NEVILL234

HUMAN IMMUNODEFICIENCY VIRUS

AND ACQUIRED IMMUNODEFICIENCY
SYNDROME
During the last two decades, more art icles have been
written on human immunodeficiency vi rus (H IV) and
its related di sease sta tes than any other infectious
process. A complete bibliography alone would be easily
th icker tha n this chapter. Ent ire texts dedicated to HiV
infection an d acquired immunodeficiency syndrome
(AiD S) are avai lab le and should be consulted for more
detailed in formation .
AiD S came int o the lim elight in i 981. By 19 92, 8 million
peop le worldwide were thought to have been
infected by HiV, wit h more than 5 million progressingto
AIDS. Estimations at th at time suggested the United
States had between I and 1.5 million inhabitants infected
with HIV. From the beginning of the epidemic to thedawn
of the new cent ury, 733,374 cases of AiDS have been
repo rted in the United States to the Centers for Disease
Cont rol; of the se individuals, 430,44 1 are dead. At the
time of publication of the fi rst edition of this text, the
infectio n was thought to be nearly 100% fat al. Through
treatment advances, the ann ual incidence of AIDS and
related deaths have been dro ppi ng since 1996. This
therapy is changing the face of HIV in fecti on, with
aff ected individu al s demonstrating extended survival
(resulting in an increased percentage of the population
living wi th the virus).
In infected ind ividuals, the vi rus can be found in most
bodi ly fl uids. HIV has been recovered from serum, blood.
saliva, semen , tea rs, urine, breast mil k, ear secretions,
and vagina l secretio ns. T he most frequ ent routes of
transmission are sexua l con tact, pa renteral exposureto
blood, or transmission from moth er to fetus during the
perinata l period. Infection also has been documented to
be caused by arti ficial inseminat ion, breast-feeding from
infected moth ers, and organ transpla ntation. Although
heterosexual transmission is increasing, most of the
adul ts infected in the United States have been homosexual
or bisex ua l men, intravenous drug abusers,
hemop hi liac patients receiving factor VIII before 1985.

recipients of blood products. or heterosexual contacts

with one of the other high-ri sk gro ups.
Researchers have debated the infectiousness of oral
flu ids. HIV has been found to be pre sent in oral fluids.
but sa liva appears to reduce the ability of HIV to infect
its target cells. lymphocytes. Reports of transmi ssion by
oral fluids are rare, and it appears th is is not a signifi can
t source for the tra nsmission of AIDS. In spite of this,
anecdotal reports have documented the transmission of
AiDS during breast-feeding from the oral fiuids of postpartum
infected infants to thei r previou sly noninfected
mothers. In addi tio n, rare examples have been documented
repor ti ng the tran smission of HIV infect ion by
contamination of the oral fl uids during cunnili ngus or
repeated passionate kissi ng. Alt hough rare. these anecdotal
reports point out that oral fl uids can be infect ious
and are not completely protective against oral introduction
of HIV. In summary. the best safety against infection
isavoidance of all body fluids of infected patients.
Initially. in the Unite d States. AIDS was thought to be
adisease that primarily affected whites and male homosexuals.
Although men having sex with men remain s the
largest single ri sk factor. the nature of the epidemic is
shifting (Figure 7-32 ). When compared wi th the cumulative
data, more recent reports demonstrate a growing
proportion of patie nts with AIDSoccurr ing in blacks and
Hispanics (Figure 7-33). Since 1996. blacks have outnumbered
whites in new AIDS diagnosesand Hlv -relatcd
deaths. Altho ugh the raw numbers are worrisome. the
annual rates per 100.000 population dramaticall y highlight
the ethnic shift (Figure 7-34). The propo rtion of
women also is increasing steadily (23% in 1999). with a
greater percentage infected heterosexually rather than
through int ravenous drug use.
The primary target cell of HIV is the CD4 + helper T
lymphocyte. The DNA of HIV is incorporated into the
DNA of the lymphocyte and. th us. is present for the life
of the cel l. In most vi ral infections. host anti bodies that
are protective against the organism usually are formed.
In people with HIV infecti on, antibodies are developed
butare not protective. The virus may rema in silent. cause
cel l death. or produce syncy tiai fusio n of the cells. which
disrupts their normal function. A subsequent decrease in
l-hclper cell numbers occu rs. with a resulta nt loss in
immune function. The normal response to viruses, fungi,
and encapsulated bacteria is dim inis hed.
On in troduct ion of the HIV. an indefi nite percentage
of those infected will have an acute self-limited viral syndrome.
This is followed by an asymptomatic stage. which
averages 8 to 10 years. The length of the asym ptomatic
period is variable and may be affected by the nature of
the virus. the host immune reaction , or externa l factors
235
that may del ay or accelera te the process . Almost
inev itab ly. the finai symptomatic stage develops .
Clinical Features
HIV infectio n init iall y may be asymptomatic or an acut e
response may be seen. The acute vi ral syndrome that
occur s typi call y develops wi thin I to 6 weeks aft er exposure
in 50% to 70% of infected pat ient s. The sympto ms
bear some resemblance to those of infectio us mononuc
leosis (e.g.. generali zed lymphadenopath y. sore
th roat , fever. macu lopapular rash. headache. myalgia .
arthralgia. diarrh ea. photop hobia . peripheral neuropathies).
Oral changes may include mucosal eryt hema
and focal ulcerat ions.
The acute viral syndrome clears within a few week s;
during t his period, HIV in fection usuall y is not considered
or investiga ted. A variab le asymptomatic period follows.
Some patients have persistent generalized lymphadenopathy.
which may later resolve. In some patients
(before development of overt AIDS). there is a period of
chronic fever. weight loss. di arrhe a. oral candidiasis.
herpes zoster, and /or oral hair y leukoplakia. This has
been termed AID S- related complex (ARC).
The presentation of symptomat ic. overt AIDSis highly
variable and often is affected by a person's prior exposure
to a numb er of chro nic infections. The signs and
symptoms describ ed und er ARC are often present. along
with an increasing number of opportu nistic infections or
neoplastic processes. In 50% of the cases. pneumonia
caused by the protozoan Pneumocystis cannit is the presenti
ng featu re leadin g to the diagnosis . Othe r infec tio ns
of diagnostic significance inclu de dissemina ted cytomegalovirus
(CMV) infection, severe herpes simplex virus
(HSV) infec tion. atypical mycobacterial in fection. cryptococcal
meni ngitis. and central nervous system (CNS)
toxoplasmosis. Persistent diarrhea is commonplace and
may be bacteria i or protozoal in or igin. Clini cally significant
neuro logic dysfunction is present in 30% to 50%
of pati ent s. and the most common manife station is J progressive
encepha lopa thy know n as AIDS-d eme nt ia
complex.
Certain neoplastic processes also are associated with
AIDS. Clini cal descriptions of thesecancers are presented
in the port ion of this text dealing with the oral manifestat
ions of HIV in fecti on. A vascula r malignancy. Kapos i's
sa rcoma (KSL which otherwise is rare in the Un ited
States. has been reported in about 15% to 20% of
patients with AIDS. This cancer appears associated with
a sexually transmitted agent other than HIV: human
herpesvirus type 8. AIDS-associa ted KS occurs primarily
in homosexuals, but KS has been reported in homosexuals
withou t HIV infection. This should remind clini-

cians that homosexuals with KS should not be labeled

"H IV-infected" until th ere is serologic proof. The prevalence
of KSin HIV- inf ected pat ient s has been decreasing
and may be the result of the use of condoms, wh ich may
be preventing the tran smission of herpe sviru s 8.
Non-Hodg ki n's lympho ma is th e second most
common malignancy. It is frequent ly found in extra nodal
sites, especia lly the eN S. Oth er cancers, including oral
squamous cell ca rcinoma . have been documented in
pat ients infe cted with HIV, but the associa tion between
AIDS and the se cancers is not as strong.
A list of oral mani festat ions of AIDS is presented in
Table 7- 1. The discussion here concent rates primarily on
the clinical presentation s. (For detail ed information on the
histopa th ology, diagnosis, and treatm ent of each condition,
see the text covering the Indi vidual disease.) When
the infections are treated differently in HIV- infected
patients. the se va riat ions are pre sented here . T he most
common manifestati ons are presented fi rst, followed by
a selecti on of the less frequentl y encountered disorders .

This li st of common oral manifesta tio ns may change

because of the impact of modern therapy on the disease.
Current ant iret rovira l therapy has produced a significant
decrease in the prevale nce of HIV- related oral mani festations.
with an alte red ranking of the most commonly
encountered pathoses. In one study. therapy appea red
to decrease the frequency of oral candidias is. hai ry
leukopla kia. destr uctive per iodontal diseases. and KS;
however. It increased the prevalence of HIV-associated
saliva ry gland disease and human papil lomavirus
(HPV)-associated mucosal alte rations.
Common oral and maxillo!aciall1lalli{est aliolls
of lllV infection
Persistent generalized lymphadenopathy. Afte r seroconversion.
HIV disease often remains silent except tor persistent
genera lized lymphadenopathy (PGL). The prevalence
of this ea rly clin ical sign varies: however, in several
studies it approaches 70%. PGL consists of Iympha238
denopathv t hat has been present for longer than 3 months
and involves two or more extraingui nal sites. T he most
frequ entl y invo lved sites are the posterior and anteri or
cerv ical, submandibular, occipital. and axillary node s.
Nodal enlargement fluct uate s, usuall y is larger tha n I
em, and varie s from 0 .5 to 5.0 em (Figure 7-35l.
Because lymphoma is known to occur in th is pop ulation
, a lymph node biopsy may be indicated for locali zed
or bu lky adenopathy, when cytopenia or an elevated
erythrocyte sedimentatio n rate is present . or wh en
requested tor pat ient reassurance. Histopat hologic examinat
ion reveals flor id fo llicul ar hyperplasia. Although not
as predictive as oral candidiasis or hairy leukoplaki a,
PGl does warn of progression to AIDS; alm ost one third
of affected and untreated patients will have dia gnostic
featu res of AIDS wit hin 5 years.
Candidiasis. Oral candidia sis is the most common
intra ora l manifestatio n of HiV infection and often is the

presenting sign that leads to the initial diagno sis (Figure

7-36l. Its pr esence in a patien t inf ected with HIV is not
diagnostic of AiDS but appears to be predi ctive for the
subsequent development of full-b lown AIDSin untreated
patients with in 2 year s. Prevalence stud ies vary Widely,
but approximate ly one third of Hlv- Infectcd individuals
and more than 90% of patients with AIDS develop oral
candidiasisat some time during their disease course.The
following four cli ni cal pattern s are seen;
Pseudom embranous
Erythematous
Hyperplastic
Angu lar cheili tis
The fir st tw o variants const itute most of th e cases (see
page 189), Alt hough infrequently seen in lmmunocompetent
patients, chronic multifocal oral involvement is
common in patients who are infected with HIV.
The diag nosis of candidiasis of ten is obv ious fromthe
cl inical presentation but can be confirmed by cytologic
smear or biopsy. Biopsy specimens of involved mucosa
demonstrate the candidaI organisms embedded in the
super ficial keratin , b ut th e typical inflammatory reaction
often is defi cien t (Figure 7- 37).
Treatment ismuch more difficult in patlcnts wit hAIDS.
Nystatin often is ineffecti ve. Topi cal clotrimazole is associated
w ith an improved response and typically produces
a cl ini cal cu re rate that equals that of th e systemic azoles,
In spi te of thi s success, topica l th erap y is associated with
a high recurrence rate . The systemic azoles (t.c.. fluconazole,
ketoconazolc, itracona zolc) produce longer
disease-free inter vals but are associated with anotherset
of problems, Itracona zol e and kctocon a zole require gast
ric acid ity for adequate absorption, and all th ree agents
are associat ed wi th a number of drug interactions. In
addition, Widespread use of systemic azoles has led to
an increased prevalence of dr ug- resistant candidiasis.

In patients who arc receiving effective antiretroviral

therapy and have a CD4 + count exceeding 50 ccll s/ rnrn'
plus no signs of esophageal in volvement. topical clotr imazole
is the treatm ent of choice. Systemic therapy is
recommended for patient s not receiv ing effective antiretroviral
therapy or for those with either esophageal
involvement, a CD4 + count below 50, or a high viral
load. Itraconazolc in an oral solution has been shown to
beparticu larly effect ive in a swish-and-swa llow method.
Patients failing systemic azote therapy are candidates for
intravenous amphotericin B if the patient 's healt h supports
its use. Topical amphotericin Bis availabl e, but li ttle
resea rch exists on its relat ive effect iveness. Prophylact ic
antifungal therapy is not recommended unless frequent
and severe recurrences are present.
IiIV-associa ted periodontal disease. Three patterns of
periodontal disease are associated strongly with HIV
infection:
Linear gingival ery thema
Necrotiz ing ulcerative gingivitis
Necrotiz ing ulcerative periodontitis
Linear gingival erythema init iall y was termed HiV"
Iated gingivitis but ult imatel y wa s noted in association
wi th other disease pro cesses. This unusual pattern of
gingivitis appears wit h a dist inct ive lin ear band of ery thema
that involves the free gingival margin and extends
2 to 3 mm apically (Figure 7-3 8). In add ition, the alveolar
mucosa and gingiva may demonstrate punctate or
diffuseeryth ema in a significant percentage of the cases.
This form of gin giviti s typically does not respond to
improved plaque contro l and often exhibits a greater
degree of erythema than would be expected for the
amount of plaque in the area. Alt hough some investig ators
believe linear gingival erythema occurs from an
abnormal host immune response to subgingival bacteria,
most believe thi s pat tern of gingi viti s represents an
Figure 7-38 HIY-associated gingivit is. Band of erythema
involving the free gingival margin.
239
unusual pattern of candidiasis. In many instances, linear
gingival ery thema reso lves aft er profession al plaqu e
removal. improved oral hygiene, and use of ch lo rhexidin
e rin ses. Cases resistan t to initia l therapy typically
respond to systemic antifungal medication s such as fluconazo
le or ketoconazole.
Necrotizing ulcerati ve gi ngivit is (NUG) (see page
140) refers to ulceration and necrosis of one or more
inter dental papi llae with no loss of perio dontal attach ment.
Patien ts with NUG have Interp rox imal gingival
necros is, bleeding, pain , and halito sis (Figu re 7-39l.
Necrot izing ulcerative periodont is (NUP) was pr evious
ly termed HIV-associated periodontitis; however, it has
not been deemed to be speci fic fo r HIV infectio n. NUP is
charac terized by gingival ulceration and necrosis associated
wit h rapidly progressing loss of periodontal
attachment. Although severe cases can affec t all teeth,
mult iple iso lated defects often are seen and contrast with
the dif fuse pattern associated with typical chronic periodontitis.
Edema, severe pain, and spontaneous hemorrhage
are common and ofte n lead affected patients to
seek care. Deep pocketing usuall y is not seen because
exten sive gingival necro sis typi cally coincides wi th lo ss
of the adjacent alveola r bone (Figure 7- 40l. Loss of more
than 6 mm of attachment wit hin a 6-month period is not
unusual. H1V-associated periodontitis does not respond
to con vent ional periodonta l therapy.
The t reatment of NUG and NUP revolves around
debridement , ant imicrobial therap y, immediate followup
ca re, and long-te rm main tenance. The initial removal
of necrotic tissue is necessary. combined with povidoneiodine
irrigation. The use of systemic antib ioti cs usuall y
is not necessary. but metronidazole has been administered
to patients with extensive involvement tha t is associated
with severe acute pain. All pat ients should use
chlorhexid ine mouth ri nses init ia lly and for long- term

maintenance. After ini tial debr id ement . foll ow- up

removal of addit ional diseased tissue should be per formed
with in 24 hour s and again every 7 to 10 days for
two to three appointment s. depending on the pati ent' s
response. At thi s point, monthly recall s are necessary
until the process stabilizes; eva lua tions then are performed
every 3 months.
In patients with gingival necrosis, the process occasionally
extends away from the alveolar r idges and
crea tes massive areas of tissue destruction term ed
necrotizing stomatitis. The process cl inicall y resembles
noma (seepage 178) and may invo lve predominantly soft
tissue or extend into the under ly ing bone, result ing in
extensive sequestra tion (Figure 7-4 1), Alt hough this
process initially was tho ught to be an extension of NUP,
necroti zing stomatitis has arisen on the oral mucosa separate
from the gingiva (not over ly ing bone),
ORAL & MAXILLOFACIAL PATHOLOGY
Figure 7-42 HIV-associated recurrent herpetic infection.
Mucosal erosion of the anterior dorsal surface of the tongue on
the left side. Note the yellowish circinate border.
In the absence of gingival involvement , the clinical featu
res of necroti zing stomatitis are nonspecific and mandate
biopsy. In many instances, the areas of soft tissue
ulcerat ion and necrosis demonstrate infection with one
of more agent s, such as herpes simplex virus (HSVI.
cytomegalovirus (CMV), and Epstein -Barr virus (EBV).
On occasion, evaluations for HSV, CMV, and EBVarenegative,
leading onegroup to suggest that some lesionsmay
represent an unusual immune reaction to the HIV. Upon
biopsy. these ulceronecrotic lesions often demonstrate
leukocytoc!asia, histiocytic vasculi tis . and an inflammatory
infiltrate wi th numerous la rge atypical histiocytes.
Herpes simplex virus (HSV). Recurrent HSV infections
occur in about the same percentage of HIV- infected
pat ients as they do in the immunoco mpete nt populati on
(10% to 15%) ; howeve r, the lesions are more widespread,
occur in an atyp ical pattern , and may persist for
months (Figure 7-4 2). The prevalence of HSV lesions
increases signi ficantly once theCD4 + count drop sbelow
50. Herpes labial is may extend to the facial skin and
exh ib it extensive lateral spread. Persistence of active
sites of HSV infect ion for more than 1month in ~ patient
infected wit h HIV is one accepted defini tion of AIDS. The
clin ical presentations of recurrences in imrnunocornpromised
patients and appropriat e therapy and maintenance
have been discussed in the text on herpesvirus
(see page 21 7).
As mentioned in the discussion of necrotizing stomat
itis . evalu at ion for HSV should be perfo rmed in all persistent
oral ulcerations in HIV- infected individuals. In
these ulcerations. investigators have discovered HSV in
10% to 19% (with an addi tional 10% to 28% exhibiting
co- infection by HSV and CMV),
Varicella-zoster virus (VZV). Recurrent VZV infection
(herpes zoster) is fair ly common in HIV- infected patients.