Workshop 4: “Il late-presenter”Moderatori: G. Ippolito, M. MoroniDiscussant: R. Iardino

Quando cominciare: Impatto delle comorbiditàA. Cingolani

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

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

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)

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

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 ?

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,

…is it really to be considered due to IRIS?

Prospective study on 65 pts with CM, treated with AmB.

Bicanic, JAIDS 2009

Risk of IRIS in ACTG 5164

Cox Proportional Hazards Models Using Time Varying Covariate Models

Grant, PlosOne 2010

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

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.

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

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

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

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