Management of oral health in persons with HIV infection

Management of oral health in persons with HIV infection Crispian Scully, PhD, MD, MDS, FDS, FFD, MRCPath,’ Bristol, England, and London, Ontario, Canada BRISTOL

DENTAL

HOSPITAL

AND SCHOOL,

and Gillian McCarthy,

AND THE UNIVERSITY

OF WESTERN

BDS,b

ONTARIO

Prevention and treatment of oral disease is required to maintain quality of life and to improve prognosis of patients infected with the human immunodeficiency virus (HIV). Management requires a team approach, and close collaboration with the appropriate responsible physicians and other health care workers is necessary. Oral infection is frequent and usually opportunistic, and management is based on certain principles. Infections may disseminate and can be persistent and severe; multiple concurrent or consecutive infections with different microorganisms are frequent; fungal, viral, and parasitic infections are rarely curable; and long-term antimicrobial therapy may be required. This article reviews the management of oral candidiasis, hairy leukoplakia, and infections with herpes simplex virus, varicella-zoster virus, and cytomegalovirus. The management of Kaposi’s sarcome, lymphomas, aphthous ulceration, gangrenous stomatitis, bleeding, xerostomia, and adverse drug reactions is also described. Treatment should avoid further immunosuppression and inducement of xerostomia or caries, and should be designed to avoid adverse drug reactions and possible drug interactions. (ORALSURGORALMEDORAL PATHOL1992;73:215-25)

T

he management of oral health in persons infected with human immunodeficiency virus (HIV) and those with HIV disease and the acquired immunodeficiency syndrome (AIDS) was reviewed earlier in the epidemic.’ This article summarizes the present s,tate of the art as of October 1990. Prevention and the treatment of oral disease, particularly oppoitunistic infections, are especially important in HIV-infected persons, to maintain quality of life and possibly to prevent more serious complications. To this enld the highest standards of oral hygiene and nutrition must be maintained. It is evident that malnutrition is not uncommon in HIV disease, and the associated deficiencies of folate and vitamin Btz2 might well predispose to oral mucosal infection and ulceration. In contrast, dental caries may be less prevalent in so:me HIV-infected1 persons, at least in some communities, although where xerostomia is

%entre for the Study of Oral Disease, University Department of Oral Medicine, Surgery and Pathology, Bristol Dental Hospital and School. bDivision of Oral Biology, Faculty of Dentistry, The University of Western Ontario. 7/12/31461

present, caries can be a problem.3 When the HIVinfected person has an immune defect severe enough to predispose to clinical infections, or in instances when an invasive procedure is contemplated and may predispose to infection with oral or other bacteria, antimicrobial prophylaxis may also be indicated, although unequivocal evidence for this is not available. Any treatment regimens used in persons with HIV infection should avoid causing further immunosuppression, inducing caries (such as with sucrosecontaining medications), and aggravating symptoms such as xerostomia, and must take into account adverse drug reactions and possible drug interactions.4, 5 For example, aspirin may aggravate the bleeding tendency caused by thrombocytopenia. Acetoaminophen, on the other hand, was thought to increase toxic reactions from zidovudine (AZT),6 but this is probably not of practical clinical importance.7 AZT has now been used successfully to prolong survival of HIV-infected patients,s 9 and recommendations have been made to provide AZT for early stages of infection.* This means that more patients with HIV will be affected by the toxic effects of AZT, which include anemia and neutropenia, and this may affect oral management. Other antiretroviral agents 215

2I 6

Scuily and McCarthy

may also produce adverse orai effects. Dental treatment should account for other complicating factors, such as other sexually transmitted diseases, viral hepatitis, or a history of endocarditis found in some patients, especially intravenous drug abusers. lo Certain basic principles underlie the treatment of infections in HIV-infected persons”-t4: l Fungal, viral, and parasitic infections are rarely curable; long-term antimicrobial therapy may be needed. @ Most infections are opportunistic, reflect the local prevalence of such infections, and represent little or no threat to other persons. Tuberculosis, hepatitis B, and some sexually transmitted diseases, however, are exceptions. @ Multiple concurrent or consecutive infections with different microorganisms are common. e Infections are often severe and persistent, and may disseminate. Many of the oral lesions seen in HIV infection regress or clear during treatment with anti-HIV agents such as AZT. The treatment of HIV infection is not discussed here, although oral adverse effects are noted; the reader is referred to recent reviews.t5 The active treatment of specific oral disease entities is discussed later, but management of the HIV-infected person is a team approach and there should always be close collaboration with appropriate colleagues, particularly when the oral lesions are not in isolation. This article concentrates mainly on the treatment of oral lesions when they occur in isolation and mainly on the treatment of adults. Drug delivery systems may need to be modified for the care of children with HIV infection, and there is certainly a need to reduce drug dosages appropriately. The following drug therapies outline adult doses. ORAL CANDiDlAW

Early treatment of orai candidiasis is warranted not only because of the discomfort caused by the lesions but also because the foci may act as reservoirs of organisms for spread of disease. Prophylaxis should be considered, as discussed later. Xerostomia is associated with increased frequency of candidiasis in patients with HIV infection16 and should be treated. Bethanechol17 may be used; other treatment is discussed later. The Candida albicans isolates in HIV-infected persons are similar to those in the general population*8 and tend to respond to conventional treatment. The antifungal treatment of candidiasis in HIV disease has been reviewed.19, *O Topical treatment of candidiasis with nystatin, amphotericin, clotrimazole,

ORAL

SURGORAL

MEDORAL

PATHOL

February 1992 econazole, or miconazole (Table I) is often successful within about 14 days, but relapses are common’” 21l2’ and these agents are not always palatable or accepted by children. Such failures are mainly attributable to the underlying immunodeficiency, although poor patient compliance as a result of gastrointestinal upsets, unpalatable taste of some agents, drug intolerance, and the need for frequent drug administration are other factors. Systemic antifungals have therefore been advocated. The imidazole drug ketoconazole has been used orally, to be taken with food, because gastric acid is essential for its dissolution and absorption, but absorption is variable. A daily dose of 200 mg is generally recommended for treatment of candidiasis,‘* although some workers recommend up to 400 mg/ day. 23 Failures in the treatment of oral candidiasis in HIV disease with ketoconazole may be related to drug malabsorption, ketoconazole-resistant strains of C, albicans,24m26or adverse effects. These may include nausea, rashes, pruritus, and liver damage.27 Transient disturbance of liver function (e.g., increased serum aminotransferase concentrations) is so common that regular monitoring of liver function tests is essential in all patients taking ketoconazole for more than a few days. Adrenocortical suppression may also develop. 28 Drug interactions with ketoconazole are summarized in Table I. Ketoconazole may also be used topically. Other systemic antifungals include the bistriazoles, fluconazole and itraconazole, which are water soluble and principally excreted by the kidney. Absorption is good, toxicity is mild and infrequent, and drug interactions present fewer difficulties than those associated with ketoconazole29 (Table I). Fluconazole is active against oral candidiasis in HIV disease30-33and produces remission within about 1 week. Although some investigators have suggested that there is no indication that fluconazole would be any more effective than ketoconazole, econazole, clotrimazole, or miconazole,34 one randomized prospective double-blind study comparing ketoconazole (200 mg/day) with fluconazole (50 mg/day) in the treatment of oral candidiasis in HIV disease showed that fluconazole might be more effective than ketoconazole but that posttreatment relapses were common with both drugs.35 These results have now been confirmed in prospective randomized and open trials. 36-42Interestingly, fluconazoleis less effective than ketoconazole against Candida in vitro, but these results need to be confirmed in larger series. 43-46Nevertheless, fluconazole is effective, is particularly well absorbed, has a long half-life (30 hours or so), and is well tolerated, although nau-

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Volume 73 Number 2 Table

I. Antifungal

217

management of oral cand.idiasis in HIV infection

Drug Amphotericin*

Fluconazole

Nystatin*

Miconazole*

Ketoconazole$

GI, Gastrointestinal. *Dissolved in mouth slowly. tRarely 0.3-0.6 mg/kg per day intravenously; $Treat for 14 days only.

Comments

Oral dosage

Active topically; negligible absorption from GI tract; GI side effects after larger doses Reduce dose in renal disease; not recommended for children or during pregnancy or lactation; enhances warfarin, sulfonylureas, and phenytoin; activity reduced by rifampicin; may cause nausea, diarrhea, rashes, or headache Active topically; negligible absorption from GI tract; pastille better tasting than lozenge Active topically; also has antibacterial activity; negligible absorption from GI tract; theoretically best antifungal to treat angular stomatitis Contraindicated in pregnancy and liver disease; may cause nausea, rashes, pruritus, and liver damage (monitor liver function); rarely causes anaphylaxis, thrombocytopenia, or gynecomastia; enhances nephrotoxicity of cyclosporine; enhances coumarins; interacts with rifampicin and may potentiate hypoglycemic agents, phenytoin, and drugs that reduce gastric acid

may cause febrile reactions, nephrotoxicity,

sea or headache has been reported in less than 5% of patients. 47 The: usual dosage is 50 mgfday, b.ut a single oral dose of 150 mg may be more effective.4x Fluconazole is thus gaining preference over ketoconazole mainly because it is rapidly effective, has a long halflife, and has nlo serious adverse effects. Once-weekly fluconazole, 150 mg, may be effective prophylaxis after treatment o’f acute candidiasis.49 Itraconazole, 100 mg orally once: or twice daily, is probably as effective as fluconazolesO; 51 and might soon be available for topical use. Unfortunately, there is some evidence of cross-resistance of some C. albicans isolates to ketoconazole, fluconazole, and itraconazole,5” although the clinical significance of this in HIV disease remains to be established and fluconazole is active against at least some ketoconazole-resistant Candida.

lo-100 mg q 6 hrt

50-100 mg once daily

500,000 U lozenge, 100,000 U pastille, or 5 ml of 100,000 U/ml of suspension q 6 hr 250 mg tablet q 6 hr or 25 mg/ml gel used as 5 ml cl 6 hr

200-400 mg once daily with meal

and other reactions.

Chlorhexidine oral rinses may also be of some benefit in the control of oral candidiasis.54> 55 OTHER FUNGAL

INFECTIONS

Other oral fungal infections are rare in HIV disease and are usually associated with systemic involvement; systemic treatment is indicated and discussed elsewhereI 21,26,47,56 (Table II). HERPES SIMPLEX AND VARICELLA-ZOSTER VIRUS INFECTIONS

Acyclovir in daily oral doses of 1 to 4 gm in divided doses is currently the most generally accepted therapy for herpes simplex virus (HSV) and varicella-zoster infections in HIV-positive persons,17:57,58 glthough subsequent maintenance of 200 mg orally two to five tim.es daily is required if there is a need to suppress

2 1% Scully and McCarthy

ORALSURG

February 1992

Table II. Guidelines for treatment of opportunistic

infections in MIV infection /

Infection

Coccidioidomycosis Cryptococcosis

Histoplasmosis

Klebsiella pneumoniae

Proteus mirabilis/Haemophilus

in$uenzae

Pseudomonas aeruginosa Salmonella

or Shigella

Staphylococcus

aureus

Staphylococcus

epidermidis

ORAL MEDORALPATHOL

Streptococcus pyogenes Toxoplasmosis Tuberculosisf

Regimen

Amphotericin B (0.4-0.6 mg/kg/day IV) or ketoconazole (400 mg/day orally) Amphotericin B (0.4-0.6 mg/kg/day IV) with or without flucytosine (75-100 mg/kg/day orally) for 6 wk* or lluconazole (200 mg/day orally) Fluconazole (200-400 mg/day orally or IV), ketoconazole (400 mg/day orally), or itraconazole (200 mg/day orally) Piperacillin, ceftazidime, or cefoxtamine (2 gm q 6-8 hr IV), or ceftriaxone (2 gm q 6 hr IV) and aminoglycosidet As for K. pneumoniae, or cefuroxime (1.5-3 gm q 8 hr IV), and aminoglycosidet Piperacillin (4 gm q 6 hr IV) or ceftazidime (2 gm q 8 hr IV) and aminoglycosidet Ampicillin (4-8 gm/day orally), co-trimoxazole (7 mg/kg), or ciprofloxacillin (250-750 mg orally twice daily) Cloxacillin (2 gm q 4-6 hr IV) or vancomycin (500 mg q 6 hr IV) & rifampin (300 mg q 12 hr orally or IV) Vancomycin (500 mg q 6 hr IV( f aminoglycosidet +- rifampin (300 mg q 12 hr orally or IV) Penicillin G (2 million U q 6 hr IV) Pyrimethamine (25-50 mg/day orally) + sulfadiazine (100 mg/kg/day orally) for 3-6 mo Psoniazid (S-10 mg/kg/day orally (I- rifampin (IO mg/kg/day orally) f either pyrazinamide (25 mg/ kg/day orally) or streptomycin (0.75-l .O mg/kg/ day intramuscularly) for 6-9 mo (varies according to regimen)

Modified from Young, ” Klein,13 Nikoskelainen, I4 and Purdy and Plaiszwxs6 *Recurrence common without maintenance therapy. tGentamicin, tobramycin, netilmycin (150 mg every 12 hours intravenously), or amikacin (500 mg every 12 hours intravenously). ~Mycobncterium avium-intracellulare is resistant. Ciprofloxacin, amikacin, and imipenem are being used in trials (Glatt et zA’~).

recurrence.s9 HSV is sometimes resistant to acyclovir, and foscarnet may then be effective60-67 (Tables III and IV). Unfortunately, foscarnet can itself occasionally produce oral u1cers.68-70 Varicella-zoster virus may also become resistant to acyclovir, and it has been suggested that high-dose intravenous acyclovir should be used, when possible, to avoid this. It may also be necessary to use foscarnet in patients who are not responding to acyclovir therapy. 71 Acyclovir susceptibility testing may be usefu1.72 There are occasional reports that cimetidine has been beneficial in treating HSV oral lesions in HIVpositive patients. 73 Vidarabine is ineffective74 and furthermore is neurotoxic.75 HAIRY LEUKOPLAKIA INFECTION)

(EPSTEIN-BARR

discomfort to the patient, specific treatment is rarely indicated. HL in HIV-infected persons may occasionally improve spontaneously76 or with AZT,77, 78 ganciclovir,79 or desciclovir,80> ‘t and if therapy is needed, oral acyclovir up to 800 mg every 6 to 8 hours for up to 20 days can be used. 82-86Oral desciclovir, 250 mg three times daily for up to 14 days, will clear the lesions without significant adverse effects.*l Desciclovir is better absorbed orally than is acyclovir.xl Unfortunately, HL recurs after discontinuation of theraPY?*l, 83and desciclovir cannot currently be obtained. Topical tretinoin may also help regression of HL.84 Surgical removal of the clinical HL lesion has been done by some workers, but most lesions begin to recur within 3 monthsa and such a strategy seems difficult to justify.

VIRUS

Hairy leukoplakia (HL) is usually symptomless and, although it may be the source of concern or some

CYTOMEGALOVIRUS

INFECTIONS

Chronic oral ulceration associated with cytomegalovirus (CMV) infection, occasionally seen in HIV

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Table III. Antiviral

219

management of oral herpesvirus infections in HIV infection

Virus

Disease

HSV

Primary herpetic stomatitis

Recurrent herpetic infection

Herpes varicella-zoster

Chickcnpox

CMV

Zoster (shingles) Mouth ulcers

Epst.ein-Barr virus

Hairy leukolakia

Therapy

Comments*

Acyclovir, 200 mg orally 5 times/day, or 5-13 mg/kg IV q 8 hr for lo-14 days Consider systemic acyclovir as above

Acyclovir is virtually free of effects but may result in acyclovir-resistant viruses; foscarnet orally, 50 mg/kg/day for 14-21 days, may then be indicated; renal insufficiency and alterations in serum Ca++ or POq-- are common adverse effects of foscarnet

Acyclovir, 800 mg orally, or 15-30 mg/kg IV q 8 hr for lo-14 days As above Ganciclovir, 7.5-15 mg/kg/day IV for lo-14 days

Acyclovir, 800 mg orally q 8 hr, or desciclovir, 250 mg orally 3 times/day for lo-14 days

-

Treatment is indicated only for sight-threatening or severe infections; may cause neutropenia, thrombocytopenia, and eosinophilia, and may disturb liver function; foscarnet is alternative Treatment is not usually required; lesion recurs after cessation of treatment

“See also Table IV. *For systemic preparations of acyclovir, 15 rug/kg/day, use caulion in renal diseaseand pregnancy; may result in occasional increase in serum liver enzymes

and urea levels, rashes.

diseasc,ss-90 may respond to ganciclovirgl or foscarnet,92 but acyclovir ” appears less effective.93 However, occasional CMV strains are ganciclovir resistant.94 Gancicllovir should be used only in. sightthreatening or life-threatening infections. HUMAN HERPESVIRUS

TYPE 6 INFECTIONS

Human herpesvirus type 6 is susceptible to ganciclovir and foscarnet but is less affected by acyclovir.95, 96 Whether therapy is warranted is unclear because specific human herpesvirus-6-related oral lesions have not been described. PAPILLOMAVIWUS

INFECTIONS

Cryosurgery, laser therapy, or surgical excision are usually used in treatment of oral papillomatous lesions.“,88 Acyclovir has been effective in treating papillomavirusS infections in other sites,97 but there is no evidence for its usefulness against oral lesions. PERIODONTAIL

INFECTIONS

The periodontal condition in patients with HIV can deteriorate very rapidly. 98 The early diagnosis of

HIV-associated gingivitis, HIV-associated periodontitis, and necrotizing gingivitis are important for successful management. Patients with HIV infection should be advised to have periodontal assessment at 3-month intervals so that any necessary treatments can be started as soon as possible. Local debridement with the application of an antimicrobial such as povidone-iodine and the possible inclusion of antifungals to treat candidiasis have been suggested. 98-1ooAqueous chlorhexidine oral rinses twice daily also greatly help to reduce gingival erythema, bleeding, and pocket depthslo’, lo2 and may be of additional value by virtue of some anticandidal activity. There is some evidence that chlorhexidine and nystatin should not be administered concurrently. lo3 Metronidazole can also be a useful adjunct, particularly in the management of HIV-related ANUG, periodontitis,“’ and pericoronitis.lo4 ODONTOGENIC

INFECTIONS

Odontogenic infections may fail to resolve’05 or spread to produce submandibular cellulitis.‘06 Extraction sockets may become infected or heal slow-

220

Scully and McCarthy

ORALSGRGORAL

Table IV. Possible adverse reactions, interactions and contraindications of oral lesions in HIV infection

Foscarnet

Ganciclovir

-

Interactions

Contraindications

Hypersensitivity to acyclovir or to propylene glycol in cream; systemic acyclovir may cause increased blood urea and creatinine levels unless given slowly; extravasation after IV injection may lead to inflammation; IV acyciovir may cause reversible neurologic reactions. Nephrotoxic; changes serum Ca++ and POa-- levels; possible hypoglycemia, convulsions, reduced hemoglobin level Leukopenia, thrombocytopenia, eosinophilia, possible carcinogenicity, and reproductive toxicity; altered liver function; Extravasation after IV injection may cause tissue damage; various central nervous system events and effects on musculoskeletal, respiratory, or urogenital system

Probenecid increases acyclovir half-life

Reduce dose of acyclovir in renal disease; contraindicated in hypersensitivity to acyclovir

Additive toxicity with nephrotoxic agents such IV pentamidine; hypocalcemia if used with IV pentamidine

Reduce dose in renal or hepatic disease; contraindicated in hypersensitivity, pregnancy, and lactation In non-life-threatening or non-sight-threatening cytomegalovirus infections; reduce dose in renal disease; contraindicated in pregnancy and lactation, ganciclovir hypersensitivity, leukopenias, thrombocytopenia

Additive toxicity with dapsone, pentamidine, Aucytosine, vincristine, vinblastine, doxorubicin, amphotericin, co-trimoxazole, AZT; convulsions with imipenem-cilastatin

1YYlo4, lo7 and osteomyelitis and actinomycosis have been recorded. lo8 It may be prudent therefore to treat odontogenic infections vigorously with antimicrobials or to consider prophylactic therapyro4T log although, as noted previously, this is somewhat controversial. OTHER INFECTIONS

Other oral infections are rare in HIV disease and are usually associated with systemic involvement. Their treatment is discussed elsewhere26T56,lo9 and in Table II. KAPOSI’S

drugs used in treatment

Adverse reaction

Drug Acyclovir

of antiviral

MED ORALPP.TP,OL February 1992

SARCOMA

Therapy for Kaposi’s sarcoma (KS) must consider possible damage to the immune system. Hence only observation is indicated in case of an asymptomatic, limited, and stable or slowly progressing lesion. However, nearly two thirds of patients with oral KS are symptomatic, in terms of pain or discomfort, dysphagia, or esthetics. ‘lo Isolated oral lesions can be directly treated with radiotherapy (approximately 800 to 1500 cGy or equivalent fractionated therapy for 10 days). i7, “I, ‘I2 Mucositis and xerostomia tend to result in all irradiated patients, although KS lesions

regress at least partially. There is a danger of osteoradionecrosis as in other patients receiving radiotherapy in the oral region.4 Radiation therapy is therefore recommended mainly where there are obstructive symptoms.’ l3 Intralesional injections of vinblastine (0.2 mg/ml) can cause the oral lesions of KS to regress.‘t4, 115In some patients intralesional vinblastine produces pain for 1 to 3 days but this is invariably controllable with analgesics such as oxycodone. Intralesional interferon+ may also produce regression of oral KS,‘16 although systemic interferon-G was originally disappointing. ‘17-l lg Intermediate or highdose recombinant interferon therapy has revealed a significant activity against KS and may become the modality of choice when systemic treatment is required. 120,12’ Interferon-a is now being used successfully in combination with AZT, although neutropenia is a major dose-limiting complication.*“2, 123Unfortunately, interferon itself may produce mouth ulcers (see later). Laser or surgical excision is sometimes useful, mainly for palliation,‘~ I7 and cryosurgery is used by some for palliative removal of KS. Because of the disseminated nature of KS, systemic

Oral health and HIV

Volume 73 Number 2

treatment may be indicated. Apart from systemic interferon, systemic (intravenous) vinblastine124or vincristine’25: 126or alternating regimens127are active against KS; vincristine has the advantage of lack of myelotoxicity. Doxorubicin and etoposide have also been used.12* Systemic management of HIV with AZT may also cause regression of oral KS in some patients129and there is one report that oral dapsone, 100 mg/day, mlay be effective in cutaneous E;S.130 LYMPHOMAS

Therapeutic options for lymphomas are limited and consist of radiation or low-intensity cytostatic regimens.‘31Management is typically by radiotherapyx8 unless lesions are widespread, thereby warranting chemotherapeutic intervention. Initial response to chemotherapy has been achieved in more than 50% of caseswith protocols such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). However, improvement is usually temporary and longterm control has been reported only in a few patients, mainly with favorable histo1ogi.cfindings and early stage of disease.132-134 APHTHOUS-LIKE

ULCERS

Aphthous-like ulcers may first be seen during the acute illness associated with HIV seroconversion’35-137and can be associated with pharyngeal and/or esophageal lesions.‘38-140Persistent ulcers may require biopsy to exclude other causes,and microbial culture may be indicated. Although topical corticosteroids should be tried, these ulcers may be resistant to conventional treatments. Systemic prednisone, 40 to 60 mg/day, is an alternative for ulcers unresponsiveto topical corticosteroids. l7 Thalidomide is reportedly effective in oral dosesof 100 mg/day for 5 to 10 days140$ 141but is teratogenic and in prolonged useis neurotoxic.142Where ulcers are unresponsiveto thalidomide, ,alternative causes must be considered.‘43 GANGRENOUS

STOMATITIS

Gangrenous stomatitis has been described in several patients infected with HIV; the severity increases with decreasing CD4 cell counts. Although the lesions are very resistant,‘44-146treatment is essentially the same as for aphthous-like ulcers with the addition of systemic corticosteroids or antimicrobials. BLEEDING

TENDENCY

Immune thrombocytopenia affects approximately 11% of HIV-infected persons.147It occurs frequently in patients wit,h AIDS or AIDS-related complex and may be associated-with leukopenia and anemia.147,14’ Oral petechiae, ecchymoses,and a bleeding tendency

221

with spontaneousgingival hemorrhages are therefore not uncommon in HIV-infected persons.lo6,lo7Platelet transfusions and/or corticosteroids are sometimes indicated, particularly preoperatively.17 XEROSTOMIA

AND SEQUELAE

Management of xerostomia and prevention of oral sequelaeis by conventional means.88,149Dietary control, fluorides, chlorhexidine rinses, and salivary substitutes such as those containing mucin or methylcellulose are typically used. The sialogogue bethanechol, in a dosageof 25 mg three times daily up to 50 mg four times daily, may be beneficial.17 AZT may produce regression of both the symptoms and any parotid swelling.150>I51 ADVERSE

DRUG REACTIONS

IN THE MOUTH

Erythema multiforme152 and lichenoid reactions involving the oral mucosahave beendescribed in HIV disease17and there may be mucositis.‘36 There are also occasional reports of these lesions, oral ulcers, and other reactions after the use of various drugs for HIV disease,including foscarnet68and interferon.153 Leukopenia induced by anti-HIV agents such as AZT and by agents such as ganciclovir may also predispose to ulcers.‘54 The new cytidine analogue 2 ’ ,3 ’ -dideoxycytidine producesmouth ulcers in nearly two thirds of patients. Fortunately these ulcers resolve by the third week of therapy or if the drug is withdrawn, and they do not develop in patients given only low dosesof dideoxycytidine. 155 Less serious is the metallic taste reported by more than three fourths of patients treated with dithiocarb (DTC or diethyldithiocarbamate), yet the taste disturbance lasts only up to about 1 day.156The oral hyperpigmentation and lingual edema that may be related to AZT154 are of minimal consequence.Where drug effects are severe, alternative therapies or different drugs should be tried. REFERENCES 1. Greenspan JS, Greenspan D, Winkler JR. Diagnosis and management of the oral manifestations of HIV infection and AIDS. Infect Dis Clin North Am 1988;2:373-85. 2. Boudes P, Zittoun J, Sobel A. Folate, vitamin B12, and HIV infection. Lancet 1990;335:1401-2. 3. Tukutuku K, Muyembe-Tamfum L, Kayembe K, Mavuemba T, Sangua N, Sekele I. Prevalence of dental caries and gingivitis and oral hygiene status among AIDS patients hoipitalized in Kinshasa. Zaire. J Oral Path01 Med 1990:19: 271-2. 4. Scully C, Cawson RA. Medical problems in dentistry. 2nd ed. Bristol: Wright, 1987. 5. Jones JH, Mason DK, eds. Oral manifestations of systemic disease. 2nd ed. London: Ball&e Tindall, 1990:800-20.

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6. Richman DD, Fischl MA, Grieco MH, AZT Collaborative Working Group. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987;317:192-7. 7. Steffe EM, King JH, Inciardi JF; et al. The effect of acetoaminophen on zidovudine metabolism in HIV-infected patients. J AIDS 1990;3:691-4. 8. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type I (HIV) infection: a double-blind placebo-controlled trial-the AIDS Clinical Trials Group. Ann Intern Med 1990;112:72737. 9. Stambuk D, Youle M, Hawkins D, et al. The efficacy and toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex (ARC): an open uncontrolled treatment study. Q J Med 1989;70:161-74. 10. Haverkos HW. LaneeRW. Serious infections other than human immunodeficiency virus among intravenous drug abusers. J Infect Dis 1990;161:894-902. 11. Young LS. Treatable aspects of infection due to human immunodeficiency virus. Lancet 1987;2:1503-6. 12. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;318:1439-48. 13. Klein RS. Prophylaxis of opportunistic infections in individuals infected with HIV. AIDS 1989;3(suppl l):S161-S173. 14. Nikoskelainen J. Oral infections related to radiation and immunosuppressive therapy. J Clin Periodontol 1990;17:504-7. 15. Hirsch MS. Chemotherapy of human immunodeficiency virus infections: current practice and future prospects, J Infect Dis 1990;161:845-57. 16. McCarthy GM, Mackie ID, Sandhu HS, Koval J, Daley T. Factors associated with increased frequency of HIV-related oral candidiasis. J Oral Path01 Med (in mess). 17. Silverman S. Color atlas of oral manifestations of AIDS. Toronto: BC Decker, 1989. 18. Whelan WL, Kirsch DR, Kwon-Chung KJ, Wahl SM, Smith PD. Candida albicans in patients with the acquired immunodeficiency syndrome: absence of a novel or hypervirulent strain. J Infect Dis 1990;162:513-5. 19. Samaranayake LP, Holmstrup P. Oral candidiasis and human immunodeficiency virus infection. J Oral Path01 Med 1989;18:554-64. 20. Samaranayake LP, Scully C. Oral candidiasis in HIV infection. Lancet 1989;2:1491-2. 21. Holmberg K, Meyer RD. Fungal infections in patients with AIDS and AIDS-related complex. Stand J Infect Dis 1986; :8:179-92. 22. Deschamps MMH, Pape JW, Verdier RI; De Hovitz J, Thomas F, Johnson WD. Treatment of Candidu esophagitis in AIDS patients. Am J Gastroenterol 1983;83:20-1. 23. Smith DE, Gazzard BG. Fluconazole versus ketoconazole in oropharyngeal candidiasis in AIDS. Lancet 1989;1:1131. 24. Tavitian A, Raufman JP, Rosenthal LE, Weber J, Webber CA, D&soy HP. Ketoconazole-resistant Cundidu esophagitis in patients with acquired immune deficiency syndrome. Gastroenterology 1986;90:443-5. 25. Lake-Bakaar G, Tom W, Lake-Bakaar D, et al. Gastropathy and ketoconazoie malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;109:471-3. 26. De Wit S, Clumeck N. Fluconazole in the treatment of fungal infections associated with AIDS. Infection 1989;! 7: 121-3. 27. Janssen PAJ, Symoens JE. Hepatic reactions during ketoconazole treatment. Am J Med 1983;74(suppl lB):80-5. 28. Sonino N. The use of ketoconazole as an indicator of steroid production. N Engl J Med 1987;317:812-8. 29. Denning DW, Stevens DA. New drugs for systemic fungal infections. Br Med J 1989;199:407-8. 30. DuPont B, Drouhet E. Fluconazole in the management of oropharyngeal candidiasis in a predominantly HIV antibody-

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31.

32.

33. 34. 35.

36.

37.

38.

39.

40.

41.

42.

43. 44.

45.

46. 47. 48. 49.

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