1. Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Quando cominciare: Impatto delle comorbidità A. Cingolani

2. Should have we started HAART early during OIs before ACTG 5164? Effective for OI for which effective therapy does not exist or has limited efficacy (cryptosporidiosus, microsporidiosis, PML, KS) Faster resolution of OI Reduced risk of a second OI Reduced drugs absorbtion in severely ill pts HAART toxicity Drug-drug interactions Reduced adherence Dosing of HAART drugs difficult to estimate due to renal/hepatic dysfunction Risk of IRIS ProsContra

3. When to start HAART in non-TB OIs: from international to national guidelines GuidelinesRecommendations DHHS 2009-For OI without any effective tx (cryptosporidiosis, mycrosporidiosis, PML): treat as soon as possible (AIII) -Cryptococcal meningitis, non-tuberculous mycobacteria: a short delay may be warranted (CIII) -Other (such as PCP): tx should not be delayed (AI) EACS 2010As soon as possible, without delay BHIVA 2008Treat (except for TB>350 cd4/mmc) Linee guida italiane, 2010

4. ACTG 5164: Immediate treatment associated with reduced rate of AIDS progression / death Reduced rate of AIDS progression or death (14%) with immediate treatment vs deferred treatment (24%) 116 94 Immediate Deferred 0 8 16 24 32 40 48 Time to death/new AIDS defining illness (weeks) Probability of surviving withoutdeath/new AIDS defining event Time to AIDS complication or death 1.0 0.8 0.6 0.4 0.2 0 HR = 0.53 ;99% CI (0.25, 1.09) p = 0.023 Zolopa et al. PLoS One 2009;4:e5575 Time of ART initiation Immediate ARTDeferred ART Days from randomisation to ART, median (IQR) 035 Days from OI to ART, median (IQR) 12 (9–13)45 (41–55)

5. Cost-effectiveness of early HAART in OIs: ACTG 5164 model-projected 1-year survival associated with early antiretroviral therapy (ART) and deferred GRT at baseline ($31,900/QALY) GRT at treatment failure ($26,900/QALY) testing for HLAB*5701 ($39,700/QALY) guideline-recommended care for patients with diabetes mellitus and mixed dyslipidemia ($52,200/QALY) hemodialysis for critically ill patients ($158,200/QALY) Cost-effectiveness of other widely recommended interventions: Sax, HIV Clin Trials 2010

6. Is it everything clear after ACTG 5164? Have all OIs to be considered similar in terms of timing of starting HAART? When starting HAART in patients with TB? Does the risk of IRIS overweight the benefit of early initiation of HAART in specific OIs? Is immune recovery at starting HAART affected by specific Ois ?

7. Early initiation of HAART during cryptococcal meningitis treatment worsens survival 54 patients initiated HAART –Early: within 72 h of diagnosis, or –Delayed: 10 weeks after fluconazole monotherapy At 2 years follow-up, mortality rate was 82% in the early treatment group vs 37% in the delayed treatment group (p<0.006) Median survival time(early vs delayed): 28 vs 637 days (p=0.03 at log rank) Makadzange et al. Clin Infect Dis 2010,

8. …is it really to be considered due to IRIS? Prospective study on 65 pts with CM, treated with AmB. Bicanic, JAIDS 2009

9. Risk of IRIS in ACTG 5164 Cox Proportional Hazards Models Using Time Varying Covariate Models Grant, PlosOne 2010

10. When to start HAART during tuberculosis according with CD4 level CD4<100100-200A200-350>350 IDSA, 2009After 2 wks (BII)Within 2 mt (BII)After 2 mtAfter end of TB tx DHHS, 2009After 2 wksAfter 8 wksAfter 2 mt8-24 w or after end of TB tx EACS, 2009As soon as practical As soon as practical or after 2 mt At discretion BHIVA, 2005As soon as practical Aftr 2 mtAfter 6 mt E fortemente raccomandato un inizio del trattamento antiretrovirale entro i primi 3 mesi di terapia antitubercolare a prescindere dal valore dei CD4+ e della viremia [AI]. in pazienti con linfociti CD4+ < 350 cellule/ L è consigliabile iniziare la cART appena possibile, attendendo tuttavia almeno due settimane dopo linizio della TAT per una valutazione precoce di segni e sintomi legati a possibili reazioni avverse ai farmaci antitubercolari [BIII]; in pazienti con linfociti CD4+ compresi tra 350 e 500 cellule/ L si consiglia comunque un inizio precoce della terapia antiretrovirale (tra 2 settimane e due mesi dallinizio della TAT) [BIII]; in pazienti con linfociti CD4+ > 500 cellule/ L il timing della cART andrà stabilito nei singoli casi sulla base di valutazioni costo-beneficio [CIII]. Linee guida italiane, 2010

11. SAPIT: Initiation of HAART during TB treatment improves survival Months post-randomisation Survival probability (%) 0 36 9 75 70 80 85 90 95 25814710 Integrated arm (n = 429) Intensive phase of TB treatment 11 1417 2013 16 19 1215 1821 232224 100 Continuatio n phase of TB treatment Post-TB treatment Sequential arm (n = 213) Kaplan-Meier survival curve Outcome Integrated Therapy (n = 429) Sequential Therapy (n = 213) HR (95% CI) P Valu e All patients Death rate per 100 person-yrs Deaths, n 5.4 25 12.1 27 0.44 (0.25- 0.79).003 CD4+ cell count 200 cells/mm 3 Death rate per 100 person-yrs Deaths, n 8.2 23 15.3 21 0.54 (0.30- 0.98).04 CD4+ cell count > 200 cells/mm 3 Death rate per 100 person-yrs Deaths, n 1.1 2 7.0 6 0.16 (0.03- 0.79).02 Safety monitoring committee discontinued sequential treatment arm in September 2008 due to 55% lower mortality in integrated vs sequential treatment arms (5.4 vs 12.1 deaths/100 patient-yrs; P =.003) Abdool Karim SS, et al. N Engl J Med. 2010;362:697-706.

12. CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients Significantly higher incidence of IRIS with early vs late HAART –4.03 vs 1.44 per 100 person-mos, respectively (P <.0001) Blanc FX, et al. AIDS 2010. Abstract THLBB206. Wk Survival Probability, % (95% CI) P Early ArmLate Arm 50 86.1 (81.8-89.4) 80.7 (76.0-84.6).07 100 82.6 (78.0-86.4) 73.0 (67.7-77.6).006 150 82.0 (77.2-85.9) 70.2 (64.5-75.2).002 FactorMultivariate Adjusted HR (95% CI) P Late therapy1.52 (1.12-2.05).007 BMI 161.68 (1.07-2.63).01 Karnofsky score 40 4.96 (2.42-10.16)<.001` Pulmonary + extrapulmonary TB 2.26 (1.62-3.16) <.001 NTM2.84 (1.13-7.13)<.001 MDR-TB8.02 (4.00-16.07)<.001 Factors Independently Associated With Mortality Survival Probability, Early vs Late Therapy Log rank P =.0042 Wks From TB Treatment Initiation Probability of Survival 1.00 0.90 0.80 0.70 0.60 Early arm Late arm 050100150200250

13. Outcome: increase above pre-HAART level Crude and adjusted* relative hazards from fitting a Cox regression model CDC stage around HAART initiation Crude RH (95%CI) P-valueAdjusted RH (95%CI) P value >100 cells/mmc Non AIDS TB non TB AIDS 1.00 0.82 (0.67,0.99) 1.01 (0.94,1.09) 0.04 0.72 1.00 0.72 (0.57,0.92) 0.86 (0.79,0.94) 0.008 0.001 >200 cells/mmc non AIDS TB non TB AIDS 1.00 0.79 (0.64,0.98) 1.06 (0.98,1.15) 0.03 0.13 1.00 0.69 (0.52,0.91) 0.94 (0.85,1.03) 0.008 0.21 >300 cells/mmc non AIDS TB non TB AIDS 1.00 0.72 (0.57,0.93) 1.10 (1.01,1.19) 0.01 0.03 1.00 0.68 (0.49,0.93) 1.00 (0.90,1.11) 0.02 0.99 *adjusted for age, CD4, VL, CD8, HCV/HBV, year of HIV test, year of starting HAART, gender, mode of HIV transmission, nationality, type of HAART Immune response could be impaired in AIDS- patients presenting with TB 7327 pts starting HAART from ICONA, INMI, UCSC, HSR Cingolani et al, CROI 2011

14. Immediate HAART does not improve outcome of HIV-associated tuberculosis meningitis A randomised, double-blind, placebo- controlled trial compared immediate vs deferred (2 months post- randomisation) ART in 253 HIV- infected patients with tuberculosis meningitis More severe (grade 3 or 4) AEs occurred in months 1–2 in the immediate vs deferred ART arm: –86 vs 75%; p = 0.04 Similar number of deaths occurred with immediate vs delayed ART Torok et al. ICAAC 2009, Abstract H-1224 N=127 N=126

15. Conclusions Starting HAART early during OIs reduces AIDS progression and improve survival in most OI, without increasing the risk of cumulative toxicities It is highly cost-effective Starting HAART early during TB improve survival at any CD4 strata, even considering the potential immune impairment specifically attributed to TB Early initiation of HAART does not increase the incidence of IRIS in most non-TB OI, and whenever the incidence increases (TB), it does not impact on mortality Concerns still remain for tuberculous meningitis and for cryptococcal meningitis in order to confirm whether the risk of IRIS overweight the beneficial effect of HAART