Graeme MeintjesGraeme MeintjesDepartment of Medicine, University of Cape Town Department of Medicine, University of Cape Town
HIV Service, GF Jooste HospitalHIV Service, GF Jooste Hospital
TB-IRISTB-IRISResearch priorities and Research priorities and update from Kampala update from Kampala
workshopworkshop
TB-IRIS workshopTB-IRIS workshopKampala, Uganda, 28-30 Kampala, Uganda, 28-30
Nov 2006Nov 2006
TB-IRISTB-IRIS
““Unmasking” of untreated TBUnmasking” of untreated TB
Paradoxical deterioration on TB Paradoxical deterioration on TB treatmenttreatment
Paradoxical TB-Paradoxical TB-IRISIRIS
TB-IRIS paradoxical TB-IRIS paradoxical reactionsreactions
Incidence: 8-45%Incidence: 8-45% Median 2-4 weeks after ART initiationMedian 2-4 weeks after ART initiation Risk factorsRisk factors
Shorter interval between TB treatment and Shorter interval between TB treatment and ART initiationART initiation
Disseminated TBDisseminated TB Low baseline CD4 and high baseline VLLow baseline CD4 and high baseline VL Vigorous CD4/VL response to ARTVigorous CD4/VL response to ART
Life threatening complications described Life threatening complications described but mortality rare but mortality rare Lawn 2005, Shelburne 2005, Breton 2004, Narita 1998, Michailidis 2005,Ollala 2002, Breen 2004, Kumarasamy 2004, Lawn 2007
TB-IRIS in resource TB-IRIS in resource constrained settingsconstrained settings
Higher burden of TB in ART programmesHigher burden of TB in ART programmes 23% of those initiating ART on concurrent TB 23% of those initiating ART on concurrent TB
treatment (Lawn 2006) treatment (Lawn 2006)
Clinical expertise, investigations and Clinical expertise, investigations and treatment options limitedtreatment options limited
Anticipate greater impact on morbidity Anticipate greater impact on morbidity and mortalityand mortality
Prospective cohort studies neededProspective cohort studies needed
Challenges in diagnosisChallenges in diagnosisNo diagnostic test; diagnosis of No diagnostic test; diagnosis of
exclusionexclusion
ADDITIONAL DIAGNOSIS
Bacterial infectionsFungal infectionsNTM infectionsMalignancies
DRUG RESISTANCE
13/141 in Cape Town cohort of TB-IRIS suspects had
MDR or Rifampicin monoresistant
DRUG REACTION
Drug fever vs TB-IRIS feverHepatic involvement
IRIS + IRIS -
PathogenesisPathogenesis
Case definition (1)Case definition (1) Diagnosis of HIV and TB Diagnosis of HIV and TB – WHO criteria– WHO criteria Response to TB treatmentResponse to TB treatment – –
improved/stabilisedimproved/stabilised On ARTOn ART
Response documented by >1 log decrease in Response documented by >1 log decrease in HIV RNA, though HIV RNA, though seldom availableseldom available
OnsetOnset within 3 months (up to 6) of within 3 months (up to 6) of starting/changing ARTstarting/changing ART
Exclusion of alternative explanationExclusion of alternative explanationTB treatment failure due to drug resistanceTB treatment failure due to drug resistanceAnother opportunistic infection or neoplasmAnother opportunistic infection or neoplasmDrug toxicity or reactionDrug toxicity or reactionComplete non-adherence to ARTComplete non-adherence to ART
Case definition -(2)Case definition -(2)Clinical criteriaClinical criteria
Major Major 1) New/enlarging lymph nodes, cold abscesses or other 1) New/enlarging lymph nodes, cold abscesses or other
focal tissue involvementfocal tissue involvement2) New/worsening radiological features of TB2) New/worsening radiological features of TB3) Breakthrough TB meningitis or new/enlarging focal 3) Breakthrough TB meningitis or new/enlarging focal
CNS lesionCNS lesion4) New or worsening serositis4) New or worsening serositis
MinorMinor 1) Constitutional symptoms- e.g., fever, night sweats1) Constitutional symptoms- e.g., fever, night sweats2) Respiratory symptoms - e.g., cough, dyspnea, stridor2) Respiratory symptoms - e.g., cough, dyspnea, stridor3) Abdominal pain and/or hepatomegaly3) Abdominal pain and/or hepatomegaly4)4) Resolution of clinical and/or radiological findings Resolution of clinical and/or radiological findings
without change in TB treatmentwithout change in TB treatment
1 major or 2 minor1 major or 2 minor
Treatment: Treatment: corticosteroids corticosteroids
Case reports documenting response Case reports documenting response Potential complications Potential complications
KS, herpes reactivations and other side KS, herpes reactivations and other side effectseffects
Many cases self-limitingMany cases self-limiting Dose and duration?Dose and duration?
Randomised controlled trialRandomised controlled trialPrednisone vs placebo for mild and Prednisone vs placebo for mild and
moderate TB-IRISmoderate TB-IRISCape Town, South AfricaCape Town, South Africa
Severe TB-IRIS excluded Severe TB-IRIS excluded Neurological, respiratory failure, airway Neurological, respiratory failure, airway
compromisecompromise Prednisone or placeboPrednisone or placebo
1,5mg/kg/d x 2 weeks then 0,75mg/kg/d 1,5mg/kg/d x 2 weeks then 0,75mg/kg/d x 2 weeksx 2 weeks
Primary endpointsPrimary endpoints Hospitalisation and proceduresHospitalisation and procedures
62 of 100 patients enrolled62 of 100 patients enrolledMeintjes, Rebe, Rangaka, Pepper, Wilkinson, Maartens
PreventionPreventionOptimal timing of ART initiation in those on Optimal timing of ART initiation in those on
TB treatment?TB treatment?
EARLY DELAYED
IRIS and otherconcerns
Risk of disease progression and death
““Unmasking” TB-Unmasking” TB-IRIS IRIS
““Unmasking” TB-IRIS in Unmasking” TB-IRIS in developing country settingsdeveloping country settings High rates of incident TB in the High rates of incident TB in the
period after ART initiation period after ART initiation 17.6/100 person years (Bonnet 2006)17.6/100 person years (Bonnet 2006) 23/100 person years in first 90 days 23/100 person years in first 90 days
(Lawn 2006) (Lawn 2006) Cases of accelerated TB (John 2006)Cases of accelerated TB (John 2006) Background of high TB incidence in Background of high TB incidence in
those not on ART those not on ART Unclear extent of role IRIS plays in Unclear extent of role IRIS plays in
the presentation of incident TB early the presentation of incident TB early after ART initiation after ART initiation
Post-ART TBPost-ART TB
Is the Is the incidenceincidence of TB increased in first 6 of TB increased in first 6 months of ART?months of ART?
Is the Is the presentationpresentation of TB accelerated? of TB accelerated?
Are Are paradoxical reactionsparadoxical reactions more common? more common?
What is the most effective method to What is the most effective method to screenscreen for active TB prior to ART initiation? for active TB prior to ART initiation?
PRIORITY ISSUESPRIORITY ISSUES
1.1. Validation of case definition for Validation of case definition for paradoxical TB-IRISparadoxical TB-IRIS
2.2. Defining the role of steroids in treatment Defining the role of steroids in treatment of paradoxical TB-IRISof paradoxical TB-IRIS
3.3. Timing of ART in patients on TB treatmentTiming of ART in patients on TB treatment
4.4. Screening for active TB pre-ARTScreening for active TB pre-ART
AcknowledgementsAcknowledgements
Kampala workshop organisers in particular Kampala workshop organisers in particular Bob Colebunders and William WorodriaBob Colebunders and William Worodria
Infectious Diseases Institute, Makerere Infectious Diseases Institute, Makerere University University
European and Developing Countries Clinical European and Developing Countries Clinical Trials Partnership Programme (EDCTP)Trials Partnership Programme (EDCTP)
Belgian General Development CooperationBelgian General Development Cooperation