Nesli Basgoz MD Massachusetts General Hospital

1. Nesli Basgoz MD Massachusetts General Hospital

2. Pro Early ART Improved immune response to OI/OM OI/OM without good treatment Prevention of next OI/OM Potential for better immune reconstitution with earlier ARVs Prevention of non-infectious complications Timing of ARVs in the ICU (or acutely ill with Opportunistic Infections or Malignancies ie OI or OM) Pro Delayed ART • Inability to tell toxicity of OI/OM treatment from ARVs • Making end organ dysfunction worse • Inability to tell OI/OM worsening from ARVs • IRIS • Drug-drug interactions • Malabsorption

3. ARV during Chemotherapy: What Made This Change Possible? • Development of safer ARVs (non myelosuppressive, less associated with peripheral neuropathy, less associated with multiorgan system dysfunction in patients presenting in fulminant stage of lymphoma or other malignancy • Retrospective and prospective cohort data demonstrating good tolerance and then improved outcomes with early ARV in OM • Similar data in early ARVs in OI

4. ACTG 5164: Early (<2 week) vs Deferred (> 2 week) ARV in Acute Ois Study Design Opportunistic InfectionTreatmentStarts ImmediateART 48wks 48wks Deferred ART RecommendedStart window -14 0 2 28 42 84 224 Study day 4 – 32 Weeks Randomization Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.

5. ACTG 5164 • Majority of OI were PCP • Included ICU patients • Most received corticosteroids for moderate to severe PCP • TB was excluded from the study • Median time to ARV initiation was 12 days • No difference between early vs delayed groups in primary, composite endpoint

6. A5164: Early ARV Associated with Reduced Risk of AIDS/Death 1.00 n=116 Probability of surviving withoutdeath/new AIDS defining event 0.9 0.8 n=94 0.7 0.6 HR=0.5395%CI (0.25,1.09)p=0.023 0.5 0.4 0.3 Early ART Deferred ART 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 • No difference in rate of virologic suppression • No difference in IRIS (10 immediate, 13 deferred) or chng. ARV • Conclusion: In this population, start ARV within 2 weeks • CAN THIS BE GENERALIZED? Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.

7. Timing of ARV in ICU • Sao Paulo, Brazil • Retrospective analysis • 278 ICU admissions ’96 –’06 • Median CD4 <50 • Multivariate logistic regression analysis • Decreased 6-month mortality if ART initiated in the ICU Initiated in the ICU • HR 0.627 (95%CI 0.393-0.999) Initiated in the 1st 4 days of the ICU admission Croda J, et al. IAS Mexico (2008); Abst.3436

8. Considerations in the ICU • All HIV ICU patients are not alike • Unlikely we will be able to do prospective studies stratifying patients, but more retrospective data should be available • Are there available drugs for Ois and for ARVs which are relatively safe with multiorgan system dysfunction? • Role of rapid diagnostics • Treat appropriate infections • Avoid multiple empiric therapies • Role of adrenal insufficiency and steroids

9. Ultimately, How Likely is the Patient to Survive without ARVs? • Many scoring systems exist which predict in-ICU mortality • Not validated specifically for HIV ICU patients, but could be • Do no harm, but in many cases, significant treatment-associated risk can be justified by knowing the statistical probability of death without ARVs • This is a calculus that can be understood by most providers and most families

10. Future Directions • We need to move past treating the sickest ICU patients with the lowest probability of survival without ARV • To prevent infections in the ICU, improved early testing and early ARVs should prevent Icu admission