IRIS? IRIS? No thank you, I prefer RosesNo thank you, I prefer Roses

Allison AgwuAllison Agwu

LEAH Adolescent Grand RoundsLEAH Adolescent Grand Rounds

Advanced HIV ManagementAdvanced HIV Management

October 9, 2009October 9, 2009

Clinical CaseClinical Case

18* year old AA male with a history of AIDS18* year old AA male with a history of AIDS Prior history of candida esophagitisPrior history of candida esophagitis Two week history of acute onset fevers,Two week history of acute onset fevers, headaches and headaches and

anorexiaanorexia Associated weight lossAssociated weight loss Started on HAART one month priorStarted on HAART one month prior Nadir CD4 count 5 cells/Nadir CD4 count 5 cells/µLµL, Viral load >750,000 copies/ml, Viral load >750,000 copies/ml

*case slightly altered from original*case slightly altered from original

HistoryHistory

Medications: Efavirenz (Sustiva), Didanosine (Videx), Medications: Efavirenz (Sustiva), Didanosine (Videx), Stavudine (Zerit) , Paxil, Iron, Bactrim, PrilosecStavudine (Zerit) , Paxil, Iron, Bactrim, Prilosec

Physical ExaminationPhysical Examination Temp 103Temp 103°F°F, PR 120bpm, RR 22 cpm, BP 106/90 mmHg, PR 120bpm, RR 22 cpm, BP 106/90 mmHg Cachectic, acutely ill looking maleCachectic, acutely ill looking male Tender hepatomegaly with liver edge palpable 4cm below Tender hepatomegaly with liver edge palpable 4cm below

the right costal marginthe right costal margin

Work-upWork-up

CBC-WBC 6.6, CBC-WBC 6.6, HCT 24.0HCT 24.0, Platelet count 149, Platelet count 149 BMP- BMP- Na 128Na 128 otherwise WNLotherwise WNL Ca 8.2, Alb 2.6, Ca 8.2, Alb 2.6, ALT 136, AST 222, Alk phos 360ALT 136, AST 222, Alk phos 360 Lumbar puncture- negativeLumbar puncture- negative Cultures of blood (including AFB), stool, urine - negativeCultures of blood (including AFB), stool, urine - negative Imaging - Hepatomegaly, contracted gallbladder, no Imaging - Hepatomegaly, contracted gallbladder, no

biliary tract dilatation or obstructionbiliary tract dilatation or obstruction

PathologyPathology

Liver biopsy- Granulomas and multiple AFB Liver biopsy- Granulomas and multiple AFB consistent with mycobacteria infectionconsistent with mycobacteria infection

What is Responsible for Patient’s What is Responsible for Patient’s Clinical Presentation ?Clinical Presentation ?

Severe immune deficiency secondary to HIV ?Severe immune deficiency secondary to HIV ? Severe inflammatory reaction after immune reconstitution ?Severe inflammatory reaction after immune reconstitution ? Drug Toxicity ?Drug Toxicity ?

HIV and the Immune Reconstitution HIV and the Immune Reconstitution Inflammatory Syndrome (IRIS)Inflammatory Syndrome (IRIS)

A Challenge to the Recovering Immune System?A Challenge to the Recovering Immune System?

ObjectivesObjectives

Briefly review our current understanding of the effects of Briefly review our current understanding of the effects of HIV infection on the immune systemHIV infection on the immune system

Review proposed mechanisms of Immune reconstitution by Review proposed mechanisms of Immune reconstitution by Highly Active Antiretroviral Therapy (HAART)Highly Active Antiretroviral Therapy (HAART)

Discuss the epidemiology, pathogenesis, common Discuss the epidemiology, pathogenesis, common presentations and management of IRISpresentations and management of IRIS

Identify gaps in current IRIS knowledge baseIdentify gaps in current IRIS knowledge base Take home points!!!Take home points!!!

ABP Adolescent Medicine Content SpecificationsABP Adolescent Medicine Content Specifications

Identify the major opportunistic infections most commonly Identify the major opportunistic infections most commonly encountered in immunocompromised hosts with acquired encountered in immunocompromised hosts with acquired immunodeficiency syndrome (AIDS)immunodeficiency syndrome (AIDS)

Understand the importance of close monitoring of Understand the importance of close monitoring of adolescents infected with human immunodeficiency virus adolescents infected with human immunodeficiency virus (HIV) to determine the co-occurrence of opportunistic (HIV) to determine the co-occurrence of opportunistic infectionsinfections

Virologic and Immunologic Dynamics of Virologic and Immunologic Dynamics of HIV InfectionHIV Infection

Fauci AS et al. Ann Intern Med 1996

CD4 level and Risk of CD4 level and Risk of Opportunistic Infections (OIs)Opportunistic Infections (OIs)

HAART: Current DrugsHAART: Current Drugs

Fusion InhibitorFusion Inhibitor

Enfuvirtide/T-20 Enfuvirtide/T-20 (Fuzeon, SQ inj)(Fuzeon, SQ inj)

Integrase InhibitorsIntegrase Inhibitors

Raltegravir (Isentress)Raltegravir (Isentress)

CCR5 InhibitorsCCR5 Inhibitors

Maraviroc (Selzentry)Maraviroc (Selzentry)

VicrivirocVicriviroc

NNRTIsNNRTIsEfavirenz (Sustiva,)Efavirenz (Sustiva,)Nevirapine (Viramune)Nevirapine (Viramune)Delavirdine (Rescriptor)Delavirdine (Rescriptor)Etravirine (Intelence)Etravirine (Intelence)

Protease InhibitorsProtease InhibitorsRitonavir (Norvir)Ritonavir (Norvir)Saquinavir-HGC Saquinavir-HGC

(Invirase)(Invirase)Indinavir (Crixivan)Indinavir (Crixivan)Nelfinavir (Viracept)Nelfinavir (Viracept)Fosamprenavir (Lexiva)Fosamprenavir (Lexiva)Lopinavir/r (Kaletra)Lopinavir/r (Kaletra)Atazanavir (Reyataz)Atazanavir (Reyataz)Tipranavir (Aptivus)Tipranavir (Aptivus)Darunavir (Prezista)Darunavir (Prezista)

NRTIsNRTIsZidovudine/AZT Zidovudine/AZT

(Retrovir,(Retrovir,Stavudine/d4T (Zerit,Stavudine/d4T (Zerit,Didanosine/ddI Didanosine/ddI

(Videx-EC)(Videx-EC)Lamivudine/3TC (Epivir,)Lamivudine/3TC (Epivir,)Abacavir/ABC (Ziagen)Abacavir/ABC (Ziagen)Zalcitabine/ddC (Hivid)Zalcitabine/ddC (Hivid)Tenofovir/TDF (Viread)Tenofovir/TDF (Viread)Emtricitabine (Emtriva)Emtricitabine (Emtriva)AZT/3TC (Combivir)AZT/3TC (Combivir)AZT/3TC/abacavir AZT/3TC/abacavir

(Trizivir)(Trizivir)ABC/3TC (Epzicom)ABC/3TC (Epzicom)TDF/FTC (Truvada)TDF/FTC (Truvada)TDF/FTC/EFV (Atripla)TDF/FTC/EFV (Atripla)

Virologic Response to HAARTVirologic Response to HAART

CD4 RecoveryCD4 Recovery

Battegay et al. Lancet Inf Dis 2006

Immune Recovery following HAARTImmune Recovery following HAART

First Phase (3-6 months)First Phase (3-6 months)REDISTRIBUTIONREDISTRIBUTION Release of activated memory CD4 cells trapped in lymphoid Release of activated memory CD4 cells trapped in lymphoid

tissues and reduction in apoptotic cell deathtissues and reduction in apoptotic cell death Second phase (6 months- 4years)Second phase (6 months- 4years)

RECONSTITUTIONRECONSTITUTION Naive CD4 cells and memory CD4 contribute to reconstitutionNaive CD4 cells and memory CD4 contribute to reconstitution

Immune Reconstitution Inflammatory SyndromeImmune Reconstitution Inflammatory Syndrome

A pathologic inflammatory immune recognition of antigens A pathologic inflammatory immune recognition of antigens associated with a known or unknown replicating infection associated with a known or unknown replicating infection or persistent non-replicating antigens from a previous or persistent non-replicating antigens from a previous infectioninfection

Results in spectrum of presentations ranging from clinical Results in spectrum of presentations ranging from clinical worsening of a treated opportunistic infection (OI), atypical worsening of a treated opportunistic infection (OI), atypical presentation of an unrecognized OI or autoimmune presentation of an unrecognized OI or autoimmune disorders such as Graves’ diseasedisorders such as Graves’ disease

Occurs in subset of HIV-infected patients on HAARTOccurs in subset of HIV-infected patients on HAART

Categories of IRISCategories of IRIS

Related to underlying opportunistic infectionRelated to underlying opportunistic infection Inflammatory “unmasking” of a previously untreated Inflammatory “unmasking” of a previously untreated

infectioninfection Paradoxical clinical deterioration of an infective process Paradoxical clinical deterioration of an infective process

for which patient is on appropriate treatmentfor which patient is on appropriate treatment Autoimmune e.g Graves DiseaseAutoimmune e.g Graves Disease Malignancies e.g worsening of Kaposi’s sarcomaMalignancies e.g worsening of Kaposi’s sarcoma

Historical View of Non-HIV IRISHistorical View of Non-HIV IRIS

Paradoxical responses well described among non-HIV Paradoxical responses well described among non-HIV infected patients treated for infected patients treated for Mycobacterium tuberculosisMycobacterium tuberculosis (MTB)(MTB)

Thought to be linked to reversal of immunosuppression Thought to be linked to reversal of immunosuppression induced by MTB infectioninduced by MTB infection

Inflammatory reactions during treatment routine in patients Inflammatory reactions during treatment routine in patients with with Mycobacterium lepraeMycobacterium leprae

Recovery of immune cells following bone marrow Recovery of immune cells following bone marrow transplantation or chemotherapytransplantation or chemotherapy

Infections associated with HIV IRISInfections associated with HIV IRIS MycobacteriaMycobacteria

Mycobacterium tuberculosisMycobacterium tuberculosis Mycobacterium aviumMycobacterium avium complex complex M. lepraeM. leprae

CytomegalovirusCytomegalovirus Herpes VirusesHerpes Viruses

Herpes zoster virusHerpes zoster virus Herpes simplex virusHerpes simplex virus Human Herpes virus-8 associated Human Herpes virus-8 associated

Kaposi’s SarcomaKaposi’s Sarcoma Cryptococcus neoformansCryptococcus neoformans BacteriaBacteria

B. HenselaeB. Henselae

Pneumocystis jiroveciiPneumocystis jirovecii pneumonia pneumonia Histoplasma capsulatumHistoplasma capsulatum DermatophytosisDermatophytosis ToxoplasmosisToxoplasmosis Hepatitis B virusHepatitis B virus Hepatitis C virusHepatitis C virus JC virus-PMLJC virus-PML Parvovirus B19Parvovirus B19 Molluscum contagiosumMolluscum contagiosum Strongyloides stercoralisStrongyloides stercoralis & other & other

parasitic infectionsparasitic infections

Most Commonly Seen EntitiesMost Commonly Seen Entities

In a case series and literature review of 182 episodes In a case series and literature review of 182 episodes of IRIS, the most frequently reported associated of IRIS, the most frequently reported associated infections were:infections were: localized herpes zoster (22 percent)localized herpes zoster (22 percent) M. tuberculosis M. tuberculosis (20 percent)(20 percent) M. aviumM. avium complex (17 percent) complex (17 percent) CMV (12 percent)CMV (12 percent) Cryptococcus (6.5 percent)Cryptococcus (6.5 percent)

Shelburne, SA etal. Medicine (Baltimore) 2002; 81:213. Shelburne, SA etal. Medicine (Baltimore) 2002; 81:213.

Non-infectious HIV IRIS EtiologiesNon-infectious HIV IRIS Etiologies

Graves DiseaseGraves Disease Systemic lupus erythematosus (SLE)Systemic lupus erythematosus (SLE) Rheumatoid arthritisRheumatoid arthritis SarcoidosisSarcoidosis Guillain-Barre syndromeGuillain-Barre syndrome AIDS related lymphomaAIDS related lymphoma

Difficulties with Definition of HIV IRISDifficulties with Definition of HIV IRIS

Wide variety of underlying OIsWide variety of underlying OIs Need to incorporate both unmasking of clinically silent Need to incorporate both unmasking of clinically silent

infections and worsening of previously diagnosed OIsinfections and worsening of previously diagnosed OIs Difficulty in establishing that patient’s clinical presentation Difficulty in establishing that patient’s clinical presentation

is not due to a new microbial process or drug toxicityis not due to a new microbial process or drug toxicity

Proposed Diagnostic Criteria for HIV IRISProposed Diagnostic Criteria for HIV IRIS

HIV positiveHIV positive Receiving HAARTReceiving HAART

Decrease in HIV-1 RNA level from baselineDecrease in HIV-1 RNA level from baseline Increase in CD4+ cells from baselineIncrease in CD4+ cells from baseline

Clinical symptoms consistent with inflammatory Clinical symptoms consistent with inflammatory processprocess

Clinical course not consistent with:Clinical course not consistent with: Expected course of previously diagnosed OIExpected course of previously diagnosed OI Expected course of newly diagnosed OIExpected course of newly diagnosed OI Drug toxicityDrug toxicity

Shelburne et al. Medicine 2002

EpidemiologyEpidemiology

Develops in 15-25% of patients receiving HAARTDevelops in 15-25% of patients receiving HAART Up to 45% incidence rate in patients with known Up to 45% incidence rate in patients with known

opportunistic infectionsopportunistic infections Most cases develop within the first 3 months of treatment Most cases develop within the first 3 months of treatment

(median 6-8 weeks)(median 6-8 weeks) Reports of patients presenting up to 2 years after initiation of Reports of patients presenting up to 2 years after initiation of

treatmenttreatment

Why Do These Why Do These Inflammatory Reactions Occur?Inflammatory Reactions Occur?

PathogenesisPathogenesis

Not well understoodNot well understood May vary from one infection to the otherMay vary from one infection to the other The trigger for this paradoxical reaction is The trigger for this paradoxical reaction is probablyprobably an an

excessive enhancement of immune response to excessive enhancement of immune response to disease-specific antigens leading to an overproduction of disease-specific antigens leading to an overproduction of inflammatory mediators. inflammatory mediators.

Host genetic susceptibility –carriage of specific HLA allelesHost genetic susceptibility –carriage of specific HLA alleles

HIV IRIS SymptomsHIV IRIS Symptoms

Depends on prevailing opportunistic infections in the Depends on prevailing opportunistic infections in the environmentenvironment

Corresponds to patients’ specific underlying Corresponds to patients’ specific underlying condition and locationcondition and location M. tuberculosis, M. tuberculosis, zoster, zoster, M. aviumM. avium complex, CMV, complex, CMV,

Cryptococcus Cryptococcus

Shelburne et al. Medicine 2002

Paradoxical HIV Tuberculosis IRISParadoxical HIV Tuberculosis IRIS

Recurrent, worsening or new clinical or radiologic Recurrent, worsening or new clinical or radiologic manifestations of TBmanifestations of TB

Return of symptoms, fever, enlargement of nodes, Return of symptoms, fever, enlargement of nodes, worsening radiographic pulmonary infiltratesworsening radiographic pulmonary infiltrates

CNS involvement with tuberculomata or tuberculous CNS involvement with tuberculomata or tuberculous meningitismeningitis

Paradoxical TB IRIS LymphadenitisParadoxical TB IRIS Lymphadenitis

Dhasmana et al. Drugs 2008

Paradoxical TB IRISParadoxical TB IRIS

Dhasmana et al. Drugs 2008

At HAART Initiation 10 Days into TB IRIS

Non-Tuberculous MycobacteriaNon-Tuberculous Mycobacteria

Usual presentation is pulmonary disease or bacteremic Usual presentation is pulmonary disease or bacteremic wasting illness associated with fever, gastrointestinal wasting illness associated with fever, gastrointestinal disease and anemiadisease and anemia

MAC IRIS presents with more focal inflammatory diseaseMAC IRIS presents with more focal inflammatory disease Peripheral lymphadenitis with or without abscess formation, Peripheral lymphadenitis with or without abscess formation,

intraabdominal disease and involvement of joint, skin, soft intraabdominal disease and involvement of joint, skin, soft tissues and spinetissues and spine

MAC IRISMAC IRIS

Abdominal lymphadenopathy with evidence of psoas abscess

CMV IRIS-Immune Recovery UveitisCMV IRIS-Immune Recovery Uveitis

Patients present with visual impairment and floatersPatients present with visual impairment and floaters Occurs in patients with prior CMV infectionOccurs in patients with prior CMV infection Distinct from necrotizing retinitis with minimal intraocular Distinct from necrotizing retinitis with minimal intraocular

inflammation of classic CMV retinitisinflammation of classic CMV retinitis High intensity of inflammatory response inducing High intensity of inflammatory response inducing

proliferative vitroretinopathy and posterior subcapsular proliferative vitroretinopathy and posterior subcapsular cataractscataracts

Diagnosis requires a high level of suspicionDiagnosis requires a high level of suspicion

CMV RetinitisCMV Retinitis

CMV RetinitisNormal Retina

Paradoxical Cryptococcal IRISParadoxical Cryptococcal IRIS

Presents with recurrent meningitis symptomsPresents with recurrent meningitis symptoms CSF shows inflammation with marked leukocytosis but CSF shows inflammation with marked leukocytosis but

fungal cultures typically negativefungal cultures typically negative Neuroimaging shows significant inflammationNeuroimaging shows significant inflammation Other findings include cryptococcomas, cerebellitis, Other findings include cryptococcomas, cerebellitis,

lymphadenitis, mediastinitis, cavitating pneumonia and skin lymphadenitis, mediastinitis, cavitating pneumonia and skin lesionslesions

Patients typically have raised intracranial pressure requiring Patients typically have raised intracranial pressure requiring serial lumbar punctures.serial lumbar punctures.

Mortality up to 66%Mortality up to 66%

Neuroimaging in Cryptococcal IRISNeuroimaging in Cryptococcal IRIS

Zoster HIV IRISZoster HIV IRIS

Dermatomal varicella zoster comprises 9-40% of IRIS cases Dermatomal varicella zoster comprises 9-40% of IRIS cases in large observational IRIS cohortsin large observational IRIS cohorts

Patients present with typical or atypical dermatomal Patients present with typical or atypical dermatomal involvement without dissemination or systemic symptomsinvolvement without dissemination or systemic symptoms

Complications such as encephalitis, myelitis, cranial and Complications such as encephalitis, myelitis, cranial and peripheral nerve palsies possible but rare.peripheral nerve palsies possible but rare.

Risk Factors for HIV IRIS?Risk Factors for HIV IRIS?

Design: Retrospective cohort identified through a city-wide Design: Retrospective cohort identified through a city-wide prospective surveillance programprospective surveillance program

Method: Retrospective chart review of 180 HIV infected Method: Retrospective chart review of 180 HIV infected patients on HAART coinfected with patients on HAART coinfected with Mycobacterium Mycobacterium TuberculosisTuberculosis, , Mycobacterium avium complexMycobacterium avium complex or or Cryptococcus neoformansCryptococcus neoformans between 1997-2000 between 1997-2000

AIDS 2005, 19:399-406

Shelburne et al. AIDS 2005

CD4 and Viral Load Response CD4 and Viral Load Response as IRIS Risk Factorsas IRIS Risk Factors

Shelburne et al. AIDS 2005

Determinants of IRISDeterminants of IRIS

1) extent of CD4+ T-cell 1) extent of CD4+ T-cell immune suppression prior to immune suppression prior to the initiation of HAART the initiation of HAART (rapidity of increase)(rapidity of increase)

2) degree of viral 2) degree of viral suppression and immune suppression and immune recovery following the recovery following the initiation of HAART initiation of HAART

3) Prior opportunistic 3) Prior opportunistic infections (known or infections (known or unknown)unknown)

Design: Case-control studyDesign: Case-control study Methods: Patients from Johns Hopkins HIV Clinic who had Methods: Patients from Johns Hopkins HIV Clinic who had

IRIS were identified and matched with 4 controls without IRIS were identified and matched with 4 controls without IRIS who initiated HAART within 6 months of the caseIRIS who initiated HAART within 6 months of the case

Journal of Acquired Immune Deficiency Syndrome Dec 2007

Manabe et al. J Acquir Immune Defic Syndr 2007

*BPI- boosted protease inhibitor

Risk Factors for IRISRisk Factors for IRIS

An active or subclinical OIAn active or subclinical OI A nadir CD4 cell count below 100 cells/µl (or 50 cells/µl A nadir CD4 cell count below 100 cells/µl (or 50 cells/µl

as reported in other studies)as reported in other studies) Robust immunologic response to HAARTRobust immunologic response to HAART The initiation of HAART within the first 4–8 weeks of The initiation of HAART within the first 4–8 weeks of

starting therapy for an OIstarting therapy for an OI Being ART naïve at the time of OI diagnosisBeing ART naïve at the time of OI diagnosis

DiagnosisDiagnosis

Clinical- History! History! History!Clinical- History! History! History! Investigations to exclude alternative explanations for Investigations to exclude alternative explanations for

clinical deteriorationclinical deterioration Failure of antimicrobial therapyFailure of antimicrobial therapy Suboptimal drug concentrations due to non-adherence or Suboptimal drug concentrations due to non-adherence or

malabsorptionmalabsorption Adverse drug reactionAdverse drug reaction Alternative infection or malignancyAlternative infection or malignancy

TreatmentTreatment

No randomized control trials available so largely based on No randomized control trials available so largely based on anecdotal reportsanecdotal reports

Treatment for the underlying pathogen should generally be Treatment for the underlying pathogen should generally be started or continued in patients who develop IRIS. started or continued in patients who develop IRIS. For most patients with untreated HIV and known OIs with effective For most patients with untreated HIV and known OIs with effective

antimicrobial therapies, reasonable to delay HAART for 1-2 months antimicrobial therapies, reasonable to delay HAART for 1-2 months while treating the OIs in an attempt to decrease the likelihood of IRIS. while treating the OIs in an attempt to decrease the likelihood of IRIS.         

Continue HAART in the majority of cases. However, if Continue HAART in the majority of cases. However, if the manifestations of IRIS are considered to be life or the manifestations of IRIS are considered to be life or organ-threatening, discontinuation of HAART is organ-threatening, discontinuation of HAART is sometimes necessary.sometimes necessary.

Corticosteroids or NSAIDS may help decrease the Corticosteroids or NSAIDS may help decrease the inflammatory response in some patients with IRIS.inflammatory response in some patients with IRIS.

PrognosisPrognosis

Usually self-limited, especially if the preexisting infection is Usually self-limited, especially if the preexisting infection is effectively treated. effectively treated.

Retrospective review Retrospective review IRIS patients had 1.34 more hospital admissions and 2.52 more IRIS patients had 1.34 more hospital admissions and 2.52 more

invasive procedures after 12 monthsinvasive procedures after 12 months Patients with IRIS had greater likelihood of successful immune Patients with IRIS had greater likelihood of successful immune

reconstitution (RR 2.24; P= 0.003) and increased rate of viral reconstitution (RR 2.24; P= 0.003) and increased rate of viral suppression (RR 3.32; P,< 0.001) after 24 monthssuppression (RR 3.32; P,< 0.001) after 24 months

No significant difference in mortality 24months after No significant difference in mortality 24months after starting HAARTstarting HAART

•Shelburne et al AIDS 2005

Unanswered QuestionsUnanswered Questions

Disease specific guidelines?Disease specific guidelines? True pathophysiology of IRIS ?True pathophysiology of IRIS ? Genetic markers to help predict patients who will develop Genetic markers to help predict patients who will develop

HIV-IRIS?HIV-IRIS? Predictors of HIV IRIS?Predictors of HIV IRIS? Optimal treatment for HIV IRIS?Optimal treatment for HIV IRIS? Optimal timing to start HAART in patients with Optimal timing to start HAART in patients with

opportunistic infections?opportunistic infections? Impact of IRIS on successful HAART implementation in Impact of IRIS on successful HAART implementation in

developing countries?developing countries?

Back to the PatientBack to the Patient

Received clarithromycin, ethambutol and rifabutin for MAI Received clarithromycin, ethambutol and rifabutin for MAI treatmenttreatment

Went on to develop CMV retinitis and dermatomal zoster Went on to develop CMV retinitis and dermatomal zoster thought related to IRISthought related to IRIS

Currently on HAART with CD4 count of 419 and an Currently on HAART with CD4 count of 419 and an undetectable viral loadundetectable viral load

Patient doing very wellPatient doing very well

Take Home PointsTake Home Points

History! History! History!History! History! History! Specific symptoms and time courseSpecific symptoms and time course History of OI’s including recently diagnosed OI’sHistory of OI’s including recently diagnosed OI’s Treatment of OI’s including initiation, medication adherence, therapy duration Treatment of OI’s including initiation, medication adherence, therapy duration

and clinical responseand clinical response ART initiation: date, regimen, adherenceART initiation: date, regimen, adherence Nadir CD4 count and viral loadNadir CD4 count and viral load Current CD4 count and HIV viral loadCurrent CD4 count and HIV viral load Medications especially new medicationsMedications especially new medications

HIV IRIS is a diagnosis of exclusionHIV IRIS is a diagnosis of exclusion Be suspicious!Be suspicious!

http://www.tac.org.za/community/files/Avelile%20before%20and%20after%20ART.jpg

AcknowledgementsAcknowledgements

Dr Seun Falade-NwuliaDr Seun Falade-Nwulia

ReferencesReferences

Hung YF, Ross FC Luis PV . AIDS Science and Society 4Hung YF, Ross FC Luis PV . AIDS Science and Society 4thth Edition Edition Shelburne SA et al. Immune reconstitution Syndrome. Emergence of a Unique Shelburne SA et al. Immune reconstitution Syndrome. Emergence of a Unique

Syndrome During Highly Active Antiretroviral Therapy. Medicine 2002:81. Syndrome During Highly Active Antiretroviral Therapy. Medicine 2002:81. 213-27213-27

Shelburne SA, Richard JH. The Immune Reconstitution Inflammatory Shelburne SA, Richard JH. The Immune Reconstitution Inflammatory Syndrome. AIDS Rev 2003;5:67-79Syndrome. AIDS Rev 2003;5:67-79

Dhasmana DJ et al. Immune Reconstitution Inflammatory Syndrome in HIV-Dhasmana DJ et al. Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Receiving Antiviral therapy. Pathogenesis, Clinical Infected Patients Receiving Antiviral therapy. Pathogenesis, Clinical Manifestations and Management. Drugs 2008:68(2) 191-208Manifestations and Management. Drugs 2008:68(2) 191-208

Shelburne SA et al. Incidence and risk factors for immune reconstitution Shelburne SA et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399-4062005;19:399-406

Shelburne SA et al Immune reconstitution inflammatory syndrome: more Shelburne SA et al Immune reconstitution inflammatory syndrome: more answers, more questions. Journal of Antimicrobial therapy (2006) 57: 167-answers, more questions. Journal of Antimicrobial therapy (2006) 57: 167-170170

Manabe YC et al. Immune Reconstitution Inflammatory Syndrome. Risk Manabe YC et al. Immune Reconstitution Inflammatory Syndrome. Risk facors and Treatment Implications. J Acquir Immune Defic Syndr facors and Treatment Implications. J Acquir Immune Defic Syndr 2007:46(4)456-462 2007:46(4)456-462

ReferencesReferences

Murdoch D et al. Immune reconstitution inflammatory syndrome (IRIS): Murdoch D et al. Immune reconstitution inflammatory syndrome (IRIS): review of commom infectious manifestations and treatment options. AIDS review of commom infectious manifestations and treatment options. AIDS Research and Therapy 2007 4:9Research and Therapy 2007 4:9

Boer M et al. Immune restoration disease in HIV-Infected individuals Boer M et al. Immune restoration disease in HIV-Infected individuals receiving highly active antiretroviral therapy: clinical and immunologic receiving highly active antiretroviral therapy: clinical and immunologic characteristics. Netherlands Journal of Medicine 2003;61(12)408-412characteristics. Netherlands Journal of Medicine 2003;61(12)408-412

French et al. Immune restoration disease after the treatment of French et al. Immune restoration disease after the treatment of immunodeficient HIV infected patients with highly active antiretroviral immunodeficient HIV infected patients with highly active antiretroviral therapy. HIV Medicine 2000;1107-115therapy. HIV Medicine 2000;1107-115

Jevtovic et al. The prevalence and risk of immune restoration disease in Jevtovic et al. The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy. HIV HIV-infected patients treated with highly active antiretroviral therapy. HIV Medicine 2005;6:140-143Medicine 2005;6:140-143

Murdoch D et al. Incidence and risk factors for the immune reconstitution Murdoch D et al. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008 22:601- 610study. AIDS 2008 22:601- 610

““Atazana….who?” Atazana….who?” A Discussion of Antiretrovirals for the A Discussion of Antiretrovirals for the

Management of HIV InfectionManagement of HIV Infection

Allison Agwu, M.D. Allison Agwu, M.D. Alice Jenh, PharmDAlice Jenh, PharmD

Adolescent Grand RoundsAdolescent Grand RoundsJune 26, 2009June 26, 2009

ObjectivesObjectives

To review important considerations, To review important considerations, contraindications and precautions in contraindications and precautions in selecting/reviewing an antiretroviral selecting/reviewing an antiretroviral regimen (first-line and subsequent). regimen (first-line and subsequent).

To recognize appropriate and inappropriate To recognize appropriate and inappropriate regimens and relevant medication regimens and relevant medication interactions interactions and adverse effects. and adverse effects.

ABP Adolescent Medicine Content OutlineABP Adolescent Medicine Content Outline

Primary Provider & HIV-Infected PatientsPrimary Provider & HIV-Infected Patients

Make no assumptions about medications (names, doses)Make no assumptions about medications (names, doses) Be able to recognize an appropriate/inappropriate regimenBe able to recognize an appropriate/inappropriate regimen Be cognizant of potential for drug-drug interactions (need for dose Be cognizant of potential for drug-drug interactions (need for dose

adjustments)adjustments) Be aware of contraindications/precautions when initiating other Be aware of contraindications/precautions when initiating other

medications!!!medications!!! Suspect and recognize adverse affects of therapy and medicationsSuspect and recognize adverse affects of therapy and medications Maintain open communication with HIV provider & ID serviceMaintain open communication with HIV provider & ID service Utilize pharmacy review and assistanceUtilize pharmacy review and assistance

Potential Drug InteractionsPotential Drug Interactions

CHECK EVERYTHING!!!CHECK EVERYTHING!!! PIs- cytochrome P450 inhibitors/inducers can have major PIs- cytochrome P450 inhibitors/inducers can have major

interactions with:interactions with: anticonvulsants, azoles; OCPs; rifampin, rifabutin; lipid-lowering anticonvulsants, azoles; OCPs; rifampin, rifabutin; lipid-lowering

agents (simvastatin/atorvastatin- contra-indicated); H2 blockers agents (simvastatin/atorvastatin- contra-indicated); H2 blockers (ATV!!!); CCBs, anticoagulants, anti-depressants, methadone, (ATV!!!); CCBs, anticoagulants, anti-depressants, methadone, anti-histamines, inhaled steroids; macrolides anti-histamines, inhaled steroids; macrolides

NNRTIs-lipid-lowering agents (reduces), OCPs, NNRTIs-lipid-lowering agents (reduces), OCPs, anticoagulants, methadoneanticoagulants, methadone

NRTIs- metforminNRTIs- metformin

Recognize adverse effects of ARVsRecognize adverse effects of ARVs

Lactic acidosis (NRTIs)Lactic acidosis (NRTIs) Pancreatitis (NRTIs, primarily DDI)Pancreatitis (NRTIs, primarily DDI) ABC - hypersensitivity (HLA B*5701), myocardial riskABC - hypersensitivity (HLA B*5701), myocardial risk Renal calculi (IDV)Renal calculi (IDV) Peripheral neuropathy (NRTIs)Peripheral neuropathy (NRTIs) Teratogenecity (EFV)Teratogenecity (EFV) Tenofovir (bone loss, renal dysfunction)Tenofovir (bone loss, renal dysfunction) Metabolic syndrome (PIs)Metabolic syndrome (PIs) Lipodystrophy (NRTIs, PIs)Lipodystrophy (NRTIs, PIs)

HIV ResourcesHIV Resources

Utilize resources Utilize resources HIV specialists HIV specialists IPC teamIPC team ID consultation service ID consultation service ALICE JENH, PHARMD (PAGERBOX-ABLE)ALICE JENH, PHARMD (PAGERBOX-ABLE)

THANK YOU!!!THANK YOU!!!

Other topics that you want to hear about?Other topics that you want to hear about?