and thus the
Prevalence of OC in HIV Infected Adults in Various Countries (Reports Published After 2001)
Umadevi, et al. (2007) 
Sharma, et al. (2006) 
Ranganathan, et al. (2006) 
Shobhana, et al. (2004) 
Ranganathan, et al. (2004) 
Kerdpon, et al. (2004) 
Kerdpon, et al. (2004) 
Nittayanata, et al. (2001) 
Khongkunthian, et al. (2001) 
Schmidt-Westhausen, et al. (2004) 
Bendick, et al. (2002) 
Pichith, et al. (2001) 
Liu, et al. (2006) 
Lim AA, et al. (2001) 
Tirwomwe, et al. (2007) 
Josephine, et al. (2006) 
Chidzonga MM (2003) 
Taiwo, et al. (2006) 
Agbelusi and Wright (2005) 
Anteyi, et al. (2003) 
Kamiru and Naidoo (2002) 
Butt, et al. (2007) 
Butt, et al. (2001) 
Latin and South America
Ramirez-Amador, et al. (2003) 
Pinheiro, et al. (2004) 
Bravo, et al. (2006) 
Gileva, et al. (2004) 
Kroidl, et al. (2005) 
Nicolatou-Galitis (2004) 
Zakrzewska and Atkin (2003) 
Shiboski, et al. (2001) 
ABBREVIATIONS: OC (oral candidosis), PC (pseudomembranous candidosis), EC (erythematous candidosis), AC (angular cheilitis), HC (hyperplastic candidosis), OI (opportu-
nistic infections), ARV (anti-retroviral), HAART (highly active anti-retroviral therapy).
Thailand (North & South)
Nigeria (Plateau state)
Russia (Perm region)
Oral Candidosis in HIV-Infected Patients Current HIV Research, 2008, Vol. 6, No. 6 487
higher frequency of OC in older HIV-infected patients could
therefore be related to the use of dental prostheses .
tion between OC and age [7, 23]. These contradictory find-
ings suggest a need for further studies on this subject. None-
theless, OC has value in predicting the progression to AIDS
in children as well . According to the consensus classifi-
cation for oral lesions in children, using the frame-work of
the EC-Clearinghouse and WHO , OC, especially EC,
PC and angular cheilitis (AC) are considered as group 1 le-
sions commonly associated with pediatric HIV infection. Its
prevalence in children reported after 2001 varies from 11%
(Uganda: 109 HIV-infected children older than 18 months
) to 63% (South Africa: 98 HIV-infected outpatients
: Table 2). Iosub, et al. reported that 50% of 42 children
with perinatal HIV infection or pediatric AIDS had oral and
cutaneous candidosis in the first year of life as opposed to
10% of 20 children who were diagnosed to have AIDS after
this period .
In contrast, other investigators have reported no associa-
4) Gender and OC in HIV Infection
on the association between OC and gender. Since HIV infec-
tion affects an increasing number of women in the US, Shi-
boski, et al. investigated the role played by gender in the
occurrence of HIV-related oral conditions in a prospective
study of 3 epidemiological cohorts in the early 1990s .
The occurrence of OC was higher in men (24%) than in
women (13%) during the study period. In contrast, an earlier
study by Arendorf, et al. reported that OC was slightly more
prevalent in women (46%) compared to men (37%) among
600 HIV-infected heterosexuals in South Africa . On the
other hand, in contrast to aforementioned studies Ramirez-
Amador, et al. reported no gender predilection in OC among
436 HIV-infected patients in Mexico from 1989 to 1996
. This tendency is consistent with a recent study by
Sroussi, et al. investigated among 415 HIV-infected patients
treated in 2005 in the US .
Similar to that of age confusing results has been reported
transmission in several populations. The study by Arendorf,
et al. reported that 88 homosexual males had a higher preva-
OC has also been associated with specific modes of HIV
lence of OC (49%) than 115 heterosexual males (37%) .
This could be due to the increased practice of oro-genital sex
among homosexuals in comparison to heterosexuals .
OC in the foregoing information could be due to various
factors that include race, gender, age, risk behaviors, geo-
graphical location, socio-economic and immune status, dura-
tion of HIV infection, medication, method of subject selec-
tion, number of subjects examined, diagnostic criteria used,
and timing of evaluation of subjects [16, 35]. In addition,
inappropriate assessment and diagnosis of OC in HIV-
infected patients by non-specialists may result in such varia-
tions [36-38]. For instance, Hilton, et al. reported a signifi-
cant difference in the diagnostic accuracy between medical
and dental specialists regarding HIV-related oral lesions in
HIV-infected patients, which indicated a lower diagnostic
ability of medical specialists in comparison to dental special-
ists, and they thus concluded that the true association of spe-
cific oral lesions with other HIV phenomena, such as the
time until full-blown AIDS develops, may therefore be
stronger than the literature has previously suggested .
HIV-related OC is considered to be a useful adjunct to labo-
ratory data, such as CD4 counts, for understanding the epi-
demiology of HIV disease. Hence, well-designed and -
documented studies using the same data collection methods
are necessary to make a correct assessment of the nature and
magnitude of this opportunistic infection, if oral health
measures are to be effectively formulated for the HIV-
The large variations reported in prevalence studies for
CLINICAL FEATURES OF CLINICAL VARIANTS
are PC, EC, AC and hyperplastic candidosis (HC). Of these
the most common presentations include PC and EC, which
are equally predictive of the development of AIDS . Re-
cent information (Table 1), reveal that PC and EC occur in
more than one in two individuals with OC. AC is the next
most common entity followed by HC. Clinically, a combina-
tion of PC, EC and AC could often appear in a single indi-
vidual with HIV infection. Another noteworthy feature of
OC in HIV infection is the presentation of the disease in
The four distinct clinical variants of OC in HIV infection
Prevalence of Clinical Variants of Oral Candidosis in Children with HIV Infection (Reported After 2001)
Authors (Year) [Ref.] Country (Region) No. of Subjects (% Male) OC
Reichart, et al. (2003) 
Khongkunthian, et al. (2001) 
Ranganathan, et al. (2006) 
Blignaut E (2007) 
Naidoo and Chikte (2004) 
Bakaki, et al. (2001) 
Miziara, et al. (2006) 
Magalhaes, et al. (2001) 
Santos, et al. (2001) 
Vaseliu, et al. (2006) 
Flaitz, et al. (2001) 
ABBREVIATIONS: OC (oral candidosis), PC (pseudomembranous candidosis), EC (erythematous candidosis), AC (angular cheilitis), HC (hyperplastic candidosis), OI (opportu-
nistic infections), ARV (anti-retroviral).
98 (55) outpatients
71 (54) institution patients
136 (NA) <18 months
109 (NA) >18 months
488 Current HIV Research, 2008, Vol. 6, No. 6 Egusa et al.
multiple oral sites. This phenomenon has infrequently been
documented in HIV-negatives as chronic multifocal OC.
1) Psudomembranous Candidosis
adherent, whitish yellow, soft and creamy or sometimes con-
fluent membranes (Fig. 1A) caused by overgrowth of fungal
hyphae mixed with desquamated epithelium and inflamma-
tory cells. The membranous plaques can be wiped off from
the mucosa by wiping with a gauze swab leaving a raw,
erythematous and sometimes a slightly bleeding surface.
This acute disease may persist intermittently for several
months or even years in HIV-infected patients if untreated.
The lesions may be associated with a variety of symptoms
such as a burning mouth, problems of eating spicy food, and
changes in taste. PC can occur in any area of the oral mucosa
involving tongue, hard palate, soft palate and buccal mucosa
 and may sometimes spread into the adjacent mucosa,
particularly that of the oesophagus and upper respiratory
tract. The combination of OC and oesphageal candidal infec-
tion is particularly prevalent in HIV disease . The clini-
cal diagnosis is based on the patient’s appearance, as well as
on the patient’s medical history and virologic status.
PC or classically termed as “thrush” presents as a semi
2) Erythematous Candidosis
oral manifestation of HIV disease . Similar to that of PC,
the diagnosis is based on appearance. The condition presents
as a red, flat, subtle lesion most frequently affecting the hard
or soft palates (Fig. 1B), buccal mucosa, and the dorsum of
the tongue with associated depapillation [40, 43]. EC should
be differentiated from other red lesions, such as Kaposi's
EC may be the most underdiagnosed and misdiagnosed
sarcoma or erythroplakia. EC may present as a “kissing”
lesion – if a lesion is present on the tongue, and the palate
should be examined for a matching lesion, and vice versa
. The condition tends to be symptomatic, with patients
complaining of oral burning, most frequently while eating
salty or spicy foods or drinking acidic beverages. Ramirez-
Amador, et al. reported that patients who contracted HIV
through blood transfusion were more likely to present EC
than subjects who acquired HIV through sexual transmis-
sion, thus suggesting a significant association between EC
and blood transfusion .
3) Angular Cheilitis
erythematous fissuring at one or both angles of the mouth,
with or without ulceration (Fig. 1C), and may be accompa-
nied by subjective symptoms of soreness, tenderness, burn-
ing or pain. It can appear alone or in conjunction with an-
other form of candidiasis such as EC or Candida associated
denture stomatitis. Organisms other than Candida are impli-
cated as interacting factors in AC. These include especially
Staphylococcus aureus and streptococci.
AC also known as angular stomatitis or perleche is an
4) Hyperplastic Candidosis
common variant in OC in HIV-positive patients, and the le-
sions appear white and hyperplastic (Fig. 1D) whilst others
may present as papillary hyperplasia (Fig. 1E) . The
white areas are due to hyperkeratosis and, unlike the plaques
of PC, cannot be removed by scraping. HC lesions are also
associated with tobacco smoking . These lesions may be
confused with hairy leukoplakia and hence diagnosis of HC
Also known as candidal leukoplakia, HC is the least
Fig. (1). (A) Pseudomembranous candidosis (PC) of the labial mucosa and maxillary gingiva of an AIDS patient. (B) Erythematous candido-
dis (EC) of the palatal mucosa in an HIV-positive patient. (C) Angular cheilitis (AC) in an HIV-infected child. (D, E) Appearance of hyper-
plastic candidosis in the right buccal mucosa of an HIV-negative patient (D) and in the palatal mucosa of an HIV-infected patient (E). Figu-
res (A) and (B) were taken from J Oral Pathol Med  and (E) from J Oral Pathol Med  with permission from the authors.
Oral Candidosis in HIV-Infected Patients Current HIV Research, 2008, Vol. 6, No. 6 489
is based on the histological appearance of hyperkeratosis and
the presence of hyphae. Furthermore, biopsy is also impor-
tant as HC is considered to be premalignant.
PATHOGENESIS AND ETIOLOGIC FACTORS
fection may have a predisposition to develop candidal infec-
tions in the oral cavity are depicted in Fig. (2).
The possible pathogenic mechanisms by which HIV in-
1) Pathogen in HIV-Associated OC
i) Prevalence of Candida Species in HIV-Associated OC
infected patients. While C. albicans is generally considered
to be the most pathogenic of all Candida species, a variety of
other members of this genus, notably C. krusei, C. parapsi-
losi, C. glabrata, C. tropicalis, and C. dubliniensis, have
been cited as the causative agents of OC and isolated in
HIV-associated OC [9, 46]. A study of 125 HIV/AIDS pa-
tients in India who had no history of prior antifungal treat-
ment reported colonization of the oral cavity with more than
one Candida species including C. albicans (86%), C. parap-
silosi (8%), C. grabata (3%) and C. krusei (3%) .
Schmidt-Westhausen, et al. reported that C. albicans, in
comparison to non-albicans species, is significantly more
prevalent in HIV-infected patients than in healthy patients in
Multi-species oral yeast colonization is common in HIV-
Cambodia . Although C. albicans is the most common,
they also noted a high carriage rate of C. krusei in HIV-
infected population (11.2%). This may be because the later is
intrinsically resistant to fluconazole commonly prescribed
for candidosis in HIV infection. Since C. albicans is the
most virulent of all Candida species it could be surmised that
it has the potential to survive and overcome the antifungals
and thrive in an environment of immune depletion. Indeed,
recent studies have shown the ability of C. albicans to un-
dergo ‘genetic shuffling’ that favors its continued persistence
in the oral cavity in HIV-infected individuals . Another
study reported that the phenotypical expression of C. albi-
cans changes in the majority of HIV-infected individuals
during the progression of their disease . C. dubliniensis,
which is closely related to C. albicans, has been implicated
in OPC in HIV-infected individuals and has been recovered
from the oral cavities of HIV-negative individuals as well
[50, 51]. Most reports on C. dubliniensis are in relation to
HIV-infected patients , although this species seems to be
less frequently isolated in adult HIV-infected individuals [9,
46, 47]. There is a distinct difference between the oral yeast
species carried by adults and children infected by HIV. Blig-
naut reported that the prevalence of C. albicans was lower
(40.4%) while the prevalence of C. dubliniensis (26.3%), C.
grabata (10.5%) and C. tropicalis (10.5%) was significantly
Fig. (2). A diagram of etiologic factors of importance in the pathogenesis of HIV-associated OC.
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490 Current HIV Research, 2008, Vol. 6, No. 6 Egusa et al.
higher among the children than among adult HIV/AIDS pa-
tients in South Africa .
ii) Drug Resistance in Candida
came a clinical issue with the arrival of the AIDS epidemic.
In patients with HIV-associated OPC, acquired resistance to
fluconazole was widely reported at the peak of this epidemic.
In vitro resistance was seen to be closely correlating with the
clinical therapeutic failure . Acquired resistance has been
more commonly reported in species other than C. albicans.
C. glabrata is generally documented as being the second
most common cause of invasive candidiasis and it has a re-
duced susceptibility to fluconazole in comparison to C. albi-
cans. The mechanisms of acquired resistance are varied and
complex [55-57]. Azole resistance appears to involve an
increased expression of multidrug transporter genes, causing
azole efflux from the fungal cells. There may also be muta-
tional changes to the cell’s Erg 11 gene, and/or overproduc-
tion of ergosterol.
iii) Candidal Virulence and HIV Infection
Acquired resistance by Candida to antifungal agents be-
show an enhanced virulence, as implicated by antifungal
sensitivity  and enhanced adherence capacity to epithe-
lial cells , which is independent of their immune status.
In addition, some studies showed that the secretion of se-
creted aspartyl proteinases (SAP), one of the major virulence
factors of C. albicans, is produced to a higher extent by C.
albicans isolates from HIV-positive individuals in compari-
son to isolates from uninfected subjects [60-62]. Further-
more, the HIV-1 envelope protein gp160 as well as its
transmembrane gp41 subunit are able to bind to Candida
species and selectively enhance candidal virulence, increas-
ing SAP production after this interaction [63-65]. These in-
teractions of HIV-1 with Candida species may thus affect
the outcome of fungal infection in HIV-associated OC.
Some C. albicans isolates from HIV-infected subjects
2) HIV-Infected Host Factors Against OC
i) Cell-Mediated Immunity
Cell-Mediated Immunity (CMI) by CD4+ Th1 (T helper
1)-type cells is considered to be the predominant host de-
fense mechanism against OC in HIV-infected individuals, as
evidenced by the high incidence of OC in HIV-infected pa-
tients with reduced CD4+ T cell numbers, systemically drop-
ping below 200 cells/μL . OC with CD4 counts of
<98/μl are reported to be associated with severe immuno-
suppression in the HIV-infected individuals [67, 68]. Some
early studies in HIV-positive patients suggested the suscep-
tibility to OPC to be enhanced under reduced CD4+ T-cells,
due to either a lack of protective Th1-type responses and/or a
shift to susceptible Th2-type responses . However, there
have been a recent study evaluating peripheral blood mono-
nuclear cells (PBML) reactivity in HIV-negative and HIV-
positive persons, with or without symptomatic OPC and
stratified by CD4+ T-cell numbers. This study showed that
Candida-specific systemic CMI, including Candida-specific
proliferation or Th1/Th2 cytokine production, does not ap-
pear to be appreciably different between the groups despite
the correlation of OPC with reduced CD4+ T cell counts in
HIV-positive persons . These findings suggest that the
Candida-specific T-cells themselves are not becoming defec-
tive with immunosupression, but that a threshold number of
CD4+ T-cells in peripheral blood under the weakened sys-
temic immune system is required to protect the oral cavity
Below the CD4+ cell threshold in HIV-infected individu-
als, protection becomes dependent on several locally associ-
ated immune mechanisms. HIV-infected individuals with
OPC have a shift in the Th cytokines in saliva from Th1- to
Th2-type . The cytokines produced by Th1 cells, such as
interferon (IFN)-gamma, transforming growth factor (TGF)-
beta, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha,
and IL-12, are known to activate phagocytic cells, thus lead-
ing them to transform into a candidacidal state. In contrast,
the cytokines produced by Th2 cells, such as IL-4 and IL-10,
inhibit Th1 development and deactivate phagocytic effector
cells. Tascini, et al. reported the inhibition of candidacidal
activity in polymorphonuclear leukocytes (PMNL) by IL-4
and IL-10 and this phenomenon is emphasized in HIV-
infected patients, thus suggesting that these cytokines may
thus play a role in mediating an increased susceptibility to
OC during AIDS progression .
ported to be associated with the accumulation of CD8+ T-
cells at a considerable distance from the Candida located
superficially at the outer epithelium . In addition, the
accumulated CD8+ cell number is significantly higher in the
oral lesions from HIV-positive persons with OPC than from
those without OPC, suggesting an important role of CD8+ T-
cell for oral host defense against HIV-associated OPC .
The accumulated mucosal migratory-challenged CD8+ T-
cells were further characterized, thus indicating that they are
not natural killer (NK) T-cells or anti-HIV CD8+ T-cells but
normal memory T cells in an activated state . The accu-
mulated CD8+ T-cells in OPC-infected tissue is correlated
with a significant reduction in the adhesion molecule E-
cadherin , which is normally localized to the epithelium
and necessary for CD8+ T-cell migration. This suggests a
dysfunction in the local microenvironment of this subset of
OPC-infected individuals. Using CD8 knockout transgenic
mice expressing HIV-1 a recently study demonstrated that
CD8+ T-cells participate in the HIV-infected host defense
against OC . These findings indicate that CD8+ T-cells
and E-cadherin appear to be a major local factors in suscep-
tibility to OC with reduced tissue associated E-cadherin as a
microenvironment dysfunction, which inhibits the migration
of the normal memory CD8+ T-cells to the organism. This
process thus contributes to the occurrence of OC in those
HIV-positive individuals with low CD4+ T-cell levels.
ii) Innate Cellular Immunity
The local CMI against OC in HIV-infected person is re-
defense against mucosal C. albicans infections . Oral
epithelial cells have been shown to inhibit the growth of
Candida species in vitro with a strict requirement for cell
contact with the pathogens . This direct anti-Candida
activity is reduced in HIV-positive subjects with OC ,
providing support for epithelial cells as an innate protective
mechanism and when that activity is reduced, it contributes
to the susceptibility to infection. In addition, oral epithelial
cells actively respond to candidal invasion and cell injury by
Oral epithelial cells and PMNL are the first line of host
Oral Candidosis in HIV-Infected Patients Current HIV Research, 2008, Vol. 6, No. 6 491
producing both cytokines and chemokines, which may con-
tribute to the innate and/or adaptive immune response [80-
82]. Lilly, et al. reported low Candida-induced epithelial cell
cytokine production from HIV-positive persons, although
these cells can contribute, at some level, to the oral cytokine
milieu in response to Candida infection .
tion [84, 85], particularly in the later stages of the disease
with a selective defect in CD88 expression on PMNL .
PMNL is essential for an effective antifungal response and
PMNL dysfunction is thus a critical risk factor for develop-
ing disseminated invasive fungal disease . In addition,
PMNL seems to play a role at a local site as an anti-OC
mechanism, since a study using reconstituted human oral
epithelium showed that PMNL enhance oral epithelial re-
sponses for Th1-type cytokines but inhibit Th2-type cytoki-
nes associated with protection against Candida infection
. Therefore, the abnormal function of PMNL at the local
infection site may predispose HIV-infected individuals to
PMNL function is impaired in the course of HIV-1 infec-
immunity, thereby playing a role in the early defense against
fungal infections . Antifungal immunity mediated by NK
cells occurs by the secretion of cytokines, such as IFN-
gamma, which activate phagocytes . Recently,
Murciano, et al. demonstrated that C. albicans inhibits IFN-
gamma secretion by NK cells in response to the Toll-like
receptor ligands . In addition, progressive immunosup-
pression by infection with HIV-1 includes suppression of the
natural immunity mediated by NK cells, primarily because
of their qualitative defect reducing responsiveness to IFN-
alpha . Therefore, the weakened NK cell activity due to
HIV infection and C. albicans interaction would contribute
to promote C. albicans survival in the oral mucosa of HIV-
infected individuals. Further studies are warranted to evalu-
ate the direct and/or indirect effects of HIV infection on oral
mucosal immunity affecting CMI and the innate immunity
which predisposes an individual to develop OC.
iii) Humoral Immunity
NK cells constitute an important component of innate
(IgG) and mucosal IgA and IgG, can be detected both in
most healthy and HIV-infected individuals . Early stud-
ies that examined humoral immunity in saliva during HIV
infection reported that, among the several changes in total
IgA and IgG antibody levels, levels of Candida-specific IgA
antibodies were elevated in HIV-positive persons, in com-
parison to the levels in HIV-negative persons [94-96]. In one
study, in which saliva samples were examined from HIV-
infected individuals with and without OPC, elevated levels
of IgA antibodies specific to C. albicans-SAP were found in
persons with OPC, although these antibodies were not effi-
cient in limiting candidal infection . However, a recent
study by Wozniak, et al. showed that the humoral immunity
does not actively play a role in protection against or suscep-
tibility to OC in HIV-positive patients. They conducted a
comprehensive analysis of saliva from HIV-negative and
HIV-positive individuals, stratified by their OPC status and
peripheral CD4+ cell count, to measure the levels of total and
Candida-specific IgA and IgG antibodies. After the appro-
priate normalization of their data, their results showed that
Candida-specific antibodies in saliva were found to be simi-
Anti-Candida antibodies, circulating immunoglobulin G
lar in those with or without OPC. Hence it seems that Can-
dida-specific antibodies have little to no role in humoral
immunity in resistance or susceptibility to OPC that would
account for the prevalence of OPC among HIV-positive in-
3) Other Factors
prerequisite for initial colonization and subsequent infection.
One study evaluated the factors affecting the adherence of C.
albicans to buccal epithelial cells (BEC) in HIV, and showed
that C. albicans adhered more readily to BECs from HIV-
infected individuals than to cells from an HIV-free cohort.
This finding also correlated with use of zidovudine, antibac-
terials and antiparasitics, suggesting that the quality of BEC,
thus including their receptivity to Candida may play an im-
portant part in increasing the oral yeast carriage in HIV in-
Recent studies have implicated an increase in gonococ-
cal, genital chlamydial and Methicillin-resistant Staphylo-
coccus aureus (MRSA) infections in HIV-infected individu-
als [99, 100]. Broad-spectrum antibiotics used in the treat-
ment of a wide range of disease conditions have also been
attributed as a predisposing factor of OC possibly because of
changes in oral environment (fine balance of fungal and bac-
terial flora) and/or in the immune response reducing neutro-
phil candidacidal activity .
Candida adherence to oral epithelial cells is an essential
infected individuals accompanied by altered state of local
immunity . Slavinsky, et al. reported that smokers often
acquire OP when CD4 cell levels drop to <500 cells/μL al-
though 200 CD4 cells/μL is the most common threshold
Cigarette smoking is a major risk factor for OC in HIV-
changed the course of HIV infection. Concurrently, a marked
decrease in the overall incidence of oral lesions, especially
OC, was reported in patients receiving HAART [8, 103-
105]. The marked decrease of oral lesions following
HAART is attributed to immune reconstruction after the re-
duction of the viral burden. Nicolatou-Galitis, et al. reported
that the introduction of HAART was associated with a sig-
nificant decrease in the prevalence of OC coupled with an
improved CD4 count . Furthermore, recent reports re-
vealed HAART to be effective as antifungals against C. albi-
cans. Greenspan, et al. showed that HAART reduced the
incidence of EC (5.48% to 2.99%) and PC (6.7% to 2.85%)
and that recurrence of OC was also reduced independent of
CD4 and HIV-RNA . HAART therapy involves the use
of at least three anti retro-viral (ARV) agents including pro-
tease inhibitors (PI). Several studies evaluated the direct,
early, immune reconstitution-independent effect of PI on the
prevention of OC, which was attributed to the induction of
SAP by HIV envelope proteins . Isoforms of SAP are
identified as major virulence factors of the C. albicans and
contribute to the pathogenesis in HIV-positive individuals.
HIV PI have a direct attenuating effect on C. albicans se-
creted SAP [107, 108]. An investigation was prompted by
the fact that both SAP and HIV protease belonged to the
The introduction of HAART in 1996 dramatically
492 Current HIV Research, 2008, Vol. 6, No. 6 Egusa et al.
superfamily of aspartic proteinases and by the observation
that mucocutaneous infections which, resolved even in the
absence of an immunological improvement of the host. In
addition, HIV PI were found to attenuate adhesion of C. al-
bicans to epithelial cells . Some believe that the anti-
fungal effect of antiretroviral PI is equivalent to fluconazole
[107, 110]. However, the HIV PI, ritonavir does not inhibit
all protease-secreting oral yeast isolates, possibly because
there is a synergistic effect between ritonavir and oral anti-
fungals against fungal resistance . The interaction be-
tween antiretroviral PI and routine oral antifungals needs to
be further investigated. In the future, derivatives of HIV PI,
being more specific for the fungal SAP, and preferably cov-
ering all SAP isoenzymes, may form an alternative for
treatment of OC in HIV-infected individuals insensitive to
currently available antimycotics .
On the other hand, OC has been proposed to be a clinical
marker of HAART success or failure as well. A study that
examined 151 patients with HIV/AIDS showed that the pres-
ence of OC was closely related to immune failure in patients
with HIV/AIDS undergoing HAART. The probability of
immune failure in the presence of OC was 91% for men who
have sex with men, 95.5% for heterosexuals, and 96% for
intravenous drug users . Another study using 124 HIV-
infected patients who used HAART for a minimum of six
months were prospectively evaluated. OC had a high predic-
tive value for immune failure and a moderated predictive
value for virologic failure suggesting that OC seems to be a
better predictor of immune and virologic failure in patients
undergoing HAART . In the post-HAART era, OC has
been less frequent, and it either recurs or develops de novo
with HAART failure and multi-drug resistance. Furthermore
new and poorly understood paradigms are emerging includ-
ing a possible upsurge in the prevalence of oral warts 
and with the possibility that, CD4+ T-cell counts and the
prevalence of OC may not correlate with time .
are used to treat OC in HIV-positive patients. The main
classes of antifungals in recent clinical use are the polyenes
(nystatin and amphotericin B), the imidazoles (ketoconazole,
clotrimazole and miconazole), the triazoles (fluconazole,
itraconazole and posaconazole) , and newer agents such
as caspofungins . Table 3 shows the different treatment
regimens employed to treat OC in HIV infected adult pa-
A number of topical and systemic antifungal medications
Comparison of Drug Regimens and Efficacy in the Treatment of OC in Individuals with HIV Infection
Drug A Drug B
Drug (n) Dose and Duration
Drug (n) Dose and Duration
De Wit, et al.
De Wit, et al.
Graybill, et al.
Phillips, et al.
Koletar, et al.
Pons, et al.
Vazquez, et al.
Pons, et al.
Linpiyawan, et al.
Murray, et al.
Smith, et al.
et al. (1996) 
Van Roey, et al.
Fluconazole (n=18) 50 mg/d/28days 100%
Ketoconazole (n=19) 200 mg/d/28days 75%
Fluconazole (n=20) 150 mg stat 75% Itraconazole (n=20) 100 mg/d/7days 24%
200 mg on day 1
87% Itraconazole (n=64)
Fluconazole (n=86) 100 mg/d/14day s 90% Itraconazole (n=79)
Fluconazole (n=19) 100 mg/d/14days 100% Clotrimazole (n=20) 10 mg troches/5x per day/14days 65%
Fluconazole (n=176) 100 mg/d/14days 91% Clotrimazole (n=158)
10 mg/5x per day/14days 85%
200 mg on day 1
200 mg on day 1
200 mg on day 1
87% Nystatin (n=84) 500,000 U/4x per day/14days 52%
Itraconazole (n=14) 100 mg/10ml/b.i.d/7days
66.7% Clotrimazole (n=15) 10 mg/5x per day/7days 73.3%
Itraconazole (n=61) 200 mg/d/14days 77% Clotrimazole (n=62) 10 mg/5x per day/14days 70%
Itraconazole (n=59) 200 mg/d/28days 93% Ketoconazole (n=52) 200 mg/b.i.d/28days 93%
Itraconazole (n=51) 200 mg/d/14days 71% Ketoconazole (n=55) 200 mg/d/14days 60%
Miconazole nitrate (n=178)
10 mg/d/7-14days 87% Ketoconazole (n=179) 400 mg/d/7-14days 90%
Ravera, et al.
Arathoon, et al.
Miconazole (n=85) 250 mg/ 4x per day/7 days 100%
Nystatin 1,000,000 IU/3x per day/ 7 days 100%
Capsofungin acetate (n=105)
35-70 mg/d/7-14days 74-91% Amphotericin B (n=35) 0.5 mg/Kg body weight/7-14days 63%
Oral Candidosis in HIV-Infected Patients Current HIV Research, 2008, Vol. 6, No. 6 493
inhibitors, are commonly used for the treatment of OC asso-
ciated with HIV/AIDS. Although the use of amphotericin B
preparations is complicated by its significant toxicity, intra-
venous amphotericin B has been found to be effective in the
treatment of azole-refractory candidiasis. Clinical cure rates
of 63% have been reported for intravenous amphotericin B
. Topical amphotericin B therapies are effective for
uncomplicated OPC; however, patients relapsed more
quickly than those treated with oral systemic antifungal ther-
apy . Nystatin appears to be less effective than the
azoles in the treatment of OC . Clinical cure rates for
nystatin range from 52%  to 100% . These
polyenes may be an option to be considered in the empirical
therapy of primary OC, since the inappropriate use of the
more useful azoles as the first drug of choice may result in
eventual emergence of resistant strains, thus rendering the
drug worthless .
Amphotericin B and nystatin, the ergosterol biosynthesis
OC, and its main indication is for secondary OC, such as in
chronic mucocutaneous candidosis . With ketocona-
zole, the clinical response rate lies with between 60% 
and 93% . As Ketoconazole interferes with the metabo-
lism of certain therapeutics, drug interactions should be
taken into consideration when prescribing it for patients.
Clotrimazole or miconazole as a cream or gel are particularly
useful in the treatment of AC where concurrent bacterial and
fungal infection is present. Clotrimazole has been reported to
have clinical cure rates ranging from 65%  to 85%
. The development of cross resistance of C. albicans to
different imidazoles during treatment of with a single azole
derivative has been described . The emergence of resis-
tance of C. albicans to clotrimazole in HIV-infected children
has been reported . It is therefore, salutary to keep this
behavior of C. albicans in mind when planning treatment
protocols involving azoles against OC in HIV-infected pa-
Ketoconazole has no place in the treatment of primary
for the treatment and prophylaxis of OC in HIV/AIDS pa-
tients . Fluconazole and itarconazole appear to be more
effective in managing OC in HIV infected patients in com-
parison to nystatin or clotrimazole [124, 125, 129]. The effi-
cacy of fluconazole is reported to range from 87%  to
100% , thus resulting in an almost complete clinical
response. However, one of the drawbacks with both the imi-
dazoles and the triazoles is the frequent relapse of the condi-
tion after clinical recovery and cessation of treatment. There
are reports of relapse in fluconazole treated groups ranging
from 18%  to 34% . Nevertheless, either mainte-
nance therapy or intermittent therapy with fluconazole is
essential to prevent relapses after cessation of treatment.
Revankar, et al. found that in patients with frequent recur-
rences, continuous fluconazole was more effective than in-
termittent administration in preventing clinical episodes from
occurring . Others feel that maintenance therapy is not
warranted and intermittent therapy is adequate .
Fluconazole is the drug routinely and widely prescribed
zole increases the risk of developing azole-resistant C. albi-
cans and selection of non-albicans Candida species such as
C. glabrata , which further complicates patient man-
agement. OC refractory to fluconazole is emerging world
wide and has been documented in 4-5% of HIV-infected
patients, especially in those with advanced disease .
The use of another triazole antifungal, itraconazole, with
systemic properties has resulted in clinical improvement of
fluconazole refractory OC in HIV-infected patients. The
clinical response from itraconazole treatment for 14 days
seems to bring a 71%  to 97%  clinical response
rate. In one study Saag, et al. reported clinical responses in
55% of HIV/AIDS patients with fluconazole-unresponsive
OC . However, it is generally preferred not to use itra-
conazole or another member of this class when drug resis-
tance to fluconazole in Candida species is observed. There
are data from a study of Candida isolates in HIV-positive
patients indicating a high level of cross-resistance to itra-
conazole in fluconazole-resistant C. glabrata and C. tropi-
calis in comparison to C. albicans and C. krusei isolates
. Unless in vitro susceptibility testing is readily avail-
able, it would therefore be sensible to avoid itraconazole
where fluconazole resistance has been reported .
There is another concern that prolonged use of flucona-
tent in vitro activity against Candida species other than C.
albicans, such as C. glabrata and C. krusei. A recent multi-
center randomized trial demonstrated that posaconazole was
as effective as fluconazole for producing a successful clinical
outcome and it more effectively demonstrated a sustained
clinical success after treatment was stopped . In addi-
tion, posaconazole is an effective treatment option for HIV-
infected subjects with azole-refractory OC. Skiest, et al.
evaluated the efficacy of posaconazole for HIV-infected sub-
jects with OC who were clinically refractory to treatments
with oral fluconazole or itraconazole, thus resulting in the
clinical response rates of 73 and 74%, respectively .
Posaconazole is an extended-spectrum triazole with po-
and it is a synthetic derivative of fluconazole, with fungicidal
activity against moulds . It is generally well tolerated,
and the reported side effects rarely lead to the drug therapy
being discontinued. Clinical findings suggest that voricona-
zole may become an effective therapeutic option for candidi-
asis because of increases in fluconazole resistant Candida
isolates. In a multicenter, randomized, double-blind, double-
dummy study, voriconazole was shown to be at least as ef-
fective as fluconazole in the treatment of oral and esophageal
candidiasis in immunocompromised patients . Further-
more, voriconazole has also been used successfully in flu-
conazole-refractory mucosal candidiasis in HIV-positive
iv) Other Notable Antifungals for OC
Voriconazole belongs to a second generation of triazoles
candin class and is administered intravenously. The clinical
cure rate for capsofungin could vary between 74 to 91%
. Caspofungin appears to possess an efficacy for treat-
ment of oropharyngeal and esophageal candidosis, compara-
ble to that of a standard dose of amphotericin B  and
may provide a better-tolerated alternative option to conven-
tional amphotericin for patients who require parenteral ther-
apy, such as those with azole-refractory Candida infections.
Caspofungin is an antifungal agent of the novel echino-
494 Current HIV Research, 2008, Vol. 6, No. 6 Egusa et al.
sive topical alternative therapies such as gentian violet,
which has a long history of safe use. A randomized un-
blinded study compared the efficacy of gentian violet mouth
washes (1.5 ml 0.5% aqueous solution twice daily), oral ke-
toconazole (200 mg/day, after a meal) and nystatin (200,000
U oral suspension four times daily) mouth washes. It was
observed that after 14 days OC lesions had disappeared in
similar proportions of patients treated with gentian violet
(42%) and ketoconazole (43%) and in a lower proportion of
patients treated with nystatin (9%) . Recently,
Traboulsi, et al. compared the fungicidal effects of inexpen-
sive topical alternatives, oil of melaleuca (tea tree oil), chlor-
hexidine, povidone iodine and gentian violet with the widely
prescribed triazole drug, fluconazole. Interestingly, gentian
violet was shown to exhibit the most potent activity against
all 91 clinical Candida isolates from the oral cavity of AIDS
patients tested. Furthermore unlike the other candidates, it
had fungicidal activity and was effective against even the
fluconazole-resistant strains . In addition, they demon-
strated that the combination of fluconazole and gentian violet
has no antagonistic interactions. These studies suggest that
gentian violet might be considered as a potential preventive
or adjunct inexpensive therapeutic agent in the management
of OC in HIV-infected patients in resource-poor countries.
v) Antimycotic Treatment of OC in HIV-Infected Children
Some studies have shown a benefit in the use of inexpen-
OC in children. Hernandez-Sampelayo reported a clinical
cure rate of 88% with fluconazole when administered at a
dose of 3 mg/Kg/day . This study also revealed a clini-
cal cure of 81% for ketoconazole when the children were
treated at a dose of 7 mg/Kg/day for 5-49 days. Both groups
had a high rate of relapse 2-4 weeks after treatment. A high
clinical cure rate was observed with fluconazole (91%) in
another study when children were treated with a dose of 2-3
mg/Kg/day for 14 days in comparison to nystatin (400,000 U
four times daily) which was 51% . They concluded that
fluconazole has a better efficacy, safety and tolerance in
comparison to nystatin in children.
vi) Antimycotics Efficacy in the Prevention of OC
There have so far been few reports on the treatment of
their prophylactic potential. Table 4 summarizes the results
of few such studies. The period of prophylactic drug treat-
ment varied from 12 weeks to more than a year in some stud-
ies. Even though the prophylactic efficacy of itraconazole,
The above mentioned antifungals were also evaluated for
ketaconazole, clotrimazole and nystatin was not conclusive,
fluconazole appears to be more effective at preventing recur-
rences and emergence of new infections. For any given anti-
fungal, clinical relapse and adverse effects may be encoun-
tered. Hence, when evaluating the choice and the dose of an
antifungal for treatment or prevention, factors such as the
level of immune suppression, extent and severity of OC,
patient compliance, route of administration, drug resistance
and drug interaction should also be taken into consideration.
vii) Identification of Candida Species for OC Management
increasingly important in the management of OC using an-
timycotic agents. One reason for this is that Candida species
differ in their susceptibility to antifungal agents. For in-
stance, C. krusei is often innately azole resistant, C. glabrata
has been reported to acquire resistance in vitro and in vivo,
and C. dubliniensis isolates have been observed to rapidly
develop resistance to fluconazole. Furthermore, C. glabrata
and C. krusei infections often require maximum doses of
amphotericin B to be effective, are resistant to itraconazole
and have high MIC for voriconazole [148-151]. Therefore,
the identification of the infecting species is highly predictive
of the likely drug susceptibility and it can also be used as a
guide to therapy . In addition, it is now apparent that a
reduced susceptibility as well as a strong resistance to anti-
fungal agents is an issue of clinical importance . Hence,
antifungal susceptibility testing (AFST) could therefore be a
valuable tool for predicting the efficacy of a given agent
, and could thus help to guide empiric therapy for high-
risk patients with known predisposing factors for developing
serious candidal infection.
The identification of Candida species has also become
OPC in HIV patients remain to be established globally,
nonetheless several measures could be taken to prevent or
minimize the emergence of resistant Candida, including the
dosage, length of the treatment and the use of intermittent
instead of continuous treatment.
The optimal antifungal regimens for the treatment of
miological and clinical marker in HIV infection. However,
its prevalence in the community has decreased owing to re-
cent advances in anti HIV therapy. Taking a meticulous his-
tory and performing a detailed intra oral examination of the
patient’s oral cavity are thus important parts of the physical
The presence of OC can be used as an important epide-
Comparison of Drug Regimens and Efficacy in the Prevention of OC in Individuals with HIV Infection
Authors (Year) [Ref.] Experimental Group Comparison Group Duration % Reinfected/Relapse
Leen, et al. (1990) 
Stevents, et al. (1991) 
Just-Nubling, et al. (1991) 
Marriott, et al. (1993) 
Schuman, et al. (1997) 
Pagani, et al. (2002) 
McKinsey, et al. (1999) 
MacPhail, et al. (1996) 
Fluconazole 150 mg/wk
Fluconazole 100 mg/d
Fluconazole 50 mg/d
Fluconazole 100 mg/d
Fluconazole 150 mg/wk
Fluconazole 200 mg/wk
Fluconazole 150 mg/wk
Itraconazole 200 mg/d
Nystatin 200,000 U/d
Nystatin 400,000 U/d
Placebo: 100%; Fluconazole: 22.2%
Placebo: 61.5%; Fluconazole: 0%
Placebo: 95.2%; Fluconazole 50 mg: 11.1%;
Fluconazole 100 mg: 21.1%
Placebo: 96.2%; Fluconazole: 41.9%
Placebo: 42.2%; Fluconazole: 25.9%
Placebo: 90%; Fluconazole: 61%
Placebo 16%; Itraconazole: 15%
Placebo 70%; Nystatin: 200,000 U/d: 73%;
Nystatin: 400,000 U/d: 4%
Oral Candidosis in HIV-Infected Patients Current HIV Research, 2008, Vol. 6, No. 6 495
examination. Diagnosis of OC requires extensive clinical
experience and appropriate investigative techniques. Early
recognition, diagnosis, identification of the specific causative
Candida species and treatment of HIV-associated OC may
reduce morbidity. It is therefore imperative that both clini-
cians and dentists should always be vigilant for the underly-
ing pathology when they encounter a patient with OC. The
sudden occurrence of OC in patients under medical treatment
for HIV infection should be treated as appropriate since the
presence of OC might also be indicative of a patient nonad-
herent to therapy. The experienced infectious disease physi-
cian should also consider an evaluation of current anti-
retroviral therapy for any possible failure.
been discussed, however, a greater understanding of host
factors, especially local immunity in HIV-infected individu-
als, is expected to play an important role in the development
of interventions to reduce candidal infection and to prevent
prevalence of OC. In addition, the co-infection of HIV with
Candida may be an important exogenous factor that influ-
ences the severity and rate of disease progression in HIV-
infected individuals and therefore the dynamic interrelation-
ship between HIV and Candida virulence needs to be further
The pathogenesis specific to HIV-associated OC has
prevalence of non-albicans Candida species associated with
OC in HIV infection complicates the treatment modalities in
the use of traditional antifungals. However, the recent devel-
opment of a detailed nuclear receptor-like pathway regulat-
ing multidrug resistance in fungi  may lead to en-
hancement of novel therapeutic targets for the treatment of
multi-drug-resistant fungal infections. In the meantime, fur-
ther clinical explorations evaluating the efficacy of inexpen-
sive topical alternatives with less drug resistance and adverse
effects, such as gentian violet, in the treatment of OC are
warranted to decrease the OC prevalence in the HIV-infected
peoples especially for those in developed countries.
The possibility of emerging drug resistance and increase
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Received: May 2, 2008
Revised: August 20, 2008 Accepted: August 22, 2008