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CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS

CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS. Dr. Andrew D. Kambugu Infectious Diseases Institute Makerere University College of Health Sciences Uganda. Discussion outline. Why co-infections in this era? Challenges of managing co-infections in RLS ART initiation in TB studies

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CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS

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  1. CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS Dr. Andrew D. Kambugu Infectious Diseases Institute Makerere University College of Health Sciences Uganda

  2. Discussion outline Why co-infections in this era? Challenges of managing co-infections in RLS ART initiation in TB studies ART initiation in Cryptococcal meningitis Conclusions

  3. Patients starting ART at higher CD4+ cell counts overall, but disparities remain 246 262 307 252 118 137 234 140 185 145-176 Low income 89 200 225 Middle income 286 150 High income 1. Mugglin C, et al. CROI 2012. Abstract 100; 2. Truong HH, et al. CROI 2012. Abstract 139. CD4+ cell count at start of ART (cells/mm3), 20091 In San Francisco study, overall trends of starting ART at higher CD4+ counts, but pts initiating ART at CD4+ counts >350 cells/mm3 significantly more likely to be white, older, MSM, non-poor, and diagnosed by private provider2

  4. The HIV care cascade 100 Factors involved in the diagnosis, access to care, retention andtreatment of HIV infection in the United States and Mozambique United States Mozambique 80 60 The challenge of retention is a reality for both developed and developing world settings Percent of persons 40 20 0 Diagnosis ofHIV infection Linkageto care Retentionin care or eligibilityfor ART Receiptof ART Adherenceto ART Data for adherence to ART for the US represent the proportion of persons withviral suppression For Mozambique, the data represent the proportion of persons with adherence to ART, according to responses on questionnaires and pill counts among persons who were retained in care for >1 year (as viral levels were not obtained) Piot P. and Quinn TC. N Engl J Med 2013;368:2210–8

  5. Forest plot of estimates of mortality at 12 months by individual studies and pooled by region 0.17 (0.11, 0.24) Sub-Saharan Africa Sub-Saharan Africa 0.11 (0.10, 0.13) Asia 0.07 (0.007, 0.20) Americas 0.08 (0.06, 0.10) Multi-regional 0.14 (0.10, 0.20) Combined 0.0 0.1 0.2 0.3 0.4 Proportion (95% confidence interval) 0.0 0.1 0.2 0.3 0.4 Proportion (95% confidence interval) Asia Americas Multi- regional Gupta A, et al. PLoS ONE 2011;6:e2869

  6. Impact of ART on mortality:Ugandan cohort study All cause mortality in adults aged 15–59 years, pre- and post-ART roll-out The impact of ART treatment on mortality trends of HIV-positive adults in rural Uganda: a longitudinal population-based study, 1999–2009 Kasamba I, et al. Trop Med Int Health 2012;17:e66–73

  7. Current realities in RLS Leaky HIV care cascade: Low ART coverage Low CD4 at ART initiation Substantial (early) mortality with ART Early mortality in ART cohorts driven largely by opportunistic infections (OIs) (co-infection)

  8. The ART eligibility pendulum Moderate immune suppression Early HIV infection Advance immune suppression Early ART StartDelayed ART Start

  9. ART initiation dilemmawith co-infections PILL BURDEN DRUG –DRUG INTERACTIONS LOSS TO FOLLOW-UP IRIS EVENTS OI RISK Early ART StartDelayed ART Start

  10. IRIS: A case report summary Patient attending clinic at IDI - with kind permission of patients and study team

  11. When to start ART in TB:Building on previous studies 1. Blanc IAC, 2010; 2. AbdoolKarim SS, et al. N Engl J Med 2010;362:697–706

  12. Effect of ART timing on TB death (CAMELIA) or death/AIDS progression (STRIDE, SAPIT) Earlier: 2–4 weeks after TB treatment started 19% ↓ P=0.45 Later: 8–12 weeks after TB treatment started 34% ↓ P=0.004 11% ↓ P=0.73 Blanc FX, et al. N Engl J Med 2011;365:1471–81; Havlir DV, et al. N Engl J Med 2011;365:1482–91; AbdoolKarim SS, et al. N Engl J Med 2011;365:1492–501

  13. Significant reduction in death/AIDS amongthose with TB and CD4 <50 cells/mm3 Earlier: 2–4 weeks after TB treatment started 42% ↓ P=0.02 68% ↓ P=0.06 Later: 8–12 weeks after TB treatment started 34% ↓ P=0.004 Blanc FX, et al. N Engl J Med 2011;365:1471–81; Havlir DV, et al. N Engl J Med 2011;365:1482–91; Abdool Karim SS, et al. N Engl J Med 2011;365:1492–501

  14. Greater reduction in mortality at lower CD4 P=0.004 P=0.45 P=0.73 Blanc FX, et al. N Engl J Med 2011;365:1471–81; Havlir DV, et al. N Engl J Med 2011;365:1482–91; Abdool Karim SS, et al. N Engl J Med 2011;365:1492–501

  15. ART in TB/HIV co-infection Suggested timing of ART initiation in TB/HIV co-infection according to CD4/mm3: EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  16. ART initiation within the first2 weeks of Cryptococcal Meningitis isassociated with higher mortality:A Multisite Randomized Trial David R Boulware, David B Meya, Conrad Muzoora, Melissa A Rolfes, Kathy HupplerHullsiek, Abdu Musubire, KabandaTaseera, Henry W Nabeta, Charlotte Schutz, Darlisha Williams, RadhaRajasingham, Joshua Rhein, Melanie W Lo, Friedrich Thienemann, Andrew Kambugu, Yukari Manabe, Edward N. Janoff, Paul R Bohjanen, Graeme Meintjes, and the COAT Team Cryptococcal Optimal ART Timing (COAT) Trial Clinicaltrials.gov NCT01075152

  17. Equipoise:

  18. Existing conflicting data ACTG a5164, median 12 days vs. 42 days after OIs: CROI 20081 • Fewer deaths and new AIDS events, P=0.035 • 14% early ART vs. 24% deferred ART, overall • N=41 cryptococcal meningitis enrolled • Trend favoring early ART (OR: ~0.2, 95% CI: 0.05 to 1.5) Zimbabwe RCT, n=54 CROI 20092 • ART at <72 hours (median <24 Hr) (n=26) vs. 10 weeks after CM (n=28) • Fluconazole 800 mg for induction Rx with d4T/3TC/NVP • 88% vs. 54% mortality in immediate vs. delayed ART arms • Per Protocol Analysis, censoring of persons w/delayed ART lost early Botswana RCT, n=27 no difference 20133 • Early ART more IRIS 1. Zolopa A, et al. PLoS One 2009;4:e5575; 2. Makadzange AT, et al. Clin Infect Dis 2010;50:1532–8; 3. Bisson G, et al. Clin Infect Dis 2013;56:1165–73

  19. Randomized strategy trialCryptococcal Optimal ART Timing (COAT) trial Randomization stratified by site and by altered mental status Clinicaltrials.gov NCT01075152

  20. COAT trial endpoints Primary: Survival at 26-weeks Intention to Treat Secondary: Cryptococcal-IRIS incidence through 46 weeks Survival through 46 weeks, by time-to-event Functional Status (Karnofsky) through 46 weeks Microbiologic clearance a. Quantitative clearance (log10 CFU/mL CSF/day) b. Sterile CSF culture at 14-days of amphotericin c. Cryptococcal relapse incidence Virologic suppression at 26 weeks Tolerability (ART discontinuation ≥3 days) Safety (DAIDS Grade ≥3 events)

  21. Enrollment criteria Inclusion: Exclusion: Prior cryptococcal meningitis Pregnancy or breastfeeding Cannot attend regular visits Chemotherapy Inability to take enteral meds Serious co-morbidities, co-infections, or laboratory values who should not receive ART immediately or have ART delayed Females must use >2 methods of contraception (fluconazole is teratogenic in 1st trimester) • HIV-infection • ART naïve • Age >14 years • Cryptococcal meningitis by : • CSF culture • CSF cryptococcal antigen • Receiving amphotericin-based therapy • Informed consent

  22. COAT trial treatment for cryptococcal meningitis 1Longer duration of consolidation therapy if CSF culture positive at 2-weeks Therapeutic LPs at diagnosis, Day 7, Day 14, and additional LPs as needed for pressure control

  23. CONSORT diagram Screened N=389 147 alternate concomitant diagnosis 4 death 1 left hospital N=152 Positive for Cryptococcal meningitis N=237 33 died 15 not eligible 6 left hospital against medical advice 4 declined 2 received HIV care elsewhere N=60 Randomized N=177 Kampala N=115 Mbarara N=35 Cape Town N=27

  24. Baseline characteristics by arm

  25. Overall survival 1.0 1. Early ART 0.8 2. Deferred ART 70% 55% Cumulative probability of survival 0.6 P=0.03 0.4 0 1 2 4 6 8 10 12 Months from randomization

  26. Overall survival for those with baseline GCS <15 1.0 0.8 1. Early ART 2. Deferred ART 0.6 Cumulative probability of survival 0.4 0.2 P=0.05 0 1 2 4 6 8 10 12 Months from randomization

  27. Overall survival for those with CSF WBC <5at randomization 1.0 0.8 1. Early ART 2. Deferred ART 0.6 Cumulative probability of survival 0.4 0.2 P=0.01 0 1 2 4 6 8 10 12 Months from randomization

  28. Overall survival for those with CSF WBC ≥5at randomization 1.0 0.8 1. Early ART 2. Deferred ART 0.6 Cumulative probability of survival 0.4 0.2 P=0.73 HR=0.80 0 1 2 4 6 8 10 12 Months from randomization

  29. IRIS incidence Odds Ratio: 1.7 (95% CI: 0.65–4.54) for IRIS with early ART

  30. Causes of death Early vs. Deferred: • Cryptococcosis(21 vs. 10) • Septicemia (8 vs. 5) • TB (2 vs. 2) • IRIS-related (1 vs. 2) Adjudication still ongoing

  31. Time to grade 4 or 5 adverse event (grade 5 events not related to CM) 1.0 0.8 1. Early ART 0.6 2. Deferred ART Log rank P=0.19 Event probability 0.4 0.2 0 0 1 2 4 6 8 10 12 Months from randomization

  32. Conclusions There’s no one-size-fits all model for optimal timing of ART in setting of co-infections as disease-specific studies indicate opposing recommendations Earlier ART initiation before onset of OIs may alleviate the complexity of optimal timing Disease-specific approaches to ART timing will still inform practice in RLS due to health systems (and resource) constraints

  33. Acknowledgements • The Infectious Diseases Institute (IDI), Makerere University College of Health Sciences David Meya Abdu Musubire Henry Nabetta • Mbarara University of Science and Technology (MUST) Conrad Muzoora KabandaTessera • University of Minnesota (UMN) David Boulware Paul Bohjanen Joshua Rhein • University of Cape Town (UCT) Graham Meintjes

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