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TITLE: ROUNDTABLE FOR THE DEVELOPMENT OF DRUGS AND VACCINESAGAINST ACQUIRED IMMUNODEFICIENCY SNYDROME (AIDS)

SUBTITLE: Developing Effective Therapies for Aids-RelatedInfections

PRINCIPAL INVESTIGATOR: Robin Weiss

CONTRACTING ORGANIZATION: National Academy of SciencesNational Research Council2101 Constitution AvenueWashington, DC 20418

REPORT DATE: 1992

TYPE OF REPORT: Conference Summary

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Robin Weiss

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National Academy of SciencesNational Research Council2101 Constitution AvenueWashington, DC 20418

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Conference held April 9-10, 1991 -- Developing Effective Therapiesfor Aids-Related Infections

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Conference Summary

Developing Effective Therapies forAIDS-Related Infections

1992

•c e • .,peC4RIot Avta4il. .Ir /

DEVELOPING EFFECTIVE THERAPIESFOR AIDS-RELATED INFECTIONS

Conference SummaryApril 9-10, 1991

Roundtable for the Development of Drugsand Vaccines Against AIDS

Institute of Medicine

NATIONAL ACADEMY PRESSWashington. D.C. 1992

This conference summary was prepared by the Institute of Medicine'sRoundtable for the Development of Drugs and Vaccines Against AIDS.chaired by Howard Temin and Paul Volberding and directed by LeslieHardy. The document reports major themes of the conference discussions;these themes, however, do not represent policy statements by the Instituteof'Medicine.

The report has been reviewed by a group other than the authorsaccording to procedures approved by a Report Review Committeeconsisting of members of the National Academy of Sciences. the NationalAcademy of Engineering, and the Institute of Medicine.

The Institute of Medicine was chartered in 1970 by the NationalAcademy of Sciences to enlist distinguished members of appropriateprofessions in the examination of policy matters pertaining to the healthof the public. In this, the Institute acts under both the Academy's 1863congressional charter responsibility to be an advisor to the federalgovernment, and its own initiative in identifying issues of medical care,research, and education.

The Roundtable is supported by the American Foundation for AIDSResearch, the Merck Company Foundation, the Pharmaceutical Manufac-turers Association, the U.S. Army, the U.S. Public Health Service, and theU.S. Department of Veterans Affairs.

Division of Health Promotion and Disease PreventionInstitute of Medicine

2101 Constitution Avenue. N.W.Washington. D.C. 20418

(202) 334-2453

The serpent has been a symbol of long life, healing, and knowledgeamong almost all cultures and religions since the beginning of recordedhistory. The image adopted as a logotype by the Institute of Medicine isbased on a relief carving from ancient Greece, now held by the St,,at-lichemuseen in Berlin.

ROUNDTABLE FOR THE DEVELOPMENT OFDRUGS AND VACCINES AGAINST AIDS

HOWARD M. TEMIN (Co-chair),* American Cancer Society Professorof Viral Oncology and Cell Biology, McArdle Laboratory for CancerResearch, University of Wisconsin, Madison

PAUL A. VOLBERDING (Co-chair),* Chief, AIDS Program and ClinicalOncology, San Francisco General Hospital. San Francisco, California

JAMES ALLEN,* Director, National AIDS Program Office, U.S. PublicHealth Service, Washington, D.C.

ARTHUR J. AMMANN,* Director of Clinical Research, Genentech, Inc.,South San Francisco, California

DAVID BARR, Assistant Director of Policy, Gay Men's Health Crisis,New York, New York

DAVID W. BARRY, Vice President of Research, The Wellcome ResearchLaboratories, Burroughs Wellcome Co., Research Triangle Park, NorthCarolina

LAWRENCE S. BROWN,' Senior Vice President, Division of MedicalServices, Evaluation, and Research, Urban Resources Institute and theAddiction Research and Treatment Corporation, Brooklyn, New York

DONALD S. BURKE, Colonel, Medical Corps, U.S. Army, and Director,Division of Retrovirology, Walter Reed Army Institute of Research,Rockville, Maryland

BRUCE A. CHABNER, Director, Division of Cancer Treatment, NationalCancer Institute, National Institutes of Health, Bethesda, Maryland

MAX D. COOPER, Investigator, Howard Hughes Medical Institute, andProfessor of Medicine, Pediatrics, and Microbiology, University ofAlabama, Birmingham

MARTIN DELANEY. Co-Executive Director and President, ProjectInform, San Francisco, California

DANIEL DEYKIN, Chief, Cooperative Studies Program, VeteransAdministration Medical Center, Boston, Massachusetts

R. GORDON DOUGLAS, President, Merck Vaccine Division, Merck &Co., Inc., Rahway, New Jersey

ANTHONY S. FAUCI, Associate Director for AIDS Research, NationalInstitutes of Health, and Director, National Institute of Allergy andInfectious Diseases, National Institutes of Health, Bethesda, Maryland

GERALD FRIEDLAND, Director, AIDS Program, Yale University Schoolof Medicine. Yale-New Haven Hospital, New Haven. Connecticut

L. PATRICK GAGE, Executive Vice President, Genetics Institute, Inc.,Cambridge, Massachusetts

iii

HAROLD S. GINSBERG (Co-chair),** Eugene Higgins Professor ofMedicine and Microbiology, Department of Medicine, College ofPhysicians & Surgeons, Columbia University, New York, New York

PETER BARTON HUTT, Partner, Covington & Burling. Washington,D.C.

DAVID, KESSLER. Commissioner, Food and Drug Administration, Rock-ville, Maryland

STEPHEN W. LAGAKOS,* Professor of Biostatistics, Harvard School ofPublic Health, Boston, Massachusetts

DAVID W. MARTIN, JR.,* Executive Vice President. Research andDevelopment, The Dupont Merck Pharmaceutical Company, Wil-mington, Delaware

HELEN RODRIGUEZ-TRIAS,. Pediatric Consultant in Health Pro-gramming, Brookdale, California

BRUCE ROSS,* President, Bristol-Myers Squibb Pharmaceutical Division,Evansville, Indiana

CATHERINE M. WILFERT, Professor of Pediatrics and Microbiology,Department of Pediatrics, Division of Infectious Diseases, DukeUniversity Medical Center, Durham, North Carolina

SHELDON M. WOLFF (Co-chair),** Physician-in-Chief, New EnglandMedical Center, and Endicott Professor and Chairman, Department ofMedicine, Tufts University School of Medicine, Boston, Massachusetts

"Term began January 1, 1992."*Term expired December 31, 1991.

STAFF

LESLIE M. HARDY, Project DirectorGAIL SPEARS, Administrative AssistantGARY B. ELLIS, Director, Division of Health Promotion and Disease

Prevention

iv

CONFERENCE PARTICIPANTS

DONALD ABRAMS, Assistant Director, AIDS Activities, San FranciscoGeneral Hospital

DAVID BARR, Assistant Director of Policy, Gay Men's Health CrisisD. BRUCE BURLINGTON, Deputy Director for Scientific and Medical

Affairs, Center for Drug Evaluation and Research, Food and DrugAdministration

CHARLES CARPENTER, Professor of Medicine, Brown UniversityBRUCE CHABNER, Director, Division of Cancer Treatment, National

Cancer InstituteRICHARD CHAISSON, Director. AIDS Service. Johns Hopkins HospitalCALVIN COHEN, Research Director, Community Research Initiative of

New EnglandEDWARD CONNOR, Associate Director, Division of Allergy, Immunol-

ogy, and Infectious Diseases, Children's Hospital of New JerseyLAWRENCE DEYTON, Chief, Community Clinical Research Branch,

Division of AIDS, National Institute of Allergy and Infectious DiseasesR. GORDON DOUGLAS, President, Merck Vaccine Division, Merck &

Co., Inc.JUDITH FEINBERG, Assistant Professor of Medicine, Division of

Infectious Diseases. Johns Hopkins University School of MedicinePATRICIA FLEMING, Epidemiologist, Surveillance Branch. Division of

HIV/AIDS, Centers for Disease ControlMICHAEL FRIEDMAN, Associate Director, Cancer Therapy Evaluation

Program, National Cancer InstituteRICHARD HAFNER, Section Head for Research in Opportunistic

Infections, Division of AIDS, National Institute of Allergy andInfectious Diseases

RONALD HANSEN, Associate Dean for Academic Affairs, William E.Simon Graduate School of Business Administration, University ofRochester

SCO'I7 HOPKINS, Senior Director, Clinical Research. Pfizer CentralResearch, Pfizer, Inc.

DANIEL HOTH, Director, Division of AIDS, National Institute of Allergyand Infectious Diseases

WALTER HUGHES. Chairman, Department of Infectious Diseases, St.Jude's Children's Research Hospital

PETER BARTON HUTT, Partner, Covington and BurlingMARK JACOBSON. Assistant Professor of Medicine in Residence,

University of California. San Francisco

v

MARGARET JOHNSTON. Chief. Developmental Therapeutics Branch,Division of AIDS, National Institute of Aller'v and Infectious Diseases

ROBERT LARSEN, Chief, Communicable Diseases Inpatient Service. Lo•s

Angeles County-University of Southern California Medical CenterLOUIS LASAGNA, Dean. Sackler School of Graduate Biomedical

Sciences, Tufts UniversitySANDRA LEHRMAN. Head. Department k)f Infectious Diseases.

Burroughs Wellcome CompanyDEREK LINK, Member, ACT- UP.New YorkBENJAMIN LUFT, Associate Professor of Medicine, State Uni-,ersitv of

New York at Stony BrookDAVID MARTIN. Executive Vice President. The Dupont-Merck

Pharmaceutical CompanyKENNETH MAYER, Director, Brown University AIDS ProgramDAVID MILLER, Chair, Nueces County Medical Society Committee on

AIDSPHILIP PIZZO, Chief, Pediatric Branch, Clinical Oncology Program,

National Cancer InstituteARNOLD RELMAN, Former Editor, New England Journal of MedicineFRED SATTLER, Associate Professor of Medicine. University of Southern

California

vA

PREFACE

The Roundtable for the Development of Drugs and Vaccines AgainstAIDS was established in 1988 by the Institute of Medicine. Composed ofleaders from government, the pharmaceutical industry, academia, andpatient advocacy, its mission is to identify and help resolve impedimentsto the rapid availability of safe, effective drugs and vaccines for humanimmunodeficiency virus (HIV) infection and acquired immune deficiencysyndrome (AIDS). The Roundtable accomplishes its mission throughregular meetings of its membership, during which urgent issues areidentified and discussed, as well as through public conferences andworkshops that explore scientific and policy matters central to thedevelopment of AIDS therapeutics. This publication is the report of aconference held April 9 and 10, 1991, in Washington, D.C.

The apparent lag in opportunistic infection (01) drug research relativeto antiretroviral research has generated substantial debate about theappropriate balance between efforts to develop antiretroviral drugs andthose to develop 01 therapies. The biomedical research community andpharmaceutical industry are investing heavily in the development ofantiretroviral therapy for HIV infection, and some critics have asserted thatthis emphasis may have slowed or diverted attention from basic andclinical research related to opportunistic infections. Other factors, however,may also be important-in particular. gaps in scientific knowledge thatimpede 01 research and drug development. The purpose of the Round-table's April 1991 conference was to review what is known about theepidemiology, basic biology, and treatment of the major opportunisticinfections and to examine obstacles to the development of effective 01therapies. Various perspectives on these issues, including those of thebiomedical and clinical research communities, the pharmaceutical industry,health care providers, and patient advocates, were presented.

vii

viii PREFACE

This report is not a consensus document but rather a synthesis ofselected scientific and public policy aspects of the conference presentations.It contains no recommendations or conclusions, and the Roundtable hasneither altered nor commented on the views and opinions expressed by thespeakers, except for purposes of clarity. The Roundtable and staff wish tothank our consultant, Margie Patlak. for her assistance in preparing thissummary. Thanks are also due to Richard Hafner, chief of the Oppor-tunistic Infections Treatment Research Section, Division of AIDS. NationalInstitute of Allergy and Infectious Diseases, for his valuable contributionsin updating the table in Appendix B. We also thank, once again, theconference speakers for their thoughtful presentations and all theparticipants for the lively, provocative discussions that occurred throughoutthis event.

CONTENTS

Introduction 1

Epidemiological Trends in AIDS-Related Infections 3

Scientific Impediments to 01 Drug Developmentand Drug Trials 7

Setting 01 Research Priorities 9

Impediments to Industry's 01 Drug Development 10

Dissemination of New 01 Therapies 14

Conclusion 19

Appendix A: Conference Program 21

Appendix B: Commonly Encountered AIDS-RelatedOpportunistic Infections and Their Treatments 26

Acronyms and Abbreviations 32

ix

DEVELOPING EFFECTIVE THERAPIESFOR AIDS-RELATED INFECTIONS

INTRODUCTION

As of 1990, there were an estimated 1 million people in the UnitedStates who were infected with the human immunodeficiencv virus (HIV).In the absence of a cure for HIV infection, the majority of theseindividuals will eventually succumb to one or more of the opportunisticinfections (Os) associated with acquired immune deficiency syndrome(AIDS)-the final stage of HIV disease-or various forms of cancer.Although HIV causes AIDS and is responsible for the progressiveimmunologic deterioration that increases susceptibility to opportunisticinfections, it is these infections that account for much of the morbidity andmortality associated with AIDS, as well as the diminishing quality of lifethat frequently occurs. (It must be noted, however, that other condi-tions-such as wasting, dementia, peripheral neuropathy, nephropathy,myocardiopathy, lymphoma, and Kaposi's sarcoma [KS]-also contribute tooverall HIV-related morbidity and mortality.) The frequency and types ofopportunistic infections seen among persons Mith AIDS are changinglargely because of current 01 prophylaxis and treatment regimens, as wellas antiretroviral therapy (e.g., zidovudine [AZTI). Relatively uncommoninfections, for example, are becoming more prevalent. New and as yetunrecognized infections may appear in the future.

Although drugs are available to treat a number of the most commonAIDS-related opportunistic infections (see Appendix B), problems existwith many of these current therapies. For some such infections, therapy ishighly toxic; in addition, it may be inconvenient to administer, expensive,and not entirely effective. For others, therapy may be initially effective, butlong-term use (often required to prevent recurrence of infection) may leadto patient intolerance or pathogen drug resistance, which may necessitatedose alterations or discontinuation of treatment. For still other opportun-istic infections, no effective therapy presently exists. People in the latestages of AIDS are particularly vulnerable to drug side effects, in part

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APPENDIX B Commonly Encountered AIDS-Related Oppoirtunmisi: Infections and Their Treatments j

Infecting Agent Manifestations Treatment Toxiuties of Treatment Comment

Pnetainiocsss cannu Pneumonia (usually intersti- rnmvthopnff,,ulfa-meih- Skin -3sh. nicutropenia. ab- Tnrmethoprim, 5 m~kgtial); rarelv disseminated onazole. IS-Z0/t5-ItiO dorminal pain. fewer esery M hours, and dapsone.

mgltg per day orally or 1100 mg per -Jay, may !)e asintravenously (IV) in 3- effective aIs iriMChopriM14 divided doses for 3 sulfamethoxazole or prima-weeks quine. 30 mg per day, plus

clindamycin. 450 mg every 6hours for 21 days.

Pentamidine isethionate. Hvpoglvcemta, hyper- For failure or intolerance3-4 mg~kg pet JIay by glycemia. hvpOCalcemia. to Standard therapy, Atcwva-slow IV; 2-3 waeeks dura- azoteia.113 hepatic dysfunc. quone (BW566CS0), 750tion of therapy tion. hypotension mg orally 3 times daily (or

or 21dy.now in expandedIf intolerant or failing access clinical trials for

stndr terp, tnme- mild to moderate PCP.trexate, 45 mg/rn 2 per (For mild ta moderateday IV, ?Ius leukovorin, PCP, Atovaquone generally20 mg/m- every 6 hours preferred ower trimetrexate.)IV or orally. If (Alveolar- After episode of P. cariruiarterial) 02 gradient pneumonia or in patients>35 or P02 <?0. then with CD4+!ymplocvtesPrednisone, 40 mg twice <0.2'00 x 107/L (< 200daily for 5 days, then 20 ceII&'#L). prophylaxis rec-mg twice daily for 5-10 ommended with aerosolizeddays; then 20 mg per day pentamidine isethionste, 300for 11-21 days mg monthly, or trimetho-

primlsulfamcthoxazole. 320/1600 mng per day, or dap-sone. 50-100 mg per day.

Cysornegaloviruis Retinitis, colitis cerebritis, Ganciclovr 19-(1_3-dihy- Anemia and neutropenia Bone marrow toxicity ofpneumonitis, esophagitis, droxy-2 propoxymethyl) ganciclovir may be additiveadrenalitis guanine (DHPG)J, 5 mg/ with that of zidovudine.kg IV twic daily for 2- Maintenance therapy should3 weeks; then 5 mg/kg IV be continued indefinitely fordaily maintensance retinifi and possibly for

cerebntis; reinductions re-quired often witb bothdrugs.

a.Fosernes (phospliono- Azotemia, setzures, hypo-formate), 60 mg~kg 3 magnesemiatimes daily for 2-3 weeks,then 90-120 mg/kg IVdaily maintenance

Cwtdada albicns, Oral thrush Clotrimazole trochcs, 5 Generally free of toxicitytimes daily

a,Nystatin suspension. 5 Generally free of toxicitymL swish and swallow, 4times daily

orKetoconazole. 200-400 Hepatitis, adrenal insuffi-mg per day orally cieney

orFluconazole, 50-100 mgper day

Contnu~ed on nex pWg

APPENDIX B Conwsued

Infecting Agent Manifestations Treatment Toxicities of Treatment Comment

Esophagitis Mild: Swallow nvstatinsuspension, sucking clo-tnmazole troches

or

Ketoconazole 200-400 mg Hepatitis, adrenal insuffi-

per day orally ciency

Severe: Amphotencin B. Fever, chills, nausea, vomit-

0.3 mg/kg per day IV for ing, thrombophlebitis, azo-

5-10 days temia, hypokalemia, anemia,hypomagnesemia

or

Fluconazole 100-200 mg

per day

Rarely disseminated Amphotericin B, 0.4-0.5

mg/kg per day or as a

double dose on alternate

days for several weeks

Mycobactenum avium- Disseminated, particularly in No recognized therapy; 3 In clinical trials: clanthro-

inaacellulare bone marrow, lung, lymph to 5 drugs chosen from mycin, 500-1000 mg twice

node. liver among ethambutal, rifam- daily; Azithromycin, 600-

pin or rifabutin, cipro- 900 mg per day

floxacin, amikacin. clofa-

zimine

Mycobacraium Pulmonary; disseminated 3 or 4 drugs chosen from Short-course regimens not

atba'ulons (frequent) among isoniazid, rifam- recommended. Treatment

pin, eihambutol, pyrazina- should be a minimum of 9-

mide (streptotnycin-not 12 months with at least 2

yet available in U.S.), drugs active in vitro. Initial

and others response to therapy gener-ally good. Role for long-

term maintenance therapyremains unclear. In clinicaltrias ciprofiaxacin and

ofloacin.

Crpwcoccuzs Meningitis; pulnry jry: dis- Amphotericin B, 0.5-0.6 See above for Candida Requires indefinite mainte-

neofonnan seminaled mg/kg per day IV when albicaw treatment nance therapy, fluconazole,

used alone or 0.3-0.5 200 mg per day, or ampho-mg/kg per day when used tericin. 1 mg/kg per week

in combination with 5-

fluorocytosine (5FC,flucylosme)or in cambixr*j Wah

5-Fluorocytosine, 100 Rash, myclosuppression,

mg/kg per day in 4 di- hepatitisvided doses every 6 hoursorally

or

Fluconazole, 400 mg perday

Continued on nea page

r~J

APPENDIX B Conttued

Infecting Agent Manifestations Treatment Toxicities of Treatment Comment

To-opla-sm gondu Encephalis intracerebral Pltimethamine. loading Anemia. neutropenlia. Initial response in patients

mass: ocular disease (rare) dose of 100-200 mg oral- thro/mNo'topenia. rash who recover usually occurs

IV in 2 divided doses for within 2 to 3 weeks.

2 jays: then 50-75 mgper day for 6 weeks: thenmaintenance dose of 25-50 mg per day in singledose

PgUSSulfadiazine loading dose Usual for sulfonamides, For maintenance therapy,

of 50-75 mg/kg orally; especiallycrystalluria, hema- pyrimethamine. 25-50 mg

then 75-100 mg/kg per tuna, rash per day. plus clindamycin.

day in 4 divided doses 450 mg every 6 hour.

every 6 hours orallyplus

Folinic acid, 10 mg perday orally in single dose;alternative: pyrimetha-mine plus clindamycin,600 mg every 6 hours

Herpes simplex virus Severe mucocutaneous dis- Acyclovir, 5 mg/kg every Generally free of toxicity May recur, but maintenance

ease including penanal skin 8 hours for 7 days IV or therapy usually not indica-

200 mg orally, 5 times ted; for acyclovir-resistant

daily for 10 days herpes simplex virus, foscar-net, 40 mg/kg every 8 hours

Esophagitis; pneumonia; Acyclovir, 10 mg/kg every Azotemia, central nervous

disseminated (rare) 8 hours for 10 days IV system (CNS) change-.rash, mild hepatitis

Herpes zoster Severe cutaneous disease; Acyclovir. 500 mg/m 2 Azotemia, CNS changes.dissemination (rare) every 8 hours IV for 7 rash. mild hepatitis

days; if dermatomalacyclovir, 800 mg/M2orally 5 times daily for 7.10 days or 30 mg/kg dailfor 7 days IV

CqPTosoniu Prolonged, severe diarrhea; None proven; paramo- Protracted diarrhea. unre-

malnutrition, wasting mycin in clinical trials; spowrive to therapy, maysupportive care including lead to inanition.

antimotility agents

Isospora belli Severe diarrhea; may be Trimethopnm.Asulfameth- See above for Pneumocystis Prophylaxis using tnmetho-

indistinguishable from crypto- oxazole, 160/8M0 mg 4 carinn" prim/sulfamethoxazole, 160/

sporidiosis times daily orally for 10 800 mg 3 times weekly, or

days. then twice daily for sulfadoxineipyramethamine.3 weeks 500/25 mg once per week.

has been effective.

Salmonella sp. Septicemia. diarrhea Ampicillin, tnmethopnnm/ Ciprofloxacin may also be

sulfamethoxazole, quino- effective.lones, or chloramphen-icol, depending on micro-bial sensitivities

Adapted from A.S. Fauc, and H.C. Lane, "The Acquired Immunodeficiency Syndrome (AIDS)." Harrisons Principles of Inrnal Medicine, ed. J-D.

Wilson. E. Braunwald, K.J. Isselbacher. R.G. Petersdorf, J.B. Martin, AS. Fauci, and R.Kl Root. 12th ed. (New York: McGraw-Hill, 1991).

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