NovedadesenSíndromedeReconstituciónInmuneasociadoa

infecciónporVIHRocíoTordecilla F.

InmunólogaHospitalClínicoUniversidaddeChileProgramaVIH-HospitaldelSalvador

ProfesoraAsistente,UniversidaddeChile3deseptiembre2016

DañodelVIH• Etapa temprana: infección de

LTCD4+ memoria en tejidosmucosos linfáticos.

• Infección de LT cooperadores,macrófagos y CD en tejidoslinfáticos periféricos.

• Destrucción 1-2 x 109 LTCD4+ al día(pool total de 1012 LTCD4+).

• Supresión de LT vírgenes en timo,daño del epitelio tímico (atrofiatimica ≈involución etaria normaldel timo).

Abbasetal.Cellular andmolecularImmunology.7ed.2012

Reconstitucióndelsistemainmune

ProliferacióndeLTperiféricosdememoria(oligoclonales)

Timopoyesis activa:LTvírgenespoliclonales

WilliamsKMetal.Semin Immunol.2007Oct;19(5):318-30.

Factoresqueafectanrestauracióninmunológica

Corbeau P,Reynes J.Blood.2011

ConsecuenciasClínicas

ReconstituciónInmune

RIefectivaparainfecciones

previamenteR

Rápidaresolución

Disminuciónoaparición

RIanómalafrenteaciertos

Ag

SÍNDROMEINFLAMATORIORECONSTITUCIÓN

INMUNE

Sempowski,Annu Rev Med 2002MMWRRecomm Rep.2009

SINDROMEINFLAMATORIODERECONSTITUCIÓNINMUNE(SIRI)

Immune reconstitution inflammatory syndrome (IRIS)

DefiniciónSIRI• Síndromeinflamatorioasociadoalarestauracióndelsistema

inmuneposterioraliniciodeTAR.

• Respuestaexageradaantígeno-específica,“respuestaprotectora”perodisreguladaà deterioroclínicoapesardeusodeTAR.

• 20a35%depacientesVIHenTAR.

• Entrelosprimeros3mesesohastaañosdespuésdeliniciodeTAR.(mediana33días)

• Otrospacientes:TBC,postTMO,postQT,postterapiadeinduccióntrasplanteórganosólido,reduccióndeinmunosupresores(anti-TNF,natalizumab).

FrenchMA.ClinInfectDis.2009Mul̈lerMetal.LancetInfectDis2010

Inmunopatología SIRI

Barber DLetal.Nat Rev Microbiol.2012

Respuestainnata

Respuestaadaptativa

NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Sereti et al. Page 12

Table 1

Biomarkers of interest for potential application in IRIS prediction or diagnosis

1 C-reactive of protein (CRP): fungal, cryptococcal, mycobacterial

2 CXCL10 or Interferon-inducible protein-10 (IP-10): viral, mycobacterial

3 IL-6, IL-18, IP-10, viral, mycobacterial

4 Interferon γ: mycobacteria, fungal

Curr Opin HIV AIDS. Author manuscript; available in PMC 2011 November 1.

Sereti etal.Curr Opin HIVAIDS.2010

PCR,IL-6,dímeroDyac.hialurónico medidopreTARy1mesdespuésestánasociadosaeventosmarcadoresdeSIDA,SIRIomuerte.

NivelesdeTNFαprevioaliniciodeTARynivelesdePCR,IFNγ,IL-8,IL-6,1mesdespuésdeliniciodeTARpuedenserútilesparareconocerunsubgrupodepacientesenriesgodeSIRI.

Boulware etal.JInfect Dis.2011

EstudioCADIRIS:PrevencióndeSIRI

NiveleselevadosdemarcadoresTH1,activacióndemonocitos,coagulaciónybajosnivelesdevitaminaDfueronindependientementeasociadosariesgodeSIRI.• SIRIparadójicotuvieronnivelesmásaltosdeIFNγ ysCD14.

DímeroDyPCRfueronsignificativamentemayoresenpacientesconSIRI.

• NivelesaltosdevitaminaDfueronconsideradosprotectoresdeSIRI.

Biomarcadores talescomoPCR,sCD14,IFNγ ybajaHb enSIRI-TBC,podríanconstituirunpotencial“puntaje”deriesgoparaeldesarrollodeSIRI.

Musselwhite LWetal.EBioMedicine.2016Sierra-MaderoJGetal.LancetHIV.2014

FactoresderiesgoSIRI

BajorecuentodeCD4basales:>IO,DisregulaciónSI

Predisposicióngenética

DéficitdeRIaldiagnósticodeIO

CVVIHbasalaltaGradode

diseminacióndeIO/cargadeinfección

DuracióndettoIOprevioainicioTAR

SupresiónrápidadeCVVIH

WalkerNFetal.HIVAIDS(Auckl).2015Shelburne SAetal.AIDS.2005

Huésped

Patógeno

Tratamiento

DisminuciónCV+

AumentoCD4

InicioTARV

Empeoramientoparadojaldeenfermedadoportunista(tratadao

enmascarada)

Autolimitadoà SecuelasyMuerteSexton,D.;Immune reconstitution inflamatory syndrome,uptodate,review enero2011

DefiniciónSIRI

SIRIparadójico

WalkerNFetal.HIVAIDS(Auckl).2015

SIRIdesenmascarado

WalkerNFetal.HIVAIDS(Auckl).2015

ETIOLOGÍASYMANIFESTACIONESCLÍNICAS

PresentaciónagudaSíntomassistémicos

Condición Manifestaciónclínica

Bacterias

Mycobacterium tuberculosis Fiebre,adenopatías,infiltradosnuevosopeores, efusiónpleural,tuberculoma.

Mycobacterium noTBC( avium intracelular,genavense,kansaii,srofulaceum,xenopi,BCG,leprae)

Fiebre,adenopatías(dolorosas/supurativas),cavitacionespulmonares,masasinfiltrativas.

Bartonella sp. Esplenitisgranulomatosa

Chlamydia SíndromedeReiter

Virus

VHS Lesionesmucocutáneas, encefalomielitis

CMV SIRIUveitis (historiapreviaretinitis),retinitis(SIRIdesenmascarado)

VVZ Herpeszoster,encefalitis,mielitistransversa,queratitisestromal

EBV NuevapresentaciónLNH,linfoma Burkitt

VHH-8 SIRISarcomadekaposi,enfermedaddeCastleman.

VHB,VHC Reactivaciónhepatitis,cirrosisrápidamenteprogresiva

Virus JC LEMP paradójicoodesenmascarado

Molusco contagioso Pápulasnuevasorecurrentescondistribuciónmásflorida

PVB19 Aplasia deserieroja,encefalitis

VPH Verrugas(agudasorecaída oaumentodetamaño)

Hongos

Cryptococcus neoformans Meningitis conaumentodePIC,neumonía,inflamacióndetejblandosuoculares.

Pneumocystis jirovecii Neumoníadesenmascarada, SIRIparadójicoduranteodespuésdeltto conaumentodehipoxia,nuevosinfiltradospulmonares,neumoníaorganizativa.

Candida spp Candidiasisoraloesofágica (desenmascarado)

Parásitos

Toxoplasmagondii Lesionesnuevasomásgrandes

Cryptosporidium spp Ileitis terminal, duodenitis,colangitis,ulceraciónGI

Microsporidiumspp Queratoconjuntivitis

Autoinmunes

EnfermedaddeBasedow-Graves,SdGuillain–Barré,AR,Polimiositis,LES,policondritis

Nuevapresentaciónoempeoramiento decondiciónprevia.

Dermatológicas

Foliculitis eosinofílica, dermatitisseborreica,erupciónpruriginosapapular,acné

Presentacióninflamatoria

Otras

Sarcoidosis Inflamacióngranulomatosanuevaorecurrente,tarde(12semanaspost TAR),CD4200cél/mm3,presentaciónpulmonarmásfrecuente,cutánea(eritemanodoso,lesionespapulares)ointraabdominales.

Neumonitislinfoideintersticial Fiebre,distress respiratorio, cultivos(-)

SIRI SNC Leucoencefalopatía,desmielinización,edemacerebral.

TBCySIRI• LatuberculosiseslainfecciónmásfrecuentementeasociadaaSIRI,

sobretodoenpaísesdebajosomedianosingresos.• <1%demortalidad,mayormorbilidadycausadehospitalizaciones

ynecesidaddeprocedimientostraseliniciodeTAR.• TBCSIRISNCpeorpronóstico.• IncidenciadeSIRI-TBCparadójico30%(8-43%),presentacióndeSIRI

másfrecuente.• FR:CD4bajos,TBdiseminadayextrapulmonar,tiempocortoentre

iniciodetratamientoantiTBeiniciodeTARyrespuestainmunológica-virológicavigorosa.

• Cuadroautolimitado.• Duracióndesíntomas:medianade2meses,perohasta1año.

Meintjes etal.Lancet Infect Dis.2008Manosuthi etal.AIDSResTher (2016)

•Diagnósticodetuberculosis:TBbk(+),TBbk (-)otuberculosisextrapulmonar

•Respuestainicialatto antiTB:êfiebre,sudoración,tos,pérdidadepeso.

Antecedentes

•Mayores(nuevoopeor)(1):• Linfonodos,abscesosfríosuotrocompromisodetejido.

• Imágenesradiológicas• TuberculosisSNC•Serositis (efusiónpleural/pericárdica,ascitis).

•Menores(nuevoopeor)(2):• Síntomasconstitucionalescomofiebre,sudoraciónnocturnaopérdidadepeso.

• Tos,disneaoestridor.•Dolorabdominal+peritonitis,hepatomegalia,esplenomegaliaoadenopatíasabdominales.

Criteriosclínicos

•Falladetto antiTBporresistenciadedrogasantiTB

•Bajaadherenciaatto antiTB

•Otrainfecciónoportunistaoneoplasia

•Toxicidadoreacciónadrogas

Alternativasexcluidas

Figure 1. Illustrative case of paradoxical tuberculosis-associated IRISA 36-year-old HIV-infected man was diagnosed with culture-positive pulmonarytuberculosis (sensitive to rifampicin and isoniazid) without evidence of extrapulmonaryinvolvement. His CD4 count was 39 cells per μL and HIV-1 viral load 1 300 000 copies permL. He commenced antiretroviral therapy (ART; stavudine, lamivudine, and efavirenz) 7weeks after initiating antituberculous therapy. 1 week later he presented with a recurrence oftuberculosis symptoms and cervical node enlargement. Paradoxical tuberculosis-associatedIRIS was diagnosed. Over the next 18 months he presented with several tuberculosis-associated IRIS manifestations that sequentially emerged, despite corticosteroid therapy,then resolved. Photographs show development of massive cervical lymphadenitis (A), achest wall cold abscess (B, arrows), and a massive right psoas abscess shown here on CTscan (C, arrow) from which over 2 L of pus was aspirated (D). Repeated mycobacterialcultures of aspirates from these collections have been negative. After 6 months on ART hisCD4 count was 181 cells per μL and viral load undetectable. After 12 months his CD4 countwas 448 cells per μL and viral load 35 copies per mL. This was an unusually prolongedcourse for paradoxical tuberculosis-associated IRIS given that the median duration ofsymptoms is reported to be 2 months (see text).

Meintjes et al. Page 14

Lancet Infect Dis. Author manuscript; available in PMC 2010 January 10.

Europe PMC

Funders Author M

anuscripts Europe PM

C Funders A

uthor Manuscripts

DefinicióndeSIRI-TBCparadójico

Meintjes etal.Lancet Infect Dis.2008Manosuthi etal.AIDSResTher (2016)

SIRITBCduranteTARodesenmascarada

• DuranteTAR:pacientesintto antiTBysehacedgdeTBactivaposteriorainiciodeTAR.Pocasensibilidaddepruebasdiagnósticas?

• TBCdesenmascarada:infecciónsubclínicaasintomáticaodgnorealizadodeTByalos3mesesdeiniciodeTAR(sintto antiTB)presentasíntomasdealtaintensidad.

Figure 2. Illustrative case of unmasking tuberculosis-associated IRISA 48-year-old HIV-infected man with a CD4 count of 10 cells per μL presented with low-grade fevers, retrosternal chest pain, and a dry cough. Examination was non-contributory.He could not produce sputum and his chest radiograph showed no features of activetuberculosis (A). No other investigations for tuberculosis were available in this resource-limited setting (Uganda). Antiretroviral therapy (ART) was started (zidovudine, lamivudine,and efavirenz). 10 days later he returned acutely unwell with a productive cough. Histemperature was 38·7°C and he was in respiratory distress. Chest radiograph now showedleft mid-zone consolidation (B) and his sputum was positive for acid-fast bacilli. Theunusual rapidity and clinical severity of his tuberculosis presentation was attributed tounmasking tuberculosis-associated IRIS. He responded well to continued ART andtuberculosis treatment.

Meintjes et al. Page 15

Lancet Infect Dis. Author manuscript; available in PMC 2010 January 10.

Europe PMC

Funders Author M

anuscripts Europe PM

C Funders A

uthor Manuscripts

Meintjes etal.Lancet Infect Dis.2008.

Criptococo ySIRI• 1/3delospacientesentratamientopor

meningitiscriptocócica cursanconSIRIparadójico.

• SIRIparadójico:Incidencia13-45%• 1%depacientesqueinicianTAR

desarrollanmeningitisporcriptococo.• Entredía4hasta3años,mediana4-9

semanasdespuésdeliniciodeTAR.• Morbi-mortalidad13-36%,mortalidad

muchomayorenÁfrica.

Hadow LJetal.LancetInfectDis2010MMWRRecomm Rep.2009

PostMJetal.AJNRAmJNeuroradiol.2013

those developing CM-IRIS.90 Furthermore, a paucity of proin-flammatory cytokine responses pre-ART, evidenced by lower tu-mor necrosis factor !, lower vascular endothelial growth factor,lower granulocyte-macrophage colony–stimulating factor, andlower granulocyte colony–stimulating factor combined withheightened Th17 and Th2 responses as measured by higher levelsof interleukin 4 and interleukin 17, was predictive of futureIRIS.90 The authors postulated that these biomarkers could beused to determine when to initiate ART or to guide other inter-ventional therapies.90 With patients on ART these authors alsofound increasing levels of D-dimer and C-reactive protein to bebiomarkers pointing to an inflammatory response.90

Patients with CM-IRIS can be recognized clinically by the de-velopment of headache, fever, malaise, altered mental status,raised intracranial pressure, and cranial nerve palsies in the settingof lymphadenopathy and new pulmonary infiltrates.91 Cavitarylung lesions, suppurative mediastinal lymph nodes, and mening-ismus due to the exaggerated local inflammatory responses fromincreased reactivity to the cryptococcal antigen and higher cryp-tococcal antigen titers, a higher fungal burden in the blood, higheropening pressures in the CSF, and sometimes culture-negativeCSF are diagnostic clues that may differentiate CM-IRIS frompre-HAART cryptococcal infection.20,25,92 Initiating antiretrovi-ral therapy within 1–2 months of the diagnosis of CM20 and CD4counts below 11 cells/mm3 as well as higher baseline HIV RNAlevels have also been viewed as risk factors for CM-IRIS.25

Concerning neuroimaging, certain striking differences havebeen found in those with CM-IRIS as opposed to HAART-naïveHIV-infected patients with CM. Before the advent of HAART,leptomeningeal enhancement in CM was uncommon in patientswith AIDS because those individuals were unable to mount a suf-ficient inflammatory response.93 However, with HAART andCM-IRIS, an intense inflammatory reaction can be seen. Becauseof a restoring immune system, CT or MR imaging can demon-strate leptomeningeal enhancement (Fig 5), which can be accom-panied by a communicating hydrocephalus in CM-IRIS. The

findings of linear perivascular enhancement in the sulci and newmeningeal or choroid plexus enhancement have been shown to beimaging indicators of CM-IRIS.19,90,94 In a case illustrated by Rie-del et al,19 a cerebellar lesion with high FLAIR signal having masseffect on the fourth ventricle was seen to develop in associationwith an increase in meningeal enhancement 2 weeks after an HIV-infected patient with CM was treated with antiretroviral therapy.

While distention of the Virchow-Robin spaces manifested ashigh T2/FLAIR signal, particularly in the basal ganglia, and gelat-inous pseudocysts have been imaging features of cryptococcalmeningitis in both the pre- and post-HAART era due to the pro-duction of a viscous mucoid material by the acidic polysaccharidecapsule of the cryptococcal organism,95 enhancement of theseVirchow-Robin spaces appears characteristic of CM-IRIS as doessecondary involvement of the brain parenchyma characterized byareas of high T2/FLAIR signal (Fig 6A), restricted diffusion, andparenchymal enhancement. In a report of 2 HIV! patients withcryptococcal meningitis started on HAART with negative findingson pretreatment MR images, in 1 patient 7 months later, lepto-meningeal enhancement was observed and multiple enhancingparenchymal lesions in the cortex compatible with cryptococco-mas; whereas in the other patient, focal cortical and subcorticallesions were seen 6 months later.96 In a prospective study by Bi-canic et al,20 contrast CT scans were obtained in 4 of the 65 pa-tients with CM-IRIS. Two of these CT scans showed infarcts, ei-ther in the basal ganglia bilaterally or in the unilateral basalganglia and temporal and parietal lobes. While infarcts can cer-tainly cause restricted diffusion, the gelatinous mucoid materialproduced by the cryptococcal capsule can also restrict diffusion inthe parenchyma.97 When there is a sufficient enough inflamma-tory response induced by IRIS, contrast enhancement can be seen(Fig 6B).

Higher organism burden in the CSF at disease onset in CM-IRIS has also been reported to be associated with elevated intra-cranial pressure.91,92 This elevated intracranial pressure is due tothe blockage of CSF pathways and arachnoid villi by the produc-tion of greater amounts of mucoid material, by the higher numberof organisms, and by the greater reactivity to the cryptococcalantigens.91 A lumbar drain or ventriculostomy is often necessaryto combat the increased mortality (25%) with elevated intracra-nial pressure that has been reported.91 Because a high openingpressure in patients with CM-IRIS is considered a risk factor forincreased mortality, the suggestion has been made to delay for 1month the institution of HAART in these patients who developcryptococcal meningitis.91 Treatment with amphotericin B andflucytosine for 2 weeks and fluconazole for 8 weeks has been sug-gested in this setting.91

One word of caution should be expressed. While the imagingfindings mentioned above can be clues to the diagnosis of CM-IRIS, a negative CT or MR imaging finding or one showing onlycortical atrophy does not exclude that diagnosis. Several studieshave shown significant percentages of patients in whom the MRimaging or CT findings were negative in cryptococcal meningi-tis.98 In fact, a recent article has shown that DTI may be a usefultool in CM because it can detect changes that may be more wide-spread than anticipated from conventional MR imaging.99 Inves-tigating the neuropsychological sequelae in HIV-negative patients

FIG 5. Cryptococcal meningitis–IRIS. Axial T1-weighted image withcontrast shows enhancement along the folia of the cerebellum andthe meninges in a patient with HIV infection and cryptococcal men-ingitis who was treated with amphotericin B and then HAART.

1304 Post Jul 2013 www.ajnr.org

Hadow LJetal.LancetInfectDis2010

• Dgenfermedadporcriptococo previoainiciodeTARconcultivo(+)+característicasclínicasotintachina(+)odetecciónAg.

• Respuestaclínicainicialaterapiaantifúngica:resoluciónparcialocompletadesíntomas,signosoê Agocultivocuantitativo.

Antecedentes

• Dentrodelosprimeros12mesesdeiniciodeTAR,reintroducciónocambiodespuésdefalla.

• Deterioroclínico

Criteriosclínicos

• Terapiafúngicanoadecuadaopacientenoadherente,marcadoporcultivo(+)despuésde3mesesdetto.

• Infecciónalternativaoneoplasia

• FalladeTAR

Exclusióndeotrascausas

Definicióndecriptococo- SIRIparadójico

Hadow LJetal.LancetInfectDis2010

• IniciodeTAR• Dgenfermedadporcriptococo previoainiciodeTARconcultivo(+)+característicasclínicasotintachina(+)odetecciónAg.

• Respuestaclínicainicialaterapiaantifúngica:resoluciónparcialocompletadesíntomas,signosoê Agocultivocuantitativo.

Antecedentes

• Meningitis• Linfadenopatías• Lesiónintracraneal

• Focalidadneurológica

• Enfermedadmultifocal

• Lesionescutáneasodetejidoblando

• Neumoníaonódulospulmonares

Criteriosclínicos

• Terapiafúngicanoadecuadaopacientenoadherente,marcadoporcultivo(+)despuésde3mesesdetto.

• Infecciónalternativaoneoplasia

• FalladeTAR

Exclusióndeotrascausas

Definicióndecriptococo- SIRIparadójico

Criptococo asociadoaTARo“desenmascarado”

• 33%depacientesconantigenemia decriptococo (+)almomentodeiniciodeTAR.

• Presentaciónmásaguda• Manifestacionesinusuales,exageradasomuyinflamatorias:– Meningitisconelevadorecuentodeleucocitos(>50céls/μL)oPdesalidadeLCRrefractariaaterapia

– Adenopatíasdolorosasosupurativas– Lesionesrápidamenteexpansivas(criptococoma)– CompromisoextraSNC:pulmón,pielolinfonodos– Inflamacióngranulomatosa

• Neumonitiscavitaria onecrotizante

Hadow LJetal.LancetInfectDis2010

LEMP/SIRI• EltratamientodeLEMPeslaTAR,la

mayoríamejora.

• Entre10-20%desarrollaSIRI3-6semanas(1semana-26meses,3meses)despuésdeliniciodeTAR.

• Empeoramientooaparicióndenuevaslesiones,edemacerebralyposibleherniación.Captacióndecontraste,loquenoescomúnenLEMP(noSIRI).

• Potencialmenteletal,apesardelusodecorticoides.

CMV/SIRI• Uveitismanifestadapordisminuciónde

agudezavisual,fotofobia,visiónborrosa• Edemamacularèpérdidadevisión.• 2-84semanaspostinicioTARV(mediana

de20semanas).• Frecuenteantecedenteprevioretinitis

extensa• Manejo

– Corticoidestópicosysistémicosevidencianresultadosregulares.Valganciclovir?

MMWRRecomm Rep.2009BerenguerJetal.Clin InfectDis.2003

PostMJetal.AJNRAmJNeuroradiol.2013

developed IRIS earlier on, and who had higher MR imaging lesionloads, compared with those patients who developed IRIS simul-taneously with PML.15 Increased survival in this same report wasassociated with earlier and more prolonged use of steroids as wellas contrast enhancement on imaging studies15; 87.5% of thosepatients with a good outcome demonstrated lesional contrast en-hancement on either CT or MR imaging versus 80% with pooroutcome whose imaging demonstrated no contrast enhance-ment.15 In 2 other studies, this perilesional contrast enhancementand its intensity were found to be correlated with the sites andseverity of brain inflammation at brain biopsy.15,76,77 It appearsthen that some degree of inflammatory response followingHAART is a good thing, whether associated with the IRIS phe-nomenon or not. However, if the inflammatory response be-comes excessive and uncontrollable, morbidity and mortalityrates increase, unless mitigated by medical therapy such as ste-roids, because it is likely that much of the current mortality ofPML is linked to IRIS rather than to progressive JC virus– drivendisease.

What now makes PML-IRIS more recognizable than IRIS as-sociated with some other opportunistic diseases, in addition toatypical clinical findings, is the presence of neuroimaging abnor-malities that are not classic for untreated PML. While untreatedPML typically presents as white matter lesions, often subcortical,low on T1WI, and high on FLAIR and T2WI (due to the myelindestruction), without mass effect and without contrast enhance-ment with no diffusion restriction centrally (but only peripherallyat the active site of lesion expansion with cytotoxic edema),62,78

PML-IRIS is characterized by the development of contrast en-hancement of the PML lesions as well as mass effect and increasedhigh FLAIR/T2 signal due to interstitial edema (Figs2– 4).15,58,71,73,76-80 Usually occurring within 1–2 months ofHAART1,30 (though they can occur up to 2 years), patchy whitematter lesions with multiple areas of nodular enhancement onMR imaging can be seen, which can respond to steroids.1 Thewhite matter lesions can be confined to the posterior fossa, as wasthe case in 3 of 8 patients with PML-IRIS reported in the litera-ture.30 The peripheral enhancement of the white matter lesions

and perivascular spaces has been related to their infiltration byCD8! T-cells, sometimes accompanied by macrophages andCD4! T-cells.1,30

If this intense inflammatory response with edema, contrastenhancement, and mass effect can subsequently be mitigated, pa-tients may have an improved outcome. However, not all patientswith HIV-associated PML-IRIS demonstrate contrast enhance-ment of the PML lesions.30 Contrast enhancement may be seen inonly 56% of patients.73 Indeed, much of the underestimation ofPML-IRIS results from the assumption of clinicians that it onlyoccurs when contrast enhancement is seen in PML lesions. In fact,this enhancement may be a late and extreme consequence, withsubstantial and abnormal inflammatory changes in PML lesionsoccuring well before gadolinium contrast enhancement. Fortu-nately, a response can be seen with steroids.1,15,81

Yet another tool used to predict patient outcome in HIV-as-sociated PML-IRIS has been diffusion-weighted imaging. A studyby Buckle and Castillo74 found that in the clinically rapidly pro-gressive patients with PML-IRIS, the ADC values both centrallyand totally as well as the JCV titers pre-HAART were the highest,whereas those with lower ADC values were associated with stablelesions or remyelination. Also while the ADC values in the centerof the white matter lesion increased only slightly during a1-month time period on HAART, in those patients whose PMLprogressed slowly, there was a significant increase in ADC valuesin the total lesion and central core in those patients with rapidPML progression who had been on HAART for 1 month.74 Theimplication is that because PML is a destructive white matter le-sion, increased destruction manifested by increased diffusibilityon diffusion-weighted imaging would indicate disease progres-sion and hence poorer patient outcome.74

That PML-IRIS can be fulminating and lead to patient deathwas evident from the case report of Vendrely et al6 of a patientwith AIDS with PML started on HAART who subsequently dete-riorated neurologically. The patient’s MR imaging showed an in-crease in the number and size of the lesions, all of which enhancedcompared with the pre-HAART MR imaging.6 Biopsy showedboth demyelinating lesions as well as severe inflammation with

FIG 2. PML-IRIS. HIV-infected patient on HAART with axial FLAIR (A) showing multiple hyperintense asymmetric lesions in the white matterbilaterally and axial postcontrast T1WI (B) showing some patchy enhancement in the right parietal region due to PML-IRIS. Significant responseto corticosteroid therapy confirms IRIS.

AJNR Am J Neuroradiol 34:1297–307 Jul 2013 www.ajnr.org 1301

VHH-8/SarcomadeKaposi/ECMySIRI

• SIRIparadójico7%–31%• é oprogresiónclínicadelesionesdeSK,

ésensibilidadodoloryedemaperiférico• 1-22semanas,lasprimeras12semanasdeinicio

deTARmásfrecuente.• Riesgo>:sóloTARsinQMT,estadío Tumás

avanzado,CVVIHdetectable(>105copias/ml)yCVVHH-8detectable.

• NOutilizarcorticoidesporquepuedeempeorar,sólousodeQMT.

• ViremiadeVIHsuprimidamásriesgodeECM.• NiveleselevadosdeviremiaVHH-8secorrelacionan

fuertementeconECM(83–100%depacientesVIH(+)ECM,mientrasque36–72%deVIH/SK).

• ECMaumentaconviremiasuprimida,puedesersignodeSIRI,respuestaparadójica.

Bower Metal.JClin Oncol.2005Siegel MOetal.Int JInfect Dis.2016

VHB/VHCySIRI

• éAminotransferasas=“Flare”hepatitis=SIRIenpacientescoinfectadosconVHB/VHC.

• 6-12semanasdeiniciodeTAR• Síntomasysignosdehepatitisaguda.• Descartarotrascausas:VHAaguda,hepatotoxicidad (DILI).• Biopsiadiferenciatoxicidad(eosinófilos)yhepatitisviral

(inflamaciónportal).• SeroconversióndeAgeVHB yAgsVHB,cambiosenCVVHBno

necesarios,peropuedenayudar.• SisecambiaTAR,mantenerdrogaactivacontraVHBoVHC.

MMWRRecomm Rep.2009Crane Metal.Curr Opin HIVAIDS.2008

NUEVASDROGASYRIESGODESIRI

Raltegravir

• STARTMRK(raltegravir v/sefavirenz,conTDF/FTC)yBENCHMRK(raltegravir v/splacebo,conTARoptimizada).

• EnSTARTMRK,SIRIfuesimilaralgrupodeEFV,infrecuentementereportadocomoefectoadversoserio;sólo1pacientediscontinuóporSIRIenelgrupodeRAL.

• EnBENCHMRK,SIRIfuereportadoenbajafrecuenciaysimilaralgrupoplacebo.

Teppler Hetal.CurrHIVRes.2011

RiesgodedesarrollotempranodeLNHconnuevasdrogas

• Ensayosabiertosdeetravirina,raltegravir ymaraviroc entredic2006yenero2008(pacientesnovírgenesaTAR).

• 5nuevoscasosdeLNHentre78sujetosenrolados(incidencia64.1/1000pacientes/año).

• MedianadeaparicióndesíntomasdeLNH:5semanas.

• Los5casosdeLNHrecibieronraltegravir.1casoLNHrecibióetravirina yningunomaraviroc(nohubodiferenciasestadísticas).

Huhn etal.AIDSResearch andTherapy 2010

RiesgodedesarrollotempranodeLNHconnuevasdrogas

Tenofovir/emtricitabina/cobicistat/elvitegravir (Stribild®)

• Reportedecasosenlaliteratura– Sífilis secundaria– AdenitiscervicalporM.avium.

Khatri Aetal.Int JSTDAIDS.2015Skalweit M. Int JSTDAIDS.2016

Dolutegravir

• AnálisisentreSPRING,SPRING-2,SINGLE,FLAMINGOySAILINGalas48semanassepudoobservar:– ReactivaciónhepatitisB/CoSIRIenramadeDTGencomparaciónconlosotrosfármacos.

– 4/32individuosrecibiendoDTGysólo1/49RALfueronconsideradoscomoSIRI-VHC(coinfectadosVHC).

– EnelgrupodepacientesexperimentadosTAR(vírgenesaII/SAILING):

• 6individuosrecibiendoDTGdesarrollaronSIRI,5fueronSIRIasociadaacoinfección VHBy/oVHC.

• 3individuosrecibiendoRALtuvieronposibleoprobableSIRI,1casodeposibleSIRI-VHC.

CurtisLetal.HIVClin Trials.2014

Maraviroc¿porquésuusocomoprevención/tto deSIRI?

• AltaexpresióndeCCR5+enpacientesquedesarrollanLEMPporusodenatalizumab (Esclerosismúltiple).

• éCCR5enLTCD8+enLEMP-SIRIporVIH.• CCR5seexpresaenSNCyfacilitalainfecciónporVIH.• CCR5promueveelreclutamientodecélulasinmunesal

SNCèdesorden neurocognitivo delVIH.

• Limitaciones:– MVCnocontrolalainflamaciónatodonivel (AR)nitampoco

previenetodaslascausasdeSIRI.

– ElbloqueodeCCR5podríainhibirlamigracióndeLTreguladoresatejidosinflamadosèinmunoregulación local.

– ApesardeseguridadprobadaenlospacientesusuariosdeMVCconbuenatolerancia,existeunaumentodelriesgodeinfecciónporflavivirus quenopuedeserexcluido.

Martin-Blondel Getal.ActaNeuropathol.2015Stork Letal.ActaNeuropathol.2015

Giacomini PSetal.NEngl JMed.2014Martin-Blondel Getal.Nat Rev Neurol.2016

LEMP-SIRItratadosconMVC

• Reportedecasosclínicos.• MayoríadereporteconTARqueincluyeIP.• Buenosresultadosenpacienteenqueseiniciótratamientoprecoz

ymanifestacionesclínicasmoderadas.• Mortalidadenpacienteconmanifestacionesseveras,iniciode

tratamientotardíoyotrasmorbilidadesasociadas.

Shahani L,etal.BMJCaseRep 2015.RodríguezMetal.CaseRep Med.2014

MaravirocEstudioCADIRIS

§ Dobleciego,randomizado,placebocontrolado.§ Objetivo:determinar utilidad demaraviroc enprevención deSIRI.

• Endpoint1°:tiempo dedesarrollo deevento deSIRIomuerte hastalasemana 24.• 64eventos deSIRI,33(24%)engrupo MVCy31(23%)enPCB(p=0,74).• MVCnotuvo efecto alguno endesarrollo deSIRIdespués delinicio deTAR,

tampoco tuvo rol inmunomodulador aumentando CD4.• Limitaciones:cohorte heterogénea deSIRIylas condiciones SNCfueron pocas.

5centrosenMéxicoy1enSudáfricaen1año.276VIH(+),vírgenesaTAR,CD4<100cél/mm3,CVVIH>1000copias/ml.

MARAVIROC600BID+FTC/TDF/EFV(n=140)

PLACEBO+FTC/TDF/EFV(n=136)

Análisis ensemana 2,4,8,12,16,24,48y 60.

Seguimientohastalasemana

48

Sierra-MaderoJGetal.LancetHIV.2014.

TRATAMIENTODESIRI TratamientodelaIO:SIRIdesenmascarado

Terapiaantiinflamatoria:AINES(leve)yCorticoides (moderado-

severo)

MantenerTAR:suspenderSÓLOsihaypeligrodemuerte,

compromisoSNC?(riesgoderesistenciayprogresióndelVIH)

MicobacteriasDrenaje quirúrgico linfadenitis o

abscesos.Otras terapias:

talidomida,montelukast,pentoxifillina ohidroxicloroquina.

Drenaje deLCR:SIRIasociado acriptococosis

MMWRRecomm Rep.

2009Meintjes et

al.CurrHIV/AIDSRep.2012

LaiRP etal.Semin

Immunopathol (2016)

PrevenciónSIRI

ElretrasoodescontinuacióndelaTARnoestárecomendadoExcepciones:TBCSNC,criptococo SNC

TARprevioaetapaSIDA

PrevencióndeInfeccionesoportunistas

Screening ytratamientodeIOprevioaliniciodeTAR

IniciodeTARentiempoóptimo

WalkerNFetal.HIVAIDS(Auckl).2015MMWRRecomm Rep.2009

Manzardo Cetal.Expert Rev AntiInfect Ther.2015Mfinanga SGetal.Lancet Infect Dis.2014

Manosuthi etal.AIDSResTher (2016)

RetrasareliniciodeTARV?

• TBC(nomeníngea):– CD4<50:iniciodeTARdurantelas2semanasdeiniciodetto

antiTB– CD4>50:2-8semanasdespuésdeliniciotto antiTBC.– MeningitisTBC:4-8semanas posterioralinicio detto antiTB.

• Criptococo:– RetrasarTARalmenoshastaquesecompletelafasede

inducción– PL(-)àentre2-4semanas– Sicultivo(+),recuentobajodeGBenLCRyalteraciónde

concienciaà 5-6semanas.MMWRRecomm Rep.2009

Manzardo Cetal.Expert Rev AntiInfect Ther.2015Mfinanga SG et al. Lancet Infect Dis. 2014

Manosuthi etal.AIDSResTher (2016)

NovedadesenSíndromedeReconstituciónInmuneasociadoa

infecciónporVIHDra.RocíoTordecilla F.

InmunólogaHospitalClínicoUniversidaddeChileProgramaVIH-HospitaldelSalvador

Asistente,carreradocente,UniversidaddeChile3deseptiembre2016