Oral Lesions Associated with

Human Immunodeficiency Virus

Disease
Lauren L. Patton, DDS

KEYWORDS
 HIV  Oral candidiasis  Kaposi sarcoma  Oral hairy leukoplakia
 HIV salivary gland disease

KEY POINTS
 Human immunodeficiency virus (HIV)-associated oral lesions are numerous and diverse
and may relate to opportunistic infections that occur in the setting of immune suppression.
 Presumptive HIV oral lesion diagnosis based on clinical appearance and lesion behavior
may be sufficient for some benign-appearing lesions; whereas worrisome ulcerative le-
sions/masses require definitive diagnosis, usually based on histopathology.
 Patterns of oral disease prevalence and incidence have changed with improved HIV dis-
ease management and use of highly active antiretroviral therapy (HAART).
 HAART-related immune reconstitution inflammatory syndrome has reactivated some oral
diseases and has resulted in other medication oral side effects in some patients.
 Pharmaceutical and nonpharmaceutical management are important considerations for
HIV-associated oral lesions.

INTRODUCTION AND EPIDEMIOLOGY

Introduction
Human immunodeficiency virus (HIV) infection affects the host by targeting the CD4
positive T-lymphocyte population.1 HIV viral particles bind with lymphocytes and
use the lymphocyte as a host factory, where additional HIV viral particles are pro-
duced. During this repeated process of viral replication, the lymphocyte is exhausted
and destroyed, resulting in fewer T-helper lymphocytes available to protect the host
from a variety of viral, fungal, bacterial, and protozoal opportunistic infections and
other neoplastic diseases (Fig. 1).

The author has nothing to disclose.

Department of Dental Ecology, School of Dentistry, University of North Carolina, Room 467A,
Brauer Hall, Chapel Hill, NC 27599-7450, USA
E-mail address: lauren_patton@dentistry.unc.edu

Dent Clin N Am 57 (2013) 673–698

http://dx.doi.org/10.1016/j.cden.2013.07.005 dental.theclinics.com
0011-8532/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
674 Patton

Fig. 1. HIV life cycle and stages at which antiretroviral therapy actions occur.

HIV disease management revolves around prevention, identification of the infected

patient, and treatment of HIV with antiretroviral medications, as well as treatment of
opportunistic infections and other conditions that arise. When medical management
is effective at suppressing replication and reducing HIV viral loads to undetectable
levels for prolonged periods, the patient is more likely to remain healthy and disease
free. The standard of care is highly active antiretroviral therapy (HAART) regimens, us-
ing combinations of medications that target several stages of the HIV life cycle. The
first anti-HIV medications developed in 1987, such as zidovudine, were nucleoside
analogue reverse-transcriptase inhibitors and worked at stage 2, reverse transcription
(see Fig. 1). In 1996, HIV protease inhibitors, such as indinavir, that worked at stage 6
were introduced. The newest classes of antiretroviral drugs are the fusion inhibitors
and entry inhibitors (or CCR5 antagonists), working at stage 1 of viral binding and en-
try; and the integrase inhibitors working to block integration at stage 3.
Antiretroviral therapy is recommended for all HIV-infected individuals with the
strength of evidence for the recommendation based on the pretreatment CD4 cell
count.2 The strongest confidence in the need for therapy is among those with CD4
counts less than 500 cells/mm3, or those who are pregnant, or within the first 2 weeks
of diagnosis of an opportunistic infection, regardless of CD4 count.2 Adherence to the
antiretroviral medication regimens has long been a concern, with reasons for regimen
switching including virologic, immunologic, or clinical failure and drug toxicity or intol-
erance. Several multiclass combination antiretroviral medications have been devel-
oped to reduce the pill burden for patients.

Nature of the problem

Oral lesions caused by opportunistic diseases occur in patients with HIV infection,
whether or not they are on HAART.3 Although occurrence of some HIV-associated
oral lesions has decreased after introduction of HAART, such as Kaposi sarcoma
(KS), oral hairy leukoplakia (OHL), HIV-related gingival and periodontal disease, and
major aphthous ulcers (MAU), others such as oropharyngeal candidiasis (OPC) have
persisted. Some oral diseases, such as oral warts and HIV salivary gland disease,
seem to have increased among those on HAART.4,5
 Oral Lesions in HIV Disease 675

The oral mucosal epithelium lining the mouth plays an important role in protection of
the host against infectious microorganisms. In HIV disease, the oral epithelium un-
dergoes molecular alterations that place the host at increased susceptibility to comor-
bid oral infections.6 Although HAART is effective at increasing the quantity of CD4
lymphocytes, it provides incomplete immune recovery of the oral epithelial cells, leav-
ing the host with increased susceptibility to oral disease and also exposing the patient
to the toxic side effects of HAART. Chronic HIV disease is believed to silence the
expression of multiple cellular proteins that in healthy individuals function to combat
cellular stress and provide strong innate immune responses, further enhancing
mucosal disease risk.6

Definition
Orofacial manifestations of HIV in both adults and children were classified in the 1990s
by collaborative expert groups using the following scheme7,8:
1. Lesions strongly associated with HIV infection
2. Lesions less commonly associated with HIV infection
3. Lesions seen in HIV infection (adults) or strongly associated but rare in children
(children).
The lesions in each category are presented in Tables 1 and 2. These expert
consensus publications7,8 also provided presumptive and definitive diagnostic criteria
and treatment considerations. Presumptive diagnostic criteria refer to the clinical fea-
tures of the lesions, including signs and symptoms, whereas definitive criteria require
specific laboratory tests.

Symptom criteria
In 2009, the Oral HIV/AIDS Research Alliance of the US AIDS Clinical Trials Group
updated the HIV oral lesion case definitions in adults to make diagnosis easier for
medical care providers and investigators in clinical trials and epidemiologic studies.9
In addition to clinical descriptors, patient-reported symptoms and lesion duration
were added to the diagnostic matrix.9
Prevalence/Incidence
HIV/AIDS
Prevalence (end of 2009):
 784,701 people in the United States were alive with a diagnosis of HIV infection
(prevalence rate of 268.6 per 100,000 population).10
 476,732 persons in the United States were alive with an AIDS diagnosis (preva-
lence rate of 155.3 per 100,000 population).10

Incidence:
 Approximately 47,500 people in the United States newly acquire HIV each year,
giving an incidence rate of 18.8 per 100,000, with the highest rates among indi-
viduals aged 25 to 34 years, men, and blacks/African Americans.11

Mortality:
 All causes of death of persons with an HIV diagnosis in 2009 are estimated at
21,015 or 7.2 per 100,000 population.10
With the constant rate of new HIV infections outpacing the death rate of persons
with HIV disease, the numbers of individuals at risk for oral lesions related to HIV dis-
ease is increasing.
676 Patton

Table 1
September 1992 consensus classification of oral lesions associated with adult HIV infection

Group 1: Lesions Candidiasis

strongly associated Erythematous
with HIV infection Pseudomembranous
Hairy leukoplakia
KS
Non-Hodgkin lymphoma
Periodontal disease
Linear gingival erythema
Necrotizing (ulcerative) gingivitis
Necrotizing (ulcerative) periodontitis
Group 2: Lesions less Bacterial infections
commonly associated Mycobacterium avium intracellulare
with HIV infection Mycobacterium tuberculosis
Melanotic hyperpigmentation
Necrotizing (ulcerative) stomatitis
Salivary gland disease
Dry mouth caused by decreased salivary flow rate
Unilateral or bilateral swelling of major salivary glands
Thrombocytopenia purpura
Ulceration not otherwise specified
Viral infections
HSV
Human papillomavirus (wartlike) lesions
Condyloma acuminatum
Focal epithelial hyperplasia
Verruca vulgaris
Varicella zoster virus
Herpes zoster
Varicella
Group 3: Lesions seen Bacterial infections
in HIV infection Actinomyces israelii
Escherichia coli
Klebsiella pneumonia
Cat-scratch disease
Drug reactions (ulcerative, erythema multiforme, lichenoid, toxic
epidermolysis)
Epithelioid (bacillary) angiomatosis
Fungal infection other than candidiasis
Cryptococcus neoformans
Geotrichum candidum
Histoplasma capsulatum
Mucoraceae (mucormycosis zygomycosis)
Aspergillus flavus
Neurologic disturbances
Facial palsy
Trigeminal neuralgia
Recurrent aphthous stomatitis
Viral infections
Cytomegalovirus
Molluscum contagiosum

Data from Classification and diagnostic criteria for oral lesions in HIV infection. EC-Clearinghouse
on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations
of the Immunodeficiency Virus. J Oral Pathol Med 1993;22:289–91.
 Oral Lesions in HIV Disease 677

Table 2
Consensus classification of orofacial lesions associated with pediatric HIV infection

Group 1: Lesions commonly associated Candidiasis

with pediatric HIV infection Erythematous
Pseudomembranous
Angular cheilitis
HSV infection
Linear gingival erythema
Parotid enlargement
Recurrent aphthous ulcers
Minor
Major
Herpetiform
Group 2: lesions less commonly associated Bacterial infections of oral tissues
with pediatric HIV infection Periodontal diseases
Necrotizing (ulcerative) gingivitis
Necrotizing (ulcerative) periodontitis
Necrotizing (ulcerative) stomatitis
Seborrheic dermatitis
Viral infections
Cytomegalovirus
Human papillomavirus
Molluscum contagiosum
Varicella zoster virus
Herpes zoster
Varicella
Xerostomia
Group 3: lesions strongly associated Neoplasms
with HIV infection but rare in children KS
Non-Hodgkin lymphoma
OHL
Tuberculosis-related ulcers

Data from Ramos-Gomez FJ, Flaitz C, Catapano P, et al. Classification, diagnostic criteria, and
treatment recommendations for orofacial manifestations in HIV-infected pediatric patients.
Collaborative Workgroup on Oral Manifestations of Pediatric HIV Infection. J Clin Pediatr Dent
1999;23:85–96.

HIV oral lesions Across the globe and throughout time, OPC has been the most com-
mon HIV oral lesion among all ages, genders, and races, with pseudomembranous
candidiasis being the most readily diagnosed variant. Prevalence of various oral le-
sions varies greatly in the literature depending on the population characteristics,
research study design, methods for assessment, geographic and clinic location,
and time period of the study.3 General oral lesion prevalence ranges are given in
Table 3.
Although HAART therapy has resulted in some reduction of HIV oral lesions, they
continue to persist in many populations. In a 2 year-follow-up retrospective study in
Birmingham, Alabama among patients receiving HAART from 2000 to 2006,12 at least
1 HIV oral lesion was seen by medical providers in 35.8% of patients. OPC was most
common, occurring in 74.9% of those with lesions, followed by oral herpes simplex
virus (HSV) lesions in 10.4%, oral ulcers in 9.1%, and OHL in 3.2%.12 The potential
for OHL to have been misdiagnosed as OPC is discussed in this report. Less
commonly found were KS, undetermined stomatitis, and salivary gland swelling. Of
those with HIV-related lesions, 59% had 1 lesion and 41% had at least 2 oral lesions.
678 Patton

Table 3
HIV oral lesion prevalence

HIV Oral Lesion Prevalence in Adults (%) Prevalence in Children (%)

Oral candidiasis 0–94 18–72
OHL 0–43 0
KS 0–38 0
Non-Hodgkin lymphoma 0–5 —
Linear gingival erythema 0–22 0–48
Necrotizing ulcerative gingivitis 0–17 —
Necrotizing ulcerative periodontitis 0–23 —
HSV ulcers — 1.7–24
HIV salivary gland disease — 3–50
Aphthous ulcers — 5–7

Data from Patton LL, Phelan JA, Ramos-Gomez FJ, et al. Prevalence and classification of HIV-
associated oral lesions. Oral Dis 2002;8(Suppl 2):98–109.

In this cohort, the person-visit incidence rate and person-visit recurrence rates for all
episodes of HIV oral lesions were 2.15% and 0.66%, respectively.12 In the multicenter
Women’s Interagency HIV Study cohort of HIV-infected women in the United States,
the incidence rate (first events/person-visits) of erythematous or pseudomembranous
OPC decreased from 7.35% to 3.43% after introduction of HAART, whereas incidence
rates of OHL minimally declined from 2.54% to 2.35%, and incidence rates of warts
minimally declined from 0.62% to 0.59%.13

Worldwide/Regional Incidence and Mortality

Whereas some HIV oral lesions such as OPC, non-Hodgkin lymphoma (NHL), and HSV
ulcerations are reported among HIV-infected populations on all continents, others are
more common in certain geographic areas (Table 4).14–16 Geographic distribution of
HIV oral lesions is affected by HIV risk behaviors, gender, HIV management efficacy,
social behaviors, race/ethnicity, socioeconomic status, and other undetermined local
and regional environmental factors.3 Although many oral lesions contribute to
morbidity, only the AIDS-defining malignancies contribute to the patient’s overall
mortality.17

CLINICAL PARAMETER
Fungal Diseases
Clinical findings
Physical examination OPC (Fig. 2): on physical examination, any 1 or more of 3 vari-
ants or clinical presentations may be seen. The most common is the pseudomembra-
nous form, characterized by white, curdlike plaques that can be easily removed with
wiping with a 2  2 cotton gauze or tongue depressor, often leaving a red, raw base.
The erythematous form, also called atrophic, is characterized by erythema and loss of
papillations when involving the tongue dorsum. Angular cheilitis affects the labial com-
missures and results in cracking, ulceration, and pseudomembrane formation.
Rating scales In the clinical setting, infections are typically not rated; however, in the
research setting, scales are used for clinical trials of antifungal agents.18 For example,
signs and symptoms may be assessed as presence or absence of erythema and
 Oral Lesions in HIV Disease 679

Table 4
Worldwide distribution and mortality or HIV oral lesions in adolescents and adults

Oral Lesion Geographic Location Mortality

Fungal Infections
OPC All continents None
Viral Infections
OHL North and South America, None
Europe and Asia
HSV ulceration All continents None
Human papillomavirus North and South America None
warts and Europe
Neoplasms
KS North America and Europe; Pre-HAART 5-y survival:
sub-Saharan Africa 30.7%
Post-HAART 5-y survival:
62.5%
NHL All continents Pre-HAART 5-y survival:
16.2%
Post-HAART 5-y survival:
46.0%
Bacterial Infections
Necrotizing ulcerative North America and Europe None
gingivitis/periodontitis
Necrotizing stomatitis Africa, Asia, and None
developing countries
Other Conditions
HIV salivary gland disease Africa, Asia, and Southeast None
Asia; North America and
Europe
MAU North America and Europe None

Data from Refs.14–17

Fig. 2. Oral pseudomembranous candidiasis of buccal mucosa, tongue, and palate of an HIV-
infected patient.
680 Patton

soreness/burning, and extent of lesions may range from none, to single/localized, mul-
tiple/localized, or extensive or confluent.18

Diagnostic modalities Diagnosis is usually based on clinical appearance and

response to empirical antifungal therapy. Mycologic sampling can be made with a
swab, which shows budding yeast cells, pseudohyphae, or filaments on direct micro-
scopic examination. Potassium hydroxide or periodic-acid Schiff can be used to
improve visualization of fungal elements in cytologic specimens.19 Culture on Sabour-
aud dextrose agar medium for 24 to 48 hours can also be used. Only apparent azole-
refractory strains warrant antifungal sensitivity testing.
Imaging None.

Pathology Most OPC infections predominantly are composed of Candida albicans;

however, non-albicans species of Candida can be present in mixed infections,
commonly seen in azole-refractory infections. Colonization of the oral cavity by
Candida species is high among HIV-infected patients.20 The most commonly found
non-albicans Candida species include C glabrata, C dubliniensis, C tropicalis, C krusei,
C parapsilosis, and C novergensis.20

Viral Diseases
Clinical findings
Physical examination HIV infection places the patient at increased risk of recurrence
and prolonged course of human herpes virus and human papillomavirus (HPV)-related
diseases. Herpes viral group viruses, including HSV and Epstein-Barr virus (EBV),
along with the HPV group, are the etiologic agent underlying most virally induced le-
sions among people with HIV infection.
OHL (Fig. 3): the clinical appearance of OHL is a white lesion of varying size, usually
on the lateral border of the tongue, which may show vertical corrugations and cannot
be removed by wiping. It may occur on only 1 or on both sides of the tongue, is asymp-
tomatic, and is prone to spontaneous remission.
Oral HSV ulceration (Fig. 4): usually caused by HSV-1, oral herpes can involve the
lips (labial herpes involves the vermillion border and adjacent facial skin) or intraoral
locations (such as gingiva, palate, dorsal tongue). Typically, there is a prodrome of
symptoms of pain and burning, followed by vesicle formation, rupture to create

Fig. 3. OHL from lateral border of tongue. (From Shiboski CH, Patton LL, Webster-Cyriaque JY,
et al. The oral HIV/AIDS research alliance: updated case definitions of oral disease endpoints.
J Oral Pathol Med 2009;38:484; with permission.)
 Oral Lesions in HIV Disease 681

Fig. 4. Intraoral herpes ulcerations of palate. (From Shiboski CH, Patton LL, Webster-
Cyriaque JY, et al. The oral HIV/AIDS research alliance: updated case definitions of oral dis-
ease endpoints. J Oral Pathol Med 2009;38:484; with permission.)

ulceration and then healing in 10 to 14 days. In HIV disease, the course may be pro-
longed and the location may occur on keratinized or occasionally nonkeratinized loca-
tions, contrary to location occurrence in healthy individuals in whom HSV ulcers are
predominantly on keratinized mucosa.
Oral warts caused by HPV (Fig. 5): Oral warts, of white to mucosal color, can occur
in any location, number, and vary in size and shape from flat to raised and peduncu-
lated, and from smooth surfaced to cauliflower textured. They are asymptomatic un-
less they are traumatized by biting. They include condyloma accuminata, verruca
vulgaris, and focal epithelial hyperplasia.

Rating scales There are no rating scales. A workshop of experts in 2000 reviewed the
lack of rating scales for HIV oral lesions, such as OHL, and the complexity of trying to
determine scales with clinical usefulness.21

Diagnostic modalities OHL is usually presumptively diagnosed; however, biopsy re-

veals hyperparakeratosis, hyperplasia/acanthosis, and a papillated epithelial surface,
with a parakeratin band and ballooning cells in most cases.22 Histopathologic features
include EBV detection by immunohistochemistry and in situ hybridization.23 EBV has

Fig. 5. Oral warts on labial mucosa of HIV-infected patient. (From Shiboski CH, Patton LL,
Webster-Cyriaque JY, et al. The oral HIV/AIDS research alliance: updated case definitions
of oral disease endpoints. J Oral Pathol Med 2009;38:484; with permission.)
682 Patton

been shown in tongue lesional scrapings of OHL by polymerase chain reaction (PCR),
thereby simplifying diagnosis without need for surgical biopsy.24
Diagnosis of intraoral or labial herpes is usually by awareness of the history and pre-
senting symptoms and clinical features. During the vesicular phase, viral culture
shows HSV. Lesion specimens must be collected from the vesicle or early ulcer site
using a Dacron swab, transported in viral transport medium to a microbiology labora-
tory, and processed for HSV detection by 1 of several commercially available PCR
HSV assays or with tissue culture systems.25 Cytology with the Papanicolaou (Pap)
test or the Tzanck test can show syncytial multinucleated giant cells, ballooning cyto-
plasm, and Cowdry type A intranuclear inclusions, although detection sensitivity limits
its usefulness in immune-suppressed patients.26
Oral warts may be distinguished by appearance. If biopsy is conducted, appear-
ance under histopathology reveals keratinocytes with atypical features in the form
of hyperchromatism and karyomegaly; koilocytes are frequently seen in the upper
level keratinocytes, where HPV common antigen may be identified, and lesions
show intense proliferating cell nuclear antigen reactivity from basement membrane
to surface.27 HPV can also be isolated from oral epithelial cells in patients with warts
with a cytobrush collection tool and typed with PCR-based genotyping HPV assays.28

Imaging None.

Pathology Human herpes viruses are 4.2 to 26.2 times more prevalent in the saliva of
HIV-infected patients than controls, and prevalence in the HIV-infected patient’s saliva
was: EBV, 90%; human herpesvirus 8 (HHV-8) (which causes KS), 57%; cytomegalo-
virus (CMV), 31%; and HSV-1, 16%.29 Herpes viruses establish lifelong latency and
reactivate on stimulation with triggers or immune suppression and can present as clin-
ical disease, with several days of viral shedding and thus infectiousness occurring for
several days after resolution of clinical signs and symptoms.30 HPV was detected in
39% of oral rinses of HIV-infected patients, with 27 different genotypes detected,
low-risk HPV84, HPV55, and HPV83 being the most common, and 3% being positive
for high-risk HPV types 16 and 18 associated with oropharyngeal cancers.31

Neoplastic Diseases (KS, NHL)

Clinical findings
Physical examination KS (Fig. 6): appearance of oral KS can vary depending on dura-
tion of the lesion. Lesions can be solitary or multifocal. Early lesions tend to be asymp-
tomatic, flat, or macular, from red to purple, often resembling an ecchymosis. Later

Fig. 6. KS of gingiva, alveolar bone, and palate of an HIV-infected man.

 Oral Lesions in HIV Disease 683

lesions may become nodular, raised and ulcerated, and may be painful and prone to
traumatic bleeding. The most common intraoral locations are the palate, gingiva, and
dorsal tongue.32
NHL (Fig. 7): intraoral NHLs are firm, elastic swellings, ranging from mucosal
colored to red, with or without ulceration. The gingival and palatal mucosa, as well
as the tonsillar fossa, are the most common locations. Pain may result in later stages,
when the lesion impinges on neurologic structures.
Rating scales None.

Diagnostic modalities Biopsy and histopathologic examination are essential to diag-

nose both intraoral KS and NHL lesions, particularly if treatment is desired and the
oral lesion represents the patient’s first presentation of KS or NHL. Oral and craniofa-
cial KS occurs in 40% to 60% of patients with AIDS KS and is the first presentation of
KS in one-fifth of involved patients.33

Imaging Oral KS involving the palate and gingiva may lead to resorption of alveolar
bone supporting the teeth, which can be detected on intraoral radiographs or pano-
ramic images. Computed tomography (CT) and magnetic resonance imaging (MRI)
of expansile soft tissue masses may be helpful for large KS lesions of the head and
neck, showing significant enhancement with the contrast enhanced-CT technique.33
Extranodal NHL, such as those that occur in the Waldeyer ring area, tonsils, naso-
pharynx, mandible, gingiva, hard palate, or parotid, may be imaged by CT or more
accurately by positron emission tomography scans with 2-[18F]fluoro-2-deoxy-D-
glucose, which can image intense hypermetabolic foci in mucosal tissue.34,35

Pathology Both KS and NHL are malignant neoplasms associated with viral disease.
Underlying the cause of KS is HHV-8, also known as KS-associated herpes virus,
which is necessary but not sufficient for KS development. KS is a multicentric angio-
proliferative spindle cell tumor of endothelial origin, with pathologic and clinical hetero-
geneity and growth responsiveness to host immune factors.36 KS tumors also show
inflammatory infiltrates and leaky vasculature on histopathology.36 EBV is associated
with NHL.37 NHLs are a heterogeneous group of cancers, usually arising in lymph
nodes, with the most common extranodal location being in the gastrointestinal tract.
An estimated 85% to 90% arise from B lymphocytes. The more common and aggres-
sive diffuse large B-cell lymphoma and Burkitt lymphoma present in conjunction with
HIV disease.35

Fig. 7. NHL of the alveolar mucosa of the mandible. (From Patton LL. HIV and head and neck
cancers. In: DeSouza C, editor. Head and neck surgery. vol. 2. New Delhi (India): Jaypee
Brothers Medical Publishers (P) Ltd; 2009. p. 1177.)
684 Patton

Bacterial Diseases (Gingival and Periodontal)

Clinical findings
Physical examination Linear gingival erythema (LGE): a distinctive fiery red band of
marginal gingival tissue without ulceration or attachment loss, prone to bleeding, oc-
casionally extending beyond the mucogingival junction. The lesion redness is dispro-
portional to the amount of plaque and persists after removal of plaque.38
Necrotizing ulcerative periodontitis (NUP) (Fig. 8): the destructive diseases of the
periodontium range from involvement of gingiva only (necrotizing ulcerative gingivitis
[NUG]), to the periodontium exposing alveolar bone (NUP), to adjacent areas beyond
the periodontium, such as palatal mucosa and bone or vestibular nonkeratinized mu-
cosa (necrotizing ulcerative stomatitis [NUS]), and seem to be a continuum of the
same disease process.38,39 NUP is characterized by recession and increased attach-
ment loss with shallow probing depths, bleeding, tissue sloughing, reverse cratering
with loss of interdental papillae, fetid odor, and moderate pain. Periods of activity (tis-
sue necrosis and loss) may be followed by periods of quiescence (healing with no
signs of inflammation, but evidence of permanent residual tissue loss).

Rating scales None.

Diagnostic modalities Diagnosis of gingival and periodontal disease in HIV-infected

patients is based on clinical appearance, associated discomfort, and measurements
of recession, periodontal probing depths, attachment levels, and mobility ratings.

Imaging Dental radiographs of areas of NUP involvement may show loss of crestal
cortication associated with rapid alveolar bone loss.

Pathology The cause and pathogenesis of LGE are unknown and believed to be a
combined bacterial/fungal lesion.40,41 The subgingival flora of HIV-infected individuals
have been host to both the classic putative periodontal pathogens and a higher prev-
alence of opportunistic microorganisms, probably because of their altered immune
status, because colonization and overgrowth of atypical pathogenic species is facili-
tated by immune suppression.38,41–43 Although largely bacterial in nature, with both
typical or atypical bacteria involvement, the condition may be exacerbated by Candida
and herpeslike viruses and by an HIV disease–related increased inflammatory cyto-
kine response.39,44

Fig. 8. NUP. (From Shiboski CH, Patton LL, Webster-Cyriaque JY, et al. The oral HIV/AIDS
research alliance: updated case definitions of oral disease endpoints. J Oral Pathol Med
2009;38:485; with permission.)
 Oral Lesions in HIV Disease 685

Other Diseases (HIV Salivary Gland Disease; Major Aphthous and Other Ulcers, Not
Otherwise Specified)
Clinical findings
Physical examination HIV salivary gland disease: unilateral or bilateral parotid gland
enlargement/masses may be seen accompanied by a complaint of xerostomia or
dry mouth and reduced salivary flow. Salivary glands can become large and cosmet-
ically disfiguring.
MAU and ulcers not otherwise specified (Fig. 9): single or multiple, extremely pain-
ful, well-circumscribed ulcers, often with a pseudomembranous cover, these ulcers
measure more than 5 mm in diameter and up to 2 to 3 cm in some patients. They
may have a recurrent pattern or not, and may last for several weeks, healing with scar-
ring. They are typically found on nonkeratinized epithelial mucosa, but may rarely
occur on keratinized mucosa in immune-suppressed patients, in whom they may be
deeper and devoid of the classic erythematous halo at the ulcer margin.

Rating scales Salivary hypofunction occurs when unstimulated whole saliva flow vol-
ume is less than 0.1 mL per minute, whole chewing stimulated saliva 7 mL/min or less,
or both.45

Diagnostic modalities Parotid enlargement in HIV-seropositive patients may repre-

sent several conditions, including HIV-associated lymphoepithelial lesions, hyper-
plastic reactive lymphadenopathy, benign lymphoepithelial cysts, lymphoma, other
malignant or benign neoplasms, bacterial, mycobacterial, and viral infections, and
diffuse infiltrative lymphocytosis syndrome (DILS).46,47 Fine-needle aspirates can be
useful in differential diagnosis of salivary gland masses.47 DILS is characterized by
persistent circulating CD81 lymphocytosis accompanied by lymphocytic infiltration
involving the salivary glands in a histopathologic presentation similar to Sjögren syn-
drome.46 Confirmatory histopathologic diagnosis and immunohistochemical analysis
from a biopsy are essential to determine the nature of the salivary gland enlargement.
MAU and ulcers not otherwise specified, are idiopathic. They are diagnosed by
exclusion of other identified causes and are likely immunopathic disorders generally
occurring in severe immune suppression.48
Imaging
Parotid enlargement Ultrasonography offers a simple, rapid imaging technique to
ascertain the nature of HIV salivary gland disease.49 HIV salivary gland disease

Fig. 9. Major aphthous ulceration of the lip in an adolescent hemophiliac with HIV
infection.
686 Patton

involving the parotids has a sonographic appearance that typically falls in 1 of 4 main
distinct patterns: lymphocytic aggregations, lymphoepithelial cysts, fatty infiltration,
and lymphadenopathy only.50 CT and MRI may be useful51; however, scintiscanning
with technetium pertechnetate has been found to be of little value in delineating sali-
vary lesions in HIV-infected patients.52

Pathology
Parotid enlargement Lymphoepithelial cysts of the parotid gland can be histologi-
cally classified into 3 subtypes:
 Type I, a cystic dilation of ducts within parotid glands;
 Type II, partially demarcated cystic lesions with lymphoid stroma;
 Type III, well-encapsulated cystic lesions with lymphoid stroma containing lymph
follicular structures.53
MAU and ulcers not otherwise specified Biopsy should be obtained for lesions last-
ing more than 3 weeks.54 HHV DNA (EBV, HHV-6, and HHV-7) have been found in the
oral mucosa and peripheral blood mononuclear cells of patients with recurrent aph-
thous ulcers but seem to represent normal viral shedding rather than a direct causal
mechanism in this disorder.55
Diagnostic Dilemmas
Process of elimination
White lesions
OHL versus OPC White lesions are the most commonly detected oral lesion in HIV-
infected patients. Both OHL and OPC are characterized by oral white patches that
may be visually noticeable to the patient. Thirty-five percent of HIV-infected partici-
pants in the HIV Cost and Services Utilization Study reported having an oral white
patch, although distinction between OHL and OPC was not determined.56 In another
study of HIV patients comparing the patient’s awareness of currently having OPC or
OHL, the patient’s self-diagnosis accuracy compared with an oral medicine expert
was greater for OPC than OHL, with past history of the lesion and presence of symp-
toms improving diagnostic accuracy.57 Distinguishing hallmarks of pseudomembra-
nous OPC are the accompanying discomfort (burning/soreness) and ability to
remove the white surface material with wiping. If an HIV-infected patient is symptom-
atic with an oral white lesion, then management of the potential OPC with an antifungal
agent is warranted; if asymptomatic, observation may be warranted. A patient may
have concurrent OPC and OHL. For combined lesions, antifungal treatment may
resolve the OPC component, leaving the asymptomatic OHL. In this situation, the
oral patches on the lateral border of the tongue remain.
Oral ulcerations
HSV versus aphthous ulceration or ulcer not otherwise specified Oral ulcerative
disease in HIV-infected patients presents diagnostic challenges. The most common
ulcerative diseases are caused by HSV or are idiopathic, representing aphthous sto-
matitis or ulceration not otherwise specified. Although minor recurrent aphthous ulcers
measuring less than 5 mm in diameter are common and can be found in HIV-infected
patients, major aphthae or ulcers not otherwise specified, measuring more than 5 mm
in diameter are more debilitating and worrisome. Other ulcerative disease that can
occur in HIV-infected patients include ulceration from CMV infection, neoplasms
including squamous cell carcinoma, and possibly fungal, bacterial, or protozoal dis-
ease.58 A careful history of lesion behavior is important in the diagnostic process.
The HSV lesion has a prodrome of burning/tingling followed by blisters and then
 Oral Lesions in HIV Disease 687

ulceration, with tendency for multiple clustering small ulcers. The MAU does not have
a distinguishing prodrome and tends to present as 1 to 3 isolated lesions. Pain ap-
pears with ulcer development. Ulcers from CMV infection and squamous cell carci-
noma may be asymptomatic or painful depending on extent of invasion of local
tissue. In the healthy patient, HSV ulceration limits itself to keratinized mucosa and
aphthae occur on nonkeratinized mucosa; however, in HIV-infected patients, these
patterns are not always observed.59 The duration of both oral HSV and major aphthae
in HIV-infected patients may extend for weeks beyond the typical 10-day to 14-day
course seen in healthy patients. Biopsy of persistent large ulcers is warranted for
definitive histopathologic diagnosis.

Comorbidities
Various comorbidities have been reported for Candida infections:
 Pseudomembranous OPC: smoking.60,61
 Erythematous OPC: high alcohol consumption.61
 Any OPC: removable denture wearing.62
 Frequency of oral candidal carriage: dental caries.63

MANAGEMENT STRATEGY
Management Goals
Control of disease, morbidity, mortality and improvement in quality of life may involve
various steps:
 Prevention of initial and recurrent lesions
 Surveillance for detection of new lesion development
 Management of acute and chronic lesions
 Management of oral conditions/side effects related to antiretroviral medications
 Management of any lasting sequelae of the lesion or its treatment, once healed
Successful antiretroviral therapy plays an important role in prevention and manage-
ment of oral opportunistic infections, particularly when oral disease specific chemo-
preventive or treatment regimens do not exist.64 Diagnosis and management of oral
conditions resulting from immune reconstitution inflammatory syndrome (IRIS) is
challenging, because antiretroviral therapy initiated in patients with high viral loads
and low CD4 counts may result in unmasking of subclinical disease, resulting in
appearance or recurrence of HIV oral lesions in the first several months of therapy.64
Oral disease–specific therapy should be used in conjunction with continued antiretro-
viral therapy, while the immune reconstitution process takes several weeks or months
to resolve.

Pharmacologic Strategies
Guidelines for the prevention and treatment of opportunistic infections and conditions,
which include some but not all HIV oral lesions, among adults, adolescents, and chil-
dren are periodically updated based on evidence by expert panels representing such
national organizations as the Centers for Disease Control and Prevention, National In-
stitutes of Health, the HIV Medicine Association of the Infectious Disease Society of
America, the Pediatric Infectious Disease Society, and the American Academy of
Pediatrics.64,65

Fungal diseases
Oral candidiasis: see Tables 5 and 6.
 688
Patton
Table 5
HIV oral lesion treatment recommendations from the Centers for Disease Control and Prevention (CDC) for HIV-infected adolescents and adults

Infection Preferred Therapies and Duration
Fungal Infections
Candidiasis Initial episode, 7–14 d treatment
(mucosal) Fluconazole, 100 mg orally once daily
Clotrimazole troches, 10 mg troche orally
5 times daily
Nystatin suspension: 4–6 mL orally 4 times
daily; OR 1–2 flavored pastilles orally
4–5 times daily
Miconazole mucoadhesive tablet orally
once daily
Fluconazole-refractory OPC
Itraconazole oral solution 200 mg orally
once daily
Posaconazole oral solution 400 mg orally
twice daily
Alternative Therapies
Alternative initial episode:
Itraconazole oral solution 200 mg
orally once daily
Posaconazole oral solution 400 mg orally
twice daily, then 400 mg orally daily
Alternative fluconazole-refractory OPC:
Amphotericin B oral suspension
100 mg/mL (not available in United
States)- 1 mL orally 4 times daily
Amphotericin B deoxycholate
0.3 mg/kg IV daily
Lipid formulation of amphotericin B
3–5 mg/kg IV daily
Anidulafungin 100 mg IV once, then
50 mg IV daily
Caspofungin 50 mg IV daily
Micafungin 150 mg 150 mg IV daily
Voriconazole 200 mg orally or
IV twice daily
Other Options or Issues
Chronic or prolonged use of azoles might
promote development of resistance
Patients with fluconazole-refractory OPC
who responded to echinocandin
should be started on voriconazole or
posaconazole for secondary prophylaxis
until antiretroviral therapy produces
immune reconstitution
Suppressive therapy is usually not
recommended unless patients have
frequent or severe recurrences. If
decision is to use suppressive therapy:
Fluconazole 100 mg orally 3 times
weekly
Itraconazole oral solution 200 mg
orally daily
 Viral Infections
HSV Orolabial lesions (treatment for 5–10 d): Acyclovir-resistant HSV infection (treatment Topical formulations of neither
Valacyclovir 1 g orally twice daily for 21–28 d): trifluridine nor cidofovir are
Famciclovir 500 mg orally twice daily Topical trifluridine commercially available in the
Acyclovir 400 mg orally 3 times daily Topical cidofovir United States
Severe mucocutaneous HSV infections: Topical imiquimod Extemporaneous compounding or
Initial therapy acyclovir, 5 mg/kg IV every 8 h topical products can be prepared
After lesions begin to regress, change to using trifluridine ophthalmic solution
oral therapy as above. Continue therapy and the IV formulation of cidofovir
until lesions have completely healed
Acyclovir-resistant mucocutaneous HSV
infections:
Foscarnet 90–120 mg/kg/d IV in 2–3 divided
doses until clinical response
HHV-8 Initiation or optimization of antiretroviral
disease therapy should be performed for all
(KS) patients with KS
Visceral KS:
Chemotherapy and antiretroviral therapy

Abbreviation: IV, intravenously.

From Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: rec-
ommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm
Rep 2009;58(RR-4):1–207.

Oral Lesions in HIV Disease

689
 690
Patton
Table 6
HIV oral lesion prevention and treatment recommendations from the CDC for HIV-exposed and infected infants and children

Infection Preferred Therapies and Duration
Fungal Infections
Candidiasis Oropharyngeal disease (treatment for 7–14 d): Oropharyngeal disease (fluconazole-
Fluconazole, 3–6 mg/kg body weight
(maximum 400 mg/dose) orally once daily
Itraconazole cyclodextrin oral solution,
2.5 mg/kg body weight orally twice daily
(max 200 mg/d)
Clotrimazole troches, 10 mg troche orally
4 times daily
Nystatin suspension: 4–6 mL orally 4 times
daily; or 1–2, 200,000 U flavored pastilles
orally 4–5 times daily
Viral Infections
HSV Neonatal mouth disease:
Acyclovir, 20 mg/kg body weight IV per
dose 3 times daily for 14 d
Moderate to severe symptomatic
gingivostomatitis:
Acyclovir, 5–10 mg/kg body weight per
dose IV 3 times daily
After lesions begin to regress, change
to oral acyclovir; continue therapy
until lesions completely heal
Alternative Therapies
refractory):
Itraconazole cyclodextrin oral solution,
2.5 mg/kg body weight orally twice
daily (maximum 200–400 mg/d)
Amphotericin B oral suspension, 1 mL
(100 mg/mL) orally 4 times daily
Acyclovir-resistant HSV infection:
Foscarnet, 40 mg/kg body weight per
dose IV 3 times daily or 60 mg/kg body
weight per dose IV twice daily
Mild symptomatic gingivostomatitis:
Acyclovir, 20 mg/kg body weight
(maximum 400 mg/dose) per dose
orally 3 times daily for 5–10 d
Other Options or Issues
Itraconazole cyclodextrin oral solution should
not be used interchangeably with
itraconazole capsules
Valacyclovir is approved for use in adults and
adolescents with mucocutaneous HSV at a
dosage of 1 g orally twice daily; no pediatric
preparation exists, and data on dosing in
children are limited; could be used by older
children able to receive adult dosing
Famciclovir is approved for use in adults and
adolescents with mucocutaneous HSV
infection at a dosage of 500 mg orally twice
daily; no pediatric preparation exists, and
 data on dosing in children are unavailable;
could be used by older children able to
receive adult dosing
Suppressive secondary prophylaxis can be
considered for children with severe and
recurrent gingivostomatitis First choice is:
acyclovir, 20 mg/kg body weight (maximum
400 mg/dose) per dose orally 2 times daily,
with second-line therapy being: acyclovir,
20 mg/kg body weight (maximum 400 mg/
dose) per dose orally 2 times daily

Abbreviation: IV, intravenously.

From Mofenson LM, Brady MT, Danner SP, et al. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected
children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric
Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep 2009;58(RR-11):1–166.

Oral Lesions in HIV Disease

691
692 Patton

Viral diseases
HSV ulcerations: see Tables 5 and 6.
OHL: because of the asymptomatic and nonmorbid nature of OHL, generally no
treatment is warranted. OHL improves or resolves with topical treatments such as
podophyllum and tretinoin, and systemic therapy with antivirals such as desciclovir,
acyclovir, ganciclovir, valacyclovir, foscarnet, and famciclovir.66 Recurrence after
discontinuation of pharmacologic therapy is common. Drug side effects and the po-
tential for development of drug resistance generally weigh against pharmacologic
therapy for this benign lesion.66
HPV: pharmacologic treatment of intraoral and labial warts is not well established,
with no clinical trials and only a few case reports of therapy involving cidofovir, bleo-
mycin, cimetidine, podophyllum, or interferon a intralesional injections.66
Varicella zoster virus: see Table 5.

Bacterial diseases
NUG/NUP/LGE: local debridement of areas of NUG/NUP is followed by prescription of
systemic antibiotics, such as metronidazole or amoxicillin, and antimicrobial rinses,
such as chlorhexidine.67 Pharmacologic therapy for LGE may include antimicrobial
rinses.

Neoplastic diseases
KS: see Table 5. Systemic chemotherapy or immune modulation with various agents,
including vincristine, vinblastine, adriamycin, doxorubicin, bleomycin, etoposide,
paclitaxel, interferon a, altiretinoin, rapamycin, interleukin 12, lenalidomide, thalido-
mide, and pegylated liposomal doxorubicin, has been used in combination to treat
various forms of KS at various locations.33,66,68 Additional local pharmacologic thera-
pies for oral KS include intralesional vinblastine, 3% sodium tetradecyl sulfate, and
possibly interferon a-2b.66
NHL: multiagent systemic chemotherapy (cyclophosphamide, vincristine, doxoru-
bicin or adriamycin, and prednisolone [CHOP], with rituximab) is most often used
for treatment of large B-cell lymphomas.35

Other diseases
MAU and ulcers not otherwise specified Topical and systemic steroids are the first
choice of therapy. For isolated and accessible lesions, potent (fluticasone proprionate,
dexamethasone, fluocinonide) or ultrapotent (clobetasol propionate, halobetasol pro-
pionate) topical steroids can be used.69 For multiple ulcers, dexamethasone elixir as a
swish-and-spit can be effective. If lesions are severe, systemic steroids, such as
ingested dexamethasone or prednisone tablets, may be needed.69 Systemic thalido-
mide (200 mg daily) is effective in treatment of major aphthae in HIV-infected patients
in cases in which benefit outweighs the risks and limitations of drug toxicity, including
potential teratogenicity among pregnant women, rash, sedation, and neuropathy.66
HIV salivary gland disease Pharmacologic treatments for HIV salivary gland disease
are not common, although patients with salivary hypofunction benefit from topical
fluoride therapy to control caries. Patients with benign lymphoepithelial cysts of the
parotids have been managed with some success with intralesional bleomycin and
intracyst sclerotherapy with agents such as sodium morrhuate, alcohol, tetracycline,
and doxycycline.70–72
Oral and facial adverse effects of antiretroviral drugs should be identified and
addressed in concert with the patient’s physician (Table 7).73 If the oral effect is severe
or the patient cannot be switched by their physician to another effective antiretroviral
 Oral Lesions in HIV Disease 693

Table 7
Orofacial adverse effects of antiretroviral drugs

Orofacial Adverse Effect Antiretroviral Drugs

Xerostomia/salivary gland Didanosine, lamivudine, indinavir, nelfinavir, ritonavir,
dysfunction saquinavir
Erythema multiforme Zidovudine, didanosine, zalcitabine, abacavir, nevirapine,
efavirenz, delavirdine, saquinavir
Mucosal hyperpigmentation Zidovudine
Ulcers/stomatitis Zalcitabine, nevirapine, saquinavir
Parotid lipomatosis Indinavir, nelfinavir, amprenavir, ritonavir, saquinavir
Taste disturbance Indinavir, ritonavir
Cheilitis Indinavir
Perioral paresthesia Amprenavir, ritonavir
Facial edema Ritonavir

Data from Scully C, Diz Dios P. Orofacial effects of antiretroviral therapies. Oral Dis 2001;7:205–10.

agent that resolves the adverse effect, the dentist may need to manage the oral side
effect as a chronic condition. Salivary gland hypofunction is one of the most common
drug side effects and may require increased oral hygiene efforts, topical fluorides, and
increased dental recall intervals. Long-term use of HAART can lead to lipoatrophy of
the face, resulting in buccal or temporal fat wasting and a socially unacceptable and
stigmatizing appearance of facial skeletonization with concave cheeks, prominent
nasolabial folds, periorbital hollowing, and visible facial musculature.74 Reported in
more than half of long-term HAART users, this situation is of particular importance
among the aging HIV population, who pursue quality of life and social competence,
in addition to longevity.75,76 Referral to a dermatologist or facial plastic surgeon for
consultation about management with cosmetic dermal fillers may be warranted.77

Nonpharmacologic Strategies
Bacterial diseases
HIV-infected patients should be monitored closely to prevent irreversible periodontal
damage from chronic periodontitis or the rare necrotizing conditions. Periodontal
monitoring and early therapy are recommended independent of level of periodontal
disease in patients with immune suppression or use of HAART.78 General nonpharma-
cologic strategies for NUG/NUP include debridement and removal of plaque and
necrotic tissue with povidone iodine solution for topical anesthetic effect and bleeding
control; local anesthesia may be required. For LGE, plaque removal is recommended
with enhanced oral hygiene.

Viral diseases
Oral warts can be surgically removed if they interfere with eating and speaking or are
cosmetically displeasing. The patient should be made aware of the chance of local
recurrence. The location of wart involvement and amount of tissue deficit left after
removal should be considered when debating possible surgical resection of intraoral
or labial warts.

Neoplastic diseases
Radiation therapy and surgical or laser resection or debulking are components of
management of some cases of intraoral KS and NHL.30,35
694 Patton

Other diseases
Patients with major aphthae want to avoid spicy food and alcohol that lead to
increased pain. Those with salivary gland hypofunction may benefit from increasing
their drinking water intake and may stimulate salivary flow with sugarless gum or
candies. Xylitol sweetener is preferred for its cariostatic properties. Serial aspiration
and radiation therapy have been used to treat benign lymphoepithelial cysts of the
parotids in patients with HIV disease.72
Self-Management Strategies
Patients should be encouraged to maintain optimal oral hygiene to reduce the inci-
dence and severity of gingival and periodontal diseases. Avoidance of cariogenic
foods and sweets is important for those with underlying salivary hypofunction from
drug side effect or HIV salivary gland disorders. Patients prone to recurrent HSV ulcer-
ations should take efforts to avoid triggers to recrudescence (reactivation of clinical
disease). Patients who discover worrisome new intraoral swellings should seek pro-
fessional dental assessment.
Evaluation, Adjustment, Recurrence
In the large US HIV Outpatient Study cohort, IRIS occurred in 10.6% of adults who
responded to effective combination antiretroviral therapy.79 The most common
IRIS-defining diagnoses were candidiasis (all forms), CMV infection, disseminated
Mycobacterium avium intracellulare, Pneumocystis pneumonia, varicella zoster, KS,
and NHL.79 New oral lesion occurrence or recurrence in a patient on HAART who
has shown previous effective and sustained control of HIV replication (low or unde-
tectable viral loads), may suggest possible development of antiretroviral resistance,
resulting in a decline in immune competence, and thus need for referral to their physi-
cian for laboratory reassessment of viral load and CD4 count and possible adjustment
of the antiretroviral regimen.

SUMMARY/DISCUSSION

Dentists play an important role in managing the oral health of patients with HIV dis-
ease, which includes surveillance and management of oral mucosal and atypical
gingival/periodontal conditions associated with immune suppression. Knowledge of
HIV oral lesion clinical appearance, lesion symptoms and behavior, various treatment
approaches, and anticipated response to treatment are important for oral disease
control and oral health maintenance.

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