with HIV Infection

l

0002-9270/96/9tl 226-5$01.00rc

TltE A\|ERtcAN J2 cm) ulcers will be present. It is

problem. Commonly, a large ulcer is identified. Biopsies common practiceto biopsy esophageal ulcers both from the

reveal only ulcer with granulationtissueand no identifiable periphery and the crater (40). Viral culture of biopsy mate-

pathogens. These ulcers may be caused by established rial is not useful in diagnosing CMV since cultures are

pathogensmissed by biopsy, by HIV itself, or possibly by commonly positive when there is no histopathologic evi-

unknownpathogens (31). dence of CMV and vice versa (41). In some centers,less

Gastroesophageal reflux diseaseis uncommon in HIV- experienced the pathologyof AIDS in the gastrointestinal

in

infected individuals (2). Acid production has been reported tract, the use of immunohistochemicaland in situ DNA

to be diminished in thesepatients in one early report (32), staining,may increase diagnosticyield (40-42). Herpes

the

but in severallater reports(33,34) was found to be normal. simplex lesions appearendoscopicallyas vesicles,as a dif-

There was no differencein basal acid output, maximal acid fuse erosive esophagitis small discrete "volcano" ulcers

or

output, or peak acid output regardlessof the stageof HIV (38). Herpesvirus can be identified on biopsy, cytology, and

(35). Most patientswith HIV take a large variety of common culture.

AJG ltlov 1996 ESOPHAGEAL DISEASES ASSOCIATED WITH HIV INFECTION 2261



TREATMENT relapseoccurs,retreatment with the samedrug is reasonable

and then maintenanceis suggested.For further reoccur-

Rec'ommendation

rence, switching to the alternative drug is recommended.

Oral fluconazole is the treatment of choice for Candida After relapseon the alternativedrug, combinationtherapyis

esophagitisin patients with HIV. The role of maintenance recommendedfor both treatmentand maintenance.

therapy of Candida esophagitisis yet to be established. In Two intravenousdrugs are available in the U.S. lbr the

patients already taking fluconazole, high dose fluconazole

treatmentof CMV disease, ganciclovir and foscarnet.Both

or amphotericinB may be required.

have been approved for the treatment of CMV retinitis.

Many agentshave been usedto treat Candida esophagitis

There is every reasonto believe that the systemictreatment

such as topical agentsincluding nystatin, clotrimazole, and

of retinitis and colitis is applicable to gastrointestinal dis-

miconazole;oral agentssuch as ketoconazole, fluconazole,

ease.Ganciclovir was superiorto placebo in treating CMV

itraconazole,and 5-flucytosine; and parenteralagentssuch

colitis (54). In four uncontrolled studies (55-59), the re-

as amphotericin-Band fluconazole.Topical agentsare usu-

sponseof CMV esophagealdiseaseto intravenousganci-

ally effective against oropharyngealcandidiasis,however

esophageal diseaserequires systemic therapy. clovir is about 807o, equivalent to the responserate for

Until recently, ketoconazolewas the treatmentof choice CMV retinitis. Ganciclovir frequently induced neutropenia

for Candida esophagitis(2, 43). Problems associated with especiallyin the presence zidovudine (60). This problem

of

ketoconazole,include hepatotoxicity, resistance,and poor can now be treatedwith colony stimulatingfactors success-

absorption (44, 45). The incidence of hypochlorhydria in fully, but at considerableexpenseor by switching to fbs-

HlV-infected patients may not be as high as previously carnet. Foscarnetis effective in treating both "new" CMV

reported(33, 34). This can be clinically relevantbecause the esophageal disease (58, 61,62) and relapses failing ganci-

absorptionof ketoconazoleand itraconazoleare pH depen- clovir (63). A longer course of initial therapy of 3 to 4 wk

dent (35, 43). Ketoconazole also an agentthat can have

is may be more effective (62). Foscarnet'sprincipal side ef-

interactionswith commonly prescribeddrugs like terfena- t'ects are renal failure and electrolyte abnormalities.The

dine,cisapride,ritonavir, indiniavir, and others.Fluconazole manufacturerrecommendsthat foscarnet be administered

is a newer triazole that has greater in. vivo activity against thrice daily, although a twice daily schedulefor foscarnetin

Condidaalbicans than doesketoconazole and is much better gastrointestinal disease, has been studiedand appearsto be

absorbed, even at neutral pH (a6, 41). A recent randomized equivalent both in efficacy and in pharmacokinetics(62).

trial compared the two drugs and showed an endoscopic Esophagealstrictures have been reported after treatment

cure in 9lo/o of the fluconazole-treated of

versus 52o/o the with both drugs (63, 64), presumablyas a result of healing.

ketoconazole-treated patientswith no difference in adverse If a patient has a normal creatinineclearanceand neutrope-

events (48). In another comparative study, itraconazole, nia, foscarnet may be the drug of choice at a dose of 90

which is now FDA approvedfor the treatmentof histoplas- mg/kg i.v. b.i.r/. becauseof its toxicity profile. If a patient

mosis,was shown to have no advantages over ketoconazole has an elevated creatinine,decreased creatinine clearance,

fbr the treatment of Candida esophagitis (49). Although or electrolyte disturbances, then ganciclovir is the drug of

fluconazoleis approximatelythree times as costly as keto-

choice. If none of theseabnormalitiesexist, then the choice

it by

conazole, is considered many to be the drug of choice

is up to the treating physician. There is at least one report

(41).

that indicated that patients randomized to treatment with

Low-dose maintenance antifungal therapywith either ke-

foscarnethad a significantly better survival than those ran-

toconazole or itraconazole may prevent a recurrence of

domized to ganciclovir(65). At present, gancicloviris the

Candida esophagitis.However, the cost and potential for

least expensivetreatmentby half, and may have fewer side

inducing drug resistance must be taken into accountbefbre

effects.

implementing this strategy in all patients (50). Many pa-

When a CMV esophagealulcer recurs after multiple

tients with advancedHIV infection are already taking flu-

conazole or itraconazole for prevention of recurrence of coursesof therapy with both ganciclovir and foscarnetin-

or (5

cryptococcosis histoplasmosis l). Azole resistant Can- dividually, there is evidenceto suggestthat both drugs can

dida species emerging(52, 53). Resistance be over-

are can be used together successfully.The drugs can be used in

come by tripling the dose,but switchingto amphotericin B standarddosesconcurently, both in treatmentand mainte-

m a y b e t h e o n l y s o l u t i o ni n m a n y c a s e s . nanceof CMV infection (66). Whether to use maintenance

treatment after initial therapy is still controversial.Many

Recomntendatiort factors enter into the decision and there are no absolute

Initial therapyof esophageal CMV infection should be guidelines.After one or at most two relapses, maintenance

tailored to the patient. Both ganciclovir and foscarnet are therapy is recommended.Oral ganciclovir has been ap-

elfbctive as initial therapy.Therapy should be given for 3 to proved by the FDA fbr maintenance therapy of CMV reti-

4 wk initially, dependingon severity.The role of rnainte- nitis. The role of oral ganciclovirin the treatment CMV

of

nance therapyafterinitial therapyis yet to be established.If gastrointestinal disease yet to be established.

is

2268 DIETERICH et a/. AJG - Vol. 91, No. I1, 1996

Recommendation 6. Tom W, Aaron JS. Esophagealulcers caused by Torulopsis globrata in

a patient with acquired immonuodeficiency syndrome. Am J Gastro-

Herpes esophagitisshould be treated with acyclovir in-

enterol 1987;82:7 66-8.

travenously.Foscarnetis active against acyclovir-resistant 7. Forsmark CE, Wilcox CM, Darragh T, Cello JP. Disseminated his-

herpes simplex. toplasmosis AIDS: An unusualcaseof esophageal

in involvementand

gastrointestinal bleeding. Gastrointest Endosc 1990;36:604*5.

Herpes esophagitis rare in AIDS patients.Acyclovir is

is 8. Gould B, Kory WP, Raskin JB, Ibe MJ, Redhammer DE. Esophageal

the treatment of choice for herpes esophagitis.It usually biopsy findings in the acquired immunodeficiency syndrome: Clinical

needsto be given intravenouslyat first and then orally (67). pathologicalcorrelationin 20 patients.South Med J 1988;81:1395-6.

9. Laine L, Bonacini M, Sattler F, et al. Cytomegalovirus and Candida

If acyclovir fails due to drug resistance,

foscarnetis quite esophagitisin patienrswith AIDS. J AIDS 1992;5:605-9.

effective againstherpessimplex (68). 10. Smith PD, Eisner MS, Manischewitz JF, et al. Esophagealdiseasein

AIDS is associated with pathologic processes rather than mucosal

Recommendation human immunodeficiency virus type I. J Infect Dis 1993;167:54j-52.

11. SchechterM, PannainVLN, Viana de Loiveria A. Papova-virusasso-

If no pathogenis found on multiple adequate biopsiesof ciated esophageal ulceration in a patient with AIDS. J AIDS 1991;5:

an esophagealulcer, after thorough review by an experi- 238-9.

enced pathologist,the patient should be treated with pred- 12. Corbellina M, Lusso P, Gallo RC, et al. Disseminatedhuman hemes-

virus 6 infection in AIDS. Lancet 1993:342:1242 (letter1.

nisone 40 mg p.o. dally until symptoms improve and then

13. RabeneckL, Popovic M, Gartner S, et al. Acute HIV infection pre-

taper at 10 mg/wk. senting with painful swallowing and esophageal ulcers. JAMA 1990;

Treatment of idiopathic ulcers of the esophagusis ex- 263:2318-22.

I 4. Fusade T, Liony C, Joyl P, et al. Ulcerative esophagitis during primary

tremely difficult and controversial. Symptomatic therapy

HIV infection. Am J Gastroenterol1992;87:1523(Letter).

with antacids and sucralfate may help. H-2 blockers or 15. Bonacini M, Young T, Laine L. Histopathology of Human immuno-

proton pump inhibitors may also alleviatesymptoms.Treat- deficiency virus-associated esophageal disease. Am J Gastroenterol

1 9 9 3 ; 8 8 : 5 4 9 - 5.

I

ment of underlying HIV diseaseis an important adjunct to

16. Rosario MT, Raso CL, Comer GM. Esophageal tuberculosis.

Dig Dis

therapy of the esophageal disease. There have been reports Sci 1989;34:1281-4.

of successful treatment with corticosteroids 69-72\. In 17. Allen CM, Craze J, Grundy A. Case report: Tuberculous bronco-

esophageal fistula in the acquired immunodeficiency syndrome. Clin

severalreports of prednisonetherapy, a 90% responserate

Radiol 1991;43:60-2.

has been noted with few side effects ,69-71\. Concomitant 18. Adkins MS, Raccuia JS, Acinapura AJ. Esophagealperforation in a

ketoconazole fluconazoleis sometimesgiven as Candida

or patient with acquired immunodeficiency syndrome. Ann Thoracic

prophylaxis (50, 69-71). Corticosteroid use may increase Surg 1990;50:299-300.

19. Goodman P, Pinero SS, RanceRM, et al. Mycobacterialesophagitis in

the risk of clinical CMV in parients with AIDS ('13, i4). AIDS. GastrointestRadiol 1989;14: 103-5.

Simultaneous antifungal therapy is controversial although 20. de Silva R, Stoopack PM, Raufman JP. Esophageal fistulas associated

vigilance for opportunistic infections must be maintained with mycobacterial infection in patients at risk for AIDS. Radiology

1990:17 5:449 -53 .

while on corticosteroids.Recently, thalidomide has been 21. Poles M, Lew E, Dieterich D. Actinomyces superinfectionof esoph-

repofted to improve idiopathic esophageal ulcers (75, 76). ageal ulcers in an AIDS patient. Am J Gasrroenterol 1994;89:1569-j2.

Thalidomide is experimentalin the United States. 22. SpencerGM, Roach D, SkucasJ. Actinomyces of the esophagus a in

patient with AIDS: Findings on barium esophograms.Am J Roentge-

nol 19931161:795-6.

ACKNOWLEDGMENT 23. Ezzel JH, Bremer J, Adamec TA. Bacterial esophagitis:An often

forgotten causeof odynophagia.Am J Gastroenterol1990;85:296-8.

This practice guideline has been officially endorsedby 24. Kim J, Minamoto GY, Grieco MH. Nocardial infection as a comoli-

cation of AIDS: Report of six cases and review. Rev Infec bis

the American Gastroenterological Association and the 1991:13:624-9.

American Society of GastrointestinalEndoscopy. 25. Kazlow PG, Shah K, Bonkov KJ, et al. Esophageal cryptosporidiosis

in a child with AIDS. Gastroenrerology 1986;91:1301-3.

Reprint requests 26- Datry A, Similowski T, Jais P, et al. AlDS-associatedleishmaniasis:

and correspondence: Douglas T. Dieterich,M.D., New

York University Medical Center,345 E. 37th Sr., Ste 207, New york, N.y. An unusual gastroduodenal presentation. Trans Royal Soc Trop Med

10016. Hygeine 1990;84:239-40.

27. Grimes MM, Lapook JD, Bar MH, et al. Disseminatedpneumocystis

carinii infection in a patient with acquired immunodeficiency syn-

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