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Workshop 4: “Il late-presenter”Moderatori: G. Ippolito, M. MoroniDiscussant: R. Iardino
Quando cominciare: Impatto delle comorbiditàA. Cingolani
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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
Pros Contra
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When to start HAART in non-TB OIs: from international to national guidelines
Guidelines Recommendations
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 2010 As soon as possible, without delay
BHIVA 2008 Treat (except for TB>350 cd4/mmc)
Linee guida italiane, 2010
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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%)
Zolopa et al. PLoS One 2009;4:e5575
Time of ART initiation
Immediate ART Deferred ART
Days from randomisation to ART, median (IQR)
0 35
Days from OI to ART, median (IQR)
12 (9–13) 45 (41–55)
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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 mixeddyslipidemia ($52,200/QALY)hemodialysis for critically ill patients ($158,200/QALY)
Cost-effectiveness of other widely recommended interventions:
Sax, HIV Clin Trials 2010
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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 ?
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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,
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…is it really to be considered due to IRIS?
Prospective study on 65 pts with CM, treated with AmB.
Bicanic, JAIDS 2009
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Risk of IRIS in ACTG 5164
Cox Proportional Hazards Models Using Time Varying Covariate Models
Grant, PlosOne 2010
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When to start HAART during tuberculosis according with CD4 level
CD4<100 100-200 A200-350 >350
IDSA, 2009 After 2 wks (BII) Within 2 mt (BII) After 2 mt After end of TB tx
DHHS, 2009 After 2 wks After 8 wks After 2 mt 8-24 w or after end of TB tx
EACS, 2009 As soon as practical
As soon as practical or after 2 mt
As soon as practical or after 2 mt
At discretion
BHIVA, 2005 As soon as practical
Aftr 2 mt After 6 mt After 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 l’inizio 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 dall’inizio 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
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SAPIT: Initiation of HAART during TB treatment improves survival
Months post-randomisation
Sur
viva
l pro
ba
bili
ty (
%)
0 3 6 9
75
70
80
85
90
95
2 5 81 4 7 10
Integrated arm (n = 429)
Intensive phase of TB treatment
11 14 17 2013 16 1912 15 18 21 2322 24
100
Continuation phase of TB treatment
Post-TB treatment
Sequential arm (n = 213)
Kaplan-Meier survival curve
OutcomeIntegrated Therapy(n = 429)
Sequential Therapy(n = 213)
HR (95% CI)P
Value
All patients Death rate per 100 person-yrs Deaths, n
5.425
12.127
0.44 (0.25-0.79)
.003
CD4+ cell count ≤ 200 cells/mm3
Death rate per 100 person-yrs Deaths, n
8.223
15.321
0.54 (0.30-0.98)
.04
CD4+ cell count > 200 cells/mm3
Death rate per 100 person-yrs Deaths, n
1.12
7.06
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.
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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.
WkSurvival Probability, % (95% CI)
PEarly Arm Late 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
Factor Multivariate Adjusted HR (95% CI)
P
Late therapy 1.52 (1.12-2.05) .007
BMI ≤ 16 1.68 (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
NTM 2.84 (1.13-7.13) < .001
MDR-TB 8.02 (4.00-16.07) < .001
Factors Independently Associated With MortalitySurvival Probability, Early vs Late Therapy
Log rank P = .0042
Wks From TB Treatment Initiation
Pro
bab
ilit
y o
f S
urv
ival 1.00
0.90
0.80
0.70
0.60
Early armLate arm
0 50 100 150 200 250
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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-value Adjusted RH(95%CI)
P value
>100 cells/mmc Non AIDS TB non TB AIDS
1.000.82 (0.67,0.99)1.01 (0.94,1.09)
0.040.72
1.000.72 (0.57,0.92)0.86 (0.79,0.94)
0.0080.001
>200 cells/mmc non AIDS TB non TB AIDS
1.000.79 (0.64,0.98)1.06 (0.98,1.15)
0.030.13
1.000.69 (0.52,0.91)0.94 (0.85,1.03)
0.0080.21
>300 cells/mmc non AIDS TB non TB AIDS
1.000.72 (0.57,0.93)1.10 (1.01,1.19)
0.010.03
1.000.68 (0.49,0.93)1.00 (0.90,1.11)
0.020.99
*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
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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
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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