Review

When to initiate antiretroviral therapy in HIV-1-infected

adults: a review for clinicians and patients
Evan Wood, Robert S Hogg, P Richard Harrigan, Julio S G Montaner

One of the most controversial topics in the medical management of HIV disease is the optimal time to initiate highly Lancet Infect Dis 2005;
active antiretroviral therapy (HAART) in HIV-1-infected adults. Premature exposure to antiretrovirals may precipitate 5: 407–14

early evolution of resistance and unnecessary side-effects, whereas remaining off HAART until late in the course of HIV EW, RSH, PRH, and JSGM are at
the British Columbia Centre for
disease may lead to reduced therapeutic benefits and elevated mortality. The lack of a randomised clinical trial to
Excellence in HIV/AIDS, St Paul’s
consider this issue has resulted in ongoing revision of expert recommendations and substantial variability between Hospital, Vancouver, BC, Canada;
international consensus guidelines regarding the optimal time to initiate therapy. Since this uncertainty is a source of RSH is also at the Department of
unease for both patients and clinicians, we summarise the latest evidence regarding the optimal time to initiate HAART Health Care and Epidemiology,
EW, PRH and JSGM are also at the
with consideration of the potential benefits and drawbacks of starting HIV treatment at the different levels presently
Department of Medicine,
recommended in leading consensus guidelines. University of British Columbia,
Vancouver.
Introduction HIV disease must take a daily regimen of at least three Correspondence to:
Before the advent of modern antiretroviral therapies, antiretroviral agents—ie, highly active antiretroviral Professor Julio S G Montaner,
AIDS Research Program,
studies of HIV-1-infected individuals documented the therapy (HAART)—and follow a scheduled dosing
University of British Columbia/
predictable natural history of HIV disease. In particular, protocol that may involve coordination of dietary intake.16 St Paul’s Hospital, 667–1081
observational cohorts of untreated patients demonstrated High levels of adherence to one’s daily HAART regimen Burrard Street, Vancouver,
how the rate of CD4 cell count decline, and its strong are required to suppress the plasma HIV RNA,17,18 and BC V6Z 1Y6, Canada.
Tel +1 604 806 8036;
association with the level of plasma HIV RNA, was incomplete adherence has been associated with rapid
fax +1 604 806 8527;
associated with an eventual increased vulnerability to emergence of antiretroviral resistance.19,20 Emergence of jmontaner@cfenet.ubc.ca
opportunistic diseases and subsequent mortality.1–3 A antiretroviral resistance is of particular clinical importance
steam engine careering towards an impending train wreck since there is substantial cross-resistance within anti-
has been used as an informative metaphor for this retroviral drug classes,21 and there are major challenges in
predictable process, with the plasma HIV RNA level treating patients once multidrug-resistant HIV has
representing the speed of the train and the CD4 cell count emerged.14,19 Finally, although simpler and more tolerable
representing the length of track remaining.4 HAART regimens are being increasingly developed, the
However, since the mid-1990s there have been major long-term side-effects of HAART may be substantial,
advances in the medical management of HIV disease.5,6 In including frequently observed disfiguring lipodystrophy
particular, antiretroviral therapies have been shown to and lipoatrophy syndromes (figure 2),22,23 and less
dramatically suppress the circulating levels of HIV RNA frequently observed life-threatening toxicities, such as
in patients’ plasma and thereby bring the metaphorical
steam engine to a halt well before complications arise.7 Pre-HAART era
With the suppression of plasma HIV RNA, CD4 cell
100
counts have been shown to rebound,8 and, in turn,
80
dramatic reductions in HIV-related morbidity and
mortality have been documented among people receiving 60

antiretroviral therapy (figure 1).6,9–11 The impressive effects 40

200
of antiretroviral therapy initially led to a “hit early/hit 20
201–350
351–500
3-year probability of AIDS (%)

501–750
hard”12 approach where HIV treatment guidelines 0 750 CD4 count
55 20–55 7–20 1·5–7 1·5
recommended initiation of antiretroviral therapy when the HIV-1 RNA concentration (103 copies/mL)
(cells/L)

CD4 cell count dropped below 500 cells/µL or the plasma

HAART era
HIV RNA rose above 30 000 copies/mL, which is more
than 5 years before symptoms would be expected to 100
develop in most patients.13 80
Despite the survival benefits, the clinical management 60
of HIV disease presents major challenges for both 40
clinicians and patients. Treatment of HIV infection with 200
201–350
20 351–500
the antiretroviral regimens that are presently available 501–750
0 750 CD4 count
aims to prevent progression to AIDS or death by reducing 55 20–55 7–20 1·5–7 1·5 (cells/L)
plasma HIV RNA to as low a level as possible for as long HIV-1 RNA concentration (103 copies/mL)

as possible.14,15 The eradication of HIV from the individual

Figure 1: Prognosis according to CD4 cell count and viral load in the pre-
is not considered possible with presently available HAART and HAART eras
therapeutic agents,15 and people undergoing treatment for Reproduced with permission from reference 11.

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 Review
chemical hepatitis, renal failure, and mitochondrial
toxicity.24,25
These challenges have led to a shift away from the hit
early/hit hard approach to a strategy where patients are
encouraged to delay the initiation of HAART until the
CD4 cell count falls to 350 cells/µL or below.26 However,
although avoidance of side-effects and antiretroviral
resistance provide strong impetus for delaying HAART,
it is well recognised that if the CD4 cell count is allowed
to decline below 200 cells/µL while off treatment,
patients may become susceptible to opportunistic
infections and raised risk of mortality (figure 1).11,27 In
addition, there is a great deal of uncertainty regarding the
impact of plasma HIV RNA levels on survival after the
initiation of HAART and, as noted in some therapeutic
guidelines,28 many clinicians favour immediate initiation
of HAART if the plasma HIV RNA level rises above
100 000 cells/mL, regardless of the CD4 cell count. The
difference between initiating HAART at a CD4 cell count
of 200 cells/µL versus 350 cells/µL—or potentially even
earlier in the case of a patient with a CD4 cell count
greater 350 cells/µL but a plasma HIV RNA level greater
than 100 000 copies/mL—is a critical decision given that
it would likely represent 3–5 years of additional anti-
retroviral exposure in most patients.29
The lack of a randomised clinical trial to consider the
issue of the optimal time to initiate HAART has resulted
in ongoing revision of international HIV treatment
consensus guidelines, and there is variation between
expert recommendations on the optimal time to initiate
antiretroviral therapy.29,30 Because this uncertainty is a
source of unease for both patients and clinicians,30,31 we
summarise the latest evidence regarding the optimal
time to initiate HAART. We begin with a summary of
those instances where international consensus has been
reached, as well as those areas where there is uncertainty
within guidelines. The subsequent section will
summarise the potential benefits and drawbacks of
initiating HIV treatment at the different levels presently
recommended in therapeutic guidelines, and the final
section will outline key variables to consider when a
patient’s clinical characteristics are such that the optimal
time to initiate HAART remains uncertain.
Areas of agreement and uncertainty
Areas of agreement regarding initiating HAART
The following section will outline those clinical situations
where there is general agreement across HIV treatment
guidelines (figure 3, blue text).
Symptomatic HIV disease
Antiretroviral therapy is widely recommended for
patients who have been diagnosed with an AIDS-defining
illness or severe illness/symptoms of HIV infection,
regardless of CD4 cell count. Accordingly, the diagnosis
of common AIDS-defining illnesses, including oeso-
phageal candidiasis, Kaposi’s sarcoma, Mycobacterium
408
avium complex, non-Hodgkin lymphoma, Pneumocystis
carinii pneumonia, wasting syndrome, toxoplasmosis of
the brain, HIV-related encephalopathy, and disseminated
cytomegalovirus disease are all indications for
considering the immediate initiation of HAART. This
recommendation is based on the recognition that
additional opportunistic diseases may cause further
morbidity or mortality in patients who remain off
antiretrovirals.26
CD4 cell count below 200 cells/µL
Antiretroviral therapy is widely recommended for patients
with a CD4 cell count below 200 cells/µL, regardless of
plasma HIV RNA levels or the absence of symptoms. This
recommendation is based on data from randomised
clinical trials demonstrating a survival benefit of
antiretroviral therapy in immunocompromised patients,
and a large number of observational cohort studies that
have shown progressively diminished therapeutic benefit
among patients who initiate HAART with a CD4 cell
count below 200 cells/µL.11,26,27,32–34 The worsening
prognosis for patients initiating HAART after this level is
apparent in the lower panel of figure 1, which presents the
data from a large international collaboration of
observational HIV treatment cohorts.11 However, as also
shown in this figure, it is important to stress that even in
patients with a CD4 cell count below 200 cells/µL, there
are drastic reductions in mortality after the initiation of
HAART.35 In this context, it is noteworthy that baseline
CD4 cell count is no longer independently prognostic of
survival after 6 months on antiretrovirals.36 This point is
worth stressing because a substantial proportion of
patients have their first HIV-related interaction with
medical care after the CD4 cell count has declined below
200 cells/µL.35,37
Baseline CD4 cell count above 350 cells/µL
Antiretroviral therapy is not generally recommended in
patients with a CD4 cell count greater than
350 cells/µL.26,28,38 Consideration of HAART before a CD4
cell count of 350 cells/µL if the patient’s plasma HIV
RNA is greater than 100 000 copies/mL or if the patient
has a rapidly declining CD4 cell count has been
proposed;39 however, this proposal has not been widely
supported.26,28 The weight of evidence suggests that it is
relatively safe to delay HAART in this setting,11,26,27,32–34
primarily because of the potential longer-term risks of
toxicity (figure 2).22,24
Women and patients with a history of injection drug use
Sex is a key consideration in several areas of HIV
management, such as the evaluation of side-effects of
HAART.26,28,38 However, studies are conflicting as to
whether there are sex-specific differences in disease
progression between men and women.40,41 Although there
is some evidence to suggest that there are sex differences
in plasma HIV RNA levels,40 rates of disease progression
http://infection.thelancet.com Vol 5 July 2005
 Review

after the initiation of HAART do not appear to differ by However, it remains unknown if patients will have a
sex.11,27,33,42 As such, there is agreement across guidelines survival benefit if treatment is initiated during primary
that the timing of HAART should not be differentially HIV infection and guidelines generally suggest that
selected depending on a patient’s sex.
Similarly, although studies have indicated that patients
with a history of injection drug use may have a worse
prognosis after the initiation of HAART,11 there is
presently insufficient evidence to support earlier HAART
initiation among injection drug users. Examinations of
mortality among injection drug users have indicated that
their raised mortality rates may be explained on the basis
of raised rates of competing causes of death, such as illicit
drug overdoses, rather than a reduced effectiveness of
HAART.43 Alternatively, raised rates of HIV-specific
mortality among injection drug users may not be
unexpected at a population level, given that people with
addictions may have lower levels of adherence to
HAART.44 Thus, strategies to improve adherence to
HAART among drug users—eg, methadone maintenance
therapy or other forms of evidence-based addiction
treatment—should be considered when indicated.45,46
Nevertheless, although injection drug users may or may
not have raised rates of HIV disease progression after the
initiation of HAART, there is little evidence to suggest that
earlier or later initiation of HAART improves survival
among this population.31 Thus, guidelines presently
suggest that injection drug users should be offered
HAART at the same time as other HIV-infected
populations.

Primary HIV infection

Although there is a consensus that HAART should be
initiated in symptomatic patients, antiretroviral therapy is
not generally recommended for patients presenting
during primary infection. Consideration may be given to
the use of HAART for patients presenting with moderate
to severely symptomatic seroconversion illness,
particularly if they are not responsive to symptomatic
treatment, and if there is evidence of a decline in CD4 cell
count. However, in such instances there is no consensus
regarding the strategy to follow in terms of continuous
HAART or treatment interruption after a given period of
full viral suppression.28,38
For patients with primary HIV infection, it is
recognised that there may be a window of opportunity to
suppress HIV RNA while the genetic diversity of the
circulating virus is limited, and while the patient’s ability
to mount an immune response may be greater than it is
later in the course of infection.47,48 Thus it has been
postulated that initiating HAART at the time of primary
HIV infection may preserve HIV-specific immune
responses and alter the natural history of HIV infection.

Figure 2: The development of dorsocervical fat, or what has become known

as “buffalo hump”, is commonly reported among adults who develop HIV-
associated lipodystrophy syndrome during HAART. The syndrome is often
characterised by loss of subcutaneous fat from other body sites including
the face and extremities

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 Review
Consensus between DHHS, IAS-USA,
HIV-infected adult
and BHIVA guidelines
Noted uncertainty within guidelines
History and physical
examination
Symptoms No symptoms
Evaluate CD4 and pVL
CD4<200 cells/L CD4 200–350 cells/L* CD4 >350 cells/L
Monitor CD4/pVL every
1–3 months. Defer HAART
until CD4 200–350 cells/L†
Additional clinical considerations
1. Initial HAART regimen
Recommend HAART 2. Level of clinical monitoring
3. Hepatitis C co-infection
4. Adherence readiness
5. CD4 percentage
Figure 3: Synthesis of the US Department of Health and Human Services (DHHS), the International AIDS
Society-USA (IAS-USA), and the British HIV Association (BHIVA) guidelines regarding considerations for the
optimal time to initiate HAART
pVL=plasma HIV RNA levels. *The decision on when to initiate HAART before 200 cells/µL is optimally based on
individual patient characteristics; †Some guidelines acknowledge that many clinicians will recommend initiating
HAART if the plasma HIV RNA level rises above 100 000 copies/mL regardless of the CD4 cell count.
HAART initiation should be optional at this time, and
ideally initiated in the context of a clinical trial
examining if there is a benefit to this approach.38 Since
the potential benefit of HAART initiation during
primary HIV infection is theoretical, patients wishing to
initiate HAART at this time must be appropriately
counselled regarding the potential risks (figure 2)22,24 or
benefits of earlier HAART initiation. Further
randomised clinical trials examining the role of HAART
in primary infection would be welcome.
Areas of uncertainty regarding initiating HAART
There are two key situations where consensus guidelines
have noted substantial uncertainty regarding the optimal
time to initiate HAART.
Plasma HIV RNA levels above 100 000 copies/mL
Initiation of antiretroviral therapy in patients with
plasma HIV RNA levels greater than 100 000 copies/mL
has been proposed.39 This proposal is based on
observational studies that have indicated that baseline
plasma HIV RNA levels greater than 100 000 copies/mL
are associated with increased mortality after the initiation
of HAART.11,49 This association has persisted despite
adjustment for CD4 cell count and patient adherence.49
In the absence of a randomised clinical trial addressing
this issue, a definitive evidence-based guideline is not
available. Nevertheless, HAART is generally not
recommended among patients with a CD4 cell count
greater than 350 cells/µL, even if the plasma HIV RNA
levels are greater than 100 000 copies/mL. As will be
discussed, there are several additional considerations that
410
may be particularly important for patients who fall into
this category.
Baseline CD4 cell count between 200 and 350 cells/µL
As discussed earlier, the difference between initiating
HAART at a CD4 cell count of 200 cells/µL versus
350 cells/µL is a major decision for patients and clinicians,
since it could potentially represent a 3–5 year difference in
when antiretroviral exposure is begun in most patients.29
Although a minority of studies have indicated that there is
a small reduction in the risk of mortality if HAART is
initiated at a CD4 cell count of 350 cells/µL,50 most studies
have shown no significant survival differences among
patients who initiate HAART at any level above
200 cells/µL (figures 1 and 3).11,27,32,33
However, observational studies do not account for the
differing prognosis of patients who initiate therapy at
different CD4 cell counts or other unmeasured
differences between patient groups.51 The lack of a
randomised trial that could eliminate these potential
biases has resulted in noted uncertainty within all
guidelines considered (figure 3, brown text). As a result,
guidelines suggest that HAART should be delayed until a
CD4 cell count of 200–350 cells/µL, and that individual
patient characteristics should be factored in when
deciding where in this range therapy should be
initiated.26 A CD4 cell count fraction below 15% of the
total lymphocyte count has been shown to be an
independent prognostic factor among patients initiating
HAART between 200 cells/µL and 350 cells/µL,
indicating that low CD4 percentage may be an indication
for earlier HAART initiation.52
Benefits versus risks of “early” versus “late”
HAART initiation
Potential benefits of early use of HAART
There are several postulated benefits of initiating
HAART at a CD4 cell count at or above 350 cells/µL, or
even earlier in a patient with a plasma HIV RNA level
above 100 000 copies/mL but a high CD4 cell count.
Most importantly, among patients who suppress plasma
HIV RNA levels on HAART, there is reduced risk of
disease progression in the immediate term by
comparison with patients who remain off HAART,
among whom the CD4 cell count will slowly decline in
most patients.3,53
Clinicians favouring earlier initiation of HAART have
also noted that new, less toxic drugs are increasingly
available, and have argued that earlier initiation of
antiretroviral therapy may be associated with greater
immunological preservation or improvement and less
drug-related toxicity.39,54 Similarly, although the data are
conflicting,9 there is evidence to suggest that plasma HIV
RNA suppression will be easier to achieve and maintain if
therapy is initiated when the plasma HIV RNA level is less
than 100 000 copies/mL.55–57 A final argument to support
earlier initiation of HAART is the potential to reduce HIV
http://infection.thelancet.com Vol 5 July 2005

transmission through the reduction in plasma HIV RNA
levels;58 however, this argument is not well supported by
clinical trials.32
Potential risks of early use of HAART
Despite the postulated benefits, most studies have
suggested it is safe to delay HAART until the CD4 cell
count approaches 200 cells/µL.11,26,27,32–34 There may be
several potential risks of earlier HAART initiation. For
example, with earlier antiretroviral exposure, it is likely
that antiretroviral resistance and/or antiretroviral toxicities
will emerge much earlier than among patients who defer
HAART (figure 2).23,24,27,59,60
A review by Phillips and colleagues29 has outlined how a
small reduction in potential for elevated mortality among
patients who initiate HAART at 350 cells/µL rather than
200 cells/µL—if it exists—may be completely offset by the
longer-term benefits of delaying HAART (figure 4). The
advantages of this approach are particularly relevant given
the rapid development of new antiretroviral agents, and
the fact that deferral of HAART may offer the opportunity
to initiate treatment with more effective drugs.61,62
Also of note are the potentially major cost savings if
HAART can be safely delayed until later in the course of
HIV disease.63,64 Although these savings are most relevant
to resource-limited settings where the cost of
antiretrovirals makes them prohibitively expensive for
most HIV-infected individuals,65,66 they are also relevant to
areas of the developed world where the burgeoning costs
of HIV treatment place a growing burden on health-care
systems.67,68
Although there are many postulated benefits and risks
of initiating HAART at various stages of HIV
disease,27,29,30,32 weighting the importance of these factors
remains challenging for clinicians and patients. As will
be discussed, for patients who have a CD4 cell count in
the range 200–350 cells/µL or plasma HIV RNA levels
greater than 100 000 copies/mL, there are several key
clinical variables that should also be carefully
considered when deliberating the optimal time to
initiate HAART.
Key considerations when facing uncertainty
Initial HAART regimen
An examination of the association between plasma
HIV RNA levels greater than 100 000 copies/mL and
mortality has indicated that this association may be due
to reduced rates of viral suppression among patients
with higher plasma HIV RNA levels.69 This argument is
supported by studies indicating that higher plasma
HIV RNA levels are associated with more rapid
development of antiretroviral resistance.70 However, a
caveat regarding observational studies that have
indicated that plasma HIV RNA levels greater than
100 000 copies/mL may be associated with elevated
disease progression,11,49 is that they included patients
treated with less potent HAART regimens,11,49 and it is
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Review
Untreated
Curve depends on rate of CD4
counts decline and viral load
Risk of AIDS
Lines unlikely to re-cross
Low cumulative risk by this
point in those deferring
Deferred
Immediate Durability of reduced AIDS risk with ART
may be limited due to resistant virus
evolving and using up of drug options
0 1 2 3 4 5 Up to 50 or more years
Years from decision whether to start ART immediately
Figure 4: Risk of AIDS over time in two groups of patients with CD4 cell
counts of 350 cells/µL, one group starting HAART immediately, the other
deferring
ART=antiretroviral therapy. Reproduced from reference 29 with permission from
Lippincott Williams & Wilkins.
noteworthy that trials of more potent antiretroviral
combinations have indicated that higher plasma HIV
RNA levels are not associated with lesser virological
response.71 If these observations are confirmed, there is
likely a strong rationale for delaying HAART among
patients with high CD4 cell counts and high plasma
HIV RNA levels, but then starting patients with plasma
HIV RNA levels greater than 100 000 copies/mL on
more potent HAART regimens when the CD4 cell
count declines into a range where therapy is currently
recommended.72,73
CD4 cell count and plasma HIV RNA monitoring
As highlighted by the speeding train analogy provided
above,4 it is well recognised that the slope of the CD4 cell
count decline is strongly associated with the level of
plasma HIV RNA.1,2 As such, it is critical that the plasma
HIV RNA level and CD4 cell count be closely monitored
in patients who choose to defer the initiation of HAART.
This close monitoring is particularly relevant to patients
who remain off HAART when the CD4 cell count is
between 200 cells/µL and 350 cells/µL, and it is arguable
that these patients should consider monthly CD4
monitoring if the plasma HIV RNA level is above
50 000 copies/mL,51 because the CD4 cell count could
decline below the 200 cells/µL threshold if the patient was
not closely monitored.26,74 Natural history studies suggest
that for patients with CD4 cell counts above 350 cells/µL it
is likely safe to monitor the CD4 cell count and plasma
HIV RNA level every 3 months, with consideration of
monthly monitoring of the CD4 cell count once the level
has declined below 350 cells/µL.26 Obviously, such
recommendations would only be relevant to situations
where these tests are widely available, although it is
noteworthy that the costs of intensive plasma HIV RNA
and CD4 count monitoring would likely be much more
affordable than the drug costs were HAART initiated
earlier.
411
 Review
Co-infection with hepatitis C virus
Hepatitis C virus (HCV) co-infection has increasingly
become a key consideration for the clinical
management of HIV disease, and detailed reviews of
the implications of HCV among HIV-infected
individuals are available elsewhere.75–77 Briefly, a
number of studies have demonstrated that HCV may
progress more rapidly among HIV/HCV co-infected
patients.75,78 As such, there is a general consensus that
HCV treatment should ideally be started before the
initiation of HAART, particularly if the CD4 cell count
is above 350 cells/µL.77 Although no randomised
clinical trial has considered this issue, immediate
initiation of HAART is recommended for co-infected
patients who present with a CD4 cell count less than
200 cells/µL, and HCV treatment should be considered
once the patient is stable on HAART.11 For individuals
who must remain on HAART to avoid HIV-related
morbidity and mortality, it is possible to treat HCV at
the same time as HAART;79 however, the care of co-
infected patients is ideally supervised by highly
experienced HIV clinicians, since substantially worse
HAART-related toxicities may be experienced among
HIV/HCV co-infected patients.75–77,80 Of note,
HIV/HCV co-infected individuals who have CD4 cell
counts below 200 cells/µL and are intolerant to HAART
often benefit from HCV therapy being started before
attempting to re-initiate HAART.77
Adherence
Previous studies have indicated that patient adherence
may be the strongest determinant of virological and CD4
cell count response, and patient survival.7,33,81–84 However, it
has been shown that earlier initiation of HAART does not
reduce the deleterious effects of patient non-adherence.74
An additional challenge regarding adherence optimisation
before the initiation of HAART stems from the
demonstration that providers may be poor judges of
patient adherence.85,86 As such, physician perception
regarding a patient’s potential ability to adhere to HAART
should not be the basis for withholding treatment or the
basis to recommend earlier initiation of antiretrovirals.
Instead, patients with a CD4 cell count that warrants
initiation of HAART should be recommended to start
treatment regardless of perceptions regarding
adherence.87 Adherence support must be optimised in all
patients initiating HAART, and among patients deferring
HAART, adherence readiness strategies should be applied
so that adherence can be optimised once therapy is
begun.87–91
Conclusions
There is growing accord across consensus guidelines
regarding the optimal stage of HIV disease to initiate
HAART. In particular, there is agreement that
immediate HAART initiation should be recommended
in patients who have HIV/AIDS-related symptoms and
412
Search strategy and selection criteria
In addition to reviewing the International AIDS Society-USA
(IAS-USA), US Department of Health and Human Services
(DHHS), and the British HIV Association (BHIVA) guidelines,
PubMed databases were searched for published studies on the
topic of initiating antiretroviral therapy in HIV-infected adults
with no language or date specified, and by examining
references from relevant articles cited. Search terms were “HIV”,
“antiretroviral therapy”, “when to start”, “initiation”, and “CD4
cell count”. Key abstracts presented at international meetings
after the publication of these guidelines were also considered.
in patients in whom the CD4 cell count has declined
below 200 cells/µL. For individuals with a CD4 cell
count above 350 cells/µL it is generally accepted that
HAART be deferred. Similarly, there is insufficient
evidence to suggest a recommendation for differential
HAART initiation based on sex or history of injection
drug use, and HAART is not widely recommended for
patients presenting during primary infection.
The main areas of remaining uncertainty are the
optimal time to initiate HAART in patients with a CD4 cell
count in the range 200 cells/µL to 350 cells/µL, and in
patients who have a plasma HIV RNA level greater than
100 000 copies/mL. For these patients, the potential for
reduced risk of disease progression if HAART is initiated
earlier must be balanced with the potential benefits of
delaying therapy. Optimising the initial HAART regimen
and frequent CD4 monitoring—including CD4 fraction—
are particularly valuable in this setting. Furthermore,
individual patient characteristics including HCV/HIV co-
infection and adherence readiness will have an important
role for defining the optimal strategy for each individual
patient.
Conflicts of interest
EW has no conflicts of interest to declare. RSH is partly supported by the
Michael Smith Foundation for Health Research through a Senior
Scholar Award. He has held grant funding from the National Institutes
of Health, Canadian Institutes of Health Research National Health
Research Development Program, and Health Canada. He has received
grant funding and honoraria and/or reimbursement from the
pharmaceutical industry for participating in continued medical
education programmes and conferences from Agouron Pharmaceuticals
Inc, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb,
GlaxoSmithKline, and Merck Frosst Laboratories. PRH has worked as an
employee in the pharmaceutical industry (Glaxo Wellcome) and HIV
diagnostic industries (Virco). He has received fees for consulting,
honoraria, owned stock, acted as a consultant, and received fees or grants
from a wide range of pharmaceutical and HIV diagnostic and
therapeutic monitoring companies, including Abbott Laboratories,
Agouron Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals
Inc, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman-La Roche, Merck
Frosst Laboratories, Pfizer Inc, and Virco. JSGM has received consulting
fees, served on paid advisory boards, or received lecture fees from Avexa
Ltd, Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals Inc,
Borean Pharma AS, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Hoffman-La Roche, Immune Response Corporation,
Janssen-Ortho Inc, Kucera Pharmaceutical Company, Merck Frosst
Laboratories, Pfizer Canada Inc, Shire Biochem Inc, Tibotec
Pharmaceuticals Inc, and Trimeris Inc.
http://infection.thelancet.com Vol 5 July 2005

Acknowledgments
This work was supported by the Michael Smith Foundation for Health
Research through a Career Investigator Award and by Canadian Institutes
of Health Research through an Investigator Award to RSH. We thank
Bonnie Devlin, Elizabeth Ferris, Nada Gataric, Kelly Hsu Myrna
Reginaldo, Jennifer Adachi, and Peter Vann for their research and
administrative assistance.
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