Graeme Meintjes Department of Medicine, University of Cape Town HIV Service, GF Jooste Hospital TB-IRIS Research priorities and update from Kampala workshop.

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