Timing of ART in patients with opportunistic infections

Transcription

1 Timing of ART in patients with opportunistic infections Graeme Meintjes University of Cape Town Imperial College London HIV Congress 2014, Taj Lands End Hotel, Mumbai, 22 March 2014

2 OUTLINE Yesterday Prof Abdool Karim addressed trials of ART timing in TB: Reduced mortality/aids progression if initiate ART around 2 weeks in HIV-TB patients with CD4 < 50 This increases the risk of TB-IRIS (4-5 x) This talk will address: Recognising and managing TB-IRIS Contrast TB findings with cryptococcal meningitis and other OIs

3 Early ART in patient with OI Potential problems IRIS Co-toxicities Drug-drug PK interactions Absorption Pill burden Not treatment ready Potential benefits Reduced HIV progression Reduced mortality Clearance of OI Prevent OI recurrence

4 Earlier ART Deferred ART Risk of IRIS Risk of HIV disease progression MORTALITY MORTALITY When to start ART after recent diagnosis of OI? Several recent clinical trials Different answers for different OIs

5 ART timing and primary endpoints in patients with CD4 < 50 Death p= % Death/AIDS p= % Death/AIDS p= % * CAMELIA data represents all patients in trial, majority had CD4 < 50 (median CD4 =25)

6 SAPiT IRIS incidence (IRIS cases/100 person years) ART within 4 weeks ART 8-12 weeks 10 0 All pa ents CD4 < 50 CD4 50 Naidoo, Annals Intern Med 2012

7 Recognising and managing TB-IRIS

8 Suppression of HIV replication on ART Early reversal of immune suppression (systemically and at tissue level) 1-2 log drop in VL in first 2 weeks Kuritzkes, JID 2007 Inflammatory reactions Targeted at TB antigens Clinical deterioration with TB-IRIS IRIS = Immune reconstitution inflammatory syndrome

9 Paradoxical TB-IRIS characteristics Incidence 8 54% (15.7% in meta-analysis) Onset of symptoms: Median 14 days from ART start Hospitalisation in up to 48% Median duration 2-3 months in literature 69 days (IQR = ) in our cohort studies (n=217) Mortality infrequent Meta-analysis 3.2% (CNS TB-IRIS = 25-75%) Meintjes Lancet Infect Dis 2008;8:516, Muller Lancet Infect Dis 2010;10:251, Agarwal AIDS Res Ther 2012;9:17, Meintjes Clin Infect Dis 2009;48:667, Burman IJTLD 2007;11:1282, Bana unpublished

10 Key points in TB-IRIS diagnosis 1. Diagnosis of TB confirmed or very likely? 2. Improvement on TB treatment prior to ART? 3. Symptom onset typically 1-4 weeks on ART 4. Deterioration with inflammatory features of TB 5. Consider and exclude differential diagnoses 6. Exclude drug-resistant TB There is no confirmatory diagnostic test

11 Severity: wide spectrum Recurrent fevers and night sweats Fatal enlargement of cerebral tuberculoma complicated by cerebral oedema

12 Major TB-IRIS syndromes 1. Lymphadenitis 2. Pulmonary 3. Neurological 4. Abdominal 5. Serositis (effusions) 6. Features of systemic inflammation - High fevers, marked tachycardia, weight loss 83% multisystem manifestations in our cohort studies

13 Lymphadenitis 40% of TB-IRIS cases Prominent features of acute inflammation Typically suppurate within weeks Independent predictor of prolonged IRIS (>90 days) aor = 2.7 (95%CI = ) 6/217 patients in our cohort studies had IRIS > 365 days typically suppurative lymphadenitis Bana et al, unpublished

14 Pulmonary features 41% of TB-IRIS cases in our cohort studies Recurrent cough, with worsening pulmonary infiltrate and cavitation

15 Neurological TB-IRIS 12% with paradoxical TB-IRIS have CNS involvement Up to 47% of TBM patients starting ART develop IRIS Features Meningitis Tuberculoma/s Radiculomyelopathy Occurs in patients with or without CNS TB prior to ART Outcomes 13% mortality and 18% loss to follow-up in one series 25% and 75% mortality in other series Neurological disability Pepper et al, Clin Infect Dis 2009 Marais et al, Clin Infect Dis 2012 Agarwal et al, AIDS Res Ther 2012

16 Abdominal features Lymph node enlargement Abscess formation Peritonitis and ascites Liver involvement Splenic involvement and rupture Intestinal involvement Renal involvement

17 Pericardial effusion with tamponade (1 litre drained) New right pleural effusion

18 Rationale for steroid trial Anecdotal reports of symptomatic response Potential risks in patients with advanced HIV 110 participants (55 each arm) Life-threatening TB-IRIS was an exclusion Open-label prednisone at physician discretion if clinical deterioration/relapse Meintjes et al, AIDS 2010;24:2381

19 HIV-TB patients recently started ART with suspected TB-IRIS Assessed using a clinical case definition for TB-IRIS and alternative diagnoses excluded Inclusion criteria Informed consent Randomised Prednisone 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks Identical placebo 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks Followed for a total of 12 weeks Primary endpoint: Total number of days hospitalised + outpatients therapeutic procedures Secondary endpoints included symptom score, CXR score and steroid side effects

20 Primary endpoint Cumulative number of days hospitalized and outpatient therapeutic procedures (counted as 1 additional day), ITT analysis Placebo arm N = 55 Prednisone arm N = 55 P-value Total days hospitalized Total number outpatient procedures Cumulative primary endpoint (median, IQR) 3 (0-9) 0 (0-3) 0.04 Significant reduction in morbidity associated with prednisone treatment

21 Prednisone treatment for TB-IRIS No excess of severe infections or metabolic side effects with 4 week course of prednisone Based on these findings If clinical diagnosis of TB-IRIS is made and other reasons for deterioration excluded And symptoms are significant Prednisone starting at 1.5mg/kg/d is indicated

22 Preventing TB-IRIS in high-risk patients: Randomized placebo-controlled trial of prednisone (PredART trial) Early ART (~2 weeks) reduces mortality and progression to AIDS in patients with TB and low CD4 counts, but increases the risk of paradoxical TB-IRIS. Paradoxical TB-IRIS causes morbidity, many patients require hospitalisation and it consumes health care resources. An evidenced-based prevention strategy is required. PredART is a randomized placebo-controlled double-blind trial to determine if addition of prednisone to the first 4 weeks of ART reduces the incidence of paradoxical TB-IRIS in HIV+ patients being treated for TB who are at high risk for TB-IRIS (CD4 <100 and starting ART within 30 days of TB treatment).

23 TB TREATMENT (and CO-TRIMOXAZOLE) ART started within 30 days of TB treatment ART HIV-infected ART-naive CD4 < 100 TB diagnosed n = 240 Informed consent Randomised 1:1 Start ART + 4 weeks prednisone Start ART + 4 weeks placebo Follow-up for 12 weeks (Visits at weeks 1,2,4,8 and 12) Follow-up for 12 weeks (Visits at weeks 1,2,4,8 and 12) Dose of prednisone/placebo: 40mg/day x 2 weeks then 20mg/day x 2 weeks Primary endpoint: Development of paradoxical TB-IRIS ClinicalTrials.gov NCT

24 ART timing in cryptococcal meningitis and other OIs

25 Trials of ART timing in cryptococcal meningitis prior to the COAT trial Sample size Cryptococcal induction Rx Arms Outcome Zolopa (ACTG A5164, mainly US) 41 AmB-based Median 12 vs 45 days Trend towards lower mortality/aids progression with early ART Makadzange (Zimbabwe) 54 Fluconazole 800mg Within 3 days vs 10 weeks Higher 3-year mortality with early ART (88% vs 54%, p<0.006) Bisson (Botswana) 27 AmB-based Median 7 vs 32 days No mortality difference; increased IRIS in early arm (54% vs 0%, p=0.002) Zolopa PLoSONE 2009;4:e5575, Makadzange Clin Infect Dis 2010;50:1532, Bisson Clin Infect Dis 2013;56:1165

26 Randomized Strategy Trial Cryptococcal Optimal ART Timing (COAT) Trial Uganda and South Africa HIV-infected ART-naïve Cryptococcal meningitis HYPOTHESIS Early ART will reduce mortality EARLY ARM ART 1-2 weeks Randomization Stratified by Site and Altered Mental Status DEFERRED ARM ART 5-6 weeks PRIMARY ENDPOINT SURVIVAL AT 26 WEEKS Target enrollment = participants enrolled Enrollment halted after 17 months by NIAID Africa DSMB Clinicaltrials.gov NCT Boulware et al, CROI 2013, Abstract 144

27 70% 55% P=0.03 Hazard ratio [HR] = 1.7 (95% CI = ) Early ART: 70% mortality Recognised cryptococcal IRIS events Early ART = 17/87 (20%) Deferred ART = 9/69 (13%) p=0.32 Boulware et al, CROI 2013

28 DEFERRED ART ART Neurological dysfunction CM Rx Neuro-inflammation Weeks EARLY ART Neurological dysfunction ART CM Rx IRIS Neuro-inflammation Weeks

29 Day 14 CSF findings Early ART arm (on ART 5-6 days) vs Deferred ART arm (not on ART) WCC in CSF markers of monocyte/macrophage activation (scd14,scd163) No significant differences in cytokine concentrations Scriven et al, Abstract 859, CROI 2013

30 Cryptococcal meningitis IRIS Patient diagnosed with CM Started on treatment and improves Days to months later (median 29 days) Starts ART Meta-analysis: Incidence = 20% Mortality = 21% Other IRIS features: Cryptococcomas Lymphadenitis Develops meningitis symptoms again Typically fungal culture negative Raised intracranial pressure Bicanic, JAIDS 2009 Muller, Lancet ID 2010

31 MRI demonstrating hydrocephalus and marked periventricular, brainstem and meningeal enhancement

32 Management of CM-IRIS Consider relapse as differential diagnosis CSF for 14 day fungal culture Restart AmphoB-based treatment if severe Therapeutic LPs Analgesia CT head scan No clinical trials evidence for steroids Generally used if severe or refractory Starting with prednisone 1mg/kg/d SA HIV Clinicians Society Cryptococcal Guidelines 2013

33 ACTG A5164 trial Multicenter: United States and South Africa Treatable OI or Bacterial infection with CD4 < 200 n = 282 Median CD4 = 29 92% ART naïve ART within 14 days (Median: 12 days ) Randomised 1:1 (Stratified by infection and CD4 count) Followed 48 weeks from study entry Entry infection PCP 63% Cryptococcus 12% Bacterial 12% TB excluded ART deferred until after OI treatment (Median: 45 days) Zolopa, PLoS ONE 2009;4:e5575 Grant, PLoS ONE 2010;5:e11416

34 Time to AIDS Progression or Death Zolopa, PLoS ONE 2009;4:e HR= %CI ( ) p = Immediate Deferred Immediate Deferred Time to Death/new AIDS defining illness (weeks)

35 AIDS progression/death 14.2% in early arm 24.1% in deferred arm OR = 0.51 (95%CI = ) IRIS incidence Early arm Deferred arm p-value 5.7% 8.5% 0.49 Of patients with PCP starting ART, 4/171 (2%) developed paradoxical PCP-IRIS Zolopa, PLoS ONE 2009;4:e5575 Grant, PLoS ONE 2010;5:e11416

36 Tuberculosis Conclusions Start ART within 2 weeks if CD4 < 50 Increased risk of TB-IRIS: recognise and treat Can delay up to 8 weeks if CD4 > 50 and no other stage 4 illness Cryptococcal meningitis Defer ART to 4-6 weeks Other OIs Start within 2 weeks

37 Acknowledgements TB-IRIS research Robert Wilkinson Gary Maartens Katalin Wilkinson Suzaan Marais Charlotte Schutz Tasnim Bana Maia Lesosky Molebogeng Rangaka Chelsea Morroni Tolu Oni Dominique Pepper Kevin Rebe Rene Goliath Helen van der Plas Marc Mendelson Priscilla Mouton Bob Colebunders Anali Conesa Botella Keira Skolimowska Kerryn Matthews Rebecca Tadokera Mark Sonderup Cryptococcal research David R Boulware David B Meya Conrad Muzoora Melissa A Rolfes Kathy Huppler Hullsiek Abdu Musubire Kabanda Taseera Henry W Nabeta Monica Magwayi Brian Memela Yolisa Sigila Charlotte Schutz Darlisha Williams Radha Rajasingham Joshua Rhein Melanie W Lo Friedrich Thienemann Andrew Kambugu Yukari Manabe Edward N. Janoff Paul R Bohjanen James Scriven Lisa Graham David Lalloo

38 Research funders

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40 HIV viral load response to ART ART commenced 1-2 log drop in VL over first 2 weeks of ART Kuritzkes, JID 2007

41 CD4 recovery on ART Staszewski NEJM;341:1865 On average 75 cells/μl increase in 1st month then 75 cells/μl increase per year thereafter

42 Gene expression transcriptional profile of blood in TB-IRIS patients (n=16) Very early changes in gene expression in many cell signalling, inflammatory and other pathways Baseline Week 0.5 Week 1 Week 2 Weeks on ART Lai, Meintjes, et al Unpublished