.BOBHFNFOU PG 0QQPSUVOJTUJD *OGFDUJPOT BOE (FOFSBM … · 2013-10-10 · 53 management of...

Contents

I. Principles ................................................................................................................................... 53

II. Management of opportunistic infections .............................................................................. 54 1.Generalinformation.............................................................................................................. 54 2.Initialevaluation................................................................................................................... 54 3.CounsellingpatientsonOIsandotherconditions................................................................ 55 4.OIprophylaxisinHIV-infectedpatients............................................................................... 56 5.DiagnosisandtreatmentofOIs............................................................................................ 56 5.1.Respiratoryinfections.................................................................................................... 56 5.1.1.Bacterialrespiratoryinfections............................................................................ 57 5.1.2.Atypicalmycobacteriosis..................................................................................... 59 5.1.3.Pneumocystispneumonia.................................................................................... 61 5.1.4.Othercausesofpneumoniainimmunosuppressedpeople.................................. 61 5.2.Gastrointestinalinfections............................................................................................ 62 5.3.Candidiasis.................................................................................................................... 62 5.4.Cryptococcalmeningitis................................................................................................ 65 5.5.Histoplasmosis............................................................................................................... 66 5.6.Kaposisarcoma............................................................................................................. 67 5.7.Cervicalcancer.............................................................................................................. 68 5.8.Othercancers................................................................................................................. 68 5.8.1.Non-Hodgkinlymphoma..................................................................................... 68 5.8.2.Burkitt-typelymphoma........................................................................................ 69 5.9.Neurologicalinfections................................................................................................. 70 5.9.1.Toxoplasmosis..................................................................................................... 70 5.9.2.Herpessimplexvirus........................................................................................... 71 5.9.3.Herpeszoster....................................................................................................... 72 5.9.4.Cytomegalovirusinfection.................................................................................. 73 5.9.5.Epstein-Barrvirus-relatedconditions.................................................................. 75

III. General symptoms ................................................................................................................. 76 1.Persistentgeneralizedlymphadenopathyinadults............................................................. 76 2.Fever................................................................................................................................... 77 3.Weightlossinadults........................................................................................................... 77 4.Chronicdiarrhoeainadults................................................................................................. 77 5.Orallesions......................................................................................................................... 78 6.Skinandnailconditions...................................................................................................... 78 6.1.Dermatomycosis.......................................................................................................... 78 6.2.Onychomycosis............................................................................................................ 79 6.3.Seborrhoeicdermatitis................................................................................................. 79 6.4.Scabies......................................................................................................................... 80 6.5.Staphylococcalfolliculitis............................................................................................ 81 6.6.Molluscumcontagiosum.............................................................................................. 81

References ..................................................................................................................................... 82

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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.

• All patients with OIs – irrespective of gender or social class and including injecting drugusers(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

1. General informationHIV-relatedinfectionsandillnessesincludethefollowing(Table1).

Table 1. 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.

2. 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).

3. 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(as

observedbyfriendsandfamilymembers):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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4. OI prophylaxis in HIV-infected patients• CertainOIsthatmaydevelopinpeoplelivingwithHIV(PLHIV)canbeprevented.• ProphylaxisofOIsinPLHIVshouldbeanintegralpartofOImanagement.• 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

5.1. Respiratory infections• Lower respiratory tract infections are the most common recurrent infections in PLHIV.

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

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• Patientsmaypresentearly in thecourseofHIV infectionwithbacterialpneumonias,whichrespondreadilytoantibiotics(12).

• PatientswithHIVinfectionappeartobeparticularlypronetoinfectionswithencapsulatedor-ganismssuchasStreptococcus pneumoniaeandHaemophilus influenzae (13).

• Later,andwiththeonsetofimmunesuppression,patientsmaydevelopopportunisticpulmo-naryinfections,themostimportantofwhichispulmonaryTB.

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

Table 3. respiratory illness in plhiv

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.

5.1.1. Bacterial respiratory infections

• Bacteriallowerrespiratorytractinfectionsarecommoninthegeneralpopulation,buttheyaremorefrequentandmoresevereinimmunosuppressedpersonswithHIVinfection.

• S. pneumoniae isthemostcommonlowerrespiratorytractpathogen.• Patientswithbacterialpneumoniapresentwithcoughandfeverandoftenhavechestpain,dif-

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

infiltrates.

5.1.1.1 Diagnosis

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

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5.1.1.2. Treatment

• IfthepatientisnotseverelyillandnoPCPissuspected,treatmentmaybeprovidedathomeaccordingtoTables4and5below.

Table 4. 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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5.1.2. Atypical mycobacteriosis

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

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

5.1.2.1. Diagnosis

• BloodculturesonspecialmediaarethecornerstoneofMACdiagnosis.• Inmostsymptomaticpatients,theintensityofmycobacteraemiaissuchthatmostorallblood

culturesarepositive.• BecausetheliverandbonemarrowareofteninvolvedindisseminatedMACinfection,thebac-

teriamaybevisibleinacid-fast-stainedbiopsysamplesfromthesesites.• Presumptivediagnosisbyexaminationofabiopsiedliverspecimensavestime.

5.1.2.2. Treatment

Table 6. 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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• Thereisthepossibilityofimmunereconstitutioninflammatorysyndrome(IRIS)afterstartingART(seeProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents,sectionsClinicalfailureandImmunereconstitutioninflammatorysyndrome).

5.1.3. Pneumocystis pneumonia

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

• Patientsusuallypresentwithcough,shortnessofbreathandfever.• OccasionallypatientswithPCPhavenochestsigns.• PatientswithPCPoftenhavefeaturesofrespiratoryfailuresuchasshortnessofbreathandcya-

nosis.• Symptomsmaybeverysevere;anattackofPCPmayleadtodeathifnottreatedearlyandef-

fectively.

5.1.3.1. Diagnosis

• DiagnosisisoftenmadeonclinicalgroundswhenafebrilePLHIVpresentswithrespiratorydistress,withorwithoutcyanosis.

• Thepatientmayhaveanon-productivecough,butthemainfeatureoftheconditionisshortnessofbreath,withminimalorabsentchestsignsonphysicalexamination.

• ChestX-rays: ° Thereisnotalwaysaground-glassopacificationinthelowerzonesofbothlungfields. ° Theremaybeevidenceofpatchyinfiltratesinbothlungfieldsthatmimicsbacterialpneu-

moniaorTB. ° AconsiderableproportionofpatientswithconfirmedPCPshownochangesatallontheX-

ray.• Bronchiallavageisthegoldstandardofdiagnosis(14).Diagnosisisconfirmeduponfinding

cystsofPneumocystisinforcedsputumorinbronchiallavageaspirate.• Ifdiagnosiscannotbeestablishedduetothelackofabronchoscope,deterioratingpulmonary

functiontestsorbloodgasanalysiscanbeusedasindicators.• Treatmentshouldbestartedimmediatelyupondiagnosis.

5.1.3.2. Treatment

Patientsshouldbeadmittedtohospitalformanagement.Supportivetherapyincludingoxygenmaybenecessary.DetailsoftreatmentaregiveninTables7and8below.

Table 7. pcp first-line treatment

Antimicrobial agent Dose Frequency Route DurationTMP-SMZ 240/1200mg<60kg

320/1600 mg ≥60 kg

QID PO/IV 21days

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Table 8. 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-SMZandpentamidine.Thistreatmenthasincurredahighriskoftoxicityaccordingtocasereportsonly.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.

5.1.4. Other causes of pneumonia in immunosuppressed people

• Othercausesofpneumoniaincludefungalandviralinfections.Theyaredifficulttodiagnosewithoutsophisticatedlaboratoryfacilitiesandaredifficulttotreat.

• Viralpneumoniamaybecausedbyherpessimplexvirus, varicella-zostervirusor cytomegalo-virus.

• InadditiontoPCP,otherfungalcausesofpneumoniaincludeHistoplasma capsulatum,Crypto-coccus neoformansandAspergillus.

5.1.4.1. Diagnosis

• Whenpneumoniafailstorespondtostandardtreatment,TBorpneumoniacausedbyviruses,fungiorprotozoashouldbesuspected.

• Making a specific diagnosis of fungal or other infections requires sophisticated laboratorytests:

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

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

5.1.4.2. Treatment

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

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5.2. Gastrointestinal infections (GIIs)• GIIsinPLHIVmaybetheresultofanyofthefollowinginfections: ° HIV(directinfectionoftheGItract) ° bacterial ° fungal ° viral ° protozoal ° parasitic.• Someoftheproblemsmayarisefromatrophyoftheintestinalvilli,whichcommonlyleadsto

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

orchronic.• DiarrhoeaispersistentorchronicinpeoplewithAIDS,andanimportantcauseofdeathamong

them.• Acutediarrhoealeadstodehydrationunlessproperlytreated.• Thepassingofbloodyorblood-stainedstoolsoccurs inpersonswithshigellosisoramoebic

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

Table9summarizes theclinicalfeatures,diagnosisandtreatmentofsomeof themorecommongastrointestinalinfectionsseeninimmunosuppressedPLHIV.

Table 9. gastrointestinal infections commonly encountered in plhiv

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:Paromomycinalonefor8weeks(20, 21).Treatmentoftenfails(22).

Microsporidiosis Waterydiarrhoea,lossofappetite;afebrileDiagnosisuponstoolmicroscopy

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

5.3. Candidiasis• Candida albicanscolonizesprimarilytheGItractsofbothmenandwomen.Uptoonethirdof

allnormalwomenalsocarryC. albicansinthevagina.• Womenwithvaginalcandidiasismaydevelopavaginaldischargeandvulvovaginalpruritus.

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• Menwithgenitalcandidiasiswilldevelopbalanitisorbalanoposthitisandwillcomplainofasubpreputialdischargeanditchinessofthepenisandforeskin.

• Oralcandidiasis(thrush)leadstoinflammationofthemucosalsurfacetogetherwiththeappear-anceofadherentwhiteplaques.

• C. albicanscaninfecttheskinandcausepruriticdermatitis.• Dependingonthelevelofimmunesuppression,oralinfectionmayextendtoinvolvetheoe-

sophagus.• Bronchialanddisseminatedinfectionsarerare.

5.3.1. Symptoms

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

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

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

5.3.2. Diagnosis

• Thediagnosisoforopharyngealcandidiasisismadeonclinicalgrounds,basedondirectobser-vationandmicroscopicexaminationofmaterialobtainedfromlesions.

• Examinationof theoralcavitymayrevealrednessandinflammationof themucosa,withorwithoutpatchesofwhiteplaques.

• Inflammationmaybeseenonthepalate,throat,gums,tongueand/ortheinsideofthecheeks.Whenthetongueisaffected,itmaybesmoothandred,andthepapillaenormallyfoundonthetonguemaybeabsent.

• DiagnosishastobeconfirmedbyhistologicalexaminationoftissuebiopsiesonlyincasesofsuspectedCandidaoesophagitisoraspergillosisofthelungs.

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

nesswhenitaffectstheeyes).

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5.3.3. Treatment

• Localizedcandidiasisistreatedfirstwithrelativelyinexpensivetopicaldrugssuchasnystatin,miconazoleorclotrimazole.

• 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 10. 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 11. 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 10days

Third-line treatmentKetoconazole 200mg OD PO Dependsonresponse,

usually7–10daysItraconazole 100mg OD PO Dependsonresponse,

usually7–10days

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Table 12. 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).

5.4. Cryptococcal meningitis• Cryptococcosismostoftenappearsasmeningitis,andoccasionallyaspulmonaryordissemi-

nateddisease.• CryptococcalmeningitisisacommonsystemicfungalinfectioninPLHIV.• Without treatment, the life expectancy of patients with cryptococcal meningitis is prob-

ably less than a month.

5.4.1. Diagnosis

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

formedonserumorcerebrospinalfluid.

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5.4.2. Treatment

Table 13. 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

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

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

5.4.3. Secondary chemoprophylaxis or maintenance therapy

• Lifelongsecondarychemoprophylaxisisnecessary;itmaybeachievedwithfluconazole200mgorallyoncedailyforlife.

• Alternatelong-termsecondaryprophylaxismaybeachievedwithitraconazole200mgorallyoncedailyforlife.

• Theneedformaintenancetherapywithpatientswhohaveanimprovedimmunesystem(CD4count>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 ° oralandskinlesions ° chestsymptoms ° liver,spleenandlymphnodeenlargement.

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• Orallesionsmayappearasprotruding,necroticulcers.Theremayalsobeperforationofthepal-ateandextensivesofttissuedestruction.

5.5.1. Diagnosis

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

widelyavailable.

5.5.2. Treatment

Innormalimmunesystems,acutehistoplasmosisisself-limitinganddoesnotrequiretreatment.InimmunosuppressedpatientsitmaybetreatedasshowninTable14.

Table 14. treatment of histoplasmosis

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

Source: Johnsonetal.(28).

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

Analternativeisitraconazole200mgTIDPOx3days,then200mgPOBIDx12weeks(takenwithamealandanacidicdrink).

5.6. Kaposi sarcoma (KS)• KSiscausedbythehumanherpesvirustype8(HHV8),alsoknownastheKaposisarcoma

herpesvirus(KSHV).• AnypatientsuspectedofKSshouldbeexaminedbyanoncologistandreferredtoanoncology

clinicasneeded.• InHIV-associatedimmunosuppression,KSismoreaggressive,disseminatedandrapidlypro-

gressivethantheendemicdiseasefoundinpeoplewithoutHIVinfection.

5.6.1. Diagnosis

ThediagnosisofKSismadeonclinicalsuspicionandconfirmedbyhistologicalexaminationofbiopsiedtissue.

Clinicalsignsincludethefollowing.• Lesionsmaybefoundanywhereonskinandonanymucosalsurface.Skinlesionsarehyperpig-

mented,blueorpurplishpapulesornodulesandcanbeassociatedwithlymphoedema.Systemiclesionsarecommonlyfoundonthepalate,gastrointestinaltract,lungsorlymphnodes.

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

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• Pulmonarylesionsareinfiltrativewithpleuraleffusionandoftenleadtorespiratoryfailure.Theconditionmaybeconfusedwithbacillaryangiomatosis(bartonellosis),aninfectiveconditionseeninPLHIV.

5.6.2. 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.

5.7. Cervical cancer• Cervical cancer is one of themost common types of cancer, causing deaths amongwomen

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

premalignantandmalignantlowergenitaltractdisease,includingcervicalcancer.• Therelativeriskofcervicalintraepithelialneoplasia(CIN)is5–10timeshigherforwomenwith

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

5.7.1. Diagnosis

WhenawomanisdiagnosedwithHIV,agynaecologicevaluationwithpelvicexaminationandPapsmearshouldbeperformed.TheexaminationandPapsmearshouldberepeatedatsixmonthsandthenannually.

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

5.8. Other cancersLymphomas–includingnon-Hodgkin,intracranialandBurkitttypes–andsquamouscellcarcino-maaremorecommonlyfoundinimmunosuppressedPLHIVthaninpeoplewhodonothaveHIV.Anypatientsuspectedofcancershouldbeexaminedbyanoncologistandreferredtotheoncologyclinicasneeded.

5.8.1. Non-Hodgkin lymphoma (NHL)

NHL–usuallyB-cell,veryrarelyT-cell–occurscommonlyinimmunosuppressedPLHIV,butitsappearanceisindependentofCD4cellcount.ItisthoughtthatEBVorsomeothervirusplaysaroleinthepathogenesisofthisdisease.• MalignantNHLcellsmaybedetectedinalllocations,mostofteninthelymphnodes,aswellas

themuscles;organssuchastheliver,spleen,lung,heart,brainandGItract;and(morerarely)thebones.

• Symptomsmayvary.• Swollenlymphnodesmaybepalpableindifferentlocations.

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

thoracicandabdominalcomputerizedaxialtomography(CAT)scans,bonemarrowandcere-brospinalfluidbiopsiesandgastroscopy.

• Diagnosisisperformedbybiopsyofasuspect(enlarged)lymphnode,followedbyhistologicalexamination.

5.8.2. Burkitt-type lymphoma in PLHIV

Burkitt-typelymphomas,actuallyasubgroupofNHLs,areassociatedwithHIVinfectionandmayoccurbeforeadvancedimmunosuppressionsetsin.ThistypeoftumourisassociatedwithEBV.

5.8.2.1. Diagnosis

ThediagnosisofBurkitt-typelymphomaismadeoncarefulexaminationoflymphnodeandtumourbiopsies,confirmedbyhistologicalexamination.

5.8.2.2. Treatment of non-Hodgkin, Burkitt-type and CNS lymphomas

• ForNHL,theCHOPregimeniseffectiveandshouldbeadministeredthroughsixcycles(thenumberusuallyneededforcompleteremission)ofthefollowing:

° prednisolone100mg/dayODforfivedays ° vincristine(Oncovin)1.4mg/m²/day(maximum2mg/day)inonedoseonDay1oftreat-

ment ° 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).

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

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

Anumberofopportunisticinfections,includingbacterial,viralandfungalinfections,alsoaffectthecentralnervoussystem.(Forcryptococcalmeningitis,pleaserefertosectionII.5.4above.)5.9.1. Toxoplasmosis

ToxoplasmosisisfrequentlyencounteredinPLHIVinindustrializedcountries.Itleadstothedevel-opmentofmultipleinflammatorylesionsinthebrain.InPLHIV,itmainlyappearsasencephalitisorasdisseminateddisease.

5.9.1.1. 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).• Iftoxoplasmosisissuspected,patientsshouldbegivenatrialoftreatment.• Onlyiftheydonotrespondtothistreatmentwithintwoweeksshouldabrainbiopsybeconsid-

ered.• Thediagnosis canbe confirmedbyhistological examinationof tissueobtainedbybrainbi-

opsy.

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5.9.1.2. Treatment

Table 15. 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.,Dannemannetal.Chirgwinetal.(41–43).

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

tion.ThedecisionhastobemadeonclinicalgroundsandCATscanifavailable.• Secondaryprophylaxisisgivenusinghalfthedosageoftheacutetreatmentfromtheeffective

regimen,untilCD4countisover200cells/mm3forthreemonths.

5.9.2. Herpes simplex virus (HSV)

• HSVinfectioniscommonlyencounteredinclinicalpractice.• Followinganinitialattack,therearefrequentrecurrences.• Inimmunosuppressedpeopletheinfectionmaybeextensiveandpersistentandpossiblydis-

seminated.• Disseminationmayleadtoinfectionofthelungs,oesophagusandbrain.• HSVmayalsocausemeningoencephalitisandmeningitis.

5.9.2.1. Diagnosis

• ThediagnosisofHSVinfectionisusuallymadebasedonthetypicalclinicalpresentationofvesiclesandpainfulsuperficialsoresaroundthemouth,nose,lipsand/orgenitals.

• Itisoftendifficulttomakeadiagnosisofdisseminatedherpes.Speciallaboratorytests–suchasviralculture,radio-immunoblotassayandfluorescentandmonoclonalantibodytests–maybenecessary.

• TypicalchangesmaybeseenonCATscansof thebrain,whereherpessimplexencephalitisleadstomultiplelesions.

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5.9.2.2. Treatment

Table 16. 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: Conant et al., Ionnadis et al., Chang, Absar & Beall, Safrin (44–47).

Table 17. treatment of herpes simplex virus: recurrences


Aciclovir 800mg 5timesperday PO 7–10daysor:

Famciclovir 500mg TID PO 7–10daysor:


Table 18. treatment of herpes simplex virus: severe infection


Aciclovir 10mg/kg TID IV 7–10daysor:


Table 19. 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: Conant et al., Ionnadis et al., Chang, Absar & Beall, Safrin (44–47).

5.9.3. 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.

5.9.3.1. Diagnosis

Thediagnosisisusuallymadeonclinicalgrounds.

5.9.3.2. Treatment

Table 20. treatment of dermatomal zoster


Aciclovir 800mg 5timesaday PO 7–10daysoruntillesionscrust

or:Famciclovir 500mg TID PO 7–10days

Table 21. 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-steroidalanti-inflammatorydrugs(NSAIDs).

• Ifpaincontrolisnotachieved,amitryptiline,carbamazepineorphenytoinmaybetried.

5.9.4. Cytomegalovirus (CMV) infection

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

5.9.4.1. Diagnosis

• Themostfrequentlocalizationistheretinaandisdiagnosedbyaspecializedophthalmologist.• Otherlocalizationsrequiresophisticatedequipmentandcostlytests,suchastissuebiopsiesand

deoxyribonucleicacid(DNA)hybridizationstudies.

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5.9.4.2. Treatment

TreatmentsforCMVGIdisease,neurologicaldiseaseandretinitisarefoundinTables22–24.

Table 22. first-line treatment of cmv gi disease, neurological disease and retinitis

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

Source: Whitley et al., AIDS Research Group, Martin et al., Jacobson et al., Martin et al. (49–53).

Forsecondaryprophylaxis,long-termtreatmentwithganciclovir5mg/kggivenIVdailymaybenecessary.

Table 23. 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 24. 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,iscommoninPLHIVandothers.• PLHIVhaveincreasedamountsofEBVintheiroropharyngealsecretionsandhigherEBVanti-

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

5.9.5.1. Oral hairy leukoplakia

• OralhairyleukoplakiaoccursinPLHIVaswellassomeimmunosuppressedtransplantrecipi-ents.

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

• Itiscommonlymistakenfororalcandidiasis,astheyarefrequentlyfoundtogether.• Nospecifictreatmentisavailableforthecondition.Patientsaregenerallyadvisedongoodoral

hygiene.

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5.9.5.2. Lymphocytic interstitial pneumonitis (LIP)

• LIPoccursprimarilyinchildren,butitalsooccursinadultPLHIV.• ItischaracterizedbydiffusedinterstitialpulmonaryinfiltratesthatmaybeconfusedwithTBor

PCP.However,patientswithLIPoftendonothavesignsofsevererespiratoryillness.• NospecifictreatmentisavailableforLIP.

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III. General symptoms

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

enlargement.• Enlargedlymphnodesaregenerallypainless,firm,mobileandrubberyandaremosteasilypal-

patedintheneck,submentalarea,axillaeandthegroin.• ThepatientmayormaynothaveotherassociatedsymptomsofHIVinfection.• PGLisdefinedasthepresenceformorethanonemonthoflymphnodesmeasuringmorethan

1cmindiameterinmorethanoneareaofthebodyotherthanthegroin.• PGLisaverycommonfeatureofHIVinfection.Inmostcasesalymphnodehistologyonly

reveals“reactivehyperplasia”or“follicularhyperplasia”.Alymphnodebiopsyisnecessarytoestablishacause.

1.1. 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.

1.2. Criteria for performing a lymph node biopsyApatientwithPGLshouldbereferredforalymphnodebiopsyifpresentingwithanyofthefol-lowing:• asymmetricallymphnodeenlargement• massivelymphnodeenlargement(atleastonelymphnode>3cmindiameter)• lymphnodeenlargementoveraperiodofobservation• evidenceofTBonachestX-ray• evidenceofhilarlymphnodeenlargementonachestX-ray• evidenceofKSelsewhere• fever,nightsweatsandweightlossformorethanoneweek.

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

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2. Fever• Fevercanoccurasaresultofinfection,inflammationormalignancy.Persistentfeverinadults

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

keepinmindapossiblediagnosisofHIVinfectionwhenmanagingapatientwhopresentswithapersistentfeverandnoobviouscause.

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

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

3. Weight loss in adults• HIVinfectionisacommoncauseofweightloss.• Severeweightlossisdefinedasinvoluntarylossofmorethan10%ofone’sbodyweight.• Severe involuntaryweight loss inPLHIV isknownasHIV-associatedwasting syndromeor

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

3.1. Clinical features• Thepatientmaycomplainofinvoluntaryweightlossorlossofappetite,withorwithoutfever

anddiarrhoea.• PatientswithHIV-associatedwastingdiseaseare illandemaciatedandmaybefeverishand

dehydrated.• Oralcandidiasisiscommonlyfoundinsuchpatients.• ThepatientmayhaveotherfeaturesofAIDS,includingfeaturesofneurologicalinvolvement

suchasencephalopathyandAIDSdementiacomplex.

4. 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.

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

Table 25. description and treatment of oral lesions common in plhiv

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.)

Benzathinepenicillin2.4milliunitsIMQWforthreeweeksordoxycycline100mgPOBIDfor28daysorerythromycin500mgPOQIDfor28days

6. Skin and nail conditions

6.1. Dermatomycosis• Fungalskinrashes(dermatomycoses)occurcommonlyinPLHIVandothers.• Rashesareusuallyitchyanddry,withvisiblescalesofdeadskin.• Thelesionsmaybefoundanywhereonthebody.

6.1.1. Diagnosis

Fungalelementsmaybefoundonmicroscopicexaminationofskinscrapes.

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6.1.2. Treatment

Topicalapplicationsofantifungalointmentsandcreamswillusuallyclearthelesions.Thefollow-ingmaybeusedfortreatingdermatomycoses.

Table 26. 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 1–3months

or:

Itraconazole 100mg OD PO 1–3months

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

6.2.1. Diagnosis

• Diagnosisisusuallymadeonclinicalfindings.• Microscopicexaminationofpotassiumhydroxide(KOH)preparationsofsubungualmaterial

mayrevealfungalelements.

6.2.2. Treatment

Table 27. 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

6.3. Seborrhoeic dermatitis• Seborrhoeicdermatitis isacommonpresentingfeatureinPLHIV.It isprobablycausedbya

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

tentandrecurrent.

6.3.1. Diagnosis

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

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° scalp ° chest ° axillae ° uppertrunk ° genitalarea.

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

6.3.2. Treatment

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

creamhasalsobeenshowntobeeffective.

6.4. 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.

6.4.1. Diagnosis

• Thediagnosisisusuallymadeonfindingtherashandburrows.• Skinscrapesmayrevealmitesormiteovaonmicroscopicexamination.

6.4.2. Treatment

• Thetreatmentofchoiceisthetopicaluseofgammabenzenehexachloride1%,appliedtothewholebodyfromtheneckdownandwashedoffafter24hoursinadultsand8hoursinchildren.Asingleapplicationissufficient.

• Permethrin1%applicationsarealsouseful.Bothareappliedtoaffectedareasandwashedoffafter8hours.

• Theseagentsshouldnotbeusedduringpregnancyorlactationoronchildrenuntil2½yearsold.• Ivermectininasingleoraldoseof200µg/kgisanalternativethatiseffectiveforcrustedscabies

inimmunocompromisedpeople.• Allmembersofthehouseholdandsexualpartnersshouldalsobetreated.• Allclothes,beddingandtowelsshouldbewashedinhotwater,driedandironed.

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6.5. Staphylococcal folliculitis• Folliculitisisaskininfectionthatislocalizedinthehairfollicles.• ApustularperifolliculitisoccurscommonlyinPLHIV.• UsuallytheconditioniscausedbyStaphylococcus aureus,thoughotherorganismsmayalsobe

responsible.

6.5.1. Diagnosis

• Diagnosisismadeonclinicalfindings.• Lesionsaresmall(lessthan5mmindiameter),andfoundinmultipleerythematousfollicles

thatmayhaveapurulentcentre.• Lesionsareitchyandoftenfoundinclusters.

6.5.2. Treatment

Treatmentiswithantibiotics,suchascephalexinorcloxacillin500mgPOQIDfor7–21days.

6.6. Molluscum contagiosum• Molluscumcontagiosumisasuperficialskininfectioncausedbythemolluscumcontagiosum

virus.• The infection isspread throughclosebodycontactandmayoccur throughsharingclothing,

beddingortowelsorthroughsexualtransmission.• Theincubationperiodvariesfromseveralweekstoseveralmonths.• Shavingorscratchingmaycausetheinfectiontospread.• TheinfectionoccursmorecommonlyinimmunosuppressedPLHIV.• IncomparisontothelesionsfoundonHIV-negativepeople,thosefoundonPLHIVare: ° morewidespread ° morepersistent ° muchlarger ° moredifficulttotreat.

6.6.1. Diagnosis

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

diameter.Thelesionscontainawhitesebaceousmaterial.• Thepapulescanoccuranywhereonthebodyandoftenremainunchangedformanymonths,

afterwhichtheydisappearandmayormaynotreappear.• Nodiagnostictestforthisvirusisavailable.

6.6.2. Treatment

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

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