HIV-Positive Patients: Dental Management Considerations

Dent Clin N Am 50 (2006) 635–657

HIV-Positive Patients: Dental Management Considerations Nicholas G. Mosca, DDSa,b,*, Alicia Rose Hathorn, DMDc a

Mississippi State Department of Health, 570 East Woodrow Wilson Drive, Jackson, MS 39216, USA b Department of Pediatric and Public Health Dentistry, University of Mississippi School of Dentistry, 2500 North State Street, Jackson, MS 39216, USA c Department of Restorative Sciences, University of Mississippi School of Dentistry, 2500 North State Street, Jackson, MS 39216, USA

A research team in France in 1983, led by Luc Montagnier, identified HIV as the etiology of an immunological deficit in cell-mediated immunity known as AIDS [1]. Since the first cases of AIDS, then known as gay-related immunodeficiency syndrome (GRID) in 1981, the HIV epidemic has spread beyond gay males, Haitians, and hemophiliacs, and affects an estimated 50 million people worldwide. HIV is a blood-borne retrovirus infection transmitted primarily through contact across genital mucosal surfaces, facilitated by breaks in the mucosal barrier or local inflammation, such as genital ulcers or vaginitis. Retroviruses produce reverse transcriptase, which is a viral enzyme that allows the virus to integrate its own DNA into the genome of an infected cell and replicate itself using the infected cell’s ribosomes and protein synthesis [2]. Dr. Robert Gallo and his research team at the National Institutes of Health contributed to the discovery of HIV and were first to identify a human retrovirus in 1980, a T-cell lymphotropic virus (HTLV-1) that is associated with human T-cell leukemia [3]. Two primary types of HIV can infect humans: HIV-1, the primary infection in most of the world; and HIV-2, an infection occurring primarily in West Africa and having smaller molecular size and less pathogenicity than HIV-1. In 1999, researchers at the University of Alabama at Birmingham discovered that HIV-1 might have originated from an infection of subspecies * Corresponding author. Mississippi State Department of Health, 570 East Woodrow Wilson Drive, Jackson, MS 39216. E-mail address: [email protected] (N.G. Mosca). 0011-8532/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cden.2006.06.006 dental.theclinics.com

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of chimpanzees native to west equatorial Africa [4]. This simian virus may have spread to humans through exposure to infected blood while hunting chimpanzees, or through the consumption of infected chimpanzee ‘‘bushmeat.’’ Each virus type has viral subtypes, known as clades, that have been isolated in distinct geographical regions. Intracellular infection in human cells requires cell surface receptors and coreceptors, which exhibit genetic polymorphisms that provide specificity and modulate the virus’s ability to infect cells. In North America, clade B is the predominate viral subtype. Researchers at Johns Hopkins showed that HIV disease may progress more rapidly with certain viral clades. For example, increased virulence is associated with clade D in Africa [5]. HIV infects tissue-bound Langerhans or follicular dendritic cells, which process virus as nonself antigen to activate circulating CD4þ T lymphocytes, also called helper T cells because they serve to coordinate HIV-specific immune response. Cells with intracellular pathogens must express viral proteins in association with specific receptors at the cell surface for infection to be recognized by the cytotoxic immune cells or to stimulate antibody production. Activated CD4þ T lymphocytes transport HIV to lymphoid organs, such as the gut-associated lymphoid tissue, where virus replication is accelerated through normal antigen amplification mechanisms. HIV-specific CD8þ T lymphocytes differentiate to destroy activated CD4þ T lymphocytes infected with the virus, which in turn stimulates production of more CD4þ T lymphocytes. In 1995, Shaw and colleagues [6] demonstrated that viral loads are sustained by a delicate balance between T-cell–mediated virus replication (production) and T-cell–mediated viral destruction (clearance). Once this cycle of HIV infection is established, the immune system cannot eliminate virus completely, causing a progressive T-lymphocyte depletion, destruction of the architecture of the lymphoid organs, and inability to mount a cell-mediated immune response to any infection. HIV-positive individuals have increased susceptibility to opportunistic infections that are challenging to treat and may lead to death. HIV’s genome contains three structural and six regulatory genes that encode at least 15 viral proteins associated with its pathogenicity and viral replication. A cell envelope glycoprotein, GP160, is the principal viral antigen and has a GP120 external segment and GP41 transmembrane segment (Fig. 1). Viral proteins have become important targets for the development of antiretroviral drug therapies. In the mid-1990s, researchers found that some infected cells have beta-chemokine receptors, CCR5 and CXCR4, that participate in binding and entry of HIV into host cells, and ligands for these receptors could inhibit attachment [7]. HIV strains that use CCR5 as coreceptors are called R5 viruses and those that use CXCR4 are called X4 viruses. Clade-A HIV uses only CCR5 while clade D uses CXCR4 and may be more virulent. R5 viruses cannot infect cells with CXCR4 receptors and X4 viruses cannot infect cells with CCR5 receptors. Studies of genetic polymorphisms led to the discovery that individuals

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Fig. 1. Organization of the HIV-1 virion. (Courtesy of the Office of Communications and Public Liaison, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.)

homozygous for a deletion of 32 base pairs in the CCR5 gene could not be infected in vitro with R5 viruses [8]. These individuals comprise about 1% of white populations and are extremely resistant to HIV, even with repeated viral exposures.

High-risk behaviors and HIV testing HIV is transmitted by infection of genital mucosa, through inoculation during an injection of drugs or during a transfusion, and, rarely, by infection of oral mucosa. Transmission may also occur from an infected mother to child in utero, during delivery (peripartum), or by breastfeeding. The risk for transmission is closely linked to the plasma viral load of the transmitting HIV-positive individual. Polymerase chain reaction (PCR) test can detect HIV viral genes and is used to determine plasma viral load. The amount of viral replication is measured as viral copies per milliliter of blood, and expressed as logs of the number of infected CD4þ T cells. Mellors and colleagues [9] demonstrated this direct relation between the viral load, or set point, which is the amount of virus produced at production and destruction equilibrium, and the rate of CD4þ T-cell decline. Regardless of socioeconomic and cultural factors, the transmission of HIV occurs primarily due to risky behavior. Box 1 provides a list of risky activities and clinical symptoms for those unknowingly infected with HIV. Individuals with viral load of O50,000 copies per milliliter have a more than 50-fold increased risk of transmitting virus per risk behavior, while those with viral load of !1000 copies have lower risk [10]. PCR is expensive and very labor-intensive to use as a screening test. Since 1984, standard serologic HIV testing uses enzyme-linked immunosorbant assay (ELISA) to detect antibodies to HIV and should be performed when high-risk behaviors or symptoms of acute infection are evident. Primary

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Box 1. Indications for HIV-antibody testing Behaviors or history associated with high risk:
Having unprotected vaginal, anal, or oral sex with men who have sex with men, multiple partners, or anonymous partners
Having recent or prior sexually transmitted disease, hepatitis, or tuberculosis infections
Exchanging sex for drugs or money
Having male or female sexual partners who are at risk
Injecting drugs or steroids, or sharing injection equipment with others
Having history of receiving blood products or clotting factor between 1978 and 1985
Having unprotected sex with anyone who exhibits risky behaviors listed above Clinical conditions associated with high risk:
Sexually transmitted diseases
Thrush (ie, chronic or recurrent oral and/or vulvovaginal candidiasis)
Generalized lymphadenopathy
Recurrent herpes simplex or herpes zoster
Chronic diarrhea or wasting
Encephalopathy
Anemia, leukopenia, or thrombocytopenia
Opportunistic infections antibody production to HIV after initial infection may take 2 to 4 weeks, creating a period when ELISA will not be able to identify infection. If the initial ELISA is negative, the test should be repeated in 3 months. If positive, confirmatory testing using Western blot techniques is performed on all positive screening tests to assure reliability of results. Western blot detects antibodies to HIV-1 proteins with a low frequency of error (!0.00004% false positives). If a Western blot result is indeterminate or uncertain, nucleic acid testing for viral RNA or proviral DNA can be performed. An HIV viral core p24 antigen test is used to detect HIV in donated blood supplies, but the viral core antigen may become undetectable about 40 days after seroconversion, making the test less favorable to detect HIV when diagnosing humans [11]. HIV longitudinal studies have also demonstrated that persons exposed to HIV during risky behavior may undergo latent seroconversion, with no detectable antibody production after initial exposure [12]. Tests have also been developed for urine and oral saliva using enzyme immune assay (EIA) testing that detects IgG antibody, whose principal site of action is serum. OraSure (OraSure Technologies, Bethlehem, Pennsylvania)

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is an oral fluid test approved by the US Food and Drug Administration (FDA) and Calypte (Calypte Biomedical, Alameda, California) is a urine EIA test that can be used with needle-phobic individuals who shun blood tests. Several rapid HIV tests, which provide results in about 20 minutes, have also been approved by the FDA for use in the United States. These tests include OraQuick Rapid HIV-1 and Advance HIV- Antibody Tests (OraSure Technologies), Reveal G2 HIV-Antibody Tests (MedMira, Halifax, Canada), Multispot (Bio-Rad Laboratories, Hercules, California), and Uni-Gold Recombigen (Trinity Biotech, Bray, Ireland). As with enzyme immune assay testing, rapid test results must be confirmed by Western blot test. HIV/AIDS epidemiology The World Health Organization estimates that over 50 million people have been infected with HIV worldwide, with more than 25 million infections reported in Africa. Southeast Asia, Latin America, and Eastern Europe account for about 10 million cases, and an estimated 1.2 million people have HIV infection in North America. Western and Central Europe combined have fewer than 750,000 reported cases of HIV infection. An estimated 40,000 cases of HIV infection occur in the United States each year. In the United States, 33 states using confidential, name-based reporting, provide HIV/AIDS prevalence data to the Centers for Disease Control, and all 50 states report AIDS. In the past 2 decades, the number of reported AIDS cases has fallen due primarily to improvements in antiretroviral treatment regimens, and increased use of medical care through regional, state, and local programs funded by the federal Ryan White Comprehensive AIDS Resources Emergency Act. Trends demonstrate a decrease in AIDS among white males who have sex with males, but an increase in AIDS among non-Hispanic blacks. From 2001 through 2004 in the United States, 157,252 cases of HIV infection were reported to the Centers for Disease Control. Non-Hispanic black males had the largest percentage of HIV infections in every transmission category, and, among females, non-Hispanic blacks had the most cases (69%) [13]. Non-Hispanic blacks account for up to 12% of the United States population, yet they accounted for half of all AIDS cases diagnosed in 2004. In 2004, the rate of AIDS diagnoses for non-Hispanic black women was 23 times the rate for white women; the rate of AIDS diagnoses for non-Hispanic black men was 8 times the rate for white men. Mucosal resistance to HIV Much progress has been made in understanding protective anti–HIV-1 immune responses in mucosal tissues, such as that in the oral cavity. The first line of defense against mucosal HIV infections begins with virus neutralizing immunoglobulin or antibodies. In the oral cavity, secretory IgA

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produced by subepithelial plasma cells is trancytosed by epithelia cells. IgG is transferred from blood by passive diffusion through the gingival sulcus. CD8þ cytotoxic T lymphocytes present in the lamina propria (intraepithelial region) may limit or prevent localized virus production in epithelial Langerhans cells and subepithelial dendritic cells. Factors that limit the efficient immune system elimination of HIV include immune exhaustion, lack of adequate CD4þ T-lymphocyte function, protected viral reservoirs, potential infection of CD8þ cytotoxic cells, and defects in antigen-presenting cells [14]. HIV treatment therapies Initial infection of HIV in adults causes an acute viral syndrome within 4 to 11 days of infection, probably due to rapid viral replication in lymphoid tissues. Clinical symptoms may occur 2 to 6 weeks after viral inoculation, and the most common signs and symptoms are fever, rash, headache, lymphadenopathy, and pharyngitis. A healthy, uninfected person usually has 800 to 1200 CD4þ T cells per mm3 of blood. Transient immunosupression associated with acute infection may lead to a decrease in CD4þ T lymphocytes; interstitial inflammatory infiltrates in the skin, causing a skin rash on the upper torso; and ulcerations in the oral cavity and pharynx. Opportunistic infections, such as candidiasis, may also occur in the oropharynx. Co-infections may be transmitted with HIV, including hepatitis, syphilis, and Kaposi’s-sarcoma–associated human herpes virus 8. A small percentage of people will have no acute symptoms during initial infection. Early therapy using antiretroviral drugs can be initiated in acute infection to lower the viral load and boost the initial immune response, but this has not been effective in eradicating virus completely. The decision to begin early treatment should include consideration of the long-term effects of drug-related toxicities, and include genotypic testing to identify antiviraldrug–resistant strains of HIV. Genotypic and phenotypic drug resistance testing permits the optimal use of available antiretroviral drug therapies. Clinical drug failure occurs when control over viral replication is lost. Immune seroconversion with antiviral antibody production may take up to 3 months after the acute infection. Life expectancy with HIV infection remains unpredictable. A small group of HIV-positive people are known as long-term nonprogressors because they show no signs of immune deficiency after O16 years of infection. For the infected majority, HIV is considered a chronic disease because drug therapies have suppressed viral production but fail to completely eradicate viral replication. Between 2% and 4% of new infections in the United States are with multidrug-resistant HIV. In 2005, there were 21 anti-retroviral pharmaceuticals in use, not including multidrug-combination preparations. The spectrum of drug discovery for HIV centers on an appreciation of vulnerable targets in the replication of the virus. Antiretroviral drug therapies decrease viral set points, leading

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to an increase of CD4þ T lymphocytes, improving immune function and reducing vulnerability to opportunistic infections. Symptomatic HIV-positive patients should be treated with antiretroviral medications regardless of their CD4þ T-cell count or viral load. Asymptomatic patients with CD4þ T cells !200/mL should also begin treatment. It is generally recommended that asymptomatic patients with CD4þ T cells O350/mL and viral loads !100,000 copies/mL defer therapy due to patient readiness, probability of adherence, and drug side effects and interactions. However, those with viral loads O100,000 copies/mL should consider initiation of antiretroviral therapies. A cure for HIV infection would require an antiretroviral therapy that penetrates all cells where virus is replicating, strict adherence by patients to the drug regimen until all infected cells are destroyed, and minimal morbidity from drug toxicity and complications. Current therapies might achieve and sustain viral loads at values at least 0.5 log10 copies per mm below baseline [15]. The first effective drug against HIV was azidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), licensed in 1987. AZT was also associated with increased melanin hyperpigmentation of the tongue and oral mucosa. Other NRTIs are listed in Table 1. The subsequent phase of drug therapy focused on specific points in the virus replication cycle. Protease inhibitors were licensed in 1995. Combination therapies have proved promising, and are known as highly active antiretroviral therapies (HAART). In 2003, the FDA approved the use of enfuvirtide, which blocks the fusion of the viral envelope to the cell membrane. Therapeutic strategies have centered on the association of a given viral set point in asymptomatic untreated individuals and their prognosis for disease progression. Dental treatment Oral health and medical care providers should collaborate in the management of patients with HIV disease. The immunological deficit in cell-mediated immunity leads to oral conditions that provide a ‘‘window’’ to the onset of acute HIV infection. By examining oral conditions, care providers can measure adherence and effectiveness of antiretroviral treatment regimens, and detect changes in quality of life. The most effective professional relationships in HIV patient care are personal, caring, and ‘‘relationshipcentered.’’ To enhance patient-care relationships, the health care professional may find that the best opportunities to confer with patients are at any of the three milestones along the course of a person’s experience with HIV infection. These milestones are the initial diagnosis, the onset of clinical symptoms, and the initiation of antiretroviral treatment regimens. A detailed health history should be taken using a nonjudgmental approach. This must include specific nonjudgmental questioning about sexual activity and illicit drug use. Box 1 details health history findings that indicate the need for voluntary HIV testing.

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Table 1 Antiretroviral drug therapies for HIV infection Common abbreviation

Food restrictions

Nucleoside reverse transcriptase inhibitors or nucleoside analogues Zidovudine AZT, ZDV No food restrictions Didanosine Stavudine Lamivudine Abacavir

ddI d4T 3TC ABC

Empty stomach No food restrictions No food restrictions No food restrictions

Emtricitabine FTC No food restrictions Tenofovir TFV, TDF, PMPA No food restrictions Combination nucleoside reverse transcriptase inhibitors or nucleoside analogues Zidovudine and lamivudine AZT þ 3TC No food restrictions Lamivudine and abacavir 3TC þ ABC No food restrictions Tenofovir and emtricitabine TDF þ FTC No food restrictions Non-nucleoside reverse transcriptase inhibitors Nevirapine NVP No food restrictions Delavirdine DLV No food restrictions Efavirenz EFV Empty stomach

Common adverse reactions Anemia, neutropenia, headaches, nausea, melanin hyperpigmentation Diarrhea, pancreatitis, peripheral neuropathy Peripheral neuropathy Headache, nausea Hypersensitivity reaction (fever, malaise, rash), nausea, vomiting, diarrhea Headache, nausea, diarrhea Nausea, vomiting, flatulence, diarrhea Same as AZT, 3TC above Same as 3TC, ABC above Same as TDF, FTC above Rash Rash, impaired liver function Central nervous system effects (dizziness, somnolence, insomnia, confusion)

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Generic name

Protease inhibitors Hard-gel capsule saquinavir Indinavir Ritonovir

a

With meals Empty stomach, light snack With meals

NFV APV LPV ATV f-APV TPV

With meals No high-fat meals With meals With meals No food restrictions With meals

Diarrhea, nausea, abdominal pain Nausea, increased bilirubin, kidney stones Nausea, vomiting, diarrhea; inhibits liver enzymes (increases drug interactions) Diarrhea, nausea, vomiting Nausea, diarrhea, rash, perioral and oral parathesias Diarrhea, nausea, increased cholesterol, increased triglycerides Hyperbilirubinemia, nausea Same as amprenavir Diarrhea, nausea, vomiting, fatigue, headache

T-20

None (administered subcutaneous)

Injection reaction, insomnia, myalgia, pneumonia

Used with pediatric HIV infection.

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Nelfinavir Amprenavira Lopinavir/ritono Atazanavir Fosamprenavir Tipranavir Fusion inhibitors Enfuvirtide

SQV IDV RTV

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Many HIV-positive patients who receive medical care do not receive dental care primarily because of the burden of medical costs and a lack of dental insurance requiring additional out-of-pocket expense. A study of 635 HIVpositive patients at the University of Alabama School of Medicine showed that medical expenditures for HAART were relatively constant at approximately $10,500 per patient per year no matter the CD4þ cell count [16]. The HIV Cost and Services Use Study provides a national perspective on selfreported measures for HIV-infected persons. The study used nationally representative sample of 2466 HIV-positive subjects and a weighted design to control for nonresponse, making the sample representative of a broader population of 219,700 [17,18]. Total out-of-pocket health expenditures for this population were $20.5 million. Those working full-time or part-time spent $207 on dental treatment compared with $108 spent by those not working. Cost of care was highest for people with CD4 counts !50 cells/mL ($172) compared with higher CD4 counts. Thirty-four percent (72,700) felt their overall oral health was ‘‘fair to poor,’’ and 18% (22,000) had not revealed their HIV status to their dental provider. Xerostomia or dry mouth may occur in up to 40% of HIV-positive patients in association with side effects from antiretroviral and antidepressant medications, tobacco use, and proliferation of CD8þ T lymphocytes in salivary gland tissue. Xerostomia may significantly increase the risk for dental caries and acute gingivitis in HIV-positive patients. Patients should receive counseling about these risks and instructions to use artificial saliva products as needed.

HIV-associated opportunistic conditions Oral conditions associated with HIV infection may identify a person who is unknowingly infected with HIV; is used in staging, classification, and prediction of progression to AIDS; and may be used as clinical entry or endpoint indicators in HIV drug therapy. Most HIV-associated oral conditions are caused by opportunistic infections, which occur progressively due to immune system deficiency. While the use of HAARTs has reduced the frequency of almost all opportunistic conditions, dental care workers should be vigilant to identify signs and symptoms associated with nonoral opportunistic infections, which may appear as first signs of viral therapy failure or noncompliance with medications. Treatment recommendations for oral conditions are found in Table 2. The following are HIV-associated opportunistic conditions: Bartonellosis Bartonella is a gram-negative bacterial infection that causes cat scratch disease and an oral condition called bacillary angiomatosis, which may clinically resemble Kaposi’s sarcoma lesions in mucosa. Regional

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Table 2 Treatment recommendations for oral conditions associated with HIV Oral conditions

Treatment options

Angular cheilitis

Ketoconazole 2% cream Dispense 30 g; apply to area 4/d for 2 wk. Clotrimazole troches 10 mg Dispense 70. Dissolve in mouth 5/d for 2 wk. Nystatin oral suspension 500,000 U Swish 1 teaspoon in mouth for 5 min, 4/d for 2 wk. Fluconazole 100 mg Dispense 15 tabs, 2 tabs on first day, then 1 tab/d for rest of period. Diflucan 200 mg Dispense 5 tabs, take 1 tab/d. Acyclovir 4 g/d For temporary relief. Treatment usually not required. Cryotherapy or surgical excision Imiquimod 5% cream For lesion on lips. Dispense 3 g, apply 1/d at bedtime, 3d per wk. Orabase cream Place with a cotton swab over ulcer 3/d. Acyclovir 400 mg Dispense 30 tabs, 1 tab 3/d for 10 d. 0.12% chlorhexidine rinse With oral hygiene instruction and dental cleaning. Augmentin 875 mg Dispense 14 tabs, 1 tab 2/d for 7 d. Rigorous debridement along with 0.12% chlorhexidine rinse. Incisional biopsy With follow-up with patient’s primary physician. Possible radiation or chemotherapy as treatments.

Erythematous candidiasis

Pseudomembranous candidiasis

Oral hairy leukoplakia

Oral warts

Apthous ulcerations Ulcerations from Herpes simplex virus Linear gingival erythema Necrotizing ulcerative periodontitis

Kaposi’s sarcoma

lymphadenopathy, fever, malaise, vomiting, and headache may accompany Bartonella infections. Tissue biopsy, preferably a 5-mm punch biopsy, and Warthin–Starry silver stain or in situ immunohistochemical staining, is used to confirm the diagnosis. Treatment of choice is oral erythromycin 500 mg every 6 hours for at least 3 months. An alternative therapy is doxycycline 100 mg every 12 hours if patient compliance is problematic. Candidiasis (mucocutaneous) Oropharyngeal candida (OPC), as with esophageal and vulvovaginal candidiasis, is caused by yeast, chiefly Candida albicans, and less frequently by Candida glabata, Candida tropicalis, and Candida kruseii. Fungi are normal inhabitants of the gastrointestinal tract and colonization of oral mucosa is common. Diagnosis is made by clinical appearance, and the

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pseudomembranous variant, also known as thrush (Fig. 2), is the most common presentation, especially in HIV-positive children. The pseudomembranous variant appears as a cottage-cheese–like or curd-like exophytic material on the epithelial tissue on all locations in the oral cavity, and it can be easily wiped off. Histological examination is generally not necessary, but specimen samples can be used to confirm diagnosis. Typically, scraping with a blade or cytology brush collects material, which can be gently smeared on a glass slide and viewed microscopically after placing one or two drops of 10% potassium hydroxide solution. Fungal organisms have characteristic pseudohyphae and budding characteristic of reproduction. The erythematous or atrophic variant appears as flat or macular with red color, and is sometimes accompanied by pain (Fig. 3). It may occur simultaneously with or independent of the pseudomembranous variant. Angular cheilitis is a fungal infection of the labial commissures that characteristically appears as erythema or depigmentation with tissue fissures or ‘‘cracking’’ (Fig. 4). Mild episodes can be treated with topical antifungal medications, while moderate-to-severe conditions will typically require systemic therapy. Nystatin is a topical azole antifungal drug with minimal side effects, but sweetening agents in its suspension may be cariogenic. Clotrimazole is another azole that is available as a spray, solution, and troche for oral usage. It has few side effects but is poorly absorbed in the gastrointestinal tract and must dissolve slowly in the mouth to be effective. Clotrimazole may be less cariogenic than nystatin. Fluconazole was the first triazole drug available as tablet or suspension, and it demonstrates good gastrointestinal absorption with minimal dependence on gastric acidity or food intake. Itraconazole, available as a capsule or oral suspension, is a triazole drug that demonstrates better absorption after food intake. Voriconazole has the most significant drug interactions with some antiretroviral drugs and should be considered for use if resistance to fluconazole occurs [19]. The most commonly reported side effects for the triazole drug class are headache, dyspepsia, diarrhea, nausea, vomiting, hepatitis, and skin rash.

Fig. 2. Pseudomembranous candidiasis (thrush).

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Fig. 3. Erythematous candidiasis (hard palate).

Ketoconazole is rarely used as an oral formulation due to its dependence on gastric acidity, but it can be used as a topical agent in the treatment of angular cheilitis. Condyloma acuminatum Condyloma acuminatum is an asymptomatic mucocutaneous infection of the skin or mucosa of the oral cavity or anogenital region caused by human papilloma virus (HPV), which can be transmitted sexually (Fig. 5). More than 100 HPV types have been identified. HPV is a DNA virus type and is epitheliotropic, which means it contains epithelia growth factor and may induce distinct squamous cell proliferations. Some high-risk HPV genotypes have been associated with premalignant and malignant lesions, and HPV types 6 and 11 are most commonly associated with condylomata.

Fig. 4. Angular cheilitis.

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Fig. 5. Human papilloma virus.

Clinical presentation differs from pedunculated exophytic cauliflower-like papules to smooth, flat-topped papules known as focal epithelial hyperplasia. Infections typically have multiple papillomas and appear most commonly on the labial and buccal mucosa, tongue, and gingival. Tissue biopsy is necessary to confirm diagnosis. While there is no therapy to eradicate the infection, treatments include removal of papules using cryosurgery, electrosurgery, or scalpel incision. However, the likelihood of recurrent infection requiring re-treatment is high. Surgeons should use face shields with laser or electrosurgery to minimize exposure to aerosolized HPV. Topical podophylin or topical 5-fluorouracil have also been used to treat lesions. Cryptococcosis Cryptococcus neoformans is a fungal infection that most commonly manifests as a meningoencephalitis. Symptoms include headache, nausea, irritability, and diminished cognitive function, and physical findings include cranial nerve palsies, hyperreflexia, and papilledema. Rarely, intraoral ulcerations may occur in mucosal tissues with dissemination of cryptococcosis [20]. Treatment of crytococcal meningoencephalitis requires multiple drug therapies using amphotericin B, flucytosine, and fluconazole. Cryptosporidosis Cryptosporidium is a spore-forming protozoa infection that causes severe watery diarrhea and epigastric pain. The most common site of infection is the small intestine, and infection may be transmitted person-to-person or by drinking contaminated water. Precautions to prevent disease include proper hand washing and disinfectant cleaning or disposal of contaminated materials. Treatment includes replacement of lost fluid volume and the use of the antibiotic combination of trimethoprim and sulfamethoxazole or ciprofloxan.

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Hairy leukoplakia Hairy leukoplakia is caused by infection of epithelia cells with Epstein– Barr virus, and presents clinically as white, ragged, and corrugated or irregular lesions involving the later and dorso-lateral tongue. Lesions may be unilateral or bilateral. Diagnosis can be confirmed by tissue biopsy. Histiologically, hairy leukoplakia exhibits hyperparakeratosis, often with hair-like projections, epithelia hyperplasia, vacuolated epithelial cells (koilocyte-like), and little or no inflammatory infiltrate in the underlying connective tissue (Fig. 6). Hairy leukoplakia generally does not require treatment unless cosmetically objectionable. Treatment options include the use of zidovidine, podophyllin, and interferon. Regardless of treatment, lesions may spontaneously resolve and recur. Histoplasmosis Histoplasma capsulatum is a fungus comprised of hyphae with characteristic macroconidia or sexual spores. Histoplasma is found in soil and transmission is exogenous, but person-to-person transmission does not occur. Defense against infection requires a healthy-cell–mediated response to stimulate macrophages that engulf fungus and halt progression of disease. Histoplasmosis may infect lungs, bone, and the central nervous system, and clinical findings include fever, weight loss, skin or mucosal lesions, and respiratory symptoms, such as cough and shortness of breath. Dissemination of histoplasmosis to the oral mucosa may occur primarily on the gingival, tongue, palate, and buccal mucosa. Gingival lesions will appear as diffuse granulomatous inflammation with progressive alveolar bone erosion and loosening of teeth. Management of histoplasmosis includes obtaining blood cultures for fungal sepsis and treatment with liposomal amphotericin B or itraconazole. Kaposi’s sarcoma Kaposi’s sarcoma is the most prevalent AIDS-associated intraoral malignancy. Kaposi’s sarcoma occurs more commonly in homosexual and

Fig. 6. Oral hairy leukoplakia.

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bisexual males and is rarely seen in HIV-positive women and children. Kaposi’s sarcoma is an angioproliferative disease which may develop from human herpesvirus 8 (HHV-8) infection of mesenchymal progenitor cells. Defined as a hyperplastic reactive inflammatory disease, Kaposi’s sarcoma is characterized by mucosal lesions that begin as macular patches with red or bluish-purple color, which may become darker and exophytic with ulcerations as lesions advance (Figs. 7 and 8). Kaposi’s sarcoma may resemble bacillary epithelial angiomatosis. Male homosexuals have the highest risk of contracting Kaposi’s sarcoma. The hard palate is the most common oral site, followed by the maxillary gingival. Small intraoral lesions may be treated using intralesional injections of vinblastine sulfate or sclerosing solution sodium tetradecyl sulfate. Local anesthesia should be infiltrated before injections to minimize pain associated with intralesional chemotherapy. Linear gingival erythema Linear gingival erythema describes a deep red appearance of the marginal gingiva with increased risk for bleeding in some HIV-positive patients (Fig. 9). Linear gingival erythema is most common on the facial gingiva of the anterior teeth. It can also present on attached gingival as macular red patches. Etiology of this condition remains unknown but candida infection may have a role. Treatment consists of improving self-hygiene habits, professional gingival debridement, and twice-daily use of 5 mL 0.12% chlorhexidine gluconate mouth rinse for 14 days. Lymphoma Lymphoma is malignant neoplasm of lymphoid cells. The risk for AIDSrelated lymphomas increases with a CD4þ T-cell counts of !100 cells/mL. Lymphomas are primarily non-Hodgkin’s, B-cell (humoral) malignancies,

Fig. 7. Kaposi’s sarcoma (palate).

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Fig. 8. Kaposi’s sarcoma (palate).

possibly caused by a viral co-infection, such as Epstein–Barr virus, and B-cell gene mutations. Symptoms include fever, night sweats, weight loss, and anorexia. Lesions may occur in the oral cavity, and diagnosis is established by tissue biopsy. Treatment options include systemic chemotherapy and radiation therapy of lymphoid tumors. Mycobacterium tuberculosis Approximately one third of AIDS-related deaths worldwide are due to tuberculosis (TB), and in Africa one third of people infected with TB are infected with HIV. This pattern is most likely due to increased reactivation of latent TB infections as well as higher primary rates of TB. All patients with TB should be tested for HIV. Pulmonary TB is the most common clinical manifestation. However extrapulmonary disease affecting the liver, spleen, or kidney may occur in HIV-positive patients with CD4þ T cells !100 cells/mm3 [21]. Tuberculin skin testing with purified protein derivative (delayed-type hypersensitivity response) is used to identify latent TB. Some patients may have a problem complying with the requirement to

Fig. 9. Linear gingival erythema.

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return so that skin induration can be checked. Tests read after a delay of 72 hours or more and found to be negative should be repeated. Active TB in HIV-positive patients increases HIV viral RNA levels, which decrease after treatment of TB is initiated. Treatment includes 6 months of treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. Side effects of therapy include liver function abnormalities, rash, and peripheral neuropathy. Necrotizing periodontal diseases Two periodontal conditions have been identified in association with severe immunosuppression: necrotizing ulcerative gingivitis (NUG) and necrotizing ulcerative periodontitis (NUP). Both conditions are characterized by rapid tissue destruction, severe pain, and bleeding, and affect about 2% to 6% of HIV-positive patients. In comparison, conventional periodontitis may occur in up to 30% of HIV-positive patients. NUP can be differentiated from NUG by rapid periodontal attachment loss secondary to necrosis of alveolar bone. Molecular biologists at the Forsyth Institute discovered NUP did not possess conventional periodontopathic bacteria such as Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Actinobacillus actinomycetemcomitans [22]. Instead, 26 ‘‘novel’’ phylotypes were commonly detected in HIV-positive patients with NUP, including Bulleidia extructa, Dialister, Fusobacterium, Selenomonas, Peptostreptococcus, and Veillonella. Other research suggests that necrotizing periodontal conditions occur more frequently and progress more rapidly due to herpesvirus infection of periodontal tissues [23]. Pneumocystosis Due to the efficacy of antiretroviral agents and use of prophylactic regimens, pneumocystis carinii pneumonia (PCP) now occurs less frequently than it did during the first decade of the AIDS epidemic. The occurrence of PCP is more likely due to lack of medication compliance, poor access to medical care, or lack of awareness of HIV infection, though drug resistance is also possible. Clinical symptoms include fever, nonproductive cough, and shortness of breath. Chest radiographs reveal characteristic diffuse infiltrative pulmonary infiltrates, and diagnosis is confirmed by bronchoalveolar lavage and induced sputum examination. Trimethoprim– sulfamethoxazole remains the drug of choice in treatment, and prophylactic use of one single-strength tablet per day is still considered the standard of care for patients with CD4þ T-lymphocyte counts of !200/ml or who present with oropharyngeal candidiasis or other AIDS-defining infection. Toxoplasmosis Toxoplasma gondii, a protozoal infection in the general population, replicates intracellularly in the host tissues, yet produces no or few clinical

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manifestations in immunocompetent individuals. In immunodeficient persons, latent toxoplasma infection reactivates, most commonly in intracerebral, ocular, and pulmonary tissues. Symptoms include headache, confusion, altered mental status, low-grade fever, arthralgias, myalgias, fatigue, and sore throat accompanied by cervical or generalized lymphadenopathy. Primary prophylaxis with trimethoprim–sulfamethoxazole is used to prevent AIDS-related toxoplasmosis in persons with CD4þ T-cell counts !100 cells/mL. Vesicular-ulcerative conditions Aphthous ulceration Aphthous ulceration is the most commonly reported type of ulcers in HIV-positive patients and its etiology remains undetermined (Fig. 10). Ulcers appear clinically as painful, round-to-oval, yellow or white, and are surrounded by a halo of erythema. HIV-positive patients usually experience increased frequency and severity of typical minor aphthous ulcers. Aphthous ulcers are usually treated with topical or systemic corticosteroids. Thalidomide is also used, but pregnant women must be excluded because of thalidomide’s teratogenic effects. Herpes simplex Herpes simplex virus (HSV) is a double-stranded DNA capsule enclosed in a lipid envelope that is characteristically able to induce latency with periodic reactivation of infection. HSV-1 is associated primarily with orolabial lesions and HSV-2 with genital lesions. HIV infection on oral mucosa presents as an erythematous pruritus that develops into painful vesicles and ulcerates over a brief period, accompanied by painful regional lymphadenopathy. In contrast to the yellow or white pseudomembrane in aphthous ulcerations, HSV ulcers typically have a red center surrounded by a yellow or white border. Orolabial HSV infections may occur on all oral mucosa and can be more prolonged and severe than with HIV-negative individuals.

Fig. 10. Major aphthous ulceration.

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Diagnosis can be confirmed using cytopathologic examination of scrapings of ulcerations (Tzanck smear) or by DNA detection using PCR. Primary treatment includes oral acyclovir therapy, with the use of famiciclovir and valacyclovir as alternative agents. Cytomegalovirus oral ulceration Cytomegalovirus oral ulceration may occur in HIV-positive patients with disseminated cytomegalovirus (CMV) disease, a DNA virus that causes latency and reactivation of infection. Ulcers may occur anywhere in the oral cavity and resemble major aphthous ulceration in size. However, instead of an erythematous margin, CMV ulcers appear necrotic with a white halo. Deep tissue biopsy with biopsy punch or scalpel is used to confirm diagnosis and large intracellular inclusion bodies are characteristic of infection. Patients may develop CMV retinitis, esophagitis, colitis, pneumonitis, and neurological disease. Treatment includes the use of drugs that treat human herpesvirus infections, such as ganciclovir and foscarnet. Neutropenic ulcerations are painful and appear intraorally when a patient’s absolute granulocyte counts drop below 800/mL and appear clinically as very large, necrotic or fulminate ulcers. These ulcers may resemble squamous cell carcinoma and diagnosis should include testing for absolute neutrophil count and differential. Lesions may become secondarily infected with other opportunistic infections, and treatment requires the use of corticosteroid medications. Patients should be considered for treatment with granulocyte-colony–stimulating factor. Treatment planning considerations Dentists should obtain a thorough health history and conduct a headand-neck examination checking for enlarged lymph nodes, and a comprehensive intraoral soft tissue, periodontal and hard tissue examination at the initial assessment. A baseline laboratory assessment of HIV-positive patients performed by medical physicians usually includes a complete blood count and routine chemistries to assess liver and kidney function. While patients undergo medical treatment, dental check-ups should not be disrupted or discontinued. Pseudomembranous candidiasis and oral hairy leukoplakia are sensitive clinical markers of immunosupression. Dental providers should be vigilant to monitor these markers at each assessment visit. With the advent of HAART, the prevalence of oral candidiasis, oral hairy leukoplakia, and HIV-associated periodontal disease have decreased in adults. However, there is evidence of an increase in the benign human papilloma-virus– associated oral lesions, including papillomas, condylomas, and focal epithelial hyperplasia, since HAART use. The prevalence of Kaposi’s sarcoma has not changed. Patients should receive counseling about modifiable risk factors, such as cigarette smoking, which pose additional risks. Current smokers with low

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CD4þ T-lymphocyte counts have greater risk than nonsmokers for developing candidiasis and hairy leukoplakia. Prior or current use of alcohol and other drugs may increase complications, especially if hepatomegaly occurs with viral co-infection or drug therapy. Patients should also receive safesex counseling regarding oral sexual behaviors. For example, patients should be told that Epstein–Barr virus may be transmitted by oral sex. Dental treatment sequencing should be approached as a component of medical care. Patients with low CD4þ T-lymphocyte counts (ie, !200 cell/mL) are predisposed to HIV-associated oral infections that require specific treatment. The dentist’s first priorities are to relieve pain and treat the infection. Next, the dentist should implement prevention regimens to prevent concomitant disease. The third task is to restore function so that patients can eat and maintain their nutrition. Enhanced preventive care compromising bimonthly prophylaxis and chlorhexidine mouth rinses to prevent gingivitis may improve the patient’s psychological health, but there is no evidence that this will reduce the occurrence of AIDS-related opportunistic infections. Lastly, the dentist must provide esthetic procedures to improve self-esteem and enhance psychological health. It is both safe and desirable to assure that regular comprehensive dental care is available to HIV-positive patients. In the United States, Title I, II, III and IV of the federal Ryan White Comprehensive AIDS Resources Emergency Act supports oral health services for HIV-positive persons. Additionally, Section F of the act provides the Dental Reimbursement Program, which retrospectively compensates unreimbursed dental schools, dental hygiene programs, and postdoctoral dental training programs for providing dental care to people with HIV. Table 3 Web resources for dental care providers Website

Name

Description

http://www.hivdent.org

HIV Dent

Developed by Dr. David Resnick at Grady Health Systems in Atlanta, Georgia. Provides basic information about clinical care and about manifestations of HIV. Provides treatment guidelines and publishes Topics in HIV Medicine. Provides treatment guidelines and best practices.

http://www.iasusa.org

International AIDS Society http://www.hivguidelines.org New York State Department of Health AIDS Institute http://www.ucsf.edu/hivcntr/ National HIV/AIDS Developed by the University of Clinicians’ California at San Francisco. Consultation Center Provides treatment guidelines and best practices. http://www.critpath.org/daac/ Dental Alliance for Dental treatment site that contains AIDS/HIV Care links to other information sites.

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Dental treatment can be provided in outpatient settings without hospitalization. No modification of irreversible procedures or surgical dental treatment is recommended unless patients have reduced platelet count to !60,000 cells/mL, which may affect clotting time, or white–blood-cell neutrophil counts !500 cells /mL, which may require antibiotic prophylaxis. A careful history will detect abnormal bleeding or signs of severe bleeding disorder known as idiopathic thrombocytopenia pupura, which presents with characteristic intraoral mucosal petechiae and ecchymoses. Routine antibiotic use is contraindicated and may predispose patients to superinfection and microorganism drug resistance. Consult with the patient’s physician regarding antibiotic prophylaxis use for prosthetic joints or heart valve conditions. Antiretroviral therapies have been associated with new-onset glucose intolerance and hyperlipidemia. Patients may have periodic screening with fasting blood glucose and lipid determinations. Useful resources on the Internet for dental care providers are listed on Table 3. References [1] Fauci A. HIV and AIDS: 20 years of science. Nat Med 2003;9(7):839–43. [2] Cruse JM, Lewis RE. Atlas of immunology. 2nd edition. Boca Raton (FL): CRC Press; 2004. [3] Gallo RC. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene 2005;24(39):5926–30. [4] Gao F, Bailes E, Robertson DL, et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999;397:436. [5] Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Unganda. J Infect Dis 2005;191(9):1403–9. [6] Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995;373:117–22. [7] Doranz BJ, Berson JF, Rucker J, et al. Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1). Immunol Res 1997;16(1):15–28. [8] O’Brian SJ, Moore JP. The effect of genetic variation in chemokines and their receptors on HIV-transmission and progression to AIDS. Immunol Rev 2000;177:99–111. [9] Coombs RW, Welles SL, Hooper C. Association of plasma human immunodeficiency virus type-1 RNA level with risk of clinical progression in patients with advanced infection. J Infect Dis 1996;174:704–12. [10] Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000; 342:921. [11] Von Sydow M, Gaiens H, Sonnerberg A, et al. Antigen detection in primary HIV infection. BMJ 1988;296:238. [12] Kaul R, Rowland-Jones SL, Kimani J, et al. Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8þ responses. J Clin Invest 2001;107:341. [13] Centers for Disease Control. Racial and ethnic disparities in diagnosis of HIV/AIDSd33 states 2001–2004. MMWR Morb Mortal Wkly Rep 2006;55(MM5):121–5. [14] Gorbach SL, Bartlett JG, Blacklow N. Infectious disease. 3rd edition. Philadelphia: Lippencott Williams & Wilkins; 2004. p. 2088. [15] Saag MS, Kilby JM. HIV-1 and HAART: a time to cure, a time to kill. Nat Med 1999;5(6): 609–11. [16] Chen RY, Accorti NA, Westfall AO, et al. Distribution of health care expenditures for HIVinfected patients. Clin Infect Dis 2006;42(7):1003–10.

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[17] Freed JR, Marcus M, Freed BA, et al. Oral health findings for HIV-infected adult medical patients from the HIV Cost and Services Utilization Study. J Am Dent Assoc 2005;136(10): 1396–405. [18] Marcus M, Yamamoto JM, Der-Martirosian C, et al. National estimates of out-of-pocket dental costs for HIV-infected users of medical care. J Am Dent Assoc 2005;136(10):1406–14. [19] Reznik DA. Perspective: oral manifestations of HIV disease. Top HIV Med 2005;13(5): 143–8. [20] Glick M, Cohen SG, Cheney RT, et al. Oral manifestations of disseminated Cryptococcus neoformans in a patient with acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol 1987;64(4):454–9. [21] Jones BE, Young SM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148:1292. [22] Paster BJ, Russell MK, Alpagot T, et al. Bacterial diversity in necrotizing ulcerative periodontitis in HIV-positive subjects. Ann Periodontol 2002;7(1):8–16. [23] Slots J. Herpesvirus, the missing link between gingivitis and periodontitis? J Int Acad Periodontol 2004;6(4):113–9.