When is the Optimal Moment to Start HAART in HIV Infected Patients from PISCIS Cohort Study (Spain)?

1
When is the Optimal Moment to Start HAART in HIV
Infected Patients from PISCIS Cohort Study
(Spain)?
46th Interscience Conference on Antimicrobial
Agents and Chemotherapy, September 27th 30th,
2006 San Francisco, CA (USA). Presentation H-1059

• Jaén A, Esteve A, Montoliu A, Miro JM, Tural C,
  Podzamczer D, Riera M, Segura F, Force L, Vilaró
  J, García I, Masabeu A, Altés J, Sued O,Clotet B,
  Ferrer E, Casabona J, and PISCIS study group.
• Catalonia and Balearic Islands (Spain)

2
Background

• After the introduction of HAART, the mortality
  and morbidity of HIV infection decreased
  dramaticallyHIV infection now a chronic disease.
• However, HAART has some disadvantages (adverse
  effects, resistance).
• The decision when to start HAART in asymptomatic
  individuals with gt200 and lt350 CD4 remains
  unclear.
• In the context of observational cohort studies (
  no randomization), a major limitation to
  resolving this issue is the need to account for
  leadtime and the unseen events.

3
Aims

1. To evaluate progression to AIDS or death
   according to CD4 count and plasma HIV-RNA levels
   prior to initiating HAART among patients in the
   PISCIS Cohort.
2. To estimate the optimal time at which to initiate
   HAART before progression to AIDS using methods
   accounting for leadtime and the unseen events in
   the context of data from observational cohort
   studies

4
Methods

• PISCIS Cohort is an ongoing multicenter
  observational study of HIV infected individuals
  ( 16 years old) from
• Nine hospitals within Catalonia, and
• One from the Balearic Islands, (Spain).
• Collects clinical and epidemiological data
  through computer applications during routine
  clinical follow-up.
• PISCIS Cohort represents 70 of the new HIV
  infections notified in these two regions.
• From January 1998 to December 2004
• 6,922 patients were included,
• 17,766 person-years of follow-up.

Catalonia
Balearic Islands
5
Inclusion criteria

• For the present study we included
• HIV-infected antiretroviral naïve patients
• Who initiated HAART from January 1998 to June
  2004,
• AIDS-free before antiretroviral treatment was
  started,
• Who were on HAART for at least one month.

2,035 individuals met the inclusion criteria
6
Methods

• HAART was defined as the combination of ? 3
  antiretroviral drugs, according to Spanish and
  International Guidelines.
• Treatment regimens
• Boosted or unboosted protease inhibitors (PI)
  plus 2 nucleoside reverse transcriptase
  inhibitors (NRTI)
• 1 non-nucleoside reverse transcriptase inhibitor
  (NNRTI) plus 2 NRTI
• 3 NRTI
• other combinations
• According to the year of initiation, HAART was
  categorized into
• Early HAART period Jan1998 - Dec 2000,
• Late HAART period Jan 2001 - Jun 2004.
• Analysis by intention to treat.

7
Statistical analysisHIV disease progression or
death

• Descriptive analysis
• median values, interquartile ranges (IQR), and
  percentages.
• comparisons among CD4 groups using the
  Kruskal-Wallis and Pearsons chi-square tests.
• HIV progression to AIDS/death
• analyzed using Cox regression models.
• multivariate model was adjusted by calendar year
  of initiation of HAART (time-dependent variable).

8
PISCIS Cohort Study 1998-2004 Epidemiological
characteristics at initiation of HAART.
9
PISCIS Cohort Study 1998-2004 Clinical
characteristics at initiation of HAART.
10
PISCIS Cohort Study 1998-2004 Outcome
11
PISCIS Cohort Study 1998-2004 Risk of HIV
progression to AIDS/death.Multivariate Cox
model
Adjusted by sex, age and calendar period of
initiation of HAART.
12
PISCIS Cohort Study 1998-2004 Survival curves
and hazard ratios from initiation of HAART to
AIDS/death by CD4/ plasma HIV-RNA VL group
HR 1.24 95CI 0.49-3.14
HR 1.59 95 CI 0.76-3.30
HR 1.93 95 CI 0.83-4.47
HR 3.39 95CI 1.72-6.67
HR 5.88 95 CI 3.17-10.91
Number of patients at risk
Patients at risk
n656
n398
n176
n2,035
n1,887
n1,263
n946
13
2. Statistical analysis Accounting for leadtime
In absence of randomization, comparisons among
patients who initiate HAART at 200-350 CD4 with
those who chose to defer HAART at lt200 CD4 do
not answer the question of when to initiate HAART.

• Appropriate statistical analysis should take into
  account the leadtime and unseen events
• Leadtime defined as the time it took the
  deferred group with an early disease stage (e.g.
  CD4gt350) to reach the latter stage (e.g. CD4
  200-350).
• Unseen events previous events in patients who
  initiate HAART at late stage (fast progressors).

Cole, Rui, Anastod, Detels, Young, Chmiel,
Muñoz. Statist Med 2004 233351-3363.
14
Ideal randomized clinical trial (RCT)
RCT initiate HAART versus defer HAARTS
observed survival time from randomization to AIDS
Initiate HAART
AIDS
S
Initiate HAART at 200-350 CD4
S
AIDS
Initiate HAART
S
AIDS
Defer HAART to lt200 CD4
S
AIDS
350-200 CD4
lt200 CD4
Common origin for the time-to-event analysis
15
Observational cohort study
T observed survival time from initiation of
HAART to AIDS
Initiate HAART
AIDS
T
Initiate HAART at 200-350 CD4
T
AIDS
Initiate HAART
T
AIDS
Initiate HAART at lt200 CD4
350-200 CD4
lt200 CD4
Different origin for the time-to-event analysis
16
Observational cohort study
T observed survival time from initiation of
HAART to AIDSL unobserved survival time to
reach the latter stage (prior leadtime)
Initiate HAART
AIDS
T
Initiate HAART at 200-350 CD4
T
AIDS
Initiate HAART
T
L
AIDS
Initiate HAART at lt200 CD4
350-200 CD4
lt200 CD4
17
Observational cohort study
T observed survival time from initiation of
HAART to AIDSL unobserved survival time to
reach the latter stage (prior leadtime) fast
progressors unseen individuals who develop AIDS
before initiating HAART
Initiate HAART
AIDS
T
Initiate HAART at 200-350 CD4
T
AIDS
Initiate HAART
AIDS
T
L
Initiate HAART at lt200 CD4
AIDS
L
fast progressors
350-200 CD4
lt200 CD4
18
2. Statistical analysis Accounting for leadtime

• Accounting for leadtime was analyzed using
  statistical methods described in Cole et al.
  2004. Briefly
• Leadtime
• obtained from a log-normal distribution estimated
  with data from the pre-HAART period.
• assigned to each individual in the deferred group
  multiple times.
• added to the observed survival time to AIDS.
• The number of fast progressors (unseen events)
  and their leadtimes were estimated.
• Finally, leadtime-adjusted hazard ratios were
  computed through Cox regression models, using
  multiple imputation techniques.

Cole, Rui, Anastod, Detels, Young, Chmiel, Muñoz.
Statist Med 2004 233351-3363.
19
Probability of the time to the CD4 transition and
time to AIDS in the pre-HAART era (MACS cohort
study).
200-350 CD4
350-500 CD4

• 11.6 fast progressors
• Median time
• to 200 CD4 0.96 years
• to AIDS 4.5 years

• 3.0 fast progressors
• Median time
• to 350 CD4 0.88 years
• to AIDS 1.1 years

Cole, Rui, Anastod, Detels, Young, Chmiel,
Muñoz. Statist Med 2004 233351-3363.
20
PISCIS Cohort Study 1998-2004 Survival curves
for the time to AIDS comparing initiation of
HAART at 200-350 CD4 to initiation of HAART at
lt200 CD4
21
PISCIS Cohort Study 1998-2004 Survival curves
for the time to AIDS comparing initiation of
HAART at 200-350 CD4 to initiation of HAART at
lt200 CD4
22
PISCIS Cohort Study 1998-2004 Survival curves
for the time to AIDS comparing initiation of
HAART at gt350 CD4 to initiation of HAART at
200-350 CD4
23
PISCIS Cohort Study 1998-2004 Survival curves
for the time to AIDS comparing initiation of
HAART at gt350 CD4 to initiation of HAART at
200-350 CD4
24
Limitations

• Intention-to-treat analysis changes of treatment
  and poor adherence were not taken into account.
• Using probability models of CD4 transition and
  fast progression (natural history of HIV)
  estimated from external data (MACS cohort study).
  
• Advisable to examine probability models according
  to combinations of biomarkers (e.g. CD4/plasma
  HIV-RNA VL) and other clinical endpoints (e.g.,
  death).
• Alternative analysis models allowing causal
  inferences from observational studies.
• a large sample size is needed (pooling cohorts).

25
Conclusions

• Major determinants of HIV progression or death
• having CD4 count lt200,
• HIV-1 RNA gt100,000 copies/ml,
• HCV coinfection,
• and having initiated HAART before January 2001.
• Important findings were found after performing
  methodology accounting by leadtime
• Statistically significant risk of progression to
  AIDS in patients with 200-350 CD4.
• These results provide valuable information for
  clinical decision-making.

26
PISCIS study group

• Steering Committee J. Casabona, A. Esteve, A.
  Jaén, M. Granell, from Center for Epidemiological
  Studies on HIV/AIDS of Catalonia (CEESCAT),
  Badalona, Spain JM. Gatell, JM. Miró from Clínic
  Hospital, Barcelona, Spain C. Villalonga and S.
  Riera from Son Dureta Hospital, Palma de
  Mallorca, Spain D. Podzamcer and E. Ferrer from
  Bellvitge Hospital, Hospitalet de Llobregat,
  Spain B. Clotet and C.Tural from Germans Trias i
  Pujol University Hospital, Badalona, Spain F.
  Segura and G. Navarro from Parc Taulí Hospital,
  Sabadell, Spain L. Force from Mataró Hospital,
  Mataró, Spain J. Vilaró from General Vic
  Hospital, Vic, Spain A. Masabeu from Palamós
  Hospital, Palamós, Spain I. García from Creu
  Roja Hospital, Hospitalet de Llobregat, Spain E.
  Dorca from Manresa Hospital, Manresa, Spain and
  J. Altés from Alt Penedès Hospital, Vilafranca,
  Spain.
• Data manager and computerized support E. Puchol,
  Y. Alvaro, A. Montoliu (Centre d'Estudis
  Epidemiològics sobre la sida de Catalunya)
  Modesto Sanchez (Hospital Clínic- Idibaps,
  Universitat de Barcelona).
• Clinical Staff JL Blanco, F. Garcia-Alcaide, E.
  Martinez, J. Mallolas (Hospital Clínic- Idibaps,
  Universitat de Barcelona) G. Sirera, J. Romeu,
  A. Bonjoch, A. Jou. A. Ballesteros, E. Negredo,
  D. Fuster, J.C Martinez (Hospital Universitari
  Germans Trias i Pujol, Universitat Autónoma de
  Barcelona) M. Santin, MJ Barbera, M. Olmo, P.
  Robres, F. Bolao, J Carratala, C. Cabellos C.
  Peña.  (Hospital de Bellvitge de Barcelona) P.
  Barrufet (Hospital de Mataró) M. Guadarrama
  (Hospital Alt Penedès de Vilafranca).
• Acknowledgements The PISCIS Cohort was funded by
  3084/99 and 36354/02 projects from Fundación para
  la Investigación y la Prevención del Sida en
  España (FIPSE).