2 management of Opportunistic Infections and General ... · AIDS-RELATED OPPORTuNISTIC INfECTIONS...

2

2 management of Opportunistic Infections and General Symptoms of HIV/AIDS

ClinicalProtocolfortheWHOEuropeanRegion

2ManagementofOpportunisticInfectionsandGeneralSymptomsofHIV/AIDS

ClinicalProtocolfortheWHOEuropeanRegion

Edited by:Irina EramovaSrdan Matic Monique Munz

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Keywords

CLINICAL PROTOCOLSAIDS-RELATED OPPORTuNISTIC INfECTIONSHIV INfECTIONS – THERAPYGuIDELINESEuROPE

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Table of contents

Abbreviations .............................................................................................................................9-iv

Acknowledgements ....................................................................................................................9-vi

I. Principles .................................................................................................................................. 9-1

II. Management of opportunistic infections ............................................................................. 9-2 1. General information ............................................................................................................. 9-2 2. Initial evaluation .................................................................................................................. 9-2 3. Counselling patients on OIs and other conditions ............................................................... 9-3 4. OI prophylaxis in HIV-infected patients .............................................................................. 9-4 5. Diagnosis and treatment of OIs ........................................................................................... 9-4 5.1. Respiratory infections ................................................................................................... 9-4 5.1.1. Bacterial respiratory infections ........................................................................... 9-5 5.1.2. Atypical mycobacteriosis .................................................................................... 9-7 5.1.3. Pneumocystis pneumonia ................................................................................... 9-8 5.1.4. Other causes of pneumonia in immunosuppressed people ................................. 9-9 5.2. Gastrointestinal infections ........................................................................................... 9-9 5.3. Candidiasis ................................................................................................................. 9-10 5.4. Cryptococcal meningitis ............................................................................................. 9-13 5.5. Histoplasmosis ............................................................................................................ 9-14 5.6. Kaposi sarcoma .......................................................................................................... 9-15 5.7. Cervical cancer ........................................................................................................... 9-16 5.8. Other cancers .............................................................................................................. 9-16 5.8.1. Non-Hodgkin lymphoma .................................................................................. 9-16 5.8.2. Burkitt-type lymphoma in PLWHA .................................................................. 9-17 5.9. Neurological infections .............................................................................................. 9-18 5.9.1. Toxoplasmosis .................................................................................................. 9-18 5.9.2. Herpes simplex virus ........................................................................................ 9-19 5.9.3. Herpes zoster .................................................................................................... 9-20 5.9.4. Cytomegalovirus infection ............................................................................... 9-21 5.9.5. Epstein-Barr virus-related conditions ............................................................... 9-22

III. General symptoms .............................................................................................................. 9-24 1. Persistent generalized lymphadenopathy in adults .......................................................... 9-24 2. fever ................................................................................................................................ 9-25 3. Weight loss in adults ........................................................................................................ 9-25 4. Chronic diarrhoea in adults .............................................................................................. 9-25 5. Oral lesions ...................................................................................................................... 9-26 6. Skin and nail conditions ................................................................................................... 9-26 6.1. Dermatomycosis ....................................................................................................... 9-26 6.2. Onychomycosis ......................................................................................................... 9-27 6.3. Seborrhoeic dermatitis .............................................................................................. 9-27 6.4. Scabies ...................................................................................................................... 9-28 6.5. Staphylococcal folliculitis......................................................................................... 9-29 6.6. Molluscum contagiosum ........................................................................................... 9-29

References .................................................................................................................................. 9-30

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HIV/AIDSTREATMENTANDCARECLINICALPROTOCOLSFORTHEWHOEUROPEANREGION

AbbreviationsAfB acid-fast bacilliAIDS acquiredimmunodeficiencysyndromeART antiretroviral treatment BID twice dailyCAT computerized axial tomographyCD4 cell cluster of differentiation antigen 4 cellCHOP cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine) and prednisolone (a chemotherapy regimen)CIN cervical intraepithelial neoplasmaCMV cytomegalovirusCNS central nervous systemCRP C-reactive proteinCSF cerebrospinalfluidDNA deoxyribonucleic acidEBV Epstein-Barr virusEfV efavirenzEPOCH etoposide, prednisolone, Onconvin (vincristine), cyclophosphamide and hydroxorubicin (doxorubicin) (a chemotherapy regimen)GI gastrointestinalGII gastrointestinal infectionHAART highly active antiretroviral treatmentHHV6 human herpes virus 6HHV8 human herpes virus 8HIV humanimmunodeficiencyvirusHPV human papillomavirusHSV herpes simplex virusHSV 1/2 herpes simplex virus 1 and 2IDu injecting drug userIgG immunoglobulin GIM intramuscularlyINH isoniazidIu international unitIV intravenous, intravenouslyKOH potassium hydroxideKS Kaposi sarcomaKSHV Kaposi sarcoma herpesvirusLIP lymphocytic interstitial pneumonitisMAC Mycobacterium avium complexMAI Mycobacterium avium-intracellulareMRI magnetic resonance imagingNHL non-Hodgkin lymphomaNSAID non-steroidanti-inflammatorydrugOD once dailyOI opportunistic infectionOPC oropharyngeal candidiasisPCP Pneumocystis jirovecii pneumonia (formerly Pneumocystis carinii pneumonia)

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support for sexual and reproductive health in people living with hiv/aids

PCR polymerase chain reactionPGL persistent generalized lymphadenopathyPML progressive multifocal leukoencephalopathyPI protease inhibitorsPLWHA people living with HIV/AIDSPO per os (orally)PPD purifiedproteinderivative(tuberculinskintestreagent)QID four times dailyQW once weeklyRTV ritonavirSO2 oxygen saturationTB tuberculosisTID three times dailyTIW three times weeklyTMP-SMZ trimethoprim-sulfamethoxazole (cotrimoxazole)VZV varicella-zoster virusWHO World Health Organization

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HIV/AIDSTREATMENTANDCARECLINICALPROTOCOLSFORTHEWHOEUROPEANREGION

AcknowledgementsThis clinical protocol has been developed and written by Christian Traeder (Vivantes Auguste-Victoria-Klinikum, Germany). It is one of 13 clinical protocols released by the WHO Regional OfficeforEuropein2006asapartoftheHIV/AIDSTreatmentandCareClinicalProtocolsfortheWHO European Region.

The editors and the writer gratefully thank the following experts for reviewing and commenting on the information to ensure the technical accuracy of the protocol: Keikawus Arastéh (Vivantes Auguste-Victoria-Klinikum, Germany), Josip Begovac (university Hospital of Infectious Diseases, Croatia),VolodimirKurpita(WHOcountryoffice,Ukraine),AlexanderPolischukandNinaSau-tenkova(bothfromWHORegionalOfficeforEurope,Denmark).

SpecialthanksgotothefollowingpeopleattheWHORegionalOfficeforEuropewhocontributedat various stages of production: Bente Drachmann, Nico Kerski, Jeffrey V. Lazarus and Andrea Nelsen.

Irina Eramova, Srdan Matic and Monique MunzSexually transmitted infections/HIV/AIDS programme

WHO Regional Office for Europe

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management of opportunistic infections and general symptoms of hiv/aids

I. Principles

• Management of opportunistic infections (OIs) is an essential component of comprehensiveHIV/AIDStreatmentandcare.

• AllpatientswithOIs–irrespectiveofgenderorsocialclassandincludinginjectingdrugus-ers(IDUs),sexworkers,prisoners,immigrantsandothervulnerablepopulations–shouldbetreated.Thedecisionofwhomtotreatshouldbebasedexclusivelyonmedicalconsiderations.

• TreatmentforcomorbiditiesshouldnotstopwhileOIpreventionand/ortreatmentisbeingpro-vided.

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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION

II. Management of opportunistic infections

�. General informationHIV-relatedinfectionsandillnessesincludethefollowing.

Table �. hiv-related infections and illnesses

Bacterial infections Fungal infections Viral infections Parasitic

infections Other illnesses

TuberculosisBacterialrespira-toryinfectionsBacterialentericinfectionsAtypicalmyco-bacteriosisBartonellosis

CandidaoesophagitisCryptococcosisHistoplasmosisPneumocystisjiroveciipneumonia(PCP)Coccidioidomycosis

Herpessimplexvirus(HSV)diseaseVaricella-zostervirus(VZV)diseaseCytomegalovirus(CMV)diseaseHumanherpesvirus8(HHV8)infection,alsoknownastheKaposisar-comaherpesvirus(KSHV)Humanpapillomavirus(HPV)infectionProgressivemultifocalleu-koencephalopathyHepatitisBandC(naturalcourseofinfectioniswors-enedbyHIVcoinfection)

ToxoplasmosisCryptosporidiosisMicrosporidiosisIsosporiasisLeishmaniasis

Kaposisarcoma(KS)Non-Hodgkinlym-phoma(NHL)CervicalcancerEncephalopathyVacuolarmyelopathy

ThemostcommonOIsintheWHOEuropeanRegioninclude:• tuberculosis(TB)• bacterialinfections• PCP• herpesinfections(includingherpeszoster,CMV,HSV1and2(HSV1/2)• Candida oesophagitis• Cryptococcus meningitis• toxoplasmosis.

Lessfrequentopportunisticinfectionsandcancersinclude:• Mycobacterium aviumcomplex(MACorMAI)disease• KS• NHL• CMVinfection(retina,gastrointestinal(GI)tract,encephalitis).

Theorderofinfectionsandcancersinthelistmaychange,duetofactorsthatmayormaynotberelatedtotheHIV/AIDSepidemic.

�. Initial evaluationPatientswithunknownHIVstatuswhopresentwithinfectionsorillnessesthatareassociatedwithHIVinfectionshouldbeofferedHIVtestingandcounselling.ThephysicianshouldexplaintothepatientthereasonsforofferinganHIVtestandtheimportanceofknowingtheresultsforcorrectclinicalmanagement.However,patientshavetherighttorefusetesting(optout).

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TheinitialassessmentofHIVstatusshouldinclude:• HIVpretestcounselling;• serologicaltesting(typicallyELISAand/orrapidtests)forHIVantibodies,followedbyawest-

ernblotconfirmatorytest(whichindicatesHIVinfectioniftheresultispositive);and• post-test counselling–whether the result ispositiveornegative– including informationon

reducingriskybehaviour.

IfthepatientisHIV-positive, aninitialclinicalevaluationshouldbemadetodeterminetheclinicalstageoftheinfectionandidentifycomorbiditiesandconditions.(FormoreinformationpleaserefertoProtocol1,Patient evaluation and antiretroviral treatment of adults and adolescents)

�. Counselling patients on OIs and other conditions• Physiciansandnursesshouldcounselallpatientsand/orfamiliesaboutthechronicnatureof

HIVinfectionandthepossibleappearanceofOIs.• PatientsshouldbeinformedthatsomeOIscanbeprevented(seeTable2below).• Theyshouldknowthatitisessentialtodiagnoseanopportunisticinfectionearly,sothatthey

consulttheirphysicianwhentheysuspectanydiseaseprogressionmaybeoccurring.• TheyshouldbecounselledonsymptomsthatmightindicateOIsandtheneedtoinformtheir

physicianaboutthem: ° dyspnoea:Pneumocystis jirovecii pneumonia(PCP),TB,pneumonia; ° cough:PCP,TB,pneumonia; ° bloodysputum:TB,pneumonia; ° neurologicalchanges:cerebraltoxoplamosis,cerebrallymphomaormeningitis/encephalitis; ° weightloss,fever,nightsweats:TB,atypicalTB,lymphoma; ° visualimpairment:CMVretinitis; ° painfulswallowing:candidaoesophagitis;or ° diarrhoea:CMVcolitis,infectionwithcryptosporidiae,microsporidiae,salmonellosis,etc. ° visualfieldloss(readinganewspaperisagoodandsensitivetest); ° weaknessofarmsorlegs(cerebraltoxoplasmosis); ° anychangeofmentalstatusorbehaviouralsignsthatmaysignalmentalhealthproblems

(asobservedbyfriendsandfamilymembers;herpesmeningitis,toxoplasmosis,progressivemultifocalleukoencephalopathy(PML),etc.)

° changeinskinconditionsor(moreoften)oralthrush(possibleantiretroviraltreatment(ART)failure).

• Patientsshouldknowtheimportanceofmonitoringtheirchronicconditions. ° Patientswithchronichepatitisshouldhaveanabdominalultrasoundtwiceayearbecauseof

theriskofhepatocellularcarcinoma. ° PatientswithahistoryoftuberculosisshouldhaveachestX-rayonceayear. ° OlderoverweightHIVpatientswhohavehypertensionandareon anART regimen that

includesaproteaseinhibitor(PI)mustbecheckedforcardiovasculardisease,diabetesandotherconditions.

• Patientsshouldbegivenachecklistthatincludesascheduleoflaboratoryandclinicalteststobeundertakenonaregularbasis.Thecontentofthislistmayvaryduetocomorbidities.

For further informationoncounselling issuesplease refer toProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

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�. OI prophylaxis in HIV-infected patients• CertainOIsthatmaydevelopinpeoplelivingwithHIV/AIDS(PLWHA)canbeprevented.• ProphylaxisofOIsinPLWHAshouldbeanintegralpartofOImanagement.• After initiatingART, it ispossible todiscontinueprimaryprophylaxis if theCD4counthas

risenovertherelevantindicationlevelfor3–6months(e.g.PCP:>200cells/mm3,toxoplasmo-sis:>100cells/mm3,MAI:>50cells/mm3).SeeTable2below.Discontinuationofsecondaryprophylaxisshouldalsobepossibleinthesamesituationwithclosemonitoring.AlwaysrestartprophylaxiswhenCD4countsfallbelowtheindicationlevel.

Table2summarizesthemostrecentrecommendationsforprophylaxisstrategy.

table 2. oi prophylaxis for hiv-infected patients

Pathogen Indication First choice AlternativesPneumocystis jirovecii

CD4count<200cells/mm3

ororopharyngealcandi-diasis

TMP-SMZ(cotrimoxa-zole)double-strengthtabletPOaODb

• TMP-SMZsingle-strengthtabletPOOD(1)

• TMP-SMZdouble-strengthtabletPOTIWc(Monday,WednesdayandFriday)

• Dapsone50mgPOBIDd

• Dapsone100mgPOOD(2)• Pyrimethamine50mg

+dapsone50mg+folinicacid15mgOD

• Pentamidineinhalation300mgeverythreeweeks(3)

• Alsopossible:clindamycinoratova-quone(4, 5)

M. tuberculosis Purified protein derivative(PPD)reaction ≥5 mmorrecentcontactwithacaseofactiveTB

Isoniazid(INH)300mgPO+pyridoxine50mgPOODfor6months(6)

Furtherresearchisneededfordevelop-ingalternativeprophylaxistreatmentforTBinareaswithhighprevalenceofINHresistance.

Toxoplasma gondii, primary


TMP-SMZdouble-strengthtabletPOOD

• TMP-SMZsingle-strengthtabletPOOD(7, 8)

• Dapsone50mgPOOD +pyrimethamine50mgPOQWe

+folinicacid25mgPOQWToxoplasma gondii, secondary


TMP-SMZdouble-strengthtabletPOOD

Dapsone50mgPOOD+pyrimethamine50mgOD+folinicacid15–25mgOD

M. avium complex CD4count<50cells/mm3

Azithromycin1200mgPOQW

Clarithromycin500mgPOBID(9, 10)

Cryptococcus neo-formans


Fluconazole100–200mgPOOD(11)

aPO:peros;bOD:oncedaily;cTIW:threetimesweekly;dBID:twicedaily;eQW:onceweekly

5. Diagnosis and treatment of OIs

5.�. Respiratory infections• Lower respiratory tract infectionsare themostcommonrecurrent infections inPLWHA.

Theyareusuallylife-threateningandcanbecausedbybacteria,viruses(rarely)andfungi(alsorarely).

• Patientsmaypresentearly in thecourseofHIV infectionwithbacterialpneumonias,whichrespondreadilytoantibiotics(12).

• PatientswithHIVinfectionappeartobeparticularlypronetoinfectionswithencapsulatedor-ganismssuchasStreptococcus pneumoniaeandHaemophilus influenzae (13).

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• Later,andwiththeonsetofimmunesuppression,patientsmaydevelopopportunisticpulmo-naryinfections,themostimportantofwhichispulmonaryTB.

• As cell-mediated immunity deteriorates, patients may develop life-threatening opportunisticinfectionssuchasPCPandseverefungalandviralpneumonias.Table3summarizestherespira-toryillnessesassociatedwithHIVinfection.

table 3. respiratory illness in plWha

Type of infection Possible complicationsa

BacterialPneumococcalpneumonia Empyemab,pleuraleffusion,lungabscessH. influenzapneumonia Pleuraleffusionb,lungabscess,empyema,Klebsiellapneumonia Empyemab,pleuraleffusionStaphylococcalpneumonia Lungabscessb,empyema,pleuraleffusionM. tuberculosispneumonia Pericardialeffusion,lungabscess,empyema,pleuraleffusionMACpneumonia Rarecomplications:AbscessesespeciallywithIRISViralCytomegalovirus Pneumonitisb(highlylethal)Herpessimplexvirus Pneumonitisb(highlylethal)FungalPneumocystispneumonia PneumothoraxCryptococcosisHistoplasmosisAspergillosis LungabscessOther conditionsKS PleuralorpericardialeffusionLymphoma PleuralorpericardialeffusionCarcinoma(non-HIV-related) Pericardialeffusion

a Possiblecomplicationsareintheorderofthefrequencytheoccur.b Complicationsthatoccurmostfrequently.

5.�.�. Bacterial respiratory infections

• Bacteriallowerrespiratorytractinfectionsarecommoninthegeneralpopulation,buttheyaremorefrequentandmoresevereinimmunosuppressedpersonswithHIVinfection.

• S. pneumoniae isthemostcommonlowerrespiratorytractpathogen.• Patientswithbacterialpneumoniapresentwithcoughandfeverandoftenhavechestpain,dif-

ficultyinbreathingandtachypnoea.• ChestX-raysmayshowclassic lobarpneumonia,bronchopneumoniaoratypical (orabsent)

infiltrates.

DiagnosisThediagnosisofpneumoniaisusuallymadeonclinicalgroundsandbyachestX-ray,whichmayreveal:• lobarorpatchyconsolidation• diffuselunginfiltratesor• atypicalchanges,includingcavitarydisease.

Treatment• IfthepatientisnotseverelyillandnoPCPissuspected,treatmentmaybeprovidedathome

accordingtoTables4and5below.

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Table �. first-line antibiotic treatment of bacterial pneumonia

Antibiotic Dose Frequency Route DurationAmoxicillin

(Useapenicillinincombinationwithbetalactamaseinhibi-torifthereisachanceofpenicillin/ampicillinresistance.)

500–1000mg TIDa PO 7daysorlongeruntil

resolvedor:

Erythromycin 500mg QIDb PO 7daysor:

Clarithromycin 500mg BID PO 7daysor:

Azithromycin 500mg OD PO 3–4daysor:

Quinolone with pneumococcal activitiy (e.g. moxifloxacin) 400mg OD PO 7daysor:

Doxyciclin 100mg BID PO 7daysaTID:threetimesdaily;bQID:fourtimesdaily

• Ifpatientsdonotrespondtofirstlinetreatmentoveraperiodof72hours(nofever,C-reactiveprotein(CRP)elevationresolved,leukocytecountisnotreliable),thepatientshouldbereferredtothehospitalandsecondlinetreatmentprescribedasindicatedbelow.Patientsmayalsore-quireoxygen(inthiscasePCPshouldbesuspected).

• Severelyillpatientsshouldbereferredforhospitaladmissionimmediately.

Table 5. second line treatment of bacterial pneumonia

Antibiotic Dose Frequency Route DurationCeftriaxone

+erithromycin

2g

500mg

OD

QID

IV* 7days

or:Ampicillin+sulbactam

+erythromycin

1500mg

500mg

TID

QID

IV 7days

or:Quinolone with pneumococcal activitiy (e.g. moxifloxacin) 400mg OD IV/PO 7days

or:Chloramphenicol(ifotherdrugsarenotavailable) 12.5mg(base)

perkgofbodyweight

QID IV 7days

*intravenously

• Ifpatientsdonotrespondtothistreatment,considerPCPorTBasapossiblediagnosis.Thediagnosticgoldstandardislavagebybronchoscopytodefinethepathogenbeforestartinganti-biotics(14).Alsohelpfularebloodcultures,whichhaveahigherrateofpneumococcalidenti-ficationandmaybedoneuptofivetimes.

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5.�.�. Atypical mycobacteriosis

Mycobacterium aviumcomplex(MACorMAI)disease is lesscommonthansomeotherOIs. Itpresentswith:• fever• weightloss• nightsweats• diarrhoea• wasting.

MACorganismsmaybefoundinthebloodandexcretaofinfectedpersons.Adefiniteinfectioncanbeshownwithacid-fastbacilli(AFB)insterilefluidsorspecimens(blood,cerebrospinalfluid,bonemarrowandliver).

Diagnosis• BloodculturesonspecialmediaarethecornerstoneofMACdiagnosis.• Inmostsymptomaticpatients,theintensityofmycobacteraemiaissuchthatmostorallblood

culturesarepositive.• BecausetheliverandbonemarrowareofteninvolvedindisseminatedMACinfection,thebac-

teriamaybevisibleinacid-fast-stainedbiopsysamplesfromthesesites.• Presumptivediagnosisbyexaminationofabiopsiedliverspecimensavestime.

Treatment

Table �. atypical mycobacteriosis treatment

Antibiotic Dose Frequency Route DurationFirst-line treatment (15, 16)

Clarithromycin+

ethambutol+

rifabutin

500mg–1000mg BID PO 6months;decideonclinicalgrounds

15mg/kg OD PO 6months;decideonclinicalgrounds

300–450mg OD PO 6months;decideonclinicalgrounds

Other drugs active against MACa

Azithromycin 500–1200mg OD PO 6monthsCiprofloxacin 500mg BID PO 6months

Amikacin 15mg/kg/dayor7.5mg/kg/day

ODBID

IVIV

Nolongerthan4weeks

aRifampicinisnoteffectiveagainstMAC.

• OnceMACtreatmenthasbeenstarted,andthereisindicationthattheconditionisimprovingandthedrugsarewelltolerated,ARTshouldbeinitiated.

• Standardprocedure is tostartonART4–6weeksafterMACtreatmenthasbegun.Aftersixmonthswithanimprovedimmuneresponse(CD4count>100 cells/mm3),reduceMACtreat-mentorstopitanduseasecondaryprophylaxis.

• Stoppingthesecondaryprophylaxisispossiblewhentheimmunesystemisstableandrespon-siveformorethan3–6months.

• MACtreatmentorsecondaryprophylaxisshouldbeadministeredforsixmonthstoensureasuccessfultreatmentandavoidrelapse.

• It isimportanttobeginwithtreatmentforMACtoavoidconfusionaboutwhetheranyside-effectscomefromMACdrugsorART.

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• Thereisthepossibilityofimmunereconstitutioninflammationsyndrome(IRIS)afterstartingART(seeProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents,sectionsClinicalfailureandImmunereconstitutioninflammatorysyndrome).

5.�.�. Pneumocystis pneumonia

• PCPisacommonHIV-associatedOI,causedbythefungusPneumocystis jirovecii(formerlyknownasPneumocystis carinii).

• Patientsusuallypresentwithcough,shortnessofbreathandfever.• OccasionallypatientswithPCPhavenochestsigns.• PatientswithPCPoftenhavefeaturesofrespiratoryfailuresuchasshortnessofbreathandcya-

nosis.• Symptomsmaybeverysevere;anattackofPCPmayleadtodeathifnottreatedearlyandef-

fectively.

Diagnosis• DiagnosisisoftenmadeonclinicalgroundswhenafebrilePLWHApresentswithrespiratory

distress,withorwithoutcyanosis.• Thepatientmayhaveanon-productivecough,butthemainfeatureoftheconditionisshortness

ofbreath,withminimalorabsentchestsignsonphysicalexamination.• ChestX-rays ° Thereisnotalwaysaground-glassopacificationinthelowerzonesofbothlungfields. ° Theremaybeevidenceofpatchyinfiltratesinbothlungfieldsthatmimicsbacterialpneu-

moniaorTB. ° AconsiderableproportionofpatientswithconfirmedPCPshownochangesatallontheX-

ray.• Bronchiallavageisthegoldstandardofdiagnosis(14).Diagnosisisconfirmeduponfinding

cystsofPneumocystisinforcedsputumorinbronchiallavageaspirate.• Ifdiagnosiscannotbeestablishedduetothelackofabronchoscope,deterioratingpulmonary

functiontestsorbloodgasanalysiscanbeusedasindicators.• Treatmentshouldbestartedimmediatelyupondiagnosis.

TreatmentPatientsshouldbeadmittedtohospitalformanagement.Supportivetherapyincludingoxygenmaybenecessary.DetailsoftreatmentaregiveninTables6and7below.

Table �. pcp first-line treatment

Antimicrobial agent Dose Frequency Route DurationTMP-SMZ 400/80mg QID PO/IV 21days

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Table �. pcp second-line treatment

Antimicrobial agent Dose Frequency Route DurationClindamycin

+primaquine

600mg

15mg

QID

BID

PO/IV

PO

21days(17)

or:Pentamidine(incombinationwithabroad-spectrumantibiotictoprevent

bacterialsuperinfection,e.g.ampicillin+sulbactamfor10days)

4mg/kgIVdaily.Dosereductionto2mg/kgafter5daysoftreatment(18)

OD IV 21days

• Severelyillpatientswillrequireprednisolone,80–250mgPO/IVdailyfor1–2weeks(reducesinterstitialoedema).

• Combinationtreatmentshouldalsobeconsideredinseverecases,forexample,TMP-SMZandpentamidinemayincurahighriskoftoxicityaccordingtocasereportsonly.AseverecaseofPCPrequiresartificialventilationoranoxygensaturation(SO2)<92%.

Side-effectsshouldbemonitored,especiallythekidneys(both),pancreas(withpentamidine)andbonemarrow(withTMP-SMZ).Labanalysisshouldberequiredtwiceweekly.

AftersuccessfullytreatinganacuteepisodeofPCP:• it isnecessary tocontinuesecondaryprophylaxiswithTMP-SMZ160/800mgPOODona

long-termbasis;• prophylaxismaybediscontinuedwhenthepatient’sCD4countremainsstableat>200/mm3for

atleastthreemonths.

5.�.�. Other causes of pneumonia in immunosuppressed people

• Othercausesofpneumoniaincludefungalandviralinfections.Theyaredifficulttodiagnosewithoutsophisticatedlaboratoryfacilitiesandaredifficulttotreat.

• Viralpneumoniamaybecausedbyherpessimplexvirus, varicella-zostervirusor cytomegalo-virus.

• InadditiontoPCP,otherfungalcausesofpneumoniaincludeHistoplasma capsulatum,Crypto-coccus neoformansandAspergillus.

Diagnosis• Whenpneumoniafailstorespondtostandardtreatment,TBorpneumoniacausedbyviruses,

fungiorprotozoashouldbesuspected.• Making a specific diagnosis of fungal or other infections requires sophisticated laboratory

tests: ° pp65earlyCMVantigenfromperipheralbloodorbronchiallavage; ° polymerasechainreaction(PCR)forvirusesoftheherpesfamily(CMV,HSV1/2,VZV,

Epstein-Barrvirus(EBV),humanherpesvirus8and6(HHV8,HHV6)) ° specialculturesforslow-growingpathogens,suchasnocardia.• Closecollaborationbetweenphysicianandmicrobiologistisneeded.

TreatmentTreatmentwilldependonthecause,forexamplefoscarnetforCMVinfectionorlong-termantibiot-ics(eightweeks)fornocardia.

5.�. Gastrointestinal infections (GIIs)• GIIsinPLWHAmaybetheresultofanyofthefollowinginfections:

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° HIV(directinfectionoftheGItract) ° bacterial ° fungal ° viral ° protozoal ° parasitic.• Someoftheproblemsmayarisefromatrophyoftheintestinalvilli,whichcommonlyleadsto

malabsorption.• ThemostcommonGIproblemencounteredisdiarrhoea,whichcanbeacute,acute-on-chronic

orchronic.• DiarrhoeaispersistentorchronicinpeoplewithAIDS,andanimportantcauseofdeathamong

them.• Acutediarrhoealeadstodehydrationunlessproperlytreated.• Thepassingofbloodyorblood-stainedstoolsoccurs inpersonswithshigellosisoramoebic

dysentery.• OthercommonGIproblemsinPLWHAinclude: ° poorappetite ° nausea ° vomiting ° progressiveweightloss.

Table9summarizes theclinicalfeatures,diagnosisandtreatmentofsomeof themorecommongastrointestinalinfectionsseeninimmunosuppressedPLWHA.

Table 9. gastrointestinal infections commonly encountered in plWha

Infection Clinical features and diagnosis TreatmentNon-typhoidsalmo-nelloses

Fever,abdominalpain,diarrhoeawithorwithoutblood,weightloss,anorexia,hepatosplenomegalyDiagnosisuponbloodorstoolculture

Ciprofloxacin 500 mg PO BID for >2 weeks (19)

Shigelloses Fever,abdominalpain,bloodydiarrhoeaDiagnosisuponbloodorstoolculture

Ciprofloxacin 500 mg PO BID for 7–10 days or:Nalidixicacid500mgPOQIDfor7–10daysor:TMP-SMZ160/800mgPOBIDfor7–10days

Cryptosporidiosis Waterydiarrhoea,lossofappetite;afebrileDiagnosisuponstoolmicroscopy

Paromomycin1gPOBID+azithromycin600mgPOODfor4weeksthen:Paromycinalonefor8weeks(20, 21).Treatmentoftenfails(22).

Microsporidiosis Waterydiarrhoea,lossofappetite;afebrileDiagnosisuponstoolmicroscopy

Albendazole400mgPOBIDfor4weeks.If this does not work try:Mebendazole200mgPOTID(albendazoletendstobemoresuccessful)(23).

5.�. Candidiasis• Candida albicanscolonizesprimarilytheGItractsofbothmenandwomen.Uptoonethirdof

allnormalwomenalsocarryC. albicansinthevagina.• Womenwithvaginalcandidiasismaydevelopavaginaldischargeandvulvovaginalpruritus.• Menwithgenitalcandidiasiswilldevelopbalanitisorbalanoposthitisandwillcomplainofa

subpreputialdischargeanditchinessofthepenisandforeskin.

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• Oralcandidiasis(thrush)leadstoinflammationofthemucosalsurfacetogetherwiththeappear-anceofadherentwhiteplaques.

• C. albicanscaninfecttheskinandcausepruriticdermatitis.• Dependingonthelevelofimmunesuppression,oralinfectionmayextendtoinvolvetheoe-

sophagus.• Bronchialanddisseminatedinfectionsarerare.

Symptoms• Oralthrushcanincludeinfectionofthe: ° buccalmucosa ° tongue ° oropharynx ° gums ° hardandsoftpalates.• Patientsmayhavenosymptomsatallormaycomplainofaburningsensationinthemouth

wheneating.• Somepatientsmaycomplainofwhitepatchesinthemouth.• Ifthethrushhasextendedintotheoesophagus,patientsmaycomplainof: ° painonswallowingfood ° retrosternalpain ° excessivesalivation.

Patientsinwhomcandidiasisoccursmostfrequently:• healthypregnantwomenandhealthywomenonoralcontraceptives• healthyneonates,especiallypre-terminfants• thoseonprolongedcoursesofbroad-spectrumantibiotics• thosereceivingsteroidssystemically• thosewithdiabetesmellitus• thosewithcongenitaloracquiredimmunodeficiencies• thosesufferingfromchronicdebilitatingconditions• theseverelymalnourished• thosewithcancerandthosereceivingchemotherapyorradiotherapy.

Diagnosis• Thediagnosisoforopharyngealcandidiasisismadeonclinicalgrounds,basedondirectobser-

vationandmicroscopicexaminationofmaterialobtainedfromlesions.• Examinationof theoralcavitymayrevealrednessandinflammationof themucosa,withor

withoutpatchesofwhiteplaques.• Inflammationmaybeseenonthepalate,throat,gums,tongueand/ortheinsideofthecheeks.

Whenthetongueisaffected,itmaybesmoothandred,andthepapillaenormallyfoundonthetonguemaybeabsent.

• DiagnosishastobeconfirmedbyhistologicalexaminationoftissuebiopsiesonlyincasesofCandidaoesophagitisoraspergillosisofthelungs.

• Oropharyngealcandidiasis(OPC)isbelievedtooccuratleastonceinallPLWHA.Thesymp-tomsare:

° difficultyinswallowing ° paininthechestthatincreaseswithswallowing.• Disseminatedcandidiasiscausesfeverandsymptomsintheaffectedorgans(forexample,blind-

nesswhenitaffectstheeyes).

Treatment• Localizedcandidiasisistreatedfirstwithrelativelyinexpensivetopicaldrugssuchasnystatin,

miconazoleorclotrimazole.

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• Inpatientswithdisseminatedcandidiasisand in those inwhomtopical treatmenthas failed,systemicantifungalagentssuchasketoconazole,fluconazole,itraconazoleoramphotericinBmaybegiven.

• Fortreatmentofdrug-dependentpatientsreceivingmethadoneasopioidsubstitutiontherapy,seeTable4ofProtocol5,HIV/AIDS treatment and care for injecting drug users,fortheinterac-tionsoffluconazole,itraconazoleandketoconazolewithmethadone.

Table �0. oral candidiasis

Antifungal agent Dose Frequency Route DurationFirst-line treatment (24)

Myconazole Buccaltablets Onceaday Gumpatch 7daysor:

Fluconazole 100mg BIDfor3daysfollowedbyODfor4days

PO 7days

Second-line treatment (25)Itraconazole 200–400mg OD PO 7days

Table ��. vaginal candidiasis

Antifungal agent Dose Frequency Route DurationFirst-line treatment

Fluconazole 100mg Singledose PO OnceClotrimazole 500mg Singledose Vaginal Once

Second-line treatmentKetoconazole 200mg BID PO 3daysKetoconazole 200mg OD PO 7days

Maintenance therapyNystatin 2–4millionIU BID PO 10days

or:Fluconazole 50–200mg OD PO Everyday

Third-line treatmentKetoconazole 200mg OD PO Dependsonresponse,

usually7–10days

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Intraconazole 100mg OD PO Dependsonresponse,usually7–10days

Table ��. oesophageal and disseminated candidiasis

Antifungal agent Dose Frequency Route DurationFirst-line treatment

Ketoconazole 200–400mg BID PO 21daysor:

Fluconazole(moreeffectivethanketoconazole)

200–400mg,reduceonclinicalgroundsafter3daysto

100mg/day

OD PO/IV 14days

Second-line treatmentAmphotericinB 0.3–0.5mg/kg IV 10–14days

or:Itraconazole 200–400mg OD PO 2weeks

• Long-termmaintenancetreatmentwithfluconazole50–100mgODPO,itraconazole100mgODPOorketoconazole200mgODPOmaybenecessaryforpatientswhohavebeentreatedforcandidaloesophagitis.

• Ifthepatientfailstorespondtothistreatment,adiagnosisofCMVorHSVoesophagitisshouldbeconsidered,andthepatientshouldbereferredforanoesophagoscopy.

• Candida glabrata,C. krusei andC. tropicalis are resistant to fluconazole to someextent.Aspecimenisneededforculture;susceptibilitytestingispossibleandprescribingofamphotericinBmakesmoresense.Voriconazole,posaconazoleandcaspofunginarenewdrugsencounteringrare resistance in any fungi, includingAspergillus; all arevery expensive.Voriconazole caninteractwithARVdrugs,anditshouldnotbeprescribedtopatientstakingefavirenz(EFV)orritonavir(RTV).PatientsreceivingbothPIsandvoriconazoleshouldbecloselymonitoredforpossibleside-effects(26).

5.�. Cryptococcal meningitis• Cryptococcosismostoftenappearsasmeningitis,andoccasionallyaspulmonaryordissemi-

nateddisease.• CryptococcalmeningitisisacommonsystemicfungalinfectioninPLWHA.• Without treatment, the life expectancy of patients with cryptococcal meningitis is probably

less than a month.

DiagnosisCryptococcosisisrelativelyeasytodiagnose.Patientsusuallypresentwithheadache,fever,neckstiffnessand/orcranialnervepalsies,ortheymaybecomatose.However,signsofmeningealin-flammationsuchasfeverandneckstiffnessoftendonotoccur.Acentrifugeddepositofthecerebro-spinalfluid(CSF)shouldbeexaminedmicroscopicallyafteraddingadropofIndiaink.• Theyeastsarevisibleasorganismssurroundedbythickcapsules.• TheCSFmaybeculturedforcryptococci.

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• Thecryptococcalantigentestisusefulinassessingpatientsforcryptococcosisandcanbeper-formedonserumorcerebrospinalfluid.

Treatment

Table ��. cryptococcal meningitis treatment

Antifungal agent Dose Frequency Route Duration

First-line treatment (27)AmphotericinB

+5-flucytosine

0.7–1.0mg/kg

25mg./kg

OD

QID

IV 14days

then:fluconazole

400mg OD PO Atleast10weeks

then:fluconazole

200mg OD PO Lifelong

Second-line treatmentAmphotericinB

+5-flucytosine

0.7–1.0mg/kg

25mg/kg

OD

QID

IV 6–10weeks

or:AmphotericinB 0.7–1.0mg/kg OD IV 6–10weeksor (in mild cases):

Fluconazole 400–800mg OD PO 10–12weeksthen:

fluconazole200mg OD PO Lifelong

Secondarychemoprophylaxisormaintenancetherapy• Lifelongsecondarychemoprophylaxisisnecessary;itmaybeachievedwithfluconazole200

mgorallyoncedailyforlife.• Alternatelong-termsecondaryprophylaxismaybeachievedwithitraconazole200mgorally

oncedailyforlife.• Theneedformaintenancetherapywithpatientswhohaveanimprovedimmunesystem(CD4

count>200)ispresentlyneithersupportednorrefutedbyconcreteevidence.• Fortreatmentofdrug-dependentpatientsreceivingmethadoneasopioidsubstitutiontherapy,

seeTable4ofProtocol5,HIV/AIDS treatment and care for injecting drug users,fortheinterac-tionoffluconazolewithmethadone.

5.5. HistoplasmosisThisuncommonacuteorchronic infection iscausedby inhalingspores from the fungusHisto-plasma capsulatum.• Theoutcomeofexposuredependsontheimmunestatusofthehostaswellasthesizeofthe

inoculum.• Intactcell-mediatedimmunityisessentialforpreventingitsdissemination.Theacuteillnessis

influenza-like,with: ° fever ° anorexia ° arthralgia ° myalgia ° drycough ° chestpain.• Disseminationoccurssoonafterinitialinfectioninimmunosuppressedpatients,whodevelop: ° weightloss

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° oralandskinlesions ° chestsymptoms ° liver,spleenandlymphnodeenlargement.• Orallesionsmayappearasprotruding,necroticulcers.Theremayalsobeperforationofthepal-

ateandextensivesofttissuedestruction.

DiagnosisDiagnosisismadeonclinicalgroundsandisconfirmedbyfungalculturesorhistologicalexamina-tionofbiopsiedtissues.• AchestX-rayinacuteillnessmayshow: ° hilarlymphadenopathy ° scatteredinfiltrates ° lowerlobenodules.• Bloodandskintestshavebeendevelopedforthediagnosisofhistoplasmosis,buttheyarenot

widelyavailable.

TreatmentInnormalimmunesystems,acutehistoplasmosisisself-limitinganddoesnotrequiretreatment.InimmunosuppressedpatientsitmaybetreatedasshowninTable14.

Table ��. treatment of histoplasmosis

Antifungal agent Dose Frequency Route DurationAmphotericinB 0.7–1mg/kg OD IV 10days

Source: Johnsonetal.,2002(28).

Thisinitialtreatmentisfollowed,threemonthsafterimmunoreconstitutionwith>100CD4cells,withoneofthefollowinglong-termtreatments:• itraconazole200mgBIDPO• fluconazole200mgBIDPO• amphotericinB1mg/kgIVweekly.

Analternativeisitraconazole200mgTIDPOx3days,then200mgPOBIDx12weeks(takenwithamealandanacidicdrink).

5.�. Kaposi sarcoma (KS)• KSiscausedbythehumanherpesvirustype8(HHV8),alsoknownastheKaposisarcoma

herpesvirus(KSHV).• AnypatientsuspectedofKSshouldbeexaminedbyanoncologistandreferredtoanoncology

clinicasneeded.• InHIV-associatedimmunosuppression,KSismoreaggressive,disseminatedandrapidlypro-

gressivethantheendemicdiseasefoundinpeoplewithoutHIVinfection.

DiagnosisThediagnosisofKSismadeonclinicalsuspicionandconfirmedbyhistologicalexaminationofbiopsiedtissue.

Clinicalsignsincludethefollowing.• Lesionsmaybefoundanywhereonskinandonanymucosalsurface.Skinlesionsarehyperpig-

mented,blueorpurplishpapulesornodulesandcanbeassociatedwithlymphoedema.Systemiclesionsarecommonlyfoundonthepalate,gastrointestinaltract,lungsorlymphnodes.

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• Oral lesionsofKSmaybe foundon thehardpalateandoccasionallyon the tongue, throat,tonsilsorgums.Thelesionsarepurplepapules,usuallypainlessandsometimeslargeandpe-dunculated.

• Pulmonarylesionsareinfiltrativewithpleuraleffusionandoftenleadtorespiratoryfailure.Theconditionmaybeconfusedwithbacillaryangiomatosis(bartonellosis),aninfectiveconditionseeninPLWHA.

Treatment• KSisacancerandshouldaccordinglybetreatedbyanoncologist.• Itistreatablewithradiotherapyiflesionsarelocalizedandwithcytotoxicchemotherapyifitis

generalized.• Cytotoxicdrugcombinationsthathavebeenusedwithvaryingdegreesofsuccessinclude: ° liposomaldoxorubicinmonotherapy(bestresults)(29–31) ° bleomycin ° vincristine ° daunorubicin ° vinblastine ° etoposide.• Remissionisdifficulttoachieve,andrelapsesarecommon.• Localizedlesionsmaybesurgicallyexcisedortreatedwithliquidnitrogen(highrelapserate),

laser therapyor radiation. Intralesional injectionwithbleomycinhas alsobeen shown tobeeffective.

• KSisusuallytreatablewithARTalone;aftersuccessfulinitiationofART,KSbecomesinactiveandslowlydisappears.

5.�. Cervical cancer• Cervical cancer is one of the most common types of cancer, causing deaths among women

worldwide.Theestimatednumberofnewcasesperyearis500000(32).• Humanpapillomavirus (HPV) infection is the leadingetiologicagent in thedevelopmentof

premalignantandmalignantlowergenitaltractdisease,includingcervicalcancer.• Therelativeriskofcervicalintraepithelialneoplasma(CIN)is5–10timeshigherforwomen

withHIV/AIDS,andabnormalpathologyisobservedin20–40%oftheirPapsmears(33, 34).

DiagnosisWhenawomanisdiagnosedwithHIV,agynaecologicevaluationwithpelvicexaminationandPapsmearshouldbeperformed.TheexaminationandPapsmearshouldberepeatedatsixmonthsandthenannually.

Forfurtherinformation,pleaserefertoProtocol9,Support for sexual and reproductive health of people living with HIV/AIDS.

5.�. Other cancersLymphomas–includingnon-Hodgkin,intracranialandBurkitttypes–andsquamouscellcarcino-maaremorecommonlyfoundinimmunosuppressedPLWHAthaninpeoplewhodonothaveHIV.Anypatientsuspectedofcancershouldbeexaminedbyanoncologistandreferredtotheoncologyclinicasneeded.

5.�.�. Non-Hodgkin lymphoma (NHL)

NHL–usuallyB-cell,veryrarelyT-cell–occurscommonlyinimmunosuppressedPLWHA,butitsappearanceisindependentofCD4cellcount.ItisthoughtthatEBVorsomeothervirusplaysaroleinthepathogenesisofthisdisease.

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• MalignantNHLcellsmaybedetectedinalllocations,mostofteninthelymphnodes,aswellasthemuscles;organssuchastheliver,spleen,lung,heart,brainandGItract;and(morerarely)thebones.

• Symptomsmayvary.• Swollenlymphnodesmaybepalpableindifferentlocations.• Fever,weightlossandfatiguearecommon,butnotinevitable.• Determiningthestageofthedisease(I–IV)requiresthoroughexamination–cerebral,cervical,

thoracicandabdominalcomputerizedaxialtomography(CAT)scans,bonemarrowandcere-brospinalfluidbiopsiesandgastroscopy.

• Diagnosisisperformedbybiopsyofasuspect(enlarged)lymphnode,followedbyhistologicalexamination.

5.�.�. Burkitt-type lymphoma in PLWHA

Burkitt-typelymphomas,actuallyasubgroupofNHLs,areassociatedwithHIVinfectionandmayoccurbeforeadvancedimmunosuppressionsetsin.ThistypeoftumourisassociatedwithEBV.

DiagnosisThediagnosisofBurkitt-typelymphomaismadeoncarefulexaminationoflymphnodeandtumourbiopsies,confirmedbyhistologicalexamination.

Treatmentofnon-Hodgkin,Burkitt-typeandCNSlymphomas• ForNHL,theCHOPregimeniseffectiveandshouldbeadministeredthroughsixcycles(the

numberusuallyneededforcompleteremission)ofthefollowing: ° prednisolone100mg/dayODforfivedays ° vincristine(Oncovin)1.4mg/m²(maximum2mg/day)inonedoseonDay1oftreatment ° cyclophosphamide750mg/m²/dayinonedoseonDay1 ° doxorubicin(hydroxydaunomycin)50mg/m²/dayinonedoseonDay1.

Beginanewcycleevery21days(Day22becomesDay1,etc.).• TheEPOCHregimen,whichincludesetoposide,prednisolone,vincristine,cyclophosphamide

anddaunorubicinordoxorubicin,hasbeenshowntobeeffectiveincombinationwithART.Itisbasedonaregimenofcontinuousinfusionfor96hours,asfollows:

° etoposide50mg/m²perday(viacentralvenousline) ° doxorubicin10mg/m²/day(viacentralvenousline) ° vincristine0.4mg/m²/day(max2mg/week)(viacentralvenousline) ° cyclophosphamide375mg/m²onDay5only,inabolus(viaIV) ° prednisolone100mg/dayonDays1–5ODPO.

Repeattheregimenevery21daysuntilsixcycleshavebeenperformed.• Burkitt-typelymphomaismanagedinthesamemannerasotherlymphomas,andrespondsto

CHOPorEPOCH.Treatingthisfast-growinglymphomawithmoreaggressivechemotherapy(suchastheB-ALLregimen)isunderdiscussionsotherearenospecificrecommendationsatthepresenttime(35, 36).

• InBurkitt-type lymphomas, chemotherapyshouldbe followedby radiationof the suspectedprimarylocation.

• ItispossibletotreatNHLindependentlyofCD4cellcount,butforprolongedsuccess,ARTshouldbestartedearly.EvenduringchemotherapywithCD4count>350,thereisahighrateofrelapsewithoutART(37).

• Forintracraniallymphoma(metastasis),cranialradiationinconjunctionwithcytotoxicchemo-therapyandsteroidsisadvised(38).

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• Forprimarycentralnervoussystem(CNS)lymphoma,radiationistheonlyeffectiveevidence-based therapy.MostpatientsshowCD4counts<50withdiagnosis. Inmultivariateanalysis,highlyactiveantiretroviraltreatment(HAART)istheonlyadditionalfactorinprolongedre-mission.TherearesomereportsoftheeffectivenessofHAARTalone,soitshouldbestartedimmediately(39, 40).

5.9. Neurological infectionsInvasionofthenervoussystembyHIVleadstoencephalopathy,myelopathyandperipheralneu-ropathy.NumerousneurologicalsyndromeshavebeenascribedtoHIV,including:• cerebralatrophyanddegeneration• AIDSdementiacomplex• cerebellaratrophy• vacuolarmyelopathy• facialnerveparalysis• Guillain-Barresyndrome• painfulsensoryandmotorperipheralneuropathy.

Anumberofopportunisticinfections,includingbacterial,viralandfungalinfections,alsoaffectthecentralnervoussystem.(Forcryptococcalmeningitis,pleaserefertosectionII.5.4above.)5.9.�. Toxoplasmosis

ToxoplasmosisisfrequentlyencounteredinPLWHAinindustrializedcountries.Itleadstothede-velopmentofmultipleinflammatorylesionsinthebrain.InPLWHA,itmainlyappearsasencepha-litisorasdisseminateddisease.

Diagnosis• Toxoplasmosismaybesuspectedthroughclinicalfindings,andpatientsmaypresentwith: ° alteredmentalstatus ° fever ° seizures ° headaches ° focalneurologicalfindings,includingmotordeficits,cranialnervepalsies,movementdisor-

ders,dysmetria,visual-fieldlossandaphasia.• Patientswhopresentwithevidenceofdiffusecorticaldysfunctiondevelopevidenceoffocal

neurologicaldiseaseastheinfectionprogresses.• CATorMRIbrainscansmayrevealmultiplering-enhancinglesions.• SerologicaltestsforToxoplasmaantibody(immunoglobulinG,orIgG)mayhelpinestablishing

thediagnosisintheabsenceofneuro-imagingtechniques.• Most patientswith cerebral toxoplasmosis have serological evidenceof prior infectionwith

Toxoplasma gondii(IgG-positive).

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° Iftoxoplasmosisissuspected,patientsshouldbegivenatrialoftreatment. ° Onlyif theydonotrespondtothistreatmentwithintwoweeksshouldabrainbiopsybe

considered. ° Thediagnosis canbe confirmedbyhistological examinationof tissueobtainedbybrain

biopsy.

Treatment

Table �5. treatment of toxoplasmosis

Drug Dose Frequency Route DurationPyrimethamine 200mg Once(loadingdose) PO Singledose

Then:pyrimethamine

+folinicacid

+sulfadiazine

25mgor50mg

TIDBID

PO 6–8weeks

15mg OD PO 6–8weeks

1g QID PO 6–8weeksSources: Katlamaetal.,1996;Dannemannetal.,1992;Chirgwinetal.,2002(41–43).

• Intheregimenabove,sulfadiazinemaybereplacedbyanyofthefollowing: ° clindamycin600mgQIDIV/POforsixweeks ° azithromycin1200mgODPOforsixweeks ° clarithromycin1gBIDPOforsixweeks ° atovaquone750mgQIDPOforsixweeks.• Somepatientsneedaverylongperiodofacutetreatment.Thereisnorulefortreatmentdura-

tion.ThedecisionhastobemadeonclinicalgroundsandCATscanifavailable.• Secondaryprophylaxisisgivenusinghalfthedosageoftheacutetreatmentfromtheeffective

regimen,untilCD4countisover200cells/mm3forthreemonths.

5.9.�. Herpes simplex virus (HSV)

• HSVinfectioniscommonlyencounteredinclinicalpractice.• Followinganinitialattack,therearefrequentrecurrences.• Inimmunosuppressedpeopletheinfectionmaybeextensiveandpersistentandpossiblydis-

seminated.• Disseminationmayleadtoinfectionofthelungs,oesophagusandbrain.• HSVmayalsocausemeningoencephalitisandmeningitis.

Diagnosis• ThediagnosisofHSVinfectionisusuallymadebasedonthetypicalclinicalpresentationof

vesiclesandpainfulsuperficialsoresaroundthemouth,nose,lipsand/orgenitals.• Itisoftendifficulttomakeadiagnosisofdisseminatedherpes.Speciallaboratorytests–such

asviralculture,radio-immunoblotassayandfluorescentandmonoclonalantibodytests–maybenecessary.

• TypicalchangesmaybeseenonCATscansof thebrain,whereherpessimplexencephalitisleadstomultiplelesions.

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Treatment

Table ��. treatment of herpes simplex virus: mild infection

Antiviral agent Dose Frequency Route DurationFirst-line treatment

Aciclovir 400mg TID PO 7–10daysor:

Famciclovir 250mg TID PO 7–10daysor:

Valaciclovir 1g BID PO 7–10daysSource: Conantetal.,2002;Ionnadisetal.,1998;Chang,Absar&Beall,1995;Safrin,1992(44–47).

Table ��. treatment of herpes simplex virus: recurrences


Aciclovir 800mg 5timesperday PO 7–10daysor:

Famciclovir 500mg TID PO 7–10daysor:


Table ��. treatment of herpes simplex virus: severe infection


Aciclovir 10mg/kg TID IV 7–10daysor:


Table �9. treatment of herpes virus: severe and visceral infection


Aciclovir 10mg/kg TID IV 14–21daysSecond-line treatmentFoscarnet(whenresistancetoaciclovirissuspected)

40–60mg/kg TID IV 14days

Source: Conantetal.,2002;Ionnadisetal.,1998;Chang,Absar&Beall,1995;Safrin,1992(44–47).

5.9.�. Herpes zoster (48)

• Varicella-zostervirus(VZV)oftencausesdisseminatedinfectionafterinitialexposure.• Inchildren,initialinfectionresultsinthedevelopmentofchickenpox,thoughmostwhobe-

comeinfecteddevelopnosymptomsorsignsofinfection.• Thevirusliesdormantintheparaspinalgangliaforyears.• Withimmunesuppression,regardlessofcause,thevirusreplicatesandproduceslesionsalong

thelengthofacutaneousnerveinadermatomaldistribution.

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• Disseminationcanalsooccuratthesametime,withinvolvementofskin,nervoussystem,lungsandmucousmembranes.

• Inimmunosuppressedpatients,zosterisoftenmultidermatomalindistribution,persistent,ex-tensiveandassociatedwithseverepainanddebility.

DiagnosisThediagnosisisusuallymadeonclinicalgrounds.

Treatment

Table �0. treatment of dermatomal zoster


Aciclovir 800mg 5timesaday PO 7–10daysoruntillesionscrust

or:Famciclovir 500mg TID PO 7–10days

Table ��. treatment of disseminated, visceral or ophthalmic zoster


Aciclovir 10mg/kg TID IV 7–10daysor:

Famciclovir 500mg TID PO 7–10daysSecond-line treatment

Foscarnet 60mg/kgor40mg/kg

BIDTID

IV 7–10days

• Post-herpeticneuralgiaisacommonandseriouslydebilitatingproblem.Itcausesseverepainindermatomaldistribution,usuallyatthesiteofthelesions.

• Paincontrolisoftennecessaryandmaybeachievedwithnon-steroidanti-inflammatorydrugs(NSAIDs).

• Ifpaincontrolisnotachieved,amitryptiline,carbamazepineorphenytoinmaybetried.

5.9.�. Cytomegalovirus (CMV) infection

CMVmayaffectmultiplesystemsandorgansinimmunosuppressedindividuals.Symptomsmayinclude:• feveranddiarrhoeafromCMVcolitis• dyspnoeafromCMVpneumonitis• blindnesscausedbyCMVretinitis• theappearanceofpainfululcersinthemouth,resultingindifficultyeating.

Diagnosis• Themostfrequentlocalizationistheretinaandisdiagnosedbyaspecializedophthalmologist.• Otherlocalizationsrequiresophisticatedequipmentandcostlytests,suchastissuebiopsiesand

deoxyribonucleicacid(DNA)hybridizationstudies.

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TreatmentTreatmentsforCMVGIdisease,neurologicaldiseaseandretinitisarefoundinTables22–24.

Table ��. first-line treatment of cmv gi disease, neurological disease and retinitis

Antiviral agent Dose Frequency Route DurationGanciclovir 5mg/kg BID IV 2–3weeks

Source: Whitleyetal.,1998;anon.,1997; Martinetal.,2002;Jacobsonetal.,1999;Martinetal.,1999(49–53).

Forsecondaryprophylaxis,long-termtreatmentwithganciclovir5mg/kggivenIVdailymaybenecessary.

Table ��. second-line treatment of cmv gi disease, neurological disease and retinitis

Antiviral agent Dose Frequency Route DurationFoscarnet 90mg/kg BID IV 3weeks


Forsecondaryprophylaxis, long-termtreatmentwithfoscarnet90mg/kggivenIVdailymaybenecessary.

Table ��. secondary prophylaxis of cmv retinitis

Antiviral agent Dose Frequency Route DurationGanciclovireyeimplant

+Valganciclovir

(topreventinfectionintheothereye)

900mg OD PO

UntilCD4countisover100-150cells/mm3forminimum3

months


Secondaryprophylaxiscanbestoppedaftersixmonthsandimmunereconstitutionto100–150CD4cells/mm3.

5.9.5. Epstein-Barr virus-related conditions

• InfectionwithEBV,aherpesvirus,iscommoninPLWHAandothers.• PLWHAhave increasedamountsofEBVin theiroropharyngeal secretionsandhigherEBV

antibodytitresthanHIV-negativepeople.• EBVisthoughttocauseanumberofconditionsincluding: ° oralhairyleukoplakia ° lymphocyticinterstitialpneumonitis(LIP) ° non-Hodgkinlymphoma(seesectionII.5.8.1above) ° Burkitt-typelymphoma(seesectionII.5.8.2above) ° nasopharyngealcarcinoma.

5.9.5.�. Oral hairy leukoplakia

• OralhairyleukoplakiaoccursinPLWHAaswellassomeimmunosuppressedtransplantrecipi-ents.

• Itisanon-malignantlesionofepithelialcells,presentingasraised,white,corrugatedlesionsoftheoralmucosa,especiallyonthelateralaspectofthetongue.

• Itiscommonlymistakenfororalcandidiasis,astheyarefrequentlyfoundtogether.• Nospecifictreatmentisavailableforthecondition.Patientsaregenerallyadvisedongoodoral

hygiene.

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5.9.5.� Lymphocytic interstitial pneumonitis (LIP)

• LIPoccursprimarilyinchildren,butitalsooccursinadultPLWHA.• ItischaracterizedbydiffusedinterstitialpulmonaryinfiltratesthatmaybeconfusedwithTBor

PCP.However,patientswithLIPoftendonothavesignsofsevererespiratoryillness.• NospecifictreatmentisavailableforLIP.

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III. General symptoms

�. Persistent generalized lymphadenopathy (PGL) in adults• ThemostcommonclinicalmanifestationofHIVinfectionissymmetricgeneralizedlymphnode

enlargement.• Enlargedlymphnodesaregenerallypainless,firm,mobileandrubberyandaremosteasilypal-

patedintheneck,submentalarea,axillaeandthegroin.• ThepatientmayormaynothaveotherassociatedsymptomsofHIVinfection.• PGLisdefinedasthepresenceformorethanonemonthoflymphnodesmeasuringmorethan

1cmindiameterinmorethanoneareaofthebodyotherthanthegroin.• PGLisaverycommonfeatureofHIVinfection.Inmostcasesalymphnodehistologyonly

reveals“reactivehyperplasia”or“follicularhyperplasia”.Alymphnodebiopsyisnecessarytoestablishacause.

DiagnosisItisimportanttopalpatelymphnodesspecificallyinthefollowingareas:• anteriorandposteriortrianglesoftheneck• submentalarea• suboccipitalarea• anteriorandposteriorauricularareas• bothaxillae• epitrochlearareas• bothinguinalregions.

PatientswithPGLcausedbyHIVinfectionmayhaveotherfeaturesofHIVinfection,including:• oralthrush• oralhairyleukoplakia• pruriticskinrash• hyperpigmentednails• oralorgenitalherpes• involuntaryweightloss• unexplainedfever.

PGLmaybecausedbyanumberofconditionsotherthanHIVinfection,includingTB,leukaemia,lymphoma,KS,syphilis,Chlamydia trachomatis (lymphogranulomavenereum),CMV,toxoplas-mosis,EBV,cryptococcosis,histoplasmosisandsepticskinconditions,bubonicplagueandhepa-titisB.

CriteriaforperformingalymphnodebiopsyApatientwithPGLshouldbereferredforalymphnodebiopsyifpresentingwithanyofthefol-lowing:• asymmetricallymphnodeenlargement• massivelymphnodeenlargement(atleastonelymphnode>3cmindiameter)• lymphnodeenlargementoveraperiodofobservation• evidenceofTBonachestX-ray• evidenceofhilarlymphnodeenlargementonachestX-ray• evidenceofKSelsewhere• fever,nightsweatsandweightlossformorethanoneweek.

AdiagnosisofHIV-relatedlymphadenopathydoesnotruleoutotherseriousdiseaseslikelympho-mainunbiopsiedlymphnodes.Therefore,withanychangeincondition,persistentfeverorothersuspiciouscircumstance,abiopsyorlymphadenectomyshouldberepeated.

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�. Fever• Fevercanoccurasaresultofinfection,inflammationormalignancy.Persistentfeverinadults

isdefinedasabodytemperatureofmorethan38°Clastingformorethantwoweeks.• InPLWHA,theonlyclinicalpresentationofHIVinfectionmaybefever.Thus,itisimportantto

keepinmindapossiblediagnosisofHIVinfectionwhenmanagingapatientwhopresentswithapersistentfeverandnoobviouscause.

• InPLWHA,persistentfevermaybeaccompaniedbyfeaturesofthepossibleunderlyingcause,forexamplepneumonia,TB,gastrointestinalinfectionorlymphoma.Inadultswithpersistentfever,thefollowingfactorsmaysuggestthepresenceofHIVinfection:

° ahistoryofunsafesexualbehaviour ° apartnerorchildknowntobeHIV-infected ° otherfeaturessuggestiveofHIVinfection,suchas: - PGL - oralorgenitalthrush - oralhairyleukoplakia - pruriticskinrash - oralorgenitalherpes - involuntaryweightloss - darkeningofthenails(melanonychia) - hypopigmentationofthelips - thinningandstraighteningofthehair.

�. Weight loss in adults• HIVinfectionisacommoncauseofweightloss.• Severeweightlossisdefinedasinvoluntarylossofmorethan10%ofone’sbodyweight.• SevereinvoluntaryweightlossinPLWHAisknownasHIV-associatedwastingsyndromeor

“slimdisease”.• Thecauseofsuchwastingisnotfullyunderstood.Possibleunsubstantiatedcausesinclude: ° chronicandrecurrentinfections ° chronicdiarrhoea ° malabsorption ° HIV-inducedmyopathy ° HIV-inducedpoorappetite.

Clinicalfeatures• Thepatientmaycomplainofinvoluntaryweightlossorlossofappetite,withorwithoutfever

anddiarrhoea.• PatientswithHIV-associatedwastingdiseaseare illandemaciatedandmaybefeverishand

dehydrated.• Oralcandidiasisiscommonlyfoundinsuchpatients.• ThepatientmayhaveotherfeaturesofAIDS,includingfeaturesofneurologicalinvolvement

suchasencephalopathyandAIDSdementiacomplex.

�. Chronic diarrhoea in adults• Adultswithchronicdiarrhoeacomplainoffrequentlypassingthreeormoreconsecutiveloose

stoolsover28days.Duringthecourseoftheillnessthepatientmayalsohaveepisodesofacutediarrhoea.

• Thestooldoesnotusuallycontainblood,exceptifthereisconcomitantdysentery.• Thepatientusuallyalsohasapoorappetiteandweightloss.• Thepatientmayalsobedehydrated,anaemicandwasted.

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• Adultswithchronicdiarrhoeaoftenhave: ° skinandhairchangestypicallyassociatedwithmalnutrition ° hypopigmentationofthelips ° darklypigmentednails ° oralthrush,hairyleukoplakiaorlymphnodeenlargement.

Detailsonthemanagementofchronicdiarrhoeaandassessmentofdehydrationinadultsarepro-videdinProtocol3,Palliative care for people living with HIV/AIDS.

5. Oral lesionsBesidescandidiadis(seesectionII.5.3above),alargenumberofotherorallesionsmaybefoundinpatientswithHIVinfection.SomeofthesearedescribedinTable25.

Table �5. description and treatment of oral lesions common in plWha

Condition Description TreatmentGingivitis Swollenandredgumsthattendtobleedeasily Metronidazole400mgPOBIDfor7days

orerythromycin500mgPOQIDfor7days

Pyorrhoea Anaccumulationofpusinthegingivalmarginaroundtheteeth

GarglingwithwarmsaltywateraftereverymealandbrushingtheteethBID

Periodontitis Apainfulconditionwithrapidlossoftheboneandsofttissuesupportingtheteeth,bleedingofthegums,toothlossandpossibleulceration

Localdebridement,chlorhexidinemouthwashesAmoxycillin500mgPOTIDormetronidazole200mgPOTIDfor5days

Aphthous ulcers

Painfulpunched-outulcersonthemucosalsur-face,usuallycoveredinapurulentexudateandtendingtobleedwhentouched

Oralhygieneandtreatmentwithtopicalsteroids

Stomatitis Inflammation of the mucosa in the oral cavity, oftenassociatedwithpoororalhygieneandinvasionofanaerobicbacteria

GarglingwithwarmsaltywateraftereverymealandbrushingtheteethBID

Cheilitis Inflammation, redness and eventual pallor of thelips,commoninpatientswithadvancedim-munosuppression

No specific treatment available; vitamins A, B andCandadviceonoralhygiene

Secondary syphilis

Lesionsonthebuccalmucosa,includingmoistpapules,“snailtrack”ulcersandcondylomatalataattheanglesofthemouthandaroundthenostrils.(Insecondarysyphilis,allserologicaltestsforsyphilisarepositive.)

Primary syphilis:Benzathinepenicillin2.4milliunitsintramuscu-larly(IM)once

Secondary syphilis:Benzathinepenicillin2.4milliunitsIMQWforthreeweeksordoxycycline100mgPOBIDfor28daysorerythromycin500mgPOQIDfor28days

�. Skin and nail conditions

�.�. Dermatomycosis• Fungalskinrashes(dermatomycoses)occurcommonlyinPLWHAandothers.• Rashesareusuallyitchyanddry,withvisiblescalesofdeadskin.• Thelesionsmaybefoundanywhereonthebody.

DiagnosisFungalelementsmaybefoundonmicroscopicexaminationofskinscrapes.

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TreatmentTopicalapplicationsofantifungalointmentsandcreamswillusuallyclearthelesions.Thefollow-ingmaybeusedfortreatingdermatomycoses.

Table ��. treatment of dermatomycosis

Antifungal preparation Dose Frequency Route DurationFirst-line treatment

Topicalmiconazole TID Topical 21daysor:

Topicalclotrimazole TID Topical 21daysSecond-line treatment

Ketoconazole 200mg OD PO 1–3monthsor:

Itraconazole 100mg OD PO 1–3months

�.�. OnychomycosisNailsmayalsobecomeinfectedwithfungi(onychomycosis).Theinfectioncanresultindiscolora-tion,distortionordestructionofthenails.

Diagnosis• Diagnosisisusuallymadeonclinicalfindings.• Microscopicexaminationofpotassiumhydroxide(KOH)preparationsofsubungualmaterial

mayrevealfungalelements.

Treatment

Table ��. treatment of onychomycosis

Antifungal preparation Dose Frequency Route DurationFirst-line treatment

Terbinafine 250mg OD PO 6 weeks for fingers12weeksfortoes

or:

Itraconazole 200mg BID PO For fingers, 1 week each monthfor2months

Fortoes,1weekeachmonthfor3–4months

�.�. Seborrhoeic dermatitis• SeborrhoeicdermatitisisacommonpresentingfeatureinPLWHA.Itisprobablycausedbya

fungusknownasPityrosporum ovale(alsoknownasMalasezia furfur).• Therashiserythematousandscaly.InpersonswithHIVinfectionitmaybeextensive,persis-

tentandrecurrent.

Diagnosis• Diagnosisismadeonclinicalgrounds.Therashappearscommonlyonthe: ° face ° areaaroundnostrils ° nasolabialfolds

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° eyebrows ° scalp ° chest ° axillae ° uppertrunk ° genitalarea

Diagnosis can be confirmed by finding fungal elements on microscopic examination of skinscrapes.

Treatment• Frequentskinwashingtoremovescalesisadvised.• Shampooingwithseleniumsulfideshampooiseffective.• Topicalapplicationsof1%hydrocortisoneareprobablythemosteffective.Ketoconazole2%

creamhasalsobeenshowntobeeffective.

�.�. ScabiesScabiesiscausedbythemiteSarcoptes scabei.Thefemalemiteburrowsintotheskin,andthebur-rowsappearasraisedlinesuptoseveralcentimetreslong.• Whenapersonisinfestedwithscabiesmitesforthefirsttime,thereisusuallylittleevidenceof

infestationforthefirst2–6weeks.• Insubsequentinfestations,peopleusuallyhavebecomesensitizedtothemites,andthesymp-

tomsgenerallyoccurwithin1–4days.• Theburrowingofthemitesundertheskincausesarash,mostfrequentlyfoundonthe: ° hands(particularlythewebspacesbetweenthefingers) ° foldsofthewrist,elboworknee ° ulnarmarginsoftheforearms ° penis ° breast ° shoulderblades• Burrowsandmitesmaybefewinnumberanddifficulttofindinsomecases.• Severeitchingiscommon,especiallyatnightandfrequentlyovermuchofthebody,including

areaswherenomitesareliving.• Norwegianscabies,amoresevereformmorecommonamongimmunocompromisedpatients,

ischaracterizedbyvesiclesandtheformationofthickcrustsontheskin,accompaniedbyabun-dantmitesbutonlyslightitching.

• Complications due to infestation are usually caused by secondary bacterial infections fromscratching.

Diagnosis• Thediagnosisisusuallymadeonfindingtherashandburrows.• Skinscrapesmayrevealmitesormiteovaonmicroscopicexamination.

Treatment• Thetreatmentofchoiceisthetopicaluseofgammabenzenehexachloride1%,appliedtothe

wholebodyfromtheneckdownandwashedoffafter24hoursinadultsand8hoursinchildren.Asingleapplicationissufficient.

• Permethrin1%orlindane1%applicationsarealsouseful.Bothareappliedtoaffectedareasandwashedoffafter8hours.Theseagentsshouldnotbeusedduringpregnancyorlactationoronchildren.

• Ivermectininasingleoraldoseof200µg/kgisanalternativethatiseffectiveforcrustedscabiesinimmunocompromisedpeople.

• Allmembersofthehouseholdandsexualpartnersshouldalsobetreated.• Allclothes,beddingandtowelsshouldbewashedinhotwater,driedandironed.

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�.5. Staphylococcal folliculitis• Folliculitisisaskininfectionthatislocalizedinthehairfollicles.• ApustularperifolliculitisoccurscommonlyinPLWHA.• UsuallytheconditioniscausedbyStaphylococcus aureus,thoughotherorganismsmayalsobe

responsible.

Diagnosis• Diagnosisismadeonclinicalfindings.• Lesionsaresmall(lessthan5mmindiameter),andfoundinmultipleerythematousfollicles

thatmayhaveapurulentcentre.• Lesionsareitchyandoftenfoundinclusters.

TreatmentTreatmentiswithantibiotics,suchascephalexinorcloxacillin500mgPOQIDfor7–21days.

�.�. Molluscum contagiosum• Molluscumcontagiosumisasuperficialskininfectioncausedbythemolluscumcontagiosum

virus.• The infection isspread throughclosebodycontactandmayoccur throughsharingclothing,

beddingortowelsorthroughsexualtransmission.• Theincubationperiodvariesfromseveralweekstoseveralmonths.• Shavingorscratchingmaycausetheinfectiontospread.• TheinfectionoccursmorecommonlyinimmunosuppressedPLWHA.• IncomparisontothelesionsfoundonHIV-negativepeople,thosefoundonPLWHAare: ° morewidespread ° morepersistent ° muchlarger ° moredifficulttotreat.

Diagnosis• Thediagnosisisbasedonthecharacteristicappearanceofthebumps.• Thevirusinvadestheskin,causingtheappearanceoffirm,flesh-colouredpapules2–5mmin

diameter.Thelesionscontainawhitesebaceousmaterial.• Thepapulescanoccuranywhereonthebodyandoftenremainunchangedformanymonths,

afterwhichtheydisappearandmayormaynotreappear.• Nodiagnostictestforthisvirusisavailable.

TreatmentThegoaloftreatmentistoremovethesoftcentre,afterwhichthepapuleresolves.Assuch,eachlesionneedstobetreatedindividually.Variousmethodsareavailableforthedestructionofthele-sion,including:• curettage• chemicaldestructionwithconcentratedphenol• cryotherapy• electrocautery.

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