Effect of Early versus Deferred

Antiretroviral Therapy for HIV on

Survival
Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, Hogg RS,
Deeks SG, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Martin JN, Klein MB,
Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara
LM, Horberg MA, Silverberg MJ, Gebo KA, Goedert JJ, Benson CA, Collier AC, Van
Rompaey SE, Crane HM, McKaig RG, Lau B, Freeman AM, Moore RD; NA-
ACCORD Investigators.

N Engl J Med. 2009 Apr 30;360(18):1815-26.

Bryan Ennis, PGY-1

Tuesday, May 26th, 2009
 Current guidelines:
symptomatic w/AIDS defining illness - regardless of CD4 count or VL

asymptomatic patients with a CD4 below 350

***above 350 and viral loads above 100,000 copies/ml, some

clinicians prefer to defer treatment, whereas others will
consider starting therapy***

NO in patients with CD4 counts above 350 and VL below 100,0002,3

active hepatitis B or C virus coinfection, cardiovascular disease risk, and HIV-

associated nephropathy prompt earlier therapy1,2
 need to take into account:

 adherence potential:
– food restrictions, dosing with regard to meals, dosage regimen,
pill burden, dosing frequency, social factors
– need to be taken correctly 95% of the time1

 comorbidities:
– liver disease, depression, cardiovascular disease, pregnancy
status, adverse drug effects, and

 ADRs, potential drug-drug interactions

 In 1996, “hit hard. hit early”

 Background:
 Treatment guidelines rely on data from observational
cohort studies2

 No good controlled, randomized prospective studies

examining when to start HIV Tx

 Past studies have examined the prognosis for patients

who begin antiretroviral therapy at different CD4+ counts,

 but few have addressed deferment or acceptance of Tx

at similar CD4+3,4
 This Study
 North American AIDS Cohort Collaboration
on Research and Design (NA-ACCORD).
 Methods: Data Gathering
 North American AIDS Cohort Collaboration on
Research and Design (NA-ACCORD) of the
International Epidemiological Databases to
Evaluate AIDS project.

 NA-ACCORD is 22 research groups, from 60 sites.

 Each group of investigators submitted data on

enrolled patients.
 NA-ACCORD put the data together for this study
 Methods: Study Design
 17,517 asymptomatic HIV
 No previous HAART
 two parallel analyses : split into two arms

– CD4+ 350-500 ”deferred therapy group",

– > 500 cells per cubic millimeter "early therapy group”
– compared the relative risk of death of these two groups

 From United States or Canada

 1996 to 2005.
 Methods: study design
 adjustments for calendar year, cohort of patients,
and demographic and clinical characteristics

 Measured CD4+ yearly

 Data regarding other prognostic factors, a history

injection-drug use, hepatitis C virus infection, were
available for most of the patients.
 Methods
 Chi-square

 Multivariate Cox proportional-hazards:

– good for effect of a treatment under study has a multiplicative effect
on the subject's hazard (failure) rate.

 Wilcoxon test
– alternative to the paired t-test when the population cannot be assumed
to be normally distributed.

 Other fancy math tests

 Results
Stratification of Patients According to CD4+ Count at Baseline
 Results
 The first analysis: 351-to-500 CD4+
– the deferred therapy group had an increase
in the risk of death of 69 percent (relative
risk 1.69; 95 percent CI, P<0.001).
 the second analysis
– 94 percent increase in the risk of death
(relative risk, 1.94; 95 percent CI, 1.37 to
2.79; P<0.001).
 Discussion
 In patients with a 351-to-500 CD4+ count, the
deferral of antiretroviral therapy increases in
the risk of death of 69%,

 Among patients with a more-than-500 CD4+

count, deferred therapy was associated with
an increase in the risk of death of 94%.
 Strengths
 large size: 17,000 pts

 linkage with national death registries in both the United

States and Canada.
– Cause of death data available

 Minimize lead time bias

– Study had access to prior records
– Other studies in which patients were observed only after they
began antiretroviral therapy could not provide data regarding
AIDS events and deaths that occurred during deferral of
therapy5,6
 Cont.
 survival rather than AIDS progression or death
as the measured outcome
– death is a more definitive and all-inclusive outcome
measure than progression to an AIDS-defining event

 the use of advanced statistical methods

– makes a cohort study look more like a randomized
trial,
– Tried to control for known associations with an
increased risk of death in patients
 Limitations
 NOT a randomized trial

 patients chose when to begin therapy

– Immeasurable differences

 he causes of death are available for only 16% of

the patients who died
– Again, lifestyle differences
 Limitations cont.
 fewer patients with a history of injection-drug use and
HCV infection were in the early-therapy group.
– Patients who had a history of injection-drug use had
a higher risk of death than those with no such history

 Patients in the early-therapy group were more likely to

initiate a protease inhibitor–based regimen that did not
include a ritonavir boost;

 factors that may also affect the decision to defer

treatment.
 Do we treat?
 deferring HAART til <500 CD4s increased
risk of death 94%
 Starting therapy at progressively higher
CD4+ counts has been shown to lower the
risk of some toxic effects associated with
antiretroviral therapy7
 However, all the potential side effects of
long-term antiretroviral therapy are
unknown.
 BIBLIO
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Paterson, MB, BS, FRACP; Susan Swindells, MD; Jeffrey Mohr, MSW; Michelle Brester, RN; Emanuel
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medicine; 4 July 2000 | Volume 133 Issue 1 | Pages 21-30
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infected patients in Switzerland: prospective multicentre study: Swiss HIV Cohort Study. BMJ
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recommendations of the International AIDS Society-USA panel. JAMA 2008;300:555-570.

6. Paul E. Sax, M.D., and Lindsey R. Baden, M.D .When to Start Antiretroviral Therapy — Ready When
You Are? NEJM. Volume 360:1897-1899. April 30, 2009. Number 18
7. Lichtenstein KA, Armon C, Buchacz K, et al. Initiation of antiretroviral therapy at CD4 cell counts ≥350
cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency.
J Acquir Immune Defic Syndr 2008;47:27-35. [ISI][Medline].